CN104844566A - Kinase inhibitor with novel structure - Google Patents
Kinase inhibitor with novel structure Download PDFInfo
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- CN104844566A CN104844566A CN201410757626.7A CN201410757626A CN104844566A CN 104844566 A CN104844566 A CN 104844566A CN 201410757626 A CN201410757626 A CN 201410757626A CN 104844566 A CN104844566 A CN 104844566A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Abstract
The invention provides compounds of a novel kinase inhibitor as shown in the formula (I) or pharmaceutically acceptable salts, solvates, esters, acids, metabolites, combination drugs or prodrugs thereof. The compounds independently combines with at least one variety of other therapeutic agents and can be used to prevent or treat illnesses, disorders or diseases, and autoimmune diseases which are regulated by tyrosine kinase activity or affected by the tyrosine kinase activity or related to the tyrosine kinase activity, and specifically cancers and other cellular proliferative diseases.
Description
Technical field
The present invention relates to new compound and their tautomer and steric isomer and pharmacologically acceptable salt, ester, acid, metabolite or prodrug, the composition of these new compounds and pharmaceutically acceptable carrier, with separately other with at least one therapeutic agent of these new compounds prevent or treat regulated by tyrosine kinase activity or affect by it or wherein relate to tyrosine kinase activity disease, obstacle or illness, purposes in autoimmune disorder, especially cancer and other cell proliferation disorders.
Background technology
Tyrosylprotein kinase is that on a class catalysis ATP, γ-phosphoric acid transfers to the kinases on protein-tyrosine residue, and energy catalysis multiple substrate protein white matter tyrosine residues phosphorylation, has vital role in Growth of Cells, propagation, differentiation.Kinase function is abnormal significant in cancer, immunity, nerve, metabolism and infectious diseases.Current nearly nearly 30 kinds of different kinases are as the medicine of target spot, and the overwhelming majority is used for Therapeutic cancer.In the protein tyrosine kinase found so far, majority is the oncoprotein belonging to oncornavirus RNA, also can be produced by vertebrate proto-oncogene.
Tyrosine kinase inhibitor can be used as the competitive inhibitor that Triphosaden (ATP) is combined with Tyrosylprotein kinase, also can be used as the analogue of tyrosine, block the activity of Tyrosylprotein kinase, antiproliferative effect, has been developed as several antitumor drugs.
The kinases of encoding in human genome has 518 kinds, and almost each intracellular signaling process all needs to be got in touch with by phposphate cascade reaction (cascade): prompting suppresses kinase activity really can eliminate the physiological response of cell.Such as, suppress oncogene BCR (Breakpoint cluster region)-ABL fusion rotein to be the key factor causing chronic myelogenous leukemia to occur, its tyrosine activity has obvious therapeutic potential.Although ATP-binding site has the conservative property of height, can develop, on pharmacological characteristic, there is obviously optionally small molecules.Normal cell can tolerate kinase whose suppression usually, therefore for selectivity kills the window that tumour cell provides a treatment.Such as Dasatinib treats the chronic myelogenous leukemia CML of Imatinib resistance, almost can suppress 9 of SRC family kinases (and other multiple Tyrosylprotein kinase), but compared with traditional cell chemotherapy, its side effect or easily tolerance.Therefore, the exploitation of new kinase inhibitor has important clinical meaning.
Summary of the invention
The invention provides a kind of Azaindole kinase inhibitors, comprise compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula (I):
Wherein Z1, Z2, Z3, Z4 and Z5 are independently selected from CH or N;
X is selected from
R1 be selected from H, halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino ,-NH-the heteroaryl optionally replaced by 1-3 R6 group and on the heteroatoms (preferred atom N) being selected from N, O and S optionally by-Y-(C3-C8) heterocyclic radical that R7 group replaces, wherein Y is selected from O, NH, S, (CH
2)
0-2, NH-(CO) and (CO)-NH;
R6 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, aryl and heteroaryl;
R7 is selected from-(CO)-(C1-C8) alkyl ,-(CO)-(C2-C8) thiazolinyl ,-(CO)-(C2-C8) alkynyl ,-(CO)-(C3-C8) cycloalkyl ,-(CO)-(C1-C8) haloalkyl ,-(CO)-(C1-C8) hydroxyalkyl ,-(CO)-(C1-C8) alkylamino ,-(CO)-(C1-C8) alkyl-N-[(C1-C8) alkyl]
2,-(CO)-vinyl-(CH
2)
n-N-[(C1-C8) alkyl]
2, optionally by 1-3 R8 group replace-(CO)-aryl, optionally by 1-3 R8 group replace-(CO)-heteroaryl, optionally by 1-3 R8 group replacement-(CO)-(C3-C8) heterocyclic radical ,-(CO)-(C1-C8) alkylaryl ,-(CO)-(C1-C8) miscellaneous alkyl aryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C3-C8) cycloalkyl, optionally by 1-3 R8 group replace-(SO
2)-aryl, the heteroaryl optionally replaced by 1-3 R8 group,
R8 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group and C1-C8 halogenated alkoxy;
R2 is selected from hydrogen, halogen, nitro, amino, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, aryl and heteroaryl;
R3 and R5 be selected from independently of one another hydrogen, C1-C8 alkyl, the aryl optionally replaced by 1-3 R9 group, optionally by the heteroaryl of 1-3 R9 group replacement, halogen, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) alkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(CO)-(C2-C8) alkynyl, fragrant oxygen base, nitro, amino and hydroxyl;
R9 is selected from C1-C8 alkyl, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C1-C8) cycloalkyl ,-(SO
2)-(C1-C8) aryl and-(SO
2)-(C1-C8) heteroaryl;
R4 be selected from hydrogen, C1-C8 alkyl, optionally by 1-3 R10 group replace-(CH2)
n-(C3-C8) heterocyclic radical ,-(CH
2)
n-NH-(CO)-(C1-C8) alkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(CO)-(C2-C8) alkynyl ,-(CH
2)
n-NH-(SO
2)-(C1-C8) alkyl ,-(CH
2)
n-NH-(SO
2)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(SO
2)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(SO
2)-(C2-C8) alkynyl; With-(CH
2)
n-NH-(CO)-vinyl-(CH
2)
n-N-[(C1-C8) alkyl]
2;
R10 be selected from C1-C8 alkyl, by R11 replace-(C1-C20) alkyl, by R11 replace-[(CH
2)
2-O-]
m-(CH
2)
2-Ji, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C1-C8) cycloalkyl ,-(SO
2)-(C1-C8) aryl ,-(SO
2)-(C1-C8) heteroaryl;
R11 is selected from C1-C8 alkyl ,-NH-(CO)-(CH)
n-adamantyl (any site of this adamantyl is optionally replaced by one or more C1-C8 alkyl) and-N-[(C1-C8) alkyl]
2;
Wherein n is the integer of 0-6 independently of one another, and m is the integer of 1-6.
In one embodiment, Z1, Z2, Z3, Z4 and Z5 are CH.
In another embodiment, Z
1and Z
2for N and Z3, Z4 and Z5 are CH.
In a preferred embodiment, the invention provides a kind of Azaindole kinase inhibitors, comprise compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula (II):
Wherein R
1, R
2, R
3, R
4and R
5as previously defined.
Compound with chirality involved in the present invention, its configuration can be the racemic modification of arbitrary configuration or mixing.
The invention still further relates to the pharmaceutical composition comprising above compound, and this compound prevention or treatment is regulated by tyrosine kinase activity or affect by it or wherein relate to tyrosine kinase activity disease, obstacle or illness, method in autoimmune disorder and purposes.
Accompanying drawing explanation
Fig. 1 illustrate compound 26 on blood cell K562 (Fig. 1 a), the impact of mouse TEL-cKit-BaF3 cell (Fig. 1 b) and acute myeloid leukemia cells in children Kasumi-1 (Fig. 1 c) signal path.
Fig. 2 illustrates that compound 26 is on the apoptotic impact of blood cell K562.
Embodiment
term
Unless otherwise defined, all scientific and technical terminologies used herein all have and generally understand identical implication with claimed theme those skilled in the art.
Except as otherwise noted, the present invention adopts the ordinary methods such as mass spectrum, NMR, HPLC, protein chemistry, biological chemistry, recombinant DNA technology and pharmacology within the scope of art technology.Unless provided concrete definition, otherwise the name chemically relevant to analytical chemistry described herein, synthetic organic chemistry and medical science and pharmaceutical chemistry etc. and laboratory operation and technology, be well known by persons skilled in the art.Generally speaking, aforementioned techniques and step can by well-known in the art and implement at various general document and the ordinary method that more specifically describes in document, and these documents are cited in this manual and discuss.
" alkyl " refers to aliphatic hydrocarbon groups, can be the alkyl of side chain or straight chain.According to structure, alkyl can be monoradical or bivalent radical (i.e. alkylidene group).In the present invention, alkyl preferably has " low alkyl group " of 1-8 carbon atom.Typical alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.
" alkoxyl group " refers to-O-alkyl, and wherein alkyl is as defined herein.Typical alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.
" alkoxyalkyl " refers to that alkyl defined herein is replaced by alkoxyl group defined herein.
Term " alkylamino " refers to-N (alkyl)
xh
ygroup, wherein x and y is selected from x=1, y=1 and x=2, y=0.As x=2, the atom N that alkyl is connected with them combines and optionally can form loop systems.
" alkylaminoalkyl group " refers to that alkyl defined herein is replaced by alkylamino defined herein.
Term " aromatic base " refers to that planar rings has the π-electron system of delocalization and containing 4n+2 π-electron, wherein n is integer.Fragrance basic ring can by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic base can be optional replacement.Term " aromatic base " comprises isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " assorted aromatic base ") group (such as pyridine).This term comprises monocycle or the many rings of condensed ring (namely sharing the right ring of adjacent carbon atom) group.
Term used herein " aryl " refers to that the atom that in fragrant basic ring, each forms ring is carbon atom.Aryl rings can by five, six, seven, eight, nine or more than nine atomic buildings.Aryl can be optional replacement.The example of aryl includes but not limited to phenyl, naphthyl, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e. arylidene).
" alkyl (aryl) " refers to that alkyl defined herein is replaced by aryl defined herein.Nonrestrictive alkyl (aryl) comprises benzyl, styroyl etc.
Term " cycloalkyl " refers to monocycle or many cyclic groups, and it is only containing carbon and hydrogen.Cycloalkyl comprises the group with 3-8 annular atoms.According to structure, cycloalkyl can be monoradical or bivalent radical (such as cycloalkylidene).In the present invention, cycloalkyl preferably has the cycloalkyl of 3-8 carbon atom, more preferably has " low-grade cycloalkyl " of 3-6 carbon atom.
" alkyl (cycloalkyl) " refers to that alkyl defined herein is by cycloalkyl substituted defined herein.Nonrestrictive alkyl (cycloalkyl) comprises Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl etc.
Term used herein " assorted alkyl " refers to that the one or more skeletal chain atoms in alkyl defined herein are heteroatomss, such as oxygen, nitrogen, sulphur, silicon, phosphorus or their combination.The optional position that described heteroatoms (one or more) can be positioned at assorted alkyl inside or the position be connected with the rest part of molecule at assorted alkyl.
Term " heteroaryl " refers to that aryl comprises one or more ring hetero atom being selected from nitrogen, oxygen and sulphur.Refer in aromatic base ring to have at least a skeletal atom be nitrogen-atoms containing N " heteroaryl " part.According to structure, heteroaryl can be monoradical or bivalent radical (i.e. inferior heteroaryl).The example of heteroaryl includes but not limited to pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrryl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, pseudoindoyl, pteridyl, purine radicals, oxadiazolyl, thiadiazolyl group, furyl, benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolyl, naphthyridinyl and furopyridyl etc.
Term used herein " Heterocyclylalkyl " refers to that the atom of one or more formation ring in non-aromatic basic ring is the heteroatoms being selected from nitrogen, oxygen and sulphur.Heterocycloalkyl ring can by three, four, five, six, seven, eight, nine or more than nine atomic buildings.Heterocycloalkyl ring can be optional replacement.The example of Heterocyclylalkyl includes but not limited to lactan, lactone, the sub-glue of ring, ring thioimines, cyclic carbramates, tetrahydric thiapyran, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-diox, Isosorbide-5-Nitrae-dioxin, Isosorbide-5-Nitrae-diox, piperazine, 1,3-oxathiane, Isosorbide-5-Nitrae-oxathiin, Isosorbide-5-Nitrae-oxathiane, tetrahydrochysene-Isosorbide-5-Nitrae-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituricacidα-, dioxopiperazine, glycolylurea, dihydrouracil, morpholine, trioxane, six hydrogen-1,3,5-triazines, tetramethylene sulfide, tetrahydrofuran (THF), pyrroline, tetramethyleneimine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, tetrahydroglyoxaline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazole alkyl, oxazoline, oxazolidine, oxazolidone, thiazoline, thiazolidine and 1,3-oxathiolane.According to structure, Heterocyclylalkyl can be monoradical or bivalent radical (i.e. sub-Heterocyclylalkyl).
Term " alkyl (heteroaryl) " refers to that alkyl defined herein is replaced by heteroaryl defined herein.
Term " alkyl (Heterocyclylalkyl) " refers to that alkyl defined herein is replaced by Heterocyclylalkyl defined herein.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " haloalkyl ", " halogenated alkoxy " and " halo mix alkyl " comprise the structure of alkyl, alkoxyl group or assorted alkyl, and wherein at least one hydrogen is replaced by halogen atom.In some embodiments, if two or more hydrogen atoms are replaced by halogen atom, described halogen atom is same to each other or different to each other.
Term used herein " cyano group " refers to formula-CN group.
Term " ester group " refers to the chemical part with formula-COOR, and wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (being connected by ring carbon) and heteroalicyclyl (being connected by ring carbon).
Term " optional replace " or " replacement " refer to that mentioned group can be replaced by one or more extra group, and described extra group is separately and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxyl group, cyano group, halogen, amide group, nitro, haloalkyl, amino etc.
Term used herein " tyrosine protein kinase (tyrosine protein kinase; TPK) " is that on a class catalysis ATP, γ-phosphoric acid transfers to the kinases on protein-tyrosine residue, energy catalysis multiple substrate protein white matter tyrosine residues phosphorylation, has vital role in Growth of Cells, propagation, differentiation.
Term used herein kinase whose " suppression ", " suppression " or " inhibitor ", refer to that phosphate transferase activity is suppressed.
" metabolite " of compound disclosed herein is when this compound is by the derivative of compound formed during metabolism.Term " active metabolite " refers to when this compound is by the biologically active derivatives of compound formed during metabolism.Term used herein " by metabolism ", refers to that predetermined substance is by the process summation of organism transform (include but not limited to hydrolysis reaction and such as, by enzymatic reaction, oxidizing reaction).Therefore, enzyme can produce specific structural transformation is compound.Such as, the various oxidation of Cytochrome P450 catalysis and reduction reaction, simultaneously the glucal acid molecule of diphosphate glucose sweet acidic group transferring enzyme catalytic activation is to the conversion of aromatic alcohol, fatty alcohol, carboxylic acid, amine and free sulfydryl.Metabolic further information can from " The Pharmacological Basis ofTherapeutics ", the 9th edition, and McGraw-Hill (1996) obtains.The metabolite of compound disclosed herein can by giving host and analyzing from the tissue sample of this host or by compound and liver cell being hatched in vitro and analyzing gained compound to differentiate by compound.These two kinds of methods are all known in the art.In some embodiments, the metabolite of compound to be formed by oxidising process and corresponding with corresponding hydroxy-containing compounds.In some embodiments, compound is metabolised to pharmaceutical active metabolite.Term used herein " adjustment ", refers to directly or indirectly and target interacts, and to change the activity of target, only for example, comprises the activity of intensifier target target activity, the activity suppressing target, limit target target activity or prolongation target.
Term used herein " target protein " refer to can the protein molecule that combines by selectivity binding compounds or partial protein.In some embodiments, target protein is Tyrosylprotein kinase KIT (wild-type or various sudden change or its combination), ABL (wild-type or various sudden change or its combination), EGFR (wild-type or various sudden change or its combination), FLT3 (wild-type or various sudden change or its combination), BLK (wild-type or various sudden change or its combination), VEGFR (wild-type or various sudden change or its combination), RET (wild-type or various sudden change or its combination), PDGFR (wild-type or various sudden change or its combination), MEK (wild-type or various sudden change or its combination), BCR/ABL (wild-type or various sudden change or its combination), JAK (wild-type or various sudden change or its combination), BRAF (wild-type or various sudden change or its combination).
IC used herein
50refer to the amount of the 50% fc-specific test FC compound suppressed obtaining maximum effect in the analysis of measuring such effect, concentration or dosage.
EC used herein
50the specific reaction referring to and measure the dosage of compound, concentration or amount, it causes particular assay compound to induce, stimulate or strengthen 50% the dose-dependant reaction of maximum expression.
the kinase inhibitor that the present invention is novel
The invention provides a kind of Azaindole kinase inhibitors, comprise compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula (I):
Wherein Z1, Z2, Z3, Z4 and Z5 are independently selected from CH or N;
X is selected from
Wherein R
1, R
2, R
3, R
4and R
5as previously defined.
In one embodiment, Z1, Z2, Z3, Z4 and Z5 are CH.
In another embodiment, Z
1and Z
2for N and Z3, Z4 and Z5 are CH.
In a preferred embodiment, the invention provides a kind of Azaindole kinase inhibitors, comprise compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula (II):
Wherein, R1 is selected from H, halogen, amino, nitro, hydroxyl, C1-C8 alkyl (preferable methyl, ethyl, propyl group), C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, optionally by the-NH-heteroaryl (the preferred pyrimidyl of heteroaryl) of 1-3 R6 group replacement, with be selected from N, optionally by-Y-(C3-C8) heterocyclic radical (the preferred piperidyl of heterocyclic radical that R7 group replaces on the heteroatoms (preferred atom N) of O and S, pyrrolidyl, azetidinyl), wherein Y is selected from O, NH, S, (CH
2)
0-2, NH-(CO) and (CO)-NH (preferred O),
R6 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, aryl and heteroaryl (preferred pyridyl, particularly 2-pyridyl);
R7 is selected from-(CO)-(C1-C8) alkyl (preferable methyl, ethyl, propyl group, butyl),-(CO)-(C2-C8) thiazolinyl (preferred vinyl, propenyl),-(CO)-(C2-C8) alkynyl (preferred ethynyl),-(CO)-(C3-C8) cycloalkyl (preferred cyclopropyl),-(CO)-(C1-C8) haloalkyl (preferred chloromethyl, Chloroethyl, trifluoroethyl),-(CO)-(C1-C8) hydroxyalkyl (preferred hydroxyethyl),-(CO)-(C1-C8) alkylamino (preferred ethylamino),-(CO)-(C1-C8) alkyl-N-[(C1-C8) alkyl]
2,-(CO)-vinyl-(CH
2)
n-N-[(C1-C8) alkyl]
2, optionally by 1-3 R8 group replace-(CO)-aryl (the preferred phenyl of aryl), optionally by 1-3 R8 group replace-(CO)-heteroaryl (preferred pyridyl of heteroaryl, pyrimidyl, furyl, quinolyl, quinazolyl, benzodioxole base), optionally by 1-3 R8 group replace-(CO)-(C3-C8) heterocyclic radical (the preferred piperidyl of heterocyclic radical),-(CO)-(C1-C8) alkylaryl,-(CO)-(C1-C8) miscellaneous alkyl aryl,-(SO
2)-(C1-C8) alkyl (alkyl preferable methyl, ethyl, propyl group) ,-(SO
2)-(C3-C8) cycloalkyl (the preferred cyclopropyl of cycloalkyl), optionally by 1-3 R8 group replace-(SO
2)-aryl (the preferred phenyl of aryl), the heteroaryl (preferred purine radicals, pyrazolopyrimidine base, quinazolyl) optionally replaced by 1-3 R8 group,
R8 is selected from halogen (preferred fluorine), amino, nitro, hydroxyl, C1-C8 alkyl (preferable methyl), C1-C8 haloalkyl (preferred trifluoromethyl), C1-C8 alkoxyl group (preferred methoxyl group) and C1-C8 halogenated alkoxy;
R2 is selected from hydrogen, halogen (preferred fluorine, chlorine), nitro, amino, hydroxyl, C1-C8 alkyl (preferable methyl), C1-C8 haloalkyl (preferred trifluoromethyl), C1-C8 alkoxyl group (preferred methoxyl group), C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, aryl and heteroaryl;
R3 and R5 is independently selected from hydrogen, C1-C8 alkyl (preferable methyl), optionally by the aryl of 1-3 R9 group replacement, optionally by the heteroaryl (preferred 4-methylimidazole base) of 1-3 R9 group replacement, halogen (preferred fluorine, chlorine), C1-C8 haloalkyl (preferred trifluoromethyl), C1-C8 alkoxyl group, C1-C8 halogenated alkoxy (preferred trifluoromethoxy),-(CO)-(C1-C8) alkyl,-(CO)-(C1-C8) haloalkyl (preferred halogenated methyl),-(CH
2)
n-NH-(CO)-(C1-C8) alkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(CO)-(C2-C8) alkynyl, fragrant oxygen base, nitro, amino and hydroxyl,
R9 is selected from C1-C8 alkyl (preferable methyl, ethyl), aryl, heteroaryl ,-(CO)-(C1-C8) alkyl (preferred ethyl) ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C1-C8) cycloalkyl ,-(SO
2)-(C1-C8) aryl ,-(SO
2)-(C1-C8) heteroaryl;
R4 be selected from hydrogen, C1-C8 alkyl (preferable methyl), optionally by 1-3 R10 group replace-(CH2)
n-(C3-C8) heterocyclic radical (heterocyclic radical preferred nitrogen, oxygen and nitrogen oxa-5 ring and six-ring) ,-(CH
2)
n-NH-(CO)-(C1-C8) alkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(CO)-(C2-C8) alkynyl ,-(CH
2)
n-NH-(SO
2)-(C1-C8) alkyl ,-(CH
2)
n-NH-(SO
2)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(SO
2)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(SO
2)-(C2-C8) alkynyl;-(CH
2)
n-NH-(CO)-vinyl-(CH
2)
n-N-[(C1-C8) alkyl]
2;
R10 be selected from C1-C8 alkyl (preferable methyl, ethyl), by R11 replace-(C1-C20) alkyl, by R11 replace-[(CH
2)
2-O-]
m-(CH
2)
2-Ji, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl (preferred ethyl) ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C1-C8) cycloalkyl ,-(SO
2)-(C1-C8) aryl ,-(SO
2)-(C1-C8) heteroaryl;
R11 is selected from C1-C8 alkyl ,-NH-(CO)-(CH)
n-adamantyl (any site of this adamantyl is optionally replaced by one or more C1-C8 alkyl) and-N-[(C1-C8) alkyl]
2;
Wherein n is the integer (integer of preferred 0-2) of 0-6 independently of one another, and m is the integer (integer of preferred 1-4) of 1-6.
On the one hand, preferably provide herein and select following compound, the structure of these preferred compounds is as shown in table 1.
For each variable, the arbitrary combination of above-mentioned group is also among considering herein.Be understandable that: the substituting group on compound provided in this article and substitute mode can be selected by those skilled in the art, to provide chemically stable and the compound of technology synthesis that can use technology known in the art and set forth herein.
Described herein is novel kinase inhibitor.Also illustrate the pharmacologically acceptable salts of this compound, solvate, ester, acid, pharmaceutical active metabolite and prodrug herein.
Other or further in embodiment, produce metabolite at its internal metabolism after compound described herein being given organism in need, then the metabolite produced for generation of the effect expected, comprises the result for the treatment of of expectation.
Compound described herein can be made into and/or be used as pharmacologically acceptable salts.The type of pharmacologically acceptable salts includes but not limited to: (1) acid salt, by the free alkali form of compound and the acceptable inorganic acid reaction of pharmacy being formed, described mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc., or formed with organic acid reaction, described organic acid is as acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, oxysuccinic acid, citric acid, succsinic acid, toxilic acid, tartrate, FUMARIC ACID TECH GRADE, trifluoroacetic acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methanesulfonic, ethane sulfonic acid, 1, 2-ethionic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, 4-methyl bicycle-[2.2.2] oct-2-ene-1-formic acid, 2-naphthene sulfonic acid, tert.-butylacetic acid, glucoheptonic acid, 4, 4 '-methylene-bis-(3-hydroxyl-2-alkene-1-formic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecyl sulphate, glyconic acid, L-glutamic acid, Whitfield's ointment, hydroxynaphthoic acid, stearic acid, muconic acid etc., (2) salt, is formed when its acid proton in parent compound is replaced by metal ion, such as alkalimetal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminum ion, or with organic bases coordination.Acceptable organic bases comprises thanomin, diethanolamine, trolamine, Trimethylamine 99, N-methyl glucose osamine, etc.Acceptable mineral alkali comprises aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc.
The corresponding counterion of pharmacologically acceptable salts can use various methods analyst and qualification, and described method includes but not limited to ion-exchange chromatography, chromatography of ions, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrum, mass spectrum or their any combination.
Use at least one of following technology to reclaim described salt: filter, with non-solvent precipitation then filter, solvent evaporation, or use lyophilization when the aqueous solution.
Screening and sign pharmacologically acceptable salts, polymorphic and/or solvate can use multiple technologies to complete, and described technology includes but not limited to thermal analyses, X-ray diffraction, spectrum, microscopy, ultimate analysis.The various spectroscopic techniquess used include but not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopy includes but not limited to IR microscopy and Raman (Raman) microscopy.
pharmaceutical composition of the present invention
The application also provides pharmaceutical composition, it comprises the pharmacologically acceptable salts of the compound of at least one formula (I) or described compound, solvate, ester, acid, pharmaceutical active metabolite or prodrug, and pharmaceutically acceptable carrier or vehicle, and other therapeutical agent that person is optional.
Over the course for the treatment of, can according to circumstances use separately or with one or more other therapeutic combination.Can by injection, oral, suck, at least one in rectum and applied dermally will comprise the medicament administration of the compounds of this invention to patient.Other therapeutical agent can be selected from following medicine: immunosuppressor (such as tacrolimus, encircle rhzomorph, rapamycin, Methylaminopterin, endoxan, azathioprine, mercaptopurine, mycophenolate or FTY720), glucocorticoids medicine (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, Betamethasone Valerate, triamcinolone, hydrogen hydroxyl Ultracortene-H, beclometasone, fludrocortisone acetate, percorten, aldosterone), NSAID (non-steroidal anti-inflammatory drug) (such as salicylate, aryl alkanoic acid, 2-arylpropionic acid, N-aryl-anthranilic acid, former times health class, examine former times class or sulphonanilid), allergic reaction bacterin, antihistaminic, anti-leukotriene medicine, beta-2-agonists, theophylline, anticholinergic drug or other selective kinase inhibitors (such as mTOR inhibitors, c-Met inhibitor) or her2 antibody-drug.In addition, other mentioned therapeutical agent can also be that rapamycin (Rapamycin), gram azoles are for Buddhist nun (Crizotinib), tamoxifen, raloxifene, Anastrozole, Exemestane, letrozole, Trastuzumab
tM(Herceptin), imatinib mesylate
tM(imatinib), taxol
tM(taxol), endoxan, lovastatin, U.S. promise tsiklomitsin (Minosine), cytosine arabinoside, 5 FU 5 fluorouracil (5-FU), methotrexate (MTX), taxotere
tM(docetaxel), Zoladex
tM(goserelin), vincristine(VCR), vinealeucoblastine(VLB), R 17934, teniposide, Etoposide, gemzar
tM(gemcitabine), ebormycine (Epothilone), promise be basis, camptothecine, daunorubicin (Daunonibicin), gengshengmeisu, mitoxantrone, amsacrine, Dx (adriamycin), epirubicin or idarubicin only.Or other therapeutical agent also can be cytokine such as G-CSF (granulocyte colony-stimulating factor).Or, other therapeutical agent also can be, such as but not limited to, CMF (endoxan, methotrexate and 5 FU 5 fluorouracil), CAF (endoxan, adriamycin and 5 FU 5 fluorouracil), AC (adriamycin and endoxan), FEC (5 FU 5 fluorouracil, epirubicin and endoxan), ACT or ATC (adriamycin, endoxan and taxol) or CMFP (endoxan, methotrexate, 5 FU 5 fluorouracil and prednisone).
In embodiments of the present invention, when treating patient according to the present invention, the amount of given medicine depends on factors, as concrete dosage regimen, disease or illness type and seriousness, the curee of needs treatment or the uniqueness (such as body weight) of host, but, according to specific ambient conditions, comprise such as adopted concrete medicine, route of administration, treatment illness and treatment curee or host, application dosage can by methods known in the art routine determine.Usually, with regard to adult treatment use dosage with regard to, application dosage typically at 0.02-5000mg/ days, the such as scope of about 1-1500mg/ days.This required dosage can be expressed as (or at short notice) of potion or simultaneously administration or the divided dose at suitable interval easily, such as point agent every day two, three, four doses or more.Although it will be appreciated by persons skilled in the art that and give above-mentioned dosage range, concrete significant quantity suitably can regulate in conjunction with doctor diagnosed according to the situation of patient.
the purposes of medicine of the present invention
The compound of formula (I) can comprise its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, or pharmaceutical composition suppresses a kind of for suppressing Tyrosylprotein kinase KIT (wild-type or various sudden change or its combination), ABL (wild-type or various sudden change or its combination), EGFR (wild-type or various sudden change or its combination), FLT3 (wild-type or various sudden change or its combination), BLK (wild-type or various sudden change or its combination), VEGFR (wild-type or various sudden change or its combination), RET (wild-type or various sudden change or its combination), PDGFR (wild-type or various sudden change or its combination), MEK (wild-type or various sudden change or its combination), BCR/ABL (wild-type or various sudden change or its combination), JAK (wild-type or various sudden change or its combination), BRAF (wild-type or various sudden change or its combination) is active.Formula (I) described compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, and pharmaceutically acceptable carrier or vehicle can be used for treatment or preparation can be used for treating the disease that one or more are selected from lower group: solid tumor (comprise optimum or especially malignant class), especially sarcoma, gastrointestinal stromal tumors (Gastrointestinal Stromal Tumors, GIST), acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML), the influential leukemia of tool is suppressed to Abl tyrosine kinase activity, mesothelioma, thyroid carcinoma (thyroid carcinoma), systemic mast cell disease, hypereosinophilic syndrome (HES), fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease (GVH disease) (graft-versus-host disease, GVHD), neurofibroma, pulmonary hypertension, alzheimer's disease, spermocytoma, argyraemia, dysgerminoma, mast cell tumor, lung cancer, bronchogenic carcinoma, dysgerminoma, testis intraepithelial neoplasia is formed, melanoma, breast cancer, neuroblastoma, corpora mammillaria/follicular thyroid carcinoma, malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine tumorigenesiss, pheochromocytoma, thyroid carcinoma, parathyroid hyperplasia/adenoma, colorectal carcinoma, colorectal adenomas, ovarian cancer, prostate cancer, glioblastoma, cerebral tumor, glioblastoma, carcinoma of the pancreas, malignant pleural mesothelioma, hemangioblastoma, vascular tumor, kidney, liver cancer, adrenal carcinoma, bladder cancer, cancer of the stomach, the rectum cancer, carcinoma of vagina, cervical cancer, carcinoma of endometrium, multiple myeloma, neck and head tumor, tumorigenesis and other Hypertrophic or proliferative disease or similar disease or its combination.Particularly preferably treat gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST), acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML), thyroid carcinoma (thyroid carcinoma) or similar disease or its combination.Autoimmune disorder includes but not limited to: sacroiliitis, rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel, psoriasis arthropathica, osteoarthritis, Still disease (Still ' s disease), adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Order thyroiditis (Ord ' s hyroiditis), Graves disease (Graves ' disease), rheumatoid arthritis syndrome (
syndrome), multiple sclerosis, Guillain-Barre syndrome (Guillain-Barr é syndrome), acute disseminated encephalomyelitis, bronzed disease (Addison ' s disease), depending on property eye battle array twin-the twin syndrome of flesh battle array, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease (coeliac disease), goodpasture's syndrome (Goodpasture ' s syndrome), idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter syndrome (Reiter ' s syndrome), aortic arch syndrome (Takayasu ' s arteritis), temporal arteritis, warm type autoimmune hemolytic anemia, Wegner granulomatosis (Wegener ' s granulomatosis), psoriatic, alopecia universalis, behcet disease (Behcet ' s disease), confirmed fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia.
the preparation of compound
Use Standard synthetic techniques well known by persons skilled in the art or use methods known in the art and Combination of Methods described herein, can the compound of synthesis type (I).In addition, the solvent provided herein, temperature and other reaction conditions can change according to art technology.As further guidance, also following synthetic method can be utilized.
Described reaction can use in order, to provide compound described herein; Or they may be used for synthesizing fragment, described fragment is added subsequently by method described herein and/or methods known in the art.
In some embodiments, provided herein is preparation method and the using method thereof of tyrosine kinase inhibitor compound described herein.In some embodiments, compound described herein can use the scheme of following synthesis to synthesize.Can use and following similar method, by using suitable selectable starting raw material, synthetic compound.
Starting raw material for the synthesis of compound described herein can be synthesized or can obtain from commercial source.The compound described herein compound with different substituents relevant with other can use technology well known by persons skilled in the art and Material synthesis.The general method preparing compound disclosed herein can from reaction known in the art, and this reaction can by the reagent of being thought fit by those skilled in the art and condition amendment, to be incorporated herein the various parts in the molecule that provides.
If needed, reaction product can use routine techniques abstraction and purification, includes but not limited to the methods such as filtration, distillation, crystallization, chromatogram.These products can use ordinary method to characterize, and comprise physical constant and spectrum data.
The non-limiting example of the synthetic schemes of the compound of preparation formula (I) is see scheme I.
Scheme I
Use synthetic method described herein, and those methods known in the art, obtain tyrosine kinase inhibitor disclosed herein with good yield and purity.The compound prepared according to method disclosed herein such as, by ordinary method purifying known in the art, filtration, recrystallization, chromatogram, distillation and combination thereof.
Site on the aromatic moiety of the compound of formula (I), can be easy to various metabolic reaction occurs, therefore suitable substituting group is introduced on aromatic ring structure, such as, only illustrate, halogen can reduce, reduces or eliminate this pathways metabolism.
embodiment
Non-limiting example concrete below will be construed as merely illustrative, and limit the disclosure never in any form.Although without the need to describing in further detail, can believe that those skilled in the art based on description herein, can utilize the disclosure completely.
the synthesis of the compounds of this invention intermediate
The synthesis of 3-trifluoromethyl-4-methyl-benzoic acid methyl compound a
20mmol 3-trifluoromethyl-4-methyl-benzoic acid is dissolved in the round-bottomed flask that 60mL methyl alcohol is housed, and adds the vitriol oil of catalytic amount (3%mmol), reaction system stirring and refluxing is spent the night.Rotary Evaporators, except desolventizing, adds 30ml saturated sodium bicarbonate solution, is then extracted with ethyl acetate (2X50 milliliter), anhydrous sodium sulfate drying.Rotary Evaporators removes desolventizing and obtains product 3-trifluoromethyl-4-methyl-benzoic acid methyl compound a (productive rate: 96%).Exact Mass (calculated value): 218.06; MS (ESI) m/z (M+1)
+: 219.05.
The synthesis of 3-trifluoromethyl-4-brooethyl-methyl benzoate compound b
Respectively by 10mmol 3-trifluoromethyl-4-methyl-benzoic acid methyl compound a, 12mmol N-bromo-succinimide, 0.5mmol Diisopropyl azodicarboxylate adds round-bottomed flask, then adds 30 milliliters of tetracol phenixin.Reaction system stirring and refluxing is spent the night, Rotary Evaporators is except desolventizing, then 100 milliliters of saturated sodium bicarbonate solutions are added, then be extracted with ethyl acetate, merge organic phase and use anhydrous sodium sulfate drying, product 3-trifluoromethyl-4-brooethyl-methyl benzoate compound b (productive rate: 81%) that silica gel chromatographic column is separated.Exact Mass (calculated value): 295.97; MS (ESI) m/z (M+1)
+: 296.99.
The synthesis of 4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoro methyl benzoate compound c
8mmol 3-trifluoromethyl-4-brooethyl-methyl benzoate b, 10mmol 4-methylpiperazine and 15mmol salt of wormwood are added round-bottomed flask, then adds 20 milliliters of DMFs (DMF).Reaction system reacts 3 hours in stirring at room temperature.Rotary Evaporators is except desolventizing, and silica gel chromatographic column is separated to obtain product 4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoro methyl benzoate compound c (productive rate: 93%).Exact Mass (calculated value): 316.14; MS (ESI) m/z (M+1)
+: 317.16.
The synthesis of 4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoromethylbenzoic acid compound d
6mmol4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoro methyl benzoate compound c is dissolved in the mixing solutions of 20 milliliters of tetrahydrofuran (THF)s and water (1: 1), and adds 18mmol lithium hydroxide.Reaction system is spent the night in stirring at room temperature reaction, then with dilute hydrochloric acid, pH is adjusted to 7, use n-butanol extraction again, merge organic phase and use anhydrous sodium sulfate drying, Rotary Evaporators removes desolventizing and obtains product 4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoromethylbenzoic acid compound d (productive rate: 91%).Exact Mass (calculated value): 302.12; MS (ESI) m/z (M+1)
+: 303.15.
The synthesis of tertiary butyl 4-(2-methyl-5-nitro phenoxy group) piperidines-1-carbonate e
5mmol 2-methyl-5-nitro phenol, 6mmol 1-tertbutyloxycarbonyl-4-methanesulfonyloxy group piperidines and 10mmol Anhydrous potassium carbonate add in 15 milliliters of anhydrous DMFs (DMF) respectively successively.Reaction system is spent the night in 85 degrees Celsius of reactions, and be cooled to room temperature, reaction system is extracted with ethyl acetate, and merges organic phase and uses anhydrous sodium sulfate drying.Rotary Evaporators is except desolventizing, and thick product silica gel chromatographic column is separated to obtain product tertiary butyl 4-(2-methyl-5-nitro phenoxy group) piperidines-1-carbonate e (productive rate: 89%).Exact Mass (calculated value): 336.17; MS (ESI) m/z (M+Na)
+: 359.20.
The synthesis of tertiary butyl 4-(2-methyl-5-amino-benzene oxygen) piperidines-1-carbonate f
4mmol tertiary butyl 4-(2-methyl-5-nitro phenoxy group) piperidines-1-carbonate e is dissolved in 20 milliliters of ethyl acetate, then adds the Pd/C (10%) of 0.05 equivalent.System is reacted 5 hours under a normal atmosphere hydrogen environment.Reaction system diatomite filtration, collects filtrate also except desolventizing obtains product tertiary butyl 4-(2-methyl-5-amino-benzene oxygen) piperidines-1-carbonate f (productive rate: 96%).Exact Mass (calculated value): 306.19; MS (ESI) m/z (M+Na)
+: 329.23.
The synthesis of N-(4-methyl-3-(piperidines-4-oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide tri hydrochloride compound h
3mmol 4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoromethylbenzoic acid compound d and 3mmol tertiary butyl 4-(2-methyl-5-amino-benzene oxygen) piperidines-1-carboxylicesters f is dissolved in 6 milliliters of N, in dinethylformamide (DMF), 6mmol N is added successively under whipped state, 2-(7-azo the benzotriazole)-N of N-diisopropylethylamine (DIPEA) and 3.6mmol, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU).Reaction system reacts 2 hours in stirring at room temperature.Extraction into ethyl acetate reaction system, merge organic phase, anhydrous sodium sulfate drying, except desolventizing obtains 4-(2-methyl-5-(4-(4-methylpiperazine-1-yl) methyl)-(trifluoromethyl) benzamido) ritalin-1-carboxylic acid tert-butyl ester) the thick product of compound g, then add 4M hydrochloric ethyl acetate solution and in stirring at room temperature 3h, suction filtration obtains solid and washs by ethyl acetate, then dry product N-(4-methyl-3-(piperidines-4-oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide tri hydrochloride h (two step productive rates: 61%).Exact Mass (calculated value): 490.26; MS (ESI) m/z (M+H)
+: 491.27.
Take the synthetic method and the route that are similar to intermediate h; adopt different primary amine compounds and different carboxylic acid cpds can obtain various different condensation product through condensation reaction, condensation product through de-tertbutyloxycarbonyl protective reaction can obtain various amine intermediate (as shown in the formula).
Above amine intermediate and different acyl chlorides (synthetic method of reference compound 26) and different carboxylic acid (synthetic method of reference compound 68) or electrophilic reagent is adopted to be obtained by reacting various different target product.
The synthesis of 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds j
6-methyl-N1-(4-(3 replacements-pyridine) 2-substituted pyrimidines-) benzene-1, the 3-diamine compound i and 7mmol triethylamine (Et of 5mmol
3n) in 15mLN, dinethylformamide (DMF) is cooled to zero degrees celsius, under whipped state, add in batches 5.5mmol 4-(chloromethyl) Benzoyl chloride and under zero degrees celsius stirring reaction 1 hour.Reaction system is extracted with ethyl acetate, and merges organic phase and uses anhydrous sodium sulfate drying.Rotary Evaporators is except desolventizing, and residue over silica gel chromatographic column is separated to obtain product 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds j (productive rate: 93%).Exact Mass (calculated value): 429.14; MS (ESI) m/z (M+H)
+: 430.13.
The synthesis of 4-(methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds k
4mmol 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds j, 4.4mmol sodiumazide and 10 milliliters of N, dinethylformamide adds round-bottomed flask, and reaction system at room temperature stirring reaction is spent the night.Reaction system is extracted with ethyl acetate, and merges organic phase and directly adds Pd/C (5%), and react 6 hours at an atmospheric stirring under hydrogen.Reaction system diatomite filtration, collect organic phase and remove desolventizing, crude product purified by silica gel chromatographic column separation (methylene dichloride: methyl alcohol=10: 1) obtain product 4-(methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide (two step productive rates: 66%).Exact Mass (calculated value): 410.19; MS (ESI) m/z (M+H)+: MS:411.18.
Take the synthetic method route similar with compound k, following various amine intermediate can be obtained:
Using the amine intermediate of above formula and acyl chloride compound, acid compounds or other electrophilic group as reaction substrate, adopt the synthetic route method being similar to compound 26 and compound 68, various different target compound can be synthesized.
The synthesis of N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-4-(piperazine-1-ylmethyl) benzamide compounds 1
10mmol 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds j, DMF (DMF) 25mL, piperazine 30mmol is added successively in 100mL round-bottomed flask.Reaction system in stirred overnight at room temperature, chloroform extraction, anhydrous sodium sulfate drying.Rotary Evaporators is except desolventizing, residue over silica gel chromatographic column is separated to obtain product N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-4-(piperazine-1-ylmethyl) benzamide compounds 1 (productive rate: 86%), Exact Mass (calculated value): 479.24; MS (ESI) m/z (M+H)
+: MS:480.23.
The synthesis of 4-((4-(2-(2-(2-chloroethoxy) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds m
50mL round-bottomed flask adds 8mmol N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-4-(piperazine-1-ylmethyl) benzamide compounds 1,30mmol 1 successively, 2-two (2-chloroethoxy) ethane, 10mmol Anhydrous potassium carbonate and 20mLN, dinethylformamide (DMF).Reaction system is spent the night in 60 degrees Celsius of stirring reactions, extraction into ethyl acetate, anhydrous sodium sulfate drying.Rotary Evaporators is except desolventizing, residue over silica gel chromatographic column is separated to obtain product 4-((4-(2-(2-(2-chloroethoxy) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds m (productive rate: 72%), Exact Mass (calculated value): 629.29; MS (ESI) m/z (M+H)
+: MS:630.30.
The synthesis of 4-((4-(2-(2-(2-nitrine oxyethyl group) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds n
50mL round-bottomed flask adds 5mmol 4-((4-(2-(2-(2-chloroethoxy) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds m, 5mmol sodiumazide and 15mLN successively, dinethylformamide (DMF).Reaction system is spent the night in 70 degrees Celsius of stirring reactions, extraction into ethyl acetate, anhydrous sodium sulfate drying.Rotary Evaporators is except desolventizing, residue over silica gel chromatographic column is separated to obtain product 4-((4-(2-(2-(2-nitrine oxyethyl group) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds n (productive rate: 86%), Exact Mass (calculated value): 636.33; MS (ESI) m/z (M+H)
+: MS:637.32.
The synthesis of 4-((4-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds o
25mL round-bottomed flask adds Pd/C and the 15mL ethyl acetate of 4mmol 4-((4-(2-(2-(2-nitrine oxyethyl group) oxyethyl group) ethyl) piperazine-1-base-) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds n, 5%mmol successively.Reaction system is in an atmospheric hydrogen at room temperature stirring reaction 6h, diatomite filtration, filtrate removes desolventizing with Rotary Evaporators, residue over silica gel chromatographic column is separated to obtain product 4-((4-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds o (productive rate: 82%), Exact Mass (calculated value): 610.34; MS (ESI) m/z (M+H)
+: MS:611.35.
Table 1. structural formula of compound
Embodiment 1
The synthesis of (4-methyl-3-(N-(4 (pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-4-(propine acid amides methyl) benzamide compounds 1
Zero degrees celsius is down to 0.05mmol 4-(methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide k temperature of reaction, N-(4-methyl-3-(piperidines-4-oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) the benzamide tri hydrochloride h of 0.05mmol, 0.05mmol propynoic acid, 0.3mmol N, N-diisopropylethylamine (DIPEA) and 1 milliliter of N, dinethylformamide (DMF) adds the round-bottomed flask of 5 milliliters successively, 2-(7-azo the benzotriazole)-N of 0.06mmol is added under whipped state, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU).Reaction system reacts 2 hours in stirring at room temperature.Extraction into ethyl acetate reaction system, anhydrous sodium sulfate drying; Rotary Evaporators is except desolventizing, and thick product silica gel chromatographic column is separated to obtain product summary product Compound 1 (productive rate: 38%).Exact Mass (calculated value): 462.18; MS (ESI) m/z (M+1)
+: MS:463.19.
Embodiment 2
(E)-(4-(4-(dimethylamino)-2-acrylamide) methyl)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of benzamide compound 2
The synthesis of compound 2 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 521.25; MS (ESI) m/z (M+1)
+: 522.27.
Embodiment 3
(4-methyl-3-(N-(4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl))-4 (synthesis of-(vinylic sulfonamides methyl) benzamide compounds 3
0.05mmol 4-(methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide k adds 5 milliliters of round-bottomed flasks, then tetrahydrofuran (THF) (THF) 1 milliliter is added successively, triethylamine (Et
3n) 0.3mmol.Reaction system is cooled to zero degrees celsius, then add 0.08mmol vinylsulfonyl chloride and with stirring reaction under zero degrees celsius 1 hour.Rotary Evaporators is except desolventizing, and resistates is directly separated to obtain target product compound 3 (82%) with silica gel chromatographic column.Exact Mass (calculated value): 500.16; MS (ESI) m/z (M+1)
+: 501.17.
Embodiment 4
The synthesis of 3-(2-chloro acetylamino)-N-(4-methyl-3-((4-(3-pyridyl) pyrimidine-2-) is amino) phenyl)-5-(trifluoromethyl) benzamide compound 4
The synthesis of compound 4 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 540.12; MS (ESI) m/z (M+1)
+: 541.13.
Embodiment 5
3-(2-propiolyl amido)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of-5-(trifluoromethyl) benzamide compound 5
The synthesis of compound 5 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 516.15; MS (ESI) m/z (M+1)
+: 517.15.
Embodiment 6
3-(2-acrylamido)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of-5-(trifluoromethyl) benzamide compound 6
The synthesis of compound 6 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 518.17; MS (ESI) m/z (M+1)
+: 519.16.
Embodiment 7
3-(2-propionamido-)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of-5-(trifluoromethyl) benzamide compound 7
The synthesis of compound 7 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 518.17; MS (ESI) m/z (M+1)
+: 521.20.
Embodiment 8
The synthesis of N-(3-((1-Antiepilepsirin-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl) benzamide compounds 8
The synthesis of compound 8 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 476.28; MS (ESI) m/z (M+1)
+: 477.30.
Embodiment 9
The synthesis of N-(3-((1-chloracetyl piperidin-4-yl) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl) benzamide amine compound 9
The synthesis of compound 9 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 498.24; MS (ESI) m/z (M+1)
+: 499.25.
Embodiment 10
The synthesis of N-(4-((1-propiolyl piperidin-4-yl) oxygen base)-3-aminomethyl phenyl)-4-((4-methylpiperazine-1-yl) methyl) benzamide compounds 10
The synthesis of compound 10 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 474.26; MS (ESI) m/z (M+1)
+: 475.28.
Embodiment 11
The synthesis of (4-methyl-3-(N-(4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-4-propiolyl amido benzamide compounds 11
The synthesis of compound 11 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 448.16; MS (ESI) m/z (M+1)
+: 449.17.
Embodiment 12
The synthesis of (4-methyl-3-(N-(4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-3-propine acid amides methyl benzamide compounds 12
The synthesis of compound 12 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 462.18; MS (ESI) m/z (M+1)
+: 463.19.
Embodiment 13
The synthesis of (4-methyl-3-(N-(4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-3-chlor(o)acetamide methyl benzamide compounds 13
The synthesis of compound 13 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 486.16; MS (ESI) m/z (M+1)
+: 487.17.
Embodiment 14
The synthesis of N-(3-((1-acrylamide piperidines-3-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl) benzamide compounds 14
The synthesis of compound 14 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 476.28; MS (ESI) m/z (M+1)
+: 477.27.
Embodiment 15
3-(2-chloracetyl amido)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of benzamide compound 15
The synthesis of compound 15 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 472.14; MS (ESI) m/z (M+1)
+: 473.15.
Embodiment 16
3-(2-acrylamido)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of benzamide compound 16
The synthesis of compound 16 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 450.18; MS (ESI) m/z (M+1)
+: 451.19.
Embodiment 17
The synthesis of N-(3-((1-(ethanoyl chlorine) pyrrolidin-3-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl) benzamide compounds 17
The synthesis of compound 17 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 484.22; MS (ESI) m/z (M+1)
+: 485.23.
Embodiment 18
The synthesis of N-(3-((1-(acryl) pyrrolidin-3-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl) benzamide compounds 18
The synthesis of compound 18 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 462.2; MS (ESI) m/z (M+1)
+: 463.27.
Embodiment 19
The synthesis of N-(3-((1-(ethanoyl chlorine) piperidin-4-yl) oxygen base)-p-methylphenyl)-3-propionamido--5-(trifluoromethyl) benzamide compounds 19
The synthesis of compound 19 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 525.16; MS (ESI) m/z (M+1)
+: 526.17.
Embodiment 20
N-(3-((1-(2-chloracetyl) azepine butane-3-base) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of benzamide compounds 20
The synthesis of compound 20 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 470.21; MS (ESI) m/z (M+1)
+: 471.23.
Embodiment 21
N-(3-((1-(2-acryl) azepine butane-3-base) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of benzamide compounds 21
The synthesis of compound 21 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 448.25; MS (ESI) m/z (M+1)
+: 449.25.
Embodiment 22
The synthesis of 3-(4-methyl-1 H-imidazole-1-group)-N-(4-methyl-3-((1-nicotinoyl piperidin-4-yl) oxygen) phenyl)-5-(trifluoromethyl) benzamide compound 22
The synthesis of compound 22 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 563.21; MS (ESI) m/z (M+1)
+: 564.25.
Embodiment 23
3-(4-methylimidazole-1-base)-(4-methyl-3-(1-nicotinoyl piperidin-4-yl) oxygen) phenyl) synthesis of-5-(trifluoromethyl) benzamide compound 23
The synthesis of compound 23 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 512.20; MS (ESI) m/z (M+1)
+: 513.21.
Embodiment 24
3-(4-methylimidazole-1-base)-(4-methyl-3-(1-chloracetyl piperidin-4-yl) oxygen) phenyl) synthesis of-5-(trifluoromethyl) benzamide compound 24
The synthesis of compound 24 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 534.16; MS (ESI) m/z (M+1)
+: 535.18.
Embodiment 25
3-(4-methylimidazole-1-base)-(4-methyl-3-(1-propioloyl piperidin-4-yl) oxygen) phenyl) synthesis of-5-(trifluoromethyl) benzamide compound 25
The synthesis of compound 25 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 510.19; MS (ESI) m/z (M+1)
+: 511.20.
Embodiment 26
The synthesis of N-(3-((1-acrylic piperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 26
N-(4-methyl-3-(piperidines-4-oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) the benzamide tri hydrochloride compound h of 0.05mmol adds 5 milliliters of round-bottomed flasks, then tetrahydrofuran (THF) (THF) 1 milliliter is added successively, triethylamine (Et
3n) 0.3mmol.Reaction system is cooled to zero degrees celsius, then add 0.08mmol acrylate chloride and with stirring reaction under zero degrees celsius 1 hour.Rotary Evaporators is except desolventizing, and resistates is directly separated to obtain product compound 26 (productive rate: 86%) with silica gel chromatographic column.
1h NMR (400MHz, DMSO-d
6) δ (ppm) 10.35 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.92 (d, J=7.2Hz, 1H), 7.74 (s, 1H), 7.29 (d, J=8.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 6.84 (m, 1H), 6.13 (d, J=16.4Hz, 1H), 5.69 (d, J=10.4Hz, 1H), 4.56 (m, 1H), 3.75-3.53 (m, 6H), 2.44 (brs, 8H), 2.23 (S, 3H), 2.14 (S, 3H), 1.95 (brs, 2H), 1.68 (brs, 2H) .Exact Mass (calculated value): 544.27, MS (ESI) m/z (M+H)
+: 545.26.
Embodiment 27
The synthesis of N-(3-((1-chloracetyl piperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 27
The synthesis of compound 27 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 566.23; MS (ESI) m/z (M+1)
+: 567.24.
Embodiment 28
The synthesis of 4-((2-chlor(o)acetamide methyl)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) is amino) phenyl)-3-(trifluoromethyl) benzamide compound 28
The synthesis of compound 28 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 554.14; MS (ESI) m/z (M+1)
+: 555.16.
Embodiment 29
4-((4 (2-(2-(2-(2-((3R, 5R, 7R) 5-diamantane-1-base) kharophen) oxyethyl group) oxyethyl group) ethyl) piperazine-1-base) methyl) synthesis of-N-(4-methyl-(4-(3-pyridyl) pyrimidinyl-amino) phenyl) benzamide compounds 29
5mL round-bottomed flask adds 0.3mmol 1-adamantane acetic acid, 0.3mmol (4-(4-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-3-) methyl)-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) benzamide compounds o, 0.36mmol 2-(7-azo benzotriazole)-N successively, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), 0.45mmol N, N-diisopropylethylamine (DIPEA) and DMF (DMF) 15mL.Reaction system reacts 1h in stirring at room temperature, extraction into ethyl acetate, anhydrous sodium sulfate drying.Rotary Evaporators is except desolventizing, residue over silica gel chromatographic column is separated to obtain product 4-((4 (2-(2-(2-(2-((3R, 5R, 7R) 5-diamantane-1-base) kharophen) oxyethyl group) oxyethyl group) ethyl) piperazine-1-base) methyl)-N-(4-methyl-(4-(3-pyridyl) pyrimidinyl-amino) phenyl) benzamide (productive rate: 78%), Exact Mass (calculated value): 786.46; MS (ESI) m/z (M+1)
+: 787.49.
Embodiment 30
4-((N-(2-(dimethylamino) ethyl) acrylamido) methyl)-(4-methyl-3-(4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of benzamide compound 30
The synthesis of compound 30 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 535.27; MS (ESI) m/z (M+1)
+: 536.29.
Embodiment 31
N-(4-((1-(2-chloracetyl) piperidin-4-yl) amino)-5-methylpyrimidine base-2-base)-4-(4-methylpiperazine-1-yl) methyl) synthesis of benzamide compounds 31
The synthesis of compound 31 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 499.25; MS (ESI) m/z (M+1)
+: 500.30.
Embodiment 32
4-((4-6-(2-((1S, 3S)-diamantane-1-base) piperazine kharophen) hexyl)-1-base) methyl)-N-(4-methyl-3-((4-(3-pyridyl) pyrimidine-2-base) amino) phenyl) synthesis of benzamide compound 32
The synthesis of compound 32 is similar to the step described in embodiment 29 by use and completes.Exact Mass (calculated value): 754.47; MS (ESI) m/z (M+1)
+: 755.47.
Embodiment 33
The synthesis of N-(3-((1-acetylpiperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 33
The synthesis of compound 33 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 532.27; MS (ESI) m/z (M+1)
+: 533.29.
Embodiment 34
N-4-methyl-3-(N-(4-(pyridin-3-yl) pyrimidine-2-base) amino) phenyl) synthesis of-4-(propionic acid amide methyl) benzamide compounds 34
The synthesis of compound 34 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 466.55; MS (ESI) m/z (M+1)
+: 467.23.
Embodiment 35
The synthesis of N-(3-((1-(2-chlorine propionyl) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 35
The synthesis of compound 35 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 580.24; MS (ESI) m/z (M+1)
+: 581.26.
Embodiment 36
The synthesis of N-(the chloro-3-of 4-((1-(ethanoyl chlorine) piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 36
The synthesis of compound 36 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 586.17; MS (ESI) m/z (M+1)
+: 587.21.
Embodiment 37
The synthesis of N-(the chloro-3-of 4-((1-(acryl) piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 37
The synthesis of compound 37 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 564.21; MS (ESI) m/z (M+1)
+: 565.26.
Embodiment 38
The synthesis of N-(the chloro-3-of 4-((1-(propioloyl) piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 38
The synthesis of compound 38 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 562.20; MS (ESI) m/z (M+1)
+: 563.21.
Embodiment 39
The synthesis of N-(3-((1-propionyl piperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 39
The synthesis of compound 39 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 546.28; MS (ESI) m/z (M+1)
+: 547.30.
Embodiment 40
The synthesis of N-(3-((1-(ethanoyl chlorine) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-oil of mirbane amide compound 40
The synthesis of compound 40 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 543.22; MS (ESI) m/z (M+1)
+: 544.27.
Embodiment 41
The synthesis of N-(3-((1-(acryl) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-oil of mirbane amide compound 41
The synthesis of compound 41 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 521.26; MS (ESI) m/z (M+1)
+: 522.30.
Embodiment 42
N-(the chloro-3-of 4-(4-piperidines-oxygen base) phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of benzamide (3-trifluoromethyl) tri hydrochloride compound 42
The synthesis of compound 42 is similar to the step described in intermediate h synthesis by use and completes.Exact Mass (calculated value): 510.20; MS (ESI) m/z (M+1)
+: 511.22.
Embodiment 43
N-(4-methyl-3-(4-piperidines-oxygen base) phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of benzamide (3-trifluoromethyl) tri hydrochloride compound 43
The synthesis of compound 43 is similar to the step described in intermediate h synthesis by use and completes.Exact Mass (calculated value): 467.25; MS (ESI) m/z (M+1)
+: 468.31.
Embodiment 44
(1R, 3R, 5S, the synthesis of 7R)-3,5-dimethyl-N-(2-(2-(2-(2-(4-(4-((4-methyl-3-((4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl) carbamyl) benzene) piperazine-1-base-) oxyethyl group) oxyethyl group) oxyethyl group) ethyl) diamantane-1-benzamide compound 44
The synthesis of compound 32 is similar to the step described in embodiment 29 by use and completes.Exact Mass (calculated value): 844.50; MS (ESI) m/z (M+1)
+: 845.53.
Embodiment 45
4-((4-(1-((3R, 5R, 7R)-diamantane-1-base)-2-oxo-6,9,12-tri-oxygen base-3-mixes the tetradecane-14-base) piperazine-1-base) methyl)-(4-methyl-3-(4-(3-pyridin-2-yl-) pyrimidine-2-base) is amino) phenyl) synthesis of benzamide compound 45
The synthesis of compound 45 is similar to the step described in embodiment 29 by use and completes.Exact Mass (calculated value): 830.48; MS (ESI) m/z (M+i)
+: 831.50.
Embodiment 46
(E)-N-(3-(1-(4-(dimethylamino)-2-alkene acyl)-4-piperidyl) oxygen)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 46
The synthesis of compound 46 is similar to the step described in embodiment 1 by use and completes.Exact Mass (calculated value): 601.32; MS (ESI) m/z (M+1)
+: 602.32.
Embodiment 47
The synthesis of N-(3-((the positive butyryl piperidin-4-yl of 1-) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 47
The synthesis of compound 47 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 560.30; MS (ESI) m/z (M+1)
+: 561.32.
Embodiment 48
The synthesis of N-(3-((1-methacryloyl piperidin-4-yl) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 48
The synthesis of compound 48 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 558.28; MS (ESI) m/z (M+1)
+: 559.29.
Embodiment 49
The synthesis of N-(3-((1-pivaloyl group acyl piperidin-4-yl) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 49
The synthesis of compound 49 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 574.31; MS (ESI) m/z (M+I)
+: 575.32.
Embodiment 50
The synthesis of N-(3-((1-cyclopropyl acyl piperidin-4-yl) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 50
The synthesis of compound 50 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 558.28; MS (ESI) m/z (M+1)
+: 559.32.
Embodiment 51
The synthesis of N-(3-((1-isobutyryl piperidines 4-yl) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 51
The synthesis of compound 51 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 560.30; MS (ESI) m/z (M+1)
+: 561.33.
Embodiment 52
The synthesis of N-(3-((2-butylene acyl piperidin-4-yl) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 52
The synthesis of compound 52 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 558.28; MS (ESI) m/z (M+1)
+: 559.30.
Embodiment 53
The synthesis of N-(4-methoxyl group-3-((1-propionyl piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 53
The synthesis of compound 53 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 562.28; MS (ESI) m/z (M+1)
+: 563.29.
Embodiment 54
The synthesis of N-(4-methoxyl group-3-((the positive butyryl radicals piperidin-4-yl of 1-) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 54
The synthesis of compound 54 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 576.29; MS (ESI) m/z (M+1)
+: 577.31.
Embodiment 55
The synthesis of N-(4-methoxyl group-3-((1-acryloylpiperidine-4-base) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 55
The synthesis of compound 55 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 560.26; MS (ESI) m/z (M+1)
+: 561.29.
Embodiment 56
The synthesis of N-(3-((1-methacryloyl piperidin-4-yl) oxygen base)-4-p-methoxy-phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 56
The synthesis of compound 56 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 574.28; MS (ESI) m/z (M+1)
+: 575.30.
Embodiment 57
The synthesis of N-(3-((1-mesylpiperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 57
The synthesis of compound 57 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 568.23; MS (ESI) m/z (M+1)
+: 569.26.
Embodiment 58
The synthesis of N-(3-((1-ethylsulfonyl piperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 58
The synthesis of compound 58 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 582.25; MS (ESI) m/z (M+1)
+: 583.27.
Embodiment 59
The synthesis of N-(3-((1-positive fourth sulfonyl piperazinium base-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 59
The synthesis of compound 59 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 596.26; MS (ESI) m/z (M+1)
+: 597.28.
Embodiment 60
The synthesis of N-(3-((1-Cyclopropylsulfonyl piperazinyl-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 60
The synthesis of compound 60 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 594.25; MS (ESI) m/z (M+1)
+: 595.26.
Embodiment 61
The synthesis of N-(3-((1-benzoyl-piperazine base-4-base) oxygen base)-p-methylphenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 61
The synthesis of compound 61 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 594.28; MS (ESI) m/z (M+1)
+: 595-31.
Embodiment 62
The synthesis of N-(3-((1-(7H-purine-6-base) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 62
The synthesis of compound 62 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 608.28; MS (ESI) m/z (M+1)
+: 609.30.
Embodiment 63
N-(3-(1-(1H-pyrazolopyrimidine) (3-D-4-yl)-4-piperidyl) oxygen)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 63
The synthesis of compound 63 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 608.28; MS (ESI) m/z (M+1)
+: 609.31.
Embodiment 64
The synthesis of N-(4-methyl-3-(piperidines-4-oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide tri hydrochloride compound 64
The synthesis of compound 64 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 490.26; MS (ESI) m/z (M+1)
+: 491.27.
Embodiment 65
The synthesis of N-(4-methyl-3-((1-acryloylpiperidine-4-base) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl) benzamide compounds 65
The synthesis of compound 65 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 478.29; MS (ESI) m/z (M+1)
+: 479.31.
Embodiment 66
The synthesis of (4-methyl-3-(N-(4-(pyridin-3-yl) pyrimidine-2-base) is amino) phenyl)-3-(propionic acid amide methyl) benzamide compounds 66
The synthesis of compound 66 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 466.21; MS (ESI) m/z (M+1)
+: 467.24.
Embodiment 67
N-(4-methyl-(1-(2-carbonyl pyrimidine) 4-piperidyl) oxygen) phenyl)-(4-methylpiperazine base-1-base) methyl) synthesis of-benzamide (trifluoromethyl) compound 67
The synthesis of compound 67 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 596.27; MS (ESI) m/z (M+1)
+: 597.29.
Embodiment 68
The synthesis of N-(4-methyl-3-((1-nicotinic acid piperidyl-4-base) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 68
N-(4-methyl-3-(piperidines-4-oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide tri hydrochloride h, 0.05mmol nicotinic acid of 0.05mmol, 0.3mmol N, N-diisopropylethylamine (DIPEA) and 1 milliliter of N, dinethylformamide (DMF) adds the round-bottomed flask of 5 milliliters successively, 2-(7-azo the benzotriazole)-N of 0.06mmol is added under whipped state, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU).Reaction system reacts 2 hours in stirring at room temperature.Extraction into ethyl acetate reaction system, anhydrous sodium sulfate drying; Rotary Evaporators is except desolventizing, and thick product silica gel chromatographic column is separated to obtain product compound 68 (productive rate: 91%).
1hNMR (400MHz, DMSO-d
6) δ (ppm) 10.42 (s, 1H), 8.64 (s, 2H), 8.26-8.24 (m, 2H), 7.91-7.86 (m, 2H), 7.51-7.47 (m, 2H), 7.31 (d, J=7.6Hz, 1H), 7.13 (d, J=7.6Hz, 1H), 4.59 (m, 1H), 3.83-3.52 (m, 6H), 2.66 (brs, 8H), 2.37 (S, 3H), 2.15 (S, 3H), 1.98 (brs, 2H), 1.75 (brs, 2H) .Exact Mass (calculated value): 595.28; MS (ESI) m/z (M+H)
+: 595.28.
Embodiment 69
(4-methyl-3-(N-(1-(3; 3,3-trifluoropropyl acyl group) piperidin-4-yl) oxygen base) phenyl) synthesis of-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 69
The synthesis of compound 69 is similar to the step described in embodiment 26 by use and completes.Exact Mass (calculated value): 600.25; MS (ESI) m/z (M+1)
+: 601.28.
Embodiment 70
(S)-tertiary butyl (1-(4-(2-methyl-5-(4-(4-methylpiperazine base-1-base) methyl)-(trifluoromethyl) benzamido) benzene) piperidin-1-yl)-1-oxo-2-base) synthesis of carbamate compounds 70
The synthesis of compound 70 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 661.35; MS (ESI) m/z (M+1)
+: 662.38.
Embodiment 71
(S) synthesis of-tertiary butyl (3-(4-hydroxy phenyl)-1-(4-(2-methyl-5-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamido) phenoxy group) piperidin-1-yl)-1-oxo-2-base) carbamate compounds 71
The synthesis of compound 71 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 753.37; MS (ESI) m/z (M+1)
+: 754.40.
Embodiment 72
(S)-N-(3-((1-(2-aminopropionyl) piperidin-4-yl) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compounds 72
The synthesis of compound 72 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 561.29; MS (ESI) m/z (M+1)
+: 562.31.
Embodiment 73
(S)-N-(synthesis of 3-((1-(2-amino-3-(4-hydroxy phenyl) (piperidin-4-yl) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 73
The synthesis of compound 73 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 653.32; MS (ESI) m/z (M+1)
+: 654.36.
Embodiment 74
The synthesis of N-(4-methyl-3-((2-methyl isophthalic acid-propionyl piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 74
The synthesis of compound 74 is similar to the step described in embodiment 3 by use and completes.Exact Mass (calculated value): 560.30; MS (ESI) m/z (M+1)
+: 561.33.
Embodiment 75
The synthesis of N-(4-methyl-3-((2-methyl isophthalic acid-benzoyl piperidine-4-base) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 75
The synthesis of compound 75 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 608.30; MS (ESI) m/z (M+1)
+: 609.31.
Embodiment 76
N-(4-methyl-3-((2-methyl isophthalic acid-to methylbenzene acylpiperidine-4-base) oxygen base) phenyl) synthesis of-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 76
The synthesis of compound 76 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 608.30; MS (ESI) m/z (M+1)
+: 609.33.
Embodiment 77
The synthesis of N-(3-((1-(the fluoro-5-methyl benzoyl of 2-) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 77
The synthesis of compound 77 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 626.29; MS (ESI) m/z (M+1)
+: 627.30.
Embodiment 78
The synthesis of N-(3-((1-(3-TRIFLUOROMETHYLBENZOYL) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 78
The synthesis of compound 78 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 662.27; MS (ESI) m/z (M+1)
+: 663.29.
Embodiment 79
The synthesis of N-(3-((1-(benzenesulfonyl) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-oil of mirbane amide compound 79
The synthesis of compound 79 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 630.25; MS (ESI) m/z (M+1)
+: 631.28.
Embodiment 80
N-(3-(1-(2-furanylcarbonyl) 4-piperidyl) oxygen)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 80
The synthesis of compound 80 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 584.26; MS (ESI) m/z (M+1)
+: 585.28.
Embodiment 81
The synthesis of N-(4-methyl-3-((1-pyridine-2-formyl piperidine-4-base) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 81
The synthesis of compound 81 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 595.28; MS (ESI) m/z (M+1)
+: 596.30.
Embodiment 82
The synthesis of N-(4-methyl-3-((1-pyridine-4-formyl piperidine-4-base) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 82
The synthesis of compound 82 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 595.28; MS (ESI) m/z (M+1)
+: 596.31.
Embodiment 83
N-(4-methyl-(1-(3-carbonyl quinoline)-4-piperidyl) oxygen) phenyl)-(4-methylpiperazine-1-yl) methyl) synthesis of-benzamide (trifluoromethyl) compound 83
The synthesis of compound 83 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 645.29; MS (ESI) m/z (M+1)
+: 646.29.
Embodiment 84
N-(4-methyl-(1-(5-pyrimidine-carbonyl)-4-piperidyl) oxygen) phenyl)-(4-methylpiperazine-1-yl) methyl) synthesis of-benzamide (trifluoromethyl) compound 84
The synthesis of compound 84 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 596.27; MS (ESI) m/z (M+1)
+: 597.29.
Embodiment 85
N-(4-methyl-3-((1-(quinazoline-2-base) piperidin-4-yl) oxygen base) phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of benzamide (3-trifluoromethyl) compound 85
The synthesis of compound 85 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 646.29; MS (ESI) m/z (M+1)
+: 647.32.
Embodiment 86
The synthesis of N-(3-((1-(benzo [d] [1,3] dioxole-5-acyl group) piperidin-4-yl) oxygen base)-4-methyl) phenyl-(4-(4-methylpiperazine-1-yl) methyl) benzamide-3-(trifluoromethyl) compound 86
The synthesis of compound 86 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 638.27; MS (ESI) m/z (M+1)
+: 639.28.
Embodiment 87
N-(3-((1-(6-amino nicotinoyl) piperidin-4-yl) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compounds 87
The synthesis of compound 87 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 646.29; MS (ESI) m/z (M+1)
+: 647.32.
Embodiment 88
The synthesis of N-(3-((1-(2-aminopyrimidine-5-carboxyl) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 88
The synthesis of compound 88 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 610.29; MS (ESI) m/z (M+1)
+: 611.30.
Embodiment 89
(S)-N-(4-methyl-3-((1-(2-hydrocinnamoyl) piperidin-4-yl) oxygen base) phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compounds 89
The synthesis of compound 89 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 622.31; MS (ESI) m/z (M+1)
+: 623.32.
Embodiment 90
N-(3-(1-(6,7-dimethoxyquinazoline-4-base) 4-piperidyl) oxygen)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 90
The synthesis of compound 90 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 678.31; MS (ESI) m/z (M+1)
+: 679.32.
Embodiment 91
(R)-N-(3-((1-(2-methoxyl group-2-base) piperidin-4-yl) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compounds 91
The synthesis of compound 91 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 638.31; MS (ESI) m/z (M+1)
+: 639.32.
Embodiment 92
(S)-N-(3-((1-(2-methoxyl group-2-base) piperidin-4-yl) oxygen base)-4-aminomethyl phenyl)-4-(4-methylpiperazine-1-yl) methyl) synthesis of-3-(trifluoromethyl) benzamide compounds 92
The synthesis of compound 92 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 638.31; MS (ESI) m/z (M+1)
+: 639.34.
Embodiment 93
The synthesis of (4-methyl-3-(N-(1-(2-(pyridin-3-yl) kharophen) piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 93
The synthesis of compound 93 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 609.34; MS (ESI) m/z (M+1)
+: 610.32.
Embodiment 94
The synthesis of (4-methyl-3-(N-(1-(2-(pyridine-2-base) kharophen) piperidin-4-yl) oxygen base) phenyl)-4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 94
The synthesis of compound 94 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 609.34; MS (ESI) m/z (M+1)
+: 610.29.
Embodiment 95
N-(3-(1-(2-(dimethylamino) ethanoyl) 4-piperidyl) oxygen)-4-aminomethyl phenyl)-(4-methylpiperazine-1-yl) methyl) synthesis of-benzamide (trifluoromethyl) compound 95
The synthesis of compound 95 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 575.31; MS (ESI) m/z (M+1)
+: 576.32.
Embodiment 96
N-(4-methyl-(1-(1-4-formylation piperidines alkane and derivative thereof) 4-piperidyl) oxygen) phenyl)-(4-methylpiperazine-1-yl) methyl) synthesis of-benzamide (trifluoromethyl) compound 96
The synthesis of compound 96 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 615.34; MS (ESI) m/z (M+1)
+: 616.36.
Embodiment 97
The synthesis of N-(3-((1-(2-hydroxypropanoyl) piperidin-4-yl)-phenoxy group)-(4)-(4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) benzamide compounds 97
The synthesis of compound 97 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 562.28; MS (ESI) m/z (M+1)
+: 563.28.
Embodiment 98
(S)-(3-(1-propionyl piperidin-4-yl) oxygen)-4-aminomethyl phenyl)-4-(3-(dimethylamino) pyrrolidyl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 98
The synthesis of compound 98 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 558.28; MS (ESI) m/z (M+1)
+: 559.29.
Embodiment 99
(S)-(3-(1-nicotinoyl piperidin-4-yl) oxygen)-4-aminomethyl phenyl)-4-(3-(dimethylamino) pyrrolidyl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 99
The synthesis of compound 99 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 609.29; MS (ESI) m/z (M+1)
+: 610.30.
Embodiment 100
(R)-(3-(1-propionyl piperidin-4-yl) oxygen)-4-aminomethyl phenyl)-4-(3-(dimethylamino) pyrrolidyl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 100
The synthesis of compound 100 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 558.28; MS (ESI) m/z (M+1)
+: 559.29.
Embodiment 101
(R)-(3-(1-nicotinoyl piperidin-4-yl) oxygen)-4-aminomethyl phenyl)-4-(3-(dimethylamino) pyrrolidyl) methyl) synthesis of-3-(trifluoromethyl) benzamide compound 101
The synthesis of compound 101 is similar to the step described in embodiment 68 by use and completes.Exact Mass (calculated value): 609.29; MS (ESI) m/z (M+1)
+: 610.30.
Embodiment 102
azaindole kinase inhibitors is on the impact of growth of cancer cells
By test Azaindole kinase inhibitors on the impact of the propagation of cancer cells, we have evaluated the selectivity of done compound anticancer propagation further.In embodiment, we have selected blood cell K562 and mouse pro B lymphocyte BaF3, and above cell is all purchased from ATCC.Also select mouse TEL-cKit-BaF3 (stably express TEL-KIT activated protein kinase), this cell is built by this laboratory, construction process is: PCR is amplifying human KIT kinases region sequence respectively, and be inserted into the MSCV-Puro carrier (Clontech) holding TEL fragment with N, pass through retrovirus method, stablize and proceed to mouse BaF3 cell, and remove IL-3 somatomedin, finally obtain relying on the clone that KIT proceeds to albumen.
In an embodiment the compound of different concns (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1.11 μMs, 3.33 μMs, 10 μMs) is joined in above-mentioned cell respectively, and hatch 72 hours, (win purchased from shellfish with CCK8, China) cell viability detection kit, obtaining the stronger material of uv-absorbing by reducing to CCK8 to the reduction desaturase in viable cell, carrying out quantitative assay with microplate reader reading and detecting number of viable cells.
Table 2 is on the impact of cancer cell multiplication
Embodiment 103
azaindole kinase inhibitors is on the impact of cell-signaling pathways
At blood cell K562 (express Bcr-Abl chromosome translocation and merge carcinogenic protein) cell strain, TEL-cKit-BaF3 (stably express TEL-KIT activated protein kinase) cell strain and acute myeloid leukemia cells in children Kasumi-1 (expressing K IT N822K mutator gene, purchased from ATCC) on three strain cells, by measuring many cellular biochemistry terminals and functional terminal, have evaluated compound 26 to Bcr-Abl chromosome translocation fusion rotein in cell and the impact with this mutain other protein kinases closely-related Stat5, AKT, ErK, CrkL.With different concns 0 μM, the compound 26 of 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μMs, the imatinib (Imatinib) of 1 μM, and the Dasatinib of 0.1 μM (Dasatinib) processes blood cell K562 (express Bcr-Abl chromosome translocation and merge carcinogenic protein) cell strain, TEL-cKit-BaF3 (stably express TEL-KIT activated protein kinase) cell strain and acute myeloid leukemia cells in children Kasumi-1 (expressing K IT N822K mutator gene) three strain cells after 2 hours respectively, collection sample.Measure compound 26 to the impact (Fig. 1) of Bcr-AblY245, Stat5T694, AKT T308, AKT S473, Erk T202/204, KIT Y719, KIT Y703, KIT Y823 phosphorylation in this cell strain.
Experimental result is as shown in Figure 1: in blood cell K562 (express Bcr-Abl chromosome translocation and merge carcinogenic protein), compound 26 obviously can suppress the phosphorylation of Bcr-Abl carcinogenic protein (EC50 value is 161nM), and also has obvious restraining effect (EC50 value is 46nM) to the signaling pathway protein Stat5 phosphorylation of this proteins downstream.For with Bcr-Abl signal path associated protein AKT, ERK and CrkL tri-kinds of kinases, compound 26 also has to be affected to a certain extent.These all illustrate that compound 26 is the cell proliferation by suppressing the phosphorylation of carcinogenic protein Bcr-Abl to affect the chronic myelogenous leukemia cell cycling inhibiting carrying Bcr-Abl carcinogenic protein.On TEL-cKit-BaF3 (stably express TEL-KIT activated protein kinase) cell strain and acute myeloid leukaemia Kasumi-1 (expressing K IT N822K mutator gene) cell strain, by measuring many cellular biochemistry terminals and functional terminal, have evaluated compound 26 to c-kit kinases in cell and the impact with this mutain other protein kinase AKTs closely-related, ErK.Experimental result shows no matter at TEL-cKit-BaF3 (stably express TEL-KIT activated protein kinase) cell strain or on acute myeloid leukemia cells in children Kasumi-1 (expressing K IT N822K mutator gene) cell strain, compound 26 obviously can suppress the kinase whose phosphorylation of KIT, also has a significant effect to the phosphorylation of associated signal paths protein kinase AKT and ERK.This illustrates that compound 26 is the cell proliferation by suppressing the kinase whose phosphorylation of KIT to affect Tel-ckit-BaF3 and the acute myeloid leukemia cells in children strain Kasumi-1 carrying KIT carcinogenic protein.
Embodiment 104
azaindole kinase inhibitors is on apoptotic impact
In order to the death proving the later cell of medication is by apoptosis or necrosis, in the blood cell strain K562 carrying Bcr-Abl carcinogenic protein, have detected compound 26 and gather adenosine diphosphate (ADP)-ribose polymerase PARP, impact containing aspartic acid proteolytic ferment Caspase 3 protein cleavage of halfcystine to the closely-related DNA repair enzyme of apoptosis in cell.Blood cell K562 is processed, then respectively at 24 hours, 48 h before harvest cells with different concns 0 μM, the compound 26 of 0.1 μM, 0.3 μM, 1 μM, 3 μMs.The medicine detecting different concns with Western Blot gathers the impact of adenosine diphosphate (ADP)-ribose polymerase PARP and the shear protein containing the aspartic acid proteolytic ferment Caspase 3 of halfcystine in different time sections to DNA repair enzyme.
Experimental result is as shown in Figure 2: in blood cell K562 (express Bcr-Abl chromosome translocation and merge carcinogenic protein), act on after 24 hours and 48 hours, all can see the shearing having part DNA repair enzyme to gather adenosine diphosphate (ADP)-ribose polymerase PARP.This demonstrate that compound 26 can cause and express the apoptosis that Bcr-Abl chromosome translocation merges the blood cell K562 of carcinogenic protein.
Claims (10)
1. the compound of a formula (I) or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug:
Wherein Z1, Z2, Z3, Z4 and Z5 are independently selected from CH or N;
X is selected from
R1 be selected from H, halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino ,-NH-the heteroaryl optionally replaced by 1-3 R6 group and on the heteroatoms (preferred atom N) being selected from N, O and S optionally by-Y-(C3-C8) heterocyclic radical that R7 group replaces, wherein Y is selected from O, NH, S, (CH
2)
0-2, NH-(CO) and (CO)-NH;
R6 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, aryl and heteroaryl;
R7 is selected from-(CO)-(C1-C8) alkyl ,-(CO)-(C2-C8) thiazolinyl ,-(CO)-(C2-C8) alkynyl ,-(CO)-(C3-C8) cycloalkyl ,-(CO)-(C1-C8) haloalkyl ,-(CO)-(C1-C8) hydroxyalkyl ,-(CO)-(C1-C8) alkylamino ,-(CO)-(C1-C8) alkyl-N-[(C1-C8) alkyl]
2,-(CO)-vinyl-(CH
2)
n-N-[(C1-C8) alkyl]
2, optionally by 1-3 R8 group replace-(CO)-aryl, optionally by 1-3 R8 group replace-(CO)-heteroaryl, optionally by 1-3 R8 group replacement-(CO)-(C3-C8) heterocyclic radical ,-(CO)-(C1-C8) alkylaryl ,-(CO)-(C1-C8) miscellaneous alkyl aryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C3-C8) cycloalkyl, optionally by 1-3 R8 group replace-(SO
2)-aryl, the heteroaryl optionally replaced by 1-3 R8 group,
R8 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group and C1-C8 halogenated alkoxy;
R2 is selected from hydrogen, halogen, nitro, amino, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, aryl and heteroaryl;
R3 and R5 be selected from independently of one another hydrogen, C1-C8 alkyl, the aryl optionally replaced by 1-3 R9 group, optionally by the heteroaryl of 1-3 R9 group replacement, halogen, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 halogenated alkoxy ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) alkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(CO)-(C2-C8) alkynyl, fragrant oxygen base, nitro, amino and hydroxyl;
R9 is selected from C1-C8 alkyl, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C1-C8) cycloalkyl ,-(SO
2)-(C1-C8) aryl and-(SO
2)-(C1-C8) heteroaryl;
R4 be selected from hydrogen, C1-C8 alkyl, optionally by 1-3 R10 group replace-(CH2)
n-(C3-C8) heterocyclic radical ,-(CH
2)
n-NH-(CO)-(C1-C8) alkyl ,-(CH
2)
n-NH-(CO)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(CO)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(CO)-(C2-C8) alkynyl ,-(CH
2)
n-NH-(SO
2)-(C1-C8) alkyl ,-(CH
2)
n-NH-(SO
2)-(C1-C8) haloalkyl ,-(CH
2)
n-NH-(SO
2)-(C2-C8) thiazolinyl ,-(CH
2)
n-NH-(SO
2)-(C2-C8) alkynyl; With-(CH
2)
n-NH-(CO)-vinyl-(CH
2)
n-N-[(C1-C8) alkyl]
2;
R10 be selected from C1-C8 alkyl, by R11 replace-(C1-C20) alkyl, by R11 replace-[(CH
2)
2-O-]
m-(CH
2)
2-Ji, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO
2)-(C1-C8) alkyl ,-(SO
2)-(C1-C8) cycloalkyl ,-(SO
2)-(C1-C8) aryl ,-(SO
2)-(C1-C8) heteroaryl;
R11 is selected from C1-C8 alkyl ,-NH-(CO)-(CH)
n-adamantyl (any site of this adamantyl is optionally replaced by one or more C1-C8 alkyl) and-N-[(C1-C8) alkyl]
2;
Wherein n is the integer of 0-6 independently of one another, and m is the integer of 1-6.
2. compound as claimed in claim 1 or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, wherein Z1, Z2, Z3, Z4 and Z5 are CH.
3. compound as claimed in claim 1 or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, wherein Z
1and Z
2for N and Z3, Z4 and Z5 are CH.
4. compound as claimed in claim 1 or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, wherein said compound has following structural formula (II):
5. a pharmaceutical composition, it comprises compound according to any one of claim 1-4 or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, and pharmaceutically acceptable carrier or vehicle, and other optional therapeutical agent.
6. the compound according to any one of claim 1-4 or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug are for the preparation of suppression Tyrosylprotein kinase KIT (wild-type or various sudden change or its combination), ABL (wild-type or various sudden change or its combination), EGFR (wild-type or various sudden change or its combination), FLT3 (wild-type or various sudden change or its combination), BLK (wild-type or various sudden change or its combination), VEGFR (wild-type or various sudden change or its combination), RET (wild-type or various sudden change or its combination), PDGFR (wild-type or various sudden change or its combination), MEK (wild-type or various sudden change or its combination), BCR/ABL (wild-type or various sudden change or its combination), JAK (wild-type or various sudden change or its combination), purposes in the medicine that BRAF (wild-type or various sudden change or its combination) is active.
7. the compound according to any one of claim 1-4 or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug regulated by tyrosine kinase activity for the preparation for the treatment of, prevention or improve or affect by it or the disease, obstacle or the illness that wherein relate to tyrosine kinase activity experimenter medicine in purposes.
8. purposes as claimed in claim 7, wherein said disease, obstacle or illness are be selected from following proliferative disease: solid tumor, sarcoma, gastrointestinal stromal tumor, acute myeloblastic leukemia, chronic myelogenous leukemia, the influential leukemia of tool is suppressed to ABL (wild-type or various sudden change or its combination) and BCR/ABL (wild-type or various sudden change or its combination) tyrosine kinase activity, mesenchymoma, thyroid carcinoma, systemic mast cell disease, hypereosinophilia syndrome, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease (GVH disease), neurofibroma, pulmonary hypertension, alzheimer's disease, spermocytoma, argyraemia, dysgerminoma, mast cell tumor, lung cancer, bronchogenic carcinoma, dysgerminoma, testis intraepithelial neoplasia is formed, melanoma, breast cancer, neuroblastoma, corpora mammillaria/follicular thyroid carcinoma, malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine tumorigenesiss, pheochromocytoma, thyroid carcinoma, parathyroid hyperplasia/adenoma, colorectal carcinoma, colorectal adenomas, ovarian cancer, prostate cancer, glioblastoma, cerebral tumor, glioblastoma, carcinoma of the pancreas, malignant pleural mesothelioma, hemangioblastoma, vascular tumor, kidney, liver cancer, adrenal carcinoma, bladder cancer, cancer of the stomach, the rectum cancer, carcinoma of vagina, cervical cancer, carcinoma of endometrium, multiple myeloma, neck and head tumor, tumorigenesis and other Hypertrophic or proliferative disease, or its combination.
9. purposes as claimed in claim 8, wherein said disease, obstacle or illness are be selected from following proliferative disease: gastrointestinal stromal tumor, acute myeloblastic leukemia, chronic myelogenous leukemia, thyroid carcinoma or its combination.
10. purposes as claimed in claim 7, wherein said disease, obstacle or illness are be selected from following autoimmune disorder: sacroiliitis, rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel, psoriasis arthropathica, osteoarthritis, Still disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Graves disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, bronzed disease, depending on property eye battle array twin-the twin syndrome of flesh battle array, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter syndrome, aortic arch syndrome, temporal arteritis, warm type autoimmune hemolytic anemia, Wegner granulomatosis, psoriatic, alopecia universalis, behcet disease, confirmed fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia.
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