CN101657431A - Pyrimidine-2,4-diamine derivatives and their use as JAK2 kinase inhibitors - Google Patents

Pyrimidine-2,4-diamine derivatives and their use as JAK2 kinase inhibitors Download PDF

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CN101657431A
CN101657431A CN200880010977A CN200880010977A CN101657431A CN 101657431 A CN101657431 A CN 101657431A CN 200880010977 A CN200880010977 A CN 200880010977A CN 200880010977 A CN200880010977 A CN 200880010977A CN 101657431 A CN101657431 A CN 101657431A
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compound
acceptable salt
pharmacy acceptable
steric isomer
described compound
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H·范卡亚拉帕蒂
刘晓辉
D·J·拜尔斯
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Hump Gene
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Hump Gene
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Abstract

Pyrimidine-2,4-diamines derivatives having activity as JAK2 kinase inhibitors are disclosed, as well as pharmaceutical compositions and methods for using the same in the treatment of cancer and otherJAK2 kinase-associated conditions.

Description

Pyrimidine-2,4-diamine derivative and as the purposes of JAK2 kinase inhibitor
The cross reference of related application
The U.S. Provisional Patent Application No.US 60/892 that submit to 1 day March in 2007 among the application's request 35U.S.C. § 119 (e), the U.S. Provisional Patent Application No.60/911 that on April 13rd, 385 and 2007 submitted to, 776 interests intactly are incorporated herein by reference these provisional application.
Background
Technical field
The compound of relate generally to arrestin kinase activity of the present invention and composition and relevant method thereof.
The description of association area
Janus kinases (JAKs) belongs to kinases family, in them, there are 4 kinds to be present in (JAK1 in the Mammals, JAK2, JAK3 and TYK2), they are cytokine outside from born of the same parents, comprises interleukin-, integrate (Aringer in the signal conduction of Interferon, rabbit and a large amount of hormones, M. etc., Life Sci, 1999.64 (24): p.2173-86; Briscoe, J. etc., PhilosTrans R Soc Lond B Biol Sci, 1996.351 (1336): p.167-71; Ihle, J.N., Semin Immunol, 1995.7 (4): p.247-54; Ihle, J.N., PhilosTrans R Soc Lond B Biol Sci, 1996.351 (1336): p.159-66; Firmbach-Kraft, I. etc., Oncogene, 1990.5 (9): p.1329-36; Harpur, A.G. etc., Oncogene, 1992.7 (7): p.1347-53; Rane, S.G. and E.P.Reddy, Oncogene, 1994.9 (8): p.2415-23; Wilks, A.F., Methods Enzymol, 1991.200:p.533-46).These non--receptor tyrosine kinases combine with various cytokine receptors and by making STAT (signal transducer and transcription activator) molecular phosphorus acidifying play a part and will go into kytoplasm from the outer ligand-receptor bonded signal transduction of born of the same parents, enter nuclear then and directly transcribe various target genes (Briscoe, the J. etc. that relate to growth and propagation; Ihle, J.N. (1995); Ihle, J.N. (1996); Rawlings, J.S., K.M.Rosler and D.A.Harrison, J Cell Sci, 2004.117 (Pt 8): p.1281-3).The importance of these kinases in cell survival lacks common concomitant immunity by JAK s in the animal model and lacks and can not live that this is true and apparent (Aringer, M. etc.).JAK family enzyme is characterised in that a large amount of JAK homologys (JH) structural domain, comprises carboxyl-terminal protein tyrosine kinase domain (JH1) and adjacent kinases-spline structure territory (JH2), thinks that they regulate the activity (Harpur, A.G. etc.) of JH1 structural domain.4 kinds of JAK isotypes by specificity in conjunction with some cytokine receptor and the different signal of activation downstream gene subgroup transduction.For example, the JAK2 combination is to interleukin 3 (Silvennoinen, O. etc., Proc NatlAcad Sci U S A, 1993.90 (18): p.8429-33), erythropoietin (Witthuhn, B.A. etc., Cell, 1993.74 (2): p.227-36), granulocyte colony-stimulating factor (Nicholson, S.E. etc., Proc Natl Acad Sci U S A, 1994.91 (8): p.2985-8) and tethelin (Argetsinger, L.S. etc., Cell, 1993.74 (2): p.237-44) have specific cytokine receptor.
JAK family enzyme has become the one group of target that attracts people's attention of various blood and immune disorders; JAK2 is at present as ND, especially leukemia and lymphoma (Benekli, M. etc., Blood, 2003.101 (8): p.2940-54; Peeters, P. etc., Blood, 1997.90 (7): p.2535-40; Reiter, A. etc., Cancer Res, 2005.65 (7): p.2662-7; Takemoto, S. etc., Proc Natl Acad Sci USA, p.13897-902) and solid tumor (Walz, C. etc. 1997.94 (25):, JBiol Chem, 2006.281 (26): p.18177-83) and other myeloproliferative diseases, such as polycythemia vera (Baxter, E.J. etc., Lancet, 2005.365 (9464): p.1054-61; James, C. etc., Nature, 2005.434 (7037): p.1144-8; Levine, R.L. etc., Cancer Cell, 2005.7 (4): p.387-97; Shannon, K. and R.A.VanEtten, Cancer Cell, 2005.7 (4): great-hearted target p.291-3) is in the research especially, and this is because its downstream effect gene activation relates to propagation.Also known JAK2 suddenlys change in hematologic malignancies, makes it no longer need part in conjunction with cytokine receptor, but is in the composing type active state.This situation can be by JAK2 gene and coding ETV6, the proteic gene of BCR or PCM1 (Peeters, P. etc.; Reiter, A. etc.; Griesinger, F. etc., Genes Chromosomes Cancer, 2005.44 (3): p.329-33; Lacronique, V. etc., Science, 1997.278 (5341): the transposition p.1309-12) takes place, thereby generates and the similar tumorigenesis fusion rotein of observed BCR-ABL protein in chronic myelogenous leukemia.The overactivity of JAK2 can also take place by the sudden change of JAK2 sequence self; For example, the myeloproliferative disease polycythemia vera relates to and causes (JAK2V617F) generation point mutation (Walz, C. etc.) that Xie Ansuan-phenylalanine replaces on 617 amino acids.The small molecules JAK2 inhibitor of treatment human malignant tumor is relevant with ND and myeloproliferative disease and lack of proper care significant therein because of it.
Based on relating to a large amount of human malignant tumors, so there is demand in the specificity and the selective depressant of design treatment cancer and mediation of other JAK2 kinase protein and/or related disorders.The present invention has satisfied these demands and extra associated advantages is provided.
Summary
Relate generally to compound of the present invention (being also referred to as pyrimidine-2 in this article, the 4-diamine derivative) and comprise the pharmaceutical composition of described compound, wherein this compound has following general structure (I) or (II):
Figure G2008800109774D00031
Comprise its steric isomer and pharmacy acceptable salt, wherein R 1, W 1, W 2, X 1, X 2, Y 1, Y 2With Z such as hereinafter definition.
These compounds have to surpass extensively treats the purposes of using, and can be used for the treatment of the disease of JAK2 protein kinase mediated and/or relevant (being part at least), such as cancer.Therefore, in the present invention in one aspect, compound as herein described is mixed with the pharmaceutically acceptable composition that is used for the object administration that these needs are arranged.
The present invention provides the disease of treatment or prevention JAK2 protein kinase-mediation in one aspect of the method, such as method for cancer, this method comprises treats the compound as herein described of significant quantity or comprises the pharmaceutically acceptable composition of this compound the patient that these needs are arranged.
Another aspect relates to the JAK2 protein kinase activity that suppresses in the biological sample, and this method comprises the pharmaceutically acceptable composition that makes described biological sample contact compound as herein described or comprise this compound.
Another aspect relates to the method that suppresses patient JAK2 protein kinase activity, and this method comprises the patient is given compound as herein described or comprises the pharmaceutically acceptable composition of this compound.
These and other aspect of the present invention is apparent with reference to hereinafter detailed description the time.In order to reach this purpose, this paper has quoted from some patent and other documents of more specifically listing in each side of the present invention.These documents intactly are incorporated herein by reference separately.
Describe in detail
General aspect of the present invention provides compound and composition and the method as the JAK2 kinases inhibitor.Compound of the present invention have formula (I) or (II) shown in structure:
Figure G2008800109774D00041
Comprise its steric isomer and pharmacy acceptable salt, wherein:
Z is CH or N;
W 1And W 2Be direct key independently ,-C (=O)-or-O (CH 2) n-;
R 1For-H ,-CF 3,-OCF 3,-OCHF 2,-OCH 3,-CH 3,-OH ,-NO 2,-NH 2Or halogen;
X 1And X 2Be-H-CF independently 3,-OCF 3,-OCHF 2,-OCH 3,-CH 3,-OH ,-NO 2,-NH 2, halogen or
Figure G2008800109774D00051
Wherein Q is O or N and R does not exist or R is-C 1-6Alkyl, condition are X 1Or X 2One of be:
Figure G2008800109774D00052
Y 1And Y 2Be-H-CN, the C that halogen or quilt-CN replace independently 1-4Alkyl, condition are Y 1And Y 2Be not-H; And
N is 1,2 or 3.
Unless otherwise stated, otherwise the following term of using in this specification sheets and the claim has implication as described below:
" halogen " intention fluorine, chlorine, bromine or iodine and be generally fluorine or chlorine.
" C 1-6Alkyl " an intention 1-6 carbon atom saturated straight chain or side chain is saturated or unsaturated cyclic or acyclic hydrocarbon group, and " C 1-4Alkyl " have identical meanings, but comprise 1-4 carbon atom.Saturated straight chain or side chain C 1-4Alkyl and C 1-6The representational example of alkyl comprises methyl, ethyl, just-and propyl group, sec.-propyl, just-and butyl, isobutyl-, the second month in a season-butyl and tert-butyl, and with regard to C 1-6Alkyl just further comprising-amyl group, just-and the chain of hexyl and corresponding branching.Representational saturated cyclic alkyls comprises cyclopropyl, cyclobutyl, cyclopentyl ,-CH 2Cyclopentyl, cyclohexyl etc.; And the unsaturated cyclic alkyl comprises cyclopentenyl, cyclohexenyl etc.Unsaturated alkyl comprises at least one two keys or triple bond (being called " thiazolinyl " or " alkynyl " respectively) between adjacent carbons.Representational straight chain and branched-chain alkenyl comprise vinyl, propenyl, 1-butylene base, crotyl, isobutenyl, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-crotyl etc.; And a representational straight chain and an alkynyl group comprise ethynyl, proyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl etc.
Said structure (I) and (II) more specifically aspect in, Z is CH and described compound by following structure (III) or (IV) expression:
Figure G2008800109774D00061
Comprise its steric isomer and pharmacy acceptable salt.
In said structure (I) and others (II), Z is that N and described compound are represented by following structure (V) or (VI):
Figure G2008800109774D00062
Comprise its steric isomer and pharmacy acceptable salt.
Said structure (III) and (V) more specifically aspect in, X 1Be piperazinyl, R is methyl and W 1And W 2Be direct key and described compound respectively by structure (VII) and (VIII) expression:
Figure G2008800109774D00063
In structure (VII) and more particular embodiment (VIII), X 2For-F and described compound respectively by structure (IX) and (X) expression:
Figure G2008800109774D00071
In structure (VII) and other specific embodiment (VIII), X 2For-H and described compound respectively by structure (XI) and (XII) expression:
In other specific embodiment of structure (III), X 2Be piperazinyl, R is a methyl, W 2For-O (CH 2) 3-and W 1Be direct key, and described compound is represented by structure (XIII):
In the extra specific embodiments of structure (XIII), X 1For-OCH 3
In other specific embodiment of structure (III), X 1Be piperazinyl, W 1For-C (=O)-and W 2Be direct key, and described compound is represented by structure (XIV):
In the extra specific embodiments of structure (XIV), X 2For-H and R are that methyl or R are cyclohexyl.
At structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), in the specific embodiments (XIII) and (XIV), Y 1And Y 2Be halogen, and more particularly, Y 1Be chlorine and Y 2Be fluorine.
At structure (I), (III), (V), (VII), (VIII), (IX), (X), (XI), in the specific embodiments (XII), Y 1And Y 2For-CN and halogen, and more particularly, Y 1For-CN and Y 2Be fluorine.
At structure (I), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), in the specific embodiments (XIII) and (XIV), Y 1And Y 2The C that replaces for-H and quilt-CN 1-4Alkyl, and more particularly, Y 1For-CH 2CN and Y 2For-H.
At structure (II), in the specific embodiments (IV) and (VI), R 1For-F or R 1For-CF 3
Have the same molecular formula, but be called " isomer " at different compound aspect character or its atomic linkage order or its atom spatial disposition.Be called " steric isomer " at different isomer aspect its atom spatial disposition.Each other for the steric isomer of non-mirror image is called " diastereomer ", and be called " enantiomer " for those of non-superimposable mirror image each other.When compound has asymmetric center, for example it and 4 different group bondings, enantiomer is to being possible.Enantiomer is characterised in that the absolute configuration of its asymmetric center and is described as Cahn and the R-of Prelog and S-sequence rule (Cahn, R., Ingold, C. and Prelog, V.Angew.Chem.78:413-47,1966; Angew.Chem.Interna t.Ed.Eng.5:385-415,511,1966) or molecule along the mode of polarized light flat rotation and called after dextrorotation or left-handed (promptly being respectively (+) or (-)-isomer).Chipal compounds can be used as each enantiomer or its mixture exists.The mixture that comprises the equal proportion enantiomer is called " racemic mixture ".
Compound of the present invention can have one or more asymmetric centers; This compounds can be used as each (R)-or (S)-steric isomer thus or its mixture produces.Unless otherwise stated, otherwise describe in this specification sheets and the claim or the particular compound of name in order to comprising each enantiomer and composition thereof, otherwise be exactly racemic mixture.The method that is used to measure the steric isomer stereochemistry and separates them is well-known in the art (referring to A DVANCEDO RGANICC HEMISTRYCh.4 in discussion, the 4th edition, March, J., John Wiley andSons, New York City, 1992).
Compound of the present invention can show tautomerism and Structural Isomerism phenomenon.The present invention includes and have any tautomer that to regulate the JAK2-2 kinase activity or constitutional isomer form and composition thereof, and be not limited to any one tautomer or constitutional isomer form.
Pay close attention to compound of the present invention and can be become to regulate the metabolite of protein kinase activity such as the intravital enzymes metabolism of people by organism.This metabolite belongs to scope of the present invention.
Like this can be with compound of the present invention or its pharmacy acceptable salt to the patient, comprise people's administration or can give, wherein with above-mentioned substance and suitable carriers or mixed with excipients with the form of pharmaceutical composition.For example, can be according to latest edition R EMINGTON ' SP HARMACOLOGICALS CIENCES, Mack Publishing Co., Easton, PA are identified for preparing and giving the technology of medicine.
One or more or its pharmacy acceptable salt and other chemical ingredients in " pharmaceutical composition " intention compound as herein described are such as the mixture of pharmaceutically acceptable vehicle.The purpose of pharmaceutical composition is to help giving compound to organism.
" pharmaceutically acceptable vehicle " intention joins in the pharmaceutical composition so that further help the inert substance of compound administration.The example of vehicle comprises lime carbonate, calcium phosphate, and various sugar and various types of starch, derivatived cellulose, gelatin, vegetables oil and polyethylene glycols, but be not limited to them.
" pharmacy acceptable salt " intention keeps those salt of parent compound biological effectiveness and characteristic.This class salt can comprise: (1) free alkali by making parent compound and the salt of mineral acid or the sour addition that obtains with organic acid reaction, all example hydrochloric acids of described mineral acid, Hydrogen bromide, nitric acid, phosphoric acid, sulfuric acid and perchloric acid etc., described organic acid is such as acetate, oxalic acid, (D)-or (L)-oxysuccinic acid, toxilic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, succsinic acid or propanedioic acid etc., preferred hydrochloric acid or (L)-oxysuccinic acid; Or the acid proton that (2) exist in parent compound is by metal ion, alkalimetal ion for example, the salt that forms when alkaline-earth metal ions or aluminum ion replace; Or and organic bases, such as thanomin, diethanolamine, trolamine, Trometamol, the coordination compound that N-methylglucosamine etc. form.
" treatment significant quantity " intention with sanatory one or more remissions of institute to administered compound consumption to a certain degree.With regard to the treatment cancer, treatment significant quantity intention has the consumption of following effect: (1) reduces tumor size; (2) suppress tumor metastasis; (3) suppress tumor growth; And/or (4) alleviate one or more symptoms relevant with cancer.
Any disease or other adverse condition that term used herein " illness of JAK2 protein kinase-mediation " or the known JAK2 protein kinase of " disease " intention work.Term " illness of JAK2 protein kinase-mediation " or " disease " be those diseases or the illness of intention by using the treatment of JAK2 kinases inhibitor to alleviate also, is included in cancer hereinafter discussed in detail.
" giving " used herein or " administration " intention are for preventing or treating the protein kinase associated conditions organism is sent compound of the present invention or its pharmacy acceptable salt or comprises The compounds of this invention or the pharmaceutical composition of its pharmacy acceptable salt of the present invention.
Suitable route of administration includes, but are not limited to oral, and rectum is striden mucous membrane or enteral administration or intramuscular, and is subcutaneous, in the marrow, and in the sheath, in the direct ventricle, intravenously, in the vitreum, intraperitoneal, the interior or intraocular injection of nose.In certain embodiments, route of administration is oral and intravenously.
Selectively, can give described compound, for example by compound is directly injected solid tumor with the form of long-acting or sustained release preparation usually with the local mode of non-systemic fashion.
In addition, can be with targeted delivery systems, for example with bag by the liposome form of tumor specific antibody give described compound.In this mode, described liposome can target to tumour and optionally absorbed by tumour.
Can be by method well-known in the art, for example by conventional mixing, dissolving is granulated, and the system ingot is levigate, emulsification, packing is held back or freeze drying process prepares pharmaceutical composition of the present invention.
Can use to include to be beneficial to active compound is processed into the pharmaceutical composition that can use in one or more physiology acceptable carrier preparations the present invention of the preparation that pharmaceutically uses according to any conventional mode.Appropriate formulations depends on the route of administration of selection.
With regard to injection, compound of the present invention can be mixed with the aqueous solution, preferably at the physiological compatibility damping fluid, such as Hanks solution, in Ringer's solution or the normal saline buffer solution.With regard to striding mucosa delivery, be suitable for being used for preparation through the penetration agent of barrier.This class penetration agent is that this area is generally known.
With regard to oral administration, can be by active compound and pharmaceutically acceptable carrier well-known in the art be merged the preparation compound.This class carrier can be mixed with tablet with compound of the present invention, pill, and lozenge, lozenge, capsule, liquid, gel, syrup, slurry, suspensions etc. are so that by the oral absorption of patient.Can use solid excipient, choose wantonly and grind the gained mixture if desired and be used for the pharmaceutical preparation of oral application, thereby obtain tablet or ingot zinc in other proper auxiliary agent post-treatment granular mixture preparation of adding.Useful vehicle is in particular weighting agent, such as carbohydrate, comprises lactose, sucrose, mannitol or sorbyl alcohol; Cellulosics, such as, W-Gum for example, wheat starch, rice starch and yam starch; With other material, such as gelatin, Tragacanth, methylcellulose gum, hydroxypropylmethyl-Mierocrystalline cellulose, Xylo-Mucine and/or polyvinylpyrrolidone (PVP).If desired, can add disintegrating agent, such as cross-linked polyvinylpyrrolidone, agar or alginic acid.Can also use such as this class salt of sodiun alginate.
Suitable coatings is provided for the ingot core.For this purpose, can use priming, it can be chosen wantonly and comprise Sudan Gum-arabic, talcum powder, polyvinylpyrrolidone, carbopol gel, polyoxyethylene glycol, and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be joined in tablet or the lozenge coatings so that differentiate or characterize the combination of active compound doses.
The pharmaceutical composition that can orally use comprises the sucking fit formula capsule that is made of gelatin and by gelatin and softening agent, the soft seal capsule that constitutes such as glycerine or sorbyl alcohol.Sucking fit formula capsule can comprise active ingredient and weighting agent, and such as lactose, tackiness agent is such as starch and/or lubricant, such as the mixture of talcum powder or Magnesium Stearate and the stablizer of choosing wantonly.In soft capsule, active compound can be dissolved in and be suspended in the suitable liquid, such as fatty oil, whiteruss or liquid macrogol.In these preparations, can also add stablizer.The pharmaceutical composition that can also use comprises hard capsule.Capsule or pill can be packaged into brown glass or Plastic Bottle so that the active compound lucifuge.The containers store (15-30 ℃) under controlled room temperature that preferably will comprise the active compound capsule preparations.
For by inhalation, can by the existing technologies of any amount the compound that the present invention uses be sent with spray form expediently.In addition, sprays can be used pressurization cartridge bag or atomizer and suitable propellent, for example, but is not limited to Refrigerant 12, trichlorofluoromethane, dichloro four-fluoroethane or carbonic acid gas.With regard to pressurized aerosol, can be used to send the valve control dose unit of metered amount by installation.For example, can prepare inclusion compound and suitable powder matrix, such as the gelatine capsule that is used for sucker or insufflator and the cartridge case of the powdered mixture of lactose or starch.Selectively, can send compound with the aerosol form of not using propellent.
Can also be parenterai administration, for example by bolus injection or continuous infusion preparation compound.The preparation that is used for injecting can with for example in the interpolation of ampoule or multi-dose container the unit dosage of sanitas exist.These compositions can adopt such as suppository, this class form of solution in oil or water vehicle or emulsion and can comprise the preparation material, and such as suspension agent, stablizer and/or dispersion agent.
The pharmaceutical composition that is used for parenterai administration comprises water-soluble form, such as, but be not limited to the aqueous solution of the salt of active compound.The suspension that can prepare in addition, the active compound in lipotropy vehicle.Suitable lipotropy vehicle comprises fatty oil, and such as sesame oil, the Acrawax class is such as ethyl oleate and triglyceride or such as this class material of liposome.Aqueous injection suspension can comprise the material that increases this suspension viscosity, such as Xylo-Mucine, and sorbyl alcohol or dextran.This suspension can be chosen the reagent that also comprises suitable stabilizers and/or increase the compound dissolution degree wantonly, so that can prepare highly enriched solution.
Selectively, active ingredient can be for using suitable vehicle before use, for example the powder type of aseptic aqueous solution.
Can also use for example conventional suppository bases, such as theobroma oil or other glyceride type compound is mixed with the rectum composition, such as suppository or enema,retention.
Except that above-mentioned preparation, compound can also be mixed with prolonged action preparation.Can be by implanting (for example subcutaneous or intramuscular) or passing through this class prolonged action preparation of intramuscular administration.Can use suitable polymers or hydrophobic material (emulsion that for example contains the acceptable oil of pharmacology), ion exchange resin or as the microsolubility derivative, such as, prepare compound of the present invention but be not limited to the little this route of administration of slightly soluble salt.
The limiting examples of pharmaceutical carrier that is used for The compounds of this invention is for comprising benzylalcohol, and the non-polar surfactant is with the cosolvent system and the water of the easily molten mixed organic polymer of water, such as VPD cosolvent system.The VPD 3%w/v benzylalcohol that volume in dehydrated alcohol constitutes of serving as reasons, the solution of 8%w/v non-polar surfactant polysorbate80 and 65%w/v Liquid Macrogol.VPD cosolvent system (VPD: D5W) by with 5% in the aqueous solution glucose according to 1: 1 the dilution VPD form.This abundant dissolved compound of cosolvent system and himself produce hypotoxicity when the whole body administration.The ratio of this class cosolvent system can change naturally significantly, and can not destroy its solubleness and toxicity characteristic.In addition, can change the composition of cosolvent system: for example, can use other hypotoxicity nonsurfactant, rather than polysorbate80, can change the part size of polyoxyethylene glycol, other biocompatible polymer can substitute polyoxyethylene glycol, and for example polyvinylpyrrolidone and other carbohydrate or polyose can replace glucose.
Selectively, can use other delivery system that is used for medical compounds.Liposome and emulsion are the well-known example of hydrophobic drug delivery vehicle or carrier.In addition, can also use some organic solvent, such as methyl-sulphoxide, although will bear bigger toxicity usually.
In addition, can use slow-released system, send compound such as the semipermeability matrix of the solid hydrophobic polymkeric substance that comprises therapeutical agent.Established various slow-release materials and for those skilled in the art well-known.It is several thoughtful more than 100 days that slow releasing capsule can discharge compound according to the difference of its chemical property.
The pharmaceutical composition of this paper can also comprise suitable solid or gel phase carrier or vehicle.The example of this class carrier or vehicle includes, but are not limited to lime carbonate, calcium phosphate, and various carbohydrates, starch, derivatived cellulose, gelatin and polymkeric substance are such as polyethylene glycols.
The present invention can be regulated many in the compound of JAK2 protein kinase provides as the acceptable salt of physiology, and wherein this compound can form the kind of electronegative or positive charge.The example of the salt of the part that compound formation is positively charged includes, but are not limited to such as hydrochloride, vitriol, carbonate, lactic acid salt, tartrate, malate, this class salt of maleate and succinate.The salt of the kind that compound formation of the present invention is electronegative includes, but are not limited to sodium, potassium, the salt of calcium and magnesium.
Be applicable to that pharmaceutical composition of the present invention comprises composition, wherein comprising is enough to realize specifying purpose, for example regulates the active ingredient of the consumption of JAK2 protein kinase activity and/or treatment or prevention JAK2 protein kinase-associated conditions.
More particularly, treatment significant quantity intention is effectively prevented, and alleviates or improves disease symptoms or prolong the compound amount that institute's treatment target is survived.Measuring the treatment significant quantity is those skilled in the art's abundant ability, especially according to the content of detailed disclosure provided herein.With regard to any compound of using in the inventive method, at first can be according to cell culture test assessment treatment significant quantity or dosage.Can in animal model, prepare using dosage then so that realization comprises the IC as measuring in cell culture 50Circulation composition scope (promptly realizing the maximum test compounds concentration that suppresses of protein kinase activity half).This category information can be used for determining more accurately useful dosage then at human body.
Can be by the operation of the standard drug in cell culture or laboratory animal, for example by measuring the IC of motif compound 50And LD 50Measure the toxicity and the therapeutic efficiency of compound described herein.Data available from these cell culture tests and zooscopy can be used to prepare the dosage range that is applied to human body.This dosage can change with used the different of route of administration according to the formulation of using.Definite preparation, route of administration and dosage can be selected (for example, referring to G according to conditions of patients by each clinicist OODMAN﹠amp; G ILMAN ' ST HEP HARMACOLOGICALB ASIS OFT HERAPEUTICS, Ch.3,9 ThEd., Ed.by Hardman, J. and Limbard, L., McGraw-Hill, New York City, 1996, p.46).
Can each self aligning dosage and at interval so that the blood plasma level of the reactive specy that is enough to keep JAK2 kinases regulating effect is provided.These blood plasma levels are called minimal effective concentration (MEC).MEC is variable for every kind of compound, but can assess according to vitro data, for example can use test as herein described to determine to realize that kinases 50-90% suppresses necessary concentration.Realize that the necessary dosage of MEC depends on personal feature and route of administration.HPLC assay method or bioassay method can be used to measure plasma concentration.
Can also use MEC pH-value determination pH spacing of doses.Should use blood plasma level is kept the time that is higher than MEC 10-90%, preferred 30-90% and most preferably the scheme of 50-90% give compound.
At present, the treatment significant quantity of The compounds of this invention can be at about 2.5mg/m 2-1500mg/m 2The scope in/sky.Extra illustrative amount ranges is at 0.2-1000mg/qid, 2-500mg/qid and 20-250mg/qid.
With regard to topical or selectivity absorption, effective partial concn of medicine and plasma concentration have nothing to do and other operation as known in the art can be used to measure correct dosage and interval.
Certainly, the consumption of the composition that gives depends on the object of being treated, severity of disease, and administering mode is opened the judgement etc. according to the clinicist of prescription.
If desired, composition can be made cartridge bag or dispenser device, such as the test kit of FDA approval, its can comprise one or more comprise with group unit dosage.For example, cartridge bag can comprise metal or plastic foil, such as blister pack.Cartridge bag or dispenser device can attach the administration specification sheets.Cartridge bag or dispenser device can also attach and manage drug manufacture, the relevant precaution of container of the government administration section prescribed form of using or selling, and these precaution reflect composition or people or the animal doctor's form of medication that obtains approved by management.For example, these class precaution can be U.S. food and the prescription drugs of Drug Administration's approval or the label or the product inset of approval.Can also prepare the composition that comprises the The compounds of this invention that uses the preparation of consistency pharmaceutical carrier, put it into appropriate containers and mark can treat shown in illness.
As mentioned above, compound of the present invention and composition can be applied to JAK2 protein kinase mediated extensive disease and illness.As an example, this class disease can comprise cancer, such as leukemia (for example acute myeloid leukaemia (AML) and chronic myelogenous leukemia (CML)), lung cancer, NSCLC (nonsmall-cell lung cancer), oat-cell carcinoma, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, dermatofibrosarcoma protuberans, head and neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, colorectal carcinoma, the anal region cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, gynecological tumor (sarcoma of uterus for example, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina or carcinoma vulvae), Hodgkin, hepatocellular carcinoma, esophagus cancer, carcinoma of small intestine, endocrine system cancer (for example Tiroidina, pancreas, parathyroid gland or adrenal carcinoma), soft tissue sarcoma, urethral carcinoma, penile cancer, carcinoma of testis, prostate cancer (particularly hormone-intractable), chronic or acute leukemia, children's solid tumor, hypereosinophilia, the lymphocyte lymphoma, bladder cancer, kidney or carcinoma of ureter (for example renal cell carcinoma, carcinoma of renal pelvis), the paediatrics malignant tumour, central nerve neuroma (primary CNS lymphoma for example, spinal column axis knurl, medulloblastoma, brain stem neurospongioma or pituitary adenoma), Barrett (Barrett) oesophagus (pernicious early stage syndrome), tumorigenesis tetter, psoriatic, mycosis fungoides and benign prostatauxe, the diabetes relative disease, such as diabetic retinopathy, retinal ischemia and retinal neovascularization form, liver cirrhosis, blood vessel takes place, and cardiovascular diseases is such as atherosclerosis, immunological disease is such as autoimmune disease and nephropathy; But be not limited to them.
Compound of the present invention can with one or more other chemotherapeutics couplings.Can adjust the dosage of The compounds of this invention for any drug-drug reaction.In one embodiment, described chemotherapeutics is selected from mitotic inhibitor, alkylating agent, antimetabolite, cell cycle inhibitor, enzyme, topology is the structure enzyme inhibitors easily, such as CAMPTOSAR (irinotecan), biological response modifier, hormone antagonist, anti-angiogenesis is such as MMP-2, MMP-9 and cox 2 inhibitor, antiandrogen, platinum coordination complex (cis-platinum etc.), the ureas that replaces is such as hydroxyurea; Methyl hydrazine derivative, for example Procarbazine; The adrenal cortex inhibitor, mitotane for example, amino Rumi spy, hormone and hormone antagonist, such as adrenocortical steroid (for example prednisone), progestogens (for example hydroxycaproic acid progesterone), estrogens (for example stilboestrol), antiestrogen, such as tamoxifen, androgens, for example testosterone propionate and aromatase inhibitor are such as Anastrozole and AROMASIN (Exemestane).
The example that can be used for the alkylating agent of above-mentioned integrated processes include, but are not limited to independent Fluracil (5-FU) or its further with the combination of folinic acid; Other pyrimidine analogue, such as UFT, capecitabine, gemcitabine and cytosine arabinoside, alkyl sulfonate esters class, busulfan (being used for the treatment of chronic myelocytic leukemia) for example, improsulfan and piposulfan; Aziridines, benzodepa for example, carbaxilquinone, meturedepa and uredepa; The aziridine type and methylmelamine class, altretamine for example, Persistol, triethylenephosphoramide, triethylenethio-hosphopramide and trimethylolmelamine; And mustargen, for example Chlorambucil (being used for the treatment of chronic lymphocytic leukemia, primary macroglobulinaemia and non Hodgkin lymphoma), endoxan (is used for the treatment of Hodgkin, multiple myeloma, neuroblastoma, mammary cancer, ovarian cancer, lung cancer, wilms' tumor and rhabdosarcoma), Emcyt, ifosfamide, novembrichin, prednimustine and Uramustine (being used for the treatment of idiopathic thrombocythemia, non Hodgkin lymphoma, Hodgkin and ovarian cancer); And triazines, for example Dacarbazine (being used for the treatment of soft tissue sarcoma).
The example that can be used for the metabolic antagonist chemotherapeutics of above-mentioned integrated processes includes, but are not limited to folacin, and for example methotrexate (is used for the treatment of acute lymphoblastic leukemia, choriocarcinoma, mycosis fungoides, mammary cancer, head and neck cancer and osteogenic sarcoma) and Pteropterin; And purine analogue, such as mercaptopurine and Tioguanine, they are used for the treatment of acute myeloblastic leukemia, acute lymphoblastic leukemia and chronic myelocytic leukemia.
The example based on the chemotherapeutics of natural product that can be used for above-mentioned integrated processes includes, but are not limited to vinca alkaloids, vinealeucoblastine(VLB) (being used for the treatment of mammary gland and carcinoma of testis) for example, vincristine(VCR) and vindesine; Epipodophyllotoxin, for example Etoposide and teniposide, both all are used for the treatment of carcinoma of testis and Kaposi sarcoma for they; The microbiotic chemotherapeutics, daunorubicin for example, Dx, epirubicin, mitomycin (is used for the treatment of stomach, uterine neck, colon, mammary gland, bladder and carcinoma of the pancreas), dactinomycin, Temozolomide, primycin, bleomycin (being used for the treatment of skin, esophagus and genitourinary cancer); With the enzyme chemotherapeutics, such as the altheine enzyme.
The example of useful COX-II inhibitor comprises Vioxx, CELEBREX (celecoxib), and valdecoxib, pareira are examined former times (paracoxib), rofecoxib and Cox 189.
The case description of useful matrix metallo-proteinase inhibitor is in following document: WO96/33172 (announcement on October 24th, 1996), WO 96/27583 (announcement on May 7th, 1996), European Patent Application No. EP 97304971.1 (submission on July 8th, 1997), European Patent Application No. EP 99308617.2 (submission on October 29th, 1999), WO 98/07697 (announcement on February 26th, 1998), WO 98/03516 (announcement on January 29th, 1998), WO98/34918 (announcement on August 13rd, 1998), WO 98/34915 (announcement on August 13rd, 1998), WO 98/33768 (announcement on August 6th, 1998), WO 98/30566 (announcement on July 16th, 1998), European patent application publication No. EP 606,046 (announcement on July 13rd, 1994), European patent application publication No. EP931,788 (announcements on July 28th, 1999), WO 90/05719 (announcement on May 31 nineteen ninety), WO 99/52910 (announcement on October 21st, 1999), WO 99/52889 (announcement on October 21st, 1999), WO 99/29667 (announcement on June 17th, 1999), PCT International Publication No. PCT/I B98/01113 (submission on July 21st, 1998), European Patent Application No. EP 99302232.1 (submission on March 25th, 1999), GB Patent Application No. GB 9912961.1 (submission on June 3rd, 1999), U.S. Pat 5,863,949 (mandates on January 26th, 1999), U.S. Pat 5,861,510 (mandate on January 19th, 1999) and European patent application publication No. EP 780,386 (announcements on June 25th, 1997) intactly are incorporated herein by reference all these documents.Preferred L MP-2 and MMP-9 inhibitor for almost do not have or unrestraint MMP-1 active those.More preferably suppress those of MMP-2 and/or MMP-9 with respect to other matrix metalloproteinase (being MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13) selectivity.
Some specific examples that is used for MMP inhibitor of the present invention is AG-3340, RO32-3555, RS 13-0830 and be selected from following compound: 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-cyclopentyl)-amino]-propionic acid; 3-extroversion-3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--dicyclo [3.2.1] octane-3-formic acid oxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic acid oxyamide; 4-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-formic acid oxyamide; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-formic acid oxyamide; (R) 3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-3-formic acid oxyamide; (2R, 3R) 1-[4-(4-fluoro-2-methyl benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic acid oxyamide; 3-[[(4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-1-methyl-ethyl)-amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(4-hydroxyl amino formyl radical-tetrahydrochysene-pyrans-4-yl)-amino]-propionic acid; 3-extroversion-3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-8-oxa--dicyclo [3.2.1] octane-3-formic acid oxyamide; In the 3-to-3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--dicyclo [3.2.1] octane-3-formic acid oxyamide; (R) 3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-furans-3-formic acid oxyamide; Pharmacy acceptable salt and solvate with these compounds.
Other angiogenesis inhibitor medicine, other COX-I I inhibitor and other MMP inhibitor also can be used for the present invention.
Compound of the present invention can also with other signal transduction inhibitor coupling, such as suppressing the promoting agent that EGFR (EGF-R ELISA) replys, such as EGFR antibody, EGF antibody and be the molecule of EGFR inhibitor; VEGF (EGF-R ELISA) inhibitor; With the erbB2 acceptor inhibitor, such as organic molecule or in conjunction with the antibody of er bB2 acceptor, such as HERCEP TIN (Genentech, Inc., South San Francisco, CA).In WO95/19970 (announcement on July 27 nineteen ninety-five), WO 98/14451 (announcement on April 9th, 1998), WO 98/02434 (announcement on January 22nd, 1998) and U.S. Pat 5,747, described the EGFR inhibitor in 498 (mandates on May 5th, 1998), and this class material can as described hereinly be used for the present invention.
The EGFR-inhibitor comprises, but be not limited to monoclonal antibody C225 and anti-EGFR 22Mab (ImClone Systems, Inc., New York, NY), compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (MedarexInc., Annandale, NJ) and OLX-103 (Merck﹠amp; Co., Whi tehouse Stat ion, NJ) and the EGF fusion toxin (Seragen Inc., Hopkinton, MA).
These and other EGFR-inhibitor can be used for the present invention.The VEGF inhibitor, for example SU-5416 and SU-6668 (Sugen Inc., South San Francisco, CA) can also with compound coupling of the present invention.The VEGF inhibitor is described in for example following document: WO01/60814A 3 (announcement on August 23 calendar year 2001), WO 99/24440 (announcement on May 20th, 1999), PCT International Application PCT/I B99/00797 (submission on May 3rd, 1999), WO95/21613 (announcement on August 17 nineteen ninety-five), WO 99/61422 (announcement on December 2nd, 1999), U.S. Pat 5,834,504 (mandates on November 10th, 1998), WO01/60814, WO 98/50356 (mandate on November 12nd, 1998), U.S. Pat 5,883,113 (mandates on March 16th, 1999), U.S. Pat 5,886,020 (mandate on March 23rd, 1999), U.S. Pat 5,792,783 (mandates on August 11st, 1998), WO 99/10349 (announcement on March 4th, 1999), WO 97/32856 (announcement on September 12nd, 1997), WO 97/22596 (announcement on June 26th, 1997), WO 98/54093 (announcement on December 3rd, 1998), WO 98/02438 (announcement on January 22nd, 1998), WO99/16755 (announcement on April 8th, 1999) and WO 98/02437 (announcement on January 22nd, 1998) intactly are incorporated herein by reference all these documents.Other example that is used for some specificity VEGF inhibitor of the present invention be IM862 (Cytran Inc., Kirkland, WA); Genentech, the anti-VEGF monoclonal antibody of Inc.; With anti-VEGFR2 ribozyme (angiozyme), promptly a kind of from ribozyme (Boulder, CO) and chiron (Emeryville, synthetic ribozyme CA).These and other VEGF inhibitor can as described hereinly be used for the present invention.The pErbB2 acceptor inhibitor, such as GW-282974 (Glaxo Wellcome plc) and monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc., The Woodlands, TX) and 2B-1 (Chiron) also can with the The compounds of this invention coupling, shown in for example following document those: WO 98/02434 (announcement on January 22nd, 1998), WO 99/35146 (announcement on July 15th, 1999), WO 99/35132 (announcement on July 15th, 1999), WO98/02437 (announcement on January 22nd, 1998), WO 97/13760 (announcement on April 17th, 1997), WO 95/19970 (announcement on July 27 nineteen ninety-five), U.S. Pat 5,587,458 (mandate on December 24th, 1996) and U.S. Pat 5,877,305 (mandates on March 2nd, 1999) intactly are incorporated herein by reference all these documents.Be used for ErbB2 acceptor inhibitor of the present invention and also be described in U.S. Pat 6,284, in 764 (mandates on September 4 calendar year 2001), the document intactly is incorporated herein by reference.ErbB2 acceptor inhibitor compound and be described in above-mentioned PCT application, the material in United States Patent (USP) and the U.S. Provisional Application and other compound and material that suppresses the erbB2 acceptor can be according to the present invention and The compounds of this invention couplings.
Compound of the present invention can also with other promoting agent coupling that is used for the treatment of cancer, comprise, but be not limited to strengthen the promoting agent of anti-tumor immune response, can block the promoting agent of CTLA4 such as CTLA4 (cytotoxic lymphocyte antigen 4) antibody and other; And antiproliferative, such as other farnesyl protein transferase inhibitors, for example be described in U.S. Pat 6,258, the farnesyl protein transferase inhibitors in " background " part of 824B1 in the reference of citation.
Aforesaid method can also be united with radiotherapy and carried out, and wherein can effectively treat above-mentioned disease with the amount of the The compounds of this invention of radiotherapy coupling.
Being known in the art the technology and these technology that give radiotherapy can be in therapy coupling as herein described.Can as described hereinly determine the compound of the present invention that in this conjoint therapy, gives.
When considering following non-limiting examples, further understand the present invention.
Embodiment
Embodiment 1
The leading evaluation of computer based
The crystalline structure that actual screening is calculated based on the mixture of JAK2 kinases and Pan-Janus kinase inhibitor carries out (PDB ID:2B7A) as template.From virtual library, inner~200 and~230 ten thousand are concentrated and/or different medicine compounds carry out computer screen produced to available from Otava Chemicals ( Www.Otavachemicals.com) the storehouse in the selection of candidate compound.The 3 kinds of compound determination in inside for having activity (<42nM-1.25 μ M) in low micro-molar range, and are determined as one of Otava compound at direct JAK2 kinases and have activity in conjunction with test under<10 μ M.To be defined as belonging to pyrimidine-2, the 4-diamine derivative to the active compound of tool that the important molecular regime of specificity JAK2 kinase activity is identified.Shown in following table 1, based on combination, the required pharmacophoric group of QikProp (solubleness, perviousness) Lipinski-class standard and existence filters the compound that is selected from this class screening.
Table 1
Representational pyrimidine-2, the 4-diamine derivative
Figure G2008800109774D00211
Figure G2008800109774D00221
Figure G2008800109774D00231
Figure G2008800109774D00241
Figure G2008800109774D00251
Embodiment 2
Pyrimidine-2, the general of 4-diamine derivative synthesized
Can use conventional synthetic operation and prepare compound of the present invention by the chemical field those of ordinary skill by following general reaction scheme.
General reaction scheme:
Figure G2008800109774D00261
In brief, make 2,4-dichloro pyrimidine (1) generates intermediate (3) with aniline (2) reaction that suitably replaces.Make this intermediate (3) and another amine (4) that suitably replaces react the compound of generating structure (I) then.Selectively, make the further compound of generating structure (II) of intermediate (3) with amine (5) reaction of suitable replacement.As not having any concrete statement, then all solvents and reagent are all available from the chemical of Aldrich or VWR and can provide by the standard laboratory method as required or purifying uses.
Embodiment 3
Pyrimidine-2,4-diamine derivative synthetic
A. The general operation of the pyrimidine (3) that preparation 2-chloro-4-replaces
Figure G2008800109774D00271
To comprise 2,4-dichloro pyrimidine (1) (10mmol), aniline (2) (10mmol) and diisopropylethylamine (DIPEA) (1.5mmol) reaction mixture refluxed in 30mL Virahol (IPA) spend the night.Remove and to desolvate and use Combiflash Companion system purifying resistates (10%-70% hexane/EtOAc) obtains the pyrimidine (3) that required 2-chloro-4-replaces.
2-chloro-N-(3-chloro-4-fluorophenyl) pyrimidine-4-amine (7)
Figure G2008800109774D00272
With 2,4-dichloro pyrimidine (1) (1g, 6.71mmol, Sigma-Aldrich), 3-chloro-4-fluoroaniline (6) (0.977g, 6.71mmol, Sigma-Aldrich) and diisopropylethylamine (DIPEA) (3.47g, 26.8mmol) the reaction mixture refluxed 18h in 2-propyl alcohol (20mL).The Combiflash Companion purifying of evaporating solvent and the solvent systems by using 70% hexane and absolute dichloromethane (DCM) and 20% ethyl acetate (EtOAc) (the quick post of 40g positive RediSep, working time 50min) and obtain compound (7) (0.8g).(TLC,Rf=0.6,EtOAc)。White solid, productive rate 46.2%. 1H-NMR(400MHz,DMSO-d 6)10.18(s,1H),8.20(d,J=6.2Hz,1H),7.90(m,1H),7.50(m,1H),7.43(t,J=8.9Hz,1H),6.74(d,J=5.8Hz,1H)。ESI/MS?m/z258.0(100%),259.9(78%),261.9(18%)。
5-(2-chloropyrimide-4-base is amino)-2-fluorine benzonitrile (9)
Figure G2008800109774D00281
With 2,4-dichloro pyrimidine (1) (1g, 6.71mmol), (0.914g, 6.71mmol) 5-amino-2-fluorine benzonitrile (8) spends the night by the reaction mixture refluxed in 2-propyl alcohol (50mL) and 1mL DIPEA.Evaporating solvent and by Combiflash (12g, DCM-10%MeOH/DCM) the thick material of purifying and obtain 318mg compound (9) (TLC, Rf=0.1,6%MeOH/DCM).White solid, productive rate 19%. 1H?NMR(400MHz,CD 3OD)8.15(m,2H),7.89(m,1H),7.35(t,J=9.23Hz,1H),6.70(d,J=5.6Hz,1H)。ESI/MS?m/z?248.9(100%),250.9(33%)。
2-(3-aminophenyl) acetonitrile (11)
3-nitrophenyl acetonitrile (10) is dissolved in the mixture of dense HCl (15ml) and ethanol (15ml).At the ice-cooled SnCl that progressively drips down 2Dihydrate in ethanol (25ml) solution and this mixture at room temperature stirred 5 hours.TLC (E tOAc/ hexane 1: 1) Rf=0.1 shows that 80% finishes.Behind evaporating solvent, resistates is handled to pH 9 with NaOH.With EtOAc extraction and carry out combiflash (12g, hexane/EtOAc 10%-50% 70min) obtain 1.182g compound (11), are yellow oil. 1H-NMR(400MHz,CDCl 3)7.12(t,J=7.5Hz,1H),6.65(m,3H),3.72(br-s,1H),3.64(s,2H)。
2-(3-(2-chloropyrimide-4-base is amino) phenyl) acetonitrile (12)
Figure G2008800109774D00291
With 2, (1.127g, 7.57mmol) ((1g, 7.57mmol) reaction mixture refluxed in 2-propyl alcohol (40mL) and 15mmol triethylamine (TEA) is 2 days for 3-aminophenyl acetonitrile (11) for 2-for 4-dichloro pyrimidine (1).Evaporating solvent and by Combiflash purifying (12g, twice, CHCl 3) and obtain 932mg compound (12), be the light green crystallization.Productive rate 50%. 1H-NMR(400MHz,CDCl 3)8.16(d,J=6.15Hz,1H),7.41(m,1H),7.33(m,2H),7.18(d,J=7.5Hz,1H),6.96(br-s,1H),6.58(d,J=5.8Hz,1H),3.77(s,2H)。
B. Preparation 2, the general operation of the dibasic pyrimidine of 4-(I)
Figure G2008800109774D00292
The pyrimidine (3) that the 2-chloro-4-that is included in the 7mL Virahol is replaced (0.25mmol), (Apollo Scientific and Bionet Building Blocks, UK) reaction mixture refluxed of (0.25mmol) and TFA (0.5mmol) is spent the night for amine (4) or amine (5).After being cooled to room temperature, this reaction mixture adds NaOH (0.6mmol).Remove and to desolvate and (4g DCM-20%MeOH/DCM) obtains structure as described below (I) or compound (II) by Combiflash purifying resistates.
N4-(3-chloro-phenyl-)-N2-(4-(trifluoromethyl) phenyl) pyrimidine-2,4-diamines (compound 1-1)
Figure G2008800109774D00301
To 2-chloro-N-(3-chloro-phenyl-) pyrimidine-4-amine (13) (100mg, 0.417mmol) add 4-(trifluoromethyl) aniline (14) (67.1mg in the solution in 2-propyl alcohol (10mL), 0.417mmol), add the catalyzer trifluoroacetic acid subsequently and under reflux temperature, stir and spend the night.Evaporating solvent and the CombiflashCompanion purifying resistates by using DCM and 5%MeOH solvent systems (the quick post of 4g positive RediSep, working time 50min, flow 18ml/min) and obtain compound 1-1.(TLC,Rf=0.4,10%MeOH/DCM)。 1H?NMR(400MHz,DMSO-d 6)8.08(d,J=6.15Hz,1H),7.8(s,2H),3.39(m,1H),7.82(d,J=8.2Hz,2H),7.66(d,J=8.2Hz,2H),7.46(d,J=6.84Hz,1H),7.36(t,J=8.2Hz,1H),7.15(d,J=8.18Hz,1H),6.42(d,J=6.15Hz,1H)ES?I/MS m/z365.0(M+H) +
N4-(3-chloro-4-fluorophenyl)-N2-(4-fluorophenyl) pyrimidine-2,4-diamines (compound 1-2)
Figure G2008800109774D00302
To 2-chloro-N-(3-chloro-4-fluorophenyl) pyrimidine-4-amine (7) (60mg, 0.232mmol) add 4-fluoroaniline (15) (25.8mg in the solution in 2-propyl alcohol (10mL), 0.232mmol), add the catalyzer trifluoroacetic acid subsequently and under reflux temperature, stir and spend the night.Add triethylamine in this reaction mixture, stir 1h subsequently, the reaction of TLC demonstration is after this finished.Evaporating solvent and by using CombiflashCompanion purifying resistates (the quick post of 4g positive RediSep of hexane 70% and DCM solvent systems, working time 50min, flow 18ml/min) obtain compound 1-2 (TLC, Rf=0.35,5%MeOH/DCM). 1HNMR(400MHz,DMSO-d 6)8.01(m,2H),7.64(m,2H),3.39(m,2H),7.49(m,1H),7.35(t,J=8.23Hz,1H),7.11(m,2H),6.22(m,1H),ESI/MS?m/z?333.0(M+H) +
N4-(3-chloro-4-fluorophenyl)-N2-(4-morpholino phenyl) pyrimidine-2,4-diamines (chemical combination Thing
Figure G2008800109774D00311
To 2-chloro-N-(3-chloro-4-fluorophenyl) pyrimidine-4-amine (7) (60mg, 0.232mmol) add 4-morpholino aniline (16) (41.4mg in the solution in 2-propyl alcohol (10mL), 0.232mmol), add the catalyzer trifluoroacetic acid subsequently and under reflux temperature, stir and spend the night.By use 10% in DCM MeOH solvent systems the thick resistates of CombiFlash Companion purifying (the quick post of 4g positive RediSep, working time 50min, flow 26ml/min) and obtain compound 1-3.(TLC,Rf=0.45,10%MeOH/DCM)HPLC=94%。 1HNMR(400MHz,DMSO-d 6)8.03(m,1H),7.90(m,1H),3.39(m,2H),7.31(d,J=8.54Hz,2H),6.98(d,J=8.55Hz,2H),6.33(d,J=6.83Hz,1H),3.74(m,4H),3.10(s,4H)ESI/MS?m/z?400.1(M+H) +
N4-(3-chloro-4-fluorophenyl)-N2-(4-(4-methylpiperazine-1-yl) phenyl) pyrimidine -2,4-diamines (compound 1-4)
Figure G2008800109774D00321
Will be at the 2-chloro-N-in the 1-butanols (3-chloro-4-fluorophenyl) pyrimidine-4-amine (7) (100mg, 0.387mmol), 4-(4-methylpiperazine-1-yl) aniline (17) (74.1mg, 0.387mmol, available from Apollo Scientific, UK), DIPEA (2mL, 11.48mmol) and Dimethylamino pyridine (DMAP) reflux and to spend the night.TLC (6%MeOH/DCM) demonstration reaction is finished.Concentrate and carry out the CombiFlash purifying (4g DCM-100%EtOAc) obtains 7mg compound 1-4, and it is a purple under phospho-molybdic acid dyeing.Productive rate 48%. 1H-NMR(400MHz,DMSO-d 6)9.45(s,1H),8.98(s,1H),8.08(m,1H),7.98(d,J=4.5Hz,1H),7.45(m,3H),7.30(t,J=9.2Hz,1H),6.86(d,J=8.9Hz,2H),6.10(d,J=5.8Hz,1H),3.04(m,4H),2.43(m,4H),2.20(s,3H)。ESI/MS?m/z?413.3(100%),415.2(33%)。
N4-(3-chloro-4-fluorophenyl)-N2-(4-methoxyl group-3-(3-(4-methylpiperazine-1-yl) Propoxy-) pyrimidine-2 phenyl), 4-diamines (compound 1-5)
Figure G2008800109774D00322
(2g, 11.82mmol), (2.234g 23.65mmol) adds K to 3-chloropropyl bromine in the mixture of dimethyl formamide (DMF) in (20mL) to 2-methoxyl group-5-nitrophenols (18) 2CO 3(3.27g) and with the gained reaction mixture be heated to 80 ℃ of following 3h.TLC (EtOAc) demonstration reaction is finished.This reaction mixture is distributed between water (100mL) and the ethyl acetate (150mL).Use saturated NaHCO 3With the water washing organic layer, use MgSO then 4Drying and filtration.Concentrate this solution and obtain 19, be faint yellow solid (3.9g).(1.5g is added in 20mL 1 in 6.11mmol), and (1.373g 9.16mmol) and with the gained reaction mixture is heated to 100 ℃ of following 30h for N methyl piperazine in the 4-diox and sodium iodide to 19.Concentrate orange mixture so that remove 1, the 4-diox, and then with the dilution of 50mL ethyl acetate.After stirring 0.5h, its filtration is desalted so that remove.With NaOH solution (20mL) and water (3 * 20mL) washing organic layers.Use MgSO 4Dry and be concentrated into and obtain compound 20, be orange (1.00g). 1H-NMR(400MHz,CDCl 3)7.90(dd,J1=2.3Hz,J2=8.9Hz,1H),7.75(d,J=2.3Hz,1H),6.88(d,J=8.8Hz,1H),4.14(m,2H),3.94(s,3H),2.58(m,10H),2.43(br-s,3H),2.03(m,2H)。
Shake at Parr and to make compound 20 carry out hydrogenation 5h in the presence of the 10%Pd/C that has in the bottle in Virahol.TLC (15%MeOH/DCM) demonstration reaction is finished.Filter and concentrate by C salt and obtain compound 21 (1g), be brown oil. 1H-NMR(400MHz,CDCl 3)6.68(d,J=8.2Hz,1H),6.30(d,J=2.4Hz,1H),6.20(dd,J?1=2.4Hz,J?2=8.2Hz,1H),3.99(t,J=6.5Hz,2H),3.75(s,3H),3.46(s,3H),2.55(br-m,10H),2.32(s,3H),2.01(m,2H)。
To be included in 21 in TFA (1mL) and the 2-propyl alcohol (10mL) (100mg, 0.387mmol) and 7 (108mg, reaction mixture refluxed 0.387mmol) is spent the night.TLC (6%DCM/MeOH) shows 7 completely consumeds.Concentrate this reaction mixture and be dissolved in MeOH again.Make the TFA quencher by adding NaOH.Concentrate and carry out the CombiFlash purifying (4g DCM-15%MeOH/DCM) obtains 219mg compound 1-5, is brown foam. 1H-NMR(400MHz,DMSO-d 6)9.49(s,1H),9.01(s,1H),8.04(m,1H),8.00(d,J=5.8Hz,1H),7.4(br-s,1H),7.29(t,J=9.3Hz,1H),7.20(m,2H),6.85(d,J=8.8Hz,1H),6.13(d,J=5.8Hz,1H),3.86(t,J=6.15Hz,2H),3.88(s,3H),2.48(s,8H),2.35(s,3H),1.83(m,2H)。ESI/MSm/z,501.2(100%),503.3(33%)。
N4-(3-chloro-4-fluorophenyl)-N2-(6-(trifluoromethyl) pyridin-3-yl) pyrimidine-2,4- Diamines (compound 1-6)
To 7 (100mg, 0.387mmol) and 5-amino-2-(trifluoromethyl) pyridine (22) (62.8mg 0.387mmol) adds TEA and with this reaction mixture refluxed 24h in the mixture in 2-propyl alcohol (10mL).TLC (EtOAc, Rf=0.3) finish by the demonstration reaction.Concentrate this mixture so that remove Virahol and be dissolved in methyl alcohol again.Add NaOH with in and TFA.Further concentrate and carry out the CombiFlash purifying (4g, hexane/EtOAc 15%-90% 50min) obtain 106mg compound 1-6, are solid. 1H-NMR(400MHz,CDCl 3)8.69(s,1H),8.42(d,J=8.5Hz,1H),8.11(d,J=5.4Hz,1H),7.59(m,1H),7.53(m,1H),7.15(m,3H),6.49(s,1H),6.19(d,J=5.5Hz,1H)。ESI/MS?m/z,384.0(100%),386.0(33%)。
2-(3-(2-(4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) phenyl) Acetonitrile (compound 1-7)
Figure G2008800109774D00342
With compound 12 (100mg, 0.409mmol) and 17 (Apollo Scientific UK) is dissolved in 10mL 2-propyl alcohol and add TEA (1mL) for 78mg, 0.409mmol.The backflow of gained mixture is spent the night.TLC (20%MeOH/DCM, Rf=0.2) finish by the demonstration reaction.Add NaOH and form some white precipitates.Concentrate and carry out CombiFlash purifying (0-25%MeOH/DCM) and obtain compound 1-7 (186mg), be white solid. 1HNMR shows that may there be some aniline in inside.Productive rate 114%. 1H-NMR(400MHz,CD 3OD)7.88(d,J=6.1Hz,1H),7.79(s,1H),7.44(m,3H),7.27(t,J=7.86Hz,1H),7.00(m,3H),6.15(d,J=6.1Hz,1H),3.75(s,2H),3.27(m,4H),2.96(m,4H),2.59(s,3H)。ES?I/MS?m/z,400.1(100%)。
2-(3-(2-(4-methoxyl group-3-(3-(4-methylpiperazine-1-yl) propoxy-) phenyl amino) Pyrimidine-4-base is amino) phenyl) acetonitrile (compound 1-8)
Figure G2008800109774D00351
To 12 (100mg, 0.409mmol) and 21 (114mg 0.409mmol) adds TFA and its backflow spent the night in the mixture in 2-propyl alcohol (10mL).TLC (20%MeOH/DCM, Rf=0.1) finish by the demonstration reaction.Add NaOH and produce white precipitate.Concentrate and carry out CombiFlash purifying (0-25%MeOH: DCM) obtain compound 1-8 (236mg), be solid foam. 1H-NMR(400MHz,CD 3OD):7.90(d,J=5.8Hz,1H),7.78(s,1H),7.45(d,J=8.2Hz,1H),7.26(m,2H),6.98(m,3H),6.16(d,J=6.2Hz,1H),3.91(t,J=5.8Hz,2H),3.84(s,3H),3.74(s,2H),3.34(s,2H),2.71(br-m,2H),2.56(s,3H),1.96(m,2H)。ESI/MS?m/z,488.2(100%)。
N4-(3-chloro-4-fluorophenyl)-N2-(4-(trifluoromethyl) phenyl) pyrimidine-2, the 4-diamines (compound 1-9)
Figure G2008800109774D00352
To 7 (60mg, 0.232mmol) and 14 (37.5mg 0.232mmol) adds TFA and its backflow spent the night in the mixture in 2-propyl alcohol (7mL).TLC (6%MeOH/DCM, Rf=0.15) finish by the demonstration reaction.Add NaOH with in and TFA.Concentrate crude product and carry out the CombiFlash purifying that (4g, 0-10%MeOH/DCM 50min) obtain compound 1-9 (70mg), are white solid. 1H?NMR(400MHz,CD 3OD)7.99(d,J=5.8Hz,1H),7.95(dd,J 1=2.7Hz,J 2=6.8Hz,1H),7.79(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),7.44(m,1H),7.17(t,J=8.9Hz,1H),6.23(d,J=5.8Hz,1H)。ESI/MS?m/z,383.1(100%),385.1(33%)。
2-fluoro-5-(2-(4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) benzyl Nitrile (compound 1-10)
Figure G2008800109774D00361
With 9 (60mg, 0.241mmol) and 17 (46.2mg, 0.241mmol), ApolloScientific, mixture UK) are dissolved in 10mL 2-propyl alcohol and add catalyzer TFA.The backflow of gained mixture is spent the night.TLC (20%MeOH/DCM, Rf=0.1) finish by the demonstration reaction.Add NaOH with in and TFA.Concentrate and carry out the CombiFlash purifying (the quick post of 4g positive RediSep, working time, 40min, flow 26mL/min 0-20%MeOH/DCM) obtains compound 1-10 (82mg, 84%), is white solid. 1H?NMR(400MHz,CD 3OD)8.35(m,1H),7.92(d,J=5.8Hz,1H),7.70(m,1H),7.40(d,J=8.9Hz,2H),7.23(t,J=9.8Hz,1H),7.01(d,J=9.2Hz,2H),6.12(d,J=5.8Hz,1H),3.23(m,4H),2.70(br-s,4H),2.40(s,3H)。ESI/MS?m/z404.1(M+H)。
2-(3-(2-(3-fluoro-4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile (compound 1-11)
Figure G2008800109774D00371
With 12 (60mg, 0.245mmol) and 3-fluoro-4-(4-methylpiperazine-1-yl) aniline (23) (available from Apollo Scientific, UK) mixture in 2-propyl alcohol (7mL) and catalyzer TFA reflux and spend the night for 51.3mg, 0.245mmol.TLC (20%MeOH/DCM, Rf=0.2) finish by the demonstration reaction.Add NaOH and produce white precipitate.Concentrate and carry out the CombiFlash purifying (4g 0-20%MeOH/DCM) obtains compound 1-11 (115mg), is white solid. 1H?NMR(400MHz,CD 3OD)7.93(d,J=6.1Hz,1H),7.73(s,1H),7.61(dd,J 1=2.4Hz,J 2=4.7Hz,1H),7.53(d,J=7.8Hz,1H),7.32(t,J=8.2Hz,1H),7.20(d,J=8.9Hz,1H),7.00(m,2H),6.20(d,J=5.8Hz,1H),3.84(s,2H),3.16(br-s,4H),2.92(br-s,4H),2.56(s,3H)。ESI/MS?m/z?418.1(M+H)。
2-(3-(2-(6-(4-methylpiperazine-1-yl) pyridin-3-yl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile (compound 1-12)
Figure G2008800109774D00372
With 12 (60mg, 0.245mmol) and mixture and the catalyzer TFA backflow 24h of 6-(4-methylpiperazine-1-yl) pyridine-3-amine (24) (47.1mg, 0.245mmol is available from Bionet Building blocks UK) in 2-propyl alcohol (7mL).TLC (20%MeOH/DCM, Rf=0.1) finish by the demonstration reaction.Add NaOH with in and TFA.Concentrate and carry out the CombiFlash purifying (4g 0-20%MeOH/DCM) obtains compound 1-12 (97mg), is solid.Productive rate 99%. 1H?NMR(400MHz,CD 3OD)8.35(d,J=2.7Hz,1H),7.88(d,J=6.2Hz,1H),7.83(s,1H),7.76(dd,J 1=2.7Hz,J 2=9.2Hz,1H),7.37(d,J=8.5Hz,1H),7.27(t,J=7.9Hz,1H),7.01(d,J=7.5HZ,1H),6.88(d,J=9.2Hz,1H),6.16(d,J=5.8Hz,1H),3.81(s,2H),3.61(br-s,4H),2.87(br-s,4H),2.56(s,3H)。
N4-(3-chloro-4-fluorophenyl)-N2-(6-(4-methylpiperazine-1-yl) pyridin-3-yl) is phonetic Pyridine-2,4-diamines (compound 1-13)
Figure G2008800109774D00381
With 7 (60mg, 0.232mmol) and 24 (44.7mg, 0.232mmol) mixture in 2-propyl alcohol (7mL) and catalyzer TFA backflow 24h.TLC (20%MeOH/DCM) demonstration reaction is finished.Add NaOH, concentrate this mixture and carry out the CombiFlash purifying that (4g 100%DCM-25%MeOH/DCM) obtains compound 1-13 (86.7mg), is white solid.90% productive rate. 1H?NMR(400MHz,CD 3OD)8.23(d,J=2.4Hz,1H),7.92(m,1H),7.90(d,J=5.8Hz,1H),7.82(dd,J1=9.2Hz,J2=2.7Hz,1H),7.35(m,1H),7.12(t,J=8.9Hz,1H),6.88(d,J=9.2Hz,1H),3.61(br-s,4H),2.90(m,4H),2.59(s,3H)ESI/MS?m/z?414.1(M+H)。
N4-(3-chloro-4-fluorophenyl)-N2-(3-fluoro-4-(4-methylpiperazine-yl) phenyl) pyrimidine -2,4-diamines (compound 1-14)
Figure G2008800109774D00382
With 7 (60mg, 0.232mmol) and 23 (48.7mg, 0.232mmol) mixture in 2-propyl alcohol (7mL) and catalyzer TFA backflow 24h.After this TLC (20%MeOH/DCM, Rf=0.1) finish by the demonstration reaction.After at room temperature 3 days, form some white solids (103mg).Filter and 1H NMR shows that product is a tfa salt.Add NaOH and concentrate this mixture and (4g DCM-25%MeOH) obtains compound 1-14 (88.8mg), is white solid by CombiFlash companion purifying.Productive rate is 89%. 1H?NMR(400MHz,CD 3OD)7.90(m,2H),7.47(m,2H),7,27(dd,J1=9.6Hz,J2=2.4Hz,1H),7.14(t,J=6.4Hz,1H),6.99(t,J=9.6Hz,1H),6.15(d,J=5.8Hz,1H),3.10(br-s,4H),2.75(br-s,4H),2.43(s,3H)。ESI/MS?m/z431.0(M+H)。
(4-(4-(3-chloro-4-fluorophenyl amino) pyrimidine-2--amino) phenyl) (4-methylpiperazine -1-yl) ketone (compound 1-15)
(1g is 5.39mol) at CH with 1-methylpiperazine (26) processing 4-nitrobenzoyl chloride (25) down and in the 10min at 10 ℃ 3Solution among the CN (50mL).With this reaction mixture restir 1h, add subsequently TEA (1.49mL, 2eq) and restir half an hour.With ice cold water (150mL) dilute this reaction mixture and with EtOAc (4 * 150mL) extraction.Use MgSO 4Dry organic layer and be concentrated into and obtain 1.1g (82% productive rate) (4-methylpiperazine-1-yl) (4-nitrophenyl) ketone 27 is yellow solid.TLC:10%MeOH/DCM,Rf=0.6。 1NMR(400MHz,CDCl 3)8.28(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),3.88(br-s,4H),3.46(br-s,4H),2.40(s,3H)ESI/MS?m/z?250.0(M+H)
At H 2(60psi) pressure will be included in down (4-methylpiperazine-1-yl) (4-nitrophenyl) ketone (27) in the 20mL ethanol (200mg, 0.802mmol) and 10%Pd/C (60mg) mixture jolting 4h.After reaction is finished and filtered, concentrate and obtain 28 (83.8mg, productive rates 48%), be faint yellow oily thing. 1H-NMR(400MHz,CD3OD)7.19(dd,J1=2.0Hz,J2=6.5Hz,2H),6.68(dd,J1=2.7Hz,J2=6.5Hz,2H),3.64(br-s,4H),2.44(br-s,4H),2.31(s,3H)ESI/MS?m/z?220.0(M+H)。
With 7 (50mg, 0.194mmol) and 28 (33mg, 0.150mmol) mixture in 2-propyl alcohol (5mL) and catalyzer TFA are at 150 ℃ of following microwave treatment 1h.TLC demonstration reaction is finished.HPLC shows possible main new spot.(4g DCM-15%MeOH/DCM) obtains 32mg compound 1-15 to the CombiFlash purifying, is semisolid. 1H-NMR(400MHz,CD 3OD)7.98(d,J=6.15Hz,1H),7.94(m,1H),7.72(d,J=8.54,2H),7.36(dd,J1=2.0Hz,J?2=6.8Hz,2H),7.19(dd,J1=2.0Hz,J?2=8.8Hz,2H),6.21(d,J=6.1Hz,1H),3.65(br-s,4H),2.48(br-s,4H),2.34(s,3H)ES?I/MS?m/z?441.2(M+H)。
2-(3-(2-(4-(4-cyclohexyl piperazine-1-carbonyl) phenyl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile (compound 1-16)
Figure G2008800109774D00401
With 12 (50mg, 0.204mmol), (4-aminophenyl) (4-cyclohexyl piperazin methanone (29) (58.7mg, 0.204mmol) mixture backflow 24h in 2-propyl alcohol (5mL) and catalyzer TFA.Add NaOH and TLC (10%MeOH/DCM) and show some raw materials of existence and extra new spot.Concentrate and carry out the CombiFlash purifying (4g DCM-15%MeOH/DCM) obtains compound 1-16 (95mg), is brown solid. 1NMR(400MHz,CD 3OD)7.99(d,J=5.8Hz,1H),7.73(m,3H),7.55(d,J=8.2Hz,1H),7.35(m,3H),7.05(d,J=7.9Hz,1H),6.24(d,J=6.2Hz,1H),3.80(s,2H),3.699br-s,4H),2.75(br-s,4H),2.48(br-s,1H),1.95(br-s,2H),1.83(br-s,2H),1.65(d,J=13.0Hz,1H),1.29(br-s,4H)ESI/MS?m/z?496.1(M+H)。
2-(3-(2-(4-(4-methylpiperazine-1-carbonyl) phenyl amino) pyrimidine-4-base is amino) benzene Base) acetonitrile (compound 1-17)
Figure G2008800109774D00411
With 12 (50mg, 0.204mmol) and 28 (44.8mg, 0.204mmol) the mixture backflow 24h in 2-propyl alcohol (5mL) and catalyzer TFA.Add NaOH and TLC (10%MeOH/DCM) and show some raw materials of existence and extra new spot.Concentrate and carry out the CombiFlash purifying (4g DCM-15%MeOH/DCM) obtains compound 1-17 (52mg), is yellow solid. 1H?NMR(400MHz,DMSO-d 6)9.53(s,1H),9.40(s,1H),8.06(d,J=5.8Hz,1H),7.78(m,3H),7.58(s,1H),7.31(m,3H),6.98(d,J=7.1Hz,1H),6.27(d,J=5.5Hz,1H),4.02(s,2H),3.48(br-m,4H),2.42(br-m,4H),2.28(br-s,3H)ESI/MS?m/z428.2(M+H)。
2-(3-(2-(4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl amino) pyrimidine -4-base is amino) phenyl) acetonitrile (compound 1-18)
Figure G2008800109774D00412
With 12 (50mg, 0.204mmol) and 4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) aniline (29) (46.6mg 0.409mmol) contacts microwave condition 2.5h at 2-propyl alcohol (5mL) with mixture among the catalyzer TFA under 130 ℃.The spot that the TLC alleged occurrence is new.Make this reaction mixture quencher by adding NaOH, concentrate and carry out purifying (4g C-18,5%-100% water/CH by the CombiFlash purifying 3CN), and by HPLC check fraction.Merge pure fraction and be concentrated into and obtain 4.5mg compound 1-18, be faint yellow solid. 1H-NMR(300MHz,CDCl 3-CD 3OD)7.62(d,J=6.0Hz,1H),7.50(s,1H),7.46(d,J=9Hz,1H),7.24(s,2H),7.02(m,2H),6.70(d,J=7.2Hz,1H),5.89(d,J=5.8Hz,1H),3.45(s,1H),3.35(s,1H),3.03(s,2H),2.61(s,4H),2.29(s,4H),2.05(s,3H)。ESI/MS?m/z?468.36(M+H)。
Embodiment 4
The salt form of representational compound
Prepare the representational salt form (being HCl, vitriol, mesylate and benzene sulfonate form) of compound 1-11 and 1-18 and be listed in the following table 2 according to following operation.
2-(3-(2-(3-fluoro-4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile dihydrochloride (compound 1-11 2HCl)
Compound 1-11 (2.06g) is suspended in the 125mL 2-propyl alcohol.Add dense HCl (2.47mL, 6eq).Heat this mixture, up to obtaining settled solution.At room temperature cool off this solution, after this put it into-20 ℃ of refrigerators.After 3 days, in ar gas environment, filter and obtain two-HCl salt of compound 1-11, be the 1.823g yellow powder, productive rate 70% with the ether washing.
2-(3-(2-(3-fluoro-4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile vitriol (compound 1-11 vitriol)
350mg compound 1-11 is dissolved in 35mL acetone and adds 0.122mL (2.5eq) H 2SO 4Precipitation forms fast.This mixture storage is at room temperature spent the night.Filtration obtains the yellow hygroscopic powder of 394mg.With this solid suspension in ethanol 1 hour and filter and to obtain 350mg white powder, productive rate 68% (non-hygroscopic). 1H-NMR?300MHz,CD 3OD)7.94(d,J=7.33Hz,1H),7.76(s,1H),7.65(d,J=8.3Hz,1H),7.49(m,2H),7.29(m,3H),6.57(d,J=7.33Hz,1H),3.96(s,2H),3.74(t,J=12.45Hz,4H),3.42(m,4H),3.12(s,3H), 19F-NMR(300MHz,CD 3OD)-186.99Hz。Ultimate analysis theoretical value: C, 45.02; H, 4.60; N, 15.98; S, 10.45, measured value: C, 45.68; H, 4.30; N, 15.96; S, 9.39.
2-(3-(2-(3-fluoro-4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile mesylate (compound 1-11 mesylate)
In the warm solution of compound 1-11 (400mg) in 40mL IPA, add methylsulfonic acid (0.186mL, 3eq).Settled solution progressively becomes muddy and this mixture is stored under-20 ℃ and spends the night.At N 2In filtration residue and dry in a vacuum and obtain 400mg white powder, productive rate 68%. 1H-NMR(300MHz,CD 3OD)7.83(d,J=7.08Hz,1H),7.67(s,1H),7.55(d,J=8.55Hz,1H),7.42(m,2H),7.19(m,3H),6.43(d,J=7.33Hz,1H),3.85(s,2H),3.62(d,J=11.23Hz,4H),3.37(m,4H),3.18(d,J=11.0Hz,2H),3.04(s,3H),2.71(s,6H)。Ultimate analysis theoretical value: C 49.25, H 5.29, and N 16.08, and S 10.52, measured value: C 48.75, and H 5.50, and N 15.13, and S 10.51.
2-(3-(2-(3-fluoro-4-(4-methylpiperazine-1-yl) phenyl amino) pyrimidine-4-base is amino) Phenyl) acetonitrile benzene sulfonate (compound 1-11 benzene sulfonate)
In the solution of compound 1-11 (400mg) in 30mL ethanol, add Phenylsulfonic acid (455mg, 3eq).Settled solution forms, and after this occurs white precipitate fast.At N 2In filtration residue spend the night, dry in a vacuum and obtain 520mg white solid, productive rate 74%. 1H-NMR(300MHz,CD 3OD-CDCl 3)7.93(m,3H),7.82(d,J=7.08Hz,1H),7.66(s,1H),7.49M,5H),7.27(d,J=7.33Hz,1H),7.21(d,J=9.04Hz,1H),7.04(t,J=7.3Hz,1H),6.49(d,J=7.32Hz,1H),3.85(s,2H),3.67(d,J=10.2Hz,2H),3.63(d,J=11.7Hz,2H),3.39(s,4H),3.03(s,3H)。Ultimate analysis theoretical value: C 57.28, H 4.94, and N 13.36, and S 8.74, measured value: C 57.06, and H 4.86, and N 13.20, and S 8.66.
2-(3-(2-(4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl amino) pyrimidine -4-base is amino) phenyl) acetonitrilehydrochlorate (compound 1-18HCl)
Compound 1-18 (500mg) is difficult to be dissolved in fully 40mL IPA.Yet (0.446mL 5eq) and after the heating, obtains clear yellow solution adding HCl.This solution is cooled to room temperature and put into-20 ℃ of refrigerators 2 days.Filter and to drying, obtain the 570mg powder, productive rate 84% in vacuum. 1H-NMR(300MHz,CD 3OD)7.87(d,J=7.32Hz,1H),7.81(s,2H),7.60(m,3H),7.36(m,1H),7.22(d,J=7.82Hz,1H),6.48(d,J=7.33Hz,1H),3.89(m,3H),3.60(d,J=7.57Hz,2H),3.25(m,4H),2.99(s,3H),1.14(d,J=6.35Hz,6H,I?PA)。Ultimate analysis theoretical value: C, 53.17; H, 6.06; N, 15.50; Cl, 11.21, measured value: C, 53.27; H, 6.37; N, 14.84; Cl, 10.81.
2-(3-(2-(4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl amino) pyrimidine -4-base is amino) phenyl) acetonitrile vitriol (compound 1-18 vitriol)
In the solution of compound 1-18 (400mL) in 50mL IPA, add H 2SO 4(0.137mL, 3eq).Precipitation forms fast.At N 2In filter through weekend and to obtain 407mg yellow powder, productive rate 68%. 1H-NMR(300MHz,CD 3OD)7.89(d,J=7.32Hz,1H),7.78(m,2H),7.60(m,3H),7.36(t,J=7.32Hz,1H),7.22(d,J=7.08Hz,1H),6.48(d,J=7.33Hz,1H),3.87(s,2H),3.60(d,J=7.1Hz,2H),3.27(m,4H),3,21(s,3H)。Ultimate analysis theoretical value: C, 44.15; H, 4.65; N, 14.13; S, 9.24, measured value: C, 44.20; H, 4.65; N, 13.98; S, 9.16.
2-(3-(2-(4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl amino) pyrimidine -4-base is amino) phenyl) acetonitrile mesylate (compound 1-18 mesylate)
Adding methylsulfonic acid in the solution (almost clarification) of compound 1-18 (400mg) in 20mL acetone (0.139mL, 2.5eq).This solution becomes muddiness.This mixture was stored under-20 ℃ through weekend.Topple over and acetone.Washing solid and dry in a vacuum and obtain 429mg yellow powder, productive rate 74%. 1H-NMR(300MHz,CD 3OD)7.88(d,J=7.33Hz,1H),7.78(m,2H),7.59(m,3H),7.35(t,J=7.32Hz,1H),7.22(d,J=7.08Hz,1H),6.48(d,J=7.33Hz,1H),3.86(s,2H),3.60(d,J=7.57Hz,2H),3.27(m,4H),2.99(s,3H),2.72(s,6H)。Ultimate analysis theoretical value: C, 46.08; H, 5.06; N, 14.47; S, 9.46, measured value: C, 46.08; H, 4.93; N, 14.16; S, 10.25.
2-(3-(2-(4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl amino) pyrimidine -4-base is amino) phenyl) acetonitrile benzene sulfonate (compound 1-18 benzene sulfonate)
In the hot suspension of compound 1-18 (400mg) in IPA (30mL), add Phenylsulfonic acid (406mg, 3eq).It is at room temperature cooled off and be stored under-20 ℃ and spend the night.At N 2The middle filtration obtains 516mg yellow powder, productive rate 72%. 1H-NMR(300MHz,CD 3OD)7.81(m,7H),7.58(m,3H),7.43(m,7H),7.19(d,J=7.57Hz,1H),6.47(d,J=7.33Hz,1H),3.84(s,2H),3.58(d,2H),3.23(m,5H),2.97(s,3H), 19F-NMR(300Mz,CD 3OD)-126.58。Ultimate analysis theoretical value: C, 51.60; H, 5.05; N, 11.70; S, 7.65, measured value: C, 51.57; H, 4.96; N, 10.98; S, 7.61.
Table 2
Representational salt form
Figure G2008800109774D00451
Figure G2008800109774D00461
Embodiment 5
The activity of representational compound
A. The test of JAK2 kinase inhibition
Can measure a kind of illustrative mode of JAK2 kinase activity and be undertaken quantitatively by the ATP amount that is retained in behind external JAK2 kinase reaction in the solution, (Madison WI) carries out for Promega, Inc. to measure test kit such as kinases-Glo.The amount that is retained in the ATP in the solution behind kinase reaction obtains the substrate of the luciferase of oxyluciferin+1 photon as the catalysis fluorescein.Therefore, (Thermo Electron Corp., the ATP that exists behind the Milford, the luminous signal that MA) reads and kinase reaction amount is relevant, and is inversely proportional to the amount of kinase activity for Luminoskan Ascent Instrument.This test can effectively be measured kinase inhibitor at the kinase whose IC of JAK2 50Value.These tests are set in the 50ul volume of white in the flat 96 hole flat boards carry out in duplicate.Inhibitor is joined 1X kinase buffer liquid, 6uM ATP, the 62.5uMJAK2-specific substrate is the solution from the micromole to nanomolar concentration scope serial dilution of active JAK2 enzyme of 30ng and water.This solution was hatched 2 hours with 360rpm under 30 ℃.After hatching, in each hole, add 50ul kinases-Glo reagent, comprise all positive controls and negative control hole and at room temperature hatched 15 minutes.Read flat board by Luminoskan Ascent instrument then and use Ascent Software 2.6 editions to show the result.Inhibitor to every kind of test calculates IC then 50Value.
Also by the radioactivity measurement method; Be kinases Profiler TMWith I C50Profiler TMMeasure service system (Millipore-Upstate, Dundee, UK) test compounds.In brief, reorganization JAK2 enzyme is tested the perhaps many concentration of single concentration (being used for the single-point screening) (be used for IC having in the presence of the radiolabeled ATP 50Mensuration) compound.
JAK2 V617F mutant isotype has been obtained progress aspect the neoplastic transformation concentrating on it in the recent period.Therefore, also use SelectScreen TM(Invitrogen Corporation, Carlsbad CA), comprise that the wild-type of JAK2 and V617F mutant isotype tested compound to measure service system.These enzymes comprise proteinic JH1 and JH2 homologous region and only different on 617 amino acids.
B. JAK2 kinase inhibitor test based on cell
To be used to estimate The compounds of this invention based on the test of cell culture and suppress one or more cytoactives, such as the ability of growth of cancer cells and/or survival.A large amount of cancerous cell lines can be available from American type culture collection (ATCC) and other source.In brief, with cell inoculation go into the opaque white color flat board that 96-hole tissue culture handles (Thermo Electron, Vantaa, Finland), according to the difference of cell proliferation rate, 600-14000 cells/well (measuring) in the suitable growth medium of 100ul by ATCC.Make the medicine of cells contacting proper concn then and make its growth have 96 hours.After this, and adding 100ulCell-Titer-Glo reagent in each hole (Promega, Inc., Madison, WI).Then at room temperature with dull and stereotyped jolting 2 minutes so that lysis and at room temperature hatching 10 minutes so that luminous signal is stable.Similar with the kinases-Glo test reagent from Promega, this reagent comprises luciferase and substrate fluorescein thereof.Fluorescein is catalytically converted into oxyluciferin, promptly luminous reaction by ATP activatory luciferase in the cell lysate.The amount of the light that produces is directly proportional with the amount of ATP in the cell lysate, and the amount of ATP self is directly proportional with cell quantity and obtains the cell proliferation index.
For the specificity that detects JAK2 enzyme in the cell culture suppresses, can also carry out the western blotting test.For this purpose, with having specific damping fluid (1%Nonidet P-40 to separating and preserving protein, 120mM NaCl, 30mM Tris pH 7.4,1: 100 protease inhibitor cocktail III[Calbiochem/EMD Biosciences], 1: 100 inhibitors of phosphatases mixture 1[Sigma-Aldrich, Saint Louis, MO], 1: 100 inhibitors of phosphatases mixture 2[Sigma-Aldrich, Saint Louis, MO]) cell handled with possible JAK2 inhibitor of cracking.Use BCA protein determination test kit (Pierce) that the protein concn in these lysates is carried out quantitatively then.Make the protein of known quantity, for example 50ug goes up the 10%SDS-polyacrylamide gel and reduces sex change SDS-PAGE.Electrophoretic albumen is gone to nitrocellulose membrane, use then at STAT5, pSTAT5 (Tyr 694), the antibody of STAT3 and pSTAT3 (Tyr 705) is surveyed.Because STAT5 and the STAT3 on 694 tyrosine and 705 tyrosine is the substrate of JAK2 respectively, can provide the mode of estimating JAK2 inhibitor effect so be determined at the amount of handling the phosphorylation on these sites in the cell.
C. JAK2 kinases activity specific data
At the compound sequence number 1-4 of 300nM-10nM dilution range screening as the JAK2 inhibitor, 1-7,1-11 and 1-17 wherein use Cell-Titer-Glo test determination survival per-cent.These compounds produce separately with respect to from calculating IC 50The % survival value of the inhibitor concentration of value.The IC that these compounds produce in different carcinoma clone 50Value is lower than 10nM.
To compound sequence number 1-4,1-7,1-11 and 1-17 have measured the kinase whose IC at JAK2 50Value (using Promega kinases-Glo test).These compounds have the IC that is lower than 1uM separately after measured 50Value.
IC 50Profile TMData presentation compound sequence number 1-4,1-7, the IC of 1-11 and 1-17 50Value is lower than 1uM, and from the Invitrogen Select Screen that uses at wild-type (JAK2WT) and mutant JAK2 kinases (JAK2V617F) TMThe IC of these 4 kinds of compounds of data presentation of the compound of profiling screening 50Value is lower than 1 μ M.
Embodiment 6
Representational compound is regulated STAT3 and STAT5
A. Compound 1-4 suppresses STAT3 and STAT5 phosphorylation
In the present embodiment, the JAK2-dependency phosphorylation of STAT3 and STAT5 in the confirmation compound 1-4 minimizing AGS stomach cancer cell system.In brief, with ags cell at 25cm 2Bed board and hatched 24 hours having in the presence of the different concns compound 1-4 in the tissue culture flasks.After hatching, lysing cell and separation total protein and quantitative.50 μ g total proteins are carried out electrophoresis and go to nitrocellulose membrane, use this moment antibody to carry out western blot analysis at STAT3-phosphoric acid-Y705 and STAT5-phosphoric acid-Y 694.Also always compare with STAT 3 and STAT5.Carry out the spectrodensitometry analysis so that the amount of STAT3 in the cell of these processing and STAT5 phosphorylation is carried out quantitatively.Phosphoric acid-STAT3 and phosphoric acid-STAT5 are compared and measure the ratio of STAT phosphorylation with respect to untreated control group with total STAT3 and STAT5.Under low micro-molar concentration (5-10uM), show the STAT3 and the STAT5 phosphorylation level of decline with the cell of No. 1 compound treatment.
B. Compound 1-4 reduces the STAT3 activation
As STAT3 during by the JAK2 phosphorylation, its form homodimer and transposition to nuclear so that influence relates to the transcribing of a large amount of target genes of cell proliferation.Hatched 1,5 or 24 hour hatching the AGS stomach cancer cell on the 96 hole flat boards and having in the presence of the 5 μ M compound 1-4.After hatching, use STAT3HitKit (Thermo-Fisher) staining cell and go up use Molecular TranslocationBioApplication detection at ArrayScanVTi high-content screening instrument (Thermo-Fisher).Nuclear is coloured to blueness (Hoechst) by false plan and STAT3 is intended being coloured to green (FITC) by vacation.
In untreated cell, in nuclear, found a large amount of STAT3, show STAT3 by phosphorylation, have activity and inducible transcription.Yet in the cell that uses compound 1-4 to handle, it is outside that STAT3 dyeing is limited to nuclear, and this shows its not phosphorylation and non-activity, the i.e. effect of Yu Qi JAK2 inhibitor.When comparing with this nuclear of untreated sample STAT3 level, handling back 24h with compound 1-4, nuclear STAT3 has reduced more than 50%.
C. Compound 1-4 and 1-7 reduce STAT5 phosphorus in the cell of expressing Jak2 (V617F) Acidifying
In the present embodiment, confirm compound 1-4,1-7, the JAK2-dependency phosphorylation of STAT5 in the cell of the V617F mutant of 1-11 and 1-17 minimizing expression JAK2.In brief, with hel cell at 25cm 2Bed board and hatched 24 hours having in the presence of different concns compound sequence number 1 or 2 in the tissue culture flasks.After hatching, lysing cell and separation and quantitative total protein.Electrophoresis 50 μ g total proteins and going on the nitrocellulose membrane use the antibody at STAT5-phosphoric acid-Y694 to carry out western blot analysis this moment.Compare with total STAT5.Carry out the spectrodensitometry analysis so that the quantitative amount of STAT5 phosphorylation in these test cell.From this test, measure EC 50Value is 299nM with regard to compound 1-4, be 4nM with regard to compound 1-7, just is 266nM with regard to the compound 1-11 for 65.8nM and with regard to compound 1-17.
With relate in this specification sheets and/or the request for data list on all listed above-mentioned United States Patent (USP)s, the U.S. Patent Application Publication document, U.S. Patent application, foreign patent, foreign patent application and non-patent disclosure are incorporated herein by reference civilianly.
Although be appreciated that from above-mentioned describing specific embodiments of the present invention is for purpose of illustration, various modification can carried out without departing from the spirit and scope of the present invention.Therefore, the present invention is unrestricted, and is limited by the claim that awaits the reply.

Claims (19)

1. the compound that has following structure (I):
Figure A2008800109770002C1
Comprise its steric isomer and pharmacy acceptable salt, wherein:
Z is CH or N;
W 1And W 2Be direct key independently ,-C (=O)-or-O (CH 2) n-;
X 1And X 2Be-H-CF independently 3,-OCF 3,-OCHF 2,-OCH 3,-CH 3,-OH ,-NO 2,-NH 2, halogen or
Figure A2008800109770002C2
Wherein Q is O or N and R does not exist or R is-C 1-6Alkyl, condition are X 1Or X 2One of be:
Figure A2008800109770002C3
Y 1And Y 2Be-H-CN, the C that halogen or quilt-CN replace independently 1-4Alkyl, condition are Y 1And Y 2Be not-H; And
N is 1,2 or 3.
2. the described compound of claim 1 or its steric isomer or pharmacy acceptable salt, wherein Z is CH.
3. the described compound of claim 2 or its steric isomer or pharmacy acceptable salt, wherein X 2Be halogen.
4. the described compound of claim 3 or its steric isomer or pharmacy acceptable salt, wherein Y 2For-CN, the C that halogen or quilt-CN replace 1-4Alkyl.
5. the described compound of claim 3 or its steric isomer or pharmacy acceptable salt, wherein Y 1For-CN, the C that halogen or quilt-CN replace 1-4Alkyl.
6. the described compound of claim 2 or its steric isomer or pharmacy acceptable salt, wherein X 2For-H.
7. the described compound of claim 6 or its steric isomer or pharmacy acceptable salt, wherein Y 1For-CN, the C that halogen or quilt-CN replace 1-4Alkyl.
8. the described compound of claim 6 or its steric isomer or pharmacy acceptable salt, wherein Y 2For-CN, the C that halogen or quilt-CN replace 1-4Alkyl.
9. the described compound of claim 2 is selected from:
Figure A2008800109770003C1
Or its steric isomer or pharmacy acceptable salt.
10. the described compound of claim 2 is selected from:
Figure A2008800109770004C1
Or its steric isomer or pharmacy acceptable salt.
11. the described compound of claim 1 or its steric isomer or pharmacy acceptable salt, wherein Z is N.
12. the described compound of claim 11 or its steric isomer or pharmacy acceptable salt, wherein X 2For-H.
13. the described compound of claim 12 or its steric isomer or pharmacy acceptable salt, wherein Y 2For-CN, the C that halogen or quilt-CN replace 1-4Alkyl.
14. the described compound of claim 12 or its steric isomer or pharmacy acceptable salt, wherein Y 1For-CN, the C that halogen or quilt-CN replace 1-4Alkyl.
15. the described compound of claim 11 is selected from:
Figure A2008800109770004C2
Or its steric isomer or pharmacy acceptable salt.
16. composition comprises described compound of claim 1 and pharmaceutically acceptable vehicle.
17. the method for the disease of treatment JAK2 protein kinase-mediation, described method comprises the described composition of claim 16 of the object that these needs are arranged being treated significant quantity.
18. the described method of claim 17, wherein the disease of JAK2 protein kinase-mediation is a cancer.
19. the described method of claim 17, wherein said cancer are colorectal carcinoma, prostate cancer, carcinoma of testis, lung cancer, uterus carcinoma, ovarian cancer, cancer of the stomach, mammary cancer, carcinoma of the pancreas, leukemia or lymphoma.
CN200880010977A 2007-03-01 2008-02-29 Pyrimidine-2,4-diamine derivatives and their use as JAK2 kinase inhibitors Pending CN101657431A (en)

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CN105308033A (en) * 2013-03-14 2016-02-03 特雷罗药物股份有限公司 JAK2 and ALK2 inhibitors and methods for their use
US11013741B1 (en) 2018-04-05 2021-05-25 Sumitomo Dainippon Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
CN115029299A (en) * 2018-11-07 2022-09-09 杭州瑞普晨创科技有限公司 Application of JAK2 inhibitor in induced differentiation of islet beta cells

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105308033A (en) * 2013-03-14 2016-02-03 特雷罗药物股份有限公司 JAK2 and ALK2 inhibitors and methods for their use
CN105308033B (en) * 2013-03-14 2018-08-24 特雷罗药物股份有限公司 JAK2 and ALK2 inhibitor and its application method
US10202356B2 (en) 2013-03-14 2019-02-12 Tolero Pharmaceuticals, Inc. JAK2 and ALK2 inhibitors and methods for their use
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
US11013741B1 (en) 2018-04-05 2021-05-25 Sumitomo Dainippon Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
US11400091B2 (en) 2018-04-05 2022-08-02 Sumitomo Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
CN115029299A (en) * 2018-11-07 2022-09-09 杭州瑞普晨创科技有限公司 Application of JAK2 inhibitor in induced differentiation of islet beta cells
CN115029299B (en) * 2018-11-07 2023-11-14 杭州瑞普晨创科技有限公司 Application of JAK2 inhibitor in islet beta cell induced differentiation

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