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

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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

Benzenesulfonamide oxazole and thiazole kinase inhibitors
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a benzenesulfonamide oxazole and thiazole kinase inhibitor, pharmaceutically acceptable salts or stereoisomers thereof, a preparation method of the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the compounds, the pharmaceutically acceptable salts or the stereoisomers thereof in preparation of medicines for treating and/or preventing cancer-related diseases or non-cancer-related diseases caused by b-RAF mutation.
Background
Receptor Tyrosine Kinases (RTKs) are involved in processes such as growth, differentiation, development, proliferation, division, adhesion and the like of cells, are related to processes such as transcriptional regulation, angiogenesis, endothelial cell proliferation and the like of the cells, and have wide functions in the process of cell signal transmission. Aiming at the regulation of the kinases, the cell proliferation and differentiation can be controlled, the cell cycle can be regulated, and particularly for some tumor cells with variation, the growth of cancer cells can be obviously inhibited by regulating the activity of the overexpressed kinases, so that the effect of treating tumors is achieved.
The kinase small molecule inhibitors with targeting property have become a hotspot in the field of cancer treatment, and imatinib, erlotinib, gefitinib, sunitinib, sorafenib and lapatinib which are on the market bring gospel to cancer patients all over the world. However, these drugs have different degrees of problems, wherein the main problems faced by them are poor selectivity and easy occurrence of drug resistance, such as that sorafenib can inhibit VEGFR-2/3, b-RAF, c-RAF and PDGF, erlotinib inhibits EGFR and ERBB2, and imatinib inhibits c-kt, Bcr-Abl and the like in addition to PDGFR. Therefore, improving selectivity is an important content of small molecule inhibition research.
RAF is a key kinase in Ras/RAF/MEK/ERK pathway, and is also an important member in MAPK (mitogen-activated protein kinase) signal pathway, and RAF can play a role in signal transduction regulation in a Ras-dependent or Ras-independent manner, and has important regulation and control effects in cell proliferation, differentiation and apoptosis. The 3 subtypes of RAF kinases, including a-RAF, b-RAF and RAF-1(c-RAF), are closely related to the regulation of cell proliferation, differentiation, survival, attachment and angiogenesis. a-RAF is mainly distributed in urogenital organs such as kidney, testis and the like; the b-RAF is mainly expressed in nervous tissues, RAF-1 is widely distributed in various tissues of the body, and has the function of regulating cells without passing through Ras/RAF/MEK/ERK pathways.
The RAF mutation can cause various cancers clinically, and the incidence rate of melanoma is the highest, and the cancers are thyroid cancer and colon cancer, and also comprise liver cancer, lung cancer, breast cancer, ovarian cancer and bladder cancer. Among the mutations of RAF, b-RAF V599E is the most abundant, so that the research on b-RAF mutation inhibitors is of great significance to the cancer patients.
Currently marketed b-RAF inhibitors include sorafenib, which is a multi-target inhibitor, and other b-RAF inhibitors with certain selectivity include RAF-265, PLX-4032, XL-281, SB-590885, RO-5126766, and the like. These compounds have problems of poor selectivity or insufficient activity, so that it is necessary to develop corresponding research work to find small molecule inhibitors with good activity against b-RAF mutation.
Disclosure of Invention
The invention aims to develop a small molecule inhibitor with excellent activity and selectivity aiming at b-RAF mutation, and provides a benzenesulfonamide oxazole and thiazole kinase inhibitor with b-RAF inhibition effect. The specific technical scheme is as follows:
the invention provides a compound shown as a general formula (I), pharmaceutically acceptable salt thereof or a stereoisomer thereof:
wherein,
ring A is selected from:
(1) 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, 5-15 membered heteroaryl, 6-12 membered bridged heterocyclyl or 6-12 membered spiroheterocyclyl, which may be oxo,
(2) 6-14 membered aryl;
R1selected from hydrogen, halogen atoms, hydroxy groups, C1-6Alkyl, halo C1-6Alkyl, carboxy C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamidino, carbamoyl, halogeno C1-6Alkoxy, amino, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, cyano, nitro, C1-6Alkylcarbonyl, sulfonamido, aminosulfonyl or C1-6An alkylsulfonylamino group;
R2and R3Each independently selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano, nitro and C1-6Alkoxy radical, C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, oxo, carbamoyl, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, sulfonamido, aminosulfonyl, 3-14 membered cycloalkyl or 3-14 membered heterocyclyl;
x is selected from O or S;
m, n and p are each independently selected from 0, 1,2 or 3.
Preferably:
ring A is selected from:
(1) 3-8 membered cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, 8-10 membered bridged heterocyclyl or 8-10 membered spiroheterocyclyl, which may be oxo,
(2) 6-8 membered aryl;
R1selected from hydrogen, halogen atoms, hydroxy groups, C1-6Alkyl, halo C1-6Alkyl, carboxy C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamidino, carbamoyl, halogeno C1-6Alkoxy, amino, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, cyano, nitro, C1-6Alkylcarbonyl, sulfonamido, aminosulfonyl or C1-6An alkylsulfonylamino group;
R2and R3Each independently selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano, nitro and C1-6Alkoxy radical, C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, oxo, carbamoyl, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, sulfonicAmido, aminosulfonyl, 3-8 membered cycloalkyl or 5-10 membered heterocyclyl;
x is selected from O or S;
m, n and p are each independently selected from 0, 1,2 or 3.
Preferably:
wherein,
ring A is selected from:
(1) 5-6 membered cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, which may be oxo,
(2) 6-8 membered aryl;
R1selected from hydrogen, halogen atoms, hydroxy groups, C1-6Alkyl, halo C1-6Alkyl, carboxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, amino, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino or cyano;
R2and R3Each independently selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano, nitro and C1-6Alkoxy radical, C1-6Alkyl or halo C1-6An alkyl group;
x is selected from O or S;
m, n and p are each independently selected from 0, 1,2 or 3.
Preferably:
wherein,
ring A is selected from:
(1) a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group,
(2) 6-8 membered aryl;
R1selected from hydrogen, halogen atoms, hydroxy groups, C1-4Alkyl, amino or cyano;
R2and R3Each independently selected from hydrogen, halogen atom, carboxyl, hydroxyl, amino, cyano, nitro and C1-4Alkoxy radical, C1-4Alkyl or halo C1-4An alkyl group;
x is selected from O or S;
m, n and p are each independently selected from 0, 1,2 or 3.
Preferably:
wherein
Ring A is selected from
R1Selected from hydrogen, halogen atoms, hydroxy groups, C1-4Alkyl or amino;
R2and R3Each independently selected from hydrogen, halogen atom, hydroxyl, amino, C1-4Alkoxy or C1-4An alkyl group;
x is selected from O or S;
m, n and p are each independently selected from 0, 1 or 2.
Preferably:
wherein,
ring A is selected from
R1Selected from hydrogen or amino;
R2and R3Each independently selected from hydrogen, halogen atoms, hydroxyl or amino;
x is selected from O or S;
m, n and p are each independently selected from 1 or 2.
Detailed Description
The "halogen atom" as used herein means a fluorine atom, chlorine atom, bromine atom, iodine atom, etc. Fluorine atom and chlorine atom are preferred. More preferably a fluorine atom.
Said "C" of the present invention1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention1-4Alkyl "refers to the above-mentioned" C1-6Examples of the "alkyl group" include specific examples having 1 to 4 carbon atoms.
Said "C" of the present invention2-6The "alkenyl group" means a straight-chain or branched or cyclic alkenyl group having 2 to 6 carbon atoms and having a double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-methyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 2-methyl-3-pentenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 1-methyl-pentenyl, 2-methyl-2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenylAlkenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1,2,2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-ethyl-3-butenyl, 2-ethyl-2-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like. The double bond may optionally be cis and trans.
Said "C" of the present invention2-6Alkynyl "means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and having a triple bond, such as ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, etc, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
Said "C" of the present invention1-6Alkoxy "means" C "as defined above1-6Alkyl radicals "radicals attached to other structures via oxygen atomsGroups, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, n-butyloxy, n, 1-ethylbutoxy, 2-ethylbutoxy, 1, 2-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like. "C" according to the invention1-4Alkoxy "means" C "as defined above1-6Examples of the "alkoxy group" include specific examples having 1 to 4 carbon atoms.
Said "C" of the present invention1-6Alkylthio group "," C1-6Alkylcarbonyl group and C1-6Alkylamidino group "," C1-6Alkylamino radical and C1-6Alkylsulfonylamino group and "C1-6Alkylaminosulfonyl "refers to the above-mentioned" C "respectively1-6Alkyl "a group attached to another structure through a thio, carbonyl, amidino, amino, sulfonamido, aminosulfonyl group.
The "halo C" of the present invention1-6Alkyl group and carboxyl group C1-6Alkyl group and amino group C1-6Alkyl group "," sulfonyl group C1-6Alkyl "means halogen atom, carboxyl group, amino group, sulfonyl group respectively substituted for the above" C1-6Alkyl "and groups attached to other structures through an alkyl group.
The "halo C" of the present invention1-4Alkyl "means that the above-mentioned" halogen atom "is substituted for the above-mentioned" C1-4Alkyl "and groups attached to other structures through an alkyl group.
The "halo C" of the present invention1-6Alkoxy group "Means that the above-mentioned "halogen atom" is substituted for the above-mentioned "C1-6Alkoxy "and a group attached to another structure through an alkoxy group.
The "according to the invention" (C)1-6Alkyl radical)2Amino "means that any two atoms of the amino group which may be substituted by the above-mentioned" C "group1-6Alkyl groups "and groups attached to other structures through amino groups.
The term "3-14 membered cycloalkyl" as used herein means a cyclic alkyl group derived from an alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes 3-8 membered cycloalkyl, 6-14 membered fused cycloalkyl.
3-8 membered cycloalkyl, refers to a cyclic alkyl group derived from an alkane moiety of 3-8 carbon atoms with one hydrogen atom removed, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc.
6-14 membered fused cycloalkyl, refers to a 6-14 membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, examples of which include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentanyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentanyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5, 8 a-hexahydronaphthyl, 10-decahydrophenanthryl and the like.
The "3-to 8-membered cycloalkyl group" and "5-to 6-membered cycloalkyl group" according to the present invention refer to specific examples wherein the number of ring atoms in the "3-to 14-membered cycloalkyl group" is 3 to 8 and 5 to 6, respectively.
The "6-to 14-membered aryl group" as referred to herein means a monovalent moiety obtained by removing a hydrogen atom from a cyclic aromatic compound having 6-to 14-membered carbon atoms as ring atoms, and includes 6-to 8-membered aryl groups and 8-to 14-membered condensed ring aryl groups. The 6-to 8-membered aryl group includes phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a fused ring group formed by two or more aromatic rings sharing two adjacent carbon atoms with each other, a cyclic group in which at least one ring is an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring carbon aryl groups such as naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered cycloalkyl groups, specifically exemplified by 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. The "6-to 8-membered aryl" according to the present invention means a specific example in which the number of ring atoms in the above-mentioned "6-to 14-membered aryl" is 6 to 8.
The term "5-15 membered heteroaryl" as used herein refers to a cyclic aromatic group having 5-15 membered ring atoms and containing one or more heteroatoms, including 5-8 membered heteroaryl and 8-15 membered fused heteroaryl.
5-8 membered heteroaryl groups including, but not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl, and the like,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,2, 3-triazinyl1,2, 4-triazinyl, tetrazolyl, and the like,Triazolyl, 2H-1,2-Oxazinyl, 4H-1,2-Oxazinyl, 6H-1,2-Oxazinyl, 2H-1,3-Oxazinyl, 4H-1,3-Oxazinyl, 6H-1,3-Oxazinyl, 2H-1,4-Oxazinyl, 4H-1,4-Oxazinyl radical, iso-isomerOxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like;
an 8-15 membered fused heteroaryl group, which refers to a fused ring structure containing 8-15 ring atoms (wherein at least one heteroatom is present) joined by two or more heteroaryl rings sharing two adjacent atoms with each other, includes, but is not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazinylAzolyl, benzoAzinyl, benzimidazolyl, pyridopyridyl, pyrazolo [3,4-b]Pyridyl, purinyl, acridinyl, xanthenyl and the like.
The "5-to 10-membered heteroaryl group" and "5-to 6-membered heteroaryl group" in the present invention mean specific examples of the above-mentioned "5-to 15-membered heteroaryl group" having 5-to 10-and 5-to 6-membered ring atoms.
The term "heteroatom" as used herein means N, O, S, SO and/or SO2Etc., preferably N, O, S, more preferably N, O.
The "3-14 membered heterocyclic group" according to the present invention means a 3-14 membered cyclic group containing one or more hetero atoms, and includes a 3-8 membered heterocyclic group and a 6-14 membered heterocyclic group.
A3-8 membered heterocyclic group means a heterocyclic group containing 3 to 8 ring atoms (wherein at least one heteroatom is contained). Specific examples include, but are not limited to, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-oxazinyl, aziridinyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1, 4-dioxanyl, 1, 3-dithianyl, morpholinyl, piperazinyl, and the like.
6-to 14-membered heterocyclic group means a fused ring structure containing 6 to 14 ring atoms (wherein at least one hetero atom is contained) formed by two or more ring structures sharing two adjacent atoms with each other to be linked, such as a structure formed by a benzo 3-to 8-membered heterocyclic group, a structure formed by a 3-to 8-membered heterocyclic group and a 3-to 8-membered heterocyclic group, and the like, and specific examples include, but are not limited to:、 、、、、and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The "5-to 10-membered heterocyclic group" and "5-to 6-membered heterocyclic group" as used herein mean specific examples of the above-mentioned "3-to 14-membered heterocyclic group" having 5-to 10-and 5-to 6-membered ring atoms.
The "6-12 membered bridged heterocyclic group" as used herein refers to a 6-12 membered bridged heterocyclic group containing one or more hetero atoms formed by any two rings sharing two non-adjacent atoms, and specific examples include, but are not limited to:、、、、 、、、and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The "8-to 10-membered bridged heterocyclic group" in the present invention means specific examples wherein the number of ring atoms in the above-mentioned "6-to 12-membered bridged heterocyclic group" is 8 to 10, respectively.
The "6-12 membered spiroheterocyclic group" according to the present invention means a 6-12 membered spiroheterocyclic group containing one or more hetero atoms formed by sharing one carbon atom with at least two rings, and specific examples include, but are not limited to:、、 、、、and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The "8-to 10-membered spiroheterocyclic group" as used herein means a specific example in which the number of ring atoms in the above-mentioned "6-to 12-membered spiroheterocyclic group" is 8 to 10.
Particularly preferred compounds are:
the above compounds of the present invention can be synthesized using the methods described herein and/or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.
When ring A is pyrimidinyl, R1When m is amino and m is 1, the synthesis method is as follows:
the reaction steps are as follows:
(1) preparation of SM1
Reference is made to document US2009/298815 a1 (2009).
(2) Preparation of TM1
Dissolving SM1 in appropriate amount of dichloromethane at room temperature, adding appropriate amount of N-bromosuccinimide, and stirring at room temperature for 5 hours. After the reaction is finished, dichloromethane is added into the mixed solution, liquid separation is carried out, the organic phase is respectively washed by water and saturated sodium chloride water, anhydrous sodium sulfate is dried, the solvent is removed by rotary evaporation, and the residue is separated and purified by silica gel column chromatography to obtain TM 1.
(3) Preparation of TM2
Dissolving TM1 and SM2 in toluene, heating the mixture to 100 deg.C, and reacting for 12 hr. After the reaction is finished, the solvent is removed by rotary evaporation, and the residue is separated and purified by silica gel column chromatography to obtain TM 2.
(4) Preparation of the Compounds of the general formula (I)
Dissolving TM2 in appropriate amount of ammonia water, microwave reacting, heating to 90 deg.C, and reacting for 1.5 hr. Cooling, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography to obtain the compound of the general formula (I).
In the reaction equation, ring A, R1、R2、R3X, m, n and p are as defined above.
The pharmaceutically acceptable salt of any compound shown in the general formula (I) refers to a salt prepared from pharmaceutically acceptable and nontoxic alkali or acid, and comprises organic acid salt, inorganic acid salt, organic alkali salt and inorganic alkali salt. The organic acid salts include salts of formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like. The inorganic acid salt includes salts of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Organic base salts include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins selected from the group consisting of betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, and the like. Inorganic base salts include ammonium and salts of lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, ketone, ferrous, manganese, manganous, and the like.
The invention claims "stereoisomers" of compounds of formula (I), which compounds of the invention, if they contain one or more asymmetric centers, may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The present invention includes all stereoisomeric forms of these compounds. Including stereoisomers, geometric isomers and cis-trans isomers of the compounds of formula (I), including enantiomers and mixtures thereof, such as racemates. The different isomeric forms may be separated or resolved by conventional means, or any given isomeric form may be obtained by conventional means or by stereospecific or asymmetric synthesis.
Any of the compounds of the general formula (I) of the present invention has two or more chiral centers. The synthesis is racemic, and the desired enantiomerically pure compound can be obtained by chiral resolution: chromatography with a chiral stationary phase (like high pressure preparative liquid phase, supercritical fluid chromatography) can be used. Chiral fillers include, but are not limited to: chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The invention further claims pharmaceutical compositions comprising a compound of any of the above general formulae (I), pharmaceutically acceptable salts thereof or stereoisomers thereof together with one or more other antineoplastic agents and immunosuppressive agents. Such antineoplastic and immunosuppressive agents, such as antimetabolites, including but not limited to methotrexate, capecitabine, gemcitabine, doxifluridine; growth factor inhibitors, including but not limited to pazopanib, imatinib, gefitinib; targeting classes, including but not limited to herceptin, bevacizumab, rituximab, trastuzumab; mitotic inhibitors, including but not limited to paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin; antineoplastic hormones including, but not limited to, letrozole, tamoxifen, fulvestrant, triptorelin, flutamide, leuprolide, anastrozole; alkylating agents including, but not limited to, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine; the metal platins include, but are not limited to, carboplatin, cisplatin, oxaliplatin, and carboplatin; topoisomerase inhibitors, including but not limited to topotecan; immunosuppressive species, including but not limited to everolimus.
The invention further claims a pharmaceutical composition which comprises any compound shown in the general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof and one or more pharmaceutically acceptable carriers and/or diluents, and can be prepared into any pharmaceutically acceptable dosage form. Administered to a patient in need of such treatment by oral, parenteral, rectal, or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray. Each unit preparation contains 0.01 g to 10 g, 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 and the like of a physiologically effective amount of the compound represented by the formula (I).
The invention further provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, for the manufacture of a medicament for the treatment of a kinase-associated disease, in particular a kinase-associated disease such as Ab1, Bcr-Ab1, Bmx, BTK, b-RAF, c-RAF, CSK, cSRC, Fes, FGFR3, Flt3, IKK α, IKK β, JNK1 α 1, JNK2 α 2, Lck, Met, MKK4, MKK6, p70S6K, PAK2, PDGFR α, PKA, PKC α, PKD α, ROCK-ii, Ros, Rsk1, SAPK2 α, SAPK2 β, SAPK3, SAPK4, SGK, Syk, Tie2 or TrkB.
The invention also provides application of the compound shown in the general formula (I), pharmaceutically acceptable salt or stereoisomer thereof in preparing a medicament for treating and/or preventing cancer-related diseases or non-cancer-related diseases caused by abnormal activation or disorder of kinases, particularly a-RAF, b-RAF, c-RAF, particularly b-RAF kinase. The cancer-related diseases of the present invention include, but are not limited to: brain tumor, lung cancer, non-small cell lung cancer, squamous cell cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell cancer, solid tumors, non-hodgkin's lymphoma, glioma, glioblastoma multiforme, gliosarcoma, prostate cancer, thyroid cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, histiocytic lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma, and the like. Non-cancer related diseases include, but are not limited to, benign hyperplasia of the skin or prostate, and the like.
The compound of the invention has the following advantages:
(1) the compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof has excellent b-RAF kinase inhibitory activity and selectivity;
(2) the compound of formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof shows good biological stability, longer action and high bioavailability;
(3) the compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.
The beneficial effects of the compounds of the present invention are further illustrated below by in vitro pharmacological activity experiments, but this should not be understood as the only beneficial effects the compounds of the present invention have.
Experimental examples in vitro enzymatic Activity experiments of the Compounds of the invention
And (3) testing the sample: preparation examples of self-made compounds with chemical names and structural formulas shown in
The experimental method comprises the following steps:
the following experiments are represented by the following abbreviations in English:
HEPES (high efficiency particulate air): hydroxyethyl piperazine ethanesulfonic acid;
brij-35: dodecyl polyglycol ether;
EDTA: ethylene diamine tetraacetic acid;
fluoroescein-MAP 2K 1: fluorescein labeled MAP2K 1;
ATP: adenosine triphosphate;
DMSO, DMSO: dimethyl sulfoxide;
MgCl2: magnesium chloride.
1. Preparation of test reagent
① 1 kinase 1 fold buffer (50 mM HEPES, pH 7.5, 10 mM MgCl)2，1 mM EGTA，0.01% Brij-35)；
② 2 times of kinase solution (adding corresponding kinase into 1 time of kinase buffer solution to prepare 2 times of kinase solution, the final concentration is b-RAF 3.5 nM, b-RAF V599E 0.35 nM);
③ 4 times of substrate solution (adding fluoroescein-MAP 2K1 and ATP into 1 time of kinase buffer solution to prepare 4 times of solution, wherein the final concentration of two kinase substrates fluoroescein-MAP 2K1 is 0.2 mu M, the ATP concentration in the b-RAF kinase 4 times of substrate solution is 0.5 mu M, and the ATP concentration in the b-RAF V599E kinase 4 times of substrate solution is 1.5 mu M);
fourthly, 2 times of detection solution (2 times of detection solution is prepared, the final concentration is 2 nM of antibody and 10 mM of EDTA);
preparing 4 times compound solution (adopting 100% DMSO to prepare solution with final concentration of 100 times, diluting with 4 times gradient for 10 concentrations, then diluting with kinase buffer solution for 25 times respectively to prepare each compound solution with final concentration of 4 times gradient dilution, wherein the highest concentration of the compound is 10000 nM);
2. adding 2.5 mu L of 4 times compound solution into a 384-hole plate, and performing hole recombination;
3. adding 5 mu L of 2 times enzyme solution and incubating for 10 minutes;
4. then 2.5. mu.L of 4-fold substrate and ATP solution are added, and incubation is carried out for 1 hour at room temperature;
5. finally, 10 microliter of detection solution is added to stop the reaction, and after 30 minutes, the data is read by an enzyme-labeling instrument;
6. IC50。
calculating the RFU ratio
The inhibition ratio (%) = (maximum-sample ratio)/(maximum-minimum) × 100 was calculated
Curve fitting was performed using Xlfit software to obtain IC50 values.
Experimental results and conclusions:
TABLE 1 in vitro enzymatic inhibitory Activity of the Compounds of the invention
As can be seen from Table 1, the compound of the present invention has good inhibitory activity on b-RAF kinase and b-RAF V599E kinase, and has comparable inhibitory activity on b-RAF kinase and b-RAF V599E kinase, and can be used for treating diseases related to b-RAF kinase and b-RAFV599E kinase, especially disorders or conditions caused by b-RAF V599E kinase.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1N- (3- (5- (2-Aminopyrimidin-4-yl) -2- ((2-hydroxyethyl) amino) Oxazol-4-yl) -2-fluoro Preparation of phenyl) -2, 6-difluorobenzenesulfonamide (compound 1)
(1) Preparation of N- (3- (2- (2-chloropyrimidin-4-yl) acetyl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide
Reference is made to US2009/298815 a1 (2009) for the preparation of N- (3- (2- (2-chloropyrimidin-4-yl) acetyl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide.
(2) Preparation of N- (3- (2-bromo-2- (2-chloropyrimidin-4-yl) acetyl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide
N- (3- (2- (2-chloropyrimidin-4-yl) acetyl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide (6.2 g, 14mmol) was dissolved in dichloromethane (50 mL) at room temperature, N-bromosuccinimide (2.5 g, 14mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, dichloromethane (20 mL) was added to the mixture, and the mixture was separated, the organic phase was washed with water and saturated sodium chloride water, respectively, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =2:1) to give a yellow solid product (5.5 g, yield 75%).
(3) N- (3- (5- (2-Chloropyrimidin-4-yl) -2- ((2-hydroxyethyl) amino)Preparation of oxazol-4-yl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide
N- (3- (2-bromo-2- (2-chloropyrimidin-4-yl) acetyl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide (1 g,1.9 mmol) and 1- (2-hydroxyethyl) urea (870 mg, 8.4 mmol) were dissolved in toluene (20 mL), and the mixture was heated to 100 ℃ for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was isolated and purified by silica gel column chromatography (dichloromethane: methanol =10:1) to give a product (150 mg, yield 15%).
(4) N- (3- (5- (2-aminopyrimidin-4-yl) -2- ((2-hydroxyethyl) amino)Preparation of oxazol-4-yl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide
Reacting N- (3- (5- (2-aminopyrimidin-4-yl) -2- ((2-hydroxyethyl) amino)Oxazol-4-yl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide (100 mg, 0.2 mmol) was dissolved in aqueous ammonia (5 mL), reacted by microwave, and heated to 90 ℃ for 1.5 hours. Cooled, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol =10:1) to give the product (20 mg, yield 20%).
Molecular formula：C21H17F3N6O4S molecular weight: 506.5 LC-MS (m/z): 507.0 [ M + H]+
1H-NMR (400 MHz, MeOD) ：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).
Example 2N- (3- (5- (2-Aminopyrimidin-4-yl) -2- ((2-hydroxyethyl) amino) thiazol-4-yl) -2-fluorobenzene Preparation of phenyl) -2, 6-difluorobenzenesulfonamide (compound 2)
(1) Preparation of 1- (2-hydroxyethyl) thiourea
The preparation of thiourea was carried out in accordance with US2008/45556 a1 (2008), the reaction temperature was changed to 70 ℃, the reaction time was 10 hours, and the yield was 70%.
(2) Preparation of N- (3- (5- (2-chloropyrimidin-4-yl) -2- ((2-hydroxyethyl) amino) thiazol-4-yl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide
N- (3- (2-bromo-2- (2-chloropyrimidin-4-yl) acetyl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide (1 g,1.9 mmol) prepared in example 1, step "(2)" and 1- (2-hydroxyethyl) thiourea (348 mg, 5.7 mmol) were dissolved in toluene (20 mL), and the mixture was heated to 100 ℃ for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was isolated and purified by silica gel column chromatography (eluent dichloromethane: methanol =10:1) to give the product (200 mg, yield 19%).
(3) Preparation of N- (3- (5- (2-aminopyrimidin-4-yl) -2- ((2-hydroxyethyl) amino) thiazol-4-yl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide
N- (3- (5- (2-aminopyrimidin-4-yl) -2- ((2-hydroxyethyl) amino) thiazol-4-yl) -2-fluorophenyl) -2, 6-difluorobenzenesulfonamide (150 mg, 0.28 mmol) was dissolved in aqueous ammonia (5 mL), reacted by microwave, heated to 90 ℃ and reacted for 1.5 hours. After cooling, the solvent was removed by rotary evaporation, and the residue was isolated and purified by silica gel column chromatography (dichloromethane: methanol =10:1) (30 mg, yield 21%).
The molecular formula is as follows: c21H17F3N6O3S2Molecular weight: 522.5 LC-MS (m/z): 523.4 [ M + H]+
1H-NMR (400 MHz, MeOD) ：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. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein
Ring A is selected from
R1Selected from hydrogen or amino;
R2and R3Each independently selected from halogen atoms;
x is selected from O or S;
m, n and p are each independently selected from 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3. a pharmaceutical composition of a compound of claim 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in combination with one or more pharmaceutically acceptable carriers and/or diluents, formulated into any pharmaceutically acceptable dosage form.
4. The compound, pharmaceutically acceptable salt or stereoisomer thereof according to claim 3, wherein the pharmaceutical composition further comprises one or more antineoplastic agents and immunosuppressive agents selected from the group consisting of methotrexate, capecitabine, gemcitabine, doxifluridine, pazopanib, imatinib, gefitinib, herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, triptorelin, flutamide, leuprolide, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, carboplatin, cisplatin, oxaliplatin, carboplatin, topotecan, and everolimus.
5. The use of a compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for the manufacture of a medicament for the treatment and/or prevention of a cancer-related disease or a non-cancer-related disease caused by abnormal activation or disorder of a kinase, selected from the group consisting of non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, hepatic cancer, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer; a non-cancer related disease selected from benign hyperplasia of the skin or prostate.
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