CN103936728B - Thiazole inhibitors of kinases - Google Patents

Thiazole inhibitors of kinases Download PDF

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CN103936728B
CN103936728B CN201310019872.8A CN201310019872A CN103936728B CN 103936728 B CN103936728 B CN 103936728B CN 201310019872 A CN201310019872 A CN 201310019872A CN 103936728 B CN103936728 B CN 103936728B
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cancer
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alkyl
carcinoma
methyl
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CN103936728A (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
    • 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 logical thiazole inhibitors of kinases shown in formula I, its pharmaceutically acceptable salt or its stereoisomer, wherein R1、R2、R3、R4, 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

Thiazole inhibitors of kinases
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to thiazole inhibitors of kinases, its pharmaceutically acceptable salt or its Stereoisomer, the preparation method of these compounds, the pharmaceutical preparation containing these compounds and pharmaceutical composition, and this change The cancer that compound, its pharmaceutically acceptable salt or its stereoisomer are caused by b-RAF sudden change in preparation treatment and/or prevention Application in the medicine of relevant disease 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 cell cycle, especially to one The tumor 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 tumor.
The kinases micromolecular inhibitor with targeting has become as the focus of field of cancer, 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 nonsmall-cell lung cancer, renal carcinoma, hepatocarcinoma, gastric cancer, colon cancer with And the life cycle of the patient such as breast carcinoma, 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 poor, easily occur that drug 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 nervous tissue, and RAF-1 is distributed widely in Body Various Tissues, and have not by the Ras/RAF/MEK/ERK path i.e. function of scalable cell.
RAF sudden change can cause kinds cancer clinically, the highest with melanoma sickness rate, take second place for thyroid carcinoma and Colon cancer, also includes hepatocarcinoma, pulmonary carcinoma, breast carcinoma, ovarian cancer and bladder cancer.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.. These compounds all exist that selectivity is poor or the problem such as activity is the best, are 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 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) 3-8 unit cycloalkyl, 3-8 unit heterocyclic radical or 5-8 unit heteroaryl, above-mentioned group can be by oxo, and ring A can not For pyrimidine-4-yl, pyridin-4-yl,
(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 C1-6Alkylsulfonylamino group Base；
R2Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, (C1-6Alkyl)2Amino, C2-6Thiazolinyl, C2-6Alkynes Base, C1-6Alkyl-carbonyl, 3-14 unit cycloalkyl, 3-14 unit heterocyclic radical, 5-15 unit heteroaryl or 6-14 unit aryl, above-mentioned group can To be replaced by 1-3 Q, Q is selected from hydrogen, halogen atom, cyano group, hydroxyl, carbamoyl, C1-6Alkyl, C1-6Alkoxyl, amino C1-6Alkyl, C1-6Alkyl sulfenyl, (C1-6Alkyl)2Amino, 3-14 unit heterocyclic radical, C1-6Alkyl substituted 3-14 unit heterocyclic radical；
R3And R4Separately 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；
M, n and p are separately selected from 0,1,2 or 3.
It is preferably:
Wherein,
Ring A is selected from:
(1) 3-7 unit cycloalkyl, 3-7 unit heterocyclic radical or 5-7 unit heteroaryl, above-mentioned group can be by oxo, and ring A can not For pyrimidine-4-yl, pyridin-4-yl,
(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 C1-6Alkylsulfonylamino group Base；
R2Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, (C1-6Alkyl)2Amino, C2-6Thiazolinyl, C2-6Alkynes Base, C1-6Alkyl-carbonyl, 3-8 unit cycloalkyl, 5-10 unit heterocyclic radical, 5-8 unit heteroaryl or 6-8 unit aryl, above-mentioned group can be by 1-3 Q replaces, and Q is selected from hydrogen, halogen atom, cyano group, hydroxyl, carbamoyl, C1-6Alkyl, C1-6Alkoxyl, amino C1-6Alkane Base, C1-6Alkyl sulfenyl, (C1-6Alkyl)2Amino, 5-10 unit heterocyclic radical, C1-6Alkyl substituted 5-10 unit heterocyclic radical；
R3And R4Separately 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；
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 be by oxo, and ring A can not For pyrimidine-4-yl, pyridin-4-yl,
(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；
R2Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, (C1-6Alkyl) 2Amino, 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit heteroaryl or phenyl, above-mentioned group can be replaced by 1-3 Q, Q selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, amino C1-6Alkyl, (C1-6Alkyl)2Amino, 5-6 unit heterocyclic radical, C1-6Alkyl substituted 5-6 unit Heterocyclic radical；
R3And R4Separately selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C1-6Alkoxyl, C1-6 Alkyl or halo C1-6Alkyl；
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, above-mentioned group can by oxo, and ring A can not be pyrimidine-4-yl, Pyridin-4-yl,
(2) 6-8 unit aryl；
R1Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, amino or cyano group；
R2Selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, (C1-6Alkyl) amino, 5-6 unit cycloalkyl, 5- 6 yuan of heterocyclic radicals, 5-6 unit heteroaryl or phenyl, above-mentioned group can be replaced by 1-3 Q, Q selected from hydrogen, halogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, amino C1-6Alkyl, (C1-6Alkyl) 2Amino, 5-6 unit heterocyclic radical, C1-6Alkyl substituted 5-6 unit is miscellaneous Ring group；
R3And R4Separately selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C1-6Alkoxyl, C1-6 Alkyl or halo C1-6Alkyl；
M, n and p are separately selected from 0,1 or 2.
It is preferably:
Wherein,
Ring A is selected from
,,,,,,,,,,,,,,,,,,,,Or；
R2It is selected from
,,,,,,,,,,,,,,,,,,Or。
It is preferably:
Wherein,
Ring A is selected from
,,,,,,,,,,,,,,Or；
R2It is selected from
,,,,,, Or 。
Detailed Description Of The Invention
" halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine etc..
" 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 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-butylene base, crotyl, 3-cyclobutenyl, 1-methyl- 1-acrylic, 2-methyl-1-propylene base, 1-methyl-2-acrylic, 2-methyl-2-acrylic, 1-pentenyl, 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-pentenyl, 2-first Base-pentenyl, 3-methyl-pentenyl, 4-methyl-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-crotyl, 1,1-dimethyl-3-cyclobutenyl, 1,2-dimethyl-1-butylene Base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-cyclobutenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-2- Cyclobutenyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-cyclobutenyl, 2,3-dimethyl-1-butylene base, 2,3-diformazan Base-crotyl, 2,3-dimethyl-3-cyclobutenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-second Base-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-cyclobutenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 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-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4- Pentynyl, 1-methyl-2-butyne base, 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- Pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-first Base-4-pentynyl, 1,1-dimethyl-2-butyne base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2- Dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-first Base-2-propynyl 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 invention1-6Alkyl sulfenyl ", " C1-6Alkyl-carbonyl ", " C1-6Alkyl amidine ", " C1-6Alkyl sulphonyl ", “C1-6Alkyl sulfonyl amino ", " C1-6Alkyl amino sulfonyl " refer to " C respectively1-6Alkyl " by sulfenyl, carbonyl, amidino groups, sulphonyl 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 invention1-6Alkoxyl " 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 identical Or different " C1-6Alkyl " 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, Tetramethylene. 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.." 3-8 unit cycloalkyl " of the present invention, " 3-7 unit cycloalkyl ", " 5-6 Unit's cycloalkyl " refer to above-mentioned " 3-8 unit cycloalkyl " example medium ring atomic number be respectively 3-8 unit, 3-7 unit, 5-6 unit concrete real Example.
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: bicyclo-[3.1.0] hexyl, bicyclo-[4.1.0] heptane Base, bicyclo-[2.2.0] hexyl, bicyclo-[3.2.0] heptane base, bicyclo-[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..
" 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, including naphthyl, anthryl and phenanthryl etc., also includes 8-14 unit fractional saturation fused ring aryl, such as benzo 3-8 unit cycloalkanes Base, instantiation such as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyls, Isosorbide-5-Nitrae-dihydro naphthyl etc..The present invention Described " 6-8 unit aryl " refers to the instantiation that above-mentioned " 6-14 unit aryl " medium ring atomic number is 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-triazine radical, 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.；" 5-8 unit heteroaryl " of the present invention, " 5-7 unit heteroaryl, " 5- 6 yuan of heteroaryls " refer to that above-mentioned " 5-8 unit heteroaryl " medium ring atomic number is 5-8 unit, 5-7 unit, the instantiation of 5-6 unit.
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, pyrido pyrrole Piperidinyl, pyrazolo [3,4-b] pyridine radicals, purine radicals, acridinyl and ton base etc..
" 5-10 unit heteroaryl " of the present invention refers to that above-mentioned " 5-15 unit heteroaryl " medium ring atomic number is the concrete of 5-10 unit Example.
" 3-14 unit heterocyclic radical " of the present invention refers to containing one or more heteroatomic 3-14 cyclic group, described " hetero atom " is selected from N, S, O, CO, SO and/or SO2Deng.Including 3-8 unit heterocyclic radical and 6-14 unit condensed hetero ring base.
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, Imidazolidinyl, pyrazolidinyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithia Cyclohexyl, morpholinyl, piperazinyl etc.." 3-8 unit heterocyclic radical " of the present invention, " 3-7 unit heterocyclic radical ", " 5-6 unit heterocyclic radical " Refer to that above-mentioned " 3-8 unit heterocyclic radical " medium ring atomic number is respectively 3-8 unit, 3-7 unit, the instantiation of 5-6 unit.
6-14 unit condensed hetero ring base, refers to containing 6-14 annular atoms (at least a part of which contains a hetero atom) by two or two Individual above circulus shares two adjacent atoms each other and couples together the condensed cyclic structure formed, such as benzo 3-8 unit heterocyclic radical The structure etc. that the structure formed, 3-8 unit heterocyclic radical 3-8 unit heterocyclic radical are formed, instantiation includes but not limited to:、、、、、、、、、、、、、、、、、、、、、Replace the most commutable etc. circulus The group that hydrogen atom is formed.
" 5-10 unit heterocyclic radical " of the present invention refers to that above-mentioned " 3-14 unit heterocyclic radical " medium ring atomic number is the concrete of 5-10 unit Example.
Particularly preferred compound includes:
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 standby salt of processed with acid, including acylate, inorganic acid salt, organic alkali salt, inorganic base salts.Acylate includes first Acid, acetic acid, benzenesulfonic 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, succinic acid, wine The salt of stone acid etc..Inorganic acid salt includes the salt of hydrobromic acid, hydrochloric acid, nitric acid, sulphuric 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, ethanolamine, 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, hydroxyproline, histidine, ornithine, lysine, arginine, serine etc. Salt.Inorganic base salts includes the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, ferrum, ketone, ferrous iron, manganese, bivalent manganese etc..
" stereoisomer " of claimed formula (I) compound, the compounds of this invention contain one or more not Symmetrical centre, thus can as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and Single diastereomer.The compounds of this invention has asymmetric center, the generation two that this kind of asymmetric center respectively will be independent Optical isomer, the scope of the present invention includes all possible optical isomer and non-enantiomer mixture and pure or portion Divide pure compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.Stereoisomerism including formula (I) compound Body, geometric isomer and cis-trans-isomer, including enantiomer 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.
If the raceme that the arbitrary compou nd synthesis shown in the logical formula (I) of the present invention obtains, required enantiomer-pure Compound can be obtained by the method for chiral separation: can by have chiral stationary phase chromatography (image height compacting standby Liquid phase, supercritical fluid chromatography).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 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 dosage form.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 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, binding agent, disintegrating agent, lubricant etc..When parenteral, can be made into injection, including injection, 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..
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 immunosuppressant.Described antitumor Agent and immunosuppressant, such as anti-metabolism, include but are not limited to methotrexate, 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, hydroxy camptothecin, mitomycin, epirubicin, pirarubicin, rich come mould Element；Antitumor hormones, 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, cyclophosphamide, carmustine, Ni Mosi Spit of fland, semustine；Metal platinum class, includes but are not limited to carboplatin, cisplatin, oxaliplatin, network platinum；Topoisomerase enzyme inhibitor, Include but are not limited to Topotecan；Immunosuppressant class, includes but are not limited to everolimus.
Invention further provides the present invention lead to the compound shown in formula (I), its pharmaceutically acceptable salt or its stand Body isomer 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: cerebroma, pulmonary carcinoma, lung cancer in non-cellule type, squamous cell cancer, bladder cancer, gastric cancer, ovarian cancer, Peritoneal cancer, cancer of pancreas, breast carcinoma, head and neck cancer, cervical cancer, carcinoma of endometrium, rectal cancer, hepatocarcinoma, renal carcinoma, adenocarcinoma of esophagus, food Pipe squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, glioma, glioblastoma multiforme, glioma sarcomatosum, front Row adenocarcinoma, thyroid carcinoma, female reproductive tract cancer, cancer in situ, lymphoma, histocytic lymphoma, neurofibromatosis, thyroid Cancer, osteocarcinoma, skin carcinoma, the brain cancer, colon cancer, carcinoma of testis, small cell lung cancer, gastrointestinal stromal tumor, tumor of prostate, mastocyte Tumor, multiple myeloma, melanoma, glioma, glioblastoma multiforme, 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 bioavailability 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: the compound 4 that embodiment 4 prepares
Experimental technique:
Implication representated by following test Chinese and English abbreviation is as follows:
HEPES: hydroxyethyl piperazine second sulfacid；
Brij-35: Brij-35；
EDTA: ethylenediaminetetraacetic acid；
Fluorescein-MAP2K1: fluorescein labelling MAP2K1；
ATP: adenosine triphosphate；
DMSO: dimethyl sulfoxide；
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 enzymatic solution 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, microplate reader reads data；
6. IC50。
Calculate RFU ratio
Calculate suppression ratio (%)=(maximum-sample ratio)/(maximum-minima) × 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 4 is suitable to b-RAF kinases and the kinase whose inhibitory activity of b-RAF V599E, can For treating the disease relevant to b-RAF kinases and b-RAF V599E kinases, the disease that particularly b-RAF V599E kinases causes Disease 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.
Writing a Chinese character in simplified form in embodiment, representative is defined below:
THF: oxolane；
LC-MS: LC-MS instrument；
DIBAL-H: diisobutyl aluminium hydride；
TLC: thin layer chromatography；
Pd(dppf)Cl2: [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride；
DCM: dichloromethane；
DMAC:N, N-dimethyl acetylamide；
LiHMDS: lithium hexamethyldisilazide；
DMF:N, dinethylformamide；
DMAP: dimethylamino naphthyridine；
NBS:N-bromo-succinimide.
Embodiment 1 N-(3-(the 2-tert-butyl group-5-(tetrahydrochysene-2H-pyrans-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6- The preparation of difluorobenzenesulfonamide (compound 1)
(1) preparation of the fluoro-N-of 2,6-bis-(2-fluoro-3-(methylol) phenyl) benzsulfamide
3-(2,6-difluorobenzenesulfonamide)-2-ethyl fluoro benzoate (5.0 g, 13.9 mmol) is dissolved in dry THF In (200 mL), system nitrogen is replaced and is cooled to-25 DEG C, by the hexane solution of diisobutyl aluminium hydride (50 mL, 50 Mmol) it is slowly dropped in system, reacts 4 hours at-25 DEG C.After completion of the reaction, at-25 DEG C, saturated ammonium chloride water is dripped Solution cancellation, ethyl acetate (100 mL × 3) extracts, is dried with anhydrous sodium sulfate, and rotary evaporation removes solvent, obtains product (4 G, productivity 91%).
(2) preparation of the fluoro-N-of 2,6-bis-(2-fluoro-3-Fonnylphenyl) benzsulfamide
Fluoro-for 2,6-bis-N-(2-fluoro-3-(methylol) phenyl) benzsulfamide (4.0 g, 12.6 mmol) is dissolved in dichloro In methane (200 mL), add manganese dioxide (33 g, 0.379 mol).Reaction system is stirred at room temperature 12 hours, and LC-MS supervises Measured reaction process.After completion of the reaction, filter, remove manganese dioxide, by filtrate rotary evaporation remove solvent, obtain product (3.7 g, Productivity 93%).
(3) preparation of the fluoro-N-of 2,6-bis-(2-fluoro-3-ethoxy) benzsulfamide
Fluoro-for 2,6-bis-N-(2-fluoro-3-Fonnylphenyl) benzsulfamide (3.5 g, 11.1 mmol) is dissolved in dry In THF (50 mL), system nitrogen is replaced and is cooled to-15 DEG C, by methyl-magnesium-bromide (3M) (4.4 mL, 13.3 Mmol) it is slowly dropped in system, reacts 1 hour at-15 DEG C, be warmed to room temperature reaction 4 hours.After completion of the reaction, add saturated Aqueous ammonium chloride solution (10 mL) cancellation, ethyl acetate (50 mL × 3) extracts, is dried with anhydrous sodium sulfate, uses silica gel column chromatography Isolated and purified product (3.16 g, productivity 86%)
(4) preparation of N-(3-acetyl group-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
Fluoro-for 2,6-bis-N-(2-fluoro-3-ethoxy) benzsulfamide (3.0 g, 9.1 mmol) is dissolved in dichloromethane In (200 mL), add manganese dioxide (23.7 g, 0.27 mol).Reaction system is stirred at room temperature 12 hours, and LC-MS detects Reaction process.After completion of the reaction, filter, remove manganese dioxide, by filtrate rotary evaporation removing solvent obtain product (2.86 g, Productivity 96%).
(5) preparation of N-(3-(2-acetyl bromide)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
N-(3-acetyl group-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (2.5 g, 7.6 mmol) is dissolved in acetic acid (30 ML) in.Under the conditions of 0 DEG C, bromine (3.9 mL, 76 mmol) is dissolved in acetic acid (10 mL), and is slowly dropped to above-mentioned In solution, after dropping, then drip hydrogen bromide solution (40%, 3 mL), be warmed to room temperature reaction 12 hours.After completion of the reaction, With saturated sodium thiosulfate solution cancellation, three times (50 mL × 3) of dichloromethane extraction, rotary evaporation removes solvent, residue warp Silica gel column chromatography (petroleum ether: ethyl acetate=3:1) obtains product (2.5 g, productivity 81%).
(6) preparation of N-(3-(2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
By N-(3-(2-acetyl bromide)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (1 g, 2.45 mmol), 2,2-bis- Methyl thio propionic acid amide. (0.286 g, 2.45 mmol) is dissolved in DMAC (4 mL), at 80 DEG C, reacts 1 in microwave reactor Hour.After completion of the reaction, it is cooled to room temperature, system is poured into water, three times (25 mL × 3) of ethyl acetate extraction, anhydrous slufuric acid Sodium is dry, and rotary evaporation obtains crude product (0.8 g).
(7) preparation of N-(3-(5-bromo-2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
N-(3-(2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide crude product (0.8 g) is dissolved in In DMAC (5 mL), add NBS (0.33 g, 1.88 mmol), be stirred at room temperature 4 hours.After completion of the reaction, reactant liquor is poured into In water (20 mL), being extracted with ethyl acetate three times (20 mL × 3), anhydrous sodium sulfate is dried, by silica gel column chromatography (acetic acid second Ester: petroleum ether=1:5) isolated and purified product (0.35 g, two-step reaction productivity 28%).
(8) N-(3-(the 2-tert-butyl group-5-(3,6-dihydro-2H-pyrans-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6- The preparation of difluorobenzenesulfonamide
By N-(3-(5-bromo-2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (0.35 g, 0.69 mmol), 2-(3,6-dihydro-2H-pyrans-4-base)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane (0.145 g, 0.69 mmol)、Pd(dppf)Cl2(35 mg) and cesium carbonate (0.68 g, 2 mmol) are dissolved in 1,4-dioxy In the mixed solution of six rings (4 mL) and water (1 mL).System nitrogen is replaced, reacts 12 hours at 100 DEG C.React complete After, to filter, three times (5 mL × 3) of ethyl acetate extraction, anhydrous sodium sulfate is dried, with silica gel column chromatography (petroleum ether: ethyl acetate =3:1) separate to obtain product (140 mg, productivity 40%).
(9) N-(3-(the 2-tert-butyl group-5-(tetrahydrochysene-2H-pyrans-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluoro The preparation of benzsulfamide
By N-(3-(the 2-tert-butyl group-5-(3,6-dihydro-2H-pyrans-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6-two Fluorobenzenesulfonamide (140 mg, 0.276 mmol) is dissolved in methanol (10 mL), adds Pd/C (10%, 20 mg), is passed through hydrogen Gas, at room temperature reaction 2 hours.After completion of the reaction, filtering, rotary evaporation removes solvent, and residue is through silica gel column chromatography (oil Ether: ethyl acetate=3:1) separate to obtain product (60 mg, productivity 43%).
Molecular formula: C24H25F3N2O3S2Molecular weight: 510.59 LC-MS (m/z): 510.9 [M+H]+
1H-NMR (400 MHz, d6-DMSO) δ: 1.38 (s, 9H), 1.58 (m, 4H), 2.70 (m, 1H), 3.11 (t, 2H), 3.85 (d, 2H), 7.19～7.30 (m, 4H), 7.46 (s, 1H), 7.71 (m, 1H), 10.76 (s, 1H).
Embodiment 2 N-(3-(the 2-tert-butyl group-5-(6-pyridone-3-base) thiazole-4-yl)-2-fluorophenyl)-2,6- The preparation of difluorobenzenesulfonamide (compound 2)
(1) N-(3-(the 2-tert-butyl group-5-(6-methoxypyridine-3-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluoro The preparation of benzsulfamide
N-(3-(5-bromo-2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-two is added in round-bottomed flask (25 mL) Fluorobenzenesulfonamide (253 mg, 0.5 mmol), 2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan Alkane-2-base) pyridine (118 mg, 0.5 mmol), Pd (dppf) Cl2(37 mg, 0.05 mmol) and cesium carbonate (488 mg, 1.5 mmol), it is subsequently adding Isosorbide-5-Nitrae-dioxane (8 mL) and water (2 mL).System nitrogen is replaced, is heated to 100 DEG C React 12 hours.LC-MS monitors reaction process.After completion of the reaction, removal of solvent under reduced pressure, residue silica gel column chromatography separates pure Change to obtain product (180 mg, productivity 67%).
(2) N-(3-(the 2-tert-butyl group-5-(6-pyridone-3-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluorobenzene The preparation of sulfonamide
By N-(3-(the 2-tert-butyl group-5-(6-methoxypyridine-3-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluorobenzene Sulfonamide (140 mg, 0.26 mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2 mL), is subsequently adding concentrated hydrochloric acid (4 mL), 80 React 48 hours at DEG C.After completion of the reaction, decompression removes organic solvent, adds sodium carbonate liquor in solution, and regulation pH value is extremely 8, ethyl acetate extracts, and anhydrous sodium sulfate is dried, and recycle silicon plastic column chromatography is isolated and purified obtains product (55 mg, productivity 40%).
Molecular formula: C24H20F3N3O3S2Molecular weight: 519.56 LC-MS (m/z): 520.0 [M+H]+
1H-NMR (400 MHz, d6-DMSO) δ: 1.25 (s, 9H), 6.10 (d, 1H), 6.94 (d, 1H), 7.04 (s, 1H), 7.20 (d, 1H), 7.28～7.33 (m, 3H), 7.44 (s, 1H), 7.73 (m, 1H), 10.93 (s, 1H), 11.59 (s, 1H).
Embodiment 3 N-(3-(the 2-tert-butyl group-5-(1H-pyrazoles-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluoro The preparation of benzsulfamide (compound 3)
(1) preparation of 2-fluoro-3-nitrobenzene methyl
Fluoro-for 2-3-nitrobenzoic acid (7.5 g, 40.5 mmol) is joined in methanol (30 mL), drips concentrated sulphuric acid (2 ML), 70 DEG C of reactions are overnight.System being cooled down, sucking filtration, washing, filtrate adds water sucking filtration again, merges filtering residue, and drying under reduced pressure obtains product (7.3 g, productivity 91%).
(2) preparation of 3-amino-2-fluorophenyl carbamate
Fluoro-for 2-3-nitrobenzene methyl (657 mg, 3.3 mmol) is dissolved in ethyl acetate (10 mL), adds The palladium carbon (100 mg) of 10%, under room temperature, logical hydrogen reacts overnight.Reactant liquor sucking filtration, removes solvent by filtrate rotary evaporation, obtains Oil product (540 mg, productivity 97%).
(3) preparation of 3-(2,6-difluorobenzene sulfonamido)-2-fluorophenyl carbamate
3-amino-2-fluorophenyl carbamate (549 mg, 3.2 mmol) is dissolved in dichloromethane (10 mL), adds Pyridine (770 mg, 9.73 mmol), then system is dropped to 0 DEG C, addition 2,6-difluoro chloride (820 mg, 3.86 Mmol), room temperature reaction is overnight.Add water, be extracted with ethyl acetate, concentrating under reduced pressure, obtain product (390 with preparative hplc is isolated and purified Mg, productivity 35%).
(4) preparation of 3-(2,6-difluorobenzene sulfonamido)-2-fluoro-N-methoxy-. N-methyl Benzoylamide
In dry there-necked flask, addition 3-(2,6-difluorobenzene sulfonamido)-2-fluorophenyl carbamate (2.05 g, 5.94 mmol), N, O-dimethyl hydroxylamine hydrochloride (743 mg, 7.62 mmol), under nitrogen protection, add and heavily steam tetrahydrochysene furan Mutter (15 mL), and system is cooled to-15 DEG C, slowly drips the methyl-magnesium-bromide (9.9 mL) of 3 M, drips and complete turns again Move to 0 DEG C of condition, react 5 hours, add saturated aqueous ammonium chloride cancellation, after rotary evaporation removes oxolane, ethyl acetate Extraction, rotary evaporation removes solvent, and residue silica gel column chromatography (PE:EA=10:1-1:2) is isolated and purified obtains product (600 Mg, productivity 31%).
(5) preparation of N-(3-(2-acetyl bromide)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
N-(3-acetyl group-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (110 mg, 0.33 mmol) is dissolved in dichloromethane In alkane (3 mL), after stirring and dissolving, add pyridinium tribromide (128 mg, 0.40 mmol), room temperature reaction 4 hours.To Adding water in system, dichloromethane extracts, and rotary evaporation removes solvent, and residue silica gel column chromatography separating purification obtains crude product (150 mg)。
(6) preparation of 2,2-dimethyl thiopropionamide
Trimethyl ethamine (5.06 g, 50 mmol) is dissolved in oxolane (15 mL), adds lawesson reagent (10.1 g, 25 mmol), system back flow reaction is overnight.System rotary evaporation is removed solvent, residue silica gel column chromatography (PE:EA=10:1-1:1) isolated and purified crude product (500 mg, productivity 9%).
(7) preparation of N-(3-(2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
By N-(3-(2-acetyl bromide)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (660 mg, 1.62 mmol) and 2, 2-dimethyl thiopropionamide (189 mg, 1.61 mmol), adds dimethylamine (8 mL) and dissolves, microwave reaction 50 points at 80 DEG C Clock.Adding water in system, ethyl acetate extracts, and concentrating under reduced pressure obtains crude product (635 mg).
(8) preparation of N-(3-(5-bromo-2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
N-(3-(2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide crude product (635 mg) is dissolved in DMF (3 mL) _ in, adding N-bromo-succinimide (90 mg, 0.5 mmol), room temperature reaction 4 is little Time.Adding water in system, ethyl acetate extracts, and obtains with silica gel column chromatography (petroleum ether: ethyl acetate=10:1-3:1) is isolated and purified Product (350 mg, productivity 69%).
(9) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-the base)-1H-pyrazoles tertiary fourth of-1-formic acid The preparation of ester
By 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)-1H-pyrazoles (1.16 g, 6.0 Mmol) it is dissolved in dichloromethane (40 mL), adds Bis(tert-butoxycarbonyl)oxide (1.58 g, 7.2 mmol), add catalytic amount DMAP (102 mg, 0.84 mmol), room temperature reaction 4 hours.Adding water in system, ethyl acetate extracts, Saturated sodium-chloride water washs, and rotary evaporation removes organic facies and obtains crude product (1.5 g, productivity 85%).
(10) N-(3-(the 2-tert-butyl group-5-(1H-pyrazoles-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluorobenzene sulphur The preparation of amide
By 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)-1H-pyrazoles-1-t-butyl formate Crude product (3.7 g, 12.6 mmol) is dissolved in the mixed solution of dimethylformamide (25 mL) and water (10 mL), adds N- (3-(5-bromo-2-tertiary butyl thiazole-4-base)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (200 mg, 0.40 mmol) and carbon Acid caesium (4.0 g, 12.3 mmol), under room temperature condition, is stirred at room temperature 15 minutes under nitrogen protection, adds four triphenylphosphines Palladium (464 mg, 0.4 mmol), the lower 80 DEG C of lucifuges of nitrogen protection are reacted overnight.Ethyl acetate extracts, concentrating under reduced pressure, residue Product (80 mg, productivity 41%) is obtained with preparative hplc is isolated and purified.
Molecular formula: C22H19F3N4O2S2Molecular weight: 492.54 LC-MS (m/z): 493.0 [M+H]+
1H-NMR(400 MHz, d6-DMSO) δ: 1.35 (9H, s), 6.99 (1H, s), 7.36-7.15 (4H, m), 7.47-7.36 (2H, m), 7.71 (1H, m), 10.81 (1H, m), 12.78 (1H, d).
Embodiment 4 N-(3-(the 2-tert-butyl group-5-(pyridazine-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluorobenzene The preparation of sulfonamide (compound 4)
(1) preparation of 2,2-dimethyl thiopropionamide
To round-bottomed flask (250 mL) in, add trimethyl ethamine (5.0 g, 0.049 mol) and lawesson reagent (8.0 G, 0.020 mol), dissolve with THF (100 mL), nitrogen is protected, and 80 DEG C of oil baths are reacted 4 hours.TLC detects reaction process. After completion of the reaction, rotary evaporation removes solvent, and residue silica gel column chromatography (petroleum ether: ethyl acetate=10:1) obtains white Solid (3.7 g, productivity 65%).
(2) preparation of 2-fluoro-3-nitrobenzene methyl
Fluoro-for 2-3-nitrobenzoic acid (18.5 g, 0.10 mol), potassium carbonate (20 g, 0.14 mol) are joined In DMF (150 mL), mix homogeneously, add iodomethane (17.1 g, 0.12 mol), lucifuge under stirring, be stirred at room temperature 1 hour, LC-MS monitors reaction process.After completion of the reaction, addition ethyl acetate (200 mL), organic phases washed with water three times (30 mL × 3), Three times (30 mL × 3) of saturated sodium-chloride washing, anhydrous sodium sulfate is dried, and rotary evaporation removes solvent.Add magneton stirring, add Substantial amounts of water, separates out white solid, sucking filtration, and solid is successively by water and petroleum ether.Filter, drying under reduced pressure obtain product (19 g, Productivity 95%).
(3) preparation of 3-amino-2-fluorophenyl carbamate
Fluoro-for 2-3-nitrobenzene methyl (14.0 g, 0.070 mol) is dissolved in absolute methanol (150 mL), nitrogen Adding Pd/C catalyst (1.4 g) under gas shielded, then with hydrogen exchange, be stirred at room temperature 16 hours, TLC monitors reaction process. After completion of the reaction, with kieselguhr buchner funnel sucking filtration, organic facies rotary evaporation removes solvent, obtains product (5.7 g, productivity 96%)。
(4) preparation of 3-(2,6-difluorophenyl sulfonamido)-2-fluorophenyl carbamate
3-amino-2-fluorophenyl carbamate (5.7 g, 0.034 mol) is dissolved in dry dichloromethane (100 mL) In, adding pyridine (3.2 g, 0.040 mol) and DMAP (0.1 g), nitrogen is protected, and adds 2,6-with Dropping funnel under ice bath Difluorobenzene-1-sulfonic acid chloride (7.2 g, 0.034 mol).After dropping, it is slowly increased to room temperature, stirs 12 hours.Organic facies is used Washing three times (20 mL × 3), anhydrous sodium sulfate is dried, rotary evaporation remove solvent, residue with silica gel column chromatography (petroleum ether: Ethyl acetate=10:1) isolated and purified product (9.5 g, productivity 82%).
(5) preparation of the fluoro-N-of 2,6-bis-(the fluoro-3-of 2-(2-(pyridazine-4-base) acetyl group) phenyl) benzsulfamide
3-(2,6-difluorobenzene sulfonamido)-2-fluorophenyl carbamate (9.0 g, 0.026 mol) is dissolved in dry four In hydrogen furan (5 mL), reaction bulb is positioned in the dry ice bath, is cooled to-20 DEG C.Under nitrogen protection, then it is added dropwise over LiHMDS (50 mL, 0.050 mol) stirs half an hour, after move to, in 0 DEG C of ice bath, be slowly added dropwise 4-methyl pyridazine (2.5 by reaction bulb G, 0.027 mol), react 2 hours under ice bath after dropping, be warmed to room temperature, add saturated ammonium chloride solution (30 mL), Extract by ethyl acetate (100 mL), organic phase washed with water (30 mL) and saturated nacl aqueous solution (30 mL) washing, use anhydrous sulfur Acid sodium is dried, and rotary evaporation removes solvent, separates to obtain product (6.5 g, productivity 61%) with silica gel column chromatography.
(6) preparation of N-(3-(the bromo-2-of 2-(pyridazine-4-base) acetyl group)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
At ambient temperature, by 2, the fluoro-N-of 6-bis-(the fluoro-3-of 2-(2-(pyridazine-4-base) acetyl group) phenyl) benzsulfamide (6.1 g, 0.015 mol) is dissolved in DMAC (100 mL), adds NBS (2.64g, 0.015mol), and nitrogen is protected, and stirring is anti- Answering half an hour, LC-MS detection reaction is complete.The most purified be directly used in next step reaction.
(7) N-(3-(the 2-tert-butyl group-5-(pyridazine-4-base) thiazole-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide Preparation
In above-mentioned reaction solution, adding 2,2-dimethyl thiopropionamide (1.8 g, 0.015 mol), oil bath is heated React 2 hours to 50 DEG C.After completion of the reaction, in solution, add water (150 mL) and ethyl acetate (200 mL) extraction, separatory. Organic facies saturated sodium-chloride is washed, and anhydrous sodium sulfate is dried, concentrating under reduced pressure, and residue is through silica gel column chromatography (ethyl acetate: stone Oil ether=1:1) isolated and purified product (0.15 g, productivity 2.1%).
Molecular formula: C23H19F3N4O2S2Molecular weight: 504.6 LC-MS (m/z): 504.9 [M+H]+
1H-NMR (400 MHz, d6-DMSO) δ: 1.43 (s, 9H), 7.22 (m, 3H), 7.37 (m, 3H), 7.67 (m, 1H), 8.93 (s, 1H), 9.12 (d, 1H), 10.73 (br, 1H)。

Claims (5)

1. lead to the compound shown in formula (I), its pharmaceutically acceptable salt or its stereoisomer:
Wherein,
Ring A is selected from
R2It is selected from
R1Selected from hydroxyl；
R3And R4Separately selected from halogen atom；
M is selected from 0 or 1；
N is selected from 1；
P is 2.
2. compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, described compound selects From:
3. compound, its pharmaceutically acceptable salt or its stereoisomer as described in claim 1-2 any claim With one or more pharmaceutical carriers and/or the pharmaceutical composition of diluent, it is made into the arbitrary dosage form pharmaceutically accepted.
4. pharmaceutical composition as claimed in claim 3, it is characterised in that press down possibly together with one or more antitumor agents and immunity Preparation, selected from methotrexate, capecitabine, gemcitabine, doxifluridine, pazopanib, imatinib, gefitinib, conspicuous Sai Ting, bevacizumab, Rituximab, Herceptin, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxyl are liked Tree alkali, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, fluorine His amine, leuprorelin, Anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, Carboplatin, cisplatin, oxaliplatin, network platinum, Topotecan or everolimus.
5. compound, its pharmaceutically acceptable salt or its stereoisomer as described in claim 1-2 any claim At the cancer-related diseases that preparation is treated and/or prevention is caused by kinases abnormal activation or disorder or the medicine of non-cancer-related diseases Application in thing, the disease that described cancer is relevant is selected from lung cancer in non-cellule type, squamous cell cancer, bladder cancer, gastric cancer, ovum Nest cancer, peritoneal cancer, cancer of pancreas, breast carcinoma, head and neck cancer, cervical cancer, carcinoma of endometrium, rectal cancer, hepatocarcinoma, renal carcinoma, esophageal gland Cancer, esophageal squamous cell carcinoma, carcinoma of prostate, thyroid carcinoma, female reproductive tract cancer, cancer in situ, osteocarcinoma, skin carcinoma, the brain cancer, colon Cancer, carcinoma of testis, small cell 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
WO2011046894A1 (en) * 2009-10-12 2011-04-21 Glaxosmithkline Llc Combination

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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