CN1798734A - Novel compounds and compositions as protein kinase inhibitors - Google Patents
Novel compounds and compositions as protein kinase inhibitorsDownload PDFInfo
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- CN1798734A CN1798734ACN 200480015433CN200480015433ACN1798734ACN 1798734 ACN1798734 ACN 1798734ACN 200480015433CN200480015433CN 200480015433CN 200480015433 ACN200480015433 ACN 200480015433ACN 1798734 ACN1798734 ACN 1798734A
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Abstract
Translated fromChineseDescription
The cross reference of related application
It is the right of priority of 60/460,838 U. S. application that the application requires in the provisional application sequence number that on April 4th, 2003 submitted to, and it here is introduced into as a reference.
Background technology
Technical field
The invention provides a class new compound, comprise the pharmaceutical composition of this compounds and with such compounds for treating or prevention and tyrosine kinase activity diseases associated or illness unusual or out of control, particularly with the method for PDGF-R, c-Kit and Bcr-abl diseases associated.
Background technology
Protein kinase has been represented a big proteinoid, and it is in the adjusting of many cell processes and keep in the control cell function and play keying action.These kinases comprise receptor tyrosine kinase, as derive from receptor kinase, c-Kit and the non--receptor tyrosine kinase of hematoblastic growth factor receptor kinase (PDGF-R), STEM CELL FACTOR, as merging kinase b cr-abl.
Chronic granulocytic leukemia (CML) is a kind of human cancer that carries out broad research, and it is by causing the Abl proto-oncogene on the karyomit(e) 9 to be caused with the mutual transposition that is called as the gene fusion on the chromosome 22 of Bcr.Formed fusion rotein Bcr-abl can be by increasing the mitogenesis activity, reducing the susceptibility of pair cell apoptosis and change the adhesive power of CML progenitor cell and go back to the nest and transform the B-cell.STI-571 (Gleevec) is the inhibitor of carinogenicity Bcr-abl Tyrosylprotein kinase and is used to treat chronic granulocytic leukemia (CML).But because the kinase whose sudden change of Bcr-abl, some patients that are in the initiating cell danger phase stage of CML have resistance to STI-571.
New compound of the present invention can suppress one or more kinases; The Bcr-abl of wild-type and one or more mutants particularly, and therefore can be used for treatment and kinases diseases associated, particularly with Bcr-abl kinases diseases associated.
Summary of the invention
One aspect of the present invention provides the compound of formula I:
Wherein:
X1And X2Be independently selected from-N=and-CR4=, R wherein4Be hydrogen or C1-4Alkyl;
L be selected from key ,-O-and-NR5-, R wherein5Be hydrogen or C1-4Alkyl;
R1Be selected from-X3NR6R7,-X3OR7With-X3R7, X wherein3Be key or C1-4Alkylidene group, R6Be hydrogen or C1-4Alkyl, R7Be selected from C6-10Aryl and C5-6Heteroaryl; Wherein any aryl or heteroaryl randomly are independently selected from halogen, amino, C by 1 to 31-4Alkyl, halo C1-4Alkyl, C1-4Alkoxyl group and halo C1-4The group of alkoxyl group replaces;
R2Be selected from hydrogen, halogen, amino, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkoxyl group and halo C1-4Alkoxyl group;
R3Be selected from C3-8Heterocyclylalkyl-C0-4Alkyl, C5-10Heteroaryl-C0-4Alkyl and C6-10Aryl-C0-4Alkyl; Wherein any alkyl randomly is selected from hydroxyl, halogen and amino group by 1 to 3 and replaces; Any aryl, heteroaryl or Heterocyclylalkyl randomly are independently selected from halogen, nitro, C by 1 to 31-4Alkyl, halo C1-4Alkyl, hydroxyl-C1-6Alkyl, C1-4Alkoxyl group, halo C1-4Alkoxyl group, phenyl, C3-8Heterocyclylalkyl ,-X3C (O) NR8R8,-X3C (O) NR8R9,-X3C (O) R9,-X3S (O) NR8R8,-X3NR8R9,-X3NR8R8,-X3S (O)2NR8R8,-X3S (O)2R8,-X3S (O)2R9,-X3SNR8R8,-X3ONR8R8,-X3C (O) R8,-X3NR8C (O) R8,-X3NR8S (O)2R8,-X3S (O)2NR8R9, X3NR8S (O)2R9,-X3NR8C (O) R9,-X3NR8C (O) NR8R9,-X3NR8C (O) NR8R8,-X3C (O) OR8,=NOR8,-X3NR8OR8,-X3NR8(CH2)1-4NR8R8,-X3C (O) NR8(CH2)1-4NR8R8,-X3C (O) NR8(CH2)1-4R9,-X3C (O) NR8(CH2)1-4OR9,-X3O (CH2)1-4NR8R8,-X3C (O) NR8(CH2)1-4OR8And X3NR8(CH2)1-4R9Group replace; Wherein phenyl can further be selected from-NR8R8Or-C (O) NR8R8Group replace; X3Definition as mentioned above; R8Be hydrogen, C1-6Alkyl, hydroxyl-C1-6Alkyl or C2-6Alkenyl; R9Be hydroxyl, C6-10Aryl-C0-4Alkyl, C6-10Aryl-C0-4Alkoxyl group, C5-10Heteroaryl-C0-4-alkyl, C3-8Heterocyclylalkyl-C0-4-alkyl or C3-8Cycloalkyl; Wherein said R9Aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl or alkyl randomly further by at the most 2 be selected from halogen, hydroxyl, cyano group, amino, nitro, C1-4Alkyl, hydroxyl-C1-6Alkyl, halo C1-4Alkyl, C1-4Alkoxyl group, halo C1-4The phenyl of alkoxyl group, halo-alkyl-replacement, benzoyloxy, C5-9Heteroaryl, C3-8Heterocyclylalkyl ,-C (O) NR8R8,-S (O)2NR8R8,-NR8R8,-C (O) R10With-NR11R11Group replace R wherein10Be C5-6Heteroaryl and R11Be hydroxyl-C1-4Alkyl;
N-oxide derivative, prodrug derivant, protected derivative, one isomer and mixture of isomers with this compounds; And pharmacologically acceptable salt and solvate (for example, hydrate).
Second aspect present invention provides a kind of compound or its N-oxide derivative, one isomer and mixture of isomers that comprises formula I; Or the pharmaceutical composition of its pharmacologically acceptable salt and one or more suitable vehicle.
Third aspect present invention provide a kind of in animal treatment wherein suppress the method that the disease of the pathology of disease and/or symptom can be prevented, suppresses or be improved to kinase activity, particularly Bcr-abl activity, this method comprises to the compound of the formula I of animal administering therapeutic significant quantity or its N-oxide derivative, one isomer and mixture of isomers or pharmacologically acceptable salt.
The compound that fourth aspect present invention provides formula I preparation be used for animal treat wherein kinase activity, particularly Bcr-abl active with said disease pathology and/or the application in the medicine of symptom diseases associated.
Fifth aspect present invention provides a kind of inhibition Bcr-abl active method, and this method comprises to be made Bcr-abl and can contact with the mnyristoyl binding pocket bonded compound of Bcr-abl.
The compound that sixth aspect present invention provides a kind of preparation formula I with and the method for N-oxide derivative, prodrug derivant, protected derivative, one isomer and mixture of isomers and pharmacologically acceptable salt.
Detailed Description Of The Invention
I. definition
Unless stated otherwise, otherwise all used here scientific and technical terminologies have the common implication of understanding of one skilled in the art of the present invention.Generally speaking, used here nomenclature and organic and laboratory operation analytical chemistry are well-known and commonly used in the prior art.
" alkyl " refer to have shown in the radical of saturated aliphatic group of straight or branched of carbonatoms." low alkyl group " has at the most 7 and comprise 7, preferably at the most 4 and comprise 4 carbon.For example, C1-4Alkyl comprises methyl, ethyl, propyl group, butyl, sec.-propyl or isobutyl-.Alkenyl is defined as comprising the alkyl of at least one two key.For example, alkenyl comprises vinyl, propenyl, pseudoallyl, butenyl, isobutenyl or butadienyl." halo-alkyl " is the alkyl as defined above that some of them or all hydrogen atoms are all replaced by halogen atom.For example, halo-alkyl comprises trifluoromethyl, methyl fluoride, 1,2,3,4,5-five fluoro-phenyl or the like." hydroxyl-alkyl " for example comprises, hydroxymethyl, hydroxymethyl or the like.
" alkoxyl group " is defined as comprising the alkyl of Sauerstoffatom, for example, and methoxyl group, oxyethyl group or the like." halo-alkoxyl group " is defined as the alkoxyl group that some of them or all hydrogen atoms are replaced by halogen atom.For example, halo-alkoxyl group comprises trifluoromethoxy or the like.
" aryl " refers to monocycle or the condensed dicyclo aromatic ring group that comprises 6 to 10 ring carbon atoms.For example, aryl can be a phenyl or naphthyl, preferred phenyl." arylidene " refers to the divalent group that derives from aryl." heteroaryl " is defined as one or more ring memberses is heteroatomic aryl.For example heteroaryl comprises pyridyl, indyl, indazolyl, quinoxalinyl, quinolyl, benzofuryl, benzopyranyl, benzo thiapyran base, benzo [1,3] dioxole, imidazolyl, benzo-imidazolyl, pyrimidyl, furyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, pyrazolyl, thienyl or the like.
" cycloalkyl " refer to comprise shown in the undersaturated monocycle of saturated or part, condensed two rings of number annular atoms or many rings cyclic group of bridging.For example, C3-10Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like." Heterocyclylalkyl " refer to the ring carbon shown in one or more be selected from-O-,-N=,-NR-,-C (O)-,-S-,-S (O)-or-S (O)2-the defined cycloalkyl of the displaced the application of part, wherein R is hydrogen, C1-4Alkyl or nitrogen-protecting group group.For example, be used for describing the C of The compounds of this invention in this application3-8Heterocyclylalkyl-C0-4Alkyl comprises morpholine-4-base, morpholine-4-base-methyl, morpholine-4-base-ethyl, pyrrolidyl, piperazinyl, piperidyl, piperidone base, 1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-base or the like.
" halogen (or halo) " preferably represents chlorine or fluorine, but also can be bromine or iodine.
The pharmacologically acceptable salt of acidic cpd of the present invention is the salt that forms with alkali, be cationic salts such as an alkali metal salt and alkaline earth salt, as sodium, lithium, potassium, calcium, magnesium salts and ammonium salt, as ammonium, trimethylammonium-ammonium, diethyl ammonium and three-(hydroxymethyl)-methyl-ammonium salt.
If basic group for example pyridyl has constituted the part of structure, then also can form acid salt similarly, as mineral acid, organic carboxyl acid and organic sulfonic acid, the acid salt of hydrochloric acid, methylsulfonic acid, toxilic acid for example.
" treatment " refers to and a kind ofly alleviates or palliate a disease and/or the method for the symptom that it accompanies.
" inhibition " and " inhibitor " refers to and stops the specific effect or the compound or the method for function.
" treatment significant quantity " refers to and is enough to prevent its progress or alleviate to a certain extent by one or more symptoms of treatment situation or illness for the amount of drug compound.
Here used " composition " comprises and a kind ofly comprises the product of special component and directly or indirectly by any product of the combination results of the special component of specified quantitative with specified quantitative." pharmaceutically useful " refers to that carrier, thinner or vehicle etc. are essential can be compatible with other composition of said preparation and harmless to its recipient.
" individuality " refers to animal, as Mammals, comprises primate (for example, people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse or the like without limitation.In certain embodiments, said individuality is the people.
" IC50" be that activity or biological procedures to peptide, albumen, enzyme produces 50% inhibiting compound concentration.
" mnyristoyl binding pocket " is to be in when being suitable for mnyristoyl bonded conformation when Bcr-Abl albumen, and mnyristoyl can be in conjunction with Bcr-abl zone thereon.For example, people such as Hantschel are at " mnyristoyl/Tyrosine O-phosphate switch regulation and control c-Abl " Cell (2003), the 112nd volume, among the 845-857 and people such as Bhushan at " architecture basics that the c-Abl Tyrosylprotein kinase suppresses from body " Cell (2003), the 112nd volume is described the mnyristoyl binding pocket among the 859-871.
Can be by salt and alkali or acid being contacted and in a usual manner parent compound are separated the neutral form of the said compound of regenerating.The parent form of compound and various salt form are on some physical properties, as different aspect the solubleness in polar solvent, but for purpose of the present invention, the salt of this compound and parent form are suitable.
Except that salt form, the present invention also provides the compound of prodrug forms.Thereby the prodrug of compound described here is to be easy to take place those compounds that chemically changed provides The compounds of this invention under physiological conditions.In addition, can also in the environment that exsomatizes, prodrug be changed into compound of the present invention by chemistry or biochemical method.For example, when be placed to have suitable enzyme or chemical reagent in skin patch bank the time, prodrug can slowly be changed into compound of the present invention.
Compound of the present invention can exist with the form of non-solventization and the form of solvation (comprising hydrated form).Generally speaking, the form of solvation is suitable with the form of non-solventization, and all comprises within the scope of the invention.Some compound of the present invention can exist with polymorphic or amorphous form.Generally speaking, for the application that the present invention considered, all physical form all be equate and be included in the scope of the present invention.
Some compound of the present invention has unsymmetrical carbon (optical center) or two key; Racemic modification, diastereomer, geometrical isomer and single isomer all comprise within the scope of the invention.
II. summary
Fusion rotein Bcr-Abl is produced by the mutual transposition with Abl proto-oncogene and Bcr gene fusion.Then, Bcr-abl can transform the B-cell by increasing the mitogenesis activity.This increase makes the susceptibility of pair cell apoptosis reduce, and has changed the bounding force of CML progenitor cell and reset.The invention provides and be used for the treatment of and the kinases diseases associated, particularly with compound, composition and the method for PDGF-R, c-Kit and Bcr-abl kinases diseases associated.For example, can treat leukemia and other proliferative disorders relevant with mutant Bcr-abl by suppressing wild-type with Bcr-abl.
III. compound
A. preferred compound
In some embodiments, when mentioning the compound of formula I, compound of the present invention can be the compound of formula Ia:
Wherein L is a key; R1Be selected from-NHR7,-OR7With-R7, R wherein7Be randomly to be independently selected from halogen, amino, C by 1 to 31-4Alkyl, halo C1-4Alkyl, C1-4Alkoxyl group and halo C1-4Phenyl or pyridyl that the group of alkoxyl group replaces; R2Be hydrogen or C1-4Alkyl.
In another embodiment, R3Be randomly to be independently selected from-C (O) NR by 1 to 38R8,-C (O) NR8R9,-C (O) R9With-C (O) NR8(CH2)2NR8R8The C that replaces of group6-10Aryl-C0-4Alkyl, wherein R8Be hydrogen, C1-6Alkyl or hydroxyl-C1-6Alkyl; R9Be randomly by-C (O) NR8R8The C that replaces3-8Heterocyclylalkyl-C0-4Alkyl.
In another embodiment, R1Be-NHR7, R wherein7By halo C1-4Alkyl or halo C1-4The phenyl that alkoxyl group replaces; R2Be hydrogen; R3By-C (O) NH (CH2)2OH ,-C (O) NHR9,-C (O) R9Or-NH (CH2)2N (CH3)2The phenyl that replaces, wherein R9By-C (O) NH2Morpholine-4-base-ethyl or the piperidyl that replaces.
In another embodiment, compound of the present invention can be the compound of formula Ib:
Wherein L is a key; R1Be selected from-NHR7,-OR7With-R7, R wherein7Be randomly to be independently selected from halogen, amino, C by 1 to 31-4Alkyl, halo C1-4Alkyl, C1-4Alkoxyl group and halo C1-4Phenyl or pyridyl that the group of alkoxyl group replaces; R2Be hydrogen or C1-4Alkyl.
In another embodiment, R3Be selected from C5-6Heteroaryl-C0-4Alkyl or C6-10Aryl-C0-4Alkyl; Wherein any aryl or heteroaryl randomly are selected from C by 1 to 33-8Heterocyclylalkyl ,-C (O) NR8R8,-C (O) NR8R9,-C (O) R9,-NR8R9With-NR8(CH2)2NR8R8Group replace R wherein8Be hydrogen, C1-6Alkyl or hydroxyl-C1-6Alkyl; And R9Be C6-10Aryl-C0-4Alkyl, C5-10Heteroaryl-C0-4Alkyl, C3-8Heterocyclylalkyl-C0-4Alkyl or C3-8Cycloalkyl; R wherein9Any aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl or alkyl randomly further by at the most 2 be selected from hydroxyl, C1-4Alkyl, hydroxyl-C1-6Alkyl, C3-8Heterocyclylalkyl ,-C (O) NR8R8With-S (O)2NR8R8Group replace.
In the another one embodiment, R1Be-NHR7, R wherein7By halo C1-4Alkyl or halo C1-4The phenyl that alkoxyl group replaces; R2Be hydrogen; And R3Be randomly to be selected from-C (O) NH (CH by 1 to 32)2OH ,-C (O) NHCH (C3H7)2CH2OH ,-C (O) NH (CH2)2CH3,-C (O) N (CH3)2,-C (O) NH (CH2)2N (CH3)2,-C (O) NHR9,-C (O) N (C2H5) R9With-C (O) R9The group pyridyl or the phenyl that replace, R wherein9Be phenyl, styroyl, pyridyl, pyrrolidyl, piperidyl, morpholine-4-base or morpholine-4-base-ethyl; R wherein9Any aryl, heteroaryl, Heterocyclylalkyl or alkyl randomly further by at the most 2 be selected from hydroxyl, C1-4Alkyl ,-CH2OH ,-(CH2)2OH, pyrrolidyl, piperazinyl ,-C (O) NH2,-C (O) N (C2H5)2With-S (O)2NH2Group replace.
In another embodiment, compound of the present invention can be the compound of formula Ic:
Wherein L be key ,-NH-,-N (C2H5)-or-O-; R1Be selected from-NHR7,-OR7With-R7, R wherein7Be randomly to be independently selected from halogen, amino, C by 1 to 31-4Alkyl, halo C1-4Alkyl, C1-4Alkoxyl group and halo C1-4Phenyl or pyridyl that alkoxyl group replaces; R2Be hydrogen or C1-4Alkyl.
In another embodiment, L is a key; R3Be selected from C3-8Heterocyclylalkyl-C0-4Alkyl, C5-10Heteroaryl-C0-4Alkyl and C6-10Aryl-C0-4Alkyl; Wherein any aryl, heteroaryl or Heterocyclylalkyl randomly are independently selected from halogen, nitro, C by 1 to 31-4Alkyl, hydroxyl-C1-6Alkyl, C1-4Alkoxyl group, C3-8Heterocyclylalkyl ,-X3C (O) NR8R8,-X3C (O) NR8R9,-X3NR8R9,-X3NR8R8,-X3S (O)2NR8R8,-X3S (O)2R8,-X3S (O)2R9,-X3C (O) R8,-X3NR8C (O) R8,-X3NR8S (O)2R8,-X3S (O)2NR8R9,-X3NR8S (O)2R9,-X3NR8C (O) R9,-X3NR8C (O) NR8R9,-X3NR8C (O) NR8R8,-X3C (O) OR8,=NOR8,-X3NR8(CH2)1-4NR8R8,-XC (O) NR8(CH2)1-4NR8R8With-X3O (CH2)1-4NR8R8Group replace; R8Be hydrogen, C1-6Alkyl or hydroxyl-C1-6Alkyl; R9Be C6-10Aryl-C0-4Alkyl, C6-10Aryl-C0-4Alkoxyl group, C5-10Heteroaryl-C0-4Alkyl, C3-8Heterocyclylalkyl-C0-4Alkyl or C3-8Cycloalkyl; Wherein said R9Aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl or alkyl randomly further by at the most 2 be selected from halogen, hydroxyl, cyano group, nitro, C1-4Alkyl, hydroxyl-C1-6Alkyl, halo C1-4Alkyl, C1-4The phenyl of alkoxyl group, halo-alkyl-replacement, benzoyloxy, C5-9Heteroaryl, C3-8Heterocyclylalkyl ,-C (O) NR8R8,-S (O)2NR8R8,-NR8R8With-C (O) R10Group replace R wherein10Be C5-6Heteroaryl.
In another embodiment, R3Be selected from morpholine-4-base, 1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-base, 4-oxo-piperidines-1-base, piperazinyl, pyrrolidyl, pyridyl, phenyl, naphthyl, thienyl, cumarone-2-base, benzo [1,3] dioxa cyclopentenyl, piperidyl, pyrazinyl, pyrimidyl, imidazolyl, pyrazolyl and 1H-benzimidazolyl-; Wherein any aryl, heteroaryl or Heterocyclylalkyl randomly by 1 to 2 be independently selected from chlorine, methyl, ethyl, hydroxymethyl, methoxyl group ,-C (O) OH ,-C (O) H ,-C (O) OCH3,-C (O) N (C2H5)2,-C (O) N (CH3)2,-C (O) NHCH3,-S (O)2NH2,-S (O)2CH3, chlorine ,-NH2,-C (O) CH3,=NOCH3,-NH (CH2)2N (CH3)2,-NH (CH2)3NH2,-NH (CH2)2OH ,-C (O) NH (CH2)2N (CH3)2,-NHR9,-O (CH2)2N (CH3)2, morpholine-4-base, piperazinyl ,-NHC (O) CH3,-NHC (O) NHC4H9,-C (O) NHC4H9,-C (O) NHC3H7,-C (O) NHC5H10OH ,-C (O) N (C2H4OH)2,-C (O) NHC2H4OH ,-C (O) NH (CH2)2OH ,-NHC (O) R9,-C (O) NHR9,-NHC (O) NHR9,-C (O) R9,-NHS (O)2C4H9,-NHS (O)2CH3,-NHS (O)2R9,-S (O)2R9,-S (O)2NHR9,-C (O) NH2With-C (O) NH (CH2)2N (CH3)2Group replace; R9Be styroyl, 2-phenoxy group-ethyl, 1H-imidazolyl-propyl group, pyridyl, pyridyl-methyl, quinolyl, morpholine-4-base, piperidyl, piperazinyl, pyrrolidyl, tetrahydrochysene-furans-2-ylmethyl, furans-2-ylmethyl, thiazol-2-yl methyl, benzo [1,3] dioxole-5-ylmethyl, benzo [1,3] dioxole-5-base, 3-(2-oxo-tetramethyleneimine-1-yl)-propyl group, 3-imidazoles-1-base-propyl group, 3H-pyrazole-3-yl, morpholine-4-base-ethyl, phenyl, thienyl-methyl, benzyl, cyclohexyl or furans-2-ylmethyl; Wherein said R9Aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl or alkyl can be further randomly by at the most 2 be selected from hydroxyl-methyl, hydroxyl-ethyl, isobutyl-, nitro, amino, hydroxyl, methoxyl group, trifluoromethoxy, cyano group, sec.-propyl, methyl, ethyl, chlorine, fluorine, pyridyl, morpholine-4-base, phenoxy group, pyrrolidyl, trifluoromethyl, trifluoromethyl-replacement-phenyl ,-N (CH3)2,-C (O) NH2,-S (O)2NH2,-C (O) N (CH3)2, cyano group or-C (O) R10Group replace; R10It is furyl.
In another embodiment, L be-NH-,-N (C2H5)-or-O-; R3Be selected from C5-10Heteroaryl-C0-4Alkyl and C6-10Aryl-C0-4Alkyl; Wherein any aryl or heteroaryl randomly are independently selected from C by 1 to 31-4-alkoxyl group, C3-8Heterocyclylalkyl ,-X3C (O) NR8R8,-X3S (O)2NR8R8,-X3NR8C (O) R8With-X3NR8(CO) NR8R9Group replace; R8Be hydrogen or C1-6Alkyl; R9Be randomly by 2 halo C at the most1-4The C that alkyl replaces6-10Aryl-C0-4Alkyl.
In the another one embodiment, R3Be selected from quinolyl, pyridyl and phenyl; Wherein any aryl or heteroaryl randomly by 1 to 2 be independently selected from morpholine 4-base, methoxyl group ,-C (O) NH2,-NHC (O) NHR9With-S (O)2NH2Group replace; R9The phenyl that is replaced by trifluoromethyl.
Compound to preferred formula I in embodiment below and the Table I is described in detail.
B. the preparation of compound
The present invention also comprises the preparation method of The compounds of this invention.In described reaction, when wishing that in final product responding property functional group for example when hydroxyl, amino, imino-, sulfydryl or carboxyl, may need these radical protections are got up to avoid it to participate in reaction.Can use the GPF (General Protection False group according to standard operating procedure, for example, see T.W.Greene and P.G.M.Wuts, " ProtectiveGroups in Organic Chemistry ", John Wiley and Sons, 1991.
Wherein L is that the compound of the formula I of key can be prepared with the program of following reacting flow chart I:
Reacting flow chart I
X wherein1, X2, R1, R2And R3Definition as described in the top formula I, Q represents a kind of halogen group, for example iodine or chlorine, preferred chlorine.
The compound of formula I can react by the compound with the compound of formula 2 and formula 3 and prepare.Can there be suitable catalyzer (for example, Pd (PPh in this reaction3)4Or the like) situation under in The suitable solvent (for example, acetonitrile) and adopt suitable alkali (for example, Na2CO3) under 50-100 ℃, carry out and needed finish in 5-15 hour.
Wherein L is that the compound of the formula I of key can also carry out with the program of following reaction process Fig. 2:
Reaction process Fig. 2
X wherein1, X2, R1, R2And R3Definition as described in the top formula I and Q represent a kind of halogen group, for example iodine or chlorine, preferred iodine.
The compound that the compound of formula I can through type 2 and the compound of formula 4 react and prepare.Can there be suitable catalyzer (for example, Pd (PPh in this reaction3)4Or the like) situation under, in The suitable solvent (for example, 1,4-diox), under 60-110 ℃, carry out and needed finish in 10-20 hour.
Wherein L be-compound of the formula I of O-can be prepared with the program of following reaction process Fig. 3:
Reaction process Fig. 3
X wherein1, X2, R1, R2And R3Definition as described in the top formula I and Q represent a kind of halogen group, for example iodine or chlorine, preferred chlorine.
The compound of formula I can react by the compound with the compound of formula 2 and formula 5 and prepare.This reaction can exist suitable alkali (for example, KOtBu or the like under) the situation, to carry out under 50-100 ℃ in The suitable solvent (for example THF) and needed finish in 5-10 hour.
Wherein L-is-NR5-the compound of formula I can carry out with the program of following reaction process Fig. 4:
Reaction process Fig. 4
X wherein1, X2, R1, R2, R3And R5Definition as described in the top formula I and Q represent a kind of halogen group, for example iodine or chlorine, preferred chlorine.
The compound of formula I can react by the compound with the compound of formula 2 and formula 6 and prepare.This reaction can be at catalyzer (for example, the Pd that has suitable part (for example, IprHCl or the like), suits2(dba)3Or the like), suitable alkali (for example, KOtBu or the like under) the situation, carries out under 50-100 ℃ in The suitable solvent (for example, 1,4-diox, THF or the like) and needed finish in 2-10 hour.
The other method of preparation The compounds of this invention
Can react the form that compound of the present invention is become pharmaceutically useful acid salt with pharmaceutically useful mineral acid or organic acid by compound with free alkali form.Perhaps, can be by the compound of free form and mineral alkali or organic bases be reacted the pharmaceutically useful base addition salt for preparing The compounds of this invention.The compound of the present invention that perhaps, can prepare salt form with the salt of parent material or intermediate.
The free acid of The compounds of this invention or free alkali form can be made by corresponding base addition salt or acid salt form respectively.For example, can the compound of the present invention of acid salt form be changed into corresponding free alkali by handling with suitable alkali (for example, solution of ammonium hydroxide, sodium hydroxide or the like).Can the compound of the present invention of base addition salt form be changed into corresponding free acid by handling with suitable acid (for example hydrochloric acid or the like).
Can be by using reductive agent (for example sulphur, sulfurous gas, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide or the like) in suitable inert organic solvents (for example acetonitrile, ethanol, Han Shui diox or the like), the N-oxide compound of handling the cause The compounds of this invention under 0 to 80 ℃ prepares the not compound of the present invention of oxidised form.
The prodrug derivant of The compounds of this invention can (for example be prepared with method known to a person of ordinary skill in the art, further describe people such as seeing Saulnier in detail, (1994), Bioorganicand Medicinal Chemistry Letters, the 4th volume, the 1985th page).For example, suitable prodrug can prepare by the compound of the present invention of underivatized and suitable carbamyl agent (for example, 1,1-acyloxy alkyl carbanochloridate, right-nitrophenyl carbonate or the like) are reacted.
The protected derivative of The compounds of this invention can be prepared with the known method of those of ordinary skills.At T.W.Greene, " Protective Groups in OrganicChemistry ", the 3rd edition, John Wiley and Sons, Inc. can find the detailed description that is applicable to the technology that produces blocking group and be removed in 1999.
In the method for the invention, compound of the present invention can be prepared or be configured as solvate (for example, hydrate) form easily.The hydrate of The compounds of this invention can be prepared by use/ORGANIC SOLVENT MIXTURES recrystallization with organic solvent such as Dioxins, tetrahydrofuran (THF) or methyl alcohol easily.
Can form a pair of diastereoisomeric compound by the racemic mixture of said compound and optically active resolution reagent are reacted, with this diastereomeric separation and it is reverted to optically pure enantiomer compound of the present invention is become its one stereoisomer form.Though can carry out the fractionation of enantiomer with the diastereo-isomerism derivative of The compounds of this invention covalency, preferred easy dissociated complex body (for example, crystalline diastereomeric salt).Diastereomer has different physical properties (for example, fusing point, boiling point, solubleness, reactivity or the like) and can utilize these differences easily it to be separated.Can separate this diastereomer with chromatography, preferably separate by separation/disassemble technique based on the difference of solubleness.Then, with not causing racemic any practical approach that it is reverted to optically pure enantiomer and resolution reagent.Be applicable to go out the more detailed description of technology of the steric isomer of compound by its racemic mixture can be referring to Jean Jacques, Andre Collet, Samuel H.Wilen, " enantiomer, racemic modification and fractionation ", John Wiley ﹠amp; Sons, Inc., 1981.
In a word, the compound of formula I can be prepared with the method that comprises the steps:
(a) compound of formula 2 and the compound of formula 3,4,5 or 6 are reacted:
R3-B (OH)2R3-SnBu3R3-OH R3-NR5H
(3) (4) (5) (6)
X wherein1, X2, R1, R2, R3And R5Definition as described in the top formula I and Q represent fluorine, chlorine, bromine or iodine; Or
(b) randomly compound of the present invention is changed into pharmacologically acceptable salt;
(c) randomly the salt form of The compounds of this invention is changed into salt-independent shape;
(d) randomly the unoxidized form of The compounds of this invention is changed into pharmaceutically useful N-oxide compound;
(e) randomly the N-oxide form of The compounds of this invention is changed into its unoxidized form;
(f) randomly the single isomer of The compounds of this invention is split from isomer mixture;
(g) randomly the compound of underivatized of the present invention is changed into pharmaceutically useful prodrug derivant; With
(h) randomly the prodrug derivant of The compounds of this invention is changed into the form of its underivatized.
If specific description is not carried out in the preparation of initial substance, then these compounds are known or can similarly be prepared with method well known in the prior art or be prepared as embodiment hereinafter is disclosed.
Those skilled in the art will recognize that top conversion only is typical case's representative of preparation The compounds of this invention method, and can similarly use other well-known method.
IV. composition
Pharmaceutical composition of the present invention is those to be suitable for through intestines such as oral or rectum, thereby to suppress Bcr-abl through skin, part and parenteral admin in the Mammals that comprises the people active and be used for the treatment of the Bcr-abl dependent conditions, particularly cancer and tumor disease, as the pharmaceutical composition of leukemia (especially chronic granulocytic leukemia and acute lymphocytoblast leukemia), and comprise the pharmacologically active chemical compounds of the present invention of significant quantity and one or more pharmaceutically useful carriers.
More particularly, this pharmaceutical composition comprises the The compounds of this invention that suppresses the Bcr-abl significant quantity.
Pharmacologically active chemical compounds of the present invention can be used for preparing and comprises the said compound of significant quantity and be applicable to the vehicle of intestines or parenteral application or the pharmaceutical composition of carrier.
Preferably tablet and gelatine capsule, it comprises activeconstituents and a) thinner, for example lactose, glucose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose and/or glycine; B) lubricant, for example silicon-dioxide, talcum powder, stearic acid, its magnesium salts or calcium salt and/or polyoxyethylene glycol; For tablet, also comprise c) tackiness agent, for example neusilin, starch paste, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; If necessary, also can comprise d) disintegrating agent, for example starch, agar, alginic acid or its sodium salt or effervescent agent mixture; And/or e) absorption agent, tinting material, correctives and sweeting agent.The preferably isoosmotic aqueous solution of injectable composition or suspension, and suppository is preferably made by fats emulsion or suspension.Auxiliary agent can be sterilized and/or be comprised to said composition, as sanitas, stablizer, wetting agent or emulsifying agent, chaotropic agent (solution promoters), be used to regulate the salt and/or the buffer reagent of osmotic pressure.In addition, it can also comprise other material that therapeutic value is arranged.Said composition is to be prepared according to mixing, granulation or the coating method of routine respectively, and comprise about 0.1 to 75%, preferred about activeconstituents of 1 to 50%.
Can be with method well known in the prior art with tablet coating clothing or bag casing.
Be used for comprising significant quantity compound of the present invention and carrier through the suitable formulations that skin is used.Preferred carrier includes the acceptable absorbable solvent of pharmacology that helps by the skin of main body.For example, transcutaneous device is to comprise the backing thing, randomly carrier-containingly comprise the bank of medicine, randomly be used in long-term with predetermined controllable rate to the fast barrier of the control of the said compound of skin-communication of main body with guarantee that this device adheres to the form of bandage of the parts on the skin.Also can use the matrix type percutaneous preparation.
Be used for suitable formulations that topical application for example is used for skin and the eyes preferably well-known aqueous solution of prior art, ointment, emulsifiable paste or gel.Such preparation can comprise solubilizing agent, stablizer, raising tensile material, buffer reagent and sanitas.
These pharmaceutical preparations can only comprise the compound as defined above of the present invention that suppresses the Bcr-abl significant quantity or also comprise other therapeutical agent simultaneously.
When comprising other activeconstituents, compound of the present invention can be before or after giving other activeconstituents or administration simultaneously with it, can independently carry out administration or quilt administration together in identical pharmaceutical preparation with identical or different route of administration.
Kind, body weight, age and the individual instances and the form of medication that are depended on warm-blooded animal (Mammals) by the dosage of active compound administered.Be administered orally in about 50 to 70kg mammiferous unitary dose and can comprise about 5 to about 500mg activeconstituents.
V. method
The compound of the formula I of free or pharmaceutical acceptable salt shows valuable pharmacological character, the character that in the in vitro tests described in following " test ", shows for example, and show that therefore it can be used for treatment and active diseases associated of Bcr-abl and illness.For Bcr-abl, the compound of formula I preferably shows 1 * 10-10To 1 * 10-5The IC of M50, for wild-type Bcr-abl and at least two kinds of other Bcr-abl mutants (being selected from the mutant of G250E, E255V, T315I, F317L and M351T) preferably less than 1 μ M.For example, compound 97 (Table I) has 0.20,4.78,0.25,5.28,4.45 and 0.97 IC respectively for wild-type, G250E, E255V, T315I, F317L and M351T Bcr-abl50
The mammiferous disease of abnormal cell growth or the method for illness of comprising that the present invention also provides a kind of prevention or treatment to comprise the people, it comprises the formula I compound that suppresses PDGF-R, c-Kit and/or the active significant quantity of Bcr-abl to this administration.
PDGF (deriving from hematoblastic somatomedin) is a kind of ubiquitous somatomedin, it all plays an important role in normal growth and pathologic cell propagation, as in carcinogenesis with the vascular smooth muscle cell disease is for example seen in atherosclerosis and the thrombosis.
The compound of formula I can suppress PDGF-R, therefore also is applicable to the treatment tumor disease, as the tumour of neurospongioma, sarcoma, tumor of prostate and colon, breast and ovary.
Compound of the present invention has also suppressed to relate to STEM CELL FACTOR (SCF, be also referred to as c-kit part or steel factor) cell processes, the activation of the mapk kinase (mitogen-activated protein kinase) that stimulates as scf receptor (kit) autophosphorylation effect and SCF-.
Therefore, compound of the present invention has also suppressed the autophosphorylation effect of scf receptor (and c-kit---proto-oncogene).The MO7e cell is people's promegakaryocyte leukemia cell system, and its propagation depends on SCF.The compound of formula I has suppressed the autophosphorylation effect of SCF-R in micro-molar range.
According to described character; compound of the present invention not only can be used as the material that suppresses tumour; for example in small cell lung cancer, be used as the material that suppresses tumour; but also can be used as the non-malignant proliferation venereal disease disease of treatment; as atherosclerosis, thrombosis, psoriasis, scleroderma and Fibrotic material and can be used for protecting stem cell; for example resist the hematotoxicity effect of chemotherapeutics such as 5 FU 5 fluorouracil, and can be used for asthma.It especially can be used for treating the disease that to PDGF-R kinase whose inhibition has response.
In addition, compound of the present invention also can with other antitumour drug coupling.
Compound of the present invention can also suppress the abl kinases, especially the v-abl kinases.Therefore, compound of the present invention can also suppress the Bcr-abl kinases and therefore be applicable to treatment Bcr-abl-male cancer and tumor disease, as leukemia (especially chronic granulocytic leukemia and acute lymphocytoblast leukemia, wherein especially found the apoptotic mechanism of action), and show some effects of leukemic stem cells subtribe and (for example extracting described cell, the marrow extraction) potentiality of (for example, having carried out the implantation again of the medullary cell of purifying) are carried out behind external purifying and the cancer cells in having removed these cells these cells being implanted again in the back to these cells.
In addition, show that also compound of the present invention can be used for treatment and transplants, the illness that for example allotransplantation caused, especially tissue rejection, as bronchiolitis obliterans (OB) especially, promptly a kind of chronic rejection of allogeneic lung transplantation thing.The rising opposite with the patient who does not suffer from OB, that these patients that suffer from OB usually show PDGF concentration in the bronchoalveolar lavage fluid.Compound of the present invention may have synergy with other immunomodulator or anti-inflammatory agent material, for example, when with S-Neoral, rapamycin, or ascosin, or its immunosuppression analogue cyclosporin A (CsA) for example, S-Neoral G, FK-506, rapamycin, or suitable with it compound, reflunomide, endoxan, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, the 15-Gusperimus, immunosuppressive antibody, especially leukocyte receptors be MHC for example, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, the monoclonal antibody of CD58 or its part, or has synergy when other immunomodulatory compounds such as CTLA41g coupling.
Compound of the present invention with vascular smooth muscle cells migration and propagation (wherein PDGF and PDGF-R are usually also played a role) diseases associated such as restenosis and atherosclerosis in also effective.These to effect in the external and body of vascular smooth muscle cell proliferation or migration with and the result can prove by giving compound of the present invention, and also can by to its to physical abuse after in the body of vascellum tunica interna incrassation effect study and prove.
In addition, the present invention also provides a kind of inhibition Bcr-abl active method, this method comprise with Bcr-abl with contact with the mnyristoyl binding pocket bonded compound of Bcr-abl.In a preferred embodiment, said compound is the compound of formula I.
VI. embodiment
A. compound
The following example with the preparation that formula I compound of the present invention (embodiment) and its intermediate (reference example) are described comes the present invention is carried out non-limitative illustration.
Reference example 1. (6-chloro-pyrimidine-4-yl)-(4-trifluoromethoxy-phenyl)-amine
With 1.0g 4,6-dichloro pyrimidine (6.7mmol) and 1.2g be right-and trifluoro-methoxyaniline (6.7mmol) is dissolved in the 15mL ethanol together, then to wherein adding 1.75mL DIEA (10mmol).Reaction is 2 hours under refluxing, and then it is cooled to room temperature.After solvent evaporated,, obtain (6-chloro-pyrimidine-4-yl)-(4-trifluoromethoxy-phenyl)-amine of 1.94g white solid form with crude product purification by flash chromatography (EA/ hexane=3: 7).
Reference example 2.4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-phenylformic acid
200mg (4-chloro-pyrimidine-6-yl)-(4-trifluoromethoxy-phenyl)-amine (0.69mmol) that reference example 1 is made joins in the flask that contains 115mg 4-carboxyl phenyl boric acid (0.69mmol), 40mg tetrakis triphenylphosphine palladium (0.034mmol) and 292mg yellow soda ash (2.76mmol).In this flask, add 10mL solvent MeCN/H2O (1: 1).After filling, this flask is heated to 90 ℃ of heating 8 hours with argon gas.This thermal response solution is filtered and it is collected.In this solution, add 6NHCl solution and be lower than 5 until its pH.By filtering to this glaucous solid 4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-phenylformic acid (220mg) collect and with it with twice of 5mL water flushing.
Reference example 3.4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl]-phenylformic acid
Add 1.5g 2 in the 100mL round-bottomed flask, 4-two chloro-[1,3,5] triazines (10mmol), 231mg tetrakis triphenylphosphine palladium (0.2mmol) and 20mL 0.5M 4-(ethoxy carbonyl)-phenyl zinc iodide also mix it.In this reaction mixture, add the anhydrous THF of 10mL.Should react at room temperature and carry out a whole night.This product is directly used in next step reaction without being further purified.Right to wherein adding-trifluoromethoxy-aniline (1.77g; 10mmol) and make it at room temperature to react 2 hours.After removing THF, this crude product is dissolved in the ethyl acetate (100ml) again also with saturated ammonium chloride solution (100ml by evaporation; 3 times) and salt solution (once) it is washed.With this crude product silica gel flash column chromatography purifying, obtain the finished product of 2.8g white solid form.
With 2.8g 4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl]-ethyl benzoate is dissolved in 50mL water/acetonitrile (1: 1) mixture.Refluxed 2 hours down to wherein adding 19N NaOH solution (0.74mL) and this being reflected at 80 ℃.This reaction is cooled to room temperature and passes through to add 6N HCl its pH regulator to 5.Collect light-yellow precipitate,, obtain 4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl with 10ml water washing and dry]-phenylformic acid (2.4g).MS：m/z?377.1(M+H)+；1H?NMR(400MHz，DMSO)δ10.62(s，1H)，8.92(s，1H)，8.51(d，J＝8.0Hz，2H)，8.14(d，J＝8.1Hz，2H)，7.99(d，J＝8.1Hz，2H)，7.54(s，1H)，7.35(d，J＝8.0Hz，2H)。
Embodiment 1.N, N-dimethyl-4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-benzamide
100mg 4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl that reference example 2 is made]-phenylformic acid (0.27mmol) join 200 μ L dimethylamine (2.0M THF solution, 0.40mmol), HATU (112mg; 0.30mmol) and DIEA (232 μ L; 1.33mmol) in.After adding the 4mL solvent DMF, should react and at room temperature stir 8 hours.Except that desolvating and, carrying out wash-out, obtain the N of faint yellow solid form, N-dimethyl-4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl with MeOH/DCM (5%/95%) with the crude product purification by flash chromatography]-benzamide (101mg).MS：m/z?402.1(M+H)+；1H?NMR(400MHz，DMSO)δ8.80(s，1H)，8.05(d，J＝8.1Hz，2H)，7.83(d，J＝9.1Hz，2H)，7.58(d，J＝8.4Hz，2H)，7.37(d，J＝8.4Hz，2H)，7.30(s，1H)，2.97(s，6H)。
Embodiment 2.N-(2-morpholine-4-base-ethyl)-4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-benzamide
100mg 4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl that reference example 2 is made]-phenylformic acid (0.27mmol) joins 4-(2-amino-ethyl) morpholine (53 μ L; 0.40mmol), HATU (112mg; 0.30mmol) and DIEA (232 μ L; 1.33mmol) in.At room temperature stir 8 hours to wherein adding DMF (4mL) and should reacting.Remove and to desolvate and the crude product purification by flash chromatography, with MeOH/DCM (5%: 95%) wash-out, obtain N-(2-morpholine-4-base-ethyl)-4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl of faint yellow solid form]-benzamide (123mg).MS：m/z?488.1(M+H)+；1H?NMR(400MHz，DMSO)δ8.78(s，1H)，8.16(d，J＝8.3Hz，2H)，8.03(d，J＝8.5Hz，2H)，7.85(d，J＝10.2Hz，2H)，7.36(d，J＝8.8Hz，2H)，7.34(s，1H)，4.01(t，7.0Hz，2H)，3.66(t，6.8Hz，4H)，3.57(t，7.2Hz，2H)，3.35(t，6.9Hz，4H)。
Embodiment 3. (6-pyridin-4-yl-pyrimidine-4-yl)-(4-trifluoromethoxy-phenyl)-amine
(4-chloro-pyrimidine-6-yl)-(4-trifluoromethoxy-phenyl)-amine (100mg that reference example 1 is made; 0.35mmol) join 4-(tributyl tin)-pyridine (190mg; 0.52mmol) and tetrakis triphenylphosphine palladium (20mg; 0.018mmol) in.Solvent is anhydrous 1, the 4-diox.This is reflected under the reflux temperature under argon gas, carried out 16 hours.Except that after desolvating,,, obtain (6-pyridin-4-yl-pyrimidine-4-yl)-(4-trifluoromethoxy-phenyl)-amine (40mg) of yellow solid form with hexane/EA (35%: 65%) wash-out with the crude product purification by flash chromatography.MS：m/z?333.2(M+H)+；1H?NMR(400MHz，CDCl3)δ8.83(s，1H)，8.79(d，J＝8.2Hz，2H)，7.82(d，J＝9.0Hz，2H)，7.51(d，J＝8.4Hz，2H)，7.29(d，J＝8.4Hz，2H)，7.09(s，1H)。
Embodiment 4.[6-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-pyrimidine-4-yl]-(4-trifluoromethoxy-phenyl)-amine
(4-chloro-pyrimidine-6-yl)-(4-trifluoromethoxy-phenyl)-amine (100mg that reference example 1 is made; 0.35mmol) join 1,4-two oxa-s-8-azepine-spiral shell [4.5] decane (75mg; 0.52mmol), three-(dibenzylidene-acetone)-two palladiums (0) (8.1mg; 0.009mmol), 1,3-two (2,6-two-isopropyl phenyl)-imidazolium chloride 7.4mg (0.018mmol) and potassium tert.-butoxide (59mg; 0.52mmol) in.Solvent is anhydrous 1, the 4-diox.This is reflected under 80 ℃ under argon gas, carried out 4 hours.Remove desolvate after, with the crude product purification by flash chromatography, carry out wash-out with hexane/EA (40%/60%), obtain [6-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-pyrimidine-4-yl]-(4-trifluoromethoxy-phenyl)-amine (110mg) of white solid form.MS：m/z?397.2(M+H)+；1H?NMR(400MHz，CDCl3)δ8.27(s，1H)，7.33(d，J＝8.2Hz，2H)，7.18(d，J＝8.4Hz，2H)，6.66(s，1H)，3.99(t，J＝4.8Hz，4H)，3.67(t，J＝5.2Hz，4H)，1.70(t，J＝5.5Hz，4H)。
Embodiment 5.[6-(3-methylsulfonyl-phenyl)-pyrimidine-4-yl]-(4-trifluoromethoxy-phenyl)-amine
(6-chloropyrimide-4-yl)-(the 4-Trifluoromethoxyphen-l)-amine (510mg that makes to reference example 1; 1.76mmol) and (3-methyl sulphonyl phenyl)-boric acid (352mg, 1.76mmol) the carrying out in 0.4M aqueous sodium carbonate (17mL) and acetonitrile (17mL) degassing solution in add PPh3(100mg, 0.09mmol).With its under about 90 ℃ at N2Under stir 12 hours after, with this reaction mixture at saturated NaHCO3And CHCl3Between distribute.With water layer additional C HCl3Extract.With the organic layer MgSO that is merged4Drying is filtered and concentrating under reduced pressure.With the faint yellow oily thing of gained column chromatography purifying (SiO2, hexane/ethyl acetate (4/6)), obtain [6-(3-methane-alkylsulfonyl phenyl)-pyrimidine-4-yl]-(the 4-Trifluoromethoxyphen-l)-amine (619mg of faint yellow solid form; 86%).1HNMR(400MHz，CDCl3)δ8.81(s，1H)，8.55-8.54(m，1H)，8.30-8.28(m，1H)，8.10-8.03(m，1H)，7.71-7.68(m，1H)，7.55-7.53(m，2H)，7.28-7.27(m，1H)，7.10-7.09(m，2H)，3.11(s，3H)。
Embodiment 6.3-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-benzamide
(6-chloropyrimide-4-yl)-(the 4-Trifluoromethoxyphen-l)-amine (73mg that makes to reference example 1,0.25mmol) and (3-aminocarbonyl-phenyl)-boric acid (42mg, 0.25mmol) the carrying out in 0.4M aqueous sodium carbonate (1.3mL) and acetonitrile (1.3mL) degassing solution in add PPh3(15mg, 0.01mmol).With its under 90 ℃ at N2Under stir 12 hours after, with this reaction mixture at saturated NaHCO3And CHCl3/ 2-propyl alcohol distributes between (4/1).With water layer additional C HCl3/ 2-propyl alcohol (4/1) extracts and with the organic layer MgSO that is merged4Drying is filtered and with its concentrating under reduced pressure.Faint yellow oily thing column chromatography (SiO with gained2, ethyl acetate) and purifying, obtain 3-[6-(4-Trifluoromethoxyphen-l-amino)-pyrimidine-4-yl of white solid form]-benzamide (82mg; 88%).MS?m/z?375.10(M+1)。
Embodiment 7.[6-(3-amino-phenyl)-pyrimidine-4-yl]-(4-trifluoromethoxy-phenyl)-amine
(6-chloropyrimide-4-yl)-(the 4-Trifluoromethoxyphen-l)-amine (217mg that makes to reference example 1,0.75mmol) and (2-aminophenyl)-boric acid (130mg, 0.75mmol) the carrying out in 0.4M aqueous sodium carbonate (3.8mL) and acetonitrile (3.8mL) degassing solution in add PPh3(45mg, 0.04mmol).With this reaction mixture under about 90 ℃ at N2The suspension that stirred down 12 hours and should heat filters.With the concentrated crude product that obtains of filtrate decompression, it is used column chromatography purifying (SiO2, hexane/ethyl acetate (4/1)), obtain [6-(3-aminophenyl)-pyrimidine-4-yl]-(the 4-Trifluoromethoxyphen-l)-amine (218mg of faint yellow solid form; 84%).MS?m/z?347.10(M+1)。
Embodiment 8.N-(2-hydroxyl-ethyl)-4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl]-benzamide
4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl that reference example 3 is made]-phenylformic acid (50mg; 0.13mmol) and ethanol-amine (12 μ l; 0.2mmol), (54mg is 1.5mmol) at dry DMF (0.5mL) and DIEA (113 μ l for HATU; 0.65mmol) in mix.Should react at room temperature and carry out a whole night.Except that after desolvating, with end product reversed-phase HPLC purifying, in 10 minutes, carry out wash-out with the 5-95% acetonitrile, obtain N-(2-hydroxyethyl)-4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl]-benzamide.MS：m/z?420.1(M+H)+；1H?NMR(400MHz，DMSO)δ10.52(s，1H)，8.84(s，1H)，8.55(t，J＝6.0Hz，1H)，8.40(d，J＝8.1Hz，2H)，7.98(d，J＝9.5Hz，2H)，7.86(s，2H)，7.36(d，J＝8.0Hz，2H)，3.62(s，1H)，3.47(t，J＝6Hz，2H)，3.31(dd，J＝5.9，2H)。
Embodiment 9.N-(2-dimethylamino-ethyl)-4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl]-benzamide
4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl that reference example 3 is made]-phenylformic acid (50mg, 0.13mmol) and N, N-dimethyl-ethane-1,2-diamines (22 μ l; 0.2mmol), HATU (54mg; 1.5mmol) (113 μ l mix in 0.65mmol) at 0.5mL dry DMF and DIEA.Should react at room temperature and carry out a whole night.Except that after desolvating, with end product reversed-phase HPLC purifying, in 10 minutes, carry out wash-out with the 5-95% acetonitrile, obtain N-(2-dimethylamino-ethyl)-4-[4-(4-trifluoromethoxy-phenyl amino)-[1,3,5] triazine-2-yl]-benzamide.MS：m/z?447.2(M+H)+；1H?NMR(400MHz，DMSO)δ10.52(s，1H)，9.32(s，1H)，8.84(s，1H)，8.79(t，J＝4.5Hz，1H)，8.42(d，J＝8.1Hz，2H)，7.98(d，J＝8.2Hz，2H)，7.86(s，2H)，7.35(d，J＝8.0Hz，2H)，3.58(dd，J＝5.8Hz，2H)，3.24(dd，J＝5.9，2H)，2.81(d，J＝4.8)。
By repeating the described method of the foregoing description,, obtain determined following formula I compound in embodiment 10-14 and the table 1 with suitable parent material.
Embodiment 10.N-(2-morpholine-4-base-ethyl)-N '-(4-trifluoromethoxy-phenyl)-pyrimidine-4, the 6-diamines
White solid.MS：m/z?384.2(M+H)+，1H?NMR(400MHz，CDCl3)δ8.21(s，1H)，7.76(s，1H)，7.34(d，J＝8.2Hz，2H)，7.20(d，J＝8.4Hz，2H)，5.89(s，1H)，3.69(t，J＝4.7Hz，4H)，2.27(d，J＝4.3Hz，2H)，2.58(t，J＝5.2Hz，2H)，2.45(t，J＝5.3Hz，4H)。
Embodiment 11. (6-imidazoles-1-base-pyrimidine-4-yl)-(4-trifluoromethoxy-phenyl)-amine
White solid.MS：m/z?322.1(M+H)+，1H?NMR(400MHz，DMSO)δ9.15(s，1H)，8.67(s，1H)，8.12(s，1H)，7.77(d，J＝7.2Hz，2H)，7.51(s，1H)，7.40(d，J＝8.2Hz，2H)，7.05(s，1H)。
Embodiment 12.{6-[2-(3-imidazoles-1-base-propyl group amino)-pyridin-4-yl]-pyrimidine-4-yl }-(4-trifluoromethoxy-phenyl)-amine
Yellow solid.MS：m/z?456.2(M+H)+，1H?NMR(400MHz，DMSO)δ9.13(s，1H)，8.78(s，1H)，8.12(d，J＝6.1Hz，1H)，7.84(d，J＝7.2Hz，2H)，7.81(s，1H)，7.71(s，1H)，7.43(s，1H)，7.37(d，J＝8.5Hz，2H)，7.32(s，1H)，7.16(d，J＝5.9Hz，1H)，4.30(t，d＝6.7Hz，2H)，3.36(t，J＝6.8Hz，2H)，2.16(m，2H)。
Embodiment 13.3-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-benzsulfamide
Faint yellow solid.MS：m/z?411.1(M+H)+；1H?NMR(400MHz，DMSO)δ8.79(s，1H)，8.53(s，1H)，8.23(d，J＝8.5Hz，1H)，7.96(d，J＝5.1Hz，1H)，7.85(d，J＝6.9Hz，2H)，7.75(t，J＝7.9Hz，1H)，7.48(s，2H)，7.36(d，J＝8.2Hz，2H)，7.33(s，1H)。
Embodiment 14.N-(2-hydroxyl-ethyl)-4-{4-[6-(4-trifluoromethoxy-phenyl amino)-pyrimidine-4-yl]-pyridine-2-yl }-benzamide
Faint yellow solid.MS：m/z?496.2(M+H)+；1H?NMR(400MHz，DMSO)δ8.88(d，J＝5.1Hz，1H)，8.85(s，1H)，8.55(s，2H)，8.25(d，J＝8.4Hz，2H)，8.02(d，8.5Hz，2H)，7.96(dd，J＝5.2Hz，1H)，7.87(d，J＝8.7Hz，2H)，7.58(m，2H)，7.49(s，1H)，7.38(d，J＝8.5Hz，2H)，3.54(t，J＝6.1Hz，2H)，3.37(m，2H)。
Table 1
B. test
Compound of the present invention is tested to measure the ability of the 32D cell propagation of comparing its selectivity inhibition expression Bcr-abl (32D-p210) with parent 32D cell.Selectivity being suppressed the compound of these Bcr-abl cell transformed propagation tests the antiproliferative activity of the Ba/F3 cell of expression wild-type or mutant Bcr-abl.
Cell Bcr-abl dependency inhibition of proliferation (high-yield method)
Used murine clone is the 32D hemopoietic progenitor cell system that transforms with Bcr-abl cDNA (32D-p210).These cells are maintained in the RPMI/10% foetal calf serum (RPMI/FCS) that has added penicillin 50 μ g/mL, Streptomycin sulphate 50 μ g/mL and L-glutamine 200mM.Maintain unconverted 32D cell under the similar condition and add 15% WEHI conditioned medium as the IL3 source.
50 μ L 32D or the 32D-p210 cell suspension density with 5000 cells in every hole is added in the Greiner 384 hole microtest plates (black).In each hole, add 50 μ l test compounds (1mMDMSO storing solution) (comprising STI571) as positive control.With these cells at 37 ℃, 5% CO2Under cultivated 72 hours.In each hole, add 10 μ l, 60% Alamar Blue solution (Tek diagnosis) and these cells were cultivated 24 hours again.Use AcquestTMSystem (Molecular Devices) carries out quantitatively (excite, launch) to fluorescence intensity under 580nm under 530nm.
Cell Bcr-abl dependency inhibition of proliferation
The density of 32D-p210 cell with every hole 15,000 is added in the 96 hole TC plates.Twice serial dilutions (the C that in each hole, adds 50 μ L test compoundsMaxBe 40 μ M) (comprising STI571) as positive control.With these cells at 37 ℃, 5% CO2Under cultivate 48 hours after, in each hole, add 15 μ L MTT (Promega) and these cells cultivated 5 hours again.By spectrophotometry the optical density(OD) under the 570nm is carried out quantitatively, and measure IC by dose response curve50Value (50% suppresses required compound concentration).
The influence that cell cycle distributes
With 32D and 32D-p210 cell in the 5mL substratum with every hole 2.5 * 106The density of individual cell joins in the 6 hole TC plates and adds test compound (comprising STI571 in contrast) to the concentration with 1 or 10 μ M wherein.Then, with these cells at 37 ℃, 5% CO2Under cultivated 24 or 48 hours.The 2mL cell suspension is washed with PBS, in 70% EtOH, fix 1 hour and use PBS/EDTA/RNase A to handle 30 minutes it.Add propidium iodide (Cf=10 μ g/ml) and at FACScaliburTMSystem (BD Biosciences) goes up and by flow cytometry fluorescence intensity is carried out quantitatively.Test compound of the present invention shows the apoptosis effect to the 32D-p210 cell, but does not have cell death inducing in the 32D parental cell.
The influence of pair cell Bcr-abl autophosphorylation effect
By c-abl specificity capture antibody and anti-phosphotyrosine antibody with catch Elisa to the Bcr-abl autophosphorylation effect carry out quantitatively.With the 32D-p210 cell in 50 μ L media with every hole 2 * 105The density of individual cell adds in the 96 hole TC plates.Twice serial dilutions (the C that in each hole, adds 50 μ L test compoundsMaxBe 10 μ M) (comprising STI571) as positive control.With these cells at 37 ℃, 5% CO2Under cultivated 90 minutes.These cells were handled 1 hour with molten born of the same parents' damping fluid (50mM Tris-HCl, pH 7.4,150mM NaCl, 5mM EDTA, 1mM EGTA and 1% NP-40) that 150 μ L comprise proteolytic enzyme and inhibitors of phosphatases on ice.To prior usefulness anti--the abl specific antibody carried out adding 50 μ L cell lysates and sealing among the 96 hole Optiplate of coating.These plates were cultivated 4 hours down at 4 ℃.After with the washing of TBS-polysorbas20 damping fluid, to wherein adding anti--phosphotyrosine antibody that 50 μ L alkalescence-Phosphoric acid esterase yokes close and this plate being cultivated a whole night under 4 ℃ again.After with the washing of TBS-polysorbas20 damping fluid, to wherein adding 90 μ L luminous substrate and using AcquestTMSystem (Molecular Devices) carries out quantitatively this cold light.The test compound of the present invention that suppresses the cell proliferation of expression Bcr-abl has suppressed the effect of Bcr-abl autophosphorylation in the dose-dependently mode.
Effect to the cell proliferation of expressing mutant Bcr-abl
For The compounds of this invention the antiproliferative effect of the Ba/F3 cell of the various mutant Bcr-abl (G250E, E255V, T315I, F317L, M351T) that express wild-type or expression and cause producing resistance or the susceptibility of STI571 is reduced is tested.As mentioned above like that under 10,3.3,1.1 and 0.37 μ M (in the substratum that does not contain IL3) these compounds are tested the cell of expressing mutant-Bcr-abl and the antiproliferative effect of unconverted cell.Determine unconverted cell is not had the IC of toxic compound as mentioned above like that by the dose response curve that is obtained50Value.
Though by illustrating above-mentioned the present invention has been carried out some detailed descriptions for the purpose that can know understanding, obviously can carry out some change and modification within the scope of the appended claims with the mode of embodiment.In addition, all reference provided here all are incorporated herein by reference in full.
Claims (16)
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| CN101902912A (en)* | 2007-11-06 | 2010-12-01 | 纳幕尔杜邦公司 | Fungicidal amines |
| CN103641833A (en)* | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN104311563A (en)* | 2007-11-28 | 2015-01-28 | 达那-法伯癌症研究所 | Small molecule myristate inhibitors of BCR-ABL and methods of use |
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| CN116730925A (en)* | 2023-08-08 | 2023-09-12 | 中国药科大学 | Heterocyclic immunosuppressant, preparation method and application thereof |
| WO2025067457A1 (en)* | 2023-09-28 | 2025-04-03 | 深圳市塔吉瑞生物医药有限公司 | Heterocyclic fused ring compound, and composition and use thereof |
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- 2004-04-02CNCN 200480015433patent/CN1798734A/enactivePending
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| CN103641833A (en)* | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN101902912A (en)* | 2007-11-06 | 2010-12-01 | 纳幕尔杜邦公司 | Fungicidal amines |
| CN104311563A (en)* | 2007-11-28 | 2015-01-28 | 达那-法伯癌症研究所 | Small molecule myristate inhibitors of BCR-ABL and methods of use |
| CN104327084A (en)* | 2007-11-28 | 2015-02-04 | 达那-法伯癌症研究所 | Small molecule myristate inhibitors of bcr-abl and methods of use |
| CN104311563B (en)* | 2007-11-28 | 2016-12-07 | 达那-法伯癌症研究所 | The small molecule myristate inhibitors of BCR-ABL and using method thereof |
| CN104327084B (en)* | 2007-11-28 | 2017-06-06 | 达那-法伯癌症研究所 | The small molecule myristate inhibitors and its application method of BCR ABL |
| CN105399695A (en)* | 2015-12-11 | 2016-03-16 | 浙江大学 | Triazine-kind compounds, preparation method and applications |
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