CN103965180B - Benzsulfamide azoles and thiazole inhibitors of kinases - Google Patents

Benzsulfamide azoles and thiazole inhibitors of kinases Download PDF

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CN103965180B
CN103965180B CN201310028201.8A CN201310028201A CN103965180B CN 103965180 B CN103965180 B CN 103965180B CN 201310028201 A CN201310028201 A CN 201310028201A CN 103965180 B CN103965180 B CN 103965180B
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cancer
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CN103965180A (en
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吴永谦
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Beijing Ao He Research Institute Co Ltd
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Tonghua Jida Pharmaceutical Co Ltd
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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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention belongs to pharmaceutical technology field, be specifically related to the benzsulfamide azoles shown in formula (I) and thiazole inhibitors of kinases, its pharmaceutically acceptable salt or its stereoisomer, wherein ring A, R1、R2、R3, X, m, n and p be defined as in the description.The invention still further relates to the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and this compound, its pharmaceutically acceptable salt or its stereoisomer are relevant by the b RAF cancer that causes of sudden change in preparation treatment and/or prevention or application in the medicine of non-cancer-related diseases.

Description

Benzsulfamide azoles and thiazole inhibitors of kinases
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to benzsulfamide azoles and thiazole inhibitors of kinases, its pharmaceutically Acceptable salt or its stereoisomer, the preparation method of these compounds, the pharmaceutical preparation containing these compounds and medicine Composition, and this compound, its pharmaceutically acceptable salt or its stereoisomer preparation treatment and/or prevention by b- Application in the medicine of the RAF cancer-related diseases that causes of sudden change or non-cancer-related diseases.
Background technology
Receptor tyrosine kinase (RTKs) participates in the growth of cell, breaks up, grows, breeds, divides and the process such as adhesion, Also the most relevant to the process such as the transcriptional regulatory of cell, Angiogenesis, endotheli ocytosis, have in process of cell signal transduction Have and act on widely.For these kinase whose regulations, cell proliferation and differentiation can be controlled, regulate the cell cycle, especially to one The tumour cell morphed a bit, by regulating the kinase whose activity of process LAN, can significantly suppress the growth of cancer cell, Reach to treat the effect of tumour.
The kinases micromolecular inhibitor with targeting has become as the focus of field of cancer treatment, her horse listed Draw for Buddhist nun and Lapatinib for Buddhist nun, Erlotinib, Gefitinib, Sutent, rope, bring good fortune to global cancer patient Sound, clinical research shows, these little molecules can significantly extend non-small cell lung cancer, kidney, liver cancer, cancer of the stomach, colon cancer with And the life cycle of the patient such as breast cancer, improve the quality of life of patient, show the unique advantage of small-molecule drug.But this A little medicines there is also problem in various degree, and wherein selectivity is the most poor, easily occur that resistance is all the subject matter that they face, than As Sorafenib can suppress VEGFR-2/3, b-RAF, c-RAF and PDGF, Erlotinib suppression EGFR and ERBB2, she replaces by horse Buddhist nun, except suppression PDGFR, also suppresses c-kt, Bcr-Abl etc..Therefore, improving selectivity is the important interior of little molecules in inhibiting research Hold.
RAF is a Key kinases in Ras/RAF/MEK/ERK path, is also MAPK(mitogen-activated Protein kinase) member important in signal path, RAF can play its signal by the way of relying on or being independent of Ras Conduction regulation effect, has important regulating and controlling effect in cell proliferation, differentiation and apoptosis.The kinase whose 3 kinds of hypotypes of RAF include a- RAF, b-RAF and Raf-1 (c-RAF), with cell proliferation, break up, survive, adhere to and the regulation of Angiogenesis is closely related.a- RAF is mainly distributed on the urogenital organ such as kidney, testis；B-RAF mainly expresses in nerve fiber, and RAF-1 is distributed widely in Body Various Tissues, and have not by the function of the most adjustable cell of Ras/RAF/MEK/ERK path.
RAF sudden change can cause kinds cancer clinically, the highest with the melanoma incidence of disease, take second place for thyroid cancer and Colon cancer, also includes liver cancer, lung cancer, breast cancer, oophoroma and carcinoma of urinary bladder.In the sudden change of RAF, especially dash forward with b-RAF V599E Become at most, therefore, for the research of b-RAF inhibition from mutation agent, above-mentioned cancer patient is had great importance.
The b-RAF inhibitor listed at present includes Sorafenib, and it is a Mutiple Targets inhibitor, and other has Certain selective b-RAF inhibitor includes RAF-265, PLX-4032, XL-281, SB-590885, RO-5126766 etc.. All there is the problems such as selectively the most poor or activity is the best in these compounds, is thus necessary to carry out corresponding research work, Search out for b-RAF sudden change and there is the most active micromolecular inhibitor.
Summary of the invention
The present invention has excellent activity and selective micromolecular inhibitor as target with exploitation for b-RAF sudden change, sends out Understand benzsulfamide azoles and the thiazole inhibitors of kinases with b-RAF inhibitory action.Concrete technical scheme is as follows:
The invention provides the compound shown in logical formula (I), its pharmaceutically acceptable salt or its stereoisomer:
Wherein,
Ring A is selected from:
(1) 3-14 unit cycloalkyl, 3-14 unit heterocyclic radical, 5-15 unit heteroaryl, 6-12 unit bridge heterocyclic radical or 6-12 unit spiral shell are miscellaneous Ring group, above-mentioned group can by oxo,
(2) 6-14 unit aryl；
R1Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, halo C1-6Alkyl, carboxyl C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynes Base, C1-6Alkoxyl, C1-6Alkyl sulfenyl, C1-6Alkyl amidine, carbamoyl, halo C1-6Alkoxyl, amino, C1-6Alkyl ammonia Base, (C1-6Alkyl)2Amino, cyano group, nitro, C1-6Alkyl-carbonyl, sulfonamido, amino-sulfonyl or C1-6Alkyl sulfonyl amino；
R2And R3Separately selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C1-6Alkoxyl, C1-6 Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, oxo, carbamoyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amino sulfonyl, sulfonamido, amino-sulfonyl, 3-14 unit cycloalkyl or 3-14 unit heterocyclic radical；
X is selected from O or S；
M, n and p are separately selected from 0,1,2 or 3.
It is preferably:
Ring A is selected from:
(1) 3-8 unit cycloalkyl, 5-10 unit heterocyclic radical, 5-10 unit heteroaryl, 8-10 unit bridge heterocyclic radical or 8-10 unit spiral shell are miscellaneous Ring group, above-mentioned group can by oxo,
(2) 6-8 unit aryl；
R1Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, halo C1-6Alkyl, carboxyl C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynes Base, C1-6Alkoxyl, C1-6Alkyl sulfenyl, C1-6Alkyl amidine, carbamoyl, halo C1-6Alkoxyl, amino, C1-6Alkyl ammonia Base, (C1-6Alkyl)2Amino, cyano group, nitro, C1-6Alkyl-carbonyl, sulfonamido, amino-sulfonyl or C1-6Alkyl sulfonyl amino；
R2And R3Separately selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C1-6Alkoxyl, C1-6 Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, oxo, carbamoyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amino sulfonyl, sulfonamido, amino-sulfonyl, 3-8 unit cycloalkyl or 5-10 unit heterocyclic radical；
X is selected from O or S；
M, n and p are separately selected from 0,1,2 or 3.
It is preferably:
Wherein,
Ring A is selected from:
(1) 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical or 5-6 unit heteroaryl, above-mentioned group can by oxo,
(2) 6-8 unit aryl；
R1Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, halo C1-6Alkyl, carboxyl C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, amino, C1-6Alkyl amino, (C1-6Alkyl)2Amino or cyano group；
R2And R3Separately selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C1-6Alkoxyl, C1-6 Alkyl or halo C1-6Alkyl；
X is selected from O or S；
M, n and p are separately selected from 0,1,2 or 3.
It is preferably:
Wherein,
Ring A is selected from:
(1) 5-6 unit heterocyclic radical or 5-6 unit heteroaryl,
(2) 6-8 unit aryl；
R1Selected from hydrogen, halogen atom, hydroxyl, C1-4Alkyl, amino or cyano group；
R2And R3Separately selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C1-4Alkoxyl, C1-4 Alkyl or halo C1-4Alkyl；
X is selected from O or S；
M, n and p are separately selected from 0,1,2 or 3.
It is preferably:
Wherein
Ring A is selected from
R1Selected from hydrogen, halogen atom, hydroxyl, C1-4Alkyl or amino；
R2And R3Separately selected from hydrogen, halogen atom, hydroxyl, amino, C1-4Alkoxyl or C1-4Alkyl；
X is selected from O or S；
M, n and p are separately selected from 0,1 or 2.
It is preferably:
Wherein,
Ring A is selected from
R1Selected from hydrogen or amino；
R2And R3Separately selected from hydrogen, halogen atom, hydroxyl or amino；
X is selected from O or S；
M, n and p are separately selected from 1 or 2.
Detailed Description Of The Invention
" halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine etc..Preferably fluorine atom, chlorine is former Son.More preferably fluorine atom.
" C of the present invention1-6Alkyl " represent straight or branched the alkyl containing 1-6 carbon atom, as methyl, ethyl, N-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, 2-methyl butyl, neopentyl, 1- Ethyl propyl, n-hexyl, isohesyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3,3-dimethylbutyl, 2,2-bis- Methyl butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl fourth Base, 1,2-dimethyl propyl etc.." C of the present invention1-4Alkyl " refer to above-mentioned " C1-6Alkyl " in example containing 1-4 carbon The instantiation of atom.
" C of the present invention2-6Thiazolinyl " refer to straight or branched that the carbon number containing double bond is 2-6 or ring-type alkene Base, as vinyl, 1-acrylic, 2-acrylic, 1-methyl ethylene, 1-cyclobutenyl, 2-cyclobutenyl, 3-cyclobutenyl, 1-methyl- 1-acrylic, 2-methyl-1-propylene base, 1-methyl-2-acrylic, 2-methyl-2-acrylic, 1-pentenyl, 2-pentenyl, 3- Pentenyl, 4-pentenyl, 1-methyl isophthalic acid-cyclobutenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene Base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-cyclobutenyl, 2-methyl-3-cyclobutenyl, 3-methyl-3- Cyclobutenyl, 1,1-dimethyl-2-acrylic, 1,2-dimethyl-1-acrylic, 1,2-dimethyl-2-acrylic, 1-ethyl-1- Acrylic, 1-ethyl-2-acrylic, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl isophthalic acid- Pentenyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-2-pentenyl, 2-first Base-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-amylene Base, 4-methyl-4-pentenyl, 1,1-dimethyl-2-cyclobutenyl, 1,1-dimethyl-3-cyclobutenyl, 1,2-dimethyl-1-butylene Base, 1,2-dimethyl-2-cyclobutenyl, 1,2-dimethyl-3-cyclobutenyl, 1,3-dimethyl-1-cyclobutenyl, 1,3-dimethyl-2- Cyclobutenyl, 1,3-dimethyl-2-cyclobutenyl, 2,2-dimethyl-3-cyclobutenyl, 2,3-dimethyl-1-cyclobutenyl, 2,3-diformazan Base-2-cyclobutenyl, 2,3-dimethyl-3-cyclobutenyl, 3,3-dimethyl-1-cyclobutenyl, 3,3-dimethyl-2-cyclobutenyl, 1-second Base-1-cyclobutenyl, 1-ethyl-2-cyclobutenyl, 1-ethyl-3-cyclobutenyl, 2-ethyl-1-cyclobutenyl, 2-ethyl-2-cyclobutenyl, 2-ethyl-3-cyclobutenyl, 1,1,2-trimethyl-2-acrylic, 1-ethyl-1-methyl-2-acrylic, 1-Ethyl-2-Methyl-1- Acrylic, 1-Ethyl-2-Methyl-2-acrylic, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 2,4-penta 2 Thiazolinyl, 1,4-hexadienyl, 2,4-hexadienyl, cyclopentenyl, 1,3-cyclopentadienyl group, cyclohexenyl group and 1,4-cyclohexadiene Base etc..Double bond is optionally cis and trans.
" C of the present invention2-6Alkynyl " refer to the alkynyl of the straight or branched that the carbon number containing three keys is 2-6, such as second Alkynyl, 1-propinyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4- Pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1- Ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 4-methyl-2-penta Alkynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl- 4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-diformazan Base-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2- Propinyl etc..
" C of the present invention1-6Alkoxyl " refer to above-mentioned " C1-6Alkyl " group that is connected with other structures by oxygen atom, Such as methoxyl group, ethyoxyl, propoxyl group, 1-methyl ethoxy, butoxy, 1-methyl-prop epoxide, 2-methyl-prop epoxide, 1,1-diformazan Base oxethyl, amoxy, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1,1-dimethyl propylene epoxide, 1,2- Dimethyl propylene epoxide, 2,2-dimethyl propylene epoxide, 1-ethylpropoxy, hexyloxy, 1-methylpent epoxide, 2-methylpent epoxide, 3-methylpent epoxide, 4-methylpent epoxide, 1,1-dimethyl butyrate epoxide, 1,2-dimethyl butyrate epoxide, 1,3-dimethyl butyrate epoxide, 2,2-dimethyl butyrate epoxide, 2,3-dimethyl butyrate epoxide, 3,3-dimethyl butyrate epoxide, 1-ethyl-butoxy, 2-ethyl-butoxy, 1,1,2-trimethyl propoxyl group, 1,2,2-trimethyl propoxyl group, 1-ethyl-1-methyl-prop epoxide and 1-Ethyl-2-Methyl the third oxygen Base etc.." C of the present invention1-4Alkoxyl " refer to above-mentioned " C1-6Alkoxyl " concrete containing 1-4 carbon atom in example Example.
" C of the present invention1-6Alkyl sulfenyl ", " C1-6Alkyl-carbonyl ", " C1-6Alkyl amidine ", " C1-6Alkyl amino ", “C1-6Alkyl sulfonyl amino ", " C1-6Alkyl amino sulfonyl " refer to above-mentioned " C respectively1-6Alkyl " by sulfenyl, carbonyl, amidino groups, ammonia The group that base, sulfonamido, amino-sulfonyl are connected with other structures.
" halo C of the present invention1-6Alkyl ", " carboxyl C1-6Alkyl ", " amino C1-6Alkyl ", " sulfonyl C1-6Alkyl " point Do not refer to that halogen atom, carboxyl, amino, sulfonyl replace above-mentioned " C1-6Alkyl " on one or more hydrogen atoms, and pass through alkyl The group being connected with other structures.
" halo C of the present invention1-4Alkyl " refer to that above-mentioned " halogen atom " replaces above-mentioned " C1-4Alkyl " on one or many Individual hydrogen atom, and the group being connected with other structures by alkyl.
" halo C of the present invention1-6Alkoxyl " refer to that above-mentioned " halogen atom " replaces above-mentioned " C1-6Alkoxyl " on one Individual or multiple hydrogen atoms, and the group being connected with other structures by alkoxyl.
" (C of the present invention1-6Alkyl)2Amino " refer to that atom that in amino, any two can be replaced is by above-mentioned " C1-6 Alkyl " replaced, and the group being connected with other structures by amino.
" 3-14 unit cycloalkyl " of the present invention refers to that the paraffin section of 3-14 carbon atom is removed a hydrogen atom and spread out Raw cyclic alkyl, including 3-8 unit cycloalkyl, 6-14 unit ring cycloalkyl.
3-8 unit cycloalkyl, refers to that the paraffin section of 3-8 carbon atom removes the cyclic alkyl that a hydrogen atom is derivative, its Example includes but not limited to: cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base, methyl ring Propyl, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methyl cyclopentane base, dimethylcyclopentane Base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc..
6-14 unit ring cycloalkyl, refer to be shared two adjacent carbon atoms each other by two or more circuluses The 6-14 cyclic group formed, the example includes but not limited to: two rings [3.1.0] hexyl, two rings [4.1.0] heptane Base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, octahydro pentalene base, eight Hydrogen-1H-indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl, dicyclo [3.1.0] hex-2-thiazolinyl, dicyclo [4.1.0] hept-3-thiazolinyl, double Ring [3.2.0] hept-3-thiazolinyl, dicyclo [4.2.0] octyl-3-thiazolinyl, 1,2,3,3a-tetrahydrochysene pentalene base, 2,3,3a, 4,7, 7a-hexahydro-1H-indenyl, the octahydro naphthyl of 1,2,3,4,4a, 5,6,8a-, 1,2,4a, 5,6,8a-hexahydro naphthyl, 1,2,3, 4,5,6,7,8,9,10-decahydro phenanthryl etc..
" 3-8 unit cycloalkyl " of the present invention, " 5-6 unit cycloalkyl " refer in above-mentioned " 3-14 unit cycloalkyl " example Annular atoms number is respectively 3-8 unit, the instantiation of 5-6 unit.
" 6-14 unit aryl " of the present invention refers to that the cyclic nonaromatics that annular atoms is 6-14 unit carbon atom removes Remove the monovalent moiety that hydrogen atom obtains, including 6-8 unit aryl and 8-14 unit fused ring aryl.6-8 unit aryl includes phenyl, ring pungent four Thiazolinyl etc..8-14 unit fused ring aryl refers to be shared what two adjacent carbon atoms were formed each other by two or more aromatic rings Condensed ring group, at least ring is the cyclic group of whole undersaturated aromatic rings, including the most unsaturated condensed ring of 8-14 unit Carbon aryl, such as naphthyl, anthryl, phenanthryl etc., also includes 8-14 unit fractional saturation fused ring aryl, such as benzo 3-8 unit cycloalkyl, tool Body example such as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, DHN 1,4 dihydronaphthalene base etc..Of the present invention " 6-8 unit aryl " refers to that in above-mentioned " 6-14 unit aryl ", annular atoms number is the instantiation of 6-8 unit.
" 5-15 unit heteroaryl " of the present invention finger ring atom be 5-15 unit include one or more heteroatomic ring Shape aromatic group, including the thick heteroaryl of 5-8 unit heteroaryl and 8-15 unit.
5-8 unit heteroaryl, includes but not limited to pyrrole radicals, imidazole radicals, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazoles Base, pyridine radicals, furyl, thienyl,Oxazolyl, differentOxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl group, 1,2,4- Thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-Di azoly, 1,2,4-Di azoly, 1,2,5-Di azoly, 1,2,3-tri- Piperazine base, 1,2,4-triazine radical, tetrazole radical,Triazolyl, 2H-1,2-Piperazine base, 4H-1,2-Piperazine base, 6H-1,2-Piperazine base, 2H-1,3-Piperazine base, 4H-1,3-Piperazine base, 6H-1,3-Piperazine base, 2H-1,4-Piperazine base, 4H-1,4-Piperazine base, differentPiperazine Base, pyridazinyl, pyrimidine radicals and pyrazinyl etc.；
The thick heteroaryl of 8-15 unit, refers to containing 8-15 annular atoms (at least a part of which contains a hetero atom) by two or two Individual above hetero-aromatic ring share each other two adjacent atoms couple together formed condensed cyclic structure, include but not limited to benzofuran Base, isobenzofuran-base, benzothienyl, indyl, isoindolyl, quinolyl, isoquinolyl, indolizine base, indazolyl, phthalazines Base, quinoxalinyl, quinazolyl, benzodiazine base, benzisoxaOxazolyl, benzoPiperazine base, benzimidazolyl, pyridopyridine Base, pyrazolo [3,4-b] pyridine radicals, purine radicals, acridinyl and ton base etc..
" 5-10 unit heteroaryl " of the present invention, " 5-6 unit heteroaryl " refer to annular atoms number in above-mentioned " 5-15 unit heteroaryl " For 5-10 unit, the instantiation of 5-6 unit.
" hetero atom " of the present invention refers to N, O, S, SO and/or SO2Deng, preferably N, O, S, more preferably N, O.
" 3-14 unit heterocyclic radical " of the present invention refers to containing one or more heteroatomic 3-14 cyclic group, including 3- 8 yuan of heterocyclic radicals and 6-14 unit also heterocyclic radical.
3-8 unit heterocyclic radical, refers to the heterocyclic radical containing 3-8 annular atoms (at least a part of which contains a hetero atom).Specifically Example include but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranose, 5,6-dihydro- 4H-1,3-piperazine base, aziridine base, azetidinyl, Thietane base, tetrahydrofuran base, nafoxidine base, miaow Oxazolidinyl, pyrazolidinyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithia ring Hexyl, morpholinyl, piperazinyl etc..
6-14 unit heterocyclic radical, refer to containing 6-14 annular atoms (at least a part of which contains a hetero atom) by two or two Above circulus shares two adjacent atoms each other and couples together the condensed cyclic structure formed, as benzo 3-8 unit heterocyclic radical is formed Structure, the structure etc. that 3-8 unit heterocyclic radical 3-8 unit heterocyclic radical are formed, instantiation includes but not limited to:、 、、、、Any commutable hydrogen atom institute shape is replaced etc. circulus The group become.
" 5-10 unit heterocyclic radical " of the present invention, " 5-6 unit heterocyclic radical " refer to annular atoms number in above-mentioned " 3-14 unit heterocyclic radical " For 5-10 unit, the instantiation of 5-6 unit.
" 6-12 unit bridge heterocyclic radical " of the present invention refer to any two ring share two non-conterminous atoms formed containing one Or multiple heteroatomic 6-12 units bridge heterocyclic radical, instantiation includes but not limited to:、、、、 、、、The base that any commutable hydrogen atom is formed is replaced etc. circulus Group etc..
" 8-10 unit bridge heterocyclic radical " of the present invention refers to that in above-mentioned " 6-12 unit bridge heterocyclic radical ", annular atoms number is respectively 8-10 Instantiation.
" 6-12 unit spiro heterocyclic radical " of the present invention refer to that at least two rings share that a carbon atom formed containing one or Multiple heteroatomic formed 6-12 unit spiro heterocyclic radicals, instantiation includes but are not limited to:、、 、、、Arbitrarily may replace etc. circulus replacement The group etc. that formed of hydrogen atom.
" 8-10 unit spiro heterocyclic radical " of the present invention refers to that in above-mentioned " 6-12 unit spiro heterocyclic radical ", annular atoms number is 8-10 unit Instantiation.
Particularly preferred compound:
Above-claimed cpd of the present invention can use method that the present invention describes and/or known to persons of ordinary skill in the art Other technology synthesizes, but is not limited only to following methods.
When ring A is pyrimidine radicals, R1For amino, when m is 1, synthetic method is as follows:
Reactions steps:
(1) preparation of SM1
Reference literature US2009/298815 A1 (2009).
(2) preparation of TM1
Under room temperature condition, SM1 is dissolved in q. s. methylene chloride, adds appropriate N-bromo-succinimide, be stirred at room temperature 5 Hour.After completion of the reaction, adding dichloromethane, separatory in mixed liquor, organic phase is washed with water, saturated sodium-chloride water respectively, Anhydrous sodium sulfate is dried, and rotary evaporation removes solvent, and residue silica gel column chromatography separating purification obtains TM1.
(3) preparation of TM2
TM1, SM2 being dissolved in q. s. toluene, mixed liquor is heated to 100 DEG C and reacts 12 hours.After completion of the reaction, steaming is rotated Sending out and remove solvent, residue obtains TM2 through silica gel column chromatography separating purification.
(4) preparation of logical formula (I) compound
TM2 is dissolved in proper ammonia, microwave reaction, is heated to 90 DEG C and reacts 1.5 hours.Cooling, reduced pressure concentration, residue Thing obtains logical formula (I) compound through silica gel column chromatography separating purification.
In reaction equation, ring A, R1、R2、R3, X, m, n and p as defined hereinabove.
Arbitrary compound pharmaceutically acceptable salt shown in the logical formula (I) of the present invention refer to by pharmaceutically acceptable, Non-toxic alkali or the salt of acid preparation, including acylate, inorganic acid salt, organic alkali salt, inorganic base salts.Acylate includes first Acid, acetic acid, benzene sulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, fumaric acid, Gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, glactaric acid, pamoic acid, pantothenic acid, butanedioic acid, wine The salt of stone acid etc..Inorganic acid salt includes the salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid etc..
Organic alkali salt includes primary, secondary and tertiary amine, is replaced amine and includes naturally occurring replacement amine, cyclammonium and basic ion exchange Resin, selected from glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-Diethylaminoethanol, 2-dimethylamine Base ethanol, monoethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, Glucosamine, Hai Baming, isopropyl Amine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), ammonia fourth three The salt of alcohol etc..Native amino hydrochlorate such as glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, Cystine, cysteine, methionine, proline, hydroxy-proline, histidine, ornithine, lysine, arginine, serine etc. Salt.Inorganic base salts includes the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous iron, manganese, bivalent manganese etc..
" stereoisomer " of claimed formula (I) compound, if the compounds of this invention is containing one or more Asymmetric center, can be as racemic modification and racemic mixture, single enantiomter, non-enantiomer mixture and list One diastereoisomer.The compounds of this invention has asymmetric center, two light of generation that this kind of asymmetric center respectively will be independent Learning isomers, the scope of the present invention includes all possible optical isomer and non-enantiomer mixture and pure or part Pure compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.Alloisomerism including formula (I) compound Body, geometric isomer and cis-trans-isomer, including enantiomter and mixture thereof, such as racemate.The different isomery bodily forms Formula conventional method is separable or splits out, or any appointment isomeric form can be by conventional method or special or not by solid Symmetrical synthetic method obtains.
Arbitrary compound shown in the logical formula (I) of the present invention has the chiral centre of two or more.Synthesis obtain be Raceme, the compound of required enantiomer-pure can be obtained by the method for chiral resolution: can be solid by having chirality Determine the chromatography (image height compacting standby liquid phase, supercritical fluid chromatography) of phase.Chirality padding includes but not limited to: Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
Further requirement of the present invention protection includes the arbitrary compound of logical formula (I) recited above, it is pharmaceutically acceptable Salt or its stereoisomer and other one or more antitumor agents and the pharmaceutical composition of immunodepressant.Described is antitumor Agent and immunodepressant, such as anti-metabolism, include but are not limited to methotrexate (MTX), capecitabine, gemcitabine, deoxidation fluorine urine Glycosides；Growth factor receptor inhibitors class, includes but are not limited to pazopanib, Imatinib, Gefitinib；Targeting class, including but not It is only limitted to Trastuzumab, bevacizumab, Rituximab, Herceptin；Mitotic inhibitor class, includes but are not limited to purple China fir alcohol, vinorelbine, docetaxel, Doxorubicin, HCPT, mitomycin, epirubicin, THP, rich come mould Element；Antitumor steroids, includes but are not limited to Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, Flutamide, bright third auspicious Woods, Anastrozole；Alkylating agent class, includes but are not limited to ifosfamide, busulfan, endoxan, BCNU, Ni Mosi Spit of fland, Semustine；Metal platinum class, includes but are not limited to carboplatin, cis-platinum, oxaliplatin, network platinum；Topoisomerase enzyme inhibitor, Include but are not limited to Topotecan；Immunosupress class, includes but are not limited to everolimus.
Further requirement of the present invention protection includes the arbitrary compound shown in above-mentioned logical formula (I), it is pharmaceutically acceptable Salt or its stereoisomer and one or more pharmaceutical carriers and/or the pharmaceutical composition of diluent, can make pharmaceutically Acceptable arbitrary formulation.It is applied to need the patient of this treatment in modes such as oral, parenteral, rectum or transpulmonary administration. When oral administration, can be made into the solid pharmaceutical preparation of routine, such as tablet, capsule, pill, granule etc.；May be made as being administered orally Liquid preparation, such as oral solution, oral suspensions, syrup etc..When making oral formulations, suitable filling can be added Agent, adhesive, disintegrant, lubricant etc..When parenteral, can be made into injection, including parenteral solution, Injectable sterile Powder and concentrated solution for injection.When making injection, the conventional method in existing pharmaceutical field can be used to produce, prepare injection Time, additives can be added without, it is possible to add suitable additives according to the character of medicine.When rectally, can be made into Suppository etc..When transpulmonary administration, can be made into inhalant or spray etc..Per unit preparation contains the formula of physiology effective dose (I) compound 0.01 g shown in～10 g, can be 0.01 g, 0.05 g, 0.1 g, 0.125 g, 0.2 g, 0.25 g, 0.3 g、0.4 g、0.5 g、0.6 g、0.75 g、1 g、1.25 g、1.5 g、1.75 g、2 g、2.5 g、3 g、4 g、5 g、 10 g etc..
Invention further provides the present invention lead to the compound shown in formula (I), its pharmaceutically acceptable salt or its stand Body isomers for the treatment disease relevant to kinases, particularly with Ab1, Bcr-Ab1, Bmx, BTK, b-RAF, c-RAF, CSK, cSRC、Fes、FGFR3、Flt3、IKKα、IKKβ、JNK1α1、JNK2α2、Lck、Met、MKK4、MKK6、p70S6K、PAK2、 PDGFRα、PKA、PKCα、PKDα、ROCK-Ⅱ、Ros、Rsk1、SAPK2α、SAPK2β、SAPK3、SAPK4、SGK、Syk、Tie2 Application in the medicine of the disease relevant with kinases such as TrkB.
Present invention also offers the present invention, to lead to the compound shown in formula (I), its pharmaceutically acceptable salt or its solid different Structure body is in preparation treatment and/or prevents by kinases, specifically refers to a-RAF, and b-RAF, c-RAF particularly b-RAF kinases is abnormal the most sharp Live or application in the medicine of the cancer-related diseases that causes of disorder or non-cancer-related diseases.Cancer of the present invention is correlated with disease Disease includes but are not limited to: brain tumor, lung cancer, lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, cancer of the stomach, oophoroma, Peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, kidney, adenocarcinoma of esophagus, food Pipe squamous cell carcinoma, solid tumor, NHL, glioma, glioblastoma multiforme, glioma sarcomatosum, front Row gland cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, lymthoma, histocytic lymphoma, neurofibromatosis, thyroid gland Cancer, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, ED-SCLC, gastrointestinal stromal tumor, tumor of prostate, mast cell Tumour, Huppert's disease, melanoma, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma Deng.Non-cancer-related diseases includes but are not limited to skin or prostatic hyperplasia of prostate etc..
The compounds of this invention has the advantage that
(1) formula (I) compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer have the b-RAF of excellence Kinase inhibiting activity and selectivity；
(2) formula (I) compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer demonstrate good biology Stability, acts on more longlasting, and bioavilability is high；
(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, it is easy to carry out large-scale industry raw Produce.
The beneficial effect of the compounds of this invention is expanded on further below by way of the experiment of external pharmacologically active, but this should not managed Solve, for the compounds of this invention, only there is following beneficial effect.
The external zymetology activity experiment of experimental example the compounds of this invention
Test sample: self-control, its chemical name and structural formula are shown in the preparation embodiment of each compound
Experimental technique:
Implication representated by following test Chinese and English abbreviation is as follows:
HEPES: hydroxyethyl piperazine second thiosulfonic acid；
Brij-35: Brij-35；
EDTA: ethylenediamine tetra-acetic acid；
Fluorescein-MAP2K1: fluorescein mark MAP2K1；
ATP: atriphos；
DMSO: dimethyl sulfoxide (DMSO)；
MgCl2: magnesium chloride.
1. test preparation of reagents
1. 1 times of kinase buffer liquid (50 mM HEPES, PH 7.5,10 mM MgCl2, 1 mM EGTA, 0.01% Brij- 35)；
2. 2 times of kinase solution (add corresponding kinases 2 times of kinase solution of preparation, final concentration in 1 times of kinase buffer liquid For b-RAF 3.5 nM, b-RAF V599E 0.35 nM)；
3. 4 times of substrate solutions (in 1 times of kinase buffer liquid, add Fluorescein-MAP2K1 and ATP, prepare 4 times molten Liquid, two kinds of kinase substrate Fluorescein-MAP2K1 final concentrations are 0.2 μM, wherein in 4 times of substrate solutions of b-RAF kinases ATP concentration is 0.5 μM, and in 4 times of substrate solutions of b-RAF V599E kinases, ATP concentration is 1.5 μMs)；
4. 2 times of detection solution (prepare 2 times and detect solution, final concentration of antibody 2 nM, EDTA 10 mM)；
5. (using the solution of 100% DMSO preparation final concentration 100 times, 4 times of gradient dilutions 10 are dense for 4 times of compound solutions Degree, dilutes 25 times with kinase buffer liquid the most respectively, is configured to each compound solution of the gradient dilution of final concentration 4 times, chemical combination Thing final concentration maximum concentration is 10000 nM)；
2. take 4 times of compound solutions of 2.5 μ L and add 384 orifice plates, multiple hole；
3. add 2 times of enzyme solutions of 5 μ L and hatch 10 minutes；
4. it is subsequently adding 4 times of substrates of 2.5 μ L and ATP solution, room temperature, hatches 1 hour；
5. being eventually adding 10 μ L detection solution and terminate reaction, after 30 minutes, ELIASA reads data；
6. IC50。
Calculate RFU ratio
Calculate inhibiting rate (%)=(maximum-sample ratio)/(maximum-minimum of a value) × 100
Use Xlfit software to carry out curve fitting, draw IC50 value.
Experimental result and conclusion:
The external zymetology inhibitory activity of table 1 the compounds of this invention
From table 1, the compounds of this invention has good inhibitory activity to b-RAF kinases and b-RAF V599E kinases, And suitable to b-RAF kinases and the kinase whose inhibitory activity of b-RAF V599E, can be used for treatment and b-RAF kinases and b-RAF The disease that V599E kinases is relevant, illness that particularly b-RAF V599E kinases causes or the patient's condition.
Detailed description of the invention
The detailed description of the invention of form by the following examples, makees the most specifically the foregoing of the present invention Bright.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to following example.All based on foregoing of the present invention The technology realized belongs to the scope of the present invention.
Embodiment 1 N-(3-(5-(2-aminopyrimidine-4-base)-2-((2-ethoxy) amino) Azoles-4-base)-2-fluorine Phenyl) preparation of-2,6-difluorobenzenesulfonamide (compound 1)
(1) preparation of N-(3-(2-(2-chlorine pyrimidine-4-yl) acetyl group)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
The preparation of N-(3-(2-(2-chlorine pyrimidine-4-yl) acetyl group)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide is with reference to literary composition Offer US2009/298815 A1 (2009).
(2) N-(3-(the bromo-2-of 2-(2-chlorine pyrimidine-4-yl) acetyl group)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide Preparation
Under room temperature condition, by N-(3-(2-(2-chlorine pyrimidine-4-yl) acetyl group)-2-fluorophenyl)-2,6-difluorobenzene sulphonyl Amine (6.2 g, 14 mmol) is dissolved in dichloromethane (50 mL), and addition N-bromo-succinimide (2.5 g, 14 Mmol), 5 hours it are stirred at room temperature.After completion of the reaction, adding dichloromethane (20 mL), separatory in mixed liquor, organic phase is respectively With water, the washing of saturated sodium-chloride water, anhydrous sodium sulfate is dried, and rotary evaporation removes solvent, residue silica gel column chromatography (oil Ether/ethyl acetate=2:1) isolated and purified yellow solid product (5.5 g, productivity 75%).
(3) N-(3-(5-(2-chlorine pyrimidine-4-yl)-2-((2-ethoxy) amino)Azoles-4-base)-2-fluorophenyl)-2, The preparation of 6-difluorobenzenesulfonamide
By N-(3-(the bromo-2-of 2-(2-chlorine pyrimidine-4-yl) acetyl group)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (1 g, 1.9 mmol), 1-(2-ethoxy) urea (870 mg, 8.4 mmol) be dissolved in toluene (20 mL), mixed liquor is heated to 100 DEG C React 12 hours.After completion of the reaction, rotary evaporation removes solvent, and residue is through silica gel column chromatography (dichloromethane: methyl alcohol=10:1) Isolated and purified product (150 mg, productivity 15%).
(4) N-(3-(5-(2-aminopyrimidine-4-base)-2-((2-ethoxy) amino)Azoles-4-base)-2-fluorophenyl)- The preparation of 2,6-difluorobenzenesulfonamide
By N-(3-(5-(2-aminopyrimidine-4-base)-2-((2-ethoxy) amino)Azoles-4-base)-2-fluorophenyl)-2, 6-difluorobenzenesulfonamide (100 mg, 0.2 mmol) is dissolved in ammoniacal liquor (5 mL), microwave reaction, is heated to 90 DEG C of reactions 1.5 little Time.Cooling, reduced pressure concentration, residue separates (dichloromethane: methyl alcohol=10:1) through silica gel column chromatography and obtains product (20 mg, productivity 20%)。
Molecular formula: C21H17F3N6O4S molecular weight: 506.5 LC-MS (m/z): 507.0 [M+H]+
1H-NMR (400 MHz, MeOD) δ: 8.06 (d, 1H), 7.57 ~ 7.61 (m, 1 H), 7.48 (m, 1H), 7.36 (m, 1H), 7.20 (m, 1H), 7.06 ~ 7.11 (m, 2 H), 6.46 (d, 1H), 3.71 (m, 2H), 3.46 (m, 2H).
Embodiment 2 N-(3-(5-(2-aminopyrimidine-4-base)-2-((2-ethoxy) amino) thiazole-4-yl)-2-fluorobenzene Base) preparation of-2,6-difluorobenzenesulfonamide (compound 2)
(1) preparation of 1-(2-ethoxy) thiocarbamide
The preparation of thiocarbamide is with reference to patent US2008/45556 A1 (2008), and reaction temperature changes 70 DEG C into, and the reaction time is 10 hours, productivity was 70%.
(2) N-(3-(5-(2-chlorine pyrimidine-4-yl)-2-((2-ethoxy) amino) thiazole-4-yl)-2-fluorophenyl)-2, The preparation of 6-difluorobenzenesulfonamide
N-(3-(the bromo-2-of 2-(2-chlorine pyrimidine-4-yl) the acetyl group)-2-that will be prepared by embodiment 1 step " (2) " Fluorophenyl)-2,6-difluorobenzenesulfonamide (1 g, 1.9 mmol), 1-(2-ethoxy) thiocarbamide (348 mg, 5.7 mmol) be molten In toluene (20 mL), mixed liquor is heated to 100 DEG C and reacts 12 hours.After completion of the reaction, rotary evaporation removes solvent, residue Through silica gel column chromatography (eluant dichloromethane: methyl alcohol=10:1) isolated and purified product (200 mg, productivity 19%).
(3) N-(3-(5-(2-aminopyrimidine-4-base)-2-((2-ethoxy) amino) thiazole-4-yl)-2-fluorophenyl)- The preparation of 2,6-difluorobenzenesulfonamide
By N-(3-(5-(2-aminopyrimidine-4-base)-2-((2-ethoxy) amino) thiazole-4-yl)-2-fluorophenyl)-2, 6-difluorobenzenesulfonamide (150 mg, 0.28 mmol) is dissolved in ammoniacal liquor (5 mL), microwave reaction, is heated to 90 DEG C of reactions 1.5 Hour.Cooling, rotary evaporation removes solvent, and residue is isolated and purified through silica gel column chromatography (dichloromethane: methyl alcohol=10:1) (30 mg, productivity 21%).
Molecular formula: C21H17F3N6O3S2Molecular weight: 522.5 LC-MS (m/z): 523.4 [M+H]+
1H-NMR (400 MHz, MeOD) δ: 7.75 (d, 1H), 7.57 ~ 7.61 (m, 2 H), 7.24 ~ 7.27 (m, 2 H), 7.07 (m, 2H), 5.79 (d, 1H), 3.71 (m, 2H), 3.43 (m, 2H).

Claims (5)

1. lead to the compound shown in formula (I), its pharmaceutically acceptable salt or its stereoisomer:
Wherein
Ring A is selected from
R1Selected from hydrogen or amino；
R2And R3Separately selected from halogen atom；
X is selected from O or S；
M, n and p are separately selected from 1 or 2.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, described compound is selected from:
3. compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer and one or more medicines With carrier and/or the pharmaceutical composition of diluent, it is made into the arbitrary formulation pharmaceutically accepted.
4. compound as claimed in claim 3, its pharmaceutically acceptable salt or the pharmaceutical composition of its stereoisomer, its It is characterised by possibly together with one or more antitumor agents and immunodepressant, selected from methotrexate (MTX), capecitabine, gemcitabine, Doxifluridine, pazopanib, Imatinib, Gefitinib, Trastuzumab, bevacizumab, Rituximab, Herceptin, Taxol, vinorelbine, docetaxel, Doxorubicin, HCPT, mitomycin, epirubicin, THP, rich next Mycin, Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, Flutamide, Leuprorelin, Anastrozole, ifosfamide, in vain Disappear peace, endoxan, BCNU, Nimustine, Semustine, carboplatin, cis-platinum, oxaliplatin, network platinum, Topotecan or depend on Wei Mosi.
5. compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer in preparation treatment and/or Prevent the application in the medicine of cancer-related diseases or the non-cancer-related diseases caused by kinases abnormal activation or disorder, described The disease that cancer is relevant is selected from lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, cancer of the stomach, oophoroma, peritoneal cancer, pancreas Gland cancer, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell Cancer, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, little carefully Born of the same parents' lung cancer；Non-cancer-related diseases, selected from skin or prostatic hyperplasia of prostate.
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WO2009137391A2 (en) * 2008-05-06 2009-11-12 Smithkline Beecham Corporation Benzene sulfonamide thiazole and oxazole compounds
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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009137391A2 (en) * 2008-05-06 2009-11-12 Smithkline Beecham Corporation Benzene sulfonamide thiazole and oxazole compounds
WO2011046894A1 (en) * 2009-10-12 2011-04-21 Glaxosmithkline Llc Combination

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Combinations of BRAF, MEK, and P13K/mTOR Inhibitors Overcome Acpuired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated by NRAS or MEK Mutations";James G. Greger et al.;《Molecular Cancer Therapeutics》;20120430;第11卷(第4期);第909-920页 *

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