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CN102775411A - Aryl ethynyl benzamide compound used as protein kinase inhibitor - Google Patents

Aryl ethynyl benzamide compound used as protein kinase inhibitor Download PDF

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Publication number
CN102775411A
CN102775411A CN2012102935870A CN201210293587A CN102775411A CN 102775411 A CN102775411 A CN 102775411A CN 2012102935870 A CN2012102935870 A CN 2012102935870A CN 201210293587 A CN201210293587 A CN 201210293587A CN 102775411 A CN102775411 A CN 102775411A
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acid
alkyl
naphthenic base
independently selected
amino
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王建平
王建国
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Zhejiang Dade Pharmaceutical Group Co Ltd
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Zhejiang Dade Pharmaceutical Group Co Ltd
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Abstract

The invention discloses a compound which is shown in a formula (I) and is used for treating or preventing diseases related to protein kinase, and a pharmaceutically acceptable salt or configurational isomer thereof. In the formula (I), the linking group L1, the ring A and the substituting groups Ra, Rb, Rc and Rd are as defined in the specification. The invention also discloses a preparation method of the compound shown in the formula (I), a medical composition containing the compound shown in the formula (I), and application of the compounds in the preparation of medicaments for preventing diseases related to protein kinase.

Description

Fragrant acetylenylbenzene Carbox amide as kinases inhibitor
Technical field
The present invention relates to medical technical field; Be specifically related to one type of acetylenylbenzene Carbox amide; 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 extended familys of being responsible for involved enzyme on the interior signal transduction structure of process of control various kinds of cell.Nearly all kinases all contains similar 250-300 amino acid whose catalytic domain.Kinases can be referred to a plurality of families according to the substrate (for example protein-tyrosine, protein-Serine, protein-Threonine, lipid etc.) of its phosphorylation, like abl, and brc-abl, Blk, Brk, c-kit, c-met; C-src, CDK, CSK, EGFR, ErbB, FGFR, ErK; Pak, Fgr, fes, Frk, Fyn, Hck, IGF-1R; INS-R, jak, KDR, Lck, Lyn, MEK etc.
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 (Al zhe imer ' sdisease) etc.Under many circumstances, can be through utilizing kinases inhibitor to treat this type disease in external and the body.
The Bcr-Abl gene is a Philadelphia chromosome, is produced by the karyomit(e) mutation, and it expresses the protein (p210Bcr-Abl) of 210KD.The proteinic Abl of Bcr-Abl partly contains the Tyrosylprotein kinase of Abl, and it receives tight adjusting in the c-Abl of prototype, but in the Bcr-Abl fused protein, is activated continuously, thereby causes the out of control of cell growth.Bcr-Abl is present among the patient of 95% chronic myelogenous leukemia, and among the patient of 10-25% acute lymphoblastic leukemia.
C-kit is a kind of growth factor receptors with tyrosine kinase activity, is that proto-oncogene c-kit produces.Hemopoietic, melanochrome are generated for c-kit and part STEMCELLFACTOR (SCF) thereof and Fertility is vital.SCF works to promote cells survival, propagation, differentiation, adhesion and function activation on the multiple level of hemopoietic growth level preface.Its particularly important in mastocyte and erythron, and on multiple potentiality stem cell and the inferior collection of progenitor cell, megalokaryocyte and lymph progenitor cell, work.The autocrine of the spontaneous mutation of c-kit and SCF/c-kit approach/paracrine activation mechanism is relevant with various malignant tumours.Through strengthening tumor growth and reducing apoptosis, c-kit activates and helps to shift.In addition, c-kit often suddenlys change and in GISTs, activates, and ligand-mediated.C-kit activates and is present in the middle of some lung cancer.The c-kit acceptor is also expressed in 64% primary is just controlled the protoblast of 10% among the AMLs of acute myeloid leukemia and 95% at least.Increment and anti--apoptosis effect among the c-kit mediation AML.C-kit expresses and in various human malignant lesions, is proved, and comprises mastocytosis, mast cell leukemia, gastrointestinal stromal tumor, spermocytoma, dysgerminoma, acute myelogenous leukemia, ovarian cancer, juvenile form T cell acute lymphoblastic leukemia (ALL), lymphatic cancer, mammary cancer and prostate cancer etc.
Platelet derived growth factor receptor (PDGFR) is to stride the film tyrosine kinase receptor.Its part is by two A chain formation, or two B chain formation.Or the special-shaped dipolymer of an A chain and a B chain forms.In a single day PDGF combines with part, platelet derived growth factor receptor forms dimerization, and its Tyrosylprotein kinase is activated, and the district sends signal downstream.The Thr6 PDGF BB signal is relevant with a series of diseases.The autocrine of growth factor signal path activates relevant with some cerebral glioma, myeloproliferative disease, tumour, multiple myeloma and sarcoma.The paracrine growth factor signal is common in epithelial cancer, and its causes the suction of matrix there, and possibly participate between epithelial cell matter transition, thereby influences growth of tumor, vasculogenesis, invasion and attack and transfer.The structural disease that Thr6 PDGF BB drives vascular disease becomes reaction; Like the disease of atherosclerosis, stricture of artery, pulmonary hypertension, retinal diseases and hepatic fibrosis, comprise interstitial pulmonary fibrosis, liver cirrhosis, scleroderma, glomerular sclerosis and myocardial fibrosis.
At present, existing multiple protein SU11752 listing is like imatinib, Sutent, lapatinibditosylate, ZD1939 etc.A kind of special tyrosine kinase inhibitors that imatinib is; Also there is the inhibition of equal extent in it to the c-kit part tyrosine-kinase enzyme activity of thrombocyte derivation growth factor beta (PDGF2 β) receptor tyrosine kinase and STEMCELLFACTOR (SCF) except suppressing BCR-ABL tyrosine-kinase enzyme activity.Yet; Clinical study subsequently shows; 15 kinds of sudden changes such as Y253H, E255V, E255K, F359V, T315I, G250E, F317L, E355G, H396P, M351T, M253H, L248V, Q252H, Y253H and Y253C have taken place to comprise in the BCR-ABL gene, and the sudden change of BCR-ABL gene causes imatinib resistance to occur.
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 ethynyl benzamide 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
Figure BDA00002026031200031
Wherein
L 1Be NR 1C (O) or C (O) NR 1
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;
R aBe independently selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
Formula I compound of the present invention one of more preferably is that its A ring is piperazine ring, has the compound of general formula II a:
Figure BDA00002026031200041
Wherein
L 1Be NR 1C (O) or C (O) NR 1
R aBe independently selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R eBe independently selected from hydrogen, alkyl, naphthenic base, thiazolinyl, alkynyl, amino, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
Formula I compound of the present invention, it is that its A ring is imidazole ring that one of choosing is more arranged, and has the compound of general formula II b:
Figure BDA00002026031200051
Wherein
L 1Be NR 1C (O) or C (O) NR 1
R aBe independently selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
Formula I compound of the present invention preferably from:
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-7-trifluoromethyl-2,3 dihydros-1H-indenes-5-yl) BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[4-(hydroxyethyl) piperazine-1-yl]-2,3 dihydros-1H-indenes-5-yl } BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[3-dimethylamino methyl tetramethyleneimine-1-yl]-2,3 dihydros-1H-indenes-5-yl } BM;
N-(3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-aminomethyl phenyl)-1-(4-N-METHYL PIPERAZINE base)-2,3-dihydro-1H-indenes-5-methane amide;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-[1-(the high piperazine of 4-methyl-1-yl)-2,3 dihydros-1H-indenes-5-yl] BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-cyanic acid-N-[1-(the high piperazine of 4-methyl-1-yl)-2,3 dihydros-1H-indenes-5-yl] BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(1-imidazolyl)-2,3 dihydros-1H-indenes-5-yl) BM.
Formula I compound according to the invention can generate salt, mineral acid: hydrochloric acid, sulfuric acid, phosphoric acid with following 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 existing a plurality of basic groups to be, can generate the polyacid additive salt.
In addition, the present invention also provides the method for synthetic formula I compound.Compound in present method (I) mainly passes through following a, b, and three segmental links through specific structure of c form.
Figure BDA00002026031200071
A wherein, b connects through the Sonogashira coupled reaction with acetylene, b, c connects with the method for amido linkage through acyl chlorides or active ester.Therefore the compound method of compound (I) mainly can be divided into two kinds: one of which, and fragment a, b connects earlier, is connected with c again; Its two, fragment b, c connect earlier, are connected with a again.Because fragment b, the amido linkage between c can have 2 kinds of orders of connection, and compound method can have following 4 kinds, and concrete grammar is described below:
Scheme one:
Figure BDA00002026031200072
Scheme two:
Scheme three:
Figure BDA00002026031200082
Scheme four:
Figure BDA00002026031200091
In these two kinds of methods, the structure of fragment a does
Figure BDA00002026031200092
The structure of fragment b is:
Figure BDA00002026031200093
The structure of fragment c is:
Figure BDA00002026031200094
Wherein the A ring structure can for:
Figure BDA00002026031200095
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.14of the A.C.S.Symposium Serier and Bioreversible Carriers in Drug Design; Ed.Edward B.Roche, AmericanPharmaceutical Association and Pergamon Press finds in 1987.
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 5, R wherein 5Be meant alkyl.
Term " alkoxyl group " is meant group-OR 6, R wherein 6Be meant alkyl.
Term " acyloxy " is meant group-OC (=O) R 7, R wherein 7Be 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
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200131
Synthesizing of step 1:5-acetylaminohydroxyphenylarsonic acid 1-chloro-2,3 dihydros-1H-indenes
(100g 0.68mol) is dissolved among the 500mlTHF 5-amino-1-indone, and (104g 1.02mol), removes ice bath, at room temperature reacts 2h under ice bath, slowly to drip diacetyl oxide.The hydrochloric acid soln 500ml that reaction finishes back adding 5% stirs 1h, and separatory is got upper organic phase; Add ETHYLE ACETATE 500ml, use 5% hydrochloric acid soln respectively, saturated sodium bicarbonate solution, saturated common salt water washing; Anhydrous magnesium sulfate drying filters then, concentrates, and obtains the off-white color solid.This solid is obtained the 5-acetylaminohydroxyphenylarsonic acid 1-indone 101g of white, yield 78% after with the methanol recrystallization.
5-acetylaminohydroxyphenylarsonic acid 1-indone (18.9g 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-acetylaminohydroxyphenylarsonic acid 1-hydroxyl-2,3-indane 17.8g, yield 93%.
5-acetylaminohydroxyphenylarsonic acid 1-hydroxyl-2, (17.8g 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-acetylaminohydroxyphenylarsonic acid 1-chloro-2, the 3-indane after concentrating.
Synthesizing of step 2:5-acetylaminohydroxyphenylarsonic acid 1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes
With the above-mentioned 5-acetylaminohydroxyphenylarsonic acid 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-acetylaminohydroxyphenylarsonic acid 1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes 14.7g, yield 58%.
Synthesizing of step 3:5-amino-1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes
5-acetylaminohydroxyphenylarsonic acid 1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes 10g is dissolved in the 100ml methyl alcohol, adds 10% sodium hydroxide solution 50ml, reflux 24h.After the cooling, add ETHYLE ACETATE 50ml, separatory goes organic phase, adds the saturated common salt water washing 2 times, and anhydrous magnesium sulfate drying filters, and concentrates.Using silica gel column chromatogram separating purification, is eluent with the methylene chloride, obtains 5-amino-1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes 5g, yield 60%.
Synthesizing of step 4:3-iodo-4-methyl-N-(1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes-5-yl) BM
In ice bath, (26.2g 0.1mol) is dissolved among the 200mlDMF, adds 1-hydroxy benzo triazole (HOBt with 3-iodo-4-tolyl acid; 16.1g, 0.12mol), add DCC (24.6g subsequently; 0.12mol), stir 1h, Dropwise 5-amino-1-(4-N-METHYL PIPERAZINE-1-yl)-2; (27.7g, DMF 0.12mol) (200ml) solution stir 24h down at 25 ℃ to 3 dihydros-1H-indenes then.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 29g, yield 61%.
Synthesizing of step 5:3-ethynyl imidazo [1,2-b] pyridazine
In 250ml exsiccant DMF, add respectively 3-bromine imidazo [1,2-b] pyridazine (19.8g, 0.1mol), the ethynyl trimethyl silane (11.8g, 0.12mol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 5.8g, 0.005mol), (1.9g 0.01mol) and diisopropylethylamine (35ml), stirs and is heated to 50 ℃ to cuprous iodide, under nitrogen protection, spends the night.After being cooled to envrionment temperature, reaction solution concentrated post, and eluent is sherwood oil/EtOAc (1:1), obtained 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine 11g, yield 51%.
(11g 51mmol) is dissolved among the 150mlTHF 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine; (20g 76mmol), stirs 30min at room temperature to add tetrabutyl ammonium fluoride; Concentrate, cross post, eluent is sherwood oil/EtOAc (1:1); Obtain 3-ethynyl imidazo [1,2-b] pyridazine 5.5g, yield 75%.
Synthesizing of step 6:3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes-5-yl) BM
Adding 3-ethynyl imidazo [1,2-b] pyridazine in 10ml DMF (1.43g, 10mmol), 3-iodo-4-methyl-N-(1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes-5-yl) BM (4.75g, 10mmol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 0.58g, 0.5mmol), cuprous iodide (0.19g, 1mol) and diisopropylethylamine (1.5ml), nitrogen protection at room temperature, stirred overnight.Reaction solution is used column chromatography separating purification after concentrating, and eluent is 10% ethanol/methylene, obtains solid 2g, yield 41%.
Synthesizing of step 7:3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes-5-yl) benzamide hydrochloride salt
In the 50ml acetonitrile, add 3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl-4-methyl-N-(1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes-5-yl) BM (4.9g; 0.01mol); Stir, be heated to 50 ℃, add 1M hydrochloric acid soln 22ml.After stirring 10min, be cooled to room temperature, filter, after the acetonitrile washing, 50 ℃ of following vacuum-dryings.
Embodiment 2
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl-4-methyl-N-(1-(1-imidazolyl)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200151
Synthesizing of step 1:5-acetylaminohydroxyphenylarsonic acid 1-bromo-2,3 dihydros-1H-indenes
(100g 0.68mol) is dissolved among the 500mlTHF 5-amino-1-indone, and (104g 1.02mol), removes ice bath, at room temperature reacts 2h under ice bath, slowly to drip diacetyl oxide.The hydrochloric acid soln 500ml that reaction finishes back adding 5% stirs 1h, and separatory is got upper organic phase; Add ETHYLE ACETATE 500ml, use 5% hydrochloric acid soln respectively, saturated sodium bicarbonate solution, saturated common salt water washing; Anhydrous magnesium sulfate drying filters then, concentrates, and obtains the off-white color solid.This solid is obtained the 5-acetylaminohydroxyphenylarsonic acid 1-indone 100g of white, yield 77% after with the methanol recrystallization.
5-acetylaminohydroxyphenylarsonic acid 1-indone (18.9g 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-acetylaminohydroxyphenylarsonic acid 1-hydroxyl-2,3-indane 17.8g, yield 93%.
5-acetylaminohydroxyphenylarsonic acid 1-hydroxyl-2, (17.8g 93mmol), is dissolved in the 50ml methylene dichloride 3-indane, under the ice bath cooling, drips phosphorus pentabromide 60g, 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-acetylaminohydroxyphenylarsonic acid 1-bromo-2, the 3-indane after concentrating.
Synthesizing of step 2:5-acetylaminohydroxyphenylarsonic acid 1-(1-imidazolyl)-2,3 dihydros-1H-indenes
With the above-mentioned 5-acetylaminohydroxyphenylarsonic acid 1-bromo-2 that obtains, the 3-indane is dissolved among the 100mlDMSO, and the adding oxine (2g, 14mmol); CuI (26.6g, 140mmol), imidazoles (7.6g, 112mmol); Salt of wormwood 20g stirs down logical Ar gas 20min, and heating is at 120 ℃ of reaction 20h.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-acetylaminohydroxyphenylarsonic acid 1-(1-imidazolyl)-2,3 dihydros-1H-indenes 11.4g, yield 51%.
Synthesizing of step 3:5-amino-1-(1-imidazolyl)-2,3 dihydros-1H-indenes
5-acetylaminohydroxyphenylarsonic acid 1-(1-imidazolyl)-2,3 dihydros-1H-indenes 10g is dissolved in the 100ml methyl alcohol, adds 10% sodium hydroxide solution 50ml, reflux 24h.After the cooling, add ETHYLE ACETATE 50ml, separatory goes organic phase, adds the saturated common salt water washing 2 times, and anhydrous magnesium sulfate drying filters, and concentrates.Using silica gel column chromatogram separating purification, is eluent with the methylene chloride, obtains 5-amino-1-(1-imidazolyl)-2,3 dihydros-1H-indenes 5g, yield 60%.
Synthesizing of step 4:3-iodo-4-methyl-N-(1-(1-imidazolyl)-2,3 dihydros-1H-indenes-5-yl) BM
In ice bath, (26.2g 0.1mol) is dissolved among the 200mlDMF, adds 1-hydroxy benzo triazole (HOBt with 3-iodo-4-tolyl acid; 16.1g, 0.12mol), add DCC (24.6g subsequently; 0.12mol), stir 1h, Dropwise 5-amino-1-(1-imidazolyl)-2; (23.9g, DMF 0.12mol) (200ml) solution stir 24h down at 25 ℃ to 3 dihydros-1H-indenes then.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 26.6g, yield 60%.
Synthesizing of step 5:3-ethynyl imidazo [1,2-b] pyridazine
In 250ml exsiccant DMF, add respectively 3-bromine imidazo [1,2-b] pyridazine (19.8g, 0.1mol), the ethynyl trimethyl silane (11.8g, 0.12mol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 5.8g, 0.005mol), (1.9g 0.01mol) and diisopropylethylamine (35ml), stirs and is heated to 50 ℃ to cuprous iodide, under nitrogen protection, spends the night.After being cooled to envrionment temperature, reaction solution concentrated post, and eluent is sherwood oil/EtOAc (1:1), obtained 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine 11g, yield 51%.
(11g 51mmol) is dissolved among the 150mlTHF 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine; (20g 76mmol), stirs 30min at room temperature to add tetrabutyl ammonium fluoride; Concentrate, cross post, eluent is sherwood oil/EtOAc (1:1); Obtain 3-ethynyl imidazo [1,2-b] pyridazine 5.5g, yield 75%.
Synthesizing of step 6:3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(1-imidazolyl)-2,3 dihydros-1H-indenes-5-yl) BM
Adding 3-ethynyl imidazo [1,2-b] pyridazine in 10ml DMF (1.43g, 10mmol), 3-iodo-4-methyl-N-(1-(1-imidazolyl)-2,3 dihydros-1H-indenes-5-yl) BM (4.75g, 10mmol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 0.58g, 0.5mmol), cuprous iodide (0.19g, 1mol) and diisopropylethylamine (1.5ml), nitrogen protection at room temperature, stirred overnight.Reaction solution is used column chromatography separating purification after concentrating, and eluent is 10% ethanol/methylene, obtains solid 2.3g, yield 50%.
Embodiment 3
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[2-(dimethylamino methyl) imidazolyl]-2,3 dihydros-1H-indenes-5-yl } BM
Figure BDA00002026031200181
Synthesizing of step 1:5-acetylaminohydroxyphenylarsonic acid 1-bromo-2,3 dihydros-1H-indenes
Concrete operations are identical with embodiment 2.
Synthesizing of step 2:2-dimethylamino methyl imidazoles
(9.6g 0.1mol) is dissolved in the 100ml methyl alcohol 2-imidazole formaldehyde, drips dimethylamine solution (40% the aqueous solution fast; 100ml); After being added dropwise to complete, add carefully in batches Peng Qinghuana (11.3g, 0.3mol); The adding of every batch of Peng Qinghuana all can have foam to produce, and temperature of reaction is controlled at about 50 ℃.Then reaction solution is warming up to 65 ℃ and stirs 4h, be cooled to room temperature, hold over night.Reaction solution concentrates under vacuum, and residual substance extracts with ETHYLE ACETATE (100ml), the saturated common salt water washing, and anhydrous magnesium sulfate drying filters, and underpressure distillation obtains title product 5.6g, yield 44.8%.
Synthesizing of step 3:5-acetylaminohydroxyphenylarsonic acid 1-(2-(dimethylamino methyl)-imidazolyl)-2,3 dihydros-1H-indenes
With the above-mentioned 5-acetylaminohydroxyphenylarsonic acid 1-bromo-2 that obtains, the 3-indane is dissolved among the 100mlDMSO, adds oxine (2g; 14mmol), and CuI (26.6g, 140mmol); 2-(dimethylamino methyl)-imidazoles (14g, 112mmol), salt of wormwood 20g; Stir down logical Ar gas 20min, heating is at 120 ℃ of reaction 20h.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-acetylaminohydroxyphenylarsonic acid 1-(2-(dimethylamino methyl)-imidazolyl)-2,3 dihydros-1H-indenes 11.4g, yield 51%.
Synthesizing of step 4:5-amino-1-(2-(dimethylamino methyl)-imidazolyl)-2,3 dihydros-1H-indenes
5-acetylaminohydroxyphenylarsonic acid 1-(2-(dimethylamino methyl)-imidazolyl)-2,3 dihydros-1H-indenes 10g is dissolved in the 100ml methyl alcohol, adds 10% sodium hydroxide solution 50ml, reflux 24h.After the cooling, add ETHYLE ACETATE 50ml, separatory goes organic phase, adds the saturated common salt water washing 2 times, and anhydrous magnesium sulfate drying filters, and concentrates.Using silica gel column chromatogram separating purification, is eluent with the methylene chloride, obtains 5-amino-1-(2-(dimethylamino methyl)-imidazolyl)-2,3 dihydros-1H-indenes 5g, yield 60%.
Synthesizing of step 5:3-ethynyl imidazo [1,2-b] pyridazine
In 250ml exsiccant DMF, add respectively 3-bromine imidazo [1,2-b] pyridazine (19.8g, 0.1mol), the ethynyl trimethyl silane (11.8g, 0.12mol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 5.8g, 0.005mol), (1.9g 0.01mol) and diisopropylethylamine (35ml), stirs and is heated to 50 ℃ to cuprous iodide, under nitrogen protection, spends the night.After being cooled to envrionment temperature, reaction solution concentrated post, and eluent is sherwood oil/EtOAc (1:1), obtained 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine 11g, yield 51%.
(11g 51mmol) is dissolved among the 150mlTHF 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine; (20g 76mmol), stirs 30min at room temperature to add tetrabutyl ammonium fluoride; Concentrate, cross post, eluent is sherwood oil/EtOAc (1:1); Obtain 3-ethynyl imidazo [1,2-b] pyridazine 5.5g, yield 75%.
Synthesizing of step 6:3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-tolyl acid
Adding 3-ethynyl imidazo [1,2-b] pyridazine in 10ml DMF (1.43g, 10mmol), 3-iodo-4-tolyl acid (2.62g, 10mmol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 0.58g, 0.5mmol), cuprous iodide (0.19g, 1mol) and diisopropylethylamine (1.5ml), nitrogen protection at room temperature, stirred overnight.Reaction solution is used column chromatography separating purification after concentrating, and eluent is 10% ethanol/methylene, obtains solid 1.38g, yield 50%.
Step 7:3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[2-(dimethylamino methyl) imidazolyl]-2,3 dihydros-1H-indenes-5-yl } BM synthetic
In ice bath, (2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-(27.7g 0.1mol) is dissolved among the 200mlDMF 4-tolyl acid with 3-; (HOBt, 16.1g 0.12mol), add DCC (24.6g subsequently to add the 1-hydroxy benzo triazole; 0.12mol), stir 1h, Dropwise 5-amino-1-(2-(dimethylamino methyl)-imidazolyl)-2; (30.7g, DMF 0.12mol) (200ml) solution stir 24h down at 25 ℃ to 3 dihydros-1H-indenes then.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 22.2g, yield 50%.
Embodiment 4
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[3-dimethylamino methyl tetramethyleneimine-1-yl]-2,3 dihydros-1H-indenes-5-yl } BM
Figure BDA00002026031200201
The operating process of the building-up process of target compound and embodiment 1 is similar, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 3-(N, N-dimethylamino) tetramethyleneimine.
Embodiment 5
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[4-(hydroxyethyl) piperazine-1-yl]-2,3 dihydros-1H-indenes-5-yl } BM
Figure BDA00002026031200202
The operating process of the building-up process of target compound and embodiment 1 is similar, and its raw material is mainly 3-bromine imidazo [1,2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 1-hydroxyethyl piperazine.
Embodiment 6
N-(3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-aminomethyl phenyl)-1-(4-N-METHYL PIPERAZINE base)-2,3-dihydro-1H-indenes-5-methane amide
Figure BDA00002026031200211
Step 1:5-cyanic acid-1-chloro-2,3-indane synthetic
5-bromo-1-indone (42.2g, 0.2mol) and cuprous cyanide (35.8g 0.4mol) mixes in 500mlDMF, stirs reflux 24h.Reaction is cooled to room temperature with reaction solution after finishing, and under agitation pours in the 2L water, removes supernatant liquid, and resistates is used the 500ml acetic acid ethyl dissolution; Remove by filter insolubles, filtrating is washed 2 times anhydrous magnesium sulfate drying again with the salt pickling of 1M 2 times with saturated common salt; Filter, concentrating under reduced pressure is crossed post; Eluent is ethyl acetate/petroleum ether (1: 2), obtains title product 14.8g, yield 47%.
5-cyanic acid-1-indone (15.7g 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-1-hydroxyl-2,3-indane 14.3g, yield 90%.
5-cyanic acid-1-hydroxyl-2, (15.9g 0.1mol), 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-1-chloro-2, the 3-indane after concentrating.
Synthesizing of step 2:1-(4-N-METHYL PIPERAZINE-1-yl)-2,3 dihydros-1H-indenes-5-formic acid
With the above-mentioned 5-acetylaminohydroxyphenylarsonic acid 1-chloro-2 that obtains, the 3-indane is dissolved in the 100ml chloroform, and adding 1-N-METHYL PIPERAZINE (10g, 0.1mol), 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-1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes 14g, yield 58%.
(24.1g 0.1mol) joins in the 2M sodium hydroxide solution (100ml) 5-cyanic acid-1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes; Stir down 12h at 100 ℃, be cooled to room temperature after, with ETHYLE ACETATE 50ml extractive reaction liquid 2 times; Regulate pH to neutral with the hydrochloric acid of 1M, filter the solid that produces, vacuum-drying; Obtain title product 17.7, yield 68%.
Step 3:N-(3 iodo-4-aminomethyl phenyl)-1-(4-N-METHYL PIPERAZINE base)-2,3-dihydro-1H-indenes-5-methane amide synthetic
In ice bath, (23.3g 0.1mol) is dissolved among the 200mlDMF, adds 1-hydroxy benzo triazole (HOBt with 3-iodo-4-monomethylaniline; 16.1g, 0.12mol), add DCC (24.6g subsequently; 0.12mol), stir 1h, Dropwise 5-carboxyl-1-(4-N-METHYL PIPERAZINE-1-yl)-2; (31.2g, DMF 0.12mol) (200ml) solution stir 24h down at 25 ℃ to 3 dihydros-1H-indenes then.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 30.9g, yield 65%.
Synthesizing of step 4:3-ethynyl imidazo [1,2-b] pyridazine
In 250ml exsiccant DMF, add respectively 3-bromine imidazo [1,2-b] pyridazine (19.8g, 0.1mol), the ethynyl trimethyl silane (11.8g, 0.12mol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 5.8g, 0.005mol), (1.9g 0.01mol) and diisopropylethylamine (35ml), stirs and is heated to 50 ℃ to cuprous iodide, under nitrogen protection, spends the night.After being cooled to envrionment temperature, reaction solution concentrated post, and eluent is sherwood oil/EtOAc (1:1), obtained 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine 11g, yield 51%.
(11g 51mmol) is dissolved among the 150mlTHF 3-(trimethyl silicane ethyl-acetylene) imidazo [1,2-b] pyridazine; (20g 76mmol), stirs 30min at room temperature to add tetrabutyl ammonium fluoride; Concentrate, cross post, eluent is sherwood oil/EtOAc (1:1); Obtain 3-ethynyl imidazo [1,2-b] pyridazine 5.5g, yield 75%.
Step 5:N-(3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-aminomethyl phenyl)-1-(4-N-METHYL PIPERAZINE base)-2,3-dihydro-1H-indenes-5-methane amide synthetic
Adding 3-ethynyl imidazo [1,2-b] pyridazine in 10ml DMF (1.43g, 10mmol), N-(3-iodo-4-aminomethyl phenyl)-1-(4-N-METHYL PIPERAZINE base)-2,3-dihydro-1H-indenes-5-methane amide (4.75g, 10mmol), four (triphenyl phosphorus base) palladium (Pd (PPh 3) 4, 0.58g, 0.5mmol), cuprous iodide (0.19g, 1mol) and diisopropylethylamine (1.5ml), nitrogen protection at room temperature, stirred overnight.Reaction solution is used column chromatography separating purification after concentrating, and eluent is 10% ethanol/methylene, obtains solid 2g, yield 41%.
Embodiment 7
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-[1-(the high piperazine of 4-methyl-1-yl)-2,3 dihydros-1H-indenes-5-yl] BM
Figure BDA00002026031200231
The operating process of the building-up process of target compound and embodiment 1 is similar, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and the high piperazine of 4-methyl.
Embodiment 8
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-[1-(4-dimethylamino piperidine-1-yl)-2,3 dihydros-1H-indenes-5-yl] BM
Figure BDA00002026031200232
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 4-dimethylamino-piperidine.
Embodiment 9
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-7-trifluoromethyl-2,3 dihydros-1H-indenes-5-yl) BM
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-7-Trifluoromethyl-1-indone and 4-N-METHYL PIPERAZINE.Wherein 5-amino-7-Trifluoromethyl-1-indone can use 7-trifluoromethyl indone through mixed acid nitrification, and zinc powder/acetic acid reductive mode obtains.
Embodiment 10
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-ethanoyl piperazine)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200242
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 4-ethanoyl piperazine.
Embodiment 11
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-sec.-propyl piperazine)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200251
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 4-sec.-propyl piperazine.
Embodiment 12
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(1-pyrrolidyl)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200252
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and tetramethyleneimine.
Embodiment 13
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-piperazine-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200253
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and N-Boc piperazine.
Embodiment 14
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-cyclopropyl piperazine)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200261
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 1-cyclopropyl piperazine.
Embodiment 15
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-morpholine-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200262
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and morpholine.
Embodiment 16
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE-3-ketone)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200271
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 1-N-METHYL PIPERAZINE-2-ketone.
Embodiment 17
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(3, the 5-lupetazin)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200272
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 2,6-lupetazin.
Embodiment 18
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-diethyl amino propylamine)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200273
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and N, N-diethyl propyldiamine.
Embodiment 19
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-6-cyanic acid-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200281
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-6 cyanic acid-1-indone and 1-N-METHYL PIPERAZINE.
Embodiment 20
4-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-2-trifluoromethyl-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200282
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 4-iodo-2-trifluoromethylbenzoic acid, 5-amino-1-indone and 1-N-METHYL PIPERAZINE.
Embodiment 21
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methoxyl group-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200291
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-methoxybenzoic acid, 5-amino-1-indone and 1-N-METHYL PIPERAZINE.
Embodiment 22
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-5-nitro-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200292
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-5-nitrobenzoic acid, 5-amino-1-indone and 1-N-METHYL PIPERAZINE.
Embodiment 23
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-cyanic acid-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200301
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-cyanobenzoic acid, 5-amino-1-indone and 1-N-METHYL PIPERAZINE.
Embodiment 24
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-N-(1-(3-5-trifluoromethylaniline)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200302
The building-up process of target compound is similar to embodiment 1, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-amino-1-indone and 3-5-trifluoromethylaniline.
Embodiment 25
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-N-(1-(2-pyridyl)-2,3 dihydros-1H-indenes-5-yl) BM
Figure BDA00002026031200303
Title compound is synthetic with the method for similar embodiment 3 through 4-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl) phenylformic acid and 5-amino-1-(2-pyridyl)-2,3 dihydros-1H-indenes.Wherein 4-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl) phenylformic acid can be synthetic according to the method for embodiment 3, and 5-amino-1-(2-pyridyl)-2,3 dihydros-1H-indenes is synthetic through following method:
5-nitro indone becomes 5-nitro-1-chlorine indenes through the method for embodiment 1 step 1.
With 5-nitro-1-chlorine indenes (19.8g 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 30mi n.Filter, concentrate, column chromatography is separated, and eluent is 5% methanol, obtains product 5-nitro-1-(2-pyridyl)-2,3 dihydros-1H-indenes 11.7g, yield 49%.
(12g 0.05mol) joins in the 200ml acetate 5-nitro-1-(2-pyridyl)-2,3 dihydros-1H-indenes, and stirring and dissolving is warmed up to 50 ℃, adds iron powder 28g in batches, adds continued reaction 5h.Be cooled to room temperature then, reaction solution is poured in the 500ml water, ethyl acetate extraction 2 times, organic phase is dry, concentrate.Column chromatography is separated, and eluent is 10% methanol.Obtain product 5-amino-1-(2-pyridyl)-2,3 dihydros-1H-indenes 8.5g, yield 81%.
Embodiment 26
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-N-(1-(3-dimethylamino phenyl)-2,3 dihydros-1H-indenes-5-yl) BM
The building-up process of title compound is similar to embodiment 22, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-nitro-1-indone and N, N-dimethyl--3-bromaniline.
Embodiment 27
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-N-(1-(2,4,6-trimethylammonium pyrimidine-5-yl)-2,3 dihydros-1H-indenes-5-yl) BM
The building-up process of title compound is similar to embodiment 22, and its main raw material is 3-bromine imidazo [1, a 2-b] pyridazine, ethynyl trimethyl silicane, 3-iodo-4-tolyl acid, 5-nitro-1-indone and 2,4,6-trimethylammonium-5-bromo pyrimi piperidine.
Embodiment 28 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.
Figure BDA00002026031200322
Figure BDA00002026031200331
Figure BDA00002026031200332
Figure BDA00002026031200333
Figure BDA00002026031200334
Figure BDA00002026031200341
The test of embodiment 29 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, under on 96 orifice plates of using 1%BSA (being dissolved in PBS) to encapsulate in advance 4 ℃, spend the night.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 1,6,7,19 is excellent.

Claims (14)

1. one kind contains compound or pharmacy acceptable salt or its prodrug that following logical formula I is represented
Figure FDA00002026031100011
Wherein
L 1Be NR 1C (O) or C (O) NR 1
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;
R aBe independently selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
2. compound according to claim 1, its A ring has general formula II a for piperazine ring
Figure FDA00002026031100021
Wherein
L 1Be NR 1C (O) or C (O) NR 1
R aBe independently selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R eBe independently selected from hydrogen, alkyl, naphthenic base, thiazolinyl, alkynyl, amino, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
3. compound according to claim 1, its A ring has general formula II b for piperazine ring
Figure FDA00002026031100031
Wherein
L 1Be NR 1C (O) or C (O) NR 1
R aBe independently selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
4. compound according to claim 2 has general formula III a
Figure FDA00002026031100041
Wherein
R aBe independently selected from hydrogen, halogen, alkyl, naphthenic base, alkoxyl group, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R eBe independently selected from hydrogen, alkyl, naphthenic base, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NHR 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
5. compound according to claim 3 has general formula III b
Figure FDA00002026031100051
Wherein
R aOn the spot be selected from halogen, alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyanic acid, NR 2R 3, NR 1C (O) R 4, C (O) NR 2R 3, S (O) 2NR 2R 3, NR 1S (O) 2R 4, NR 1(CH 2) mR 4, (CH 2) mNR 2R 3, NHC (O) NH R 4, (CH 2) mNHC (O) R 4, NHC (NH) R 4
R bBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R cBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R dBe independently selected from hydrogen, halogen, alkyl, alkoxyl group, naphthenic base, hydroxyl, sulfydryl, amino, nitro, cyanic acid;
R 1Be independently selected from hydrogen, alkyl, naphthenic base, aryl, heterocyclic aryl;
R 2, R 3Be 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 4Be independently selected from alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl;
Above-described alkyl, naphthenic base, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical; The hydridization alkyl 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 0,1,2,3,4;
Z is 0,1,2,3;
W is 0,1,2,3,4;
M is 1,2,3,4,5,6.
6. according to the described compound of claim 1-5 preferably certainly:
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-2,3 dihydros-1H-indenes-5-yl) BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(4-N-METHYL PIPERAZINE)-7-trifluoromethyl-2,3 dihydros-1H-indenes-5-yl) BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[4-(hydroxyethyl) piperazine-1-yl]-2,3 dihydros-1H-indenes-5-yl } BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-{1-[3-dimethylamino methyl tetramethyleneimine-1-yl]-2,3 dihydros-1H-indenes-5-yl } BM;
N-(3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-aminomethyl phenyl)-1-(4-N-METHYL PIPERAZINE base)-2,3-dihydro-1H-indenes-5-methane amide;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-[1-(the high piperazine of 4-methyl-1-yl)-2,3 dihydros-1H-indenes-5-yl] BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-cyanic acid-N-[1-(the high piperazine of 4-methyl-1-yl)-2,3 dihydros-1H-indenes-5-yl] BM;
3-(2-(imidazo [1,2-b] pyridazine-3-yl) ethynyl)-4-methyl-N-(1-(1-imidazolyl)-2,3 dihydros-1H-indenes-5-yl) BM.
7. according to the described compound of claim 1-6 or contain at least one alkaline salt forming group, acid salifiable with it 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 existing a plurality of basic groups to be, can generate the polyacid additive salt.
8. pharmaceutical composition, its comprise effective therapeutic dose at least a claim 1-7 each can prevent or treat compound and the pharmaceutically acceptable carrier or the thinner of protein kinase related disorder state.
9. method of regulating protein kinase activity is comprising each described compound of said protein kinase and claim 1-7 is contacted.
10. method according to claim 9, wherein said protein kinase is selected from wherein said protein kinase and is selected from Abl, Bcr-Abl.
11. be used for treating the application of the medicine of disease or imbalance based on each described compound of claim 1-7 in preparation, wherein said disease or imbalance are relevant with protein kinase activity or unusual relevant with cell proliferation.
12. application according to claim 11, 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.
13. application according to claim 12, 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.
14. application according to claim 12, wherein said autoimmune disorder is selected from the type mellitus, autoimmunity thyroid disorders and alzheimer's disease.
CN2012102935870A 2012-08-17 2012-08-17 Aryl ethynyl benzamide compound used as protein kinase inhibitor Pending CN102775411A (en)

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GB2518873A (en) * 2013-10-03 2015-04-08 Agency Science Tech & Res Bicyclic alkyne derivatives and uses thereof
CN104557939A (en) * 2013-10-23 2015-04-29 南京圣和药业股份有限公司 Hydrochloride of pyrrolo-pyrazine compound and application of hydrochloride
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EP3186247A4 (en) * 2014-08-26 2017-07-05 Astar Biotech LLC Protein kinase inhibitors
CN104327083A (en) * 2014-09-12 2015-02-04 辽宁大学 Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof
CN104910101A (en) * 2015-05-18 2015-09-16 武汉利宝瑞医药科技有限公司 Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride
CN106167491A (en) * 2015-05-19 2016-11-30 重庆大学 The compound of a kind of effective suppression lung cancer metastasis and application thereof
WO2016188421A1 (en) * 2015-05-25 2016-12-01 中国医学科学院药物研究所 2-phenylimidazole derivative containing propynamide groups, preparation method therefor, pharmaceutical composition thereof, and uses thereof
CN106699729A (en) * 2015-11-12 2017-05-24 浙江大德药业集团有限公司 Benzamide compounds containing acetenyl group
CN111004240A (en) * 2019-12-13 2020-04-14 山东铂源药业有限公司 Synthetic method of ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine

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