CN104876879A - Novel BCR-ABL kinase inhibitor - Google Patents

Novel BCR-ABL kinase inhibitor Download PDF

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CN104876879A
CN104876879A CN201510172534.7A CN201510172534A CN104876879A CN 104876879 A CN104876879 A CN 104876879A CN 201510172534 A CN201510172534 A CN 201510172534A CN 104876879 A CN104876879 A CN 104876879A
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bcr
compound
alkyl
abl kinase
amino
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CN104876879B (en
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刘静
刘青松
梁小飞
王蓓蕾
王傲莉
刘晓川
陈程
齐紫平
王文超
赵铮
王黎
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Hefei Institutes of Physical Science of CAS
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Hefei Institutes of Physical Science of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • 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
    • C07D401/02—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
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links

Abstract

The invention relates to a novel BCR-ABL kinase inhibitor which comprises a compound in a formula I or pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, wherein R1, R2, R3, R4, R5 and R6 are defined in the specification. The invention further relates to a pharmaceutical composition comprising the compound in the formula I and application of the compound provided by the invention in preparation of medicines for treating BCR-ABL kinase-activated and mediated diseases. The formula I is shown in the specification.

Description

A kind of novel BCR-ABL kinase inhibitor
Technical field
The application relate to a class as the inhibitor of BCR-ABL Tyrosylprotein kinase compound, comprise these compounds pharmaceutical composition and use these compounds and composition to be used for the treatment of the illness mediated by BCR-ABL kinase activation, particularly cancer and other the purposes of cell proliferation disorders and method.Be specifically related to one and be used for the treatment of chronic myelocytic leukemia (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid carcinoma or its BCR-ABL tyrosine kinase combined, and its purposes.
Background technology
The Tyrosylprotein kinase that BCR-ABL track fusion goes out can cause cell proliferation, stick and the change of character of surviving, and causes the generation of kinds of tumors.Such as, oncogene c-ABL on human body No. 9 karyomit(e)s is linked to the breakpoint Cu Ji district (BCR) on No. 22 karyomit(e), form p210BCR-ABL fusion gene and p185BCR-ABL fusion gene, these two kinds of fusion genes make corresponding BCR-ABL Tyrosylprotein kinase sustained activation, cause cell proliferation, stick and the change of character of surviving, cause respectively producing chronic myelocytic leukemia (CML) and acute myeloblastic leukemia (ALL).BCR-ABL Tyrosylprotein kinase is suppressed effectively to grow by Tumor suppression.
In the past in more than 20 year, researchist finds that BCR-ABL kinases plays a significant role at cell signalling with in transforming, and it impels the unlimited hyperplasia of the ripe granulocyte of CML by phosphorylation and a series of stream substrates of activation.BCR-ABL does not express in normal cell, so it is the drug targets that treatment CML is desirable.Early 1990s, researchist expects to suppress BCR-ABL fusion gene to play a role by RNA approach, but effectively could not treat CML.Along with illustrating of fusion gene structure and expression product, investigator diversion on the design and development of small-molecule drug that can directly act on BCR-ABL protein.
Treat this kind of disease before and mainly rely on monoclonal antibody drug, until after calendar year 2001, U.S. FDA have approved the BCR-ABL tyrosine kinase imatinib of first treatment CML, find micromolecular compound and suppress BCR-ABL Tyrosylprotein kinase to treat the focus that above-mentioned disease becomes people's concern gradually.Due to the appearance of imatinib-resistant, develop new BCR-ABL tyrosine kinase extremely urgent.At present, s-generation BCR-ABL tyrosine kinase is gone on the market, and key agents has Dasatinib and AMN107.Although Dasatinib and AMN107 demonstrate challenging first-stage success, some investigators report that they cause new sudden change by ABL kinases district after using.Ray etc. have identified 17 kinds of sudden changes in this kinases district, comprising the sudden changes (K247N, E282K, K285N, V289L, L273F, E292K, N297T, H375P, T406I, W430L and E431G) of 6 kinds of known imatinib-resistant sudden change (M244V, Y253H, F359C/V/I, G250E, E255K and T315I) and 11 kinds increases in addition.Due to the appearance of s-generation BCR-ABL tyrosine kinase resistance, the BCR-ABL tyrosine kinase developing renewal is necessary.
Summary of the invention
The present invention relates to a kind of BCR-ABL kinase inhibitor, it comprises compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula I:
Wherein:
R 1be selected from C1-C8 alkylamino, C1-C8 alkyl sulphonyl, optionally by 1 or 2 R independently 7the arylamino replaced, optionally by 1 or 2 R independently 7the aryloxy replaced, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of Heterocyclylalkyl oxygen bases, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of heterocyclalkylamino and 5 yuan or 6 yuan of Heterocyclylalkyl-(C1-C8 alkylaminos);
R 2be selected from hydroxyl, amino, sulfydryl, cyano group, halogen, C1-C8 alkylamino and C1-C8 alkoxyl group etc.;
R 3be selected from C1-C8 alkyl;
R 4, R 5and R 6be selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 alkylamino and aryl etc. independently of one another, or adjacent R 4, R 5and R 6in any two form heterocyclic radical together;
R 7independently selected from amino, nitro, hydroxyl, halogen, sulfydryl, cyano group, amino-sulfonyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, C1-C8 alkoxyl group, C1-C8 alkyl sulphonyl, C1-C8 alkyl sulphinyl, C2-C8 alkylamidoalkyl and C2-C8 alkenyl amide base etc.; And
R 8be selected from C1-C8 alkyl-carbonyl, C1-C8 halogenated alkyl carbonyl, C2-C8 alkenyl carbonyl, C2-C8 alkynylcarbonyl groups and amino protecting group.
In one embodiment, R 1be selected from C1-C4 alkylamino, C1-C4 alkyl sulphonyl, optionally by 1 or 2 R independently 7(preferably 3 and/or 4 are optionally by 1 or 2 R independently for the phenyl amino that replaces 7the phenyl amino replaced), optionally by 1 or 2 R independently 7(preferably 4 optionally by R for the phenoxy group replaced 7the phenoxy group replaced), heteroatoms is optionally by R 85 yuan that replace or 6 yuan of azacycloalkyl oxygen bases, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of azacycloalkyl amino and 5 yuan or 6 yuan of Heterocyclylalkyl-(C1-C4 alkylaminos).
In one embodiment, R 2be selected from hydroxyl, amino, C1-C4 alkylamino and C1-C4 alkoxyl group.
In one embodiment, R 3be selected from C1-C4 alkyl, and R 3be preferably placed at 4 or 6 of phenyl ring, particularly 6.
In one embodiment, R 4, R 5and R 6be selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyl group and phenyl independently of one another, or adjacent R 4, R 5and R 6in any two form heterocyclic radical together, particularly dioxa cyclopentenyl, and R 4, R 5and R 6be preferably placed at 2,3,4 or 5 of phenyl ring.
In one embodiment, R 7independently selected from amino, nitro, amino-sulfonyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino, C1-C4 alkyl sulphonyl, C1-C4 alkyl sulphinyl, C2-C4 alkylamidoalkyl and C2-C4 alkenyl amide base.
In one embodiment, R 8be selected from C1-C4 alkyl-carbonyl, C1-C4 halogenated alkyl carbonyl, C2-C4 alkenyl carbonyl, C2-C4 alkynylcarbonyl groups and amino protecting group, such as tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), 9-fluorenylmethyloxycarbonyl (F-moc), benzyl (Bn) and p-methoxyphenyl (PMP).
On the other hand, the application provides a kind of pharmaceutical composition, it comprises at least one compound provided herein or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug for the treatment of significant quantity, and pharmaceutically acceptable carrier or vehicle, and other optional therapeutical agent.
On the other hand, the application relates to the method for suppressing BCR-ABL tyrosine kinase activity, comprises and uses formula I or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug, or comprise the pharmaceutical composition of formula I.
In another, the present invention relates to formula I or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or prodrug or comprise the purposes of pharmaceutical composition in the medicine of the disease kinase mediated by BCR-ABL for the preparation for the treatment of of formula I.Described disease selected from chronic granulocyte leukemia (CML), acute myeloblastic leukemia (ALL), gastrointestinal stromal tumor (GIST), thyroid carcinoma or its combination etc.
Accompanying drawing explanation
Fig. 1 illustrates the impact of compound 11 on Ku812 (a), MEG-01 (b), K562 (c) cell-signaling pathways.
Fig. 2 illustrates that compound 11 is on the apoptotic impact of MEG-01 (a), K562 (b).
Fig. 3 illustrates the plates of cells Colony forming experimental result of compound 11 couples of MEG-01 (a), K562 (b), Ku812 (c) cell strain.
Fig. 4 illustrates the cell counting experimental result of compound 11 couples of MEG-01 (a), Ku812 (b), K562 (c) cell strain.
Fig. 5 illustrates the impact of compound 11 on the cell cycle distribution of Ku812 (a), MEG-01 (b), K562 (c) cell strain.
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 branched-chain or straight-chain alkyl.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 (preferred 1-6) carbon atom.Typical alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.Term " C1-C8 " refers to that carbonatoms is 1-8, namely the carbonatoms being selected from C1, C2, C3, C4, C5, C6, C7 and C8 or the subrange formed arbitrarily is comprised, such as C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C3-C6, C3-C8, C4-C8, C4-C6, C6-C8 etc.Term " C2-C8 " refers to that the scope of carbonatoms is 2-8, namely the carbonatoms being selected from C2, C3, C4, C5, C6, C7 and C8 or the subrange formed arbitrarily is comprised, such as C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C3-C6, C3-C8, C4-C8, C4-C6, C6-C8 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.
" alkylsulfonyl " refer to sulfonic acid lose hydroxyl after functional group, specifically refer to-S (=O) 2-." sulfinyl " refer to-S (=O)-." alkyl sulphonyl " refers to alkyl-S (=O) 2-, " alkyl sulphinyl " refer to alkyl-S (=O)-, " amino-sulfonyl " refers to NH 2-S (=O) 2-.
" 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.
Term " amide group " is the functional group generated after carboxylic acid and ammonia condensation, and be expressed as-CO-NH-, such as formamido-refers to CH 3-CO-NH-.
Term " alkyl-carbonyl " refers to further by the carbonyl of an alkyl replacement.
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) " or " arylalkyl " or " aralkyl " refer 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 3-10 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) " or " cycloalkylalkyl " refer 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 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, epimino, 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 " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " haloalkyl ", comprise alkyl, 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 " 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, sulfydryl, amino-sulfonyl, alkylamino, alkyl sulphonyl, alkyl sulphinyl, alkylamidoalkyl, alkenyl amide base, alkyl-carbonyl, alkenyl carbonyl, alkynylcarbonyl groups, amino protecting group etc.
Term " amino protecting group " includes, but are not limited to tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), 9-fluorenylmethyloxycarbonyl (F-moc), benzyl (Bn) and p-methoxyphenyl (PMP) etc.
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 PharmacologicalBasis 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.
GI used herein 50be the drug level needed for phalangeal cell 50% growth-inhibiting, namely medicine makes the growth of 50% cancer cells be inhibited or control, drug level now.
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.
bCR-ABL kinase inhibitor of the present invention
The present invention relates to a kind of BCR-ABL kinase inhibitor, it comprises compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula I:
Wherein:
R 1be selected from C1-C8 alkylamino, preferred C1-C4 alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino; C1-C8 alkyl sulphonyl, preferred C1-C4 alkyl sulphonyl, such as methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, fourth alkylsulfonyl; Optionally by 1 or 2 R independently 7the arylamino replaced, such as 3 and/or 4 are by R independently 7the phenyl amino replaced, naphthyl-amino, phenanthryl are amino; Optionally by 1 or 2 R independently 7the aryloxy replaced, such as 4 by R 7the phenoxy group, naphthyloxy, the luxuriant and rich with fragrance oxygen base that replace; Heteroatoms is optionally by R 85 yuan or 6 yuan of Heterocyclylalkyl oxygen bases replacing, wherein Heterocyclylalkyl oxygen base is preferably azacycloalkyl oxygen base, such as pyrrolidyl oxygen base, piperidyl oxygen base, imidazolidyl oxygen base; Heteroatoms is optionally by R 85 yuan or 6 yuan of heterocyclalkylamino replacing, in base, heterocyclalkylamino is preferably azacycloalkyl amino, such as piperidyl amino, pyrrolidyl is amino, imidazolidyl is amino; With 5 yuan or 6 yuan of Heterocyclylalkyl-(C1-C8 alkylaminos), such as 3-morphoinopropyl is amino, wherein Heterocyclylalkyl is such as morpholinyl, piperidyl, pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro thiapyran base or THP trtrahydropyranyl, C1-C8 alkylamino is preferably C1-C4 alkylamino, such as, be methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino;
R 2be selected from hydroxyl; Sulfydryl; Cyano group; Halogen; Amino; C1-C8 alkylamino, is preferably C1-C4 alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino; With C1-C8 alkoxyl group, be preferably C1-C4 alkoxyl group, such as methoxyl group, oxyethyl group, propoxy-, n-butoxy, isobutoxy, tert.-butoxy;
R 3be selected from C1-C8 alkyl, be preferably C1-C4 alkyl, such as methyl, ethyl, propyl group, normal-butyl, isobutyl-, the tertiary butyl, and R 3be preferably placed at 4 or 6 of phenyl ring, particularly 6;
R 4, R 5and R 6be selected from hydrogen independently of one another; C1-C8 alkyl, is preferably C1-C4 alkyl, such as methyl, ethyl, propyl group, normal-butyl, isobutyl-, the tertiary butyl; C1-C8 haloalkyl, is preferably C1-C4 haloalkyl, such as a methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trifluoroethyl, a bromotrifluoromethane, two chloropropyls, trifluoro propyl, three brombutyls; C1-C8 alkoxyl group, is preferably C1-C4 alkoxyl group, such as methoxyl group, oxyethyl group, propoxy-, n-butoxy, isobutoxy, tert.-butoxy; C1-C8 alkylamino, is preferably C1-C4 alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino; And aryl, such as phenyl, naphthyl, phenanthryl, anthryl etc., or adjacent R 4, R 5and R 6in any two form heterocyclic radical together, such as dioxa cyclopentenyl, and R 4, R 5and R 6be preferably placed at 2,3,4 or 5 of phenyl ring;
R 7independently selected from amino; Nitro; Hydroxyl; Halogen; Sulfydryl; Cyano group; Amino-sulfonyl; C1-C8 alkyl, is preferably C1-C4 alkyl, such as methyl, ethyl, propyl group, normal-butyl, isobutyl-, the tertiary butyl; C1-C8 haloalkyl, is preferably C1-C4 haloalkyl, such as a methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trifluoroethyl, a bromotrifluoromethane, two chloropropyls, trifluoro propyl, three brombutyls; C1-C8 alkylamino, is preferably C1-C4 alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino; C1-C8 alkoxyl group, is preferably C1-C4 alkoxyl group, such as methoxyl group, oxyethyl group, propoxy-, n-butoxy, isobutoxy, tert.-butoxy; C1-C8 alkyl sulphonyl, is preferably C1-C4 alkyl sulphonyl, such as methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, fourth alkylsulfonyl; C1-C8 alkyl sulphinyl, preferred C1-C4 alkyl sulphinyl, such as methylsulfinyl, ethylsulfinyl, propylsulfenyl, butylsulfinyl; C2-C8 alkylamidoalkyl, is preferably C2-C4 alkylamidoalkyl, such as acetamido, propionamido-, amide-based small; With C2-C8 alkenyl amide base, be preferably C2-C4 alkenyl amide base, such as ethernamine base, acrylamido, crotonoyl amido etc.;
R 8be selected from C1-C8 alkyl-carbonyl, be preferably C1-C4 alkyl-carbonyl, such as ethylcarbonyl group, propyl group carbonyl, butyl carbonyl; C1-C8 halogenated alkyl carbonyl, be preferably C1-C4 halogenated alkyl carbonyl, such as chloromethyl carbonyl, a fluoromethylcarbonyl, difluoromethyl-carbonyl, Trifluoromethylcarbonyl, dichloromethyl carbonyl, trifluoroethyl carbonyl, monobromo ethylcarbonyl group, dichloro propyl group carbonyl, trifluoro propyl carbonyl, three brombutyl carbonyls; C2-C8 alkenyl carbonyl, is preferably C2-C4 alkenyl carbonyl, such as vinyl carbonyl, propenyl carbonyl, butenyl carbonyl; C2-C8 alkynylcarbonyl groups, is preferably C2-C4 alkynylcarbonyl groups, such as ethynyl carbonyl, proyl carbonyl, butynyl carbonyl; And amino protecting group, such as tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), 9-fluorenylmethyloxycarbonyl (F-moc), benzyl (Bn) and p-methoxyphenyl (PMP).
Compound containing chirality involved in the present invention, its configuration can be the racemic modification of arbitrary configuration or mixing.
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 are 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) base addition 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, UV-Vis and NMR (liquid and solid state).Various microscopy includes but not limited to IR microscopy and Raman (Raman) microscopy.
medical composition and its use of the present invention
The application provides preparation for the pharmaceutical composition by suitable approach and mode administration, this pharmaceutical composition comprises one or more compounds provided herein or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of effective concentration, and pharmaceutically acceptable carrier or vehicle, and other therapeutical agent that person is optional.
The formula I of free form or salt form is also called " material of the present invention " hereinafter; because they are to the kinase whose restraining effect of BCR-ABL; the formula I of free form or pharmaceutical acceptable salt can be used for treatment and (comprises normal activity by the kinase whose activation of BCR-ABL; especially overactivity) disease, obstacle or the illness that mediate, such as proliferative disease, cancer, inflammatory diseases or anaphylactic disease, obstructive respiratory disease and/or with transplant relevant illness.
" treatment " of the present invention can be curative (as symptomatic treatment) and/or preventative.
Be preferred for the purposes for the treatment of proliferative disease, described proliferative disease is selected from optimum or malignant tumour, include but not limited to: chronic myelocytic leukemia (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid carcinoma, solid tumor, sarcoma, 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, cancer of the stomach, the rectum cancer, multiple myeloma, tumorigenesis and other Hypertrophic or proliferative disease, or its combination.
Material of the present invention can be used for treatment inflammatory or obstructive airway diseases, causes such as tissue injury, airway inflammation, segmental bronchus overreact, reinvents or the alleviating of disease progression.The inflammatory that the present invention is suitable for or obstructive airway diseases comprise the asthma of any type or cause, the asthma of bringing out after comprising endogenous (anallergic) asthma and exogenous (allergy) asthma, mild asthma, moderate bronchial asthma, severe asthma, bronchitic asthma, the asthma of exercise induced, occupational asthma and bacteriological infection.The treatment of asthma will also be understood that to be comprise the treatment to individuality, such as be less than the individuality of 4 or 5 years old, it demonstrates wheezing symptoms, to be diagnosed as or diagnosable for " wheezy infants (wheezy infant) ", this is the patient class during a kind of fixed Major medical is paid close attention to, and is usually accredited as now initial stage or early stage asthma.For convenience, this special asthma is called as " wheezy-infant syndrome ".
Prevention effects in treating asthma by the alleviating of the minimizing alleviating such as acute asthma or bronchoconstrictor attack frequency of the minimizing or severity that show as paresthesia epilepsy frequency or severity, pulmonary function improves or air flue over-activity improves.Described effect also shows as the minimizing to other symptom treatment demand, other described symptom treatment namely for or be intended at it, limit occur or stop the treatment of paresthesia epilepsy, such as antiphlogiston (such as reflunomide) or bronchodilator.May be obvious especially to the prevention benefit of asthma in the individuality having " morning falls (morning dipping) " to be inclined to." morning falls " is a kind of generally acknowledged Asthma Syndrome, usually in asthma, accounts for significant proportion, it is characterized in that such as showing effect between about 4 to 6 in the morning, that is, any time far away for the treatment of symptoms of asthma outbreak of usually using before distance.
Other inflammatory that the present invention is suitable for or obstructive airway diseases and illness comprise acute lung injury (ALI), adult type/adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, air flue or lung disease (COPD, COAD or COLD), comprise chronic bronchitis or expiratory dyspnea relevant with it, pulmonary emphysema, and treated the air flue over-activity deterioration caused by other medicines treatment, particularly other Sucked medicine.The present invention is also suitable for the bronchitis for the treatment of any type or cause, comprises such as acute bronchitis, arachidic bronchitis, catarrhal bronchitis, fibrinous bronchitis, chronic bronchitis or phthinoid bronchitis.The pneumoconiosis that other inflammatory that the present invention is suitable for or obstructive airway diseases comprise any type or cause (a kind of inflammatory, is generally professional tuberculosis, no matter be chronic or acute frequent with obstruction of the air passage, and cause by repeating to suck dust), comprise such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, iron and sink lung, silicosis, tabacism and byssinosis.
Material of the present invention is also used for the treatment of by the kinase mediated following disease of BCR-ABL, obstacle or illness: respiratory system disease, transformation reactions, rheumatoid arthritis, osteoarthritis, wind-wetness syndrome, psoriatic, ulcerative colitis, regional ileitis, septic shock, proliferative disorders, atherosclerosis, allograft rejection reaction after transplanting, diabetes, apoplexy, obesity or restenosis, leukemia, 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, 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.
Material of the present invention also can be used for treating the illness relevant to eosinophilic granulocyte, such as eosinophilia, particularly relevant to eosinophilic granulocyte airways disorders (such as relating to the lung tissue that ill eosinophilic granulocyte infiltrates), comprise oxyphie too much, because it affects air flue and/or lung, and such as by loeffler syndrome, eosinophilic pneumonia, parasite (particularly metazoan) is infected (comprising tropical eosinophilia), bronchopneumonic aspergillosis, polyarteritis nodosa (comprising Qiu-Si syndrome), that eosinophilic granuloma causes or to its airways disorders relevant with eosinophilic granulocyte walked abreast mutually, with the illness relevant to eosinophilic granulocyte affecting air flue that drug reaction causes.
Material of the present invention also can be used for treating the inflammatory of skin or allergic conditions, the inflammatory of such as psoriatic, contact dermatitis, atopic dermatitis, alopecia circumscripta, erythema multiforme, dermatitis herpetiformis, scleroderma, hickie, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus (pemphisus), acquired epidermolysis bullosa and other skin or allergic conditions.
Material of the present invention also can be used for treatment Other diseases or illness, particularly has disease or the illness of inflammatory components, such as, treats disease and the illness of eye, as conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, affect the disease of nose, comprise rhinallergosis, and wherein relate to autoimmune response or there is autoimmunization sexual element or etiologic etiological inflammatory diseases, comprise autoimmune hematological illness (such as hemolytic anemia, aplastic anemia, pure red cell anaemia and essential thrombocytopenia reduce), systemic lupus erythematous, polychondritis, scleroderma, Wegner granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Si-Yue syndrome, idiopathic sprue, autoimmune inflammatory enteropathy (such as ulcerative colitis and regional ileitis), endocrine ophthalmopathy, Graves disease, sarcoidosis, pulmonary alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior uveitis and rear uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with without nephrotic syndrome, such as comprise idiopathic nephrotic syndrome or MCN).
Other can comprise septic shock by the disease of Substance treatment of the present invention or illness, rheumatoid arthritis, osteoarthritis, proliferative disease is as cancer, atherosclerosis, allograft rejection reaction after transplanting, apoplexy, obesity, restenosis, diabetes are type i diabetes (juvenile onset diabetes) and type ii diabetes such as, diarrhea disease, local asphyxia/reperfusion injury, retinopathy is as the retinopathy of diabetic retinopathy or induced by hyperbaric oxygen, and to raise with intraocular pressure or aqueous humor secretion for the illness of feature, as glaucoma.
The validity of material of the present invention in suppression inflammatory conditions such as airway inflammatory disease can be proven in animal model, the mouse of such as airway inflammation or other inflammatory conditions or rat model, such as Szarka etc., J. Immunol.Methods (1997) 202:49-57; Renzi etc., Am.Rev.Respir.Dis. (1993) 148:932-939; Tsuyuki etc., J.Clin.Invest. (1995) 96:2924-2931; Described in Cernadas etc., Am.J.Respir.Cell Mol.Biol. (1999) 20:1-8.
Material of the present invention also can be used as coupling therapeutical agent for using with other medicines combinations of substances, as antiphlogiston, bronchodilator or antihistamine drug substances, especially for treatment obstructive or airway inflammatory disease, as mentioned above those, such as, as the synergistic agent of these pharmacological agent activity or the means as dosage needed for these medicines of minimizing or potential side effect.Material of the present invention can mix in fixed drug composition with other medicines material, or can before other medicines material is used, simultaneously or use separately afterwards.The present invention includes the combination of the drug substances such as material of the present invention mentioned above and antiphlogiston, bronchodilator or antihistaminic, described material of the present invention and described drug substance can in identical or different pharmaceutical compositions.Such antiphlogiston comprises class and admittedly hinders, particularly glucocorticosteroid is as budesonide, beclometasone, Fluticasone Propionate, ciclesonide or furancarboxylic acid dish meter Ta Song and WO0200679, WO 0288167, WO 0212266 and the compound described in WO 02100879, those as described in US5451700 of LTB4 antagonist, LTD4 antagonist is as Singulair and Zafirlukast, dopamine-receptor stimulant is as Cabergoline, bromocriptine, a tired sharp Lip river and 4-hydroxyl-7-[2-[[2-[[3-(2-phenyl ethoxy)-propyl group]-alkylsulfonyl]-ethyl]-amino] ethyl] (hydrochloride is for-2 (3H)-benzothiazolones and pharmacologically acceptable salt thereof ), and PDE4 inhibitor as (GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arofylline (AlmirallProdesfarma), PD189659 (Parke-Davis), AWD-12-281 (AstaMedica), those described in CDC-801 (Celgene) and KW-4490 (Kyowa Hakko Kogyo) and WO 98/18796 and WO 03/39544.Such bronchodilator comprises anticholinergic or antimuscarinic drug, particularly Ipratropium Bromured, Oxitropium Bromide and tiotropium salt, also have WO 01/04118, WO 02/51841, WO 02/53564, WO03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, US 5171744, those described in US 3714357 and WO 03/33495, and beta-2-adrenoceptor agonist is as salbutamol, terbutaline, Salmeterol and formoterol and pharmacologically acceptable salt thereof, announce formula I in WO 00/75114 (document being incorporated herein by reference) (free form or salt form or solvate form thereof) with pct international patent, the antihistamine drug substances of the compound coupling treatment of preferred embodiment comprises cetrizine hcl, Paracetamol, clemastine fumarate, promethazine, Loratadine, Desloratadine (desloratidine), diphenhydramine and hydrochloric acid Fexofenadine.The combination of material of the present invention and steroid, β-2 agonist, PDE4 inhibitor or LTD4 antagonist can be used for such as treating COPD or particularly asthma.The combination of material of the present invention and anticholinergic or antimuscarinic drug, PDE4 inhibitor, dopamine-receptor stimulant or LTB4 antagonist can be used for such as treating asthma or particularly COPD.Other useful combination of material of the present invention and antiphlogiston is and chemokine receptor anagonists such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, the particularly combination of the antagonist of CCR-5, described antagonist is Schering-Plough antagonist SC-351125 such as, SCH-55700 and SCH-D, Takeda antagonist is as N-[[4-[[[6, 7-dihydro-2-(4-aminomethyl phenyl)-5H-benzo ring heptene-8-base] hydroxyl] amino] phenyl]-methyl] tetrahydrochysene-N, N-dimethyl-2H-pyrans-4-ammonium chloride (TAK-770), with US6166037 (particularly claim 18 and 19), WO 00/66558 (particularly claim 8) and the CCR-5 antagonist described in WO 00/66559 (particularly claim 9).
Material of the present invention can be used by any suitable approach, such as Orally administered, as Orally administered in the form of a tablet or capsule; Parenteral such as intravenously is used; Use by sucking, such as, in the treatment of inflammatory or obstructive airway diseases; Intranasal administration, such as, in the treatment of rhinallergosis; To topical application, such as, in the treatment of atopic dermatitis; Or rectal administration, such as, in the treatment of inflammatory bowel.
Present invention also offers pharmaceutical composition, it comprises the formula I of free form or pharmaceutical acceptable salt, optionally and suitable pharmaceutically useful diluent or carrier.Said composition can contain coupling therapeutical agent, antiphlogiston as described above, bronchodilator or antihistaminic.Such composition can use technology preparation known in conventional thinner or vehicle and galenic art.Therefore, oral dosage form can comprise Tablet and Capsula agent.
Preparation for topical application can adopt the form of ointment, ointment, gelifying agent or transdermal delivery system such as patch.Composition for sucking can comprise aerosol or other aerosolizable preparation or dry powder formulations.
When composition comprises aerosol formulation, its preferably containing such as hydrogen-fluoro-alkane (HFA) propellent as HFA134a or HFA227 or these mixture, can containing one or more solubility promoters known in the art as ethanol (by weight at the most 20%), and/or one or more tensio-active agents are as oleic acid or sorbitan three olease, and/or one or more weighting agents are as lactose.When composition comprises dry powder doses, it is preferably containing such as having the formula I being no more than 10 micron grain sizes, optionally and have the diluent or carrier of required size distribution as lactose, and contributes to the compound that prevents product property to be deteriorated because making moist.When composition comprises spray agent, it is preferably containing such as dissolving or suspendible formula I in media as well, and described medium contains water, solubility promoter as ethanol or propylene glycol and stablizer, and it can be tensio-active agent.
Difference according to such as treated concrete illness, desired effect and method of application changes by the dosage of material of the present invention used in the embodiment of this invention.Usually, Orally administered suitable dose is 0.1 to 10mg/kg rank.
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 BCR-ABL kinase inhibitor compounds described herein.In some embodiments, compound described herein can use following synthetic schemes 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 table 1.
The structure of table 1. embodiment compound
Use synthetic method described herein, and methods known in the art, obtain compound 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.
embodiment 1
the synthesis of the compounds of this invention
4-(methylamino-)-2-(methylthio group) pyrimidine-5-ethyl formate (2): add tetrahydrofuran THF (10 milliliters) add the chloro-2-of 4-(methylthio group) pyrimidinecarboxylic acid ethyl ester (1.0 grams) in round-bottomed flask after, methylamine hydrochloride (0.58 gram).Then triethylamine TEA (2.1 milliliters) is added.Reaction system at room temperature, argon shield reacts 14 hours.After reaction terminates, system is solvent evaporated under reduced pressure, is extracted with ethyl acetate after gains dilute with water.Organic phase is with using anhydrous sodium sulfate drying with after water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 228.07.
4-(methylamino-)-2-(methylthio group) pyrimidine-5-formic acid (3): add methyl alcohol (20 milliliters) add 4-(methylamino-)-2-(methylthio group) pyrimidine-5-ethyl formate (1.0 grams) in round-bottomed flask after, 1 mole of often liter of sodium hydroxide solution (5 milliliters).Reaction system at room temperature, argon shield reacts 14 hours.After reaction terminates, system is solvent evaporated under reduced pressure, and after gains water (50 milliliters) dilution, the hydrochloric acid soln of dropping 6 moles often liter causes pH is 3 ~ 4.The white precipitate generated in system after filtration, obtains crude product after washing, drying, MS (ESI) m/z (M+H) +: 200.04.
3-(trifluoromethyl) Benzoyl chloride (5): add anhydrous methylene chloride (10 milliliters) add 3-(trifluoromethyl) phenylformic acid (1.0 grams) in round-bottomed flask after, makes system be cooled to 0 degree with ice-water bath after ethoxalyl chlorine (2 milliliters).Then 1 DMF is added.Reaction system at room temperature, argon shield reacts 10 hours.After reaction terminates, system under reduced pressure after solvent evaporated crude product.
N-(4-methyl-3-nitro phenyl)-3-(trifluoromethyl) benzamide (6): make system be cooled to 0 degree with ice-water bath after adding anhydrous tetrahydro furan (10 milliliters), triethylamine (4 milliliters) add 4-methyl-3-nitro aniline (1.52 grams) in round-bottomed flask after.Then 3-(trifluoromethyl) Benzoyl chloride (2.08 grams) is slowly added.Reaction system at room temperature, argon shield reacts 2 hours.After reaction terminates, system is solvent evaporated under reduced pressure, is extracted with ethyl acetate after gains dilute with water.Organic phase is with using anhydrous sodium sulfate drying with after water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 325.05.
N-(3-amino-4-aminomethyl phenyl)-3-(trifluoromethyl) benzamide (7): add methyl alcohol (10 milliliters), 10%Pd/C (0.3 gram) add N-(4-methyl-3-nitro phenyl)-3-(trifluoromethyl) benzamide (3.25 grams) in round-bottomed flask after.Then reaction system stirs 2 hours under hydrogen.After reaction terminates, system after filtration, after washing after evaporated under reduced pressure crude product, MS (ESI) m/z (M+H) +: 295.1.05.
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino)-2-(methylthio group) pyrimidine-5-methane amide (8): add N add N-(3-amino-4-aminomethyl phenyl)-3-(trifluoromethyl) benzamide (2.95 grams) in round-bottomed flask after, dinethylformamide (10 milliliters), then adds HATU (3.80 grams), DIPEA (1.29 grams) and 4-(methylamino-)-2-(methylthio group) pyrimidine-5-formic acid (2.00 grams).Reaction system at room temperature, argon shield reacts 12 hours.After reaction terminates, system is solvent evaporated under reduced pressure, is extracted with ethyl acetate after gains dilute with water.Organic phase is with using anhydrous sodium sulfate drying with after water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 476.12.
N-(2-methyl-5-(3-(trifluoromethyl) benzamide)-4-(methylamino-2-(methylsulphonic acid base) pyrimidine-5-methane amide (compound 9): add methylene dichloride (10 milliliters) add N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino)-2-(methylthio group) pyrimidine-5-methane amide (0.47 gram) in round-bottomed flask after, then add mCPBA (0.40 gram).Reaction system at room temperature, argon shield reacts 2 hours.After reaction terminates, system diluted ethyl acetate.Organic phase is with using anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 508.11.
2-(4-methyl-3-nitro aniline)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide)-4-(methylamino-) pyrimidine-5-methane amide (compound 10): add N-and (add anhydrous 1 after 2-methyl-5-(3-(trifluoromethyl) benzamide)-4-(methylamino-2-(methylsulphonic acid base) pyrimidine-5-methane amide) (0.51 gram) in round-bottomed flask, 4-dioxane (2 milliliters), then adds 4-methyl-3-nitro aniline (1.52 grams), trifluoroacetic acid (0.57 gram).Reaction system 120 degree, argon shield reacts 2 hours.After reaction terminates, system diluted ethyl acetate.Organic phase is with using anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure.Crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 580.18.
2-(3-amino-4-methylphenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide)-4-(methylamino) pyrimidine-5-methane amide (compound 11): (2-methyl-5-(3-(trifluoromethyl) benzamide)-4-(methylamino-) pyrimidine-5-methane amide (0.58 gram) adds methyl alcohol (10 milliliters) to add 2-(4-methyl-3-nitro aniline)-N-in round-bottomed flask.Then the sub-tin (2.25 grams) of dichloride is added.Reaction system 100 degree, argon shield reacts 5 hours.After reaction terminates, the system sodium hydroxide of 10 moles often liter easily regulates pH to be ~ 10.System after filtration, considers cake with the ethanol/methylene washing of 1: 1.Consider liquid and obtain crude product after evaporated under reduced pressure, crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 550.21.
2-(3-allyl amide-4-methylphenylamino)-N-(2-methyl-5-(3-trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide (compound 12): in round-bottomed flask, adding 2-(3-amino-4-methylphenylamino)-N-, (2-methyl-5-(3-(trifluoromethyl) benzamide)-4-(methylamino) pyrimidine-5-methane amide (0.055 gram) adds tetrahydrofuran (THF) (1 milliliter).Then acrylate chloride (0.009 gram) is added, DIPEA DIPEA (0.029 gram).Reaction system under 0 degree, argon shield reacts 2 hours.After reaction terminates, system diluted ethyl acetate.Organic phase is with using anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 604.22.
Embodiment 2
Tertiary butyl 2-methyl-5-nitrophenyl acid amides (15): add 2-methyl-5-nitro aniline (10.0 grams), tetrahydrofuran (THF) (50 milliliters), (Boc) in round-bottomed flask 2o (20.0 grams) and DMAP DMAP (0.3 gram).Reaction system under 0 degree, argon shield reacts 1 hour, then reaction system refluxes 12 hours.After reaction terminates, system diluted ethyl acetate.Organic phase uses anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Organic phase obtains crude product after separating-purifying.MS(ESI)m/z(M+H) +：253.01。
Tertiary butyl 5-amino-2-methyl phenyl amide (16): add 15 (10.0 grams), methyl alcohol (50 milliliters) and 10%Pd/C (1 gram) in round-bottomed flask.System stirring reaction 2 hours under hydrogen.Through filtering after reaction terminates, after washing, solvent evaporated obtains crude product MS (ESI) m/z (M+H) +: 223.11.
Tertiary butyl 4-methyl-3-(4-(methylamino-)-2-(methylthio group) pyrimidine-5-benzoic acid amides) phenyl amide (17): add N add 3 (1.99 grams) in round-bottomed flask after, dinethylformamide (20 milliliters), then 2-(7-azo benzotriazole)-N is added, N, N ', N '-tetramethyl-urea phosphofluoric acid ester HATU (3.80 grams), DIPEA DIPEA (1.29 grams) and 16 (2.23 grams).Reaction system at room temperature, argon shield reacts 12 hours.After reaction terminates, system is solvent evaporated under reduced pressure, is extracted with ethyl acetate after gains dilute with water.Organic phase uses anhydrous sodium sulfate drying with after water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 404.12.
N-(5-amino-2-tolyl)-4-(methylamine)-2-(methylthio group) pyrimidine-5-methane amide (18): add ethyl acetate (50 milliliters) add 17 (10 grams) in round-bottomed flask after, then adds the ethyl acetate (30 milliliters) of 4M hydrochloric acid.Reaction system at room temperature, argon shield reacts 12 hours.After reaction terminates, system is solvent evaporated under reduced pressure, obtains crude product, MS (ESI) m/z (M+H) after evaporated under reduced pressure +: 304.12.
N-(5-(3-anisole acid amides)-2-tolyl)-4-(methylamino-)-2-(methylthio group) pyrimidine-5-methane amide (19): make system be cooled to 0 degree with ice-water bath after adding anhydrous tetrahydro furan (5 milliliters), triethylamine (4 milliliters) add 18 (0.304 grams) in round-bottomed flask after.Then 3-(trifluoromethyl) Benzoyl chloride is slowly added.Reaction system at room temperature, argon shield reacts 2 hours.After reaction terminates, system is solvent evaporated under reduced pressure, is extracted with ethyl acetate after gains dilute with water.Organic phase is with using anhydrous sodium sulfate drying with after water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 438.15.
N-(5-(3-methoxy benzamide)-2-tolyl)-4-(methylamino-)-2-(methyl sulfone) pyrimidine-5-methane amide (compound 20): add methylene dichloride (10 milliliters) add 19 (0.47 grams) in round-bottomed flask after, then add mCPBA (0.40 gram).Reaction system at room temperature, argon shield reacts 2 hours.After reaction terminates, system diluted ethyl acetate.Organic phase uses anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure, MS (ESI) m/z (M+H) +: 470.11.
N-(5-(3-methoxy benzamide)-2-tolyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide (compound 21): add anhydrous 1 add 20 (0.51 grams) in round-bottomed flask after, 4-dioxane (2 milliliters), then adds 4-methyl-3-nitro aniline (1.52 grams), trifluoroacetic acid (0.57 gram).Reaction system 120 degree, argon shield reacts 2 hours.After reaction terminates, system diluted ethyl acetate.Organic phase uses anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Organic phase after filtration, obtains crude product after evaporated under reduced pressure.Crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 542.10.
2-(3-amino-4-monomethylaniline)-N-(5-(3-methoxy benzamide)-2-toluene)-4-(methylamino) pyrimidine-5-methane amide (compound 22): add 21 (0.58 grams) and methyl alcohol (10 milliliters) in round-bottomed flask.Then the sub-tin (2.25 grams) of dichloride is added.Reaction system 100 degree, argon shield reacts 5 hours.After reaction terminates, the system sodium hydroxide solution of 10 moles often liter regulates pH to be ~ 10.System after filtration, with the ethanol/methylene washing leaching cake of 1: 1.Filtrate obtains crude product after evaporated under reduced pressure, and crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 512.21.
2-(3-acrylamide-4-toluino)-N-(5-(3-methoxy benzamide base)-2-tolyl)-4-(methylamino-) pyrimidine-5-methane amide (compound 23): add 22 (0.055 grams) and tetrahydrofuran (THF) (1 milliliter) in round-bottomed flask.Then acrylate chloride (0.009 gram) is added, DIPEA DIPEA (0.029 gram).Reaction system under 0 degree, argon shield reacts 2 hours.After reaction terminates, system diluted ethyl acetate.Organic phase uses anhydrous sodium sulfate drying with after saturated sodium carbonate, water, saturated common salt water washing respectively.Crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 566.22.
Embodiment 3
(S) tertiary butyl 3-(5-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenylcarbamoyl)-(methylamino-) pyrimidine-2-oxygen base) pyrroles-1-carboxylic acid (compound 32): add 9 (0.58 grams), tetrahydrofuran THF (10 milliliters), (S)-tertiary butyl 3-hydroxypyrrole-1-carboxylic acid (2 grams) in round-bottomed flask, then add salt of wormwood (2.25 grams).Reaction system 100 degree, argon shield reacts 5 hours.After filtration, with the ethanol/methylene washing leaching cake of 1: 1, filtrate obtains crude product to system after evaporated under reduced pressure, and crude product obtains sterling after pressurized silica gel column chromatography is purified, MS (ESI) m/z (M+H) +: 615.20.
(S)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-)-2-(pyrroles-3-oxygen base) phonetic-5-methane amide (compound 33): add ethyl acetate (1 milliliter) add 33 (0.05 grams) in round-bottomed flask after, then add the ethyl acetate (1 milliliter) of 4M hydrochloric acid.Reaction system at room temperature, argon shield reacts 12 hours.After reaction terminates, system is solvent evaporated under reduced pressure, obtains crude product, MS (ESI) m/z (M+H) after evaporated under reduced pressure +: 515.14.
Embodiment 4
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl-2,4-bis-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 24 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：459。
Embodiment 5
2-(3,4-xylidine)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 25 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：549.22。
Embodiment 6
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-)-2-(p-monomethylaniline) pyrimidine-5-methane amide
The synthesis of compound 26 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：535.19。
Embodiment 7
N-(4-methyl-3-(3-(trifluoromethyl) benzamide) phenyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 27 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：580.18。
Embodiment 8
2-(4-methyl-3-(trifluoromethyl) phenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 28 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：602.19。
Embodiment 9
2-(4-nitrophenols)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 29 is similar to the step described in embodiment 3 by use and completes.MS(ESI)m/z(M+1) +：567.16。
Embodiment 10
2-(PAP)-N-(2-methyl 5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 30 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：537.19。
Embodiment 11
2-(4-acrylamide phenol)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 31 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：590.20。
Embodiment 12
N-(2-methyl 5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-)-2-(3-morpholine propylamine) pyrimidine-5-methane amide
The synthesis of compound 34 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：571.25。
Embodiment 13
Tertiary butyl 4-(5-(2-methyl-5-(3-(trifluoromethyl) benzamide) benzyl carbamyl)-4-(methylamino-) pyrimidine-2-is amino) piperidines-1-carboxylic acid
The synthesis of compound 35 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：627.27。
Embodiment 14
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-)-2-(piperidines-4-is amino) pyrimidine-5-base acid amides
The synthesis of compound 36 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：527.22。
Embodiment 15
2-(1-(2-chloracetyl) piperidines-4-is amino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 37 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：。604.19
Embodiment 16
2-(1-acrylamide piperidines-4-is amino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 38 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：582.26。
Embodiment 17
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-)-2-(1-propionic acid amide piperidines-4-is amino) pyrimidine-5-methane amide
The synthesis of compound 39 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：584.26。
Embodiment 18
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl-4-(methylamino-)-2-(1-propine acid amides piperidines-4-is amino) pyrimidine-5-methane amide
The synthesis of compound 40 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：579.22。
Embodiment 19
N-(5-biphenyl-3-methane amide-2-tolyl)-4-(methylamino-)-2-methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 41 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：516.16。
Embodiment 20
N-(5-(3,5-dimethylamino benzophenone acid amides)-2-tolyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 42 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：468.16。
Embodiment 21
N-(5-(3,5-t-butylbenzamide)-2-tolyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 43 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：552.25。
Embodiment 22
N-(2-methyl-5-(3-methyl benzamide) phenyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 44 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：454.14。
Embodiment 23
N-(5-(3-(dichloromethyl) benzamide)-2-tolyl-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 45 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：522.16。
Embodiment 24
N-(5-biphenyl-3-methane amide-2-tolyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 46 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：588.21。
Embodiment 25
N-(5-(3,5-dimethyl benzamide)-2-tolyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 47 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：540.22。
Embodiment 26
N-(5-(3,5-t-butylbenzamide)-2-tolyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 48 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：624.10。
Embodiment 27
2-(4-methyl-3-nitro aniline)-N-(2-methyl-5-(3-methyl benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 49 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：525.21。
Embodiment 28
N-(5-(3-(dichloromethyl benzamide)-2-tolyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 50 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：594.13。
Embodiment 29
2-(3-amino-4-methyl benzamide)-N-(5-biphenyl-3-methane amide-2-tolyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 51 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：578.25。
Embodiment 30
2-(3-amino-4-toluino)-N-(5-(3,5-dimethyl benzamide)-2-methylamino-)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 52 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：510.26。
Embodiment 31
2-(3-amino-4-toluino)-N-(5-(3,5-t-butylbenzamide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 53 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：594.34。
Embodiment 32
2-(3-amino-4-methylphenylamino)-N-(2-methyl-5-(this acid amides of 3-methyl) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 54 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：496.23。
Embodiment 33
2-(4-methyl-3-(methylsulfonyl) aniline-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 55 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：613.17。
Embodiment 34
Tertiary butyl 4-(5-(2-methyl-5-(3-(trifluoromethyl) this base acid amides) benzyl carbamyl amine)-4-(methylamino-) pyrimidine-2-oxygen base) piperidines-1-acid
The synthesis of compound 56 is similar to the step described in embodiment 3 by use and completes.MS(ESI)m/z(M+1) +：629.16。
Embodiment 35
N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-)-2-(piperidines-4-oxygen base) pyrimidine-5-methane amide
The synthesis of compound 57 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：528.21。
Embodiment 36
2-(1-acrylamide piperidines-4-oxygen base)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 58 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：583.22。
Embodiment 37
N-(2-methyl-5-(3-(trifluoromethyl) benzoyl) phenyl)-4-(methylamino-)-2-(1-propionic acid amide piperidines-4-oxygen base) pyrimidine-5-methane amide
The synthesis of compound 59 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：585.23。
Embodiment 38
2-(4-methyl-3-(methylamino-) aniline)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 60 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：564.22。
Embodiment 39
2-(3-(dimethylamino)-4-methylphenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 61 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：578.24。
Embodiment 40
2-(4-methyl-3-(methylsulfonyl) phenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 62 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：597.18。
Embodiment 41
2-(4-methyl-3-sulfonamide phenyl is amino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 63 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：614.30。
Embodiment 42
4-methoxyl group-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 64 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：509.10。
Embodiment 43
4-hydroxyl-2-(4-methyl-3-nitro phenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl) pyrimidine-5-methane amide
The synthesis of compound 65 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：567.15。
Embodiment 44
2-(3-amino-4-methylphenylamino)-4-hydroxy-n-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl) pyrimidine-5-methane amide
The synthesis of compound 66 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：537.17。
Embodiment 45
4-(dimethylin)-N-(2-methyl 5-(3-(trifluoromethyl) benzamide) phenyl)-2-(Toluidrin) pyrimidine-5-methane amide
The synthesis of compound 67 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：522.13。
Embodiment 46
4-(dimethylamino)-2-(4-methyl-3-nitro phenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl) pyrimidine-5-methane amide
The synthesis of compound 68 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：594.19。
Embodiment 47
2-(3-amino-4-methylphenylamino)-4-(dimethylin)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl) pyrimidine-5-carboxamide hydrochloride
The synthesis of compound 69 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：564.22。
Embodiment 48
2-(4-methyl-3-propionamido-phenylamino)-N-(2-methyl-5-(3-(trifluoromethyl) benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 70 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：606.23。
Embodiment 49
N-(5-(3-methoxy benzamide)-2-aminomethyl phenyl)-2-(4-methyl-3-propionamido-phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 71 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：568.25。
Embodiment 50
N-(5-(4-methoxy benzamide)-2-methylamino)-2-(4-methyl-3-nitro phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 72 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：542.20。
Embodiment 51
2-(3-amino-4-methylphenylamino)-N-(5-(4-methoxy benzamide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 73 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：512.23。
Embodiment 52
N-(5-(4-methoxy benzamide)-2-aminomethyl phenyl)-2-(4-methyl-3-propionic acid phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 74 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：568.25。
Embodiment 53
2-(3-acrylamide-4-methylphenylamino)-N-(5-(4-methoxy benzamide)-2-methylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 75 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：566.24。
Embodiment 54
2-(3-nitro-4-methyl phenylamino)-N-(5-(3,5-dimethoxybenzarnide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 76 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：572.21。
Embodiment 55
2-(3-amino-4-methylphenylamino)-N-(5-(3,5-dimethoxybenzarnide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 77 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：542.14。
Embodiment 56
N-(5-(3,5-dimethoxybenzarnide)-2-aminomethyl phenyl)-2-(4-methyl-3-propionic acid amide phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 78 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：598.27。
Embodiment 57
2-(3-acrylamide-4-methylphenylamino)-N-(5-(3,5-dimethoxybenzarnide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 79 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：596.25。
Embodiment 58
N-(5-(3,4-dimethoxybenzarnide)-2-aminomethyl phenyl)-2-(4-methyl-3-nitro aniline)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 80 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：572.21。
Embodiment 59
2-(3-amino-4-methylphenylamino)-N-(5-(the basic formyl of 3,4-dimethoxy)-2-aminomethyl phenyl-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 81 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：542.24。
Embodiment 60
N-(5-(3,4-dimethoxybenzarnide)-2-aminomethyl phenyl)-2-(4-methyl-3-propionic acid phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 82 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：598.27。
Embodiment 61
2-(3-acrylamide-4-methylphenylamino)-N-(5-(3,4-dimethoxybenzarnide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 83 is similar to the step described in embodiment 2 by use and completes.MS(ESI)m/z(M+1) +：596.25。
Embodiment 62
2-(4-methyl-3-nitro aniline)-N-(2-methyl-5-(the basic formyl of 3,4,5-trimethoxy) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 84 is similar to the step described in embodiment 2 by use and completes.MS(ESI)m/z(M+1) +：602.22。
Embodiment 63
2-(3-amino-4-methylphenylamino)-N-(2-methyl-5-(3,4,5-trimethoxy-benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 85 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：572.25。
Embodiment 64
2-(4-methyl-3-propionic acid phenylamino)-N-(2-methyl-5-(3,4,5-trimethoxy-benzamide) phenyl)-4-(methylamine) pyrimidine-5-methane amide
The synthesis of compound 86 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：628.28。
Embodiment 65
2-(3-acrylamide-4-methylphenylamino)-N-(2-methyl-5-(3,4,5-trimethoxy-benzamide) phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 87 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：626.26。
Embodiment 66
2-(3-amino-4-methylphenylamino)-N-(5-(benzo [d] [1,3] dioxy ring-5-methane amide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 88 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：526.21。
Embodiment 67
N-(5-(benzo [d] [1,3] dioxy ring-5-methane amide)-2-aminomethyl phenyl)-2-(4-methyl-3-propionic acid phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 89 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：582.23。
Embodiment 68
2-(3-acrylamide-4-methylphenylamino)-N-(5-(benzo [d] [1,3] dioxy ring-5-methane amide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 90 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：580.22。
Embodiment 69
N-(5-(2-methoxy benzamide)-2-aminomethyl phenyl)-2-(4-methyl-3-nitro phenylamino)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 91 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：542.10。
Embodiment 70
2-(3-amino-4-methylphenylamino)-N-(5-(2-methoxy benzamide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 92 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：512.23。
Embodiment 71
N-(5-(2-methoxy benzamide)-2-aminomethyl phenyl)-2-(4-methyl-3-propionic acid phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 93 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：568.25。
Embodiment 72
2-(3-acrylamide-4-methylphenylamino)-N-(5-(2-methoxy benzamide)-2-aminomethyl phenyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 94 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：566.24。
Embodiment 73
N-(5-(4-methoxy benzamide)-2-aminomethyl phenyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 95 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：470.14。
Embodiment 74
N-(5-(2-methoxy benzamide)-2-aminomethyl phenyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 96 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：470.14。
Embodiment 75
N-(5-(3,5-trimethoxy-benzamide)-2-aminomethyl phenyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 97 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：500.15。
Embodiment 76
N-(2-methyl-5-(3,4,5-trimethoxy-benzamide) phenyl)-4-(methylamino-)-2-(methylsulfonyl) pyrimidine-5-methane amide
The synthesis of compound 98 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：530.16。
Embodiment 77
N-(5-(benzo [d] [1,3] dioxy ring-5-methane amide)-2-aminomethyl phenyl)-4-(methylamino-)-2-(methylsulfonyl)-4-(methylamino-) pyrimidine-5-methane amide
The synthesis of compound 99 is similar to the step described in embodiment 1 by use and completes.MS(ESI)m/z(M+1) +：484.12。
Embodiment 78
bCR-ABL kinase inhibitor increases the impact of nitre to cancer cells
By test b CR-ABL kinase inhibitor on the impact of cancer cell multiplication, we have evaluated compound 9, compound 10, compound 11, compound 67, compound 68, compound 69 and contrast medicine BCR-ABL kinase inhibitor Imatinib further, (Imatinib and Nilotinib is all purchased from Hao Yuan Chemexpress company for Nilotinib, Shanghai) impact on the growth of cancer cells, we also have evaluated the selectivity of compound 9, compound 10, compound 11, compound 67, compound 68, compound 69 anticancer propagation further.In embodiment, we have selected CHL cells CHL, Chinese hamster ovary cell CHO (Cricetulusgriseus, hamster, Chinese, ovary), human B cell chronic lymphocytic leukemia cell strain MEG-01 (express BCR-ABL gene), Leukemia K562 cell (expressing BCR-ABL gene), human chronic myeloblastic leukemia Ku812 (expressing BCR-ABL gene), mouse pro B lymphocyte BaF3, above cell is all purchased from ATCC.Also select mouse Tel-BMX-BaF3 (stably express BMX kinases), mouse Tel-Abl-BaF3 (stably express ABL kinases), mouse BaF3-BCR-ABL (activated protein kinase that stably express BCR-ABL suddenlys change), mouse Tel-cKit-BaF3 (stably express cKIT kinases), mouse TEL-KIT-N822K (activated protein kinase that stably express cKIT N882K suddenlys change), mouse TEL-KIT-D816V (activated protein kinase that stably express cKIT D816V suddenlys change), mouse TEL-ABL-T315I-BaF3 (activated protein kinase that stably express ABL T315I suddenlys change).Above-mentioned cell strain builds by this laboratory, construction process is: PCR is amplifying human BMX, ABL, BCR-ABL, cKIT, cKITN882K, cKIT D816V, ABL T315I kinases region sequence respectively, and be inserted into the MSCV-Puro carrier (Clontech) holding TEL fragment with N respectively, pass through retrovirus method, stablize and proceed to mouse BaF3 cell, and remove IL-3 somatomedin, finally obtain relying on the clone that BMX, ABL, BCR-ABL, cKIT, cKIT N882K, cKIT D816V, ABL T315I proceeds to albumen.
In an embodiment the compound 9 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), compound 10, compound 11, compound 67, compound 68, compound 69 and contrast medicine Imatinib, Nilotinib are joined in above-mentioned cell respectively, and hatch 72 hours, use (Promega, the U.S.) chemical luminous method cell viability detection kit, detects number of viable cells by carrying out quantitative assay to the ATP in viable cell.Concrete outcome is in table 3.
Table 3. is on the impact of growth of cancer cells (result is expressed as GI50 value, unit be μM)
Embodiment 79
the impact of signal path on cell
In human chronic myeloblastic leukemia Ku812 (expressing BCR-ABL gene), human B cell chronic lymphocytic leukemia cell strain MEG-01 (expressing BCR-ABL gene), Leukemia K562 cell (expressing BCR-ABL gene) (all purchased from ATCC), by measuring many cellular biochemistry terminals and functional terminal, have evaluated the impact of compound 11 on protein kinase B CR-ABL, AKT, Crkl, ERK, Stat5 relevant in cell.With the Imatinib of different concns 0 μM, the compound 11 of 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μMs and 1 μM, the Dasatinib of 0.1 μM (purchased from Hao Yuan Chemexpress company, Shanghai) process KU812 cell strain, MEG-01 cell strain, K562 cell strain three strain cell respectively after 1 hour, collect sample.Measure compound 11 to the impact of BCR-ABL, AKT, Crkl, ERK, Stat5 phosphorylation in this three strains cell strain.Result is see Fig. 1.
Experimental result shows, compound 11 has restraining effect clearly to the phosphorylation of BCR-ABL, ERK, Stat5 in KU812 cell strain, MEG-01 cell strain, K562 cell strain, and this absolutely proves that compound 11 is BCR-ABL kinase inhibitor.
Embodiment 80
compound 11 on cell on apoptotic impact
In order to the death proving the later cell of medication is by apoptosis or necrosis, in human B cell chronic lymphocytic leukemia cell strain MEG-01 (express BCR-ABL gene), Leukemia K562 cell (expressing BCR-ABL gene) cell strain (all purchased from ATCC), have detected compound 11 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.With different concns 0 μM, 0.001 μM, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, the control compound Imatinib of compound 11,0.5 μM (in DMSO) of 0.3 μM, 1 μM (in DMSO), the control compound Dasatinib of 0.5 μM (in DMSO) process MEG-01, K562 cell strain, respectively then respectively at 12 hours, 24 hours, 48 h before harvest cells.The medicine detecting different concns with Westerm 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.Result is see Fig. 2.
Experimental result is as shown in Figure 2: for the human B cell chronic lymphocytic leukemia cell strain MEG-01 and the Leukemia K562 cell cell strain that carry BCR-ABL gene, when the Drug level of compound is 0.03 μM, acts on after 12 hours and just can see that obviously DNA repair enzyme gathers the shearing of adenosine diphosphate (ADP)-ribose polymerase PARP.For the human B cell chronic lymphocytic leukemia cell strain MEG-01 cell strain carrying BCR-ABL gene, when the Drug level of compound is 0.1 μM, act on after 24 hours, the shearing of the aspartic acid proteolytic ferment Caspase 3 containing halfcystine can be observed, act on after 48 hours, the shearing of the aspartic acid proteolytic ferment Caspase 3 containing halfcystine clearly can be observed.After similarly using the control compound Imatinib of 0.5 μM and control compound Dasatinib to act on 48 hours, also can observe the shearing of the aspartic acid proteolytic ferment Caspase 3 containing halfcystine, but obvious not as the action effect of compound 11.Embodiment 80 demonstrates the apoptosis that compound 11 can cause the human leukemia cell carrying BCR-ABL gene.
Embodiment 81
plate clone forms experiment
Adopt conventional trysinization propagating method, the human B cell chronic lymphocytic leukemia cell strain MEG-01 (expressing BCR-ABL gene) of exponential phase of growth, Leukemia K562 cell (expressing BCR-ABL gene), human chronic myeloblastic leukemia Ku812 (expressing BCR-ABL gene) cell are made cell suspending liquid.Cell suspending liquid is blown and beaten repeatedly, and cell is fully disperseed.To human B cell chronic lymphocytic leukemia cell strain MEG-01 (expressing BCR-ABL gene), Leukemia K562 cell (expressing BCR-ABL gene), human chronic myeloblastic leukemia Ku812 (expressing BCR-ABL gene) cell counting, and regulate cell concn with substratum.
According to the ability of cell proliferation of MEG-01, K562, Ku812 cell strain carrying BCR-ABL gene, by 10 3the concentration of cells/well is inoculated in six orifice plates (diameter 4cm) containing 2mL substratum, rocks culture dish gently, make cell dispersal even with cross direction.
Culture dish is placed in 37 DEG C, 5%CO 2middle cultivation administration after 24 hours (compound 11), drug level is as follows: compound 11 is 10 μMs, 1 μM, 0.1 μM, 0.01 μM, and 0.001 μM in DMSO; Blank adopts the DMSO of same volume.
Cultivate after 72 hours, stop cultivating, discard nutrient solution, PBS liquid carefully embathes 2 times.Fix 15 minutes with methyl alcohol, discard methyl alcohol.Use violet staining.
Experimental result is as shown in Figure 3: for MEG-01, K562, Ku812 cell strain carrying BCR-ABL gene, just can the formation of obviously T suppression cell colony when the concentration of compound 11 is 0.01 μM, the acellular Colony forming substantially when the concentration of compound 11 is 0.1 μM.
embodiment 82
cell counting is tested
Adopt conventional trysinization propagating method, the human B cell chronic lymphocytic leukemia cell strain MEG-01 (expressing BCR-ABL gene) of exponential phase of growth, Leukemia K562 cell (expressing BCR-ABL gene), human chronic myeloblastic leukemia Ku812 (expressing BCR-ABL gene) cell are made cell suspension.Cell suspension is blown and beaten repeatedly, and cell is fully disperseed.To cell count, and regulate cell concn with substratum.
According to the ability of cell proliferation of MEG-01, K562, Ku812 cell strain carrying BCR-ABL gene, by 10 3the concentration of cells/well is inoculated in six orifice plates (diameter 4cm) containing 2mL substratum, rocks culture dish gently, make cell dispersal even with cross direction.
Culture dish is placed in 37 DEG C, 5%CO 2middle cultivation administration after 24 hours (compound 11), drug level is as follows: compound 11 is 10 μMs, 1 μM, 0.1 μM, 0.01 μM, and 0.001 μM in DMSO; Blank adopts the DMSO of same volume.
Cultivate after 72 hours, stop cultivating, discard nutrient solution, PBS liquid carefully embathes 2 times, adds to cell counting after trysinization, calculates IC according to cell quantity 50value.
Experimental result is as shown in Figure 4: as calculated, the IC of compound 11 pairs of MEG-01 cell strains 50value is 16nM, the IC of compound 11 pairs of K562 cell strains 50value is 28nM, the IC of compound 11 pairs of Ku812 cell strains 50value is 10nM, illustrates that compound 11 all has restraining effect strongly to the Growth of Cells of MEG-01, K562, Ku812 cell strain and the formation of cell colony that carry BCR-ABL gene.Compound 11 is extraordinary BCR-ABL kinase inhibitor.
Embodiment 83
the impact of compound 11 cell cycle on cell
In order to which growth cycle cell after studying medication is stopped in, in human B cell chronic lymphocytic leukemia cell strain MEG-01 (expressing BCR-ABL gene), Leukemia K562 cell (expressing BCR-ABL gene), human chronic myeloblastic leukemia Ku812 (expressing BCR-ABL gene) three strain cell strains, test the impact of compound 11 on the cell cycle distribution of these cell strains.With 0 μM of different concns, 0.1 μM, 0.3 μM, the compound 11 of 1 μM (in DMSO), the BCR-ABL kinase inhibitor Imatinib of 0.5 μM (in DMSO) and Dasatinib acts on the MEG-01 carrying BCR-ABL gene, K562, in Ku812 cell strain, act on after 12 hours, collecting cell, 1XPBS buffer solution twice, the ethanol of 75% fixes 24 hours in-20 DEG C, 1XPBS damping fluid washes twice again, the PI staining fluid (purchased from American BD Bioscience) adding 0.5mL 1XPBS damping fluid and 0.5mL is positioned over dark lucifuge 37 DEG C dyeing 15 minutes in cell and by cell, cell cycle distribution is detected with flow cytometer (BD FACSCalibur).Result is see Fig. 5.
Experimental result is as shown in Figure 5: in MEG-01, K562, Ku812 cell strain carrying BCR-ABL gene, along with the drug level of compound 11 is increased to 1 μM from 0.1 μM, the cell of the G0-G1 phase of catching respectively: from 46.32% being increased to 55.78%, being increased to 61.01% from 44.61%, being increased to 69.53% from 59.51%; In MEG-01, K562, Ku812 cell strain carrying BCR-ABL gene, the cell of the G0-G1 phase that the control compound BCR-ABL kinase inhibitor Imatinib that selectivity is stronger and Dasatinib catches 0.5 μM time is respectively 45.66% and 51.75%, 46.68% and 56.11%, 65.18% and 68.83%.
Embodiment 83 demonstrate compound 11 can will carry BCR-ABL gene MEG-01, K562, Ku812 cell stop in the G0-G1 phase, and cell cycle be distributed with very strong impact (Fig. 5).

Claims (16)

1. a BCR-ABL kinase inhibitor, it comprises compound or its pharmacologically acceptable salts, solvate, ester, acid, metabolite or the prodrug of formula I:
Wherein:
R 1be selected from C1-C8 alkylamino, C1-C8 alkyl sulphonyl, optionally by 1 or 2 R independently 7the arylamino replaced, optionally by 1 or 2 R independently 7the aryloxy replaced, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of Heterocyclylalkyl oxygen bases, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of heterocyclalkylamino and 5 yuan or 6 yuan of Heterocyclylalkyl-(C1-C8 alkylaminos);
R 2be selected from hydroxyl, amino, sulfydryl, cyano group, halogen, C1-C8 alkylamino and C1-C8 alkoxyl group;
R 3be selected from C1-C8 alkyl;
R 4, R 5and R 6be selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyl group, C1-C8 alkylamino and aryl independently of one another, or adjacent R 4, R 5and R 6in any two form heterocyclic radical together;
R 7independently selected from amino, nitro, hydroxyl, halogen, sulfydryl, cyano group, amino-sulfonyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, C1-C8 alkoxyl group, C1-C8 alkyl sulphonyl, C1-C8 alkyl sulphinyl, C2-C8 alkylamidoalkyl and C2-C8 alkenyl amide base; And
R 8be selected from C1-C8 alkyl-carbonyl, C1-C8 halogenated alkyl carbonyl, C2-C8 alkenyl carbonyl, C2-C8 alkynylcarbonyl groups and amino protecting group.
2. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 1be selected from C1-C4 alkylamino, C1-C4 alkyl sulphonyl, 3 and/or 4 optionally by 1 or 2 R independently 7the phenyl amino replaced, 4 optionally by R 7the phenoxy group replaced, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of azacycloalkyl oxygen bases, heteroatoms are optionally by R 85 yuan that replace or 6 yuan of azacycloalkyl amino and 5 yuan or 6 yuan of Heterocyclylalkyl-(C1-C4 alkylaminos).
3. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 2be selected from hydroxyl, amino, C1-C4 alkylamino and C1-C4 alkoxyl group.
4. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 3be selected from C1-C4 alkyl, and be positioned at 4 or 6 of phenyl ring.
5. BCR-ABL kinase inhibitor, wherein R as claimed in claim 4 3it is the methyl of 6 being positioned at phenyl ring.
6. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 4, R 5and R 6be selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyl group and phenyl independently of one another, or adjacent R 4, R 5and R 6in any two form heterocyclic radical together.
7. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 4, R 5and R 6be positioned at 2,3,4 or 5 of phenyl ring separately.
8. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 7independently selected from amino, nitro, amino-sulfonyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino, C1-C4 alkyl sulphonyl, C1-C4 alkyl sulphinyl, C2-C4 alkylamidoalkyl and C2-C4 alkenyl amide base.
9. BCR-ABL kinase inhibitor, wherein R as claimed in claim 1 8be selected from C1-C4 alkyl-carbonyl, C1-C4 halogenated alkyl carbonyl, C2-C4 alkenyl carbonyl, C2-C4 alkynylcarbonyl groups, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 9-fluorenylmethyloxycarbonyl, benzyl and p-methoxyphenyl.
10. BCR-ABL kinase inhibitor as claimed in claim 1, it is selected from:
11. 1 kinds of pharmaceutical compositions, it comprises the BCR-ABL kinase inhibitor according to any one of claim 1-10, pharmaceutically acceptable carrier or vehicle and other optional therapeutical agent.
12. 1 kinds, for suppressing the method for BCR-ABL kinase activity, comprise the BCR-ABL kinase inhibitor or pharmaceutical composition as claimed in claim 11 used according to any one of claim 1-10.
13. BCR-ABL kinase inhibitor according to any one of claim 1-10 or pharmaceutical composition as claimed in claim 11 are for the preparation of the purposes for the treatment of in the medicine of the illness mediated by BCR-ABL kinase activation.
14. purposes as claimed in claim 13, the wherein said illness mediated by BCR-ABL kinase activation is proliferative disorders.
15. purposes as claimed in claim 14, wherein said proliferative disease is selected from: solid tumor, sarcoma, chronic myelogenous leukemia, chronic myelocytic leukemia (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid carcinoma, cancer of the stomach, the rectum cancer, multiple myeloma, tumorigenesis and other Hypertrophic or proliferative disease or its combination.
16. purposes as claimed in claim 15, wherein said proliferative disease is selected from: chronic myelocytic leukemia (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid carcinoma or its combination.
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