CN103373971A - Urea compounds serving as protein kinase inhibitors - Google Patents
Urea compounds serving as protein kinase inhibitors Download PDFInfo
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- CN103373971A CN103373971A CN2012101229432A CN201210122943A CN103373971A CN 103373971 A CN103373971 A CN 103373971A CN 2012101229432 A CN2012101229432 A CN 2012101229432A CN 201210122943 A CN201210122943 A CN 201210122943A CN 103373971 A CN103373971 A CN 103373971A
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- alkyl
- urea
- trifluoromethyl
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- 0 C*(CC(C)(C)NC(NI)=O)c1ccccc1 Chemical compound C*(CC(C)(C)NC(NI)=O)c1ccccc1 0.000 description 6
- JHIWTCULLSLMNG-UHFFFAOYSA-N CN(C)CC#Cc(c1ccc2)nc(N)cc1c2-c(cc1)ccc1NC(Nc(cc(C(F)(F)F)cc1)c1F)=O Chemical compound CN(C)CC#Cc(c1ccc2)nc(N)cc1c2-c(cc1)ccc1NC(Nc(cc(C(F)(F)F)cc1)c1F)=O JHIWTCULLSLMNG-UHFFFAOYSA-N 0.000 description 1
- GMSBBPNBATUEBS-UHFFFAOYSA-N CN1CCN(CCCNc(c2ccc3)nc(N)cc2c3-c(cc2)ccc2NC(Nc(cc(C(F)(F)F)cc2)c2F)=O)CC1 Chemical compound CN1CCN(CCCNc(c2ccc3)nc(N)cc2c3-c(cc2)ccc2NC(Nc(cc(C(F)(F)F)cc2)c2F)=O)CC1 GMSBBPNBATUEBS-UHFFFAOYSA-N 0.000 description 1
- WOUDZHXKXDKGNN-UHFFFAOYSA-N NC1=C[IH]C=C1 Chemical compound NC1=C[IH]C=C1 WOUDZHXKXDKGNN-UHFFFAOYSA-N 0.000 description 1
- DOPJTDJKZNWLRB-UHFFFAOYSA-N Nc(ccc([N+]([O-])=O)c1)c1O Chemical compound Nc(ccc([N+]([O-])=O)c1)c1O DOPJTDJKZNWLRB-UHFFFAOYSA-N 0.000 description 1
- JGYJZHYTADCWIK-UHFFFAOYSA-N [O-][N+](c(cc1O2)ccc1NC2=O)=O Chemical compound [O-][N+](c(cc1O2)ccc1NC2=O)=O JGYJZHYTADCWIK-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
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- 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
-
- 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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides urea compounds serving as protein kinase inhibitors and medicinal salts of the urea compounds, as well as medicine compositions containing the compounds and application of the compounds as protein kinase inhibitors.
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 simultaneously this compounds as the application of kinases inhibitor in the treatment cancer.
Technical background:
Known at present, all there is the Ras/Raf/Mek/Erk Signal Transduction Pathways in all eukaryotic cells, Ras/Raf/MEK/ERK path mitogen activated protein kinase (MAPKs) is by the transmission of a large amount of cell surface receptor mediation intracellular signal.The factor of most of stimulate cell growth, comprise EGF, PDGF, VEGF and c-KIT, after the receptors bind of cell surface, can at first activate Ras by the mode of receptor tyrosine kinase autophosphorylation, Ras further activates again the Raf/MEK/ERK signal transduction pathway, brings the signal of somatomedin into nucleus, realize signal by the extracellular to endonuclear transmission, the trigger cell biologically is such as cell proliferation, differentiation, conversion and apoptosis etc.
All there is the rise of this path in many tumour cells, and Raf can bring into play its signal transcription regulating effect by the mode that relies on or do not rely on Ras as a crucial kinases in this path.As the kinase whose downstream of Raf substrate, the MEK phosphorylation ERK of activation, and ERK is by acting on multiple substrate to regulate cell function.In case this path generation excessive activation, the acceleration of cell proliferation and the prolongation of cells survival phase can be led oncogenic formation and development.
Raf has 3 isozymes as the crucial kinases in this path, is respectively A-Raf, B-Raf and C-Raf, and they are all closely related with the adjusting of cell proliferation, differentiation and vasculogenesis.Known in the human tumor cell A-Raf and C-Raf sudden change very rare, the B-Raf sudden change then accounts for 7%.Somatic mutation rate after B-Raf is activated in melanoma up to 50%～70%, reach 35% in the ovarian cancer, reach 30% in the thyroid carcinoma, reach 10% in the colorectal carcinoma, therefore B-RafV600E receives investigator's concern day by day as the target for the treatment of human cancer, is one of important target spot of present antitumor drug research.
The small molecules kinase inhibitor that contains urea structure begins just to be placed high hopes from the nineties in early days, is used for the treatment of cancer and inflammation.And BAY 43-9006 can hinder the signal conduction that the Raf/MEK/ERK path mediates on the one hand as first Raf kinase inhibitor with ureas structure, and the propagation of inhibition tumor cell directly suppresses tumor growth; On the other hand, the growth of tumour and transfer depend on the formation of new vessel, VEGF and PDGF are important angiogenic factors, Xarelto is just by suppressing the activity of VEGFR (such as VEGER-2, VEGER-3) and PDGFR (PDGFR-β) Tyrosylprotein kinase, the blocking-up tumor-blood-vessel growth suppresses tumor growth indirectly.Have dual antitumor action, so it is referred to as many kinase inhibitor.
Preclinical study shows that Xarelto has widely anti-tumor activity to the zoografting model of people's tumour, comprises colorectal carcinoma, carcinoma of the pancreas, lung cancer, mammary cancer and ovarian cancer, and its antitumor action is relevant with inhibition Raf/MEK/ERK path; In the tumour with Ras or B-Raf transgenation, observed too the anti-tumor activity of Xarelto; In addition, in human colon carcinoma (HT-29 and Colo205) and mammary cancer (MDA-MB-231) zoografting model, Xarelto can obviously suppress the formation of new vessel.
Summary of the invention:
The object of the present invention is to provide shown in the general formula (I) carbamide compounds, pharmaceutical salts, hydrate and solvate and corresponding isomer, prodrug or chemoprotectant form as kinases inhibitor.
Wherein:
M independently is selected from 0,1,2,3 or 4;
L is independently selected from
X is selected from and is independently selected from O or (CH
2)
n
Aforementioned n is selected from 0,1,2,3 or 4;
Y is selected from and is independently selected from CH or N;
The S ring is independently selected from phenyl ring, pyrrole ring;
R
1Be independently 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 the L choosing
The 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 halogens;
Aforementioned p independently is 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 randomly further by C
1-8Alkyl replaces;
Aforementioned R
9Be selected from C
3-10Heterocyclylalkyl, described C
3-10Heterocyclylalkyl is randomly further by C
1-8Alkyl replaces;
Described p independently is selected from 0,1,2,3 or 4.
When L is selected from
As general formula (I a) shown in:
Wherein:
M independently is selected from 0,1,2,3 or 4;
R
1Be independently selected from hydrogen, halogen, C
1-8Alkyl, halo C
1-8Alkyl; R preferably
1Be hydrogen, halogen, C
1-5Alkyl, halo C
1-5Alkyl, halo C
1-5Alkoxyl group; R more preferably
1Be 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;
R preferably
3Be C
3-7Heteroaryl, halo C
3-7Heteroaryl;
R more preferably
3Be pyrimidyl, Chloropyrimide base, pyridyl;
Aforementioned p independently is selected from 0,1,2,3 or 4.
When L is selected from
Shown in general formula (Ib):
Wherein:
M independently is selected from 0,1,2,3 or 4;
X is selected from and is independently selected from O or (CH
2)
n
Aforementioned n is selected from 0,1,2,3 or 4;
R
1Be independently selected from hydrogen, halogen, C
1-8Alkyl, halo C
1-8Alkyl; R preferably
1Be hydrogen, halogen, C
1-5Alkyl, halo C
1-5Alkyl, halo C
1-5Alkoxyl group; R more preferably
1Be hydrogen, F, Cl, Br, methyl, methoxyl group, trifluoromethyl;
R
4Independently be selected from hydrogen, halogen, C
1-8Alkyl; R preferably
4Be hydrogen, F, Cl, Br, C
1-3Alkyl; R more preferably
4Be 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 halogens;
R preferably
6Independent C
1-5Alkyl, C
6-10Aryl, C
3-7Heteroaryl, described C
6-10Aryl or C
3-7Heteroaryl is optional further to be replaced by halogen;
R more preferably
6Independently be selected from methyl, ethyl, phenyl, pyridyl, chlorophenyl, chloro-pyridine base.
Aforementioned p independently is selected from 0,1,2,3 or 4.
When L is selected from
Shown in general formula (Ic):
Wherein:
M independently is selected from 0,1,2,3 or 4;
X is selected from and is independently selected from O or (CH
2)
n
Aforementioned n is selected from 0,1,2,3 or 4;
Y is selected from and is independently selected from CH or N;
The S ring is independently selected from phenyl ring, pyrrole ring;
R
1Be independently 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; R preferably
1Be 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; R more preferably
1Be 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; R preferably
4Be hydrogen, F, Cl, Br, C
1-3Alkyl; R more preferably
4Be 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;
R preferably
7Be 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;
R more preferably
7Be hydrogen, morpholinyl, methylpiperazine base, Pyrrolidine base, O (CH
2)
pR
8, NH (CH
2)
pR
9, 3-methoxy propyl alkynyl, 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 randomly further by C
1-8Alkyl replaces;
R preferably
8Be selected from C
1-5Alkoxyl group, C
6-10Aryl or C
3-8Heterocyclylalkyl, described C
6-10Aryl or C
3-18Heterocyclylalkyl is randomly further by C
1-3Alkyl replaces;
R more preferably
8Be selected from methoxyl group, piperazinyl, methylpiperazine base, morpholinyl;
Aforementioned R
9Be selected from C
3-10Heterocyclylalkyl, described C
3-10Heterocyclylalkyl is randomly further by C
1-8Alkyl replaces;
R preferably
9Be selected from C
3-8Heterocyclylalkyl; Described C
3-8Heterocyclylalkyl is randomly further by C
1-5Alkyl replaces;
R more preferably
9Be selected from piperazinyl, methylpiperazine base, morpholinyl;
Aforementioned p independently is selected from 0,1,2,3 or 4.
A second aspect of the present invention relates to the pharmaceutical composition that comprises the compound shown in the general formula (I), and wherein pharmaceutical composition preferably also comprises auxiliary material, the pharmaceutically useful carrier of described Optimization of Adjuvant and/or vehicle, wherein said vehicle preferred diluent.
The invention still further relates to comprise and be used for the treatment of in general formula (I) compound and the pharmaceutical composition or the medicine of prophylaxis of tumours or the application of conduct preparation treatment or prophylaxis of tumours.
The invention still further relates to the compound shown in the general formula (I) as the purposes of kinases inhibitor in the preparation medicine.Described pharmaceutical use can by suppress the Raf/MEK/ERK signal transduction pathway, also can be blocked tumor neovasculature formation by suppressing vegf receptor, thereby reach 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, acute marrow sample hypercytosis, chronic marrow sample hypercytosis, peritoneal cancer, mesothelioma, myelodysplastic syndrome, cancer of the stomach.
Unless otherwise indicated, term " halogen " expression fluorine, chlorine, bromine or iodine that the present invention uses, preferred fluorine or chlorine.
Unless otherwise indicated, the term " C of the present invention's use
6-14Aryl " refer to any from functional group or substituting group that simple aromatic nucleus derives.Preferred C
6-10Aryl, more preferably C
6-8Aryl, especially preferred phenyl, suitable embodiment such as phenyl.Described aryl is optional to be replaced by one or more substituting groups that independently are selected from halogen, alkyl, alkoxyl group, nitro or cyano group, is preferably replaced suitable embodiment such as difluorophenyl by halogen.
Unless otherwise indicated, the term " C of the present invention's use
3-10Heteroaryl " or " halo C
3-10Heteroaryl " expression comprises 1 heteroatomic aromatic group that is selected from N, O and S at least.Preferred heteroaryl is C
3-8Heteroaryl or halo C
3-8Heteroaryl, more preferably C
3-7Heteroaryl or halo C
3-7Heteroaryl.The embodiment of described heteroaryl comprises for example above-mentioned group of imidazolyl, pyridyl, pyrimidyl, pyrryl, thienyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl and halogen replacement.More preferably pyridyl, pyrimidyl, pyrryl, triazolyl, especially preferred pyridyl, pyrimidyl, Chloropyrimide.
Unless otherwise indicated, the term " C of the present invention's use
3-10Heterocyclylalkyl " represent that comprising at least 1 is selected from the heteroatomic aliphatics groups of naphthene base such as N, O and S.Be preferably C
3-8Heterocyclylalkyl.The embodiment of described Heterocyclylalkyl comprises for example 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 that mentions herein
1-8Alkyl " or " halo C
1-8Alkoxyl group " refer to that this group is straight or branched, is preferably halo C
1-5Alkyl.The embodiment of suitable halogenated alkyl group comprises such as trifluoromethyl, trifluoroethyl, difluoromethyl, two fluoro ethyls.
" the two C that mention herein
1-8Alkylamino " be preferably two C
1-5Alkylamino, more preferably two C
1-3Alkylamino, the embodiment of suitable two alkylamino groups comprise dimethylamino, diethylin, dipropyl amino.
Term " the C that the present invention uses
3-8Alkynyl " refer to contain a triple bond and straight chain and 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 alkylaminos " refer to C
3-8α position hydrogen atom on the alkynyl is by two C
1-8Alkylamino replaces.Be preferably two C
1-5The C that alkylamino replaces
3-5Alkynyl, suitable embodiment comprise 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 the alkynyl is by C
1-8Alkoxyl group replaces.Be preferably C
1-5The C that alkoxyl group replaces
3-5Alkynyl, suitable embodiment comprise 3-methoxy propyl alkynyl.
The pharmacy acceptable salt of indication of the present invention is formula (I) and the formed salt of any acid, and pharmaceutically acceptable acid.Suitable acid comprises mineral acid such as phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, Hydrogen bromide and similarly acid; Or organic acid such 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 similarly acid.
The isomer of indication of the present invention refers to that one or more stereoisomer forms exist, and comprise various three-dimensional enantiomers, diastereomer, tautomer and geometrical isomer.The present invention includes compound formula (I), its steric isomer and acceptable salt pharmaceutically thereof.Compound of the present invention may be with mixture, the single stereoisomers of steric isomer or the form appearance with opticity.
" solvate " of indication of the present invention is used for the mixture of expression solute (for example salt of compound, compound) and solvent in this article at conventional meaning.If solvent is water, solvate can be called as hydrate, such as monohydrate, dihydrate, trihydrate etc. aptly so.
" the chemoprotectant form " of indication of the present invention refers to that at conventional meaning wherein one or more reactive functional groups are protected to avoid at the lower compound that undesirable chemical reaction occurs of defined terms (for example, pH, temperature, irradiation, solvent etc.) in this article.In practice, can adopt well-known chemical process reversibly to make those otherwise the functional group that reacts is not reacted under prescribed condition.In chemoprotectant form, one or more reactive functional groups are protected or blocking group (be also referred to as masked or shelter group or be blocked or blocking group).By protective reaction functional group, can relate to other not protected reactive functional groups reaction and do not affect protected group; Blocking group usually can be removed in step subsequently and basically not affect the remainder of molecule.Simultaneously, the invention discloses the preparation method of preparation the compounds of this invention and pharmaceutical salts thereof.
" prodrug " of indication of the present invention relates to when the compound that is produced required active compound by metabolism when (for example in vivo).Usually, prodrug is non-activity, and perhaps activity is lower than active compound, but can provide favourable processing, use or metabolisming property.
For example, some prodrugs are esters (for example on the physiology in the acceptable metabolism unsettled ester) of active compound.Between metabilic stage, ester group (C (=O) OR) is cleaved, produces active medicine.This class ester can form by esterification; the for example esterification of any hydroxy-acid group in the parent compound (C (=O) OH), in suitable situation, in advance protection is present in any other reactive group in the parent compound; if necessary, then go protection.
And, thereby some prodrugs are generated active compound by enzyme activation or generate the compound (such as in ADEPT, GDEPT, LIDEPT etc.) of active compound after further chemical reactions.For example, prodrug can be sugar derivatives or other glucosides conjugates, perhaps can be amino acid ester derivative.
" pharmaceutical composition " of indication of the present invention refers to and will mix or merge the product of gained more than a kind of activeconstituents, comprise the fixing of activeconstituents and on-fixed combination.Term " fixed combination " refers to activeconstituents, and for example formula (I) compound and concomitant medication are applied to the patient simultaneously with single entities or dosage.Term " on-fixed combination " refers to activeconstituents, for example formula (I) compound and concomitant medication, with independent entity simultaneously, common or restrictedly be applied to successively the patient without specified time, this using as the treatment level of significance of two or more compound is provided in the patient body wherein.
The invention provides following particular compound:
1-(4-((9-phenmethyl-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-((9-(pyridine-2-methyl)-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-((9-methyl-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-((9-(3-fluorobenzene methyl)-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-morpholinyl isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(4-methylpiperazine-1-yl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) propoxy-) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-Pyrrolidine base isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(2-fluoro-5-aminomethyl phenyl) urea
1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-aminomethyl phenyl) urea
1-(4-(3-amino-1-(2-morpholine oxyethyl group) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-trifluoromethyl) urea
1-(4-(3-amino-(2-methoxy ethoxy) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-trifluoromethyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) the third amino) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-methoxy propyl alkynyl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-dimethylamino proyl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(2-amino-7H-pyrroles [2,3-d] pyrimidine) (7-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(2-amino-4-(4-methylpiperazine-1-yl)-7H-pyrroles [2,3-d] pyrimidine) (7-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(pyridine-2-base-methyl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
1-phenmethyl-3-(2-oxo-3-(pyridine-2-base-methyl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
1-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(6-chloropyrimide-4-yl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
1-phenmethyl-3-(2-oxo-3-(6-chloropyrimide-4-yl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
Unless otherwise indicated, term used herein " the compounds of this invention " refers to compound shown in the general formula (I), preferred above-mentioned particular compound, particularly preferably embodiment compound.
Embodiment
Compound can prepare by the following method shown in the general formula of the present invention (I):
1) preparation of compound shown in the general formula (Ia):
A, take 2-amino-5-nitro-phenol as raw material, make first 6-Xiao base benzoxazole-2 (3H)-ketone (2),
B, make the 6-Xiao base benzoxazole-2 (3H) of replacement-ketone (3);
C, make the amino benzoxazole-2 (3H) of 6-of replacement-ketone (4) compound;
D, obtain target compound with the aniline reaction that replaces again.
2) preparation of compound shown in the general formula (Ib):
A, take 6-chloro-9H-purine as raw material, with the 6-chloro-9H-purine compound of formula (II) compound formation formula (III);
B, again with the 6-oxo-aniline of the replacement of formula (IV) compound formation formula (V)-9H-purine compound;
C, obtain target compound with formula (VI) reaction again.
3) when Y is C, the preparation of compound shown in the general formula (Ic):
A, take the amino benzenes compounds (V) that replaces as raw material, make formula (VII) phenyl ureas compound;
B, formula (IV) 5-bromo-3-aminoisoquinoline analog derivative and the reaction of formula (VII) phenyl ureas compound obtain target compound:
4) when Y is N, the preparation of compound shown in the general formula (Ic):
A, with R
1The aniline that replaces is raw material, first reaction phenyl ureas compound processed;
B, again with R
7The amino reaction of 7H-pyrrolo-[2, the 3-d] pyrimidine that replaces-2-obtains target compound:
Part abbreviation 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-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
The preparation of steps A: 4-(9-phenmethyl-9H-purine-6-oxygen) aniline
Take by weighing 244mg 6-chloro-9H-purine and be dissolved among the 20ml DMF, add K
2CO
3Stir 0.5h, slowly drip the 205.2mg toluene(mono)chloride, reaction 20h pours reaction solution in the frozen water into, regulates PH to 5-6, ethyl acetate extraction, and column chromatography gets white solid.
Amino-phenol 102mg, Cs
2CO
3652mg, THF/DMF (9ml/3ml), stir-activating 2h, step gained compound 122mg in the adding, the KI of catalytic amount and Bu
4NBr is warming up to 85 ℃.TLC monitors basic complete reaction.Add water, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, desolventizing gets pink solid.
The preparation of step B:1-(4-((9-phenmethyl-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
0.317g (1mmol) 4-(9-phenmethyl-9H-purine-6-oxygen) aniline is in 100ml three neck round-bottomed flasks, add 20ml methylene dichloride stirring and dissolving, add 0.243g (1.5mmol) dicarbapentaborane imidazoles (CDI), behind the stirring at room 2h, add 0.234g (1.2mmol) 4-chloro-3-5-trifluoromethylaniline, continue at room temperature to stir, after question response is complete, concentrated, column chromatography for separation gets 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-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
Take 4-(9-(pyridine-2-methyl)-9H-purine-6-oxygen) aniline and 4-chloro-3-5-trifluoromethylaniline as raw material, the preparation method with embodiment 1 obtains 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-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
Take 4-(9-methyl-9H-purine-6-oxygen) aniline and 3-trifluoromethyl-4-chloroaniline as raw material, the preparation method with embodiment 1 gets 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-fluorobenzene methyl)-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
4-(9-(3-fluorobenzene methyl)-9H-purine-6-oxygen) aniline and 4-chloro-3-5-trifluoromethylaniline are raw material, and the preparation method with embodiment 1 gets 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
The preparation of steps A: 1-(2-fluoro-5-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea
Under condition of ice bath first with 5.37g (30mmol) 2-fluoro-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, slowly is added dropwise to above-mentioned reaction solution (keeping the temperature of reaction solution between 5～10 ℃), dropwise rear continuation and under condition of ice bath, react 0.5h.Remove ice bath, 20ml is dissolved with 30mmol under normal temperature condition the methylene dichloride mixed solution of aminoboronic acid pinacol ester and 3.03g (30mmol) triethylamine is added dropwise in the above-mentioned reaction solution, stirring is spent the night.Reaction is poured the 50ml shrend into to reaction solution and is gone out after finishing, and (2 * 20ml), water (40ml), saturated sodium-chloride (40mL) washing are concentrated behind the anhydrous sodium sulfate drying successively with dichloromethane extraction.Concentrated solution obtains the white powder solid with the silica gel column chromatography separation, is 1-(2-fluoro-5-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea.
The preparation of step B:1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 0.6mmol 1-; 4; 5; 5-tetramethyl--1; 3-dioxolane-2-yl) phenyl) urea, 0.3mmol5-bromo-3-aminoisoquinoline, 0.018mmol tetra-triphenylphosphine palladium, 1ml10% aqueous sodium carbonate, 2ml ethanol and 2ml toluene join in the 25ml two neck bottles; after the nitrogen protection; be heated to 110 ℃ of backflows; reaction 8h; with the reaction solution precipitation that reduces pressure, add methylene chloride and water dissolution, behind extraction, the precipitation; cross post, recrystallization gets faint yellow solid, fusing point: 152.3～153.2 ℃.
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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, get the 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4,4,5 for 3-with 1-, 5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-morpholinyl isoquinoline 99.9 are raw material, with the preparation method of embodiment 5 step B, get the 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(4-methylpiperazine-1-yl) isoquinoline 99.9 are raw material, with the preparation method of embodiment 5 step B, get the 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(3-(4-methylpiperazine-1-yl) propoxy-) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5, get the 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-Pyrrolidine base isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, get 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-yl) phenyl)-3-(2-fluoro-5-aminomethyl phenyl) urea
(2-fluoro-5-aminomethyl phenyl)-(4-(4,4,5 for 3-with 1-, 5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-aminoisoquinoline are raw material, with the preparation method of embodiment 5 step B, get 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-yl) phenyl)-3-(2-fluoro-5-aminomethyl phenyl) urea (SHP-12)
(2-fluoro-5-aminomethyl phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, get the 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-yl) phenyl)-3-(2-fluoro-5-trifluoromethyl) urea
(2-fluoro-5-trifluoromethyl)-(4-(4,4,5 for 3-with 1-, 5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(2-morpholine oxyethyl group) isoquinoline 99.9 are raw material, with embodiment 5 synthetic methods, get the 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-yl) phenyl)-3-(2-fluoro-5-trifluoromethyl) urea
(2-fluoro-5-trifluoromethyl)-(4-(4,4,5 for 3-with 1-, 5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(2-methoxy ethoxy) isoquinoline 99.9 are raw material, with embodiment 5 synthetic methods, get the 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-yl) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
Be raw material with 1-(4-chloro-3-trifluoromethyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-aminoisoquinoline, with embodiment 5 synthetic methods, get the 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) the third amino) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-amino-1-(3-(4-methylpiperazine-1-yl) the third amino) isoquinoline 99.9 is raw material, with embodiment 5 step B synthetic methods, get the 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-yl) phenyl)-3-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) urea
With 1-(4-((4-methylpiperazine-1-yl) methyl))-3-trifluoromethyl)-(4-(4 for 3-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenyl) urea and 5-bromo-3-aminoisoquinoline are raw material, with embodiment 5 step B synthetic methods, get the 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-methoxy propyl alkynyl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenylurea and 5-bromo-1-(3-methoxy propyl alkynyl) isoquinoline 99.9-3-amino is raw material, with embodiment 5 step B synthetic methods, 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-dimethylamino proyl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
(2-fluoro-5-(trifluoromethyl) phenyl)-(4-(4 for 3-with 1-, 4,5,5-tetramethyl--1,3-dioxolane-2-yl) phenylurea and 5-bromo-1-(3-dimethylamino proyl) isoquinoline 99.9-3-amino is raw material, with embodiment 5 step B synthetic methods, 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
The preparation of steps A 1-(2-fluoro-5-(trifluoromethyl) phenyl)-3-(4-iodophenyl) urea
2.97g (10mmol) triphosgene is dissolved in the methylene dichloride of 20ml, under condition of ice bath again with 5.37g (30mmol) 2-fluoro-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 ℃), dropwise rear continuation and under condition of ice bath, react 0.5h.Remove ice bath, 20ml is dissolved with 4-iodobenzene ammonia that 30mmol replaces and the methylene dichloride mixed solution of 3.03g (30mmol) triethylamine under normal temperature condition and is added dropwise in the above-mentioned reaction solution, stirring is spent the night.Reaction is poured the 50mL shrend into to reaction solution and is gone out after finishing, and (2 * 20ml), water (40ml), saturated sodium-chloride (40ml) washing are concentrated behind the anhydrous sodium sulfate drying successively with dichloromethane extraction.Concentrated solution obtains the white powder solid with the silica gel column chromatography separation.
The preparation of step B 1-(4-(2-amino-7H-pyrroles [2,3-d] pyrimidine) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
With 0.75mmol 1-(2-fluoro-5-(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 places single neck bottle of 50mL, 110 ℃ of reactions of nitrogen protection 16h.Reaction adds entry and ethyl acetate extraction after finishing, and gets organic layer, precipitation, and column chromatography for separation obtains 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-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
Be raw material with 1-(2-fluoro-5-(trifluoromethyl) phenyl)-3-(4-iodophenyl) urea and 4-(4-methylpiperazine-1-yl)-7H-pyrroles [2,3-d] pyrimidine-2-amino, the synthetic method with embodiment 20 step B obtains 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-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(pyridine-2-base-methyl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) 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 is heated to 65 ℃, backflow 5h.After TLC detection raw material reaction was complete, stopped reaction was spin-dried for solvent and gets oily matter.Add the hydrochloric acid soln salify of 2M, filter to get yellow solid, the acetonitrile recrystallization gets 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 that contains the 70ml acetonitrile, and reflux after all dissolving, adds chloromethylpyridine 1ml, 65 ℃ of backflow 8h.TLC detects to reacting completely, and stopped reaction is spin-dried for solvent, and Virahol (about 150ml) recrystallization gets 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) are dissolved in the round-bottomed flask of the mixed solvent that 40ml ethyl acetate and ethanol are housed, are heated to 60 ℃.Until all adding tin protochloride 3.0g after the dissolving, reaction solution becomes oyster white by clarification, and behind the 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 neutrality or weakly alkaline 7-8, dichloromethane extraction three times (20ml * 3), organic layer Na
2SO
4Dried overnight is spin-dried for solvent and gets the blush solid.
The preparation of step D:1-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(pyridine-2-base-methyl)-2,3-dihydrobenzo [d] oxazole-6-yl) urea
Step C gains 0.22g (0.9mmol) and CDI 0.21g (1.3mmol) are joined in the three-necked bottle of 50ml; under the nitrogen protection condition, add the 15ml anhydrous methylene chloride, react 12h under the room temperature condition; the TLC detection reaction; when raw material point disappeared, the solution pulpous state that is white in color added 4-chloro-3-methyl fluoride aniline 0.3g (1.5mmol); solution becomes clear by white pulpous state; continue reaction 4h, solution adularescent precipitation produces, and solution is pulpous state.Filter, washed with dichloromethane gets crude product, the THF recrystallization, and getting white solid is 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, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
Take 2-Amino-5-nitrophenol, chloromethylpyridine and benzylamine as raw material, the synthetic method with embodiment 22 gets 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-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(6-chloropyrimide-4-yl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
With 2-Amino-5-nitrophenol, 4,6-dichloro pyrimidine and 4-chloro-3-5-trifluoromethylaniline are raw material, with the synthetic method of embodiment 22, get the pale 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-yl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
With 2-Amino-5-nitrophenol, 4,6-dichloro pyrimidine and benzylamine are raw material, with the synthetic method of embodiment 22, get the pale 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: the test of part of compounds anti tumor activity in vitro
Adopt the MTT test
1. collect the logarithmic phase cell, adjust concentration of cell suspension, make cell concn 1 * 10
5About, be inoculated into respectively 96 orifice plates in, every hole 100ul.
2. put 37 ℃, 5%CO
2Cultivate in the incubator and make cell attachment.
3. add the medicine (medicine will be through suitably processing, such as solvability, degerming etc.) of different concns, the basis of time experiment needs, and is generally 48 hours.
4. carefully suck supernatant liquor, PBS washs gently, again abandons supernatant.
5. every empty fresh RPMI1640 nutrient solution of 180ul that adds adds 20ulMTT solution (5mg/ml, i.e. 0.5%MTT) again, continues to cultivate 4h.
6. stop cultivating, carefully suck nutrient solution in the hole.
7. every hole adds the 150ul dimethyl sulfoxide (DMSO), puts low-speed oscillation 10min on the shaking table, and crystallization is fully dissolved.
8. measure the light absorption value in each hole 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
The test of embodiment 27:B-raf enzymic activity
The test embodiment of the invention 13 suppresses the ability of B-raf activity
1), testing compound (embodiment 13), reference compound or water (contrast) with contain enzyme (24ng) damping fluid and mix.The control substrate test, not enzyme-added in the 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), add 15nM substrate (the un-activation MEK1 of histidine mark) and 1 μ M ATP, incubated at room 30min.
3), hatch end, adding 13mM EDTA stopped reaction.
4) it is anti-histidine-tagged, behind the 5min, add the phosphorylation MEK1/2 antibody of europium inner complex mark, to add subsequently Ulight-.
5), behind the 1h, microplate reader is measured fluorescence and is shifted, 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 is expressed as the inhibition percentage of living with respect to the control group enzyme.It is the Raf-1 inhibitor that standard suppresses the curve object of reference, is equipped with several concentration to measure its IC in each test
50Value.
The inhibition percentage that the embodiment of the invention 13 is alive with respect to the control group enzyme
The test of embodiment 28:VEGFR-2 enzymic activity
The test embodiment of the invention 17 suppresses the ability of VEGFR-2 activity
1), testing compound (embodiment 17), reference compound or water (contrast) with contain enzyme (0.88ng) damping fluid and mix.The control substrate test, not enzyme-added in the 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), add 100nM substrate Ulight-CAGAGAIETDKEYYTVKD (JAK1) and 25 μ M ATP, incubated at room 60min.
3), hatch end, adding 13mM EDTA stopped reaction.
4), behind the 5min, add the phosphorylation PT66 antibody of europium inner complex mark
5) behind the 1h, microplate reader is measured fluorescence and is shifted, 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 is expressed as the inhibition percentage of living with respect to the control group enzyme.It is staurosporine that standard suppresses the curve object of reference, is equipped with several concentration to measure its IC in each test
50Value.
The inhibition percentage that the embodiment of the invention 17 is alive with respect to the control group enzyme
Embodiment 29: Pharmacokinetic Evaluation
The pharmacokinetics test of the embodiment of the invention 12 compounds
Take the SD rat as animal subject, use the LC/MS/MS method and measured rat oral gavage and give the drug level in the different constantly blood plasma behind embodiment 12 compounds.Its oral absorption characteristics of pharmacokinetics is estimated in the pharmacokinetics behavior of research the compounds of this invention in the rat body.
1. testing program:
Test drug: embodiment 12 compounds
Experimental animal: 12 of healthy SD rats (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 U.S. applying biological system
The triple level Four bar of the API-5000 of system company 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 quantitative scope: linearity range: 0.5-250ng/mL; Linear dependence (R
2): 0.9960
3. administration and blood sampling scheme
12 of healthy SD rats (male, body weight 224～300g), 3 every group, the about 16h of fasting before the test freely drinks water; Drug excipient is 10% ethanol, 20%PEG200,70% physiological saline.
Gavage gives embodiment 12 compounds, and dosage is 7mg/kg, and the administration volume is 5mL/kg.The unified feed that gives behind the administration 4h.Before administration and administration after 0.17,0.33,0.67,1,2,4,8,24h gets blood 0.3mL through the jugular vein intubate, put in the EDTA centrifuge tube, under 4 ℃ of conditions, the centrifugal 10min separated plasma of 3200g.Except during the sample analysis, all plasma samples are collected and are placed on-the 20C Refrigerator store.
4. operation: get plasma sample 50uL, add the 150uL methanol extraction, centrifugal twice after the suspendible vibration, get supernatant liquor and carry out LC-MS/MS and analyze.Main pharmacokinetic parameter uses WinNonlin (5.3 editions) to calculate according to non-compartment model.
5. pharmacokinetic parameters result
The blood pharmacokinetic parameters of male SD rat embodiment 12 after gavage gives 7mg/kg embodiment 12
Claims (9)
1. compound and pharmaceutical salts thereof, hydrate, solvate, corresponding isomer, prodrug or chemoprotectant form shown in the general formula (I):
Wherein:
M independently is selected from 0,1,2,3 or 4;
L is independently selected from
X is selected from and is independently selected from O or (CH
2)
n
Aforementioned n is selected from 0,1,2,3 or 4;
Y is selected from and is independently selected from CH or N;
The S ring is independently selected from phenyl ring, pyrrole ring;
R
1Be independently 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 the L choosing
The 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 halogens;
Aforementioned p independently is 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 randomly further by C
1-8Alkyl replaces;
Aforementioned R
9Be selected from C
3-10Heterocyclylalkyl, described C
3-10Heterocyclylalkyl is randomly further by C
1-8Alkyl replaces;
Described p independently is selected from 0,1,2,3 or 4.
2. compound or pharmaceutically acceptable salt thereof or the prodrug of general formula according to claim 1 (I) are when L is selected from
The time, shown in general formula (Ia):
Wherein:
M independently is selected from 0,1,2,3 or 4;
R
1Be independently selected from hydrogen, halogen, C
1-8Alkyl, halo C
1-8Alkyl; R preferably
1Be hydrogen, halogen, C
1-5Alkyl, halo C
1-5Alkyl, halo C
1-5Alkoxyl group; R more preferably
1Be 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;
R preferably
3Be C
3-7Heteroaryl, halo C
3-7Heteroaryl;
R more preferably
3Be pyrimidyl, Chloropyrimide base, pyridyl;
Aforementioned p independently is selected from 0,1,2,3 or 4.
3. compound or pharmaceutically acceptable salt thereof or the prodrug of general formula according to claim 1 (I) are when L is selected from
The time, shown in general formula (Ib):
Wherein:
M independently is selected from 0,1,2,3 or 4;
X is selected from and is independently selected from O or (CH
2)
n
Aforementioned n is selected from 0,1,2,3 or 4;
R
1Be independently selected from hydrogen, halogen, C
1-8Alkyl, halo C
1-8Alkyl; R preferably
1Be hydrogen, halogen, C
1-5Alkyl, halo C
1-5Alkyl, halo C
1-5Alkoxyl group; R more preferably
1Be hydrogen, F, Cl, Br, methyl, methoxyl group, trifluoromethyl;
R
4Independently be selected from hydrogen, halogen, C
1-8Alkyl; R preferably
4Be hydrogen, F, Cl, Br, C
1-3Alkyl; R more preferably
4Be 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 halogens;
R preferably
6Independent C
1-5Alkyl, C
6-10Aryl, C
3-7Heteroaryl, described C
6-10Aryl or C
3-7Heteroaryl is optional further to be replaced by halogen;
R more preferably
6Independently be selected from methyl, ethyl, phenyl, pyridyl, chlorophenyl, chloro-pyridine base.
Aforementioned p independently is selected from 0,1,2,3 or 4.
4. compound or pharmaceutically acceptable salt thereof or the prodrug of general formula according to claim 1 (I) are when L is selected from
The time, shown in general formula (Ic):
Wherein:
M independently is selected from 0,1,2,3 or 4;
X is selected from and is independently selected from O or (CH
2)
n
Aforementioned n is selected from 0,1,2,3 or 4;
Y is selected from and is independently selected from CH or N;
The S ring is independently selected from phenyl ring, pyrrole ring;
R
1Be independently 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; R preferably
1Be 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; R more preferably
1Be 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; R preferably
4Be hydrogen, F, Cl, Br, C
1-3Alkyl; R more preferably
4Be 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;
R preferably
7Be 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;
R more preferably
7Be hydrogen, morpholinyl, methylpiperazine base, Pyrrolidine base, O (CH
2)
pR
8, NH (CH
2)
pR
9, 3-methoxy propyl alkynyl, 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 randomly further by C
1-8Alkyl replaces;
R preferably
8Be selected from C
1-5Alkoxyl group, C
6-10Aryl or C
3-8Heterocyclylalkyl, described C
6-10Aryl or C
3-18Heterocyclylalkyl is randomly further by C
1-3Alkyl replaces;
R more preferably
8Be selected from methoxyl group, piperazinyl, methylpiperazine base, morpholinyl;
Aforementioned R
9Be selected from C
3-10Heterocyclylalkyl, described C
3-10Heterocyclylalkyl is randomly further by C
1-8Alkyl replaces;
R preferably
9Be selected from C
3-8Heterocyclylalkyl; Described C
3-8Heterocyclylalkyl is randomly further by C
1-5Alkyl replaces;
R more preferably
9Be selected from piperazinyl, methylpiperazine base, morpholinyl;
Aforementioned p independently is selected from 0,1,2,3 or 4.
5. compound or pharmaceutically acceptable salt thereof shown in the general formula according to claim 1 (I), wherein said general formula (I) compound preferably from:
1-(4-((9-phenmethyl-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-((9-(pyridine-2-methyl)-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-((9-methyl-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-((9-(3-fluorobenzene methyl)-9H-purine-6-yl) oxygen) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-morpholinyl isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(4-methylpiperazine-1-yl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) propoxy-) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-Pyrrolidine base isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(2-fluoro-5-aminomethyl phenyl) urea
1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-aminomethyl phenyl) urea
1-(4-(3-amino-1-(2-morpholine oxyethyl group) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-trifluoromethyl) urea
1-(4-(3-amino-(2-methoxy ethoxy) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-trifluoromethyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(4-chloro-3-trifluoromethyl) urea
1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) the third amino) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-aminoisoquinoline-5-yl) phenyl)-3-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-methoxy propyl alkynyl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-dimethylamino proyl) isoquinoline 99.9-5-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(2-amino-7H-pyrroles [2,3-d] pyrimidine) (7-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-(2-amino-4-(4-methylpiperazine-1-yl)-7H-pyrroles [2,3-d] pyrimidine) (7-yl) phenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea
1-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(pyridine-2-base-methyl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
1-phenmethyl-3-(2-oxo-3-(pyridine-2-base-methyl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
1-(4-chloro-3-trifluoromethyl)-3-(2-oxo-3-(6-chloropyrimide-4-yl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea
1-phenmethyl-3-(2-oxo-3-(6-chloropyrimide-4-yl)-2, and the 3-dihydrobenzo [d] oxazole-6-yl) urea.
6. the described compound of any one and pharmaceutical salts thereof according to claim 1-5, it is characterized in that described pharmaceutical salts be by the compound with general formula (I) with preferably from mineral acid such as phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, Hydrogen bromide; Or organic acid forms such 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.
7. a pharmaceutical composition comprises each described general formula (I) compound of claim 1-6 or its pharmacy acceptable salt and pharmaceutically useful carrier or vehicle.
Among the claim 1-7 the described compound or pharmaceutically acceptable salt thereof of any one as kinases inhibitor the treatment or prophylaxis of tumours in application.
9. the described compound or pharmaceutically acceptable salt thereof of any one is as the application in the pharmaceutical composition of the medicine for preparing treatment or prophylaxis of tumours or conduct preparation treatment or prophylaxis of tumours among the claim 1-7 or 8, and wherein said tumour is melanoma, liver cancer, kidney, mammary cancer, lung cancer, nonsmall-cell lung cancer, thyroid carcinoma, bladder cancer, colorectal carcinoma, the rectum cancer, prostate cancer, carcinoma of the pancreas, ovarian cancer, myelomatosis, head and neck cancer, bladder cancer, acute marrow sample hypercytosis, chronic marrow sample hypercytosis, peritoneal cancer, mesothelioma, myelodysplastic syndrome, cancer of the stomach.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437140A (en) * | 2019-07-16 | 2019-11-12 | 中国人民解放军总医院 | It is a kind of inhibit SREBP-1 target spot compound and its application |
| WO2020186202A1 (en) | 2019-03-14 | 2020-09-17 | Board Of Regents, The University Of Texas System | Small molecule grb2 stabilizers for ras map kinase inhibition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008125014A1 (en) * | 2007-04-13 | 2008-10-23 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Urea compounds, preparation methods and pharmaceutical uses thereof |
| CN101296928A (en) * | 2005-10-28 | 2008-10-29 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| US20090291949A1 (en) * | 2003-11-19 | 2009-11-26 | Yoshiaki Washio | Substitute isoquinolines useful in the treatment of diseases such as cancer and atherosclerosis |
| CN102216300A (en) * | 2009-09-30 | 2011-10-12 | 浙江贝达药业有限公司 | Compounds and compositions as protein kinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090291949A1 (en) * | 2003-11-19 | 2009-11-26 | Yoshiaki Washio | Substitute isoquinolines useful in the treatment of diseases such as cancer and atherosclerosis |
| CN101296928A (en) * | 2005-10-28 | 2008-10-29 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| WO2008125014A1 (en) * | 2007-04-13 | 2008-10-23 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Urea compounds, preparation methods and pharmaceutical uses thereof |
| CN102216300A (en) * | 2009-09-30 | 2011-10-12 | 浙江贝达药业有限公司 | Compounds and compositions as protein kinase inhibitors |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020186202A1 (en) | 2019-03-14 | 2020-09-17 | Board Of Regents, The University Of Texas System | Small molecule grb2 stabilizers for ras map kinase inhibition |
| US20220151991A1 (en) * | 2019-03-14 | 2022-05-19 | Board Of Regents, The University Of Texas System | Small molecule grb2 stabilizers for ras map kinase inhibition |
| EP3937919A4 (en) * | 2019-03-14 | 2023-04-12 | Board of Regents, The University of Texas System | Small molecule grb2 stabilizers for ras map kinase inhibition |
| CN110437140A (en) * | 2019-07-16 | 2019-11-12 | 中国人民解放军总医院 | It is a kind of inhibit SREBP-1 target spot compound and its application |
| CN110437140B (en) * | 2019-07-16 | 2021-08-03 | 中国人民解放军总医院 | Compound for inhibiting SREBP-1 target and application thereof |
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| Publication number | Publication date |
|---|---|
| CN103373971B (en) | 2015-08-19 |
| CN105153162A (en) | 2015-12-16 |
| CN105153162B (en) | 2017-05-03 |
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