CN104876879B - A kind of BCR-ABL kinase inhibitors - Google Patents

A kind of BCR-ABL kinase inhibitors Download PDF

Info

Publication number
CN104876879B
CN104876879B CN201510172534.7A CN201510172534A CN104876879B CN 104876879 B CN104876879 B CN 104876879B CN 201510172534 A CN201510172534 A CN 201510172534A CN 104876879 B CN104876879 B CN 104876879B
Authority
CN
China
Prior art keywords
bcr
compound
alkyl
amino
abl kinase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510172534.7A
Other languages
Chinese (zh)
Other versions
CN104876879A (en
Inventor
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Institutes of Physical Science of CAS
Original Assignee
Hefei Institutes of Physical Science of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hefei Institutes of Physical Science of CAS filed Critical Hefei Institutes of Physical Science of CAS
Priority to CN201510172534.7A priority Critical patent/CN104876879B/en
Priority to PCT/CN2015/081220 priority patent/WO2016165205A1/en
Publication of CN104876879A publication Critical patent/CN104876879A/en
Application granted granted Critical
Publication of CN104876879B publication Critical patent/CN104876879B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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 present invention relates to a kind of BCR abl kinase inhibitors, including the compound of Formulas I or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, wherein R1、R2、R3、R4、R5、R6It is defined as in the description.The invention further relates to the pharmaceutical compositions including compound of formula I and the compound of the present invention to prepare to treat the purposes by the drug of the illness of BCR ABL kinase activations mediation.

Description

A kind of BCR-ABL kinase inhibitors
Technical field
Compound this application involves a kind of inhibitor as BCR-ABL tyrosine kinase includes these compounds Pharmaceutical composition and the illness mediated using these compounds and composition for treatment by BCR-ABL kinase activations, especially It is cancer and the purposes and method of other cell proliferation disorders.It is used to treat chronic myelocytic leukemia more particularly to one kind (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid cancer or the BCR-ABL junket ammonia of its combination Acid kinase inhibitor and its purposes.
Background technology
The tyrosine kinase that BCR-ABL track fusions go out can cause cell Proliferation, stick change with nature of life, Cause the generation of kinds of tumors.For example, the oncogene c-ABL on No. 9 chromosomes of human body is linked to the breakpoint on No. 22 chromosome Gathering area (BCR), forming p210BCR-ABL fusions and p185BCR-ABL fusions, both fusions makes accordingly BCR-ABL tyrosine kinase sustained activations, cause cell Proliferation, stick change with nature of life, cause to generate respectively slow Property granulocytic leukemia (CML) and acute myeloblastic leukemia (ALL).Inhibiting BCR-ABL tyrosine kinase can effectively inhibit swollen Knurl is grown.
In past more than 20 years, it is important that researcher has found that BCR-ABL kinases plays in cell signalling and conversion Effect, it is by phosphorylation and activates a series of stream substrates, promotes the unlimited hyperplasia of CML maturation granulocytes.BCR-ABL is normal It is not expressed in cell, so it is the treatment preferable drug targets of CML.In the early 1990s, researcher is expected that by RNA Approach inhibits BCR-ABL fusions and plays a role, but could not effectively treat CML.With fusion structure and expression product Illustrate, researcher is transferred to attention in the design and exploitation for the small-molecule drug that can directly act on BCR-ABL protein.
This kind of disease is treated before and relies primarily on monoclonal antibody drug, until U.S. FDA in 2001 has approved first After the BCR-ABL tyrosine kinase Imatinib for treating CML, find micromolecular compound and inhibit BCR-ABL tyrosine Kinases is increasingly becoming hot spot of concern to treat above-mentioned disease.Due to the appearance of imatinib-resistant, develop new BCR-ABL tyrosine kinase is extremely urgent.At present, second generation BCR-ABL tyrosine kinase has listed, main Drug is wanted to have Dasatinib and nilotinib.Although Dasatinib and nilotinib show encouraging first-stage success, Some researchers will trigger new mutation in ABL kinases area after reporting their uses.Ray etc. has identified 17 kinds in the kinases area On mutation, including known to 6 kinds imatinib-resistant mutation (M244V, Y253H, F359C/V/I, G250E, E255K and T315I) and 11 kinds in addition it is increased mutation (K247N, E282K, K285N, V289L, L273F, E292K, N297T, H375P, T406I, W430L and E431G).Due to the appearance of second generation BCR-ABL tyrosine kinase drug resistance, exploitation It is necessary to go out newer BCR-ABL tyrosine kinase.
The content of the invention
The present invention relates to a kind of BCR-ABL kinase inhibitors, including the compound of Formulas I or its pharmaceutically acceptable salt, Solvate, ester, acid, metabolin or prodrug：
Wherein：
R1Selected from C1-C8 alkyl aminos, C1-C8 alkyl sulphonyls, optionally by 1 or 2 independently R7Substituted aryl ammonia Base, optionally by 1 or 2 independently R7Substituted aryloxy group, hetero atom are optionally by R8Substitution 5 yuan or 6 membered heterocycloalkyl oxygroups, Hetero atom is optionally by R85 yuan or 6 membered heterocycloalkyl amino and 5 yuan or 6 membered heterocycloalkyls-(C1-C8 alkyl aminos) of substitution；
R2Selected from hydroxyl, amino, sulfydryl, cyano, halogen, C1-C8 alkyl aminos and C1-C8 alkoxyl etc.；
R3Selected from C1-C8 alkyl；
R4、R5And R6It is each independently selected from hydrogen, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1-C8 alkane Base amino and aryl etc. or adjacent R4、R5And R6In any two form heterocycle together；
R7Independently selected from amino, nitro, hydroxyl, halogen, sulfydryl, cyano, amino-sulfonyl, C1-C8 alkyl, C1-C8 Halogenated alkyl, C1-C8 alkyl aminos, C1-C8 alkoxyl, C1-C8 alkyl sulphonyls, C1-C8 alkyl sulphinyls, C2-C8 alkane Base amide groups and C2-C8 eneamide bases etc.；And
R8Selected from C1-C8 alkyl-carbonyls, C1-C8 halogenated alkyl carbonyls, C2-C8 alkenyl carbonyls, C2-C8 alkynylcarbonyl groups and Amino protecting group.
In one embodiment, R1Selected from C1-C4 alkyl aminos, C1-C4 alkyl sulphonyls, optionally by 1 or 2 independence Ground R7(preferably 3 and/or 4 optionally by 1 or 2 independently R for substituted phenyl amino7Substituted phenyl amino), optionally by 1 Or 2 independently R7(preferably 4 optionally by R for substituted phenoxy group7Substituted phenoxy group), hetero atom is optionally by R85 yuan of substitution Or 6 yuan of azacycloalkyl oxygroups, hetero atoms are optionally by R85 yuan or 6 yuan of azacycloalkyl amino and 5 yuan or 6 circle heterocycles of substitution Alkyl-(C1-C4 alkyl aminos).
In one embodiment, R2Selected from hydroxyl, amino, C1-C4 alkyl aminos and C1-C4 alkoxies.
In one embodiment, R3Selected from C1-C4 alkyl, and R34 or 6 of phenyl ring are preferably placed at, particularly 6 Position.
In one embodiment, R4、R5And R6It is each independently selected from hydrogen, C1-C4 alkyl, C1-C4 halogenated alkyls, C1- C4 alkoxies and phenyl or adjacent R4、R5And R6In any two form heterocycle together, particularly dioxane penta Alkenyl, and R4、R5And R6It is preferably placed at 2,3,4 or 5 of phenyl ring.
In one embodiment, R7It is halogenated independently selected from amino, nitro, amino-sulfonyl, C1-C4 alkyl, C1-C4 Alkyl, C1-C4 alkyl aminos, C1-C4 alkyl sulphonyls, C1-C4 alkyl sulphinyls, C2-C4 alkylamidoalkyls and C2-C4 Eneamide base.
In one embodiment, R8Selected from C1-C4 alkyl-carbonyls, C1-C4 halogenated alkyl carbonyls, C2-C4 alkenyl carbonyls, C2-C4 alkynylcarbonyl groups and amino protecting group, such as tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl (F- Moc), benzyl (Bn) and p-methoxyphenyl (PMP).
On the other hand, the application provides a kind of pharmaceutical composition, and at least one including therapeutically effective amount carries herein The compound of confession or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug and pharmaceutically acceptable carrier Or excipient and optional other therapeutic agents.
On the other hand, this application involves for inhibiting the method for BCR-ABL tyrosine kinase activities, including applying Formulas I Compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug or the medicine group including compound of formula I Close object.
It yet still another aspect, the present invention relates to compound of formula I or its pharmaceutically acceptable salt, solvate, ester, acid, metabolism Object or prodrug or pharmaceutical composition including compound of formula I are preparing the medicine for treating by disease kinase mediated BCR-ABL Purposes in object.The disease is selected from chronic myelocytic leukemia (CML), acute myeloblastic leukemia (ALL), Gastrointestinal Stromal Knurl (GIST), thyroid cancer or its combination etc..
Description of the drawings
Fig. 1 shows influence of the compound 11 to Ku812 (a), MEG-01 (b), K562 (c) cell-signaling pathways.
Fig. 2 shows influence of the compound 11 to MEG-01 (a), K562 (b) Apoptosis.
Fig. 3 shows that compound 11 is real to the plates of cells Colony forming of MEG-01 (a), K562 (b), Ku812 (c) cell lines Test result.
Fig. 4 show compound 11 to MEG-01 (a), Ku812 (b), K562 (c) cell lines cell count experimental result.
Fig. 5 show compound 11 to Ku812 (a), MEG-01 (b), K562 (c) cell lines cell cycle distribution shadow It rings.
Specific embodiment
Term
Unless otherwise defined, all scientific and technical terminologies used herein all have the skill with claimed theme fields Art personnel are commonly understood by identical meaning.
Unless otherwise indicated, the mass spectrum of the invention used in the range of art technology, NMR, HPLC, protein chemistry, life The conventional methods such as object chemistry, recombinant DNA technology and pharmacology.Unless provide specific definition, otherwise with analysis described herein The chemically relevant name of chemistry, synthetic organic chemistry and medicine and pharmaceutical chemistry etc. and laboratory operation and technology, are these Known to field technology personnel.In general, aforementioned techniques and step can be by well-known in the art and various one As conventional method described in document and more specific document implement, these documents are cited and discuss in the present specification.
" alkyl " refers to aliphatic hydrocarbon groups, can be branched-chain or straight-chain alkyl.According to structure, alkyl can be monovalent radical Group or bivalent radical (i.e. alkylidene).In the present invention, alkyl is preferably with the " rudimentary of a (preferably 1-6) carbon atoms of 1-8 Alkyl ".Typical alkyl include but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, oneself Base etc..Term " C1-C8 " refers to that carbon number for 1-8, that is, it is former to include the carbon selected from C1, C2, C3, C4, C5, C6, C7 and C8 Subnumber or the subrange arbitrarily formed, for example, 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 carbon original The scope of subnumber is 2-8, that is, includes the carbon number selected from C2, C3, C4, C5, C6, C7 and C8 or the subrange arbitrarily formed, Such as C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C3-C6, C3-C8, C4-C8, C4-C6, C6-C8 etc..
" alkoxy " refers to-O- alkyl, wherein alkyl as defined herein.Typical alkoxy includes but not limited to methoxy Base, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..
" sulfonyl " refers to that sulfonic acid loses the functional group after hydroxyl, in particular to-S (=O)2-." sulfinyl " refers to-S (=O)-." alkyl sulphonyl " refers to alkyl-S (=O)2-, " alkyl sulphinyl " refer to alkyl-S (=O)-, " aminosulfonyl Base " refers to NH2- S (=O)2-。
" alkoxyalkyl " refers to that alkyl defined herein is substituted by alkoxy defined herein.
Term " alkyl amino " refers to-N (alkyl)xHyGroup, wherein x and y are selected from x=l, y=l and x=2, y=0.Work as x When=2, alkyl N atoms connected to them, which are combined together, can be optionally formed loop system.
Term " amide groups " is carboxylic acid and the functional group generated after ammonia condensation, is expressed as-CO-NH-, such as formamido is Refer to CH3-CO-NH-。
Term " alkyl-carbonyl " refers to further by an alkyl-substituted carbonyl.
Term " aromatic radical " refers to that planar rings have the pi-electron system of delocalization and containing 4n+2 pi-electron, and wherein n is Integer.Fragrant basic ring can be by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic radical can optionally substitute.Art Language " aromatic radical " includes isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") group (such as pyrrole Pyridine).The term includes polycyclic (ring for the sharing adjacent carbon atom pair) group of monocyclic or condensed ring.
Terms used herein " aryl " refers to that the atom that each in fragrant basic ring forms ring is carbon atom.Aryl rings It can be by five, six, seven, eight, nine or more than nine atomic buildings.Aryl can optionally substitute.The example of aryl include but It is not limited to phenyl, naphthalene, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e. Arlydene).
" alkyl (aryl) " or " aryl alkyl " or " aralkyl " refer to alkyl defined herein by aryl defined herein Substitution.Nonrestrictive alkyl (aryl) includes benzyl, phenethyl etc..
Term " cycloalkyl " refers to monocyclic or polycyclic group, only contains carbon and hydrogen.Cycloalkyl includes having 3-10 ring original The group of son.According to structure, cycloalkyl can be monoradical or bivalent radical (such as cycloalkylidene).In the present invention, ring Alkyl is preferably the cycloalkyl with 3-8 carbon atom, more preferably has " low-grade cycloalkyl " of 3-6 carbon atom.
" alkyl (cycloalkyl) " or " cycloalkyl-alkyl " refer to that alkyl defined herein is substituted by cycloalkyl defined herein. Nonrestrictive alkyl (cycloalkyl) includes Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl etc..
Terms used herein " miscellaneous alkyl " refers to that one or more of alkyl defined herein skeletal chain atoms are Hetero atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or combination thereof.The hetero atom (one or more) can be located in miscellaneous alkyl Any position in portion or in the position that miscellaneous alkyl is connected with the rest part of molecule.
Terms used herein " Heterocyclylalkyl " refers to that one or more atoms for forming ring are to be selected from non-aromatic basic ring The hetero atom of nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine atomic buildings.Heterocycle Alkyl ring can optionally substitute.The example of Heterocyclylalkyl includes but not limited to lactams, lactone, epimino, epithio generation Asia Amine, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- bioxin, 1,3- dioxanes, 1,4- bis- Evil English, 1,4- dioxanes, piperazine, 1,3- thioxane, 1,4- oxathiins, 1,4- thioxane, tetrahydrochysene- 1,4- thiazines, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-, dioxopiperazine, Hydantoins, dihydrouracil, morpholine, trioxanes, hexahydro -1,3,5- triazines, thiophane, tetrahydrofuran, pyrrolin, pyrroles Alkane, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1,3- dioxanes Pentane, 1,3- dithioles, 1,3- dithiolane, isoxazoline, isoxazole alkyl, oxazoline, oxazolidine, oxazolidines Ketone, thiazoline, thiazolidine and 1,3- oxathiolanes.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 " halogenated alkyl ", including 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, the halogen atom is same or different to each other.
Term " optionally substituting " or " substituted " refer to that mentioned group can be by one or more additional groups Substitution, the additional group is each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, cyanogen Base, halogen, amide groups, nitro, halogenated alkyl, amino, sulfydryl, amino-sulfonyl, alkyl amino, alkyl sulphonyl, alkyl are sub- Sulfonyl, alkylamidoalkyl, eneamide base, alkyl-carbonyl, alkenyl carbonyl, alkynylcarbonyl groups, amino protecting group etc..
Term " amino protecting group " includes, but are not limited to tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), 9- fluorenes methoxy carbonyls Base (F-moc), benzyl (Bn) and p-methoxyphenyl (PMP) etc..
" inhibition ", " inhibition " or " inhibitor " of terms used herein kinases, refers to that phosphate transferase activity is pressed down System.
" metabolin " of compound disclosed herein is the derivative of the compound formed when the compound is metabolized.Art Language " active metabolite " refers to the biologically active derivatives of the compound formed when the compound is metabolized.Art used herein Language " is metabolized ", refers to the process of that predetermined substance (includes but not limited to hydrolysis and by enzymatic by organism transform summation Reaction, such as oxidation reaction).Therefore, enzyme can generate specific structure and be changed into compound.For example, Cytochrome P450 Various oxidations and reduction reaction are catalyzed, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is extremely The conversion of aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from《The Pharmacological Basis of Therapeutics》, the 9th edition, McGraw-Hill (1996) is obtained.It is disclosed herein The metabolin of compound can be by giving compound to host and analyzing tissue sample from the host or by that will change Object is closed to be incubated in vitro with liver cell and analyze gained compound to differentiate.Both approaches are all known in the art. In some embodiments, the metabolin of compound is to be formed by oxidation process and corresponding with corresponding hydroxy-containing compounds. In some embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting ", refer to directly or It connects and interacts with target, it is only for example, active, suppression target including intensifier target target to change the activity of target Activity, limit target target activity or the activity for extending target.
GI used herein50Refer to the drug concentration needed for 50% growth inhibition of cell, i.e. drug makes 50% cancer cell Growth is inhibited or controls, drug concentration at this time.
IC used herein50Refer to that the 50% of ceiling effect is obtained in the analysis of effect as measurement inhibits specific Test amount, concentration or the dosage of compound.
EC used herein50Refer to the dosage, concentration or the amount that measure compound, particular assay compound is caused to induce, The 50% maximum dose-dependant expressed of the specific reaction for stimulating or strengthening reacts.
The BCR-ABL kinase inhibitors of the present invention
The present invention relates to a kind of BCR-ABL kinase inhibitors, including the compound of Formulas I or its pharmaceutically acceptable salt, Solvate, ester, acid, metabolin or prodrug：
Wherein：
R1Selected from C1-C8 alkyl aminos, preferably C1-C4 alkyl aminos, such as methylamino, dimethylamino, ethyl ammonia Base, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tertiary butyl ammonia Base；C1-C8 alkyl sulphonyls, preferably C1-C4 alkyl sulphonyls, such as mesyl, ethylsulfonyl, the third sulfonyl, fourth sulphonyl Base；Optionally by 1 or 2 independently R7Substituted arylamino, such as 3 and/or 4 by independently R7Substituted phenyl amino, Naphthyl-amino, phenanthryl amino；Optionally by 1 or 2 independently R7Substituted aryloxy group, such as 4 by R7Substituted phenoxy group, naphthalene Oxygroup, luxuriant and rich with fragrance oxygroup；Hetero atom is optionally by R85 yuan or 6 membered heterocycloalkyl oxygroups of substitution, wherein Heterocyclylalkyl oxygroup is preferably nitrogen Heterocyclylalkyl oxygroup, such as pyrrolidinyl oxygroup, piperidyl oxygroup, imidazolidinyl oxygroup；Hetero atom is optionally by R85 yuan of substitution Or 6 membered heterocycloalkyl amino, heterocyclalkylamino is preferably azacycloalkyl amino in base, such as piperidyl amino, pyrrolidines Base amino, imidazolidinyl amino；With 5 yuan or 6 membered heterocycloalkyls-(C1-C8 alkyl aminos), such as 3- morphoinopropyl amino, Wherein Heterocyclylalkyl be, for example, morpholinyl, piperidyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro thiapyran base or THP trtrahydropyranyl, C1-C8 alkyl aminos are preferably C1-C4 alkyl aminos, are, for example, methylamino, dimethylamino, ethyl ammonia Base, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tertiary butyl ammonia Base；
R2Selected from hydroxyl；Sulfydryl；Cyano；Halogen；Amino；C1-C8 alkyl aminos are preferably C1-C4 alkyl aminos, such as Methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, positive fourth Base amino, isobutylamino, tert-butylamino；And C1-C8 alkoxyl, preferably C1-C4 alkoxies, such as methoxyl group, ethoxy Base, propoxyl group, n-butoxy, isobutoxy, tert-butoxy；
R3Selected from C1-C8 alkyl, preferably C1-C4 alkyl, such as methyl, ethyl, propyl, normal-butyl, isobutyl group, tertiary fourth Base, and R34 or 6 of phenyl ring are preferably placed at, particularly 6；
R4、R5And R6It is each independently selected from hydrogen；C1-C8 alkyl, preferably C1-C4 alkyl, such as methyl, ethyl, third Base, normal-butyl, isobutyl group, tertiary butyl；C1-C8 halogenated alkyls, preferably C1-C4 halogenated alkyls, a such as methyl fluoride, difluoro first Base, trifluoromethyl, chloromethyl, dichloromethyl, trifluoroethyl, a bromoethyl, two chloropropyls, trifluoro propyl, three brombutyls； C1-C8 alkoxyl, preferably C1-C4 alkoxies, such as methoxyl group, ethyoxyl, propoxyl group, n-butoxy, isobutoxy, tertiary fourth Oxygroup；C1-C8 alkyl aminos, preferably C1-C4 alkyl aminos, such as methylamino, dimethylamino, ethylamino, diethyl Base amino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino；And virtue Base, such as phenyl, naphthalene, phenanthryl, anthryl etc. or adjacent R4、R5And R6In any two form heterocycle, example together Such as dioxa cyclopentenyl, and R4、R5And R6It is preferably placed at 2,3,4 or 5 of phenyl ring；
R7Independently selected from amino；Nitro；Hydroxyl；Halogen；Sulfydryl；Cyano；Amino-sulfonyl；C1-C8 alkyl, preferably C1-C4 alkyl, such as methyl, ethyl, propyl, normal-butyl, isobutyl group, tertiary butyl；C1-C8 halogenated alkyls are preferably C1-C4 halogen Substituted alkyl, such as a methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trifluoroethyl, a bromoethyl, two Chloropropyl, trifluoro propyl, three brombutyls；C1-C8 alkyl aminos, preferably C1-C4 alkyl aminos, such as methylamino, diformazan Base amino, ethylamino, diethylamino, n-propyl amino, dipropylamino, isopropylamino, n-butylamino, isobutyl group Amino, tert-butylamino；C1-C8 alkoxyl, preferably C1-C4 alkoxies, such as methoxyl group, ethyoxyl, propoxyl group, positive fourth oxygen Base, isobutoxy, tert-butoxy；C1-C8 alkyl sulphonyls, preferably C1-C4 alkyl sulphonyls, such as mesyl, second sulphur Acyl group, the third sulfonyl, fourth sulfonyl；C1-C8 alkyl sulphinyls, preferably C1-C4 alkyl sulphinyls, such as methylsulfinyl Base, ethylsulfinyl, propylsulfenyl, butylsulfinyl；C2-C8 alkylamidoalkyls are preferably C2-C4 alkylamides Base, such as acetamido, propionamido-, amide-based small；With C2-C8 eneamide bases, preferably C2-C4 eneamide bases, example Such as ethernamine base, acrylamido, crotonoyl amido；
R8Selected from C1-C8 alkyl-carbonyls, preferably C1-C4 alkyl-carbonyls, such as ethylcarbonyl group, propyl carbonyl, butyl carbonyl Base；C1-C8 halogenated alkyl carbonyls, preferably C1-C4 halogenated alkyl carbonyls, such as chloromethyl carbonyl, a fluoromethylcarbonyl, two Fluoromethylcarbonyl, Trifluoromethylcarbonyl, dichloromethyl carbonyl, trifluoroethyl carbonyl, monobromo ethylcarbonyl group, dichloro propyl carbonyl, Trifluoro propyl carbonyl, three brombutyl carbonyls；C2-C8 alkenyl carbonyls, preferably C2-C4 alkenyl carbonyls, such as vinyl carbonyl, third Alkenyl carbonyl, cyclobutenyl carbonyl；C2-C8 alkynylcarbonyl groups, preferably C2-C4 alkynylcarbonyl groups, such as acetenyl carbonyl, propinyl carbonyl Base, butynyl carbonyl；And amino protecting group, such as tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl (F- Moc), benzyl (Bn) and p-methoxyphenyl (PMP).
Compound involved in the present invention containing chirality, configuration can be arbitrary configuration or the racemic modification of mixing.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt Type includes but not limited to：(1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction It is formed, the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.；Or formed with organic acid reaction, it is described Organic acid for example acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, Succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4- hydroxy benzoyls) benzoic acid, Chinese cassia tree Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acids, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, toluenesulfonic acid, 4- methyl Bicyclic-[2.2.2] oct-2-ene -1- formic acid, 2- naphthalene sulfonic acids, butylacetic acid, glucoheptonic acid, 4,4' methylene bis-(3- hydroxyls Base -2- alkene -1- formic acid), 3- phenylpropionic acids, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl Naphthoic acid, stearic acid, muconic acid etc.；(2) base addition salts, the shape when acid proton in parent compound is replaced by metal ion Into, such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion；Or match somebody with somebody with organic base Position.Acceptable organic base includes ethanolamine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamines, etc..It can connect The inorganic base received includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
The corresponding ion balance of pharmaceutically acceptable salt can analyze and be identified using various methods, the described method includes But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma, atomic absorption spectrum, mass spectrum or Any combination of them.
The salt is recycled using at least one of following technology：Filtering is then filtered, evaporation of the solvent with non-solvent precipitation, Or desivac is used in the case of aqueous solution.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be completed using multiple technologies, described Technology includes but not limited to heat analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.The various spectral techniques used Including but not limited to Raman, FTIR, UV-Vis and NMR (liquid and solid state).Various microscopies include but not limited to IR microscopies and Raman (Raman) microscopy.
The medical composition and its use of the present invention
The application offer is formulated for the pharmaceutical composition being administered by appropriate approach and mode, the pharmaceutical composition bag Containing effective concentration provided herein is one or more compounds or its pharmaceutically acceptable salt, solvate, ester, acid, metabolism The other therapeutic agents of object or prodrug and pharmaceutically acceptable carrier or excipient and person optionally.
The compound of formula I of free form or salt form is hereinafter also known as " substance of the invention ", since they are right The compound of formula I of the inhibitory action of BCR-ABL kinases, free form or pharmaceutical acceptable salt can be used for treatment to be swashed by BCR-ABL Disease, the obstruction and illness that the activation of enzyme is mediated (including normal activity, especially overactivity), such as proliferative diseases, Cancer, inflammatory disease or anaphylactia, obstructive respiratory disease and/or the illness related with transplanting.
" treatment " of the present invention can be curative (such as symptomatic treatment) and/or preventative.
It is preferred for treating the purposes of proliferative diseases, the proliferative diseases are selected from benign or malignant tumour, including But it is not limited to：Chronic myelocytic leukemia (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), first shape Gland cancer, solid tumor, sarcoma, chronic myelogenous leukemia, to ABL (wild type or it is various mutation or its combination) and BCR/ABL it is (wild Type or various mutation or its combination) tyrosine kinase activity inhibits have influential leukaemia, stomach cancer, the carcinoma of the rectum, multiple bone Myeloma, knurl formation and other Hypertrophic or proliferative diseases or its combination.
The substance of the present invention can be used for treatment inflammatory or obstructive airway diseases, cause such as tissue damage, airway inflammation, The mitigation of bronchus overreact, remodeling or disease development.The applicable inflammatory of the present invention or obstructive airway diseases include any The asthma of type or cause is roared including endogenous (anallergic) asthma and exogenous (allergia) asthma, mild asthma, moderate The asthma induced after asthma, severe asthma, bronchitic asthma, the asthma of exercise induced, occupational asthma and bacterium infection.It roars The treatment of asthma is also understood as including the treatment to individual, is, for example, less than the individual of 4 or 5 years old, shows wheezing symptoms, examined Break and be or diagnosable for " wheezy infants (wheezy infant) ", this is the patient in a kind of fixed Major medical concern Classification, is typically now accredited as initial stage or asthma in early days.For convenience, this special asthma is referred to as that " wheezy infants are comprehensive Simulator sickness ".
Prevention effect in treating asthma will appear as paresthesia epilepsy frequency reduction or severity mitigation for example The reduction of the acute asthma or bronchoconstrictor attack frequency or mitigation of severity, lung function improvement or air flue over-activity change It is kind.Described effect is also embodied by the reduction to other symptom treatment demands, and other symptom treatments are used for or are directed at The treatment of paresthesia epilepsy, such as anti-inflammatory agent (such as corticosteroid) or bronchodilators are limited or stopped when it occurs. Having may be particularly evident to the prevention benefit of asthma in the individual of " morning dipping (morning dipping) " tendency." morning dipping " is one Kind of generally acknowledged Asthma Syndrome, usually accounts for significant proportion in asthma, it is characterized in that for example break out in the morning between about 4 to 6 points, That is, the time breaking-out of the arbitrary treatment for asthma symptoms usually applied before distance farther out.
The applicable other inflammatories of the present invention or obstructive airway diseases and illness include acute lung injury (ALI), adult type/ Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, air flue or lung disease (COPD, COAD or COLD), including slow Property bronchitis or expiratory dyspnea associated therewith, pulmonary emphysema and treated by other medicines, particularly other Sucked medicines control Air flue over-activity caused by treatment deteriorates.The present invention is further adapted for the bronchitis for treating any types or cause, including for example anxious Property bronchitis, arachidic bronchitis, catarrhal bronchitis, fibrinous bronchitis, chronic bronchial Scorching or phthinoid bronchitis.The applicable other inflammatories of the present invention or obstructive airway diseases include the dirt of any types or cause Lung (a kind of inflammatory is usually professional tuberculosis, whether chronic or acute to be often accompanied by airway obstruction, and by repeating Sucking dust causes), sink lung, silicosis, tabacism including such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, iron And byssinosis.
The substance of the present invention is additionally operable to treatment by following diseases kinase mediated BCR-ABL, obstruction and illness：Respiratory system Disease, allergy, rheumatoid arthritis, osteoarthritis, wind-wetness syndrome, psoriasis, ulcerative colitis, limitation are returned Allograft rejection reaction after enteritis, septic shock, proliferative disorders, atherosclerosis, transplanting, glycosuria Disease, apoplexy, obesity or restenosis, leukaemia, mesenchymoma, thyroid cancer, systemic mast cell disease, eosinophil increase More syndromes, fibre modification, rheumatoid arthritis, panarthritis, chorionitis, lupus erythematosus, graft versus host disease(GVH disease), nerve Fibroma, pulmonary hypertension, Alzheimer disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchiolar carcinoma, Dysgerminoma, the formation of testis intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, mamillary/follicular thyroid cancer, Malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine knurl formation, pheochromocytoma, thyroid cancer, parathyroid gland Hyperplasia/adenoma, colon cancer, colorectal adenomas, oophoroma, prostate cancer, spongioblastoma, brain tumor, malignant nerve glue Matter knurl, cancer of pancreas, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney, liver cancer, adrenal, carcinoma of urinary bladder, stomach Cancer, the carcinoma of the rectum, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor, knurl are formed and other increasings Natural disposition or proliferative diseases or its combination.
The substance of the present invention can be additionally used in treatment and the relevant illness of eosinophils, such as eosinophilia, special Be not with the relevant airways disorders of eosinophils (such as being related to the lung tissue of ill eosinophils infiltration), it is thin including acidophilus Born of the same parents are excessive, because it influences air flue and/or lung and for example by loeffler syndrome, eosinophilic pneumonia, parasite (spy It is not metazoa) infect (including tropical eosinophilia), bronchial aspergillosis, nodular polyarteritis (bag Include Qiu-this syndrome), caused by eosinophilic granuloma or with its phase it is parallel with the relevant airways disorders of eosinophils, With influence air flue caused by drug response and the relevant illness of eosinophils.
The present invention substance can be additionally used in treat skin inflammatory or allergic conditions, such as psoriasis, contact dermatitis, It is atopic dermatitis, alopecia circumscripta, erythema multiforme, dermatitis herpetiformis, chorionitis, hickie, allergic vasculitis, nettle rash, big Blister pemphigoid, lupus erythematosus, pemphigus (pemphisus), the inflammation of acquired epidermolysis bullosa and other skins Property or allergic conditions.
The substance of the present invention can also be used to treat Other diseases or illness, disease or disease particularly with inflammatory components Disease, such as the disease and illness for the treatment of eye, such as conjunctivitis, keratoconjunctivitis sicca and spring conjunctivitis；The disease of nose is influenced, Including allergic rhinitis；And it is directed to autoimmune response or there is autoimmunity sexual element or etiologic etiological inflammatory disease Disease, including autoimmune hematological illness (such as hemolytic anemia, alpastic anemia, pure red cell anaemia and Te Fa Property decrease of platelet), systemic loupus erythematosus, polychondritis, chorionitis, Wegner's granulomatosis, dermatomyositis, chronic work The syndrome of dynamic property hepatitis, myasthenia gravis, Si-about, idiopathic sprue, autoimmune inflammatory enteropathy (such as ulcer Property colitis and regional enteritis), endocrine ophthalmopathy, Graves disease, sarcoidosis, pulmonary alveolitis, chronic allergic pneumonia, Multiple sclerosis, primary biliary cirrhosis, uveitis (anterior uveitis and rear uveitis), drying property Keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with not companion There is nephrotic syndrome, such as including idiopathic nephrotic syndrome or minute nephropathy).
It is other that the disease of Substance treatment of the invention or illness can be used to include septic shock, rheumatoid joint Allograft rejection reaction, apoplexy after inflammation, osteoarthritis, proliferative diseases such as cancer, atherosclerosis, transplanting, Obesity, restenosis, diabetes such as type-1 diabetes mellitus (juvenile-onset diabetes) and type-2 diabetes mellitus, diarrhea disease, part lack The retinopathy of blood/reperfusion injury, retinopathy such as diabetic retinopathy or induced by hyperbaric oxygen and with eye The illness that internal pressure raises or aqueous humor secretion is characterized, such as glaucoma.
Validity of the substance of the present invention in terms of inflammatory conditions such as airway inflammatory disease is inhibited can be in animal model In be proven, such as the mouse or rat model of airway inflammation or other inflammatory conditions, such as such as Szarka, J.Immunol.Methods(1997)202:49-57；Renzi etc., Am.Rev.Respir.Dis. (1993) 148:932-939； Tsuyuki etc., J.Clin.1nvest. (1995) 96:2924-2931；With Cernadas etc., Am.J.Respir.Cell Mol.Biol.(1999)20:Described in 1-8.
The substance of the present invention is alternatively arranged as combination therapeutic agent for being applied in combination with other medicines substance, such as anti-inflammatory agent, branch Tracheaectasy medicine or antihistamine drug substances, particularly for treating obstructive or airway inflammatory disease, as mentioned above Those, such as these drug therapies activity synergist or as reduce these drugs needed for dosage or potential pair The means of effect.The substance of the present invention can mix in fixed drug composition with other medicines substance or can be at it It is administered alone prior to, concurrently with, or after the application of its drug substance.The present invention include invention discussed above substance with it is anti-inflammatory The combination of the drug substances such as medicine, bronchodilators or antihistamine, the substance and the drug substance of the present invention It can be in identical or different pharmaceutical composition.Such anti-inflammatory agent hinders admittedly including class, particularly glucocorticosteroid such as cloth Ground shrinkage porosite, beclomeasone propionate, Fluticasone Propionate, ciclesonide or furancarboxylic acid dish meter Ta Song and WO 0200679, WO 0288167, Compound, LTB4 antagonists described in WO 0212266 and WO 02100879 as described in US5451700, LTD4 Antagonist such as montelukast and zafirlukast, dopamine-receptor stimulant such as Cabergoline, bromocriptine, tired sharp Lip river and 4- hydroxyls Base -7- [2- [[2- [[3- (2- phenyl ethoxies)-propyl]-sulfonyl]-ethyl]-amino] ethyl] -2 (3H)-benzothiazoles (hydrochloride is for ketone and its officinal salt- AstraZeneca) and PDE4 inhibitor is such as (GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH- 351591 (Schering-Plough), arofylline (AlmirallProdesfarma), PD189659 (Parke-Davis), AWD-12-281 (AstaMedica), CDC-801 (Celgene) and KW-4490 (Kyowa Hakko Kogyo) and WO 98/ Those described in 18796 and WO 03/39544.Such bronchodilators includes anticholinergic drug or antimuscarinic drug, Particularly Ipratropium Bromured, Oxitropium Bromide and tiotropium salt also have WO 01/04118, WO 02/51841, WO 02/ 53564、WO 03/00840、WO 03/87094、WO 04/05285、WO 02/00652、WO 03/53966、EP 424021、 Those described in US 5171744, US 3714357 and WO 03/33495 and beta-2-adrenoceptor agonist such as sand Butylamine alcohol, Terbutaline, salmeterol and Formoterol and its officinal salt and pct international patent announce WO 00/75114 Compound of formula I (free form or salt form or solvate form thereof) in (which is incorporated herein by reference), preferably The antihistamine drug substances of the compound combination treatment of embodiment include Cetirizine Hydrochloride, paracetamol, fumaric acid chlorine Maas fourth, fenazil, Loratadine, Desloratadine (desloratidine), diphenhydramine and hydrochloric acid Fexofenadine.This hair The combination of bright substance and steroids, β -2 agonists, PDE4 inhibitor or LTD4 antagonists can be used for for example treating COPD or spy It is not asthma.Substance and the anticholinergic drug or antimuscarinic drug of the present invention, PDE4 inhibitor, dopamine-receptor stimulant or The combination of LTB4 antagonists can be used for for example treating asthma or particularly COPD.The present invention substance and anti-inflammatory agent it is other useful Combination be with chemokine receptor anagonists such as CCR-l, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, The combination of CCR-8, CCR-9, CCR10, CXCRl, CXCR2, CXCR3, particularly CXCR4, CXCR5, the antagonist of CCR-5, institute State antagonist such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N- [[4- [[[6,7- dihydros -2- (4- aminomethyl phenyls) -5H- benzo ring heptene -8- bases] hydroxyl] amino] phenyl]-methyl] tetrahydrochysene - N, N- dimethyl -2H- pyrans -4- ammonium chlorides (TAK-770) and US6166037 (particularly claim 18 and 19), WO 00/ CCR-5 antagonists described in 66558 (particularly claims 8) and WO 00/66559 (being particularly claim 9).
The substance of the present invention can be applied by any appropriate approach, such as be administered orally, such as with tablet or capsule Form is administered orally；Parenteral for example intravenous application；It is applied by sucking, such as controlling in inflammatory or obstructive airway diseases In treatment；Intranasal administration, such as in the treatment of allergic rhinitis；To topical application, such as the treatment in atopic dermatitis In；Or rectal administration, such as in the treatment of inflammatory bowel disease.
The present invention also provides pharmaceutical composition, it includes free form or the compound of formula I of pharmaceutical acceptable salt, optionally Ground and suitable pharmaceutically useful diluent or carrier.Said composition can contain combination therapeutic agent, as described above anti-inflammatory Medicine, bronchodilators or antihistamine.Such composition can use conventional diluent or excipient and Galenic formula In field prepared by known technology.Therefore, peroral dosage form can include tablets and capsules.
Cream, ointment, gelling agent or transdermal delivery system such as patch may be employed in formulations for topical administration Form.Composition for inhalation can include aerosol or other aerosolizable preparations or dry powder formulations.
When composition includes aerosol formulation, such as hydrogen-fluoro- alkane (HFA) propellant such as HFA134a is preferably comprised Or HFA227 or these mixture, one or more cosolvents known in the art such as ethyl alcohol can be contained (by weight extremely It is more 20%) and/or one or more surfactant such as oleic acid or three olease of sorbitan and/or one or more Filler such as lactose.When composition includes dry powder doses, such as Formulas I chemical combination with no more than 10 micron grain sizes is preferably comprised Object optionally and has the diluent or carrier such as lactose of required particle diameter distribution and helps to prevent product property because making moist And the compound being deteriorated.When composition includes spray formulation, the Formulas I for for example dissolving or being suspended in media as well is preferably comprised Object is closed, the medium contains water, cosolvent such as ethyl alcohol or propylene glycol and stabilizer, can be surfactant.
The dosage of substance of the present invention used in the embodiment of this invention will be according to the specific illness, desired for example treated Effect and method of application difference and change.In general, the suitable dose of oral administration is 0.1 to 10mg/kg ranks.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art with being described herein Method combination, the compound of formula (I) can be synthesized.In addition, solvent given herein, temperature and other reaction conditions can roots Change according to art technology.As further guidance, following synthetic method can also be utilized.
The reaction can use in order, to provide compound described herein；Or they can be used for synthesizing segment, The segment is then added in by method described herein and/or methods known in the art.
In some embodiments, it provided herein is the preparations of BCR-ABL kinase inhibitor compounds described herein Method and its application method.In some embodiments, compound described herein can be synthesized using following synthetic schemes.It can With use with following similar methods, by using appropriate selectable starting material, synthesize compound.
Starting material for synthesizing compound described herein can be synthesized or can be obtained from commercial source.Herein The compound of description can use technology well known by persons skilled in the art to other related compounds with different substituents And Material synthesis.The conventional method for preparing compound disclosed herein can come from reaction known in the art, and the reaction It can be changed by the reagent and condition thought fit by those skilled in the art, it is each in the molecule of offer to be incorporated herein Kind part.
If desired, reaction product can use routine techniques to separate and purify, including but not limited to filter, distill, knot The methods of crystalline substance, chromatography.These products can be characterized using conventional method, including physical constant and spectrum data.
The non-limiting example of the synthetic schemes of the compound of formula (I) is prepared referring to table 1.
The structure of 1. embodiment compound of table
Using synthetic method described herein and methods known in the art, obtained herein with good yield and purity Disclosed compound.The compound prepared according to method disclosed herein is purified by conventional method known in the art, such as Filtering, recrystallization, chromatography, distillation and combinations thereof.
Site on the aromatic moiety of the compound of formula (I) may be easy to that various metabolic responses occur, therefore appropriate Substituent group be introduced on aromatic ring structure, for example, only for example, halogen can reduce, this metabolism is reduced or eliminated Approach.
Embodiment
Non-limiting example in detail below is to be interpreted as being merely illustrative, not limit in any way originally It is open.Although need not be described in further detail, it is believed that those skilled in the art can be based on description herein, completely profit Use the disclosure.
Embodiment 1
The synthesis of the compounds of this invention
Scheme 1
4- (methylamino) -2- (methyl mercapto) pyrimidine -5- Ethyl formates (2)：4- chloro- 2- (first sulphur is added in round-bottomed flask Base) pyrimidinecarboxylic acid ethyl ester (1.0 grams) adds in tetrahydrofuran THF (10 milliliters), methylamine hydrochloride (0.58 gram) afterwards.It is subsequently added into three Ethamine TEA (2.1 milliliters).Reaction system at room temperature, argon gas protection reaction 14 it is small when.After reaction, system is under reduced pressure Solvent evaporated, gains are extracted with ethyl acetate after being diluted with water.Organic phase after water, saturated common salt water washing with respectively with using nothing Aqueous sodium persulfate is dried.Organic phase is filtered, and crude product, MS (ESI) m/z (M+H) are obtained after evaporated under reduced pressure+:228.07。
4- (methylamino) -2- (methyl mercapto) pyrimidine -5- formic acid (3)：4- (methylamino) -2- (first is added in round-bottomed flask Sulfenyl) pyrimidine -5- Ethyl formates (1.0 grams) add in methanol (20 milliliters), 1 mole of every liter of sodium hydroxide solution (5 milliliters) afterwards.Instead Answer system at room temperature, argon gas protection reaction 14 it is small when.After reaction, system solvent evaporated under reduced pressure, gains water 6 moles every liter of hydrochloric acid solution is added dropwise after (50 milliliters) dilutions and causes pH as 3~4.The white precipitate generated in system is filtered, washes Wash, dry after crude product, MS (ESI) m/z (M+H)+:200.04。
3- (trifluoromethyl) chlorobenzoyl chloride (5)：3- (trifluoromethyl) benzoic acid (1.0 grams) is added in round-bottomed flask afterwards to add Enter anhydrous methylene chloride (10 milliliters), with ice-water bath system is made to be cooled to 0 degree after ethoxalyl chlorine (2 milliliters).1 drop N is subsequently added into, Dinethylformamide.Reaction system at room temperature, argon gas protection reaction 10 it is small when.After reaction, system is steamed under reduced pressure Crude product is obtained after dry solvent.
N- (4- methyl-3-nitros phenyl) -3- (trifluoromethyl) benzamide (6)：Added in round-bottomed flask 4- methyl- 3- nitroanilines (1.52 grams) are added in afterwards after anhydrous tetrahydro furan (10 milliliters), triethylamine (4 milliliters) makes system cold with ice-water bath But to 0 degree.Then it is slowly added to 3- (trifluoromethyl) chlorobenzoyl chloride (2.08 grams).Reaction system at room temperature, argon gas protection it is anti- Answer 2 it is small when.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase With being dried respectively with after water, saturated common salt water washing with anhydrous sodium sulfate.Organic phase is filtered, and crude product, MS are obtained after evaporated under reduced pressure (ESI)m/z(M+H)+:325.05。
N- (3- amino -4- aminomethyl phenyls) -3- (trifluoromethyl) benzamide (7)：N- (4- first is added in round-bottomed flask Base -3- nitrobenzophenones) -3- (trifluoromethyl) benzamide (3.25 grams) adds in methanol (10 milliliters), 10%Pd/C (0.3 afterwards Gram).Then reaction system stir under hydrogen 2 it is small when.After reaction, system is filtered, after washing after evaporated under reduced pressure slightly Product, MS (ESI) m/z (M+H)+:295.1.05。
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (methyl mercapto) pyrimidines -5- Formamide (8)：N- (3- amino -4- aminomethyl phenyls) -3- (trifluoromethyl) benzamide (2.95 grams) is added in round-bottomed flask N,N-Dimethylformamide (10 milliliters) is added in afterwards, is subsequently added into HATU (3.80 grams), DIPEA (1.29 grams) and 4- (first ammonia Base) -2- (methyl mercapto) pyrimidine -5- formic acid (2.00 grams).Reaction system at room temperature, argon gas protection reaction 12 it is small when.Reaction knot Shu Hou, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase is used to be used water, satisfies respectively It is dried with after brine It with anhydrous sodium sulfate.Organic phase is filtered, and crude product, MS (ESI) m/z (M+H are obtained after evaporated under reduced pressure )+:476.12。
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) -4- (methylamino -2- (pyrovinic acid base) pyrimidine -5- first Amide (compound 9)：N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamines are added in round-bottomed flask Base) -2- (methyl mercapto) pyrimidine -5- formamides (0.47 gram) add in dichloromethane (10 milliliters) afterwards, it is subsequently added into mCPBA (0.40 Gram).Reaction system at room temperature, argon gas protection reaction 2 it is small when.After reaction, system is diluted with ethyl acetate.Organic phase is used It is dried respectively with after saturated sodium carbonate, water, saturated common salt water washing with anhydrous sodium sulfate.Organic phase is filtered, after evaporated under reduced pressure Obtain crude product, MS (ESI) m/z (M+H)+:508.11。
(2- methyl -5- (3- (trifluoromethyl) benzamide) -4- (methylamino) is phonetic by 2- (4- methyl-3-nitros aniline)-N- Pyridine -5- formamides (compound 10)：N- (2- methyl -5- (3- (trifluoromethyl) benzamide) -4- are added in round-bottomed flask (methylamino -2- (pyrovinic acid base) pyrimidine -5- formamides) (0.51 gram) adds in anhydrous Isosorbide-5-Nitrae-dioxane (2 milliliters) afterwards, connects Addition 4- methyl-3-nitros aniline (1.52 grams), trifluoroacetic acid (0.57 gram).Reaction system is in 120 degree, argon gas protection reaction 2 it is small when.After reaction, system is diluted with ethyl acetate.Organic phase is with respectively with saturated sodium carbonate, water, saturated common salt washing It is dried after washing with anhydrous sodium sulfate.Organic phase is filtered, and crude product is obtained after evaporated under reduced pressure.After the pressurized silica gel column chromatography purification of crude product Obtain sterling, MS (ESI) m/z (M+H)+:580.18。
2- (3- amino -4- methylphenylaminos)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) -4- (methyl ammonia Base) pyrimidine -5- formamides (compound 11)：2- (4- methyl-3-nitros aniline)-N- (2- methyl -5- are added in round-bottomed flask (0.58 gram) of (3- (trifluoromethyl) benzamide) -4- (methylamino) pyrimidine -5- formamides add in methanol (10 milliliters).Then plus Enter dichloride stannous (2.25 grams).Reaction system is when 100 degree, argon gas protect reaction 5 small.After reaction, system is rubbed with 10 The sodium hydroxide of every liter of that easily adjusts pH as~10.System is filtered, with 1:Cake is considered in 1 ethanol/methylene washing.Consider liquid Crude product is obtained after evaporated under reduced pressure, sterling, MS (ESI) m/z (M+H) are obtained after the pressurized silica gel column chromatography purification of crude product+:550.21。
2- (3- allyl amide -4- methylphenylaminos)-N- (2- methyl -5- (3- trifluoromethyls) benzamide) phenyl) - 4- (methylamino) pyrimidine -5- formamides (compound 12)：2- (3- amino -4- methylphenylaminos)-N- is added in round-bottomed flask ((0.055 gram) addition tetrahydrochysene furan of 2- methyl -5- (3- (trifluoromethyl) benzamide) -4- (methylamino) pyrimidine -5- formamides It mutters (1 milliliter).It is subsequently added into acryloyl chloride (0.009 gram), n,N-diisopropylethylamine DIPEA (0.029 gram).Reaction system exists Under 0 degree, argon gas protection reaction 2 it is small when.After reaction, system is diluted with ethyl acetate.Organic phase with using unsaturated carbonate respectively It is dried after sodium, water, saturated common salt water washing with anhydrous sodium sulfate.Sterling, MS are obtained after the pressurized silica gel column chromatography purification of crude product (ESI)m/z(M+H)+:604.22。
Embodiment 2
Tertiary butyl 2- methyl-5-nitrophenyls amide (15)：2- methyl-5-nitro aniline is added in round-bottomed flask (10.0 grams), tetrahydrofuran (50 milliliters), (Boc)2O (20.0 grams) and 4-dimethylaminopyridine DMAP (0.3 gram).Reactant Tie up under 0 degree, argon gas protection reaction 1 it is small when, then reaction system reflux 12 it is small when.After reaction, system ethyl acetate Dilution.Organic phase is dried respectively with after saturated sodium carbonate, water, saturated common salt water washing with anhydrous sodium sulfate.Organic phase is through separation Crude product is obtained after purification.MS(ESI)m/z(M+H)+:253.01。
Tertiary butyl 5- amino-2-methyls phenyl amide (16)：15 (10.0 grams), methanol (50 millis are added in round-bottomed flask Rise) and 10%Pd/C (1 gram).System be stirred to react under hydrogen 2 it is small when.It is filtered after reaction, solvent evaporated after washing Obtain crude product MS (ESI) m/z (M+H)+:223.11。
Tertiary butyl 4- methyl -3- (4- (methylamino) -2- (methyl mercapto) pyrimidine -5- benzoic acid amides) phenyl amide (17)： 3 (1.99 grams) are added in round-bottomed flask and add in n,N-Dimethylformamide (20 milliliters) afterwards, are subsequently added into 2- (7- azos benzos three Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester HATU (3.80 grams), N, N- diisopropylethylamine DIPEA (1.29 grams) With 16 (2.23 grams).Reaction system at room temperature, argon gas protection reaction 12 it is small when.After reaction, system is evaporated under reduced pressure Solvent, gains are extracted with ethyl acetate after being diluted with water.Organic phase after water, saturated common salt water washing respectively with using anhydrous slufuric acid Sodium is dried.Organic phase is filtered, and crude product, MS (ESI) m/z (M+H) are obtained after evaporated under reduced pressure+:404.12。
N- (5- amino -2- tolyls) -4- (methylamine) -2- (methyl mercapto) pyrimidine -5- formamides (18)：In round-bottomed flask It adds in 17 (10 grams) and adds in ethyl acetate (50 milliliters) afterwards, be subsequently added into the ethyl acetate (30 milliliters) of 4M hydrochloric acid.Reaction system At room temperature, when argon gas protection reaction 12 is small.After reaction, system solvent evaporated under reduced pressure, after evaporated under reduced pressure crude product, MS(ESI)m/z(M+H)+:304.12。
N- (5- (3- methoxybenzenes amide) -2- tolyls) -4- (methylamino) -2- (methyl mercapto) pyrimidine -5- formamides (19)：It is added in round-bottomed flask after 18 (0.304 grams) add in anhydrous tetrahydro furan (5 milliliters), triethylamine (4 milliliters) afterwards and uses ice Water-bath makes system be cooled to 0 degree.Then it is slowly added to 3- (trifluoromethyl) chlorobenzoyl chloride.Reaction system at room temperature, argon gas protect When shield reaction 2 is small.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Have Machine with after water, saturated common salt water washing with anhydrous sodium sulfate mutually with being dried respectively.Organic phase is filtered, is obtained slightly after evaporated under reduced pressure Product, MS (ESI) m/z (M+H)+:438.15。
N- (5- (3- methoxy benzamides) -2- tolyls) -4- (methylamino) -2- (methyl sulfone) pyrimidine -5- formamides (compound 20)：19 (0.47 grams) are added in round-bottomed flask and add in dichloromethane (10 milliliters) afterwards, are subsequently added into mCPBA (0.40 gram).Reaction system at room temperature, argon gas protection reaction 2 it is small when.After reaction, system is diluted with ethyl acetate.Have Machine is mutually dried with after saturated sodium carbonate, water, saturated common salt water washing with anhydrous sodium sulfate respectively.Organic phase is filtered, and decompression is steamed Crude product, MS (ESI) m/z (M+H) are obtained after dry+:470.11。
N- (5- (3- methoxy benzamides) -2- tolyls) -2- (4- methyl-3-nitros aniline) -4- (methylamino) is phonetic Pyridine -5- formamides (compound 21)：20 (0.51 grams) are added in round-bottomed flask and add in anhydrous 1,4- dioxane (2 millis afterwards Rise), it is subsequently added into 4- methyl-3-nitros aniline (1.52 grams), trifluoroacetic acid (0.57 gram).Reaction system is protected in 120 degree, argon gas When shield reaction 2 is small.After reaction, system is diluted with ethyl acetate.Organic phase is respectively with saturated sodium carbonate, water, saturated common salt It is dried after water washing with anhydrous sodium sulfate.Organic phase is filtered, and crude product is obtained after evaporated under reduced pressure.The pressurized silica gel column chromatography of crude product carries Sterling, MS (ESI) m/z (M+H) are obtained after pure+:542.10。
2- (3- amino -4- methylanilines)-N- (5- (3- methoxy benzamides) -2- toluene) -4- (methylamino) pyrimidine - 5- formamides (compound 22)：21 (0.58 grams) and methanol (10 milliliters) are added in round-bottomed flask.It is subsequently added into dichloride Asia Tin (2.25 grams).Reaction system is when 100 degree, argon gas protect reaction 5 small.After reaction, 10 moles every liter of hydrogen of system It is~10 that sodium hydroxide solution, which adjusts pH,.System is filtered, with 1:1 ethanol/methylene washing filter cake.Filtrate is through evaporated under reduced pressure Crude product is obtained afterwards, and sterling, MS (ESI) m/z (M+H) are obtained after the pressurized silica gel column chromatography purification of crude product+:512.21。
2- (3- acrylamide -4- toluidinos)-N- (5- (3- methoxy benzamides base) -2- tolyls) -4- (first ammonia Base) pyrimidine -5- formamides (compound 23)：22 (0.055 grams) and tetrahydrofuran (1 milliliter) are added in round-bottomed flask.Then Add in acryloyl chloride (0.009 gram), n,N-diisopropylethylamine DIPEA (0.029 gram).Reaction system is under 0 degree, argon gas protection React 2 it is small when.After reaction, system is diluted with ethyl acetate.Organic phase is respectively with saturated sodium carbonate, water, saturated salt solution It is dried after washing with anhydrous sodium sulfate.Sterling, MS (ESI) m/z (M+H) are obtained after the pressurized silica gel column chromatography purification of crude product+: 566.22。
Embodiment 3
(S) (5- (2- methyl -5- (3- (trifluoromethyl) benzamide) carbaniloyl)-(methylaminos) is phonetic by tertiary butyl 3- Pyridine -2- oxygroups) pyrroles -1- carboxylic acids (compound 32)：9 (0.58 grams), tetrahydrofuran THF (10 millis are added in round-bottomed flask Rise), (S)-tertiary butyl 3- hydroxypyrrole -1- carboxylic acids (2 grams), be subsequently added into potassium carbonate (2.25 grams).Reaction system 100 degree, When argon gas protection reaction 5 is small.System is filtered, with 1:1 ethanol/methylene washing filter cake, filtrate obtain after evaporated under reduced pressure Crude product obtains sterling, MS (ESI) m/z (M+H) after the pressurized silica gel column chromatography purification of crude product+:615.20。
(S)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (pyrroles's -3- oxygen Base) phonetic -5- formamides (compound 33)：33 (0.05 grams) are added in round-bottomed flask and add in ethyl acetate (1 milliliter) afterwards, then Add in the ethyl acetate (1 milliliter) of 4M hydrochloric acid.Reaction system at room temperature, argon gas protection reaction 12 it is small when.After reaction, body System's solvent evaporated under reduced pressure, after evaporated under reduced pressure crude product, MS (ESI) m/z (M+H)+:515.14。
Embodiment 4
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl -2,4- two (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 24 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 459。
Embodiment 5
2- (3,4- dimethylanilines)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) Pyrimidine -5- formamides
The step of synthesis of compound 25 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 549.22。
Embodiment 6
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (p- methylanilines) is phonetic Pyridine -5- formamides
The step of synthesis of compound 26 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 535.19。
Embodiment 7
N- (4- methyl -3- (3- (trifluoromethyl) benzamide) phenyl) -2- (4- methyl-3-nitros aniline) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 27 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 580.18。
Embodiment 8
2- (4- methyl -3- (trifluoromethyl) phenylamino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) benzene Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 28 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 602.19。
Embodiment 9
2- (4- nitrophenols)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) is phonetic Pyridine -5- formamides
The step of synthesis of compound 29 is by using similar to described in embodiment 3 is completed.MS(ESI)m/z(M+1)+: 567.16。
Embodiment 10
2- (4-aminophenol)-N- (2- methyl 5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) pyrimidine - 5- formamides
The step of synthesis of compound 30 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 537.19。
Embodiment 11
2- (4- acrylamides phenol)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) Pyrimidine -5- formamides
The step of synthesis of compound 31 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 590.20。
Embodiment 12
N- (2- methyl 5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (3- morpholine propylamines) pyrimidine - 5- formamides
The step of synthesis of compound 34 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 571.25。
Embodiment 13
(5- (2- methyl -5- (3- (trifluoromethyl) benzamide) benzyl carbamyl) -4- (methylamino) is phonetic by tertiary butyl 4- Pyridine -2- amino) piperidines -1- carboxylic acids
The step of synthesis of compound 35 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 627.27。
Embodiment 14
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (piperidines -4- amino) is phonetic Pyridine -5- base amides
The step of synthesis of compound 36 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 527.22。
Embodiment 15
2- (1- (2- chloracetyls) piperidines -4- amino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) benzene Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 37 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1 )+:。604.19
Embodiment 16
2- (1- acrylamide piperidines -4- amino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 38 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 582.26。
Embodiment 17
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (1- propionamide piperidines -4- Amino) pyrimidine -5- formamides
The step of synthesis of compound 39 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 584.26。
Embodiment 18
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl -4- (methylamino) -2- (1- propine amides piperidines - 4- amino) pyrimidine -5- formamides
The step of synthesis of compound 40 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 579.22。
Embodiment 19
N- (5- biphenyl -3- formamide -2- tolyls) -4- (methylamino) -2- mesyls) pyrimidine -5- formamides
The step of synthesis of compound 41 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 516.16。
Embodiment 20
N- (5- (3,5- dimethylamino benzophenones amide) -2- tolyls) -4- (methylamino) -2- (mesyl) pyrimidine -5- formyls Amine
The step of synthesis of compound 42 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 468.16。
Embodiment 21
N- (5- (3,5- t-butylbenzamides) -2- tolyls) -4- (methylamino) -2- (mesyl) pyrimidine -5- first Amide
The step of synthesis of compound 43 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 552.25。
Embodiment 22
N- (2- methyl -5- (3- methyl benzamides) phenyl) -4- (methylamino) -2- (mesyl) pyrimidine -5- formyls Amine
The step of synthesis of compound 44 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 454.14。
Embodiment 23
N- (5- (3- (dichloromethyl) benzamide) -2- tolyls -4- (methylamino) -2- (mesyl) pyrimidine -5- first Amide
The step of synthesis of compound 45 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 522.16。
Embodiment 24
N- (5- biphenyl -3- formamide -2- tolyls) -2- (4- methyl-3-nitros aniline) -4- (methylamino) pyrimidines -5- Formamide
The step of synthesis of compound 46 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 588.21。
Embodiment 25
N- (5- (3,5- dimethyl benzamides) -2- tolyls) -2- (4- methyl-3-nitros aniline) -4- (methylamino) Pyrimidine -5- formamides
The step of synthesis of compound 47 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 540.22。
Embodiment 26
N- (5- (3,5- t-butylbenzamides) -2- tolyls) -2- (4- methyl-3-nitros aniline) -4- (methylamino) Pyrimidine -5- formamides
The step of synthesis of compound 48 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 624.10。
Embodiment 27
2- (4- methyl-3-nitros aniline)-N- (2- methyl -5- (3- methyl benzamides) phenyl) -4- (methylamino) is phonetic Pyridine -5- formamides
The step of synthesis of compound 49 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 525.21。
Embodiment 28
N- (5- (3- (dichloromethyl benzamide) -2- tolyls) -2- (4- methyl-3-nitros aniline) -4- (methylamino) Pyrimidine -5- formamides
The step of synthesis of compound 50 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 594.13。
Embodiment 29
2- (3- amino -4- methyl benzamides)-N- (5- biphenyl -3- formamide -2- tolyls) -4- (methylamino) is phonetic Pyridine -5- formamides
The step of synthesis of compound 51 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 578.25。
Embodiment 30
2- (3- amino -4- toluidinos)-N- (5- (3,5- dimethyl benzamides) -2- methylaminos) -4- (methylamino) Pyrimidine -5- formamides
The step of synthesis of compound 52 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 510.26。
Embodiment 31
2- (3- amino -4- toluidinos)-N- (5- (3,5- t-butylbenzamides) -2- aminomethyl phenyls) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 53 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 594.34。
Embodiment 32
2- (3- amino -4- methylphenylaminos)-N- (2- methyl -5- (this amide of 3- methyl) phenyl) -4- (methylamino) is phonetic Pyridine -5- formamides
The step of synthesis of compound 54 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 496.23。
Embodiment 33
2- (4- methyl -3- (mesyl) benzene amine-n-(2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 55 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 613.17。
Embodiment 34
(5- (2- methyl -5- (3- (trifluoromethyl) this base amide) benzyl carbamyl amine) -4- (methylamino) is phonetic by tertiary butyl 4- Pyridine -2- oxygroups) piperidines -1- acid
The step of synthesis of compound 56 is by using similar to described in embodiment 3 is completed.MS(ESI)m/z(M+1)+: 629.16。
Embodiment 35
N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) -2- (piperidines -4- oxygroups) is phonetic Pyridine -5- formamides
The step of synthesis of compound 57 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 528.21。
Embodiment 36
2- (1- acrylamide piperidines -4- oxygroups)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 58 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 583.22。
Embodiment 37
N- (2- methyl -5- (3- (trifluoromethyl) benzoyl) phenyl) -4- (methylamino) -2- (1- propionamide piperidines -4- Oxygroup) pyrimidine -5- formamides
The step of synthesis of compound 59 is by using similar to described in embodiment 1 is completed.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- formamides
The step of synthesis of compound 60 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 564.22。
Embodiment 39
2- (3- (dimethylamino) -4- methylphenylaminos)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) benzene Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 61 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 578.24。
Embodiment 40
2- (4- methyl -3- (mesyl) phenylamino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) benzene Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 62 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 597.18。
Embodiment 41
2- (4- methyl -3- sulfonamide phenyls amino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 63 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 614.30。
Embodiment 42
4- methoxyl groups-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) -2- (mesyl) pyrimidines -5- Formamide
The step of synthesis of compound 64 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 509.10。
Embodiment 43
4- hydroxyls -2- (4- methyl-3-nitros phenylamino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) benzene Base) pyrimidine -5- formamides
The step of synthesis of compound 65 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 567.15。
Embodiment 44
2- (3- amino -4- methylphenylaminos) -4- hydroxy-ns-(2- methyl -5- (3- (trifluoromethyl) benzamide) benzene Base) pyrimidine -5- formamides
The step of synthesis of compound 66 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 537.17。
Embodiment 45
4- (dimethylamino)-N- (2- methyl 5- (3- (trifluoromethyl) benzamide) phenyl) -2- (Methanesulfomide) pyrimidine - 5- formamides
The step of synthesis of compound 67 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 522.13。
Embodiment 46
4- (dimethylamino) -2- (4- methyl-3-nitros phenylamino)-N- (2- methyl -5- (3- (trifluoromethyl) benzoyls Amine) phenyl) pyrimidine -5- formamides
The step of synthesis of compound 68 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 594.19。
Embodiment 47
2- (3- amino -4- methylphenylaminos) -4- (dimethylamino)-N- (2- methyl -5- (3- (trifluoromethyl) benzoyls Amine) phenyl) pyrimidine -5- carboxamide hydrochlorides
The step of synthesis of compound 69 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 564.22。
Embodiment 48
2- (4- methyl -3- propionamido-s phenylamino)-N- (2- methyl -5- (3- (trifluoromethyl) benzamide) phenyl) - 4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 70 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 606.23。
Embodiment 49
N- (5- (3- methoxy benzamides) -2- aminomethyl phenyls) -2- (4- methyl -3- propionamido-s phenylamino) -4- (first Amino) pyrimidine -5- formamides
The step of synthesis of compound 71 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 568.25。
Embodiment 50
N- (5- (4- methoxy benzamides) -2- methylaminos) -2- (4- methyl-3-nitros phenylamino) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 72 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 542.20。
Embodiment 51
2- (3- amino -4- methylphenylaminos)-N- (5- (4- methoxy benzamides) -2- aminomethyl phenyls) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 73 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 512.23。
Embodiment 52
N- (5- (4- methoxy benzamides) -2- aminomethyl phenyls) -2- (4- methyl -3- propionic acids phenylamino) -4- (first Amino) pyrimidine -5- formamides
The step of synthesis of compound 74 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 568.25。
Embodiment 53
2- (3- acrylamide -4- methylphenylaminos)-N- (5- (4- methoxy benzamides) -2- methylaminos) -4- (first Amino) pyrimidine -5- formamides
The step of synthesis of compound 75 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 566.24。
Embodiment 54
2- (3- nitro-4-methyls phenylamino)-N- (5- (3,5- dimethoxybenzarnides) -2- aminomethyl phenyls) -4- (first Amino) pyrimidine -5- formamides
The step of synthesis of compound 76 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 572.21。
Embodiment 55
2- (3- amino -4- methylphenylaminos)-N- (5- (3,5- dimethoxybenzarnides) -2- aminomethyl phenyls) -4- (first Amino) pyrimidine -5- formamides
The step of synthesis of compound 77 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 542.14。
Embodiment 56
N- (5- (3,5- dimethoxybenzarnides) -2- aminomethyl phenyls) -2- (4- methyl -3- propionamides phenylamino) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 78 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 598.27。
Embodiment 57
2- (3- acrylamide -4- methylphenylaminos)-N- (5- (3,5- dimethoxybenzarnides) -2- aminomethyl phenyls) - 4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 79 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 596.25。
Embodiment 58
N- (5- (3,4- dimethoxybenzarnides) -2- aminomethyl phenyls) -2- (4- methyl-3-nitros aniline) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 80 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 572.21。
Embodiment 59
2- (3- amino -4- methylphenylaminos)-N- (5- (the basic formyl of 3,4- dimethoxies) -2- aminomethyl phenyls -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 81 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 542.24。
Embodiment 60
N- (5- (3,4- dimethoxybenzarnides) -2- aminomethyl phenyls) -2- (4- methyl -3- propionic acids phenylamino) - 4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 82 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 598.27。
Embodiment 61
2- (3- acrylamide -4- methylphenylaminos)-N- (5- (3,4- dimethoxybenzarnides) -2- aminomethyl phenyls) - 4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 83 is by using similar to described in embodiment 2 is completed.MS(ESI)m/z(M+1)+: 596.25。
Embodiment 62
2- (4- methyl-3-nitros aniline)-N- (2- methyl -5- (the basic formyl of 3,4,5- trimethoxies) phenyl) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 84 is by using similar to described in embodiment 2 is completed.MS(ESI)m/z(M+1)+: 602.22。
Embodiment 63
2- (3- amino -4- methylphenylaminos)-N- (2- methyl -5- (3,4,5- trimethoxy-benzamides) phenyl) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 85 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 572.25。
Embodiment 64
2- (4- methyl -3- propionic acids phenylamino)-N- (2- methyl -5- (3,4,5- trimethoxy-benzamides) benzene Base) -4- (methylamine) pyrimidine -5- formamides
The step of synthesis of compound 86 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 628.28。
Embodiment 65
2- (3- acrylamide -4- methylphenylaminos)-N- (2- methyl -5- (3,4,5- trimethoxy-benzamides) benzene Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 87 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 626.26。
Embodiment 66
2- (3- amino -4- methylphenylaminos)-N- (5- (benzo [d] [1,3] dioxy ring -5- formamides) -2- methylbenzenes Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 88 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 526.21。
Embodiment 67
N- (5- (benzo [d] [1,3] dioxy ring -5- formamides) -2- aminomethyl phenyls) -2- (4- methyl -3- propionic acid benzene Amino) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 89 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 582.23。
Embodiment 68
2- (3- acrylamide -4- methylphenylaminos)-N- (5- (benzo [d] [1,3] dioxy ring -5- formamides) -2- methyl Phenyl) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 90 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 580.22。
Embodiment 69
N- (5- (2- methoxy benzamides) -2- aminomethyl phenyls) -2- (4- methyl-3-nitros phenylamino) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 91 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 542.10。
Embodiment 70
2- (3- amino -4- methylphenylaminos)-N- (5- (2- methoxy benzamides) -2- aminomethyl phenyls) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 92 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 512.23。
Embodiment 71
N- (5- (2- methoxy benzamides) -2- aminomethyl phenyls) -2- (4- methyl -3- propionic acids phenyl) -4- (first ammonia Base) pyrimidine -5- formamides
The step of synthesis of compound 93 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 568.25。
Embodiment 72
2- (3- acrylamide -4- methylphenylaminos)-N- (5- (2- methoxy benzamides) -2- aminomethyl phenyls) -4- (first Amino) pyrimidine -5- formamides
The step of synthesis of compound 94 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 566.24。
Embodiment 73
N- (5- (4- methoxy benzamides) -2- aminomethyl phenyls) -4- (methylamino) -2- (mesyl) pyrimidine -5- first Amide
The step of synthesis of compound 95 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 470.14。
Embodiment 74
N- (5- (2- methoxy benzamides) -2- aminomethyl phenyls) -4- (methylamino) -2- (mesyl) pyrimidine -5- first Amide
The step of synthesis of compound 96 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 470.14。
Embodiment 75
N- (5- (3,5- trimethoxy-benzamides) -2- aminomethyl phenyls) -4- (methylamino) -2- (mesyl) pyrimidine - 5- formamides
The step of synthesis of compound 97 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 500.15。
Embodiment 76
N- (2- methyl -5- (3,4,5- trimethoxy-benzamides) phenyl) -4- (methylamino) -2- (mesyl) is phonetic Pyridine -5- formamides
The step of synthesis of compound 98 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 530.16。
Embodiment 77
N- (5- (benzo [d] [1,3] dioxy ring -5- formamides) -2- aminomethyl phenyls) -4- (methylamino) -2- (methylsulfonyls Base) -4- (methylamino) pyrimidine -5- formamides
The step of synthesis of compound 99 is by using similar to described in embodiment 1 is completed.MS(ESI)m/z(M+1)+: 484.12。
Embodiment 78
Influence of the BCR-ABL kinase inhibitors to cancer cell multiplication
By influence of the test b CR-ABL kinase inhibitors to cancer cell multiplication, we further have evaluated compound 9, Compound 10, compound 11, compound 67, compound 68, compound 69 and comparison medicine BCR-ABL kinase inhibitors Imatinib, Nilotinib (Imatinib and Nilotinib are purchased from Hao Yuan Chemexpress companies, Shanghai) are right The influence of the growth of cancer cell, we also further have evaluated compound 9, compound 10, compound 11, compound 67, chemical combination Object 68, compound 69 inhibit the selectivity of cancer cell multiplication.We have selected CHL cells CHL, China in embodiment Hamster ovary cell CHO (Cricetulus griseus, hamster, Chinese, ovary), human B cell chronic lymphocytic Leukemia cell line MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes), people are chronic Myelogenous leukemia Ku812 (expression BCR-ABL genes), mouse pro B lymphocyte BaF3, more than cell are purchased from ATCC.Also select Mouse Tel-BMX-BaF3 (stablizing expression BMX kinases), mouse Tel-Abl-BaF3 (stablizing expression ABL kinases), mouse BaF3- It is BCR-ABL (activated protein kinase for stablizing expression BCR-ABL mutation), mouse Tel-cKit-BaF3 (stablize expression cKIT kinases), small Mouse TEL-KIT-N822K (activated protein kinase for stablizing expression cKIT N882K mutation), mouse TEL-KIT-D816V (stablize expression The activated protein kinase of cKIT D816V mutation), mouse TEL-ABL-T315I-BaF3 (stablize the activation of expression ABL T315I mutation Kinases).Above-mentioned cell line is built by this laboratory, and construction method is：PCR expand respectively mankind BMX, ABL, BCR-ABL, CKIT, cKIT N882K, cKIT D816V, ABL T315I kinases region sequences, and be inserted respectively into N-terminal TEL segments MSCV-Puro carriers (Clontech), by retrovirus method, stabilization is transferred to mouse BaF3 cells, and removes IL-3 Growth factor finally obtains and relies on BMX, ABL, BCR-ABL, cKIT, cKIT N882K, cKIT D816V, ABL T315I are transferred to The cell line of albumen.
In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM) compound 9, compound 10, compound 11, compound 67, change Close object 68, compound 69 and comparison medicine Imatinib, Nilotinib are added separately in above-mentioned cell, and be incubated 72 it is small when, With Cell Titer-(Promega, the U.S.) chemistry self-luminous method cell viability detection kit, by living cells In ATP quantitative determined to detect number of viable cells.Concrete outcome is shown in Table 3.
Influence of the table 3. to growth of cancer cells (result is expressed as GI50 values, and unit is μM)
Embodiment 79
The influence of signal path on cell
It is thin in human chronic myeloblastic leukemia Ku812 (expression BCR-ABL genes), human B cell chronic lymphocytic leukemia In born of the same parents' strain MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes) (being purchased from ATCC), By measuring many cellular biochemistry terminals and functional terminal, compound 11 is had evaluated to relevant protein kinase in cell The influence of BCR-ABL, AKT, Crkl, ERK, Stat5.With 0 μM of various concentration, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM of compound 11 and 1 μM of Imatinib, 0.1 μM of Dasatinib (purchased from Hao Yuan Chemexpress companies, Shanghai) handle respectively three plants of KU812 cell lines, MEG-01 cell lines, K562 cell lines cells 1 it is small when after, collect sample.It measures Influence of the compound 11 to BCR-ABL, AKT, Crkl, ERK, Stat5 phosphorylation in this three plants of cell lines.As a result referring to Fig. 1.
The experimental results showed that compound 11 in KU812 cell lines, MEG-01 cell lines, K562 cell lines to BCR- The phosphorylation of ABL, ERK, Stat5 have apparent inhibitory action, this absolutely proves that compound 11 is a BCR-ABL kinases suppression Preparation.
Embodiment 80
Influence of the compound 11 on cell to Apoptosis
In order to the death for proving cell after medication be by apoptosis or necrosis, it is white in human B cell chronic lymphocytic In blood disease cell line MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes) cell line (being purchased from ATCC) has detected poly- two phosphorus of adenosine of pair DNA repair enzyme closely related with Apoptosis in cell of compound 11 The influence of acid-ribose polymerase PARP, 3 protein cleavages of aspartic acid proteolytic enzyme Caspase containing cysteine.With not With 0 μM of concentration, 0.001 μM, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, the compound 11 of 0.3 μM, 1 μM (in DMSO), The control compound Dasatinib difference of the control compound Imatinib of 0.5 μM (in DMSO), 0.5 μM (in DMSO) Handle MEG-01, K562 cell line, then respectively when 12 is small, 24 it is small when, 48 it is small when after collect cell.With Western Blot The medicine of various concentration is detected in different time sections adenosine diphosphate-ribose polymerase PARP poly- to DNA repair enzymes and containing half Guang ammonia The influence of the shear protein of the aspartic acid proteolytic enzyme Caspase 3 of acid.As a result referring to Fig. 2.
Experimental result is as shown in Figure 2：For carrying the human B cell chronic lymphocytic leukemia cell of BCR-ABL genes Strain MEG-01 and Leukemia K562 cell cell line, when the Drug level of compound is 0.03 μM, when effect 12 is small after just It can be seen that the obviously shearing of the poly- adenosine diphosphate of DNA repair enzymes-ribose polymerase PARP.For carrying BCR-ABL The human B cell chronic lymphocytic leukemia cell line MEG-01 cell lines of gene, when the Drug level of compound is 0.1 μM When, effect 24 it is small when after, be able to observe that the shearing of the aspartic acid proteolytic enzyme Caspase 3 containing cysteine, act on 48 it is small when after, be able to observe that the shearing of the apparent aspartic acid proteolytic enzyme Caspase 3 containing cysteine.Equally After when ground is small using 0.5 μM of control compound Imatinib and control compound Dasatinib effect 48, it can also observe and contain The shearing of the aspartic acid proteolytic enzyme Caspase 3 of cysteine, but be not as apparent as the effect of compound 11.Implement Example 80, which demonstrates compound 11, can cause the apoptosis for the human leukemia cell for carrying BCR-ABL genes.
Embodiment 81
Plate clone forms experiment
Using conventional pancreatin had digestive transfer culture method, by the human B cell chronic lymphocytic leukemia cell of exponential phase of growth Strain MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes), human chronic myeloblastic leukemia Cell suspending liquid is made in Ku812 (expression BCR-ABL genes) cell.Cell suspending liquid is blown and beaten repeatedly, makes cell fully dispersed.It is right Human B cell chronic lymphocytic leukemia cell line MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes), human chronic myeloblastic leukemia Ku812 (expression BCR-ABL genes) cell count, and adjusted with culture medium thin Born of the same parents' concentration.
According to the ability of cell proliferation for MEG-01, K562, Ku812 cell line for carrying BCR-ABL genes, by 103Cell/ The concentration in hole is inoculated into six orifice plates (diameter 4cm) of the culture medium containing 2mL, is gently rocked culture dish with ten word directions, is made cell It is uniformly dispersed.
Culture dish is placed in 37 DEG C, 5%CO2It is middle culture 24 it is small when after be administered (compound 11), drug concentration is as follows：Chemical combination Object 11 is 10 μM, and 1 μM, 0.1 μM, 0.01 μM, 0.001 μM in DMSO；Blank control uses the DMSO of same volume.
Cultivate 72 it is small when after, terminate culture, discard culture solution, PBS liquid carefully embathes 2 times.15 minutes are fixed with methanol, is abandoned Remove methanol.Use violet staining.
Experimental result is as shown in Figure 3：For carrying MEG-01, K562, Ku812 cell line of BCR-ABL genes, compound 11 concentration just has been able to obviously inhibit the formation of cell colony when being 0.01 μM, when the concentration of compound 11 is Substantially acellular Colony forming at 0.1 μM.
Embodiment 82
Cell count is tested
Using conventional pancreatin had digestive transfer culture method, by the human B cell chronic lymphocytic leukemia cell of exponential phase of growth Strain MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes), human chronic myeloblastic leukemia Cell suspension is made in Ku812 (expression BCR-ABL genes) cell.Cell suspension is blown and beaten repeatedly, makes cell fully dispersed.To cell Numeration, and adjust cell concentration with culture medium.
According to the ability of cell proliferation for MEG-01, K562, Ku812 cell line for carrying BCR-ABL genes, by 103Cell/ The concentration in hole is inoculated into six orifice plates (diameter 4cm) of the culture medium containing 2mL, is gently rocked culture dish with ten word directions, is made cell It is uniformly dispersed.
Culture dish is placed in 37 DEG C, 5%CO2It is middle culture 24 it is small when after be administered (compound 11), drug concentration is as follows：Chemical combination Object 11 is 10 μM, and 1 μM, 0.1 μM, 0.01 μM, 0.001 μM in DMSO；Blank control uses the DMSO of same volume.
Cultivate 72 it is small when after, terminate culture, discard culture solution, PBS liquid carefully embathes 2 times, add in pancreatin digestion after to thin Born of the same parents count, and IC is calculated according to cell quantity50Value.
Experimental result is as shown in Figure 4：It is computed, compound 11 is to the IC of MEG-01 cell lines50It is worth for 16nM, compound 11 To the IC of K562 cell lines50It is worth for 28nM, compound 11 is to the IC of Ku812 cell lines50It is worth for 10nM, illustrates that compound 11 is right The cell growth of MEG-01, K562, Ku812 cell line and the formation of cell colony for carrying BCR-ABL genes are respectively provided with very Strong inhibitory action.Compound 11 is extraordinary BCR-ABL kinase inhibitors.
Embodiment 83
The influence of the cell cycle on cell of compound 11
It is thin in human B cell chronic lymphocytic leukemia in order to study which growth cycle cell after medication is stopped in Born of the same parents' strain MEG-01 (expression BCR-ABL genes), Leukemia K562 cell (expression BCR-ABL genes), the white blood of people's chronic Myelogenous In sick three plants of cell lines of Ku812 (expression BCR-ABL genes), cell cycle distribution of the compound 11 to these cell lines is tested Influence.With 0 μM of various concentration, 0.1 μM, 11,0.5 μM of the compound (in DMSO) of 0.3 μM, 1 μM (in DMSO) BCR-ABL kinase inhibitors Imatinib and Dasatinib act on MEG-01, K562, the Ku812 for carrying BCR-ABL genes In cell line, when effect 12 is small after, collect cell, 1XPBS buffer solutions wash twice, and it is small that 75% ethyl alcohol in -20 DEG C fixes 24 When, 1XPBS buffer solutions wash twice again, add the PI dyeing liquors of 0.5mL 1XPBS buffer solutions and 0.5mL (purchased from U.S. BD Bioscience) into cell and by cell be positioned over dark be protected from light 37 DEG C dye 15 minutes, with flow cytometer (BD FACS Calibur cell cycle distribution) is detected.As a result referring to Fig. 5.
Experimental result is as shown in Figure 5：In MEG-01, K562, Ku812 cell line for carrying BCR-ABL genes, with change Closing the drug concentration of object 11 increases to 1 μM from 0.1 μM, the cell difference of the G0-G1 phases of capture：Increase to from 46.32% 55.78%th, increase to 61.01% from 44.61%, increase to 69.53% from 59.51%；Carrying the MEG- of BCR-ABL genes 01st, in K562, Ku812 cell line, the stronger control compound BCR-ABL kinase inhibitors Imatinib of selectivity and The cell for the G0-G1 phases that Dasatinib is captured at 0.5 μM is respectively 45.66% and 51.75%, 46.68% and 56.11%, 65.18% and 68.83%.
Embodiment 83, which demonstrates compound 11, to hinder MEG-01, K562, Ku812 cell for carrying BCR-ABL genes Only in the G0-G1 phases, and strong influence (Fig. 5) is distributed in cell cycle.

Claims (15)

1. a kind of BCR-ABL kinase inhibitors, including the compound of Formulas I or its pharmaceutically acceptable salt：
Wherein：
R1Selected from optionally by 1 or 2 independently R7Substituted phenyl amino；
R2For methylamino；
R3Selected from C1-C8 alkyl；
R4、R5And R6It is each independently selected from hydrogen, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1-C8 alkyl ammonia Base and phenyl or adjacent R4、R5And R6In any two form dioxa cyclopentenyl together；And
R7Independently selected from amino, nitro, hydroxyl, halogen, sulfydryl, cyano, amino-sulfonyl, C1-C8 alkyl, C1-C8 alkyl halides Base, C1-C8 alkyl aminos, C1-C8 alkoxyl, C1-C8 alkyl sulphonyls, C1-C8 alkyl sulphinyls, C2-C8 alkylamides Base and C2-C8 eneamide bases.
2. BCR-ABL kinase inhibitors as described in claim 1, wherein R1Selected from 3 and/or 4 optionally by 1 or 2 independence Ground R7Substituted phenyl amino.
3. BCR-ABL kinase inhibitors as described in claim 1, wherein R3Selected from C1-C4 alkyl, and positioned at 4 of phenyl ring or 6.
4. BCR-ABL kinase inhibitors as claimed in claim 3, wherein R3It is the methyl of 6 positioned at phenyl ring.
5. BCR-ABL kinase inhibitors as described in claim 1, wherein R4、R5And R6It is each independently selected from hydrogen, C1-C4 alkane Base, C1-C4 halogenated alkyls, C1-C4 alkoxies and phenyl or adjacent R4、R5And R6In any two form two together Oxole base.
6. BCR-ABL kinase inhibitors as described in claim 1, wherein R4、R5And R6It is each located on 2,3,4 or the 5 of phenyl ring Position.
7. BCR-ABL kinase inhibitors as described in claim 1, wherein R7Independently selected from amino, nitro, amino-sulfonyl, C1-C4 alkyl, C1-C4 halogenated alkyls, C1-C4 alkyl aminos, C1-C4 alkyl sulphonyls, C1-C4 alkyl sulphinyls, C2-C4 Alkylamidoalkyl and C2-C4 eneamide bases.
8. BCR-ABL kinase inhibitors as described in claim 1, are selected from：
9. a kind of pharmaceutical composition, including as any one of claim 1-8 BCR-ABL kinase inhibitors, pharmacy Upper acceptable carrier or excipient and optional other therapeutic agents.
10. BCR-ABL kinase inhibitors or medicine group as claimed in claim 9 as any one of claim 1-8 Close purposes of the object in the drug for inhibiting BCR-ABL kinase activities is prepared.
11. BCR-ABL kinase inhibitors or medicine group as claimed in claim 9 as any one of claim 1-8 Close purposes of the object in the drug for treating the illness mediated by BCR-ABL kinase activations is prepared.
12. purposes as claimed in claim 11, wherein the illness mediated by BCR-ABL kinase activations is proliferative diseases Disease.
13. purposes as claimed in claim 12, wherein the proliferative disorders are selected from solid tumor.
14. purposes as claimed in claim 12, wherein the proliferative disorders are selected from：It is sarcoma, chronic myelogenous leukemia, chronic Granulocytic leukemia (CML), gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid cancer, stomach cancer, rectum Cancer, Huppert's disease, knurl are formed or its combination.
15. purposes as claimed in claim 14, wherein the proliferative disorders are selected from：Chronic myelocytic leukemia (CML), stomach Intestinal Stromal Tumors (GIST), acute myeloblastic leukemia (ALL), thyroid cancer or its combination.
CN201510172534.7A 2015-04-14 2015-04-14 A kind of BCR-ABL kinase inhibitors Active CN104876879B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201510172534.7A CN104876879B (en) 2015-04-14 2015-04-14 A kind of BCR-ABL kinase inhibitors
PCT/CN2015/081220 WO2016165205A1 (en) 2015-04-14 2015-06-11 Novel bcr-abl kinase inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510172534.7A CN104876879B (en) 2015-04-14 2015-04-14 A kind of BCR-ABL kinase inhibitors

Publications (2)

Publication Number Publication Date
CN104876879A CN104876879A (en) 2015-09-02
CN104876879B true CN104876879B (en) 2018-05-18

Family

ID=53944596

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510172534.7A Active CN104876879B (en) 2015-04-14 2015-04-14 A kind of BCR-ABL kinase inhibitors

Country Status (2)

Country Link
CN (1) CN104876879B (en)
WO (1) WO2016165205A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10722484B2 (en) 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
WO2019006548A1 (en) * 2017-07-04 2019-01-10 Trillium Therapeutics Inc. Fluorinated 2,4-diaminopyrimidine compounds as mer tyrosine kinase (mertk) inhibitors and uses thereof
CN108103186B (en) * 2018-02-28 2021-07-02 固安博健生物技术有限公司 Molecular markers for diagnosis of rheumatoid arthritis and osteoarthritis

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1842529A (en) * 2003-08-28 2006-10-04 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN1898208A (en) * 2003-12-25 2007-01-17 日本新药株式会社 Amide derivative and medicine
WO2007059157A1 (en) * 2005-11-14 2007-05-24 Genentech, Inc. Bisamide inhibitors of hedgehog signaling
CN101023063A (en) * 2004-07-01 2007-08-22 阿斯利康(瑞典)有限公司 Azine-carboxamides as anti-cancer agent
CN101080396A (en) * 2004-10-15 2007-11-28 阿斯利康(瑞典)有限公司 Quinoxalines as B Raf inhibitors
WO2008144253A1 (en) * 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof
CN101522636A (en) * 2006-10-30 2009-09-02 诺瓦提斯公司 3-amino-pyrazole-4-carboxamide derivatives useful as inhibitors of protein kinases

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1842529A (en) * 2003-08-28 2006-10-04 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN1898208A (en) * 2003-12-25 2007-01-17 日本新药株式会社 Amide derivative and medicine
CN101023063A (en) * 2004-07-01 2007-08-22 阿斯利康(瑞典)有限公司 Azine-carboxamides as anti-cancer agent
CN101080396A (en) * 2004-10-15 2007-11-28 阿斯利康(瑞典)有限公司 Quinoxalines as B Raf inhibitors
WO2007059157A1 (en) * 2005-11-14 2007-05-24 Genentech, Inc. Bisamide inhibitors of hedgehog signaling
CN101522636A (en) * 2006-10-30 2009-09-02 诺瓦提斯公司 3-amino-pyrazole-4-carboxamide derivatives useful as inhibitors of protein kinases
WO2008144253A1 (en) * 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof

Also Published As

Publication number Publication date
WO2016165205A8 (en) 2023-03-30
WO2016165205A1 (en) 2016-10-20
CN104876879A (en) 2015-09-02

Similar Documents

Publication Publication Date Title
CN104844589B (en) A kind of PI3K kinase inhibitors
WO2017101803A1 (en) Novel egfr and alk dual inhibitor
EP1606289B1 (en) Carboxamide derivatives
AU2018275277B2 (en) Pharmaceutically acceptable salt of EGFR inhibitor, crystal form thereof, preparation method therefor and application thereof
ES2292988T3 (en) USEFUL NICOTINAMIDE DERIVATIVES AS PDE INHIBITORS 4.
CN104936951B (en) Benzimidizole derivatives as kinase inhibitor
JP4012068B2 (en) Muscarinic antagonist
CN104844566B (en) A kind of kinase inhibitor of new structure
CN106928231B (en) Novel EGFR wild type and mutant kinase inhibitors
CN114057771B (en) Macrocyclic compounds, their preparation and use
EP1400521B1 (en) Piperazine compounds
JP5232143B2 (en) Benzylpiperazine derivatives as motilin receptor antagonists
CN1642551A (en) Inhibitors of histone deacetylase
CN103965120A (en) Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
EP3640248B1 (en) Aminopyrimidine derivatives, preparation method therefor and use thereof
RU2600928C2 (en) Cyanoquinoline derivatives
EP2896620A1 (en) Alkynyl heteroaromatic ring compound and application thereof
CN108727363A (en) A kind of novel cell cyclin-dependent kinase CDK9 inhibitor
CN107176951A (en) A kind of carbamide compounds, its preparation method and its medical usage
CN104876879B (en) A kind of BCR-ABL kinase inhibitors
CN107245075A (en) Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines
KR20140118575A (en) Novel hydroxamate derivative
CN104250253B (en) Substituted-tetrahydro naphthoyl aminated compounds and its pharmaceutically acceptable salt and preparation method and application
CN109320473A (en) Thiazoleamino benzamide acetogenin and application thereof
CA2384018C (en) Muscarinic antagonists

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant