CN102807558A - Fluorine-containing dihydroindene amide compound used as protein kinase inhibitor - Google Patents
Fluorine-containing dihydroindene amide compound used as protein kinase inhibitor Download PDFInfo
- Publication number
- CN102807558A CN102807558A CN2012103115258A CN201210311525A CN102807558A CN 102807558 A CN102807558 A CN 102807558A CN 2012103115258 A CN2012103115258 A CN 2012103115258A CN 201210311525 A CN201210311525 A CN 201210311525A CN 102807558 A CN102807558 A CN 102807558A
- Authority
- CN
- China
- Prior art keywords
- acid
- base
- amino
- methyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *C(CC1)CC2=*(*)CC=*(*)C=C2C1C1=CCC(N)=CC=CC=C1 Chemical compound *C(CC1)CC2=*(*)CC=*(*)C=C2C1C1=CCC(N)=CC=CC=C1 0.000 description 2
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses compounds used for curing or preventing diseases related to protein kinase shown in the formula (I), medicinal salt thereof or a configurational isomer thereof, wherein a linking group L1, loops A, B and C and substituents R1, R2, R3, R4 and R5 are as defined in the specification. The invention also discloses a preparation method of the compounds shown in the formula (I), a medicine composition and applications of medicine prepared by the compounds for curing or preventing the diseases related to the protein kinase.
Description
Technical field
The present invention relates to medical technical field; Be specifically related to fluorine indane amide compound; Or this compounds pharmacy acceptable salt, unite with one or more other pharmaceutically active compounds separately or randomly and be used to treat the disease that response is arranged for the arrestin kinase activity.
Background technology
Protein kinase is one type of phosphotransferase, and its effect is that the γ phosphate of ATP is transferred on the substrate specified amino acid residues, makes protein phosphorylation.These phosphorylations are served as the open/close transmodulator of molecule of adjustable or the proteinic biological function of goal of regulation and control, finally outer and other stimulator and being triggered in response to various kinds of cell.These stimulator comprise that environment and chemistry stress signals (for example shock, heat-shocked, uviolizing, bacterial endotoxin and H
2O
2), cytokine (for example wrap cell stay-1 with neoplasm necrosis shadow α and growth factor).The extracellular stimulus thing may influence one or more cell response such as cell growth, migration, differentiation, hormone secretion, transcription factor activation, Muscle contraction, glucose metabolism, protein synthesis control.
Protein kinase activity not normal can cause many relevant diseases.These diseases comprise that cancer, autoimmune disease, inflammation, metabolic disease, nervous system disease, cardiovascular disorder close Alzheimer (Alzheimer ' s disease) etc.Under many circumstances, can be through utilizing kinases inhibitor to treat this type disease in external and the body.
ABL (Abelson leukemia virus) Tyrosylprotein kinase is present in tenuigenin and the nucleus; In cytodifferentiation, division, cell adhesion and stress response process, play an important role; Gene transposition causes B-cell receptor, and (B cell receptor BCR) merges formation fusion gene BCR-ABL with abl gene end to end.The BCR-ABL kinases has a plurality of functional domains, comprises SH2, SH3 structural domain, appraises and decides bit architecture territory and 3 dna structure territories, and its activation helps leukemic generation.Tyrosine kinase activity is essential for the function of BCR-ABL, and some signal pathway of BCR-ABL activated is similar with hemopoieticgrowth factor activated approach, like Ras, PI3K, JAK/STAT etc.The excessive activation of BCR-ABL changes adhesion, the inducing cell skeleton dysfunction of hematopoietic cell, through number of ways interference cell cycle and cell adhesion, promotes the generation and the development of tumour.
The Imatinib of early 1990s discovery can the specific activity that suppresses the BCR-ABL LCK.It can effectively suppress the autophosphorylation of ABL, PDGF acceptor (PDGFR), Kit acceptor and ARG Tyrosylprotein kinase under micro-molar concentration; Become and treat a leukemic line important drugs clinically, but found the resistance phenomenon behind patient's life-time service.Discover that chemical sproof molecular basis is the variant of the kinases structural region appearance of BCR-ABL to the Imatinib resistance, two mutants comprises Y253H, E255V, E255K, F359V, T315I, G250E, F317L, E355G, H396P, M351T, M253H, L248V, Q252H, Y253H and Y253C etc.
More than the big kinds of Diseases relevant of kinases inhibitor quantity with proliferative and other protein kinases; And problems such as resistance have appearred in existing medicine; We need develop the compound of new kind; With as kinases inhibitor, be used to treat the relevant disease of these protein kinases.Therefore, the present invention has found a kind of new fluorine-containing indane amide derivatives, is used to prevent or treatment relevant disease unusual with protein kinase activity or out of control.
Summary of the invention
The present invention provides a kind of compound or pharmacy acceptable salt or its prodrug that following logical formula I is represented that contain
Wherein
L
1Be NR
dC (O) or C (O) NR
d
Ring A represents one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl, and 1-3 heteroatoms is independently selected from O in the ring, N and S;
Ring B, C represent one 5 or 6 yuan heterocycle or Heterocyclylalkyl, and 1-3 heteroatoms is independently selected from O in the ring, N and S;
R
1Be independently selected from hydrogen, halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR
aR
b, NR
dC (O) R
c, C (O) NR
aR
b, S (O)
2NR
aR
b, NR
dS (O)
2R
c, NR
d(CH
2)
nR
c, (CH
2)
nNR
aR
b, NHC (O) NH R
c, (CH
2)
nNHC (O) R
c, NHC (NH) R
c
R
2, R
3, R
4, R
5Be independently selected from hydrogen respectively, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, alkylamino, dialkylamine, nitro, cyanic acid, carboxyl, carbalkoxy, acyloxy;
R
a, R
bBe independently selected from hydrogen respectively, alkyl, naphthenic base, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R
cBe independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
R
dBe independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; Heterocyclylalkyl can be replaced by following any one or more groups: halogen, amino, alkylamino, dialkylamine, acid amides, aryl; Heterocyclic radical, nitro, cyanic acid, carboxyl, carbalkoxy, hydroxyl; Alkoxyl group, acyloxy ,=O ,=S ,=NH;
X is 0,1,2,3;
Y is 0,1,2;
Z is 0,1,2,3,4;
M is 0,1,2,3,4;
N is 1,2,3,4,5,6;
W is 1,2,3,4,5.
In formula I compound according to the invention, general formula II compound preferably:
Wherein
Ring A is a saturated cyclic amino, is selected from piperidyl, piperazinyl, pyrrolidyl, azelidinyl, morpholinyl;
Ring B is monocyclic heteroaryl, and it is preferably from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl ， oxazolyl ， isoxazolyl, triazolyl, pyrazolyl;
The heteroaryl or the Heterocyclylalkyl of ring C monocycle or condensed ring, it is preferably from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl; Thiazolyl, isothiazolyl, imidazolyl ， oxazolyl ， isoxazolyl, triazolyl; Pyrazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, Pyrazolopyridine base, Imidazopyridazine base, pyrazolopyrimidine base; Quinolyl, isoquinolyl, quinazolyl, piperazinyl, piperidyl, morpholinyl;
R
1Be independently selected from hydrogen, halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR
aR
b, NR
dC (O) R
c, C (O) NR
aR
b, S (O)
2NR
aR
b, NR
dS (O)
2R
c, NR
d(CH
2)
nR
c, (CH
2)
nNR
aR
b, NHC (O) NH R
c, (CH
2)
nNHC (O) R
c, NHC (NH) R
c
R
2, R
3, R
4, R
5Be independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, alkylamino, dialkylamine, nitro, cyanic acid, carboxyl, carbalkoxy, acyloxy;
R
a, R
bBe independently selected from hydrogen respectively, alkyl, naphthenic base, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R
cBe independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
R
dBe independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; Heterocyclylalkyl can be replaced by following any one or more groups: halogen, amino, alkylamino, dialkylamine, acid amides, aryl; Heterocyclic radical, nitro, cyanic acid, carboxyl, carbalkoxy, hydroxyl; Alkoxyl group, acyloxy ,=O ,=S ,=NH;
X is 0,1,2,3;
Y is 0,1,2;
Z is 0,1,2,3,4;
M is 0,1,2,3,4;
N is 1,2,3,4,5,6;
W is 1,2,3,4,5.
Formula I compound according to the invention or its pharmacy acceptable salt or its prodrug, wherein said compound more preferably from:
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-dimethylamino piperidine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-hydroxyethyl piperazine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(the high piperazinyl of 4-methyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(3-dimethylamino pyrrolidyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-thiophene-2-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyrazine-2-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-methylimidazole base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(2,4,6-trimethylammonium pyrimidine-5-yl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide.
Formula I compound according to the invention is at pharmacy acceptable salt, or contains at least one alkaline salt forming group, and acid salifiable with it can be mineral acid or organic acid pharmaceutically commonly used, comprises mineral acid: hydrochloric acid, sulfuric acid, phosphoric acid; Organic carboxyl acid: acetate, propionic acid, trifluoroacetic acid, oxyacetic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, Hydrocerol A, oxalic acid, various natural or synthetic amino acid, phenylformic acid, Whitfield's ointment, 4-aminosallcylic acid, racemic melic acid, styracin, nicotinic acid, Yi Yansuan; Organic sulfonic acid: methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2-naphthene sulfonic acid.When having a plurality of basic group, can generate the polyacid additive salt.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvolyte or hydrate.In general, the form form of solvolyte or hydrate and non-solventization or non-hydrated is equal to, and contains within the scope of the invention in the lump.Some compound among the present invention might exist polycrystal or unbodied form.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
All steric isomers that are form of mixtures or are the The compounds of this invention of pure form are contained in the present invention.The definition of The compounds of this invention comprises all possible steric isomer and composition thereof.It comprises racemic form and isolating optical isomer with given activity very particularly.Racemic form can split through physical method, and said physical method is such as the diastereomer verivate being carried out fractional crystallization, separate or separating through the chiral column chromatogram.Can through ordinary method for example optical activity acid form salify follow crystallization and obtain independent optical isomer from racemic modification.
The present invention also comprises the prodrug of said compound.Prodrug is to be derived and next a kind of compound by parent drug, and in a single day it get in the body, and prodrug is just changed into parent drug by metabolism.Prodrug can replace through the one or more functional groups to parent drug and prepare, and its substituted radical can be discharged parent compound by enzyme catalysis in vivo.The preparation of prodrug and use can be at T.Higuchi and V.Stella; " Pro-drugs as Novel Delivery System "; Vol.14 of the A.C.S.Symposium Serier and Bioreversible Carriers in Drug Design; Ed.Edward B.Roche, AmericanPharmaceutical Association and Pergamon Press finds in 1987.
In addition, the present invention also provides the method for synthetic formula I compound.Compound of the present invention can obtain through following method.
4-bromo-2-trifluoromethylbenzoic acid refluxes in chlorination reagent (like thionyl chloride, POCl3 etc.) and obtains Benzoyl chloride 99min. (1-2).Midbody 1-2 is fed ethylene gas under lewis acidic catalysis, obtained 1-3, cyclization obtains 5-bromo-7-trifluoromethyl-2,3-bihydrogen-1-indenone (1-4) as catalyzer with Lewis acid again.
5-bromo-7-trifluoromethyl-2,3-bihydrogen-1-indenone with the cuprous cyanide pyroreaction, are substituted by cyanic acid with bromine in the DMF solvent, obtain midbody 5-cyanic acid-7-trifluoromethyl-2,3-bihydrogen-1-indenone (2-1).2-1 reduced in a kind of solvent system such as methyl alcohol with a kind of reductive agent such as Peng Qinghuana obtain alcohol intermediate (2-2); With chlorination reagent such as thionyl chloride hydroxyl is become chlorine (2-3) then; Chlorine is replaced by aminocompound again, uses triethylamine or salt of wormwood to be alkali, thereby obtains midbody 2-4.The hydrolysis under alkaline condition of cyanic acid among the 2-4 obtains carboxylic acid (2-5).
Final product (3-2) be with carboxylic acid (2-5) with contain substituent aniline through the acyl chlorides midbody method or directly connect into acid amides with coupling agent such as DCC/HOBt and obtain.
The invention still further relates to the pharmaceutical composition of acceptable carrier on the formula I compound that comprises significant quantity and the pharmacology, that said composition is applicable to is partial, in the intestines or the outer administration of intestines, can be inorganic or organic, solid-state or liquid.For oral, especially with tablet or capsule.This tablet or capsule comprise activeconstituents and thinner (like lactose, glucose, sucrose, mannitol, sorbyl alcohol, Mierocrystalline cellulose, USP Kosher), lubricant (like talcum, stearate), polyoxyethylene glycol.Tablet also can comprise tackiness agent, starch, gelatin, methylcellulose gum; Xylo-Mucine and/or Vinylpyrrolidone polymer also can comprise disintegrator (like starch, agar, alginic acid and salt thereof), effervescent mixture, or sorbent material in case of necessity; Dyestuff, seasonings, sweetener.The form of all right administered parenterally of these compsns or suitable with the form quilt of injection.Preferred isotonic aqueous solution of this type of formulation or emulsion, as under the situation of the lyophilised compsns of only being made up of activeconstituents and a kind of carrier (like N.F,USP MANNITOL), this type of solution can prepare before use.These pharmaceutical compositions can be aseptic, or comprise vehicle, or the salt of solubilizing agent, adjusting osmotic pressure.
The present invention also provides a kind of method of regulating protein kinase activity, comprising said protein kinase is contacted with the formula I compound.Wherein said protein kinase is selected from wherein said protein kinase and is selected from Abl, Bcr-Abl.
The present invention also provides a kind of pharmaceutical composition, and it comprises the formula I compound that can prevent or treat the protein kinase related disorder state and the pharmaceutically acceptable carrier or the thinner of effective therapeutic dose.
The present invention also provides the formula I compound to be used for treating the application of the medicine of disease or imbalance in preparation; Wherein said disease or imbalance are relevant with protein kinase activity or unusual relevant with cell proliferation; Like cancer, inflammation, autoimmune disorder; Metabolic disease, central nervous system disease and cardiovascular disorder.
Embodiment
To describe exemplary of the present invention in detail below.Yet these embodiments are merely illustration purpose, are not intended to limit the scope of the invention.
It below is the definition of the term that can use in this manual.Except as otherwise noted, the original definition that this patent provides with regard to group or term is applicable at said group or the term of specification sheets in the whole text, uses separately or uses as the part of another group no matter be.
Term " alkyl " is meant unsubstituted alkyl straight chain or side chain; It has 1-20 carbon atom; Preferably 1-6 carbon atom refers in particular to methyl, ethyl, propyl group (comprising n-propyl and sec.-propyl), butyl (comprising normal-butyl, isobutyl-, the tertiary butyl) etc.
Term " thiazolinyl " is meant the alkyl with one or more carbon-carbon double bonds, like vinyl, propenyl, 1,3-butadiene, maleic, anti-butylene etc.
Term " alkynyl " is meant to have an a plurality of carbon carbon triple-linked alkyl, like ethynyl, proyl etc.
Term " halogen " perhaps " halo " is meant fluorine (fluoro), chlorine (chloro), bromine (bromo), iodine (iodo).
Term " aryl " is meant monocycle or polycyclic aromatic hydrocarbons, for example benzene, naphthalene, anthracene, phenanthrene etc.
Term " heterocyclic aryl " is meant optional substituted aromatic series ring-type group, wherein contains a carbon atom at least and is replaced by other heteroatoms, and heteroatoms comprises nitrogen, oxygen, sulphur.This nitrogen and sulfur heteroatom also can be chosen wantonly oxidized, and nitrogen heteroatom also can be chosen wantonly by quaternized.This heterocyclic group can connect at any heteroatoms or carbon atom place.Preferred heterocyclic aryl includes but not limited to pyridine, pyrazine, pyrimidine, pyridazine, triazine, furans, thiophene, imidazoles, triazole, tetrazolium, thiazole, isothiazole, pyrroles, pyrazoles 、 oxazole 、 isoxazole, cumarone, benzothiazole, thionaphthene, indoles, quinoline, isoquinoline 99.9, purine, carbazole, benzoglyoxaline, pyrrolopyridine, pyrrolopyrimidine etc.
Term " naphthenic base " is meant the carbocyclic ring of non-aromatic, comprises monocycle, condensed ring or volution.Naphthenic base also comprises having the ring that one or more aromatic nucleus condense (a common key is promptly arranged), has one or more aromatic nucleus condensed naphthenic base to be connected with other groups through aromatic nucleus or non-aromatic ring part.
Term " Heterocyclylalkyl " is meant nonaromatic heterocycles, and wherein one or more become annular atoms is heteroatoms, like oxygen, nitrogen, sulphur atom.Heterocyclylalkyl can comprise monocycle or many ring (if any 2,3,4 fused rings), volution.Preferred Heterocyclylalkyl comprises Soluol XC 100, azetidine, THF, THTP, tetramethyleneimine 、 oxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidines etc.Heterocyclylalkyl also comprises having one or more aromatic nucleus condensed heterocycle, for example 2, and 3-Dihydrobenzofuranes, 1,3-benzo dioxolane, phendioxin, 4-diox, benzenedicarboxamide etc.Having one or more aromatic nucleus condensed heterocycle alkyl can be connected with other group through aromatic nucleus or non-aromatic ring part.
Term " oxo " is meant divalent group=O.
Term " carboxamido-group " is meant group-C (=O) NH-.
Term " cyanic acid " is meant group-CN.
Term " nitro " is meant group-NO
2
Term " sulfydryl " is meant group-SH.
Term " alkylamino " is meant by the substituted amino of alkyl.
Term " dialkylamine " is meant that group is by two substituted amino of identical or different alkyl.
Term " carboxyl " is meant group-COOH.
Term " alcoxyl carbon back " is meant group-C (=O) OR
6, R wherein
6Be meant alkyl.
Term " alkoxyl group " is meant group-OR
7, R wherein
7Be meant alkyl.
Term " acyloxy " is meant group-OC (=O) R
8, R wherein
8Be meant alkyl.
" optional " means that subsequently incident or the situation described can take place or not take place, said description parade one's wealth example that wherein said incident or situation take place and its example of not taking place wherein.
" pharmaceutically acceptable carrier " used herein comprise the whole solvent of any nuclear, dispersion medium, dressing, antibacterium and antifungal medicine, etc. blend absorption delay agent etc.Such medium and medicament are used for pharmaceutically active substances and are well known in the art.Only if it is any conventional media or medicament are incompatible with the Mars composition, expected during its application in therapeutic compsn.Supplementary active ingredients also can be incorporated in the compsn.
Embodiment 1
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
Steps A: 5-bromo-7-trifluoromethyl-2,3-indone synthetic
(134.5g 0.5mol) is dissolved in the 750ml thionyl chloride 4-bromo-2-trifluoromethylbenzoic acid, stirs reflux 4h.Behind the pressure reducing and steaming solvent thionyl chloride, product is steamed 133 ℃/10mmHg, obtain 4-bromo-2-trifluoromethyl benzoyl chloride 133.9g, yield 90% with the rectification under vacuum device.MS(M+1)=285.9。
(28.8g 0.1mol) is dissolved in the 100ml ethylene dichloride 4-bromo-2-trifluoromethyl benzoyl chloride, and (13.3g is in ethylene dichloride suspension-s 0.1mol) at room temperature to be added dropwise to aluminum chloride.Then suspension-s is placed on the dark place, and, feeds ethylene gas 3h with the ice bath cooling, complete up to acyl chloride reaction.Reaction solution is stirred overnight at room temperature.Reaction solution is cooled to 0 ℃, uses hydrochloric acid soln (30ml, 0.12mol) cancellation of 4M then.Separatory, water extracts with ethylene dichloride.Merge organic phase, the difference water, saturated sodium bicarbonate solution, the saturated common salt water washing, drying is filtered, and concentrates, and obtains thick product, and the step reacts under directly being used for.
(159.6g, 1.2mol), (42.1g 0.72mol) after the mixing, is heated to 130 ℃ of pulps to sodium-chlor to aluminum chloride.The 4-bromo-2-trifluoromethyl chloropropyl ketone that single step reaction obtains in the adding stirs and is warmed up to 180 ℃, reaction 6h.Reaction solution is with ice and concentrated hydrochloric acid (120ml, 1.2mol) cancellation.With the ethylene dichloride extraction, organic phase is water respectively then, saturated sodium bicarbonate, and the saturated common salt water washing, drying is filtered concentrating under reduced pressure.Column chromatography is separated, and eluent is petrol ether/ethyl acetate=4, obtains solid 5-bromo-7-trifluoromethyl-2,3-indone 15.3g, yield 55%.MS(M+1)=278.0。
Step B:1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2,3-indane-5-formic acid synthetic
5-bromo-7-trifluoromethyl-2, (27.9g 0.1mol) is dissolved among the 250mlDMF 3-indone, and (13.5g 0.15mol), stirs, and is heated to backflow, reaction 24h to add cuprous cyanide.After reaction finished, cool to room temperature was under agitation poured reaction solution in the 1000ml water, with 500ml ethyl acetate extraction 3 times, collected organic phase, wash 2 times, and anhydrous magnesium sulfate drying, filtration, concentrated.Column chromatography is separated, and eluent is petrol ether/ethyl acetate=4, obtains solid 5-cyanic acid-7-trifluoromethyl-2,3-indone 10.1g, yield 45%.MS(M+1)=225.0。
5-cyanic acid-7-trifluoromethyl-2, the 3-indone (22.5g 0.1mol) is dissolved in the 100ml methyl alcohol, after the dissolving, slowly add in batches Peng Qinghuana (4.6g, 0.12mol).Stirring at room 4h filters, and concentrates.Residue is dissolved in ETHYLE ACETATE, adds saturated solution of sodium bicarbonate washing 2 times, saturated salt washing 2 times, anhydrous magnesium sulfate drying filters, and concentrates and obtains 5-cyanic acid-7-Trifluoromethyl-1-hydroxyl-2,3-indane 21.1g, yield 93%.MS(M+1)=227.0。
5-cyanic acid-7-Trifluoromethyl-1-hydroxyl-2, (22.1g 93mmol), is dissolved in the 50ml methylene dichloride 3-indane, under the ice bath cooling, drips sulphinyl chlorine 10.2ml, drips off in the 20min.Remove ice bath, with the reaction solution 5h that refluxes, cooling concentrates.The reaction solution residue is dissolved in ETHYLE ACETATE, adds saturated solution of sodium bicarbonate washing 2 times, saturated salt washing 2 times, anhydrous magnesium sulfate drying filters, and obtains 5-cyanic acid-7-Trifluoromethyl-1-chloro-2, the 3-indane after concentrating.
With the above-mentioned 5-cyanic acid-7-Trifluoromethyl-1-chloro-2 that obtains, the 3-indane is dissolved in the 100ml chloroform, and adding 1-N-METHYL PIPERAZINE (9.3g, 93mmol), salt of wormwood 20g, stirring heating is spent the night 60 ℃ of reactions.With reacting liquid filtering, wash after reaction finishes, drying concentrates.Using silica gel column chromatogram separating purification, is eluent with the methylene chloride, obtains 5-cyanic acid-7-Trifluoromethyl-1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes 16.7g, yield 58%.MS(M+1)=309.1。
(15.5g 0.05mol) joins in the 0.1M sodium hydroxide solution (100ml) 5-cyanic acid-7-Trifluoromethyl-1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes, is heated to 100 ℃, stirred overnight.After the cooling, the hydrochloric acid soln of adding 0.1M is adjusted to 8.0 with the pH value of reaction solution, and the adularescent solid is separated out, and filters.The solid that filters is used recrystallizing methanol, obtain 1-(4-N-METHYL PIPERAZINE-1-yl)-7-trifluoromethyl-2,3 indane-5-formic acid 10g, yield 61%.MS(M+1)=328.2。
Step C:1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
In ice bath, with 1-(4-N-METHYL PIPERAZINE-1-yl)-(32.8g 0.1mol) is dissolved among the 200mlDMF 7-trifluoromethyl-2,3 indane-5-formic acid; Adding 1-hydroxy benzo triazole (HOBt, 16.1g, 0.12mol); (24.6g 0.12mol), stirs 1h to add DCC subsequently; (33.2g, DMF 0.12mol) (200ml) solution stir 24h down at 25 ℃ then to drip N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine.Remove by filter not tolerantly, filtrating concentrates under vacuum.Residue is used the 600ml ether dissolution, filters, use respectively then 10%HCl solution (2 * 100mL), saturated NaHCO
3Solution (2 * 100mL) with the saturated common salt aqueous solution (2 * 50mL) washing, anhydrous magnesium sulfate drying.Concentrating the back and use column chromatography separating purification, is eluent with sherwood oil/EtOAc (1:1), obtains title product 35.8g, yield 61%.MS(M+1)=587.3。
Embodiment 2
1-(4-dimethylamino-piperidine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, N methyl piperazine.
Embodiment 3
1-(4-hydroxyethyl piperazine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, N-hydroxyethyl piperazine.
Embodiment 4
1-(4-acetylpiperazine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, N-acetylpiperazine.
Embodiment 5
1-(4-sec.-propyl piperazinyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, N-sec.-propyl piperazine.
Embodiment 6
1-(the high piperazinyl of 4-methyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, the high piperazine of N-methyl.
Embodiment 7
1-pyrrolidyl-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, tetramethyleneimine.
Embodiment 8
1-(3-dimethylamino pyrrolidyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, 3-dimethylamino tetramethyleneimine.
Embodiment 9
1-morpholinyl-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, morpholine.
Embodiment 10
1-(4-N-METHYL PIPERAZINE base-3-ketone)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, 1-N-METHYL PIPERAZINE-2-ketone.
Embodiment 11
1-(3,5-lupetazin base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, 2,6-lupetazin.
Embodiment 12
1-diethylamino ethylamine-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process of the building-up process of title compound and embodiment 1 is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, N, N-diethyl ethylenediamine.
Embodiment 13
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-(4-pyrimidine-5-yl pyrimidines-2-yl) amino) phenyl-2,3-indane-5-methane amide synthetic
Title compound is with 1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2, and 3-indane-5-formic acid and 4-methyl-3-((4-pyrimidine-5-yl) pyrimidine-2-base) aniline is synthetic through the method that is similar to embodiment 1 step C.1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2 wherein; 3-indane-5-formic acid prepares with the method among the embodiment 1; 4-methyl-3-(4-(pyrimidine-5-yl) pyrimidine-2-base) aniline is through 5-acetyl pyrimidine and N, after the reaction of dinethylformamide dimethyl acetal, again with the Guanidinium hydrochloride cyclization; The butt joint of 3-bromo-4-monomethylaniline obtains, and concrete grammar is following:
Synthesizing of steps A: 3-(3-dimethylamino allyl acyl group) pyrimidine
5-acetyl pyrimidine (61g, 0.5mol) and N, the dinethylformamide dimethyl acetal (89.4,0.75mol) in 100 ℃ of reaction 24h; Add methylene dichloride-sherwood oil mixed solvent behind the concentrating under reduced pressure, refrigerator is placed crystallization, filters washing; Drying gets yellow crystals 44.3g, yield 50%.MS(M+1)=177.1。
Synthesizing of step B:4-(pyrimidine-5-yl) pyrimidine-2-ammonia
(17.7g 0.1mol) is dissolved in the 200ml ethanol 3-(3-dimethylamino allyl acyl group) pyrimidine, adds Guanidinium hydrochloride (7.1g; 0.12mol) and sodium hydroxide (5.5g, 0.13mol), reflux 24h; Stopped reaction, crystallisation by cooling filters and obtains thick product; Use recrystallizing methanol again, obtain solid 13.8g, yield 80%.MS(M+1)=173.1。
Synthesizing of step C:4-methyl-3-(4-(pyrimidine-5-yl) pyrimidine-2-is amino) aniline
(17.3g, 0.1mol) (21.6g 0.1mol) is dissolved among the 200ml DMF 4-(pyrimidine-5-yl) pyrimidine-2-ammonia, and (1.9g, 0.01mol), salt of wormwood 40g is stirred and heated to 120 ℃, reaction 12h to add cuprous iodide with 2-bromo-4-nitrotoluene.Stopped reaction filters concentrating under reduced pressure.Column chromatography is separated, and eluent methylene chloride=9 obtain product 2-methyl-N-(4-(pyrimidine-5-yl) pyrimidine-2-base) 5-N-methyl-p-nitroaniline 15g, yield 51%.MS(M+1)=308.1。
2-methyl-N-(4-(pyrimidine-5-yl) pyrimidine-2-base) 5-N-methyl-p-nitroaniline (30.8g 0.1mol) is dissolved among the methyl alcohol 100ml, adds gac 1g, ferric chloride (FeCl36H2O) 0.5g, 65% Hydrazine Hydrate 80 (100g, 2mol), back flow reaction 8h.Pressurization boils off solvent, and precipitate is used ethyl alcohol recrystallization, obtains product 22.5g, yield 81%.MS(M+1)=278.1。
Embodiment 14
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-quinazolyl-5-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide synthetic
Title compound is with 1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2, and 3-indane-5-formic acid and 4-methyl-3-((4-pyrimidine-5-yl) pyrimidine-2-base) aniline is synthetic through the method that is similar to embodiment 1 step C.1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2 wherein, 3-indane-5-formic acid is with the preparation of the method among the embodiment 1, and 4-methyl-3-(4-(quinazoline-5-yl) pyrimidine-2-base) aniline synthesizes according to the method described in the embodiment 13.
Embodiment 15
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-thiophene-2-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide synthetic
The synthetic embodiment 13 that is similar to of title compound, its main raw material is the 2-acetyl thiophene, N, dinethylformamide dimethyl acetal, Guanidinium hydrochloride, 2-bromo-4-nitrotoluene and 1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2,3-indane-5-formic acid.
Embodiment 16
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-thiazol-2-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The synthetic embodiment 13 that is similar to of title compound, its main raw material is a 2-acetyl thiazole, N, dinethylformamide dimethyl acetal, Guanidinium hydrochloride, 2-bromo-4-nitrotoluene and 1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2,3-indane-5-formic acid.
Embodiment 17
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyrazine-2-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide synthetic
The synthetic embodiment 13 that is similar to of title compound, its main raw material is the 2-acetylpyrazine, N, dinethylformamide dimethyl acetal, Guanidinium hydrochloride, 2-bromo-4-nitrotoluene and 1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2,3-indane-5-formic acid.
Embodiment 18
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4,5-dimethyl--3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The synthetic embodiment 13 that is similar to of title compound, its main raw material is a 3-acetylpyridine, N, dinethylformamide dimethyl acetal, Guanidinium hydrochloride, 2-bromo-4-nitrotoluene and 1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-2,3-indane-5-formic acid.
Embodiment 19
1-(4-methylimidazole base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The synthetic operating process with embodiment 1 of title compound is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 4-bromo-2-trifluoromethylbenzoic acid, gas ethene, 4-methylimidazole.
Embodiment 20
1-(2-pyridyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The operating process according to embodiment 1 of title compound is synthetic, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 1-(2-pyridyl)-7-trifluoromethyl-5-cyanic acid-2,3-indane.1-(2-pyridyl)-7-trifluoromethyl-5-cyanic acid-2 wherein, the compound method of 3-indane is following:
With 5-cyanic acid-7-Trifluoromethyl-1-chlorine indenes (24.5g 0.1mol) is dissolved among the 150ml exsiccant THF, feeds the Ar gas shiled, is cooled to-50 ℃, stirs, drip n-Butyl Lithium (16%, 88g, 0.22mol).After dripping off, low temperature stirs 2h, and (15.8g, THF 0.1mol) (50ml) solution behind the low-temp reaction 1h, rises to room temperature, stirred overnight to drip the 2-bromopyridine then.Add 95% ethanol 50ml then, stir 30min.Filter, concentrate, column chromatography is separated, and eluent is 5% methanol, obtains product 1-(2-pyridyl)-5-cyanic acid-7-trifluoromethyl-2,3 dihydros-1H-indenes 14.1g, yield 49%.
Embodiment 21
1-(2,4,6-trimethylammonium pyrimidine-5-yl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide synthetic
The synthetic operating process with embodiment 20 of title compound is similar, and its main raw material is N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-aminopyrimidine, 5-cyanic acid-7-Trifluoromethyl-1-chlorine indenes, 2,4,6-trimethylammonium-5-bromo pyrimi piperidine.
Embodiment 22 pharmaceutical prepn prescriptions
The invention provides several kinds and be used to treat or the prescription of the pharmaceutical composition of the disease that prevention is relevant with protein kinase, its pharmaceutical composition has tablet, capsule, injection, aerosol etc.Below with " active compound " expression compound shown in the present.
The test of embodiment 23 external activities
Compound of the present invention is tested the adjusting of protein kinase activity and the restraining effect of cell proliferation, and the protein kinase of selecting for use is human wild type ABL kinases and T315I mutant ABL kinases.Also the T315I clone of BCR-ABL sudden change is tested in addition.
A. the test of kinase activity
Testing compound adds 1mlDMSO, is made into the solution of 10mM, adds in the dry hole of 384 hole polystyrene culture plates.The human wild type ABL kinases and the T315I mutant ABL kinases of purifying are dissolved among the full LANCE kinases buffer (LKB), and LKB comprises 20mM NaHEPES (pH is 7.4), 0.1mg/mL BSA, 1mM ATP, 10mM MgCl
2, and 0.41mM DTT, spending the night under 4 ° of C on 96 orifice plates of using 1%BSA (being dissolved in PBS) to encapsulate in advance.Reacted at room temperature incubation 90 minutes.Add the 15nM suppressor factor, the phosphotyrosine antibody of 6nM europium mark (phosphorylation site is on the tyrosine the 66th), and the streptavidin of 60nM allophycocyanin mark, termination reaction.The at room temperature dark incubation of brassboard 20 minutes, use Wallac Victor2V reader read 615 with the fluorescent value at 665nm place.In the hole, insert 3 times of serial dilutions of suppressor factor in the data MV, read 665nm place fluorescent value again, calculate IC
50Value.Its numerical value is as shown in table 1.Carried out controlled trial with imatinib simultaneously.
The test of B.BaF3 cytoactive
The Ba/F3 cell is grown in the medium of the foetal calf serum that contains 90% IMDM and 10%.Matter is given an account of in cell counting and using, and to adjust to cell density be 4 * 10
4/ ml.Ba/F3 clone is pressed every hole 4 * 10
3Individual cell distribution is in 96 orifice plates.Test compounds is dissolved among the DMSO, carries out serial dilution, concentration range is 0-625nM.The DMSO solution of 0.5 μ l is transferred in the Tissue Culture Plate from each hole of test compounds plate.Tissue Culture Plate is hatched 72h in 37 ℃ in thermostatic constant wet chamber.CellTiter-Glo reagent with 100 μ l is added in each hole of cell plate then, and in shaking table, mixes 2 minutes, impels lysis.Write down luminous intensity with Flexstation3.Calculate IC
50Value, its numerical value is as shown in table 1.Carried out controlled trial with imatinib simultaneously.
Table 1 active compound suppresses situation to protein kinase and cell activity
Can find out that from result shown in the table 1 compound shown in the embodiment of the invention all has the kinase activity of inhibition and cytoactive, especially with 1,2,5,6,8,20 is excellent.
Claims (12)
1. one kind contains compound or its pharmacy acceptable salt or its prodrug that following logical formula I is represented:
Wherein
L
1Be NR
dC (O) or C (O) NR
d
Ring A represents one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl, and 1-3 heteroatoms is independently selected from O in the ring, N and S;
Ring B, C represent one 5 or 6 yuan heterocycle or Heterocyclylalkyl, and 1-3 heteroatoms is independently selected from O in the ring, N and S;
R
1Be independently selected from hydrogen, halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR
aR
b, NR
dC (O) R
c, C (O) NR
aR
b, S (O)
2NR
aR
b, NR
dS (O)
2R
c, NR
d(CH
2)
nR
c, (CH
2)
nNR
aR
b, NHC (O) NH R
c, (CH
2)
nNHC (O) R
c, NHC (NH) R
c
R
2, R
3, R
4, R
5Be independently selected from hydrogen respectively, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, alkylamino, dialkylamine, nitro, cyanic acid, carboxyl, carbalkoxy, acyloxy;
R
a, R
bBe independently selected from hydrogen respectively, alkyl, naphthenic base, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R
cBe independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
R
dBe independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; Heterocyclylalkyl can be replaced by following any one or more groups: halogen, amino, alkylamino, dialkylamine, acid amides, aryl; Heterocyclic radical, nitro, cyanic acid, carboxyl, carbalkoxy, hydroxyl; Alkoxyl group, acyloxy ,=O ,=S ,=NH;
X is 0,1,2,3;
Y is 0,1,2;
Z is 0,1,2,3,4;
M is 0,1,2,3,4;
N is 1,2,3,4,5,6;
W is 1,2,3,4,5.
2. compound according to claim 1 has following general formula II:
Wherein
Ring A represents one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl, and 1-3 heteroatoms is independently selected from O in the ring, N and S;
Ring B, C represent one 5 or 6 yuan heterocycle or Heterocyclylalkyl, and 1-3 heteroatoms is independently selected from O in the ring, N and S;
R
1Be independently selected from hydrogen, halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR
aR
b, NR
dC (O) R
c, C (O) NR
aR
b, S (O)
2NR
aR
b, NR
dS (O)
2R
c, NR
d(CH
2)
nR
c, (CH
2)
nNR
aR
b, NHC (O) NH R
c, (CH
2)
nNHC (O) R
c, NHC (NH) R
c
R
2, R
3, R
4, R
5Be independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, alkylamino, dialkylamine, nitro, cyanic acid, carboxyl, carbalkoxy, acyloxy;
R
a, R
bBe independently selected from hydrogen respectively, alkyl, naphthenic base, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R
cBe independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
R
dBe independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; Heterocyclylalkyl can be replaced by following any one or more groups: halogen, amino, alkylamino, dialkylamine, acid amides, aryl; Heterocyclic radical, nitro, cyanic acid, carboxyl, carbalkoxy, hydroxyl; Alkoxyl group, acyloxy ,=O ,=S ,=NH;
X is 0,1,2,3;
Y is 0,1,2;
Z is 0,1,2,3,4;
M is 0,1,2,3,4;
N is 1,2,3,4,5,6;
W is 1,2,3,4,5.
3. compound according to claim 2, wherein
Ring A is a saturated cyclic amino, is selected from piperidyl, piperazinyl, pyrrolidyl, azelidinyl, morpholinyl;
Ring B is monocyclic heteroaryl, and it is preferably from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl ， oxazolyl ， isoxazolyl, triazolyl, pyrazolyl;
The heteroaryl or the Heterocyclylalkyl of ring C monocycle or condensed ring, it is preferably from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl; Thiazolyl, isothiazolyl, imidazolyl ， oxazolyl ， isoxazolyl, triazolyl; Pyrazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, Pyrazolopyridine base, Imidazopyridazine base, pyrazolopyrimidine base; Quinolyl, isoquinolyl, quinazolyl, piperazinyl, piperidyl, morpholinyl;
R
1Be independently selected from hydrogen, halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR
aR
b, NR
dC (O) R
c, C (O) NR
aR
b, S (O)
2NR
aR
b, NR
dS (O)
2R
c, NR
d(CH
2)
nR
c, (CH
2)
nNR
aR
b, NHC (O) NH R
c, (CH
2)
nNHC (O) R
c, NHC (NH) R
c
R
2, R
3, R
4, R
5Be independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, alkylamino, dialkylamine, nitro, cyanic acid, carboxyl, carbalkoxy, acyloxy;
R
a, R
bBe independently selected from hydrogen respectively, alkyl, naphthenic base, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R
cBe independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
R
dBe independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; Heterocyclylalkyl can be replaced by following any one or more groups: halogen, amino, alkylamino, dialkylamine, acid amides, aryl; Heterocyclic radical, nitro, cyanic acid, carboxyl, carbalkoxy, hydroxyl; Alkoxyl group, acyloxy ,=O ,=S ,=NH;
X is 0,1,2,3;
Y is 0,1,2;
Z is 0,1,2,3,4;
M is 0,1,2,3,4;
N is 1,2,3,4,5,6;
W is 1,2,3,4,5.
4. according to each described compound of claim 1-3 or its pharmacy acceptable salt or its prodrug, wherein said compound preferably from:
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-dimethylamino piperidine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-hydroxyethyl piperazine base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(the high piperazinyl of 4-methyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(3-dimethylamino pyrrolidyl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-thiophene-2-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-N-METHYL PIPERAZINE base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyrazine-2-yl pyrimidines-2-yl) amino) phenyl)-2,3-indane-5-methane amide;
1-(4-methylimidazole base)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide;
1-(2,4,6-trimethylammonium pyrimidine-5-yl)-7-trifluoromethyl-N-(4-methyl-3-((4-pyridin-3-yl pyrimidine-2-base) amino) phenyl)-2,3-indane-5-methane amide.
According to the described compound of claim 1-4 at pharmacy acceptable salt, or contain at least one alkaline salt forming group, acid salifiable with it can be mineral acid or organic acid pharmaceutically commonly used, comprises mineral acid: hydrochloric acid, sulfuric acid, phosphoric acid; Organic carboxyl acid: acetate, propionic acid, trifluoroacetic acid, oxyacetic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, Hydrocerol A, oxalic acid, various natural or synthetic amino acid, phenylformic acid, Whitfield's ointment, 4-aminosallcylic acid, racemic melic acid, styracin, nicotinic acid, Yi Yansuan; Organic sulfonic acid: methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2-naphthene sulfonic acid.When having a plurality of basic group, can generate the polyacid additive salt.
6. pharmaceutical composition, its comprise effective therapeutic dose at least a claim 1-4 each can prevent or treat compound and the pharmaceutically acceptable carrier or the thinner of protein kinase related disorder state.
7. method of regulating protein kinase activity is comprising each described compound of said protein kinase and claim 1-4 is contacted.
8. method according to claim 7, wherein said protein kinase is selected from wherein said protein kinase and is selected from Abl, Bcr-Abl.
9. be used for treating the application of the medicine of disease or imbalance according to each described compound of claim 1-4 in preparation, wherein said disease or imbalance are relevant with protein kinase activity or unusual relevant with cell proliferation.
10. application according to claim 9, wherein said disease relevant with protein kinase and imbalance are selected from cancer, inflammation, autoimmune disorder, metabolic disease, central nervous system disease and cardiovascular disorder.
11. application according to claim 10, wherein said disease are and the unusual relevant various cancers of cell proliferation that it is selected from white blood disease, lymphoma, prostate cancer, colorectal carcinoma; Mammary cancer, liver cancer, bronchogenic carcinoma, cholangiocarcinoma, cancer of the stomach, ovarian cancer; Cervical cancer, lung cancer, small cell lung cancer, kidney, bladder cancer, carcinoma of the pancreas; Gastrointestinal stromal tumor, spongioblastoma, brain tumor, melanoma, gonioma, neuroblastoma liposarcoma; Chondrosarcoma, osteogenic sarcoma, angiosarcoma, endotheliosarcoma, myosarcoma, one or more in the chordoma.
12. application according to claim 9, wherein said autoimmune disorder is selected from the type mellitus, autoimmunity thyroid disorders and alzheimer's disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103115258A CN102807558A (en) | 2012-08-29 | 2012-08-29 | Fluorine-containing dihydroindene amide compound used as protein kinase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103115258A CN102807558A (en) | 2012-08-29 | 2012-08-29 | Fluorine-containing dihydroindene amide compound used as protein kinase inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102807558A true CN102807558A (en) | 2012-12-05 |
Family
ID=47231444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103115258A Pending CN102807558A (en) | 2012-08-29 | 2012-08-29 | Fluorine-containing dihydroindene amide compound used as protein kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102807558A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254121A (en) * | 2013-04-08 | 2013-08-21 | 洛阳师范学院 | Synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine |
| CN104045632A (en) * | 2014-06-03 | 2014-09-17 | 辽宁大学 | Antitumor drugs benzodihydropyran(thiapyran)amide compounds and pharmaceutically acceptable salts, and preparation method and application thereof |
| CN112552194A (en) * | 2020-12-21 | 2021-03-26 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of drug intermediate for treating idiopathic blood diseases |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060009453A1 (en) * | 2004-05-07 | 2006-01-12 | Geuns-Meyer Stephanie D | Protein kinase modulators and method of use |
| CN1944398A (en) * | 2005-01-11 | 2007-04-11 | 中国医学科学院药物研究所 | New benzoyl amide compounds and its preparing method and medicine use |
| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
| WO2012089106A1 (en) * | 2010-12-27 | 2012-07-05 | Sun Shuping | Aromatic alkyne derivative as protein kinase inhibitor and medical use thereof |
-
2012
- 2012-08-29 CN CN2012103115258A patent/CN102807558A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060009453A1 (en) * | 2004-05-07 | 2006-01-12 | Geuns-Meyer Stephanie D | Protein kinase modulators and method of use |
| CN1944398A (en) * | 2005-01-11 | 2007-04-11 | 中国医学科学院药物研究所 | New benzoyl amide compounds and its preparing method and medicine use |
| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
| WO2012089106A1 (en) * | 2010-12-27 | 2012-07-05 | Sun Shuping | Aromatic alkyne derivative as protein kinase inhibitor and medical use thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254121A (en) * | 2013-04-08 | 2013-08-21 | 洛阳师范学院 | Synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine |
| CN103254121B (en) * | 2013-04-08 | 2015-08-26 | 洛阳师范学院 | A kind of method of synthesis (3R, 4R)-N-PG-4-methyl-3-methylamino piperidines |
| CN104045632A (en) * | 2014-06-03 | 2014-09-17 | 辽宁大学 | Antitumor drugs benzodihydropyran(thiapyran)amide compounds and pharmaceutically acceptable salts, and preparation method and application thereof |
| CN112552194A (en) * | 2020-12-21 | 2021-03-26 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of drug intermediate for treating idiopathic blood diseases |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5707335B2 (en) | Process for producing dihydroindeneamide compounds, pharmaceutical compositions containing these compounds, and use as protein kinase inhibitors | |
| CN105153028B (en) | Compound as c-Met kinase inhibitor | |
| CN104327084B (en) | The small molecule myristate inhibitors and its application method of BCR ABL | |
| CN103467454B (en) | As the spiro substituted compounds of AI | |
| CN102775411A (en) | Aryl ethynyl benzamide compound used as protein kinase inhibitor | |
| CN103965120B (en) | Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application | |
| CN110291086A (en) | Aminothiazole compounds as C-KIT inhibitor | |
| CA2958503A1 (en) | Indazole compounds as fgfr kinase inhibitor, preparation and use thereof | |
| BRPI0712816B1 (en) | pyrrolpyrimidine compounds and their use | |
| CN103987700A (en) | 4-quinazoline amine derivative and application thereof | |
| AU2017287553A1 (en) | Imidazopyrazinamine phenyl derivative and use thereof | |
| CN103354809A (en) | Arylurea compound, intermediate and use thereof | |
| CN103596568A (en) | Methods and compositions for treating Parkinson disease | |
| WO2022135432A1 (en) | Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof | |
| CN102958921A (en) | Urea compounds as well as preparation methods, intermediates and uses thereof | |
| CN103833759A (en) | Pteridinone derivatives as BLK and FLT3 inhibitors and applications thereof | |
| CN102807558A (en) | Fluorine-containing dihydroindene amide compound used as protein kinase inhibitor | |
| CN106699729A (en) | Benzamide compounds containing acetenyl group | |
| CN103130775B (en) | As the dihydroindole ketone derivate of tyrosine kinase inhibitor | |
| CN103130791B (en) | A kind of new benzamides compounds | |
| CN108218874A (en) | A kind of phosphodiesterase inhibitors and application thereof | |
| CN110467620A (en) | Novel S type or R type tetrahydronaphthalene amides compound and its pharmaceutically acceptable salt and preparation method and application | |
| CN102617578B (en) | Imidazole derivative and medicine application thereof | |
| CN107235906B (en) | Pyrazole amide derivatives and application thereof | |
| TWI781497B (en) | Cyano-substituted pyridine and cyano-substituted pyrimidine compounds, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20121205 |