CN103539777B - PI3 kinase modulator and using method thereof and purposes - Google Patents

PI3 kinase modulator and using method thereof and purposes Download PDF

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CN103539777B
CN103539777B CN201310296776.8A CN201310296776A CN103539777B CN 103539777 B CN103539777 B CN 103539777B CN 201310296776 A CN201310296776 A CN 201310296776A CN 103539777 B CN103539777 B CN 103539777B
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compound
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CN103539777A (en
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习宁
李卓
王婷瑾
吴族平
温秋玲
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Add And Open Up Scientific Co
Guangdong HEC Pharmaceutical
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Add And Open Up Scientific Co
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention belongs to pharmaceutical field and be specifically related to be used for the treatment of compound, the composition and use thereof of cancer, being specifically related to PI3 kinase modulator and using method thereof and purposes.The invention provides a kind of such as formula the compound shown in (I), its pharmacy acceptable salt, and pharmaceutical preparation, for the kinase whose activity of Function protein, and regulate iuntercellular or intracellular signal response.The present invention also relates to the pharmaceutical composition comprising the compounds of this invention simultaneously, and uses this medicine composite for curing Mammals, the particularly method of mankind's hyperproliferative disease.

Description

PI3 kinase modulator and using method thereof and purposes
This application claims and to submit on 07 13rd, 2012 that Patent Office of the People's Republic of China, application number are 201210241206.4 to, denomination of invention be " PI3 kinase modulator and using method and purposes " thereof Chinese patent application and on 04 03rd, 2013 submission Patent Office of the People's Republic of China, application number be 201310116869.8, denomination of invention is the right of priority of the Chinese patent application of " PI3 kinase modulator and using method and purposes " thereof, its full content combines in this application by reference.
Technical field
The invention belongs to pharmaceutical field and be specifically related to be used for the treatment of compound, the composition and use thereof of cancer.Especially, compound of the present invention can as phosphoinositide 3-kinase conditioning agent.
Background technology
Phosphoinositide 3-kinase (PI3 kinases or PI3Ks), as a family of lipid kinase, at many cellular processes, as in the survival of cell, breeding and differentiation, plays important regulating effect.As the major influence factors in receptor tyrosine kinase and G-protein-coupled receptor downstream conduction, PI3Ks is by producing phosphatide by the intracellular signaling from all kinds of growth factor and the factor in cell ,activate Ser-ine-threonine protein kinase AKT(also referred to as protein kinase B (PKB)) and other downstream passages.Cancer suppressor gene or PTEN(homology Phosphoric acid esterase-tensin) be most important reverse conditioning agent (" Small-moleculeinhibitorsofthePI3Ksignalingnetwork. " FutureMedChem.2011 in PI3K signal path, 3 (5), 549-565).
Phosphoinositide 3-kinase (PI3K) path causes a tumorigenic common signal of interest Signal Transduction Pathways.The result that PI3K activates impels phosphatide-4,5-bisphosphate (PIP2) phosphorylation, produces phosphatide-3,4,5-triphosphoric acid (PIP3).PIP3 by homology Phosphoric acid esterase-tensin (PTEN) dephosphorylation, can stop PI3K signal transduction then.The PI3K of enrichment can activate such bars chain: first, impel the thr308 of phosphoinositide dependent kinases 1 (PDK1) phosphorylated protein silk-threonine kinase AKT, thus activation AKT; Afterwards, the AKT of phosphorylation activates Mammals rapamycin target protein, guides the phosphorylation of other downstream molecules further.
According to structures and characteristics, PI3K can be divided three classes: I class, II class and III class.Wherein, I class can be divided into again Ia and Ib two kinds of hypotypes.II class PI3Ks is class macromolecule (170-210kDa) albumen, and the catalysis region of albumen can mediate the calcium of classical Five Protein Kinase C Isoforms/fat bonding.III class PI3Ks, with the Yeast protein by VSP34 genes encoding for representative, only phosphorylation PtdIns, impels and produces PtdIns (3) P; They are regarded as the attemperator (" TargetingPI3Ksignalingincancer:opportunities, challengesandlimitations. " NatureReviewCancer, 2009,9,550) of vesicle transport.
Ia type PI3Ks(PI3K α, PI3K β, PI3K γ and PI3K δ) be p110 α respectively by catalytic subunit p110(, p110 β, p110 γ and p110 δ) and regulator subunit p85(is such as: p85 α, p85 β, p55 δ, p55 α and p50 α) dimer protein that forms.The p110 subunit with catalytic activity uses ATP phosphorylation Ptdlns, PtdIns4P and PtdIns (4,5) P2.The discovery of PI3K catalytic subunit α-subtype gene (PIK3CA), confirms the vital role of Ia type PI3Ks in cancer.This gene is encoded by p110 α, usually undergos mutation in human tumor and increases, such as ovarian cancer (Campbelletal., CancerRes.2004,64,7678-7681; Levineetal., Clin.CancerRes.2005,11,2875-2878; Wangetal., Hum.Mutat.2005,25,322; Leeetal., GynecolOncol.2005,97,26-34), cervical cancer, breast cancer (Bachmanetal., CancerBiol.Ther.2004,3,772-775; Levineetal., BreastCancerRes.Treat2006,96,91-95; Saaletal., CancerRes.2005,65,2554-2559; SamuelsandVelculescu, CellCycle2004,3,1221-1224), colorectal cancer (Samuelsetal., Science2004,304,554; Velhoetal., Eur.JCancer2005,41,1649-1654), carcinoma of endometrium (Odaetal., CancerRes.2005,65,10669-10673), cancer of the stomach (Byunetal., MJCancer2003,104,318-327; Lietal., Oncogene2005,24,1477-1480), liver cancer (Leeetal., id), minicell and nonsmall-cell lung cancer (Tangetal., LungCancer2006, Jl, 181-191; Massionetal., AmJRespirCritCareMeaf2004,170,1088-1094), thyroid carcinoma (Wuetal., JClin.EndocrinolMet α b2005,90,4688-4693), acute myelocytic leukemia (AML) (Sujobertetal., Blood1997,106,1063-1066), chronic myelocytic leukemia (CML) (HickeyandCotterJBiolChem.2006,281,2441-2450), and glioblastoma multiforme (Hartmannetal., ActaNeurop α thol (Berl) 2005,109,639-642).
MTOR is the silk-threonine kinase of high conservative, has lipid kinase activity, is one of influence factor of PI3K/AKT path.There are two kinds of distinct mixtures in mTOR, mTORC1 and mTORC2, and by regulating nutrition supply and cellular energy levels, plays its vital role in cell proliferation.The downstream targets of mTORC1 is Ribosomal protein 1 and eukaryotic translation initiation factor 4E Binding Protein 1, both to albumen synthesis, there is important effect (" PresentandfutureofPI3Kpathwayinhibitionincancer:perspect ivesandlimitations. " CurrentMed.Chem.2011,18,2647-2685).
The conclusion that cancer is brought out in the imbalance of mTOR intracellular signaling comes from the research that pharmacology disturbs mTOR, and the medicine of research comprises rapamycin, its homologue temsirolimus (CCI-779) and everolimus (RAD001).Rapamycin is mTOR inhibitors, and the induction G1 phase blocks and apoptosis.The formation of rapamycin and FK-Binding Protein 12 (FKBP-12) mixture, is considered to relevant to rapamycin growth-inhibiting mechanism.These mixture specific bindings mTOR, suppresses it active, stops protein translation and Growth of Cells.The cytosis of mTOR inhibitors also shows in the cell containing the PTEN with property inactivation.Therefore, the antitumour activity of rapamycin obtains approval, and a series of rapamycin homologue, such as temsirolimus and everolimus, be also used for the treatment of the cancer of some types by U.S. food and drugs administration approved.
Just because of PI3Ks and mTOR plays an important role at bioprocess and disease stage; researching and developing these kinase whose inhibitor is (" Phosphatidylinositol3-kinaseisoformsasanoveldrugtargets. " CurrentDrugTargets highly expected; 2011; 12,1056-1081; " Progressinthepreclinicaldiscovryandclinicaldevelopmentof classIanddualclassI/IVphosphoinositide3-kinase (PI3K) inhibitors. " CurrentMed.Chem.2011,18,2686-2714).
Summary of the invention
In view of this, the invention provides a class new compound, can be used for suppressing, control and/or regulate PI3K or mTOR active, also can be used for treating human pcna disease, such as cancer.The present invention also provides the method for this compounds of preparation, the method for the treatment of human pcna disease and the pharmaceutical composition containing this compounds.
On the one hand, the invention provides a kind of such as formula the compound shown in (I) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
( I)，
Wherein:
W is D, CN, N 3, C 5-12spiral shell bicyclic group or wherein, described C 5-12spiral shell bicyclic group optionally by 1,2,3 or 4 independently selected from D, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced;
X is H, D, C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) or comprise heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, Br, CN, N 3, C 1-4alkyl, OR a, SR aand NR ar bsubstituting group replaced;
R 1for H, D, Cl, OR a, C 1-6alkyl or C 3-6cycloalkyl, wherein, described each C 1-6alkyl and C 3-6cycloalkyl is optionally independently selected from D by 1,2,3 or 4, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced;
R 2for C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl or comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, Br, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced;
Each R aand R bbe H, C independently 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical, C 6-10aryl, comprises heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) ,-(C 1-4alkylidene group)-(C 6-10aryl) or-(C 1-4alkylidene group)-(comprising heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N); Work as R aand R bwhen being connected with same nitrogen-atoms, R a, R b, and together with the nitrogen-atoms connected with them, optionally can also form substituted or non-substituted 3-8 former molecular heterocyclic radical.
In some embodiments, W is CN, C 5-12spiral shell bicyclic group or wherein, described C 5-12spiral shell bicyclic group optionally by 1,2,3 or 4 independently selected from D, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced.
In other embodiments, X is H, D, C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) or comprise heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, CN, C 1-3alkyl, OR aand NR ar bsubstituting group replaced.
In some embodiments, R 1for H, D, Cl or OR a.
In other embodiments, R 2for C 1-6alkyl, C 3-6cycloalkyl or C 6-10aryl, wherein, described each C 1-6alkyl, C 3-6cycloalkyl and C 6-10aryl optionally replaced by 1,2,3 or 4 substituting group independently selected from D, F and Cl.
In some embodiments, R 1for Cl or OMe.
In other embodiments, each R aand R bbe H, C independently 1-3alkyl, C 1-3haloalkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical, C 6-10aryl, comprises heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N ,-(C 1-2alkylidene group)-(C 3-6heterocyclic radical) ,-(C 1-2alkylidene group)-(C 6-10aryl) or-(C 1-2alkylidene group)-(comprising heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N); Work as R aand R bwhen being connected with same nitrogen-atoms, R a, R b, and together with the nitrogen-atoms connected with them, that can also optionally form replacement or non-substituted 3-8 former molecular heterocyclic radical.
On the other hand, present invention also offers a kind of pharmaceutical composition, comprise compound of the present invention and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
In some embodiments, also comprise additional treatment agent, described additional treatment agent is selected from chemotherapeutic agent, antiproliferative, is used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis or their combination.
In some embodiments, described additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelinanalogues), megestrol (megestrol), prednisone (prednisone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferonalfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximabvedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.
On the other hand, present invention also offers and use compound of the present invention or described pharmaceutical composition for the preparation of the purposes of medicine protecting, process, treat or alleviate patient's proliferative disease.
In some embodiments, proliferative disease of the present invention is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, the cancer of the brain, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.On the other hand, present invention also offers and use compound of the present invention or the next purposes for the preparation of the medicine of suppression or adjustment phosphoinositide 3-kinase (PI3 kinases or PI3Ks) and/or mTOR activity in biological sample of pharmaceutical composition, described method comprises use the compounds of this invention or pharmaceutical composition contacts with described biological sample.
On the other hand, the invention provides some pharmaceutical compositions, it comprises the compound of the present invention as phosphoinositide 3-kinase (PI3 kinases or PI3Ks) and/or mTOR inhibitors, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.
In some embodiments, pharmaceutical composition provided by the present invention comprises and can be used as PI3K signal response inhibitor, the compound of mTOR signal response inhibitor, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, or pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.
In other embodiments, pharmaceutical composition of the present invention further comprises additional treatment agent.
On the other hand, the present invention relates to a kind of method suppressing PI3K or mTOR activity, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described kinases.
In some embodiments, the present invention relates to a kind of method suppressing PI3K or mTOR signal response, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described acceptor.Other embodiment is, suppresses the activity of PI3K or mTOR signal response in cell or multicellular organisms.According to method of the present invention, the method comprises use the compounds of this invention or its pharmaceutical composition carries out administration to described multicellular organisms.In some embodiments, described multicellular organisms refers to Mammals.In other embodiment, described multicellular organisms refers to the mankind.In some embodiments, the method for the invention further comprises additional treatment agent and contacts with described kinases.
On the other hand, the present invention relates to a kind of method of antiproliferative effect activity, described method comprises the effective therapeutic dose and cells contacting that use the compounds of this invention or its pharmaceutical composition energy Inhibit proliferaton.In some embodiments, the method for the invention further comprises additional treatment agent and cells contacting.
In some embodiments, the present invention relates to a kind of method for the treatment of Patient cells's proliferative disease, effective therapeutic dose that described method comprises use the compounds of this invention or its pharmaceutical composition carries out administration to patient.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
In some embodiments, the present invention relates to a kind of method suppressing patient tumors to grow, effective therapeutic dose that described method comprises use the compounds of this invention or its pharmaceutical composition carries out administration to patient.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to the preparation of compound that formula (I) comprises, the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Embodiment
definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim defines.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description, or as the scope that the present patent application controls.
Unless other aspects show, the present invention by application to give a definition: according to object of the present invention, chemical element according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " OrganicChemistry ", UniversityScienceBooks, Sausalito:1999, andSmithetal., " March'sAdvancedOrganicChemistry ", JohnWiley & Sons, NewYork:2007, therefore all contents have all merged reference.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, the compounds that subclass and the present invention comprise.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term." optionally " or " optionally " meaning refer to subsequently described event or situation can but may not occur, and this description comprises the situation that this event or situation wherein occur, and the situation of this event or situation does not wherein occur.Such as: " to be independently selected from by 1 or 2 group of D, F replace " meaning heterocyclyl refer to this D, F can but may not exist, and this description comprise wherein heterocyclic radical be independently selected from by 1 or 2 the group of D, F situation about replacing, and the unsubstituted situation of heterocyclic radical.
Generally speaking, term " replacement " or " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but is not limited to deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
The term " alkyl " that the present invention uses or " alkyl group ", represent the saturated straight chain containing 1-20 carbon atom or side chain monovalence hydrocarbon polymer atomic group.Wherein said alkyl group can independently optionally replace by one or more substituting group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom ;some of them embodiment is, alkyl group contains 1-10 carbon atom; Other embodiment is, alkyl group contains 1-8 carbon atom; Other embodiment is, alkyl group contains 1-6 carbon atom; Other embodiment is, alkyl group contains 1-4 carbon atom; Other embodiment is, alkyl group is containing 1-3 carbon atom; Other embodiment is, alkyl group is containing 1-2 carbon atom.
The example of alkyl group comprises but is not limited to methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr, i-propyl ,-CH (CH 3) 2), normal-butyl (n-Bu, n-butyl ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu, i-butyl ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu, s-butyl ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu, t-butyl ,-C (CH 3) 3), n-pentyl (n-pentyl ,-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl etc.And alkyl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, aralkyl etc.
Term used in the present invention " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.
The term " alkylidene group " that the present invention uses, represents the saturated bivalent hydrocarbon radical obtained from straight or branched saturated hydrocarbon cancellation two hydrogen atoms.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and some of them embodiment is, alkylidene group contains 1-6 carbon atom; Other embodiment is, alkylidene group contains 1-4 carbon atom; Other embodiment is, alkylidene group contains 1-3 carbon atom; Other embodiment is, alkylidene group contains 1-2 carbon atom.The example of alkylidene group comprises, but is not limited to, methylene radical (-CH 2-), ethylidene (-CH 2cH 2-), propylidene (-CH 2cH 2cH 2-), ethylidine (-CH (CH 3)-), secondary sec.-propyl (-CH (CH 3) CH 2-) etc.Alkylidene group can be further substituted, and this substituting group is selected from, but is not limited to deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " thiazolinyl " represents the monovalent hydrocarbon of straight or branched, and wherein at least one position is undersaturated condition, and namely a C-C is sp 2double bond.Unless otherwise detailed instructions, thiazolinyl contains 2-12 carbon atom, and some of them embodiment is, thiazolinyl contains 2-8 carbon atom; Other embodiment is, thiazolinyl contains 2-6 carbon atom; Other embodiment is, thiazolinyl contains 2-4 carbon atom.The concrete example of thiazolinyl comprises, but is not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2) etc.The group of its alkenyl groups can independently optionally replace by one or more substituting group described in the invention, comprise the location that group has negation, " just ", " E " or " Z ".
Term " alkynyl " represents the monovalent hydrocarbon of straight or branched, and wherein at least one position is undersaturated condition, and namely a C-C is sp triple bond.Unless otherwise detailed instructions, alkynyl contains 2-12 carbon atom; In certain embodiments, alkynyl contains 2-8 carbon atom; In other embodiment, alkynyl contains 2-6 carbon atom; In other embodiment, alkynyl contains 2-4 carbon atom.The concrete example of alkyl includes, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH 2c ≡ CH) etc.Wherein hydrocarbyl group can independently optionally replace by one or more substituting group described in the invention.
Term " haloalkyl ", " halogenated alkenyl " or " halogenated alkoxy " represent alkyl, alkenyl or alkoxy base replace by one or more halogen atom, such example comprises, but is not limited to trifluoromethyl, trifluoromethoxy etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-20 carbon atom, and some of them embodiment is, alkoxy base contains 1-10 carbon atom; Other embodiment is, alkoxy base contains 1-8 carbon atom; Other embodiment is, alkoxy base contains 1-6 carbon atom ;other embodiment is, alkoxy base contains 1-4 carbon atom; Other embodiment is, alkoxy base contains 1-3 carbon atom.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH 3) 3), 1-pentyloxy (n-pentyloxy ,-OCH 2cH 2cH 2cH 2cH 3), 2-pentyloxy (-OCH (CH 3) CH 2cH 2cH 3), 3-pentyloxy (-OCH (CH 2cH 3) 2), 2-methyl-2-butoxy (-OC (CH 3) 2cH 2cH 3), 3-methyl-2-butoxy (-OCH (CH 3) CH (CH 3) 2), 3-methyl-l-butoxy (-OCH 2cH 2cH (CH 3) 2), 2-methyl-l-butoxy (-OCH 2cH (CH 3) CH 2cH 3) etc.
Term " alkylthio " represents that alkyl group is connected with molecule rest part by bivalent sulfur atom, and wherein alkyl group has implication as described in the present invention.In certain embodiments, the alkyl in alkylthio is C 1-10the alkyl of straight or branched; Other embodiment is, the alkyl in alkylthio is more rudimentary C 1-3alkyl.The example of alkylthio comprises, but is not limited to methylthio group (CH 3s-).
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " virtue amino " represent amine groups replace by one or two aromatic yl group, such example comprises, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on fragrant amino can independently optionally replace by one or more substituting group described in the invention.
Term " carbocyclic ring ", " carbocylic radical " or " carbocyclic ring " refer to monovalence or multivalence, non-aromatic, the saturated or undersaturated monocycle of part.In certain embodiments, carbocyclic ring is containing 3-12 carbon atom.In certain embodiments, carbocyclic ring is cyclic aliphatic group.Suitable cyclic aliphatic group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group comprises further, but be never limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl etc.Described " cycloalkyl " refers to monovalence or multivalence, saturated monocycle.In certain embodiments, cycloalkyl is containing 3-12 carbon atom.And cycloalkyl can be further substituted, this substituting group is selected from, but is not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " cycloalkyl alkylidene group " represent alkyl group can replace by one or more group of naphthene base, wherein alkyl and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, and namely group of naphthene base is connected to C 1-6alkyl group on.Other embodiment is that group of naphthene base is connected to C 1-4alkyl group on.Other embodiment is that group of naphthene base is connected to C 1-2alkyl group on.Such example comprises, but is not limited to, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc.Cycloalkyl alkylidene group can be further substituted, and this substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle or bicyclic system, wherein on ring one or more atom independent optionally replace by heteroatoms, ring can be completely saturated or comprise one or more degree of unsaturation, but be never the fragrant same clan, the rest part only having a tie point to be connected to molecule gets on.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocycle ", and " heterocyclic radical " or " heterocycle " group is the monocycle of 3-8 ring, it comprises 2-7 carbon atom and is selected from N, O, P, 1-3 the heteroatoms of S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, when described ring is triatomic ring, wherein only have a heteroatoms; In other embodiment, heterocycle ", " heterocyclic radical " or " heterocycle " group is the dicyclo of 7-10 unit; it comprises 4-9 carbon atom and is selected from N, O, P; 1-3 the heteroatoms of S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group.
Heterocyclic radical can be carbon back or heteroatoms base.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl.The example of heterocyclic group also comprises, the pyrimidine dione base that on ring, two carbon atoms are replaced by oxygen (=O) and 1,1-dioxidothiomorpholinyl.Described heterocyclic radical is independent optionally to be replaced by the one or more substituting groups in the present invention, wherein substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " heterocycloalkylene " represent alkyl group can replace by one or more heterocyclyl groups, wherein alkyl and heterocyclyl groups have implication as described in the present invention.Some of them embodiment is, heterocycloalkylene group refers to " more rudimentary heterocycloalkylene " group, and namely heterocyclyl groups is connected to C 1-6alkyl group on.Other embodiment is that heterocyclyl groups is connected to C 1-4alkyl group on.Other embodiment is that heterocyclyl groups is connected to C 1-2alkyl group on.Such example comprises, but is not limited to, 2-tetramethyleneimine ethyl, 1-morpholine ethyl, 1-morpholine methyl, 1-Pyrrolidine methyl etc.Heterocycloalkylene can be further substituted, and this substituting group may be, but not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " heteroatoms " represents one or more O, S, N, P or Si, comprises the form of any oxidation state of N, S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Such as, or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, N(is as the N in 3,4-dihydro-2 h-pyrrole base), NH(is as the NH in pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).
Term " halogen " refers to F, Cl, Br or I.
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as is connected with Sauerstoffatom, forms oh group.
Term " D " or " 2h " represent single D atom.Such atomic group is connected with a methyl, forms list-deuterated methyl (-CDH 2); Two D atoms are connected with a methyl, form two-deuterated methyl (-CD 2h); Three D atoms are connected with a methyl, form three deuterated methyl (-CD 3).
Term " N 3" represent a nitrine structure.This group can be connected with other groups, such as, is connected with methyl group, can form triazonmethane (triazo-methane, MeN 3); Or be connected with phenyl group, form aziminobenzene (PhN 3).
Term " aryl " can be used alone or as " aralkyl ", " aralkoxy " or " aryloxy alkyl " most, represent the monocycle altogether containing 6-14 ring, the carbocyclic ring system of dicyclo or three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use, and aromatic nucleus can comprise phenyl, naphthyl and anthracene.And described aryl can be substituted or non-substituted, wherein substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue be amino etc.
Term " aryl alkylene " represent alkyl group can replace by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, some of them embodiment is, arylalkylene groups refers to " more rudimentary aryl alkylene " group, namely aromatic yl group is connected to C 1-6alkyl group on.Other embodiment is that arylalkylene groups refers to containing C 1-4" the benzene alkylene " of alkyl.Other embodiment is that arylalkylene groups refers to containing C 1-2" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Aryl alkylene can be further substituted, and this substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " heteroaryl " can be used alone or as most of " heteroaralkyl ", represent the monocycle containing 5-14 annular atoms, dicyclo or three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " fragrant heterocycle " or " heteroaromatics " and use.And described heteroaryl can be substituted or non-substituted, wherein substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl or 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl or 4-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl are (as 2-quinolyl, 3-quinolyl or 4-quinolyl) and isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroarylalkylenyl " represent alkyl group can replace by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, some of them embodiment is, heteroarylalkylenyl group refers to " more rudimentary heteroarylalkylenyl " group, namely heteroaryl groups is connected to C 1-6alkyl group on.Other embodiment is that heteroaryl groups is connected to C 1-4alkyl group on.Other embodiment is that heteroaryl groups is connected to C 1-2alkyl group on.Wherein specific examples comprises 2-picolyl, 3-furylethyl etc.Can be substituted further on heteroarylalkylenyl, this substituting group may be, but not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo ", represent that a ring originates from ring-type carbon special on another ring, such as, as below described by formula a, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution " or " spiral shell dicyclo ".Each ring in volution can be carbocyclic ring or heterocycle.Such example comprises, but is not limited to 5-azaspiro [2.4] heptane-5-base, (R)-4-azaspiro [2.4] heptane-6-base etc.Spiral shell bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, cyano group, azido-, hydroxyl, alkyl, thiazolinyl, alkynyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, virtue amino etc.
Formula a
Term " undersaturated " used in the present invention represents that part is containing one or more degree of unsaturation.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
As described in the invention, substituting group is drawn a key and is connected to the member ring systems that the ring at center is formed, and shown in b, representing substituting group any commutable position on ring can replace.Such as, formula b represents any position that may be substituted on B ring, shown in c.
Formula b formula c
Unless other aspects show, structural formula described in the invention comprises all isomeric forms, as enantiomerism, and diastereo-isomerism, and rotamerism (or conformational isomerism).Such as containing R, S configuration of asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " tautomer " or " tautomeric form " represent that the structure isomeride with different-energy can cross low energy barrier, thus transform mutually.For example, proton tautomer (i.e. prototropy) comprises and carries out change by proton shifting, as the change of keto-enol formula and imine-enamine isomerization.Valence tautomers comprises is recombinated by some bonding electronss and carries out change.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug p-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises OH group, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: Higuchietal., Pro-drugsasNovelDeliverySystems, Vol.14, A.C.S.SymposiumSeries; Rocheetal., ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987; Rautioetal., Prodrugs:DesignandClinicalApplications, NatureReviewsDrugDiscovery, 2008,7,255-270, andHeckeretal., ProdrugsofPhosphatesandPhosphonates, J.Med.Chem., 2008,51,2328-2345, every section of document is contained in this by reference.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by obtaining through oxidation, reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method to drug compound.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: Parkeretal., ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYorkandElieletal., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm acolSci, 1977,66,1-19, described.The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacts the inorganic acid salt formed, example hydrochloric acid salt, hydrobromate, phosphoric acid salt, vitriol, perchlorate etc. with amino group; And organic acid salt, as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate etc., or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate etc.The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.Pharmacy acceptable salt comprises the amine positively charged ion that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed further, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refers to that a substituting group is connected with amino group and blocks or protect in compound amino functional, and suitable amido protecting group comprises ethanoyl, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes Asia methoxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl etc.Can reference for the general description of blocking group: Greeneetal., ProtectiveGroupsinOrganicSynthesis, JohnWiley & Sons; NewYork, 1991andKocienskietal., ProtectingGroups; Thieme, Stuttgart, 2005.
compound
The quinolines that the present invention relates to, its pharmacy acceptable salt, and pharmaceutical preparation, to protein kinase, especially the disease of PI3K or mTOR adjustment or the treatment of illness have potential purposes.
Particularly, the present invention relates to a kind of such as formula the compound shown in (I) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
(I)。
Wherein, each R 1, R 2with W, there is definition as described below.
W is D, CN, N 3, C 5-12spiral shell bicyclic group or wherein, described C 5-12spiral shell bicyclic group optionally by 1,2,3 or 4 independently selected from D, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced.
In some embodiments, W is CN, C 5-12spiral shell bicyclic group or wherein, described C 5-12spiral shell bicyclic group optionally by 1,2,3 or 4 independently selected from D, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced.
X is H, D, C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) or comprise heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, Br, CN, N 3, C 1-4alkyl, OR a, SR aand NR ar bsubstituting group replaced.
In some embodiments, X is H, D, C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) or comprise heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, CN, C 1-3alkyl, OR aand NR ar bsubstituting group replaced.
R 1for H, D, Cl, OR a, C 1-6alkyl or C 3-6cycloalkyl, wherein, described each C 1-6alkyl and C 3-6cycloalkyl is optionally independently selected from D by 1,2,3 or 4, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced.
In some embodiments, R 1for H, D, Cl or OR a; In other embodiments, R 1for Cl or OM e.
R 2for C 1-6alkyl, C 3-6cycloalkyl, C 0-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl or comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, Br, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced.
In some embodiments, R 2for C 1-6alkyl, C 3-6cycloalkyl or C 6-10aryl, wherein, described each C 1-6alkyl, C 3-6cycloalkyl and C 6-10aryl optionally replaced by 1,2,3 or 4 substituting group independently selected from D, F and Cl.
Each R aand R bbe H, C independently 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical, C 6-10aryl, comprises heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) ,-(C 1-4alkylidene group)-(C 6-10aryl) or-(C 1-4alkylidene group)-(comprising heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N); Work as R aand R bwhen being connected with same nitrogen-atoms, R a, R b, and together with the nitrogen-atoms connected with them, optionally can also form substituted or non-substituted 3-8 former molecular heterocyclic radical.
In some embodiments, each R aand R bbe H, C independently 1-3alkyl, C 1-3haloalkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical, C 6-10aryl, comprises heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N ,-(C 1-2alkylidene group)-(C 3-6heterocyclic radical) ,-(C 1-2alkylidene group)-(C 6-10aryl) or-(C 1-2alkylidene group)-(comprising heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N); Work as R aand R bwhen being connected with same nitrogen-atoms, R a, R b, and together with the nitrogen-atoms connected with them, that can also optionally form replacement or non-substituted 3-8 former molecular heterocyclic radical.
In the present invention, R aand R bwhen being connected with same nitrogen-atoms, R a, R band together with the nitrogen-atoms to be connected with them, optionally can also form 3-8 former molecular heterocyclic radical, i.e. R a, R bwith together with the nitrogen-atoms to be connected with them, can form the heterocyclic radical of 3-8 atom, also can not form heterocyclic radical, be other structures well known to those skilled in the art, as N-R a-R bor R a-N-R bdeng.
The compound of formula of the present invention (I) structure includes but not limited to following particular compound or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
Or (29) (28).
Unless other aspects show, all steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and the pharmaceutically acceptable prodrug of compound of the present invention all belongs to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid; Toxilic acid; Succsinic acid; Amygdalic acid; Fumaric acid; Propanedioic acid; Pyruvic acid; Oxalic acid; Hydroxyethanoic acid; Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia, comprises uncle's ammonia, parahelium, tertiary ammonia; Alkali metal hydroxide or alkaline earth metal hydroxides etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine; Ammonia, as uncle ammonia, parahelium and tertiary ammonia; Ring-type ammonia, as piperidines, morpholine and piperazine etc.; From sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, namely the disease of mediation is there is for the production of pharmaceutical prod treatment acute and chronic blood vessel, comprise those described in the invention, compound of the present invention is producing the application in cancer therapy drug.Compound of the present invention is used for alleviating for the production of one equally, stops, and controls or treat the medical supplies of the disease mediated by PI3K or mTOR.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and at least one pharmaceutically acceptable carrier, the effective treatment consumption needed for the combination of assistant agent or thinner.
The present invention comprises the disease that treatment patient vessel occurs to mediate equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.
composition
According to another aspect, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I), the compound listed by the present invention, or the compound in embodiment, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound detectably can suppress the protein kinase in biological sample or patient body effectively.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, the salt of pharmaceutically acceptable prodrug, salt, ester, ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, compound described by other aspects of the present invention, its meta-bolites or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier further, assistant agent, or vehicle, these are applied as the present invention, comprise any solvent, thinner or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant etc., be suitable for distinctive target formulation.As with described by Publication about Document: Troyetal., Remington:TheScienceandPracticeofPharmacy, 21sted., 2005, LippincottWilliams & Wilkins, PhiladelphiaandSwarbricketal., EncyclopediaofPharmaceuticalTechnology, eds.1988-1999, MarcelDekker, NewYork.The content of comprehensive document herein, shows that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but is not limited to, ion-exchanger; Aluminium; Aluminum stearate; Yelkin TTS; Serum protein, as human serum protein; Buffer substance is as phosphoric acid salt; Glycine; Sorbic Acid; Potassium sorbate; The partial glyceride mixtures of saturated vegetable fatty acid; Water; Salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt; Colloidal silicon; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylate; Wax; Polyethylene-polyoxypropylene-blocking-up polymer; Lanolin; Sugar, as lactose, dextrose plus saccharose; Starch, as W-Gum and potato starch; Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia; Natural gum powder; Fructus Hordei Germinatus; Gelatin; Talcum powder; Auxiliary material is as cocoa butter and suppository wax; Oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycol compound, as propylene glycol and polyoxyethylene glycol; Ester class is as ethyl oleate and Ethyl Lauroyl acid esters; Agar; Buffer reagent is as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Isotonic salt; Lin Ge (family name) solution; Ethanol; Phosphate buffer solution; Other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate; Tinting material; Releasing agent; Coating agents; Sweeting agent; Seasonings; Spices; Sanitas; Antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, per rectum administration, nose administration, containing taking administration, vagina administration or by the administration of implantable medicine box.Term as used herein " through injection " comprise in subcutaneous, vein, intramuscular, IA, synovial membrane (chamber), intrasternal, film, intraocular, in liver, intralesional with the injection of encephalic or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.The injection system of composition sterile of the present invention can be water or oleaginous suspension.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is the nontoxic acceptable thinner of injection or solvent, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil by convention can as solvent or suspension medium.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Lipid acid, as oleic acid and its glyceride derivative can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain alcohol diluents or dispersion agent, and as carboxymethyl cellulose or similar dispersing agents, the pharmaceutical preparation being generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.Other conventional tensio-active agents, as the reinforcer of Tweens, spans and other emulsifying agents or bioavailability, are generally used for pharmaceutically acceptable solid, liquid or other formulations, and can be applied to the preparation of targeted drug formulation.
The pharmaceutically acceptable composition of the present invention can be carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to, capsule, tablet, water suspension or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
In addition, the pharmaceutically acceptable composition of the present invention can with the form rectal administration of suppository.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum, thus melts in the rectum and discharge medicine.Such material comprises cocoa butter, beeswax and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal relating to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable using topical preparations can prepare and be applied to these fields or organ.
Rectal suppository (see above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot also can medication like this.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carrier containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitable carrier comprises, but is not limited to, mineral oil, sapn (Arlacel-60), tween (polysorbate ), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
Preparation can be prepared into for eye, pharmaceutically acceptable composition; as isotonic micronized suspension; the Sterile Saline of pH regulator or other aqueous solution, preferably, the Sterile Saline of isotonic solution and pH regulator or other aqueous solution can add disinfection preservative as benzalkonium chloride.In addition, the pharmaceutically acceptable composition for eye can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by the gaseous solvents of nose or inhalation.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, use phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent to improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, and such as, water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1 ,3-butyleneglycol, dimethyl formamide, grease (particularly cottonseed, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection, as aseptic parenteral solution or oleaginous suspension, can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic aseptic parenteral solution, suspension or the emulsion made through acceptable thinner or solvent parenterally, such as, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise list or the DG of synthesis.In addition, lipid acid such as oleic acid can be applied to injection.
Injection can be aseptic, as defended metre filter by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other sterile injectable medium before use.In order to extend the effect of compound of the present invention, usually need the absorption being slowed down compound by subcutaneous injection or intramuscularly.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on and depends on grain size and crystal shape successively by its dissolution rate.In addition, can be dissolved in oil vehicles by compound or disperse to have come the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and the microcapsule matrix as many lactic acid-polyglycolide formation compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and poly-(acid anhydrides).Injection storage form also can embed the liposome compatible with bodily tissue by compound or microemulsion prepares.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can prepare by the auxiliary material of compound of the present invention and suitable non-perfusing or carrier being mixed, as cocoa butter, polyoxyethylene glycol or suppository wax, they are solid in room temperature but are then liquid under body temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes, as Trisodium Citrate with the pharmaceutically acceptable inert excipient of at least one or carrier; Calcium phosphate; A) weighting agent, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; B) tackiness agent, as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic; C) wetting Agent for Printing Inks, as glycerine; D) disintegrating agent, as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) retarding agent solution, as paraffin; F) absorption enhancer, as quaternary ammonium compounds; G) wetting agent, as hexadecanol and glyceryl monostearate; H) absorption agent, as white bole and bentonite; I) lubricant, as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material used has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can by dressing, add shell such as known coating method on enteric coating and other drug preparation and prepare.They optionally can comprise opalizer, or preferably, in certain part of enteron aisle, at random with the sole active agent in the method release composition postponed.As implant compositions can comprise multimeric species and wax.
Active compound can form microcapsule formulations together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula by dressing or can add shell, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, lactose or starch.Such formulation also can comprise substance besides inert diluents as general application, if tableting lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They optionally can comprise tranquilizer, or preferably, in certain part of enteron aisle, with the sole active agent in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but is not limited to, polymer and wax.
Compound of the present invention by local or formulation through percutaneous drug delivery comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any required sanitas or required buffer reagent under sterile conditions.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it is delivered in body at control compound more advantage, and such formulation can by dissolving or preparing in decentralized compound to suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate controls film or compound is scattered in polymer matrix or gelatin to control its speed.
Compound of the present invention is preferably prepared into dosage unit form to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit type " refer to that patient obtains the physical dispersion unit of the required medicine of suitably treatment herein.But, should be appreciated that compound of the present invention or composition every day total usage will judge determine according to reliable medical science scope by doctor in charge.Concrete effective dose level for any one special patient or organism by depend on many factors comprise the seriousness of illness and the illness be treated, the activity of particular compound, concrete composition used, age of patient, body weight, healthy state, the discharge rate of sex and food habits, administration time, route of administration and particular compound used, time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
The change that can produce the consumption of the compound of the present invention of single dosage form composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is, composition can be prepared into the inhibitor of dosage in 0.01-200mg/kg body weight/day by formulation method, and the amount being accepted composition by patient carries out administration.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with the agent of one or more other additional treatment (pharmacy), wherein drug combination causes acceptable untoward reaction, and this has special meaning for the treatment of high proliferative disease as cancer.In this case, compound of the present invention can in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents and their mixture and combination.As used in the present invention, the disease that the normal drug treatment of additional treatment agent is special is exactly known " suitably disease therapy "." additional treatment agent " used in the present invention comprises chemotherapeutic agent or other antiproliferative medicines can in conjunction with compounds for treating proliferative disease of the present invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA; MS-275; MGO103; Those compounds described by following patent: WO2006/010264, WO03/024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899; Demethylating agent, includes, but are not limited to, and 5-mixes nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the compound described by Publication about Document: US6,268137, US5, and 578,716, US5,919,772, US6,054,439, US6,184,211, US6,020,318, US6,066,625, US6,506,735, US6,221,849, US6,953,783, US11/393,380.
Other embodiment is, chemotherapeutics or other anti-proliferative drugs can in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutics comprises, but is not limited to, other therapies that can use with anti-cancer agent in combination of the present invention or cancer therapy drug; Operation; Radiotherapy, a little example is as gamma-radiation, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system isotope therapy; Endocrinotherapy; Taxanes, as taxol (Taxol), Docetaxel (Taxotere); Platinum derivatives, as cis-platinum (Cisplatin), carboplatin (Carboplatin), oxaliplatin (oxaliplatin), Satraplatin (satraplatin); Biological response modifier, as Interferon, rabbit, interleukin; Tumour necrosis factor, as TNF, TRAIL receptor target thing; Overheated and psychrotherapy; Alleviate the reagent of any untoward reaction, as antiemetic; With other approved chemotherapeutics, include, but are not limited to, alkylating drug, as mustargen (mechlorethamine), Chlorambucil (chlorambucil), endoxan (cyclophosphamide), melphalan (melphalan), ifosfamide (Ifosfamide); Metabolic antagonist, as methotrexate (Methotrexate), pemetrexed (Pemetrexed); Purine antagonist and Pyrimidine antagonists, as 6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil (5-Fluorouracil), cytosine arabinoside (Cytarabile) gemcitabine (Gemcitabine); Spindle poison, as vinealeucoblastine(VLB) (Vinblastine), vincristine(VCR) (Vincristine), vinorelbine (Vinorelbine); Podophyllotoxin, as Etoposide (Etoposide), irinotecan (Irinotecan), Hycamtin (Topotecan); Microbiotic, as Zorubicin (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin); Nitrosourea, as carmustine (Carmustine), lomustine (Lomustine); Cell division cycle inhibitor, if KSP is by mitotic kinesin inhibitors, CENP-E and CDK inhibitor; Enzyme, as asparaginase (Asparaginase); Hormone, as tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol), dexamethasone (Dexamethasone) etc.; Angiogenesis inhibitor reagent, as Avastin (Avastin) etc.; Monoclonal antibody, as Baily monoclonal antibody (Belimumab), Brentuximab, Cetuximab (Cetuximab), WAY-CMA 676 (Gemtuzumab), her monoclonal antibody (Ipilimumab), Ofatumumab, Victibix (Panitumumab), Lucentis (Ranibizumab), Rituximab (Rituximab), tositumomab (Tositumomab), Herceptin (Trastuzumab) ;kinase inhibitor, if imatinib (Imatinib), Sutent (Sunitinib), Xarelto (Sorafenib), Tarceva (Erlotinib), Gefitinib (Gefitinib), Dasatinib (Dasatinib), AMN107 (Nilotinib), lapatinibditosylate (Lapatinib), gram Zhuo are for Buddhist nun (Crizotinib), Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.; .Drug inhibition or activate the approach of cancer, as mTOR, HIF(hypoxia inducible factor) approach and other.Http:// www.nci.nih.gov/ is shown in cancer therapy more widely forum, the oncologic inventory of FAD accreditation is shown in http://www.fda.gov/cder/cancer/druglist-rame.htm and Merck Manual, 18 edition .2006, all contents are all combine reference.
Other embodiment is, compound of the present invention can in conjunction with cytotoxic anticancer agent.Such carcinostatic agent can find the 13 edition the Merck index (2001) is inner.These carcinostatic agents comprise, but be never limited to, asparaginase, bleomycin, carboplatin, carmustine, Chlorambucil, cis-platinum, L-ASP, endoxan, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin, Zorubicin (Dx), epirubicin, Etoposide, 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna, methotrexate, ametycin, mitoxantrone, prednisolone, prednisone, Procarbazine, raloxifene, streptozocin, tamoxifen, Tioguanine, Hycamtin, vinealeucoblastine(VLB), vincristine(VCR) and vindesine.
Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: GoodmanandGilman'sThePharmacologicalBasisofTherapeutics (NinthEdition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but are never limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-azacytidine, CldAdo (cladribine), busulfan (busulfan), stilboestrol, 2,2'-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (fludarabinephosphate), Fluoxymesterone (fluoxymesterone), flutamide (flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (melphalan), mitotane (mitotane), taxol, pentostatin (pentostatin), N-phosphate base-L-Aspartic acid (PALA), Plicamycin (plicamycin), Me-CCNU (semustine), teniposide (teniposide), Uniteston, phosphinothioylidynetrisaziridine (thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
What other were suitable comprises newfound cytotoxic substance with the cytotoxin class carcinostatic agent of compound combined utilization of the present invention, comprising, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), capecitabine (capecitabine), Macrolide antitumour drug and derivative that is natural or synthesis thereof, Temozolomide (temozolomide) (Quinnetal., J.Clin.Oncol., 2003, 21 (4), 646-651), tositumomab (bexxar), Trabedectin(Vidaletal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, and kinesin spindle body protein inhibitor Eg5(Woodetal. abstract3181), Curr.Opin.Pharmacol., 2001, 1, 370-377).
Other embodiment is, compound of the present invention can in conjunction with other signal transduction inhibitors.What is interesting is signal transduction inhibitor using EGFR family as target, as EGFR, HER-2 and HER-4(Raymondetal., Drugs, 2000,60 (Suppl.l), 15-23; Hararietal., Oncogene, 2000,19 (53), 6102-6114) and their respective parts.Such reagent comprises, but is never limited to, and antibody therapy is as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also comprises, but is never limited to, and small molecule kinase inhibitors is as imatinib (imatinib), Sutent (sunitinib), Xarelto (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), AMN107 (nilotinib), lapatinibditosylate (lapatinib), Ke Zhuo is for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, pazopanib, Ah method is for Buddhist nun (afatinib), amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941(Folkesetal., J.Med.Chem., 2008,51,5522), BZE235 etc.
Other embodiment is, compound of the present invention can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824(Ottmannetal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, abstract3024), LBH-589(Becketal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, abstract3025), MS-275(Ryanetal., ProceedingsoftheAmericanAssociationofCancerResearch, 2004, 45, abstract2452), FR-901228(Piekarzetal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, and MGCDOI03(US6 abstract3028), 897, 220).
Other embodiment is, compound of the present invention can in conjunction with other carcinostatic agents as proteasome inhibitor and mTOR inhibitors.These comprise, but be never limited to, Velcade (bortezomib) (Mackayetal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004,23, Abstract3109) and CCI-779(Wuetal., ProceedingsoftheAmericanAssociationofCancerResearch, 2004,45, abstract3849).Compound of the present invention in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, can also include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition comprising compound of the present invention, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thus obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption (those compositions comprising an additional treatment agent are as described in the invention) of additional treatment agent in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises the amount of therapeutical agent as the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as sole active therapeutical agent.Comprise in the composition of additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.
the purposes of compound and composition
Above-claimed cpd provided by the invention and pharmaceutical composition can be used for the medicine for the preparation of protecting, processing, treat or alleviate proliferative disease, also may be used for the medicine for the preparation of suppression or Function protein kinase activity.
Specifically, in composition of the present invention compound amount can effectively detectably arrestin kinases as the activity of PI3K or mTOR.The deleterious effect of PI3K or mTOR signal response will to be treated or reduced to the compounds of this invention to patient as antitumor drug.
Compound of the present invention will be applied to, but never be limited to, and use the significant quantity of compound of the present invention or composition prevent patient's administration or treat patient's proliferative disease.Such disease comprises cancer, especially metastatic carcinoma; Atherosclerosis and pulmonary fibrosis.
The treatment being applied to knurl is comprised cancer and metastatic carcinoma by compound of the present invention, includes, but are not limited to further, cancer; As bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoetic tumor, as leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma; Marrow system hematopoetic tumor, as acute and chronic myelocytic leukemia, myelodysplastic syndrome and promyelocitic leukemia; The tumour of mesenchymal cell origin, as fibrosarcoma, rhabdosarcoma and other sarcomas, as soft tissue and cartilage; Maincenter peripheral nervous system knurl, as astrocytoma, neuroblastoma, neurospongioma and schwannoma; With other tumours, as melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma thyroid follicle knurl and Ka Bo Ji (family name) sarcoma.
Compound of the present invention and pharmaceutical composition also can be used for treating eye disease, and the new vessel of such as corneal graft rejection, eye is formed, retinal neovascularazation (comprising damage or the formation of metainfective new vessel); Diabetic retinopathy; Retrolental fibroplasia; Neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease, as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises the hemangiofibroma of baby's hemangioendothelioma, nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds are equally also used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention and pharmaceutical composition can also for the treatment of the situation relevant to diabetes as diabetic retinopathy and microangiopathies.Compound of the present invention and pharmaceutical composition are equally for the situation of cancer patients's volume of blood flow minimizing.Compound of the present invention and pharmaceutical composition reduce patient tumors transfer also has beneficial effect.
Compound of the present invention and pharmaceutical composition, except useful to human treatment, also can be applicable to veterinary treatment pet, the animal of introduced variety and the animal on farm, comprise Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and when salt etc., it also means single compound, salt etc.
Comprise the methods for the treatment of of compound of the present invention or composition administration, comprise the administration to patient's additional treatment agent (combination therapy) further, wherein additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition are as single formulation, or the compound separated or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or different time administration.The situation of the latter, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carries out.
The present invention comprises expressing the cytostatic method of PI3K or mTOR equally, and this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.
The invention provides the method suppressing PI3K or mTOR activity in biological sample, this method comprises and compound of the present invention or composition being contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of vitro, include, but not limited to, cell cultures or cell extraction; From the examination of living tissue material that Mammals or its extract obtain; Blood, saliva, urine, ight soil, seminal fluid, tears or other living tissue liquid substance and extract thereof.Suppress kinase activity in biological sample, particularly PI3K or mTOR active, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to, hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on the general condition, the severity of infection, special factor, administering mode etc. of race, age, patient.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, has been used to overcome restenosis (shrinking again of vessel wall after injury).But patient uses stem or other implantable devices to have the risk of clot formation or platelet activation.These disadvantageous effects can stop by using the pharmaceutically acceptable composition precoating device comprising compound of the present invention or alleviate.
The general preparation method of suitable dressing and the dressing of implantable device at document US6,099,562; US5,886,026; And US5,304, described by having in 121, dressing be typically biocompatible polymeric material as hydrogel polymer, poly-methyl two silicon ether, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester and composition thereof.Dressing can optionally further cover by suitable dressing, as fluoro Simethicone, polysaccharidase, polyoxyethylene glycol, phospholipid or their combination, carry out the feature of performance group compound Co ntrolled release.Another aspect of the present invention comprises the implantable device using compound of the present invention coating.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or provide " medicine storage institute " with polymkeric substance or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.
the synthetic method of compound
For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiments, only be to provide and put into practice method of the present invention.
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemicalCompany, ArcoChemicalCompanyandAlfaChemicalCompany, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited and Haiyang Chemical Plant, Qingdao buy and obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether are through sodium Metal 99.5 backflow drying and obtain.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, two triplet).Coupling constant hertz (Hz) represents.
The condition of Algorithm (MS) data is: Agilent1200 or Agilent6120SeriesLCMS(pillar model: ZorbaxSB-C18,2.1 × 30mm, 3.5 microns, 6min, and flow velocity is 0.6mL/min, and moving phase: 5-95%(is containing the CH of 0.1% formic acid 3cN) (containing the H of 0.1% formic acid 2o) ratio in, detects at 210/254nm UV, by low-response EFI pattern (ESI).
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), detects at 210nm and 254nm UV.Pillar operates usually at 40 DEG C.
The use of brief word below runs through the present invention:
BBr 3boron tribromide
Two diphenyl phosphine-1, the 1'-dinaphthalene of BINAP2,2'-
BOC, Boc tert-butoxycarbonyl
BSA bovine serum albumin
N-BuLi n-Butyl Lithium
CDC1 3deuterochloroform
CHCl 3chloroform
CH 2cl 2, DCM methylene dichloride
CH 3sO 2cl, MsCl Tosyl chloride
Cs 2cO 3cesium carbonate
Cu copper
CuI cuprous iodide
DAST diethylaminosulfur trifluoride
DBU1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
DEAD diethyl azodiformate
DIAD diisopropyl azodiformate
DIBAL diisobutyl aluminium hydride
DIEA, DIPEA diisopropyl ethyl amine
DMAP4-Dimethylamino pyridine
DMFN, N'-dimethyl formamide
DMSO dimethyl sulfoxide (DMSO)
DPPA diphenyl phosphate azide
EDCI1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, EA ethyl acetate
EtOH ethanol
Et2O ether
Et3N, TEA triethylamine
FBS foetal calf serum
Fe iron
G gram
H hour
HATUO-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
HBr Hydrogen bromide
HBTUO-benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate
HCl hydrochloric acid
H 2hydrogen
H 2o water
H 2o 2hydrogen peroxide
HOA c, A coH acetic acid
HOBt1-hydroxybenzotriazole
K 2cO 3salt of wormwood
KOH potassium hydroxide
KOAc Potassium ethanoate
LiHMDS LHMDS
LDA lithium diisopropyl amido
MCPBA metachloroperbenzoic acid
MeCN, CH 3cN acetonitrile
MeI methyl iodide
MeOH, CH 3oH methyl alcohol
2-MeTHF2-methyltetrahydrofuran
MgSO 4magnesium sulfate
ML, ml milliliter
Min minute
N 2nitrogen
NaBH 4sodium borohydride
NaBH 3cN sodium cyanoborohydride
NaCl sodium-chlor
NaClO 2textone
NaH sodium hydride
NaHCO 3sodium bicarbonate
NaH 2pO 4sODIUM PHOSPHATE, MONOBASIC
NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na 2sO 4sodium sulfate
Na 2sO 3s-WAT
NBSN-bromo-succinimide
NH 3ammonia
NH 4c1 ammonia chloride
NMPN-methyl-2-pyrrolidone
PBS phosphate buffered saline (PBS)
P (t-Bu) 3three (tertiary butyl) phosphine
Pd/C palladium/carbon
Pd 2(dba) 3two (dibenzyl subunit acetone) palladium
Pd (dppf) Cl 2two (diphenylphosphino) ferrocene palladium chloride of 1,1'-
Pd (dppf) Cl 2cH 2cl 2[two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex
Pd (OAc) 2palladium
Pd (OH) 2palladium hydroxide
Pd (PPh 3) 4tetrakis triphenylphosphine palladium
Pd (PPh 3) 2cl 2two (triphenylphosphine) palladium chloride
PE sherwood oil (60-90 DEG C)
POC1 3phosphorus oxychloride
I-PrOH Virahol
PyBop1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
TBAB Tetrabutyl amonium bromide
TBAHSO 44-butyl ammonium hydrogen sulfate
TBTUO-(1H-benzotriazole-1-base)-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester
TFA trifluoroacetic acid
TEAC bis-(tetraethyl ammonium) carbonate
THF tetrahydrofuran (THF)
Zn (CN) 2zinc cyanide
μ L microlitre
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.Unless otherwise indicated, each R 1, R 2with W, there is definition as described in the present invention, W 2the optional C replaced 5-12spiral shell bicyclic group, X 2the optional C replaced 3-6heterocyclic radical, R 3and R 4be H or C independently 1-4alkyl.
Synthetic schemes 1
Such as formula ( 6) the boron ester cpds shown in formula can be prepared by synthetic schemes 1:
First, nitropyridine derivatives ( 1) in acid condition, use reductive agent as Fe powder convert to aminocompound ( 2).Compound ( 2) and SULPHURYL CHLORIDE ( 3) react in the basic conditions, obtain bromo sulfonamide compounds ( 4), afterwards, bromo sulphonamide ( 4) and connection boric acid pinacol ester ( 5) under the existence of the Pd catalyzer be applicable to, there is Suzuki coupling, generate boron ester derivative (6).
Synthetic schemes 2
The part of compounds that formula (I) defines can be prepared by synthetic schemes 2:
Para-bromoaniline ( 7) and Michaelis acid ( 8) and triethly orthoacetate ( 9) in alcohol, carry out condensation, obtain compound ( 10), compound ( 10) high boiling solvent as: in dichlorobenzene backflow obtain the bromo-4-hydroxyquinoline of 6-( 11).Compound ( 11) in hydroxyl and chlorinating agent as phosphorus oxychloride, at relatively high temperatures, be obtained by reacting chloroquinoline compound ( 12), compound ( 11) continue with iodination reagent as sodium iodide, be obtained by reacting iodoquinoline compound ( 13).Iodoquinoline compound ( 13) and compound ( 14) in the presence of suitable catalysts, there is coupling or substitution reaction, obtain intermediate ( 15).Finally, compound ( 15) and boron ester derivative ( 6) at the Pd catalyzer be applicable to as under: two (triphenylphosphine) palladium chloride exists, there is Suzuki linked reaction, obtain PI3K and/or mTOR inhibitors (I).
Synthetic schemes 3
Other compounds in the present invention can be prepared by synthetic schemes 3:
The bromo-4-chloroquinoline of 6-is prepared according to the method in synthetic schemes 2 or additive method (12), compound ( 12) and spiral shell dicyclic compound ( 16) occur substitution reaction obtain quinoline ( 17).Then, compound ( 17) and boron ester derivative ( 6) at the Pd catalyzer be applicable to as under: two (triphenylphosphine) palladium chloride exists, there is Suzuki linked reaction, obtain PI3K and/or mTOR inhibitors ( 18), i.e. the compound that defines of formula (I).
Synthetic schemes 4
Other compounds in the present invention can be prepared by synthetic schemes 4:
According to the method in synthetic schemes 2 or additive method prepare the bromo-4-iodine quinoline of 6-( 13), compound ( 13) and Zn (CN) 2at the Pd catalyzer be applicable to as under: tetrakis triphenylphosphine palladium exists, there is linked reaction, obtain the bromo-4-cyano quinolines (19) of 6-.Then compound ( 19) and boron ester derivative ( 6) at the Pd catalyzer be applicable to as under: two (triphenylphosphine) palladium chloride exists, there is Suzuki coupling, obtain PI3K and/or mTOR inhibitors ( 20), i.e. the compound that defines of formula (I).
Synthetic schemes 5
Other compounds in the present invention can be prepared by synthetic schemes 5:
According to the method in synthetic schemes 2 or additive method prepare the bromo-4-iodine quinoline of 6-( 13), compound (13) and alkynyl compounds ( 21) in the presence of suitable catalysts, there is Sonogashira coupling, obtain hydroxylation and thing ( 22), compound ( 22) be obtained by reacting with methylsulfonyl chloride in the basic conditions sulphonate ( 23).Then, sulphonate ( 23) and heterogeneous ring compound ( 24) occur substitution reaction, obtain compound ( 25), finally, compound ( 25) and boron ester derivative ( 6) at the Pd catalyzer be applicable to as under: two (triphenylphosphine) palladium chloride exists, there is Suzuki linked reaction, obtain PI3K and/or mTOR inhibitors ( 26), i.e. the compound that defines of formula (I).
The present invention adopts following methods to carry out biological test to the compound shown in formula (I):
1, the generality of kinase assay describes
Kinase assay by detection mix γ- 33the myelin basic protein (MBP) of P-ATP has come.Prepare MBP (Sigma#M-1891) Tutofusin tris buffer salt solution (TBS of 20 μ g/mL; 50mMTrispH8.0,138mMNaCl, 2.7mMKCl), wrap by white 384 orifice plates (Greiner) of high associativity, every hole 60 μ L.4 DEG C, hatch 24 hours.Plate is washed 3 times afterwards with 100 μ LTBS.Kinase reaction is kinase buffer liquid (5mMHepespH7.6,15mMNaCl, 0.01% bovine serum albumin (Sigma#I-5506), the 10mMMgCl of 34 μ L at cumulative volume 2, 1mMDTT, 0.02%TritonX-100) in carry out.By compound dissolution in DMSO, add in each hole, the ultimate density of DMSO is 1%.Each data determination twice, the mensuration of each compound at least carries out twice test.Such as, the ultimate density of enzyme is 10nM or 20nM.Add do not have markd ATP (10 μMs) and γ- 33aTP (every hole 2 × 10 of P mark 6cpm, 3000Ci/mmole) start reaction.Reaction at room temperature concussion is carried out 1 hour.The PBS cleaning of 384 orifice plate 7x, then adds the scintillation solution of every hole 50 μ L.By WallacTrilux counter detected result.To those of ordinary skill in the art, this is only the one in numerous detection method, and other method also can.
The IC that above-mentioned test method can be inhibited 50and/or suppress constant K i.IC 50be defined as under test conditions, suppress compound concentration during 50% enzymic activity.The extension rate of 1/2log is utilized to make the curve comprising 10 concentration point, estimation IC 50value (such as, making a typical curve by following compound concentration: 10 μMs, 3 μMs, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).
Kinase assay in the present invention has been come (MilliporeUKLtd, DundeeTechnologyPark, DundeeDD21SW, UK) by Millipore company of Britain.
Result shows, compound provided by the invention has good restraining effect to lipid kinase PI3K and mTOR, also has good restraining effect to the growth of tumour.
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
the fluoro-N-of embodiment 1:2,4-bis-(5-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base)-2-methoxyl group pyrrole pyridine-3-base) benzsulfamide
step 1) the bromo-2-methoxyl group of 5--3-nitropyridine
At 0 DEG C, in MeOH (10mL) solution of sodium methylate (0.52g, 9.64mmol), add the chloro-3-nitropyridine (0.57g, 2.41mmol) of the bromo-2-of 5-.Reaction solution maintains 0 DEG C and stirs 1 hour, then returns to room temperature, continues stirring 18 hours.After cancellation that reaction solution adds water (20mL), be adjusted to pH7 with 3M hydrochloric acid, and filter.The organic phase be separated is through concentrating under reduced pressure, and obtaining title compound is light yellow solid (0.4g, 71.4%).
LC-MS(ESI,pos.ion)m/z:233[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.93(s,3H),8.08(s,1H),8.89(s,1H)。
step 2) the bromo-2-methoxypyridine of 5--3-amine
Bromo-for 5-2-methoxyl group-3-nitropyridine (0.4g, 1.72mmol) is suspended in EtOH (5mL) and H 2in the mixed solution of O (5mL), add Fe powder (0.38g, 6.87mmol) and NH wherein 4cl (0.39g, 7.21mmol).Reaction solution reflux, after 1 hour, is cooled to room temperature, and concentrating under reduced pressure.Raffinate EtOAc (10mL) dilution, gained mixture diatomite filtration.Filtrate extracts with EtOAc (10mLx3), and the organic phase of merging is washed through saturated aqueous common salt (10mL), anhydrous Na 2sO 4drying, and concentrating under reduced pressure, obtaining title compound is yellow solid (0.3g, 86%).
LC-MS(ESI,pos.ion)m/z：203[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.92(s,3H),4.86(s,2H),7.03(d,J=2.0Hz,1H),7.41(d,J=2.0Hz,1H)。
step 3) N-(the bromo-2-methoxypyridine of 5--3-base)-2,4 difluorobenzene sulphonamide
2,4 difluorobenzene-1-SULPHURYL CHLORIDE (16.47g, 77.5mmol) is added in pyridine (25mL) solution of 5-bromo-2-methoxypyridine-3-amine (6.3g, 31mmol).Reaction solution stirs after 24 hours at 23 DEG C, concentrating under reduced pressure, makes liquor capacity be reduced to original 1/2.Filter, collect solid, i-PrOH (5mLx2) and Et used successively by solid 2o (5mL) washes.Gained solid and NaOH (2.48g, 62mmol) are suspended in MeOH (25mL), after reaction solution stirs 1 hour at 23 DEG C, concentrating under reduced pressure.Raffinate DCM (20mL) and 2M hydrochloric acid (20mL) dilution, through 5%NaHCO 3after the aqueous solution is adjusted to pH7, extract with DCM (20mLx3).The organic phase merged is washed through saturated aqueous common salt (20mL), anhydrous Na 2sO 4drying, and concentrating under reduced pressure, obtaining title compound is light yellow solid (8.2g, 69.9%).
LC-MS(ESI,pos.ion)m/z:379[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.89(s,3H),6.90-7.01(m,2H),7.80-7.83(d,J=2.24Hz,1H),7.86-7.93(m,2H)。
step 4) 2,4-bis-fluoro-N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2- base) pyridin-3-yl) benzsulfamide
Under nitrogen protection, by N-(the bromo-2-methoxypyridine of 5--3-base)-2,4 difluorobenzene sulphonamide (0.5g, 1.31mmol), connection boric acid sodium alcohol ester (0.5g, 1.97mmol) and Pd (dppf) Cl frequently 2cH 2cl 2(80mg, 0.1mmol) is suspended in Isosorbide-5-Nitrae-dioxane (10mL), and adds KOAc (0.52g, 5.24mmol) wherein.Reaction solution after 3 hours, is cooled to room temperature 90 DEG C of heated and stirred.Mixed solution 5%NaHCO 3the aqueous solution (10mL) dilutes, and extracts with DCM (20mLx3).The organic phase saturated aqueous common salt (25mL) merged is washed, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (0.31g, 55.3%).
LC-MS(ESI,pos.ion)m/z:427[M+H] +。
step 5) 5-(((4-bromophenyl) is amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone
4-bromaniline (100g, 0.58mol) and triethyl orthoformate (103.5mL, 0.62mol) are suspended in EtOH (300mL), and add Michaelis acid (98.03g, 0.68mol) wherein.Reaction solution after 4 hours, is cooled to 0 DEG C 85 DEG C of mechanical stirring.Filter, collect solid, the cold ethanol (300mL) of solid is washed, and obtaining title compound is pale solid (176g, 92%).
LC-MS(ESI,pos.ion)m/z:326[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.75(s,6H),7.13(m,2H),7.55(m,2H),8.57(d,J=14.16Hz,1H),11.20(d,J=13.44Hz,1H)。
step 6) the bromo-4-hydroxyquinoline of 6-
By 5-(((4-bromophenyl) is amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone (50g, 1,2-dichlorobenzene (500mL) solution 154mmol) is heated to 188 DEG C, and stirring reaction is after 3.5 hours, be cooled to 0 DEG C, continue stirring 3 hours.Filter, collect solid, solid is through the tertiary ether of first (100mL) drip washing, and obtaining title compound is brown solid (30.6g, 87%).
LC-MS(ESI,pos.ion)m/z:224[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):6.32(d,J=7.32Hz,1H),7.48(d,J=9.08Hz,1H),7.77(dd,J=8.88Hz,2.32Hz,1H),7.95(d,J=7.32Hz,1H),8.34(d,J=2.28Hz,1H)。
step 7) the bromo-4-chloroquinoline of 6-
Slowly POCl is added in toluene (20mL) solution of the bromo-4-hydroxyquinoline (14.55g, 64.9mmol) of 6- 3(6.05mL, 64.9mmol).Reaction solution is cooled to 0 DEG C after stirring 4 hours in 115 DEG C, and adds DCM (400mL) dilution.Gained mixed solution uses the 4MNaOH aqueous solution (70mL) and salt solution (100mL) to wash successively, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.By residue recrystallization in normal heptane (150mL), obtaining title compound is yellow solid (5.5g, 32%).
LC-MS(ESI,pos.ion)m/z:242[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):7.50(d,J=4.72Hz,1H),7.82(dd,J=8.96Hz,2.16Hz,1H),7.98(d,J=8.92Hz,1H),7.95(d,J=2.16Hz,1H),8.34(d,J=4.68Hz,1H)。
step 8) the bromo-4-iodine quinoline of 6-
The HCl diethyl ether solution (7.4mL, 14.8mmol) of 2M is added in anhydrous THF (50mL) solution of 6-bromo-4-chloroquinoline (3g, 12.4mmol).Reaction solution stirring at room temperature is after 30 minutes, and concentrating under reduced pressure, obtaining 6-bromo-4-chloroquinoline hydrochloride is off-white color solid (3.46g).
Bromo-for 6-4-chloroquinoline hydrochloride (3.46g) is suspended in propionitrile (100mL), and adds anhydrous sodium iodide (9.3g, 62mmol) wherein.Reaction solution is cooled to room temperature after refluxing 96 hours, and uses 10%K successively 2cO 3the aqueous solution (50mL) and 5%Na 2sO 3the aqueous solution (20mL) processes.DCM (50mLx3) extraction of gained mixed solution, the organic phase of merging is washed through saturated aqueous common salt (50mL), anhydrous Na 2sO 4drying, and concentrating under reduced pressure, obtaining title compound is off-white color solid (3.4g, 82.3%).
LC-MS(ESI,pos.ion)m/z:334[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):7.78-7.83(m,1H),7.89-7.93(d,J=8.9Hz,1H),7.98-8.02(m,1H),8.21(s,1H),8.44-8.47(d,J=4.5Hz,1H)。
step 9) the bromo-4-of 6-(3-hydroxyl-1-propine-1-base) quinoline
By bromo-for 6-4-iodine quinoline (0.5g, 1.5mmol), Pd (PPh 3) 2cl 2(53mg, 75 μm of ol) and CuI (14.3mg, 75 μm of ol) are suspended in DMF (2mL), and add the third-2-alkynes-1-alcohol (84mg, 1.5mmol) and Et wherein 3n (0.63g, 6.2mmol).Reaction solution stirring at room temperature, after 1 hour, adds 5%NaHCO 3the aqueous solution (10mL) dilutes, and extracts with DCM (20mLx3).The organic phase saturated aqueous common salt (20mL) merged is washed, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.By residue recrystallization in EtOAc (5mL), obtaining title compound is light yellow solid (0.3g, 76.9%).
LC-MS(ESI,pos.ion)m/z:262[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):2.49(s,1H),4.68(s,2H),7.46-7.49(d,J=4.48Hz,1H),7.78-7.83(m,1H),7.96-8.00(d,J=8.96Hz,1H),8.35-8.38(d,J=2.16Hz,1H),8.84-8.88(d,J=4.48Hz,1H)。
step 10) 2,4-bis-fluoro-N-(5-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine -3-base) benzsulfamide
By bromo-for 6-4-(3-hydroxyl third-1-alkynes-1-base) quinoline (0.54g, 2.06mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.56g, 1.31mmol) and Pd (PPh 3) 2cl 2(175mg, 0.25mmol) is suspended in DMF (8mL) and H 2in O (1mL), and add Na wherein 2cO 3(0.6g, 7.5mmol).Reaction solution microwave reaction at 120 DEG C, after 20 minutes, is cooled to room temperature.Mixed solution 5%NaHCO 3(10mL) aqueous solution dilution, and extract with DCM (20mLx3).The organic phase saturated aqueous common salt (20mL) merged is washed, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (48mg, 8.6%).
LC-MS(ESI,pos.ion)m/z:482[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):2.22(s,1H),3.98(s,3H),4.69(s,2H),6.93-6.97(m,2H),7.52(d,J=15.6Hz,1H),7.89-7.92(m,2H),8.17-8.19(m,2H),8.25(d,J=22.8Hz,1H),8.37(d,J=20.4Hz,1H),8.89(d,J=4.4Hz,1H)。
the fluoro-N-of embodiment 2:2,4-bis-(5-(4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine -3-base) benzsulfamide
step 1) the bromo-4-of 6-(3-hydroxyl fourth-1-alkynes-1-base) quinoline
This step title compound prepares with reference to the method described by embodiment 1 step 9, namely uses the bromo-4-iodine quinoline (0.5g, 1.5mmol) of 6-, fourth-3-alkynes-2-alcohol (105mg, 1.5mmol), Pd (PPh 3) 2cl 2(53mg, 75 μm of ol), CuI (14.3g, 75 μm of ol) and Et 3dMF (2mL) the mixed solution preparation of N (0.63g, 6.2mmol), the thick product of gained is recrystallization in EtOAc (5mL), and obtaining title compound is light yellow solid (0.35g, 85.4%).
LC-MS(ESI,pos.ion)m/z:276[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.67(d,J=7.6Hz,3H),2.29(d,J=7.6Hz,1H),4.92-4.94(m,1H),7.48(d,J=4.4Hz,1H),7.79-7.82(m,1H),7.97(d,J=9.6Hz,1H),8.36(d,J=2.4Hz,1H),8.86(d,J=4.4Hz,1H)。
step 2) 2,4-bis-fluoro-N-(5-(4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3- base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxyl fourth-1-alkynes-1-base) quinoline (0.57g, 2.06mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.56g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2the mixed solution preparation of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (85mg, 13.4%).
LC-MS(ESI,pos.ion)m/z:496[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.70(m,3H),3.49(s,1H),3.98(s,3H),4.95(s,1H),6.93-6.97(m,2H),750(d,J=4.4Hz,1H),7.90(d,J=8.4Hz,2H),8.17(d,J=8.0Hz,2H),8.26(s,1H),8.36(s,1H),8.87(d,J=4.0Hz,1H)。
the fluoro-N-of embodiment 3:2,4-bis-(5-(4-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxy yl pyridines-3-base) benzsulfamide
step 1) the bromo-4-of 6-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline
This step title compound prepares with reference to the method described by embodiment 1 step 9, namely uses the bromo-4-iodine quinoline (0.5g, 1.5mmol) of 6-, 2-methyl fourth-3-alkynes-2-alcohol (126mg, 1.5mmol), Pd (PPh 3) 2cl 2(53mg, 75 μm of ol), CuI (14.3mg, 75 μm of ol) and Et 3dMF (2mL) the mixed solution preparation of N (0.63g, 6.2mmol), the thick product of gained is recrystallization in EtOAc (5mL), and obtaining title compound is light yellow solid (0.36g, 82.7%).
LC-MS(ESI,pos.ion)m/z:290[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.74(s,6H),2.19(s,1H),7.47(d,J=4.4Hz,1H),7.79-7.82(m,1H),7.97(d,J=7.6Hz,1H),8.34(d,J=2.4Hz,1H),8.86(d,J=4.4Hz,1H)。
step 2) 2,4-bis-fluoro-N-(5-(4-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxyl group pyridin-3-yl) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline (0.6g, 2.06mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.56g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (46mg, 6.9%).
LC-MS(ESI,pos.ion)m/z:510[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.76(s,6H),2.44(s,1H),3.97(s,3H),6.92-6.97(m,2H),7.49(d,J=4.4Hz,1H),7.89-7.93(m,2H),8.16(s,1H),8.16-8.20(m,1H),8.26(d,J=2.4Hz,1H),8.37(d,J=2.0Hz,1H),8.87(d,J=4.4Hz,1H)。
the fluoro-N-of embodiment 4:2,4-bis-(5-(4-(7-hydroxyl spiral shell [2.4] heptane-5-base) quinoline-6-base)-2-methoxyl group pyridin-3-yl) benzsulfamide
step 1) 5-(6-bromoquinoline-4-base)-5-azaspiro [2.4] heptane-7-alcohol
Under nitrogen protection, in DMF (2mL) suspension of the bromo-4-chloroquinoline (0.29g, 1.2mmol) of 6-, add 5-azaspiro [2.4] heptane-7-alcohol (0.34g, 3mmol).Reaction solution is cooled to room temperature after stirring 3 hours at 90 DEG C.Mixture adds CHCl 3(5mL) dilute, and wash with water (5mL).Gained solution is through anhydrous Na 2sO 4drying, concentrating under reduced pressure, obtaining title compound is light yellow solid (0.33g, 86.8%).
LC-MS(ESI,pos.ion)m/z:319[M+H] +。
step 2) 2,4-bis-fluoro-N-(5-(4-(7-hydroxyl spiral shell [2.4] heptane-5-base) quinoline-6-base)-2-methoxyl group pyrrole pyridine-3-base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 5-(6-bromoquinoline-4-base)-5-azaspiro [2.4] heptane-7-alcohol (0.66g, 2.06mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.56g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (90mg, 12.8%).
LC-MS(ESI,pos.ion)m/z:538[M+H] +。
the fluoro-N-of embodiment 5:2,4-bis-(2-methoxyl group-5-(4-(3-morpholine third-1-alkynes-1-base) quinoline-6-base) pyridine -3-base) benzsulfamide
step 1) 3-(6-bromoquinoline-4-base) third-2-alkynes-1-methanesulfonates
Under nitrogen protection, bromo-for 6-4-(3-hydroxyl third-1-alkynes-1-base) quinoline (1.66g, 6.33mmol) is dissolved in DCM (40mL), is cooled to-10 DEG C, adds Et successively wherein 3n (1.28g, 12.65mmol) and MsCl (1.09g, 9.5mmol).Reaction solution uses saturated NaHCO after stirring 1 hour at-10 DEG C 3the aqueous solution (8mL) cancellation, and return to room temperature.The organic phase be separated is through anhydrous Na 2sO 4drying, concentrating under reduced pressure, obtains title compound.Products therefrom is not purified, is directly used in next step reaction.
LC-MS(ESI,pos.ion)m/z:340[M+H] +。
step 2) 4-(3-(6-bromoquinoline-4-base) third-2-alkynes-1-base)quinoline
Morpholine (1.1g, 1.1mL, 12.6mmol) is added in MeCN (10mL) solution of 3-(6-bromoquinoline-4-base) third-2-alkynes-1-methanesulfonates.Reaction solution stirring at room temperature is after 12 hours, and add water (8mL) cancellation, and extracts with EtOAc (30mLx3).The organic phase saturated aqueous common salt (30mL) merged is washed, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is yellow solid (0.91g, 43%).
LC-MS(ESI,pos.ion)m/z:331[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):2.72(t,J=4.6Hz,4H),3.71(s,2H),3.81(t,J=4.6Hz,4H),7.50(d,J=4.4Hz,1H),7.80(dd,J=9.0Hz,2.2Hz,1H),8.40(d,J=9.0Hz,1H),8.39(d,J=2.2Hz,1H),8.85(d,J=4.5Hz,1H)。
step 3) 2,4-bis-fluoro-N-(2-methoxyl group-5-(4-(3-morpholine third-1-alkynes-1-base) quinoline-6-base) pyridine-3- base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 4-(3-(6-bromoquinoline-4-base) third-2-alkynes-1-base) morpholine (0.23g, 0.7mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.2g, 0.47mmol), Pd (PPh 3) 2cl 2(66mg, 94 μm of ol) and Na 2cO 3(0.3g, 2.82mmol) is suspended in DMF (4mL) and H 2prepare in the mixed solution of O (0.5mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (50mg, 19.4%).
LC-MS(ESI,pos.ion)m/z:551[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):2.75(t,J=4.56Hz,4H),3.71(s,2H),3.81(t,J=4.56Hz,4H),3.95(s,3H),6.90-6.99(m,2H),7.52(d,J=4.44Hz,1H),7.84-7.92(m,2H),8.12(d,J=2.24Hz,1H),8.18(d,J=8.6Hz,1H),8.25(d,J=2.2Hz,1H),8.37(d,J=1.84Hz,1H),8.86(d,J=4.48Hz,1H)。
the fluoro-N-of embodiment 6:2,4-bis-(2-methoxyl group-5-(4-(3-(pyrrolidin-1-yl) third-1-alkynes-1-base) quinoline -6-base) pyridin-3-yl) benzsulfamide
step 1) the bromo-4-of 6-(3-(pyrrolidin-1-yl) third-1-alkynes-1-base) quinoline
This step title compound prepares with reference to the method described by embodiment 5 step 2, namely 3-(6-bromoquinoline-4-base) third-2-alkynes-1-mesylate (0.91g is used, 2.67mmol) prepare with MeCN (10mL) solution of tetramethyleneimine (0.88mL, 10.7mmol).The thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is yellow solid (0.21g, 25%).
LC-MS(ESI,pos.ion)m/z:315[M+H] +。
step 2) 2,4-bis-fluoro-N-(2-methoxyl group-5-(4-(3-(pyrrolidin-1-yl) third-1-alkynes-1-base) quinoline-6- base) pyridin-3-yl) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-(pyrrolidin-1-yl) third-1-alkynes-1-base) quinoline (0.21g, 0.67mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.19g, 0.45mmol), Pd (PPh 3) 2cl 2(63mg, 90 μm of ol) and Na 2cO 3(0.28g, 2.67mmol) is suspended in DMF (4mL) and H 2prepare in the mixed solution of O (0.5mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (30mg, 12.6%).
LC-MS(ESI,pos.ion)m/z:535[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.88(m,4H),2.79(m,4H),3.96(s,3H),5.29(s,2H),6.90-6.99(m,2H),7.52(d,J=4.48Hz,1H),7.84-7.92(m,2H),8.12(d,J=2.24Hz,1H),8.18(d,J=8.76Hz,1H),8.25(d,J=2.24Hz,1H),8.37(d,J=1.96Hz,1H),8.86(d,J=4.44Hz,1H)。
the fluoro-N-of embodiment 7:2,4-bis-(2-methoxyl group-5-(4-(3-morpholine fourth-1-alkynes-1-base) quinoline-6-base) pyrrole pyridine-3-base) benzsulfamide
step 1) 4-(6-bromoquinoline-4-base) fourth-3-alkynes-2-methanesulfonates
This step title compound prepares with reference to the method described by embodiment 5 step 1, namely uses 6-bromo-4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline (0.5g, 1.81mmol), Et 3dCM (6mL) the solution preparation of N (0.51mL, 3.62mmol) and MsCl (0.21mL, 2.72mmol).The title compound obtained is not purified, is directly used in next step.
LC-MS(ESI,pos.ion)m/z:354[M+H] +。
step 2) 4-(4-(6-bromoquinoline-4-base) fourth-3-alkynes-2-base) morpholine
This step title compound prepares with reference to the method described by embodiment 5 step 2, namely 4-(6-bromoquinoline-4-base) fourth-3-alkynes-2-methanesulfonates (0.64g is used, 1.81mmol) prepare with MeCN (10mL) solution of morpholine (0.31mL, 3.61mmol).The thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is yellow, viscous liquid (0.38g, 61%).
LC-MS(ESI,pos.ion)m/z:345[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.54(d,J=7.04,3H),2.62-2.68(m,2H),2.78-2.86(m,2H),3.77-3.84(m,4H),3.84-3.99(m,1H),7.48(d,J=4.48Hz,1H),7.78(dd,J=8.92Hz,2.2Hz,1H),7.85(d,J=8.96Hz,1H),8.38(d,J=2.2Hz,1H),8.84(d,J=4.44Hz,1H)。
step 3) 2,4-bis-fluoro-N-(2-methoxyl group-5-(4-(3-morpholine fourth-1-alkynes-1-base) quinoline-6-base) pyridine-3- base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 4-(4-(6-bromoquinoline-4-base) fourth-3-alkynes-2-base) morpholine (0.23g, 0.67mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.19g, 0.45mmol), Pd (PPh 3) 2cl 2(63mg, 90 μm of ol) and Na 2cO 3(0.28g, 2.67mmol) is suspended in DMF (4mL) and H 2prepare in the mixed solution of O (0.5mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (67mg, 26%).
LC-MS(ESI,pos.ion)m/z:565[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.56(d,J=7.08Hz,3H),2.66-2.74(m,2H),2.83-2.92(m,2H),3.78-3.85(m,4H),3.85-3.94(m,1H),3.94(s,3H),6.90-6.98(m,2H),7.52(d,J=4.48Hz,1H),7.83-7.92(m,2H),8.13(d,J=2.24Hz,1H),8.17(d,J=8.72Hz,1H),8.27(d,J=2.24Hz,1H),8.41(d,J=1.96Hz,1H),8.87(d,J=4.48Hz,1H)。
embodiment 8:N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonyl amine
step 1) the bromo-4-of 6-((trimethyl silicon based) ethynyl) quinoline
Under nitrogen protection, by bromo-for 6-4-iodine quinoline (0.51g, 1.53mmol), Pd (PPh 3) 2cl 2(56mg, 80 μm of ol) and CuI (18.3mg, 96 μm of ol) are suspended in DMF (4mL), and add trimethylsilyl acetylene (0.22mL, 1.56mmol) and Et wherein 3n (1mL, 7.17mmol).Reaction solution stirring at room temperature, after 20 minutes, adds 5%NaHCO 3the aqueous solution (30mL) dilutes, and uses CHCl 3(50mL) extract.The organic phase washed with water (50mL) be separated is washed, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is yellow powder (0.43g, 94.2%).
LC-MS(ESI, pos.ion)m/z:304[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):0.35(s,9H),7.71(d,J=4.4Hz,1H),7.98(dd,J=2.2Hz,8.9Hz,1H),8.04(d,J=8.9Hz,1H),8.29(d,J=2.1Hz,1H),8.94(d,J=4.4Hz,1H)。
step 2) 2,4-bis-fluoro-N-(2-methoxyl group-5-(4-((trimethyl silicon based) ethynyl) quinoline-6-base) pyridine -3-base) benzsulfamide
Under nitrogen protection; by bromo-for 6-4-((trimethyl silicon based) ethynyl) quinoline (0.43g, 1.41mmol), 2; the fluoro-N-of 4-bis-(2-methoxyl group-5-(4; 4,5,5-tetramethyl--1; 3; 2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.56g, 1.35mmol), Pd (PPh 3) 2cl 2(0.13g, 0.19mmol) is suspended in Isosorbide-5-Nitrae-dioxane (12mL) and H 2in O (2mL), and add Na wherein 2cO 3(0.66g, 6.23mmol).Reaction solution is cooled to room temperature after stirring 30 minutes at 90 DEG C.Mixture is added 5%NaHCO 3the aqueous solution (10mL) dilutes, and extracts with DCM (20mL).The organic phase anhydrous Na merged 2sO 4drying, and concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/3) purifying, and obtaining title compound is yellow oil (0.27g, 28%).
LC-MS(ESI,pos.ion)m/z:524[M+H] +。
step 3) N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
By 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4-((trimethyl silicon based) ethynyl) quinoline-6-base) pyridin-3-yl) benzsulfamide (3.86g, 7.73mmol) be dissolved in MeOH (150mL) and THF (60mL), and add MeOH (4mL) solution of KOH (0.83g, 14.82mmol) wherein.Reaction solution stirring at room temperature is after 2 hours, and concentrating under reduced pressure, residue use water (100mL) and MeOH (5mL) dilute, and extract with DCM (100mLx3).The organic phase anhydrous Na merged 2sO 4drying, and concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/3) purifying, and obtaining title compound is pink crystal (1.44g, 43.3%).
LC-MS(ESI,pos.ion)m/z:452[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):3.70(s,3H),5.13(s,1H),7.23(td,J=2.1Hz,8.2Hz,1H),7.58(td,J=2.5Hz,9.5Hz,1H),7.75(d,J=4.4Hz,1H),7.80(td,J=6.4Hz,8.5Hz,1H),7.97(d,J=2.3Hz,1H),8.13(dd,J=2.0Hz,8.8Hz,1H),,8.18(d,J=8.7Hz,1H),8.28(d,J=1.8Hz,1H),8.46(d,J=1.8Hz,1H),8.94(d,J=4.4Hz,1H),10.45(s,1H)。
embodiment 9:N-(5-(4-((1H-pyrazoles-4-base) ethynyl) quinoline-6-base)-2-methoxypyridine-3- base)-2,4 difluorobenzene sulphonamide
step 1) 4-((trimethyl silicon based) ethynyl)-1H-pyrazoles
By iodo-for 4-1H-pyrazoles (2.91g, 15mmol), Pd (PPh 3) 2cl 2(1.1g, 1.57mmol) and CuI (0.29g, 1.52mmol) are suspended in EtOH (25mL) and Et 3in the mixed solution of N (6mL), and add trimethylsilyl acetylene (2.5mL, 17.58mmol) wherein.Reaction solution is cooled to room temperature after stirring 4 hours at 70 DEG C, and concentrating under reduced pressure.By raffinate EtOAc (30mL) dilution, filter.Filtrate reduced in volume, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=3/2) purifying, and obtaining title compound is orange solids (1.97g, 79.9%).
LC-MS(ESI,pos.ion)m/z:165[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):0.19(s,9H),7.65(s,1H),8.06(s,1H),13.11(s,1H)。
step 2) 4-ethynyl-1H-pyrazoles
To 4-((trimethyl silicon based) ethynyl)-1H-pyrazoles (1.97g, MeOH (6mL) solution of KOH (1.36g, 24.29mmol) is added in MeOH (40mL) solution 11.99mmol).Reaction solution stirring at room temperature is after 5 hours, concentrating under reduced pressure.It is white powder (0.48g, 43.5%) that residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=5/2) purifying.
LC-MS(ESI,pos.ion)m/z:93[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):3.93(s,1H),7.65(s,1H),8.04(s,1H),13.08(s,1H)。
step 3) 4-((1H-pyrazoles-4-base) ethynyl)-6-bromoquinoline
Under nitrogen protection, by bromo-for 6-4-iodine quinoline (1g, 3mmol), Pd (PPh 3) 2cl 2(0.11g, 0.16mmol), CuI (36mg, 0.19mmol) and 4-ethynyl-1H-pyrazoles (0.28g, 3mmol) are suspended in DMF (8mL), and add Et wherein 3n (2mL, 14.34mmol).After reaction solution stirs 1 hour at 90 DEG C, be cooled to room temperature, mixture adds 5%Na 2cO 3the aqueous solution (20mL) dilutes, and extracts with DCM (40mL).The organic phase washed with water (40mL) merged is washed, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is white powder (0.53g, 59.7%).
LC-MS(ESI,pos.ion)m/z:298[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):7.71(d,J=4.5Hz,1H),7.96(m,1H),7.99(d,J=2.16Hz,1H),8.03(d,J=8.9Hz,1H),8.41(d,J=1.9Hz,1H),8.94(d,J=4.5Hz,1H)。
step 4) N-(5-(4-((1H-pyrazoles-4-base) ethynyl) quinoline-6-base)-2-methoxypyridine-3- base)-2,4 difluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 4-((1H-pyrazoles-4-base) ethynyl)-6-bromoquinoline (0.38g, 1.28mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.54g, 1.27mmol), PdCl 2(dppf) CH 2cl 2(0.2g, 0.24mmol) and Na 2cO 3(0.67g, 6.32mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is buff powder (51mg, 7.7%).
LC-MS(ESI,pos.ion)m/z:518[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):3.71(s,3H),5.13(s,1H),7.20(td,J=1.7Hz,8.4Hz,1H),7.55(td,J=2.4Hz,9.8Hz,1H),7.68(d,J=4.5Hz,1H),7.77(td,J=6.5Hz,8.8Hz,1H),7.98(s,1H),8.10(dd,J=2.3Hz,7.6Hz,1H),,8.14(d,J=1.8Hz,1H),8.17(d,J=8.7Hz,1H),8.37(s,1H),8.42(s,1H),8.52(d,J=2.1Hz,1H),8.91(d,J=4.4Hz,1H),13.41(s,1H)。
the fluoro-N-of embodiment 10:2,4-bis-(5-(4-((4-hydroxy piperidine-4-base) ethynyl) quinoline-6-base)-2-methoxy yl pyridines-3-base) benzsulfamide
step 1) 1-(tertbutyloxycarbonyl)-4-((trimethyl silicon based) ethynyl) piperidines-4-alcohol
Under nitrogen protection, trimethylsilyl acetylene (8.5mL, 46.07mmol) is dissolved in dry THF (40mL), is cooled to-40 DEG C, slowly adds n-BuLi (9.8mL, 24.5mmol) wherein.Reaction solution is cooled to-78 DEG C, is added dry THF (10mL) solution of 1-Boc-piperidin-4-one-(4.03g, 20.23mmol) subsequently by duplex pin wherein after stirring 1 hour at-40 DEG C.Reaction solution stirs 1 hour at-78 DEG C, returns to room temperature, and continues stirring 12 hours.Reaction is finished, and adds saturated NH 4the Cl aqueous solution (15mL) cancellation.Gained mixture adds H 2o (50mL) dilutes, and extracts with EtOAc (30mLx3).The organic phase anhydrous Na merged 2sO 4drying, concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying, and obtaining title compound is pale yellow crystals (6.08g, 94%).
LC-MS(ESI,pos.ion)m/z:298[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):0.16(s,9H),1.45(s,9H),1.84(td,J=1.7Hz,2H),2.03(s,2H),2.43(s,1H),3.20(td,2H),3.77(s,2H)。
step 2) 1-(tertbutyloxycarbonyl)-4-ethynyl piperidines-4-alcohol
By 1-(tertbutyloxycarbonyl)-4-((trimethyl silicon based) ethynyl) piperidines-4-alcohol (3.06g, 10.29mmol) be dissolved in MeOH (40mL), and add MeOH (4mL) solution of KOH (1.38g, 24.64mmol) wherein.Reaction solution stirring at room temperature is after 6 hours, and add water (40mL) dilution, and extract with EtOAc (50mLx4).Organic phase is through anhydrous Na 2sO 4drying, concentrating under reduced pressure, obtaining title compound is buff powder (1.91g, 75.9%).
LC-MS(ESI,pos.ion)m/z:226[M+H] +。
step 3) 4-((6-bromoquinoline-4-base) ethynyl)-1-(tertbutyloxycarbonyl) piperidines-4-alcohol
This step title compound prepares with reference to the method described by embodiment 1 step 9, namely 1-(tertbutyloxycarbonyl)-4-ethynyl piperidines-4-alcohol (0.7g, 3.11mmol) is used, the bromo-4-iodine quinoline of 6-(1g, 3.11mmol), Pd (PPh 3) 2cl 2(0.12g, 0.17mmol), CuI (46mg, 0.24mmol) and Et 3n (2mL, DMF (8mL) solution preparation 14.34mmol), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=7/3) purifying, and obtaining title compound is light yellow solid (1.24g, 92.74%).
LC-MS(ESI,pos.ion)m/z:431[M+H] +。
step 4) N-(5-(4-((1-(tertbutyloxycarbonyl)-4-hydroxy piperidine-4-base) ethynyl) quinoline-6-base)-2-first oxygen yl pyridines-3-base)-2,4 difluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 4-((6-bromoquinoline-4-base) ethynyl)-1-(tertbutyloxycarbonyl) piperidines-4-alcohol (0.55g, 1.28mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.54g, 1.27mmol), PdCl 2(dppf) CH 2cl 2(0.2g, 0.24mmol) and Na 2cO 3(0.67 g, 6.32mmol) and be suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/3) purifying, and obtaining title compound is yellow oil (0.37g, 44.4%).
LC-MS(ESI,pos.ion)m/z:651[M+H] +。
step 5) 2,4-bis-fluoro-N-(5-(4-((4-hydroxy piperidine-4-base) ethynyl) quinoline-6-base)-2-methoxyl group pyridin-3-yl) benzsulfamide
By N-(5-(4-((1-(tertbutyloxycarbonyl)-4-hydroxy piperidine-4-base) ethynyl) quinoline-6-base)-2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (0.37g, 0.57mmol) be dissolved in anhydrous DCM (20mL), and under room temperature, add saturated HCl ethyl acetate solution (6mL, 15mmol) wherein.Reaction solution stirring at room temperature, after 16 hours, is filtered.By gained solid 5%NaHCO 3the aqueous solution (100mL) dilutes, and extracts with the mixed solution ((50mL:1mL) x3) of DCM and MeOH.Organic phase is through anhydrous Na 2sO 4drying, concentrating under reduced pressure, residue is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is yellow powder (90mg, 28.73%).
LC-MS(ESI,pos.ion)m/z:551[M+H] + ；
1HNMR(400MHz,DMSO-d 6)δ(ppm):2.14(2H),2.24(2H),3.26(2H),3.51(2H),3.73(s,3H),6.42(s,1H),7.18(td,J=2.2Hz,8.4Hz,1H),7.48(td,J=1.7Hz,9.4Hz,1H),7.69(d,J=4.4Hz,1H),7.81(td,J=6.6Hz,8.6Hz,1H),7.99(d,J=2.1Hz,1H),8.09(dd,J=6.9Hz,1.9Hz,1H),8.16(d,J=8.8Hz,1H),8.34(d,J=1.8Hz,2H),8.91(d,J=4.4Hz,1H)。
the fluoro-N-of embodiment 11:2,4-bis-(2-methoxyl group-5-(4-((1-methyl isophthalic acid H-pyrazoles-4-base) ethynyl) quinoline quinoline-6-base) pyridin-3-yl) benzsulfamide
step 1) 4-iodo-1-methyl isophthalic acid H-pyrazoles
Under nitrogen protection; by iodo-for 4-1H-pyrazoles (3.88g; 20mmol) be dissolved in DMF (50mL); be cooled to 0 DEG C; add NaH (1.66g, 55.33mmol, 80% is scattered in mineral oil) wherein; after mixture stirs 10 minutes at 0 DEG C, continue slowly to add CH wherein 3i (2.5mL, 38.76mmol).Reaction solution stirring at room temperature is after 22 hours, and add water (100mL) cancellation, and extracts with EtOAc (200mL).Organic phase is through Na 2sO 4drying, concentrating under reduced pressure, obtaining title compound is light yellow solid (3.99g, 95.9%).
LC-MS(ESI,pos.ion)m/z:209[M+H] +。
step 2) 1-methyl-4-((trimethyl silicon based) ethynyl)-1H-pyrazoles
This step title compound prepares with reference to the method described by embodiment 9 step 1, namely uses 4-iodo-1-methyl isophthalic acid H-pyrazoles (3.99g, 19.18mmol), trimethylsilyl acetylene (3mL, 21.26mmol), Pd (PPh 3) 2cl 2(1.33g, 1.9mmol), CuI (0.36g, 1.89mmol) and Et 3etOH (40mL) the mixed solution preparation of N (8mL), gained residue, through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying, obtains thick product, and compound is not purified is directly used in next step.
LC-MS(ESI,pos.ion)m/z:179[M+H] +。
step 3) 4-ethynyl-1-methyl isophthalic acid H-pyrazoles
This step title compound prepares with reference to the method described by embodiment 8 step 3, namely MeOH (36mL) the solution preparation of 1-methyl-4-((trimethyl silicon based) ethynyl)-1H-pyrazoles and KOH (2.26g, 40.36mmol) is used.Thick product is through silica gel column chromatography (PE/EtOAc (v/v)=10/3) purifying, and obtaining title compound is yellow oil (0.55g, two step total recoverys are 27.1%).
LC-MS(ESI,pos.ion)m/z:107[M+H] +。
step 4) the bromo-4-of 6-((1-methyl isophthalic acid H-pyrazoles-4-base) ethynyl) quinoline
Under nitrogen protection, 4-ethynyl-1-methyl isophthalic acid H-pyrazoles (0.55g, 5.19mmol) is dissolved in DMF (10mL), and adds the bromo-4-iodine quinoline (1.73g, 5.19mmol) of 6-wherein, Pd (PPh 3) 2cl 2(0.19g, 0.27mmol), CuI (0.12g, 0.63mmol) and Et 3n (4mL).Reaction solution is warming up to backflow after stirring 2 hours at 90 DEG C, continues stirring 1 hour.Mixture is cooled to room temperature, adds 5%Na 2cO 3(50mL) aqueous solution dilution, and extract with the mixed solution ((100mL:1mL) x3) of DCM and MeOH.The organic phases washed with water merged, anhydrous Na 2sO 4drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is yellow powder (0.77g, 47.5%).
LC-MS(ESI,pos.ion)m/z:312[M+H] +。
step 5) 2,4-bis-fluoro-N-(2-methoxyl group-5-(4-((1-methyl isophthalic acid H-pyrazoles-4-base) ethynyl) quinoline-6- base) pyridin-3-yl) benzsulfamide
Under nitrogen protection; by bromo-for 6-4-((1-methyl isophthalic acid H-pyrazoles-4-base) ethynyl) quinoline (0.55g, 1.76mmol), 2; the fluoro-N-of 4-bis-(2-methoxyl group-5-(4; 4,5,5-tetramethyl--1; 3; 2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.55g, 1.29mmol), PdCl 2(dppf) CH 2cl 2(0.13g, 0.16mmol) is suspended in DMF (8mL) and H 2in O (1mL), and add Na wherein 2cO 3(0.67g, 6.32mmol).After reaction solution stirs 1 hour at 154 DEG C, be cooled to room temperature, mixed solution adds 5%NaHCO 3the aqueous solution (10mL) dilutes, and extracts with DCM (20mL).Organic phase anhydrous Na 2sO 4drying, and concentrating under reduced pressure, gained residue is through purification by silica gel column chromatography (PE/EtOAc (v/v)=5/3), and obtaining title compound is buff powder (226mg, 33%).
LC-MS(ESI,pos.ion)m/z:532[M+H] +;
1HNMR(400MHz,DMSO-d 6)δ(ppm):3.72(s,3H),3.91(s,3H),7.21(td,J=2.0Hz,8.3Hz,1H),7.6(td,J=2.4Hz,9.4Hz,1H),7.68(d,J=4.5Hz,1H),7.80(td,J=6.4Hz,8.6Hz,1H),7.93(s,1H),8.145(m,3H),8.32(s,1H),8.405(d,J=1.3Hz,1H),8.53(d,J=2.3Hz,1H),8.91(d,J=4.5Hz,1H),10.45(s,1H)。
embodiment 12:N-(5-(4-cyano quinolines-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
step 1) the bromo-4-cyano quinolines of 6-
Under nitrogen protection, bromo-for 6-4-iodine quinoline (1.32g, 4mmol) is dissolved in DMF (10mL), and adds Zn (CN) wherein 2(235mg, 2mmol) and Pd (PPh 3) 4(924mg, 0.8mmol).Reaction solution microwave reaction at 120 DEG C, after 30 minutes, is cooled to room temperature.Filtered by mixed solution, filtrate reduced in volume, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (0.5g, 54%).
LC-MS(ESI,pos.ion)m/z:234.1[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):7.76(d,J=4.36Hz,1H),7.94(dd,J=8.96Hz,2.12Hz,1H),8.08(d,J=8.96Hz,1H),8.36(d,J=2.04Hz,1H),9.05(d,J=4.36Hz,1H)；
13CNMR(100MHz,CDCl 3)δ(ppm):115.1,117.7,123.9,125.5,126.8,127.2,132.0,134.9,146.7,149.7。
step 2) N-(5-(4-cyano quinolines-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
By 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.64g, 1.5mmol), the bromo-4-cyano quinolines of 6-(348mg, 1.5mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (15mL), and add PdCl wherein 2(dppf) CH 2cl 2(184mg, 0.23mmol) and Na 2cO 3(636mg, 6mmol).Reaction solution is cooled to room temperature after stirring 2 hours at 90 DEG C, filters.Filtrate reduced in volume, residue is through purification by silica gel column chromatography (PE/EtOAc (v/v)=1/1), and obtaining title compound is white solid (245mg, 36%).
LC-MS(ESI,pos.ion)m/z:453[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):4.01(s,3H),6.96(td,J=8.48Hz,2.36Hz,1H),7.08(td,J=8.62Hz,1.64Hz,1H),7.40(s,1H),7.78(d,J=4.32Hz,1H),8.01(dd,J=8.80Hz,1.64Hz,1H),8.03-8.05(m,1H),8.06(d,J=2.20Hz,1H),8.15(d,J=1.80Hz,1H),8.23(d,J=2.20Hz,1H),8.29(d,J=8.76Hz,1H),9.05(d,J=4.32Hz,1H)；
13CNMR(100MHz,CDCl 3)δ(ppm):54.3,105.9,112.5,115.5,118.7,121.0,122.2,125.4,125.6,126.1,129.1,130.3,131.3,132.8,132.9,138.2,140.6,147.5,149.5,154.3,165.1,167.7。
the fluoro-N-of embodiment 13:4-(5-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3- base) benzsulfamide
step 1) N-(the bromo-2-methoxypyridine of 5--3-base)-4-fluorobenzenesulfonamide
This step title compound prepares with reference to the method described by embodiment 1 step 3, namely the bromo-2-methoxypyridine of 5--3-amine (6.3g is used, 31mmol) prepare with pyridine (25mL) solution of 4-fluorophenyl-1-SULPHURYL CHLORIDE (15.08g, 77.5mmol).Gained title compound is light yellow solid (9.12g, 81.4%).
LC-MS(ESI,pos.ion)m/z:361[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.82(s,3H),7.16(m,2H),7.84(m,2H),7.79(d,J=2.0Hz,2H)。
step 2) the fluoro-N-of 4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyrrole pyridine-3-base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 4, namely N-(the bromo-2-methoxypyridine of 5--3-base)-4-fluorobenzenesulfonamide (0.5g is used, 1.38mmol), connection boric acid is sodium alcohol ester (0.53g frequently, 2.07mmol), Pd (dppf) Cl 2cH 2cl 2isosorbide-5-Nitrae-dioxane (10mL) the mixed solution preparation of (80mg, 0.1mmol) and KOAc (0.54g, 5.54mmol).The thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (0.29g, 51.3%).
LC-MS(ESI,pos.ion)m/z:409[M+H] +。
step 3) the fluoro-N-of 4-(5-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the fluoro-N-of 4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.53g, 1.31mmol), the bromo-4-of 6-(3-hydroxyl third-1-alkynes-1-base) quinoline (0.54g, 2.06mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (59mg, 9.8%).
LC-MS(ESI,pos.ion)m/z:464[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):2.20-2.24(m,1H),3.89(s,3H),4.69(d,J=6.4Hz,2H),6.94(s,1H),7.12-7.16(m,1H),7.52(d,J=4.4Hz,1H),7.82-7.86(m,2H),7.92-7.95(m,1H),8.19(d,J=8.8Hz,1H),8.24(d,J=2.0Hz,1H),8.28(d,J=2.4Hz,1H),8.41(d,J=2.0Hz,1H),8.88(d,J=4.8Hz,1H)。
the fluoro-N-of embodiment 14:4-(5-(4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3- base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxyl fourth-1-alkynes-1-base) quinoline (0.57g, 2.06mmol), the fluoro-N-of 4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.53g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (11.3mg, 1.8%).
LC-MS(ESI,pos.ion)m/z:478[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.69(d,J=7.6Hz,3H),2.04(s,1H),3.89(s,3H),4.95(s,1H),7.11-7.15(m,2H),7.50(d,J=4.4Hz,2H),7.83-7.86(m,2H),7.93(d,J=8.8Hz,1H),8.17-8.26(m,2H),8.40(s,1H),8.87(d,J=4.8Hz,1H)。
the fluoro-N-of embodiment 15:4-(5-(4-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxyl group pyridin-3-yl) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline (0.6g, 2.06mmol), the fluoro-N-of 4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.53g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (12.8mg, 2%).
LC-MS(ESI,pos.ion)m/z:492[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.75(s,6H),3.89(s,3H),6.98(s,1H),7.11-7.15(m,1H),7.49(d,J=4.4Hz,1H),7.82-7.85(m,2H),7.93(d,J=8.4Hz,1H),8.18(d,J=8.4Hz,1H),8.26(s,2H),8.40(s,1H),8.87(d,J=4.4Hz,1H)。
the fluoro-N-of embodiment 16:4-(5-(4-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) quinoline-6-base)-2-first oxygen yl pyridines-3-base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 5-(6-bromoquinoline-4-base)-5-azaspiro [2.4] heptane-7-alcohol (0.66g, 2.06mmol), the fluoro-N-of 4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.53g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (18mg, 2.7%).
LC-MS(ESI,pos.ion)m/z:520[M+H] +。
embodiment 17:N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide
This step title compound prepares with reference to the method described by embodiment 8 step 2, by the bromo-4-of 6-((trimethyl silicon based) ethynyl) quinoline (457mg, 1.5mmol), the fluoro-N-of 4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (735mg, 1.8mmol), PdCl 2(dppf) CH 2cl 2(184mg, 0.23mmol) and Na 2cO 3(795mg, 7.5mmol) is suspended in Isosorbide-5-Nitrae-dioxane (15mL) and H 2prepare in the mixed solution of O (3mL), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/2) purifying, and obtaining title compound is white solid (23.5mg, 4%).
LC-MS(ESI,pos.ion)m/z:434[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.74(s,1H),3.90(s,3H),7.02(s,1H),7.15(t,J=8.44Hz,2H),7.60(d,J=4.44Hz,1H),7.86(dd,J=8.80Hz,5.00Hz,2H),7.91(dd,J=8.72Hz,1.92Hz,1H),8.14(d,J=2.12Hz,1H),8.21(d,J=8.76Hz,1H),8.25(d,J=2.16Hz,1H),8.37(d,J=1.80Hz,1H),8.90(d,J=4.44Hz,1H)。
embodiment 18:N-(the chloro-5-of 2-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl)-2,4-bis- fluorobenzenesulfonamide
step 1) N-(the bromo-2-chloropyridine of 5--3-base)-2,4 difluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 3, namely the bromo-2-chloropyridine of 5--3-amine (6.43g is used, 31mmol) He 2,4-difluorophenyl-1-SULPHURYL CHLORIDE (16.47g, pyridine (25mL) mixed solution preparation 77.5mmol), obtaining title compound is light yellow solid (8.48g, 71.3%).
LC-MS(ESI,pos.ion)m/z:383[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):7.26(td,J=2.56Hz,8.50Hz,1H),7.57(td,J=2.48Hz,9.60Hz,1H),7.82(td,J=6.24Hz,8.64Hz,1H),8.03(d,J=7.28Hz,1H),8.45(d,J=1.84Hz,1H)。
step 2) N-(the chloro-5-of 2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-3- base)-2,4 difluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 4, namely N-(the bromo-2-chloropyridine of 5--3-base)-2 is used, 4-difluorobenzenesulfonamide (0.5g, 1.31mmol), connection boric acid is sodium alcohol ester (0.5g frequently, 1.97mmol), Pd (dppf) Cl 2cH 2cl 2(80mg, 0.1mmol) with KOAc (0.52g, 5.24mmol) 1, prepared by 4-dioxane (10mL) mixed solution, the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, obtaining title compound is white solid (0.35g, 62.5%).
LC-MS(ESI,pos.ion)m/z:431[M+H] +。
step 3) N-(the chloro-5-of 2-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl)-2,4-difluoros benzsulfamide
Under nitrogen protection; by bromo-for 6-4-(3-hydroxyl third-1-alkynes-1-base) quinoline (0.37g, 1.41mmol), N-(the chloro-5-(4 of 2-; 4; 5,5-tetramethyl--1,3; 2-dioxaborolanes-2-base) pyridin-3-yl)-2; 4-difluorobenzenesulfonamide (568mg, 1.32mmol), PdCl 2(dppf) CH 2cl 2(0.2g, 0.24mmol) is suspended in Isosorbide-5-Nitrae-dioxane (12mL) and H 2in the mixed solution of O (1mL), and add Na wherein 2cO 3(0.6g, 5.66mmol).Reaction solution after 1.5 hours 90 DEG C of backflows, is cooled to room temperature, adds CHCl 3(20mL) and 5%NaHCO 3the aqueous solution (10mL) dilutes.The organic phase anhydrous Na be separated 2sO 4drying, and concentrating under reduced pressure, gained residue is through purification by silica gel column chromatography (PE/EtOAc (v/v)=1/1), and obtaining title compound is white powder (75mg, 11.7%).
LC-MS(ESI,pos.ion)m/z:486[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):4.53(s,2H),5.32(s,1H),7.25(td,J=2.04Hz,8.20Hz,1H),7.59(t,J=8.68Hz,1H),7.69(d,J=4.44Hz,1H),7.85(td,J=6.24Hz,8.48Hz,1H),8.16(d,J=1.96Hz,8.76Hz,1H),8.21(d,J=4.56Hz,1H),8.22(s,1H),8.46(d,J=1.84Hz,1H),8.75(s,1H),8.95(d,J=4.36Hz,1H)。
embodiment 19:N-(the chloro-5-of 2-(4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl)-2,4-bis- fluorobenzenesulfonamide
Under nitrogen protection; by bromo-for 6-4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline (379mg, 1.38mmol), N-(the chloro-5-(4 of 2-; 4; 5,5-tetramethyl--1,3; 2-dioxaborolanes-2-base) pyridin-3-yl)-2; 4-difluorobenzenesulfonamide (568mg, 1.32mmol), PdCl 2(dppf) CH 2cl 2(0.2g, 0.24mmol) is suspended in Isosorbide-5-Nitrae-dioxane (12mL) and H 2in the mixed solution of O (1mL), and add Na wherein 2cO 3(0.6g, 5.66mmol).Reaction solution adds DCM (20mL) and 5%NaHCO after stirring 1 hour at 100 DEG C 3the aqueous solution (10mL) dilutes.The organic phase anhydrous Na be separated 2sO 4drying, and concentrating under reduced pressure, residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is light yellow solid (88mg, 13.4%).
LC-MS(ESI,pos.ion)m/z:500[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):1.53(d,J=6.64Hz,3H),2.22(q,J=6.56Hz,1H),5.76(s,1H),7.25(td,J=2.08Hz,8.40Hz,1H),7.58(td,J=2.00Hz,9.52Hz,1H),7.67(d,J=4.44Hz,1H),7.84(td,J=6.24Hz,8.60Hz,1H),8.16(d,J=1.74Hz,8.76Hz,1H),8.21(d,J=8.88Hz,1H),8.23(d,J=2.24Hz,1H),8.89(d,J=1.80Hz,1H),8.75(s,1H),8.94(d,J=4.44Hz,1H)。
embodiment 20:N-(the chloro-5-of 2-(4-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline-6-base) pyridine-3- base)-2,4 difluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline (0.6g, 2.06mmol), N-(the chloro-5-(4 of 2-, 4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.56g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through purification by silica gel column chromatography (DCM/MeOH (v/v)=50/1), and obtaining title compound is light yellow solid (39mg, 5.8%).
LC-MS(ESI,pos.ion)m/z:514[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.54(s,6H),2.39(s,1H),6.95-6.99(m,2H),7.51-7.53(m,2H),7.92-7.95(m,2H),8.22(d,J=8.8Hz,1H),8.40-8.45(m,1H),8.53(d,J=2.0Hz,1H),8.92(d,J=4.8Hz,1H)。
embodiment 21:N-(5-(4-(7-amino-5-azaspiro [2.4] heptane-5-base) quinoline-6-base)-2-chloropyridine -3-base)-2,4 difluorobenzene sulfonamide hydrochloride
step 1) 5-(6-bromoquinoline-4-base)-N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine
This step title compound prepares with reference to the method described by embodiment 4 step 1, namely N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine (0.64g is used, 3mmol) with the bromo-4-chloroquinoline of 6-(0.29g, DMF (2mL) mixed solution preparation 1.2mmol), obtaining title compound is light yellow solid (0.33g, 86.8%).
LC-MS(ESI,pos.ion)m/z:418[M+H] +。
step 2) N-(5-(4-(7-((tertbutyloxycarbonyl) is amino)-5-azaspiro [2.4] heptane-5-base) quinoline-6- base)-2-chloropyridine-3-base)-2,4 difluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 5-(6-bromoquinoline-4-base)-N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine (0.86g, 2.06mmol), N-(the chloro-5-(4 of 2-, 4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.56g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through purification by silica gel column chromatography (DCM/MeOH (v/v)=50/1), and obtaining title compound is light yellow solid (98mg, 11.8%).
LC-MS(ESI,pos.ion)m/z:641[M+H] +。
step 3) N-(5-(4-(7-amino-5-azaspiro [2.4] heptane-5-base) quinoline-6-base)-2-chloropyridine-3- base)-2,4 difluorobenzene sulfonamide hydrochloride
By N-(5-(4-(7-((tertbutyloxycarbonyl) is amino)-5-azaspiro [2.4] heptane-5-base) quinoline-6-base)-2-chloropyridine-3-base)-2,4-difluorobenzenesulfonamide (50mg, 80 μm of ol) be suspended in EtOAc (1mL), and add saturated HCl ethyl acetate solution (1mL) wherein.Reaction solution stirring at room temperature is after 1 hour, and concentrating under reduced pressure, gained residual solids is recrystallization in DCM (2mL), and obtaining title compound is light yellow solid (35mg, 83.4%).
LC-MS(ESI,pos.ion)m/z:541[M+H] +。
embodiment 22:N-(the chloro-5-of 2-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl)-4-fluorobenzene sulphonamide
step 1) N-(the bromo-2-chloropyridine of 5--3-base)-4-fluorobenzenesulfonamide
This step title compound prepares with reference to the method described by embodiment 1 step 3, namely the bromo-2-chloropyridine of 5--3-amine (6.43g is used, 31mmol) with 4-fluorophenyl-1-SULPHURYL CHLORIDE (15.08g, pyridine (25mL) solution preparation 77.5mmol), obtaining title compound is light yellow solid (8.58g, 75.7%).
LC-MS(ESI,pos.ion)m/z:365[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):7.16-7.21(m,2H),7.81-7.85(m,2H),8.14(d,J=2.4Hz,1H),8.19(d,J=2.0Hz,1H)。
step 2) N-(the chloro-5-of 2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-3- base)-4-fluorobenzenesulfonamide
This step title compound prepares with reference to the method described by embodiment 1 step 4, namely N-(the bromo-2-chloropyridine of 5--3-base)-4-fluorobenzenesulfonamide (0.48g is used, 1.31mmol), connection boric acid is sodium alcohol ester (0.5g frequently, 1.97mmol), Pd (dppf) Cl 2cH 2cl 2isosorbide-5-Nitrae-dioxane (10mL) the mixed solution preparation of (80mg, 0.1mmol) and KOAc (0.52g, 5.24mmol).The thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (0.38g, 67.8%).
LC-MS(ESI,pos.ion)m/z:413[M+H] +。
step 3) N-(the chloro-5-of 2-(4-(3-hydroxyl third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl)-4-fluorobenzene sulphur acid amides
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxyl third-1-alkynes-1-base) quinoline (0.54g, 2.06mmol), N-(the chloro-5-of 2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl)-4-fluorobenzenesulfonamide (0.54g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through purification by silica gel column chromatography (DCM/MeOH (v/v)=50/1), and obtaining title compound is light yellow solid (25mg, 3.9%).
LC-MS(ESI,pos.ion)m/z:468[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):2.01(s,1H),4.63(s,2H),7.27-7.28(m,1H),7.44-7.47(m,1H),7.51-7.56(m,1H),7.62-7.66(m,1H),7.85-7.89(m,1H),7.96-7.99(m,1H),8.08(d,J=8.4Hz,1H),8.29(d,J=2.4Hz,1H),8.40(d,J=1.6Hz,1H),8.53(d,J=2.4Hz,1H),8.80(d,J=4.0Hz,1H)。
embodiment 23:N-(the chloro-5-of 2-(4-(3-hydroxyl fourth-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl)-4-fluorobenzene sulphonamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by the bromo-4-of 6-(3-hydroxyl fourth-1-alkynes-1-base) quinoline (0.57g, 2.06mmol), N-(the chloro-5-of 2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl)-4-fluorobenzenesulfonamide (0.54g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and obtaining title compound is light yellow solid (30mg, 4.7%).
LC-MS(ESI,pos.ion)m/z:482[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.68(d,J=6.0Hz,3H),4.94-4.99(m,1H),7.17-7.23(m,2H),7.55-7.57(m,1H),7.85-7.88(m,2H),7.97-8.00(m,1H),8.26(d,J=8.8Hz,1H),8.46(d,J=2.4Hz,1H),8.50(d,J=2.0Hz,1H),8.56(d,J=2.4Hz,1H),8.95(d,J=4.4Hz,1H)。
embodiment 24:N-(the chloro-5-of 2-(4-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) quinoline-6-base) pyridine -3-base)-4-fluorobenzenesulfonamide
This step title compound prepares with reference to the method described by embodiment 1 step 10, by 5-(6-bromoquinoline-4-base)-5-azaspiro [2.4] heptane-7-alcohol (0.66g, 2.06mmol), N-(the chloro-5-of 2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl)-4-fluorobenzenesulfonamide (0.54g, 1.31mmol), Pd (PPh 3) 2cl 2(175mg, 0.25mmol) and Na 2cO 3(0.6g, 5.66mmol) is suspended in DMF (8mL) and H 2prepare in the mixed solution of O (1mL), the thick product of gained is through purification by silica gel column chromatography (DCM/MeOH (v/v)=50/1), and obtaining title compound is light yellow solid (82mg, 11.9%).
LC-MS(ESI,pos.ion)m/z:524[M+H] +。
embodiment 25:N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base) benzsulfamide
step 1) N-(the bromo-2-methoxypyridine of 5--3-base) benzsulfamidein pyridine (10mL) mixed solution of 5-bromo-2-methoxypyridine-3-amine (2.51g, 12.34mmol), add benzene sulfonyl chloride (3.2mL, 25mmol), reaction solution stirring at room temperature, after 22 hours, adds H 2o (100mL) dilutes.Filter, collect solid, solid H 2o (10mL) washs.Gained solid and NaOH (1.02g, 25.5mmol) are suspended in MeOH (20mL), stirring at room temperature is after 2 hours, concentrating under reduced pressure.Mixture adds DCM (20mL) and 2M hydrochloric acid (20mL) dilution, and uses 5%NaHCO 3the aqueous solution is adjusted to pH7.The organic phase be separated is through anhydrous Na 2sO 4drying, concentrating under reduced pressure, obtaining title compound is yellow powder (3.92g, 92.6%).
LC-MS(ESI,pos.ion)m/z:343[M+H] +。
step 2) N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-3- base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 4, namely N-(the bromo-2-methoxypyridine of 5--3-base) benzsulfamide (3.92g is used, 11.42mmol), connection boric acid is sodium alcohol ester (4.34g frequently, 17.09mmol), Pd (dppf) Cl 2cH 2cl 2isosorbide-5-Nitrae-dioxane (60mL) the mixed solution preparation of (0.95g, 1.16mmol) and KOAc (4.48g, 45.64mmol).The thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is buff powder (2.44g, 54.8%).
LC-MS(ESI,pos.ion)m/z:391[M+H] +。
step 3) N-(2-methoxyl group-5-(4-((trimethyl silicon based) ethynyl) quinoline-6-base) pyridin-3-yl) benzene sulphur acid amides
This step title compound prepares with reference to the method described by embodiment 8 step 2, by the bromo-4-of 6-((trimethyl silicon based) ethynyl) quinoline (0.43,1.41mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.55g, 1.41mmol), PdCl 2(dppf) CH 2cl 2(0.12g, 0.15mmol) and Na 2cO 3(0.66g, 6.23mmol) is suspended in Isosorbide-5-Nitrae-dioxane (10mL) and H 2prepare in the mixed solution of O (2mL), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/3) purifying, and obtaining title compound is pale powder (0.26g, 37.8%).
LC-MS(ESI,pos.ion)m/z:488.2[M+H] +。
step 4) N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 8 step 3, by N-(2-methoxyl group-5-(4-((trimethyl silicon based) ethynyl) quinoline-6-base) pyridin-3-yl) benzsulfamide (0.26g, 0.54mmol) with KOH (0.11g, 1.96mmol) be dissolved in the mixed solution of THF (5mL) and MeOH (6mL) and prepare, thick product is washed through MeOH (2mL), obtaining title compound is pale yellow crystals (0.18g, 80.2%).
LC-MS(ESI,pos.ion)m/z:416[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.75(s,1H),3.88(s,3H),7.09(s,1H),7.48(m,2H),7.58(m,2H),7.85(m,2H),7.91(dd,J=2.1Hz,8.8Hz,1H),8.20(m,3H),8.38(d,J=2.0Hz,1H),8.89(d,J=4.4Hz,1H)。
embodiment 26:N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide
step 1) N-(the bromo-2-methoxypyridine of 5--3-base)-2-fluorobenzenesulfonamidethis step title compound prepares with reference to the method described by embodiment 25 step 1, namely the bromo-2-methoxypyridine of 5--3-amine (2.5g is used, 12.31mmol) with 2-fluorophenylsulfonyl chloride (4.91g, pyridine (10mL) solution preparation 25.1mmol), obtaining title compound is yellow powder (3.94g, 88.6%).
LC-MS(ESI,pos.ion)m/z:361[M+H] +。
step 2) the fluoro-N-of 2-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyrrole pyridine-3-base) benzsulfamide
This step title compound prepares with reference to the method described by embodiment 1 step 4, namely N-(the bromo-2-methoxypyridine of 5--3-base)-2-fluorobenzenesulfonamide (3.94g is used, 10.94mmol), connection boric acid is sodium alcohol ester (5.56g frequently, 21.89mmol), Pd (dppf) Cl 2cH 2cl 2(0.93g, 1.14mmol) with KOAc (4.43g, 45.14mmol) 1, prepared by 4-dioxane (60mL) mixed solution, the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/2) purifying, obtaining title compound is pink solid (2.98g, 66.7%).
LC-MS(ESI,pos.ion)m/z:409[M+H] +。
step 3) the fluoro-N-of 2-(2-methoxyl group-5-(4-((trimethyl silicon based) ethynyl) quinoline-6-base) pyridyl-3- base) benzsulfamide
Under nitrogen protection; by bromo-for 6-4-((trimethyl silicon based) ethynyl) quinoline (0.43g; 1.41mmol); the fluoro-N-of 2-(2-methoxyl group-5-(4,4,5; 5-tetramethyl--1; 3,2-dioxaborolanes-2-base) pyridin-3-yl) benzsulfamide (0.58g, 1.42mmol) and PdCl 2(dppf) CH 2cl 2(0.17g, 0.21mmol) is suspended in Isosorbide-5-Nitrae-dioxane (10mL) and H 2in O (2mL), and add Na wherein 2cO 3(0.66g, 6.23mmol).Reaction solution is cooled to room temperature, adds DCM (20mL) and 5%NaHCO after stirring 40 minutes at 97 DEG C 3the aqueous solution (10mL) dilutes.The organic phase anhydrous Na be separated 2sO 4drying, and concentrating under reduced pressure.Residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=5/3) purifying, and this product is directly used in next step.
LC-MS(ESI,pos.ion)m/z:506[M+H] +。
step 4) N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide
This step title compound prepares with reference to the method described by embodiment 8 step 3, by the fluoro-N-of 2-(2-methoxyl group-5-(4-((trimethyl silicon based) ethynyl) quinoline-6-base) pyridyl-3-base) benzsulfamide and KOH (0.17g, 3.04mmol) be dissolved in the mixed solution of THF (5mL) and MeOH (5mL) and prepare, the thick product of gained is through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purifying, obtaining title compound is light orange powder (73mg, two step total recoverys are 11.9%).
LC-MS(ESI,pos.ion)m/z:434[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):3.69(s,3H),4.12(s,1H),7.35(t,J=7.44Hz,1H),7.47(t,J=10.0Hz,1H),7.74(m,3H),7.95(d,J=2.2Hz,1H),8.12(m,2H),8.26(d,J=1.6Hz,1H),8.45(d,J=2.2Hz,1H),8.92(d,J=4.4Hz,1H),10.33(s,1H)。
embodiment 27:N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base) Toluidrin
step 1) N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrinthis step title compound prepares with reference to the method described by embodiment 25 step 1, namely the bromo-2-methoxypyridine of 5--3-amine (2.5g is used, 12.31mmol) with MsCl (2.81g, pyridine (10mL) solution preparation 24.55mmol), obtaining title compound is white powder (2.46g, 71.1%).
LC-MS(ESI,pos.ion)m/z:281[M+H] +。
step 2) N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-3- base) Toluidrin
This step title compound prepares with reference to the method described by embodiment 1 step 4, by N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrin (2.46g, 8.78mmol), connection boric acid is sodium alcohol ester (3.34g frequently, 13.15mmol), Pd (dppf) Cl 2cH 2cl 2(0.72g, 0.88mmol) with KOAc (3.63g, 36.99mmol) be suspended in 1, preparation in 4-dioxane (50mL), thick product is through silica gel column chromatography (PE/EtOAc (v/v)=5/2) purifying, obtaining title compound is white powder (1.72g, 59.9%).
LC-MS(ESI,pos.ion)m/z:329[M+H] +。
step 3) N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base) Toluidrin
This step title compound prepares with reference to the method described by embodiment 8 step 2, by the bromo-4-of 6-((trimethyl silicon based) ethynyl) quinoline (0.46g, 1.51mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) Toluidrin (0.49g, 1.5mmol), PdCl 2(dppf) CH 2cl 2(0.12g, 0.15mmol) and Na 2cO 3(0.64g, 6.04mmol) is suspended in Isosorbide-5-Nitrae-dioxane (10mL) and H 2prepare in the mixed solution of O (2mL), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/4) purifying, and obtaining title compound is white powder (0.14g, 26.4%).
LC-MS(ESI,pos.ion)m/z:354[M+H] +；
1HNMR(400MHz,DMSO-d 6)δ(ppm):3.11(s,3H),4.00(s,3H),5.09(s,1H),7.74(d,J=3.9Hz,1H),8.02(s,1H),8.16(m,2H),8.33(s,1H),8.46(s,1H),8.92(d,J=4.1Hz,1H),9.44(s,1H)。
embodiment 28:N-(5-(4-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine -3-base) Toluidrin
This step title compound prepares with reference to the method described by embodiment 8 step 2, by the bromo-4-of 6-(3-hydroxy-3-methyl fourth-1-alkynes-1-base) quinoline (434mg, 1.5mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) Toluidrin (589mg, 1.8mmol), PdCl 2(dppf) CH 2cl 2(184mg, 0.23mmol) and Na 2cO 3(795mg, 7.5mmol) is suspended in Isosorbide-5-Nitrae-dioxane (15mL) and H 2prepare in the mixed solution of O (3mL), the thick product of gained is after purification by silica gel column chromatography (PE/EtOAc (v/v)=1/1), wash with MeOH (20mL), obtaining title compound is lightpink powder (0.27g, 44%).
LC-MS(ESI,pos.ion)m/z:412[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.74(s,6H),3.08(s,3H),3.13(s,1H),4.08(s,3H),6.92(br.s,1H),7.45(d,J=4.48Hz,1H),7.93(dd,J=8.76Hz,2.12Hz,1H),8.16(d,J=8.76Hz,1H),8.20(d,J=2.24Hz,1H),8.30(d,J=2.24Hz,1H),8.36(d,J=1.96Hz,1H),8.36(d,J=4.48Hz,1H)；
13CNMR(100MHz,CDCl 3)δ(ppm):31.3,39.9,54.3,65.7,77.2,104.9,121.5,123.5,126.2,128.0,128.3,129.6,129.9,130.5,135.5,140.1,147.3,149.8,154.0。
embodiment 29:N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base) cyclopropyl-sulfonylamide
step 1) N-(the bromo-2-methoxypyridine of 5--3-base) cyclopropyl-sulfonylamidethis step title compound prepares with reference to the method described by embodiment 25 step 1, namely the bromo-2-methoxypyridine of 5--3-amine (1.5g is used, 7.39mmol) with ring third SULPHURYL CHLORIDE (2.22g, pyridine (6mL) solution preparation 14.82mmol), obtaining title compound is white powder (2.04g, 89.9%).
MS(ESI,pos.ion)m/z:307[M+H] +。
step 2) N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-3- base) cyclopropyl-sulfonylamide
This step title compound prepares with reference to the method described by embodiment 1 step 4, namely N-(the bromo-2-methoxypyridine of 5--3-base) cyclopropyl-sulfonylamide (2g is used, 6.51mmol), connection boric acid is sodium alcohol ester (2.48g frequently, 9.77mmol), Pd (dppf) Cl 2cH 2cl 2(0.53g, 0.65mmol) with KOAc (2.72g, 27.22mmol) 1, prepared by 4-dioxane (50mL) mixed solution, the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/2) purifying, obtaining title compound is white powder (2.09g, 90.62%).
LC-MS(ESI,pos.ion)m/z:355[M+H] +。
step 3) N-(5-(4-ethynyl quinoline-6-base)-2-methoxypyridine-3-base) cyclopropyl-sulfonylamide
This step title compound prepares with reference to the method described by embodiment 8 step 2, by the bromo-4-of 6-((trimethyl silicon based) ethynyl) quinoline (0.47g, 1.55mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridin-3-yl) cyclopropyl-sulfonylamide (0.55g, 1.55mmol), PdCl 2(dppf) CH 2cl 2(0.14g, 0.17mmol) and Na 2cO 3(0.71g, 6.7mmol) is suspended in Isosorbide-5-Nitrae-dioxane (10mL) and H 2prepare in the mixed solution of O (2mL), the thick product of gained is through silica gel column chromatography (PE/EtOAc (v/v)=5/3) purifying, and obtaining title compound is white powder (0.14g, 23.8%).
LC-MS(ESI,pos.ion)m/z:380[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):1.02(m,2H),1.25(m,2H),2.55(m,1H),3.73(m,1H),4.10(s,3H),6.82(s,1H),7.59(d,J=4.4Hz,1H),7.95(dd,J=2.1Hz,8.8Hz,1H),8.19(m,2H),8.33(d,J=2.2Hz,1H),8.42(d,J=1.9Hz,1H),8.89(d,J=4.4Hz,1H)。
Biological test
Method and apparatus mentioned above is adopted to carry out bioanalysis to compound prepared by the embodiment of the present invention.
Embodiment A kinase assay
pI3Kp110 α/p85 α (m) [cold test]
PI3Kp110 α/p85 α (m) is hatched in the buffered soln containing 10 μMs of phosphoric acid acyl inositol-4,5-bisphosphate and MgATP (concentration is determined according to demand).After adding ATP solution, start reaction.After incubated at room temperature 30 minutes, the stop buffer added wherein containing EDTA and vitamin H phosphatidylinositols-3,4,5-triphosphoric acid carrys out termination reaction.Finally, add detection damping fluid, comprise the anti-GST monoclonal antibody of europium mark, the GRP1PH structural domain of GST mark and streptavidin-allophycocyanin.Orifice plate is reading under time resolved fluorescence pattern, and homogeneous phase time discrimination fluorescence (HTRF) signal is determined by equation HTRF=10000x (Em665nm/Em620nm).
mTOR(h)
MTOR (h) is the HEPES of 7.0,1mMEDTA in 50mMpH value, 0.01% polysorbas20,2mg/mL substrate, 3mM Manganous chloride tetrahydrate and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Reaction is started after adding MnATP mixture.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution termination reaction wherein.Be mottled being distributed on P30 strainer by 10 μ L reaction solutions, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
Carry out PI3K (h) and mTOR (h) according to method mentioned above to the compound that the embodiment of the present invention provides to measure, result see table 1, the kinase assay result that table 1 provides for the embodiment of the present invention.
The kinase assay result of the compound that table 1 embodiment of the present invention provides
As shown in Table 1, compound of the present invention generally demonstrates very high activity in the test of PI3K (h) and mTOR (h).
Finally, it should be noted that other modes are used for implementing the present invention in addition.Correspondingly, embodiments of the invention to be illustratively described, but be not limited to content described in the invention, may be also amendment done within the scope of the present invention or equivalents added in the claims.All publications that the present invention quotes or patent all will as reference of the present invention.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.

Claims (12)

1. such as formula the compound shown in (I) or its steric isomer, tautomer, pharmacy acceptable salt:
Wherein:
W is C 5-12spiral shell bicyclic group, wherein, described C 5-12spiral shell bicyclic group optionally by 1,2,3 or 4 independently selected from D, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced;
R 1for H, D, Cl, OR a, C 1-6alkyl or C 3-6cycloalkyl, wherein, described each C 1-6alkyl and C 3-6cycloalkyl is optionally independently selected from D by 1,2,3 or 4, F, Cl, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced;
R 2for C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl or comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl, wherein, described each C 1-6alkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl) ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl and comprise 1,2,3 or 4 the heteroatomic 5-10 being independently selected from O, S and N former molecular heteroaryl and be optionally independently selected from D by 1,2,3 or 4, F, Cl, Br, CN, N 3, OR a, SR aand NR ar bsubstituting group replaced; With
Each R aand R bbe H, C independently 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical, C 6-10aryl, comprises heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N ,-(C 1-4alkylidene group)-(C 3-6heterocyclic radical) ,-(C 1-4alkylidene group)-(C 6-10aryl) or-(C 1-4alkylidene group)-(comprising heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N); Work as R aand R bwhen being connected with same nitrogen-atoms, R a, R b, and together with the nitrogen-atoms connected with them, optionally can also form substituted or non-substituted 3-8 former molecular heterocyclic radical.
2. compound according to claim 1, wherein, R 1for H, D, Cl or OR a.
3. compound according to claim 1, wherein, R 2for C 1-6alkyl, C 3-6cycloalkyl or C 6-10aryl, wherein, described each C 1-6alkyl, C 3-6cycloalkyl and C 6-10aryl optionally replaced by 1,2,3 or 4 substituting group independently selected from D, F and Cl.
4. compound according to claim 1, wherein, R 1for Cl or OMe.
5. compound according to claim 1, wherein, each R aand R bbe H, C independently 1-3alkyl, C 1-3haloalkyl, C 3-6cycloalkyl, C 3-6heterocyclic radical, C 6-10aryl, comprises heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N ,-(C 1-2alkylidene group)-(C 3-6heterocyclic radical) ,-(C 1-2alkylidene group)-(C 6-10aryl) or-(C 1-2alkylidene group)-(comprising heteroatomic 5-10 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N); Work as R aand R bwhen being connected with same nitrogen-atoms, R a, R b, and together with the nitrogen-atoms connected with them, that can also optionally form replacement or non-substituted 3-8 former molecular heterocyclic radical.
6. compound according to claim 1, has one of them structure following:
7. a pharmaceutical composition, comprises the compound described in claim 1-6 any one and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
8. pharmaceutical composition according to claim 7, also comprises additional treatment agent, and described additional treatment agent is selected from chemotherapeutic agent, antiproliferative, is used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis or their combination.
9. pharmaceutical composition according to claim 8, described additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelinanalogues), megestrol (megestrol), prednisone (prednisone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferonalfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximabvedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
10. one kind uses compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-9 any one for the preparation of the purposes of medicine protecting, process, treat or alleviate patient's proliferative disease.
The purposes of 11. compound or pharmaceutical compositions according to claim 10, wherein, described proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, the cancer of the brain, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
12. 1 kinds use the compound described in claim 1-6 any one or the next purposes for the preparation of the medicine of suppression or adjustment phosphoinositide 3-kinase and/or mTOR activity in biological sample of the pharmaceutical composition described in claim 7-9 any one.
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