CN103420986A - Compound replacing quinoidines as well as using method and application of compound - Google Patents
Compound replacing quinoidines as well as using method and application of compound Download PDFInfo
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- CN103420986A CN103420986A CN2013101796080A CN201310179608A CN103420986A CN 103420986 A CN103420986 A CN 103420986A CN 2013101796080 A CN2013101796080 A CN 2013101796080A CN 201310179608 A CN201310179608 A CN 201310179608A CN 103420986 A CN103420986 A CN 103420986A
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Abstract
The invention provides a novel compound replacing quinoidines, acceptable salts of the novel compound on pharmacy and pharmaceutical preparations of the novel compound. The novel compound is used for adjusting the activity of a protein kinase, and an intercellular signal response or an intracellular signal response. The invention meanwhile relates to pharmaceutical compositions comprising the novel compound and a method for treating the highly-proliferative diseases of mammals and particularly treating the highly-proliferative diseases of humans through the pharmaceutical compositions.
Description
Invention field
The invention relates to quinoline compound and the salt thereof of new replacement, be used for the treatment of the disease of higher proliferation, for example the cancer relevant with Mammals.The present invention is especially about the compound of arrestin tyrosine kinase activity, the activity of the application of the invention compound arrestin Tyrosylprotein kinase, thus suppress iuntercellular or intracellular signal response.The present invention is about with compound of the present invention or the composition that pharmaceutically comprises the compounds of this invention, treating Mammals equally, especially the method for mankind's hyperproliferative disease.
Background of invention
Protein kinase has represented the protein that a large class plays an important role in cellular function retentive control and various cytopathic regulation and control.Respond approach by conditioning signal, protein kinase is being controlled the metabolism of cell, the carrying out of cell division cycle, cell proliferation and apoptosis, differentiation and survival.Current existing 500 kinds of human kinase groups, wherein reach 150 kinds more than relevant to mankind's various diseases, as inflammatory diseases, cardiovascular disorder, metabolism class disease, nerve degenerative diseases and cancer.
The list of wherein said kinases part comprises abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes and Zap70.
The subfamily that protein tyrosine kinase is protein kinase, can also range growth factor receptors (as: Axl, VEGFR, c-Met (HGFR), EGFR, PDGFR and FGFR) or non-acceptor (as: c-src and bcr-abl) kinases.Receptor tyrosine kinase is transmembrane protein, can make somatomedin cross over cytolemma and keep the extracellular calmodulin binding domain CaM, and cross-film district and intracellular portion be as having kinase whose function, and phosphorylation is in a concrete protein-tyrosine residue, thereby affects cell proliferation.Abnormal expression or protein kinase activity can directly involve the pathogeny of numerous human cancers.
Vasculogenesis is to form the process of new capillary vessel from the blood vessels that prestore, and this allelotaxis for embryo in women/jenny reproduction recycle system plays critical effect, and the while also also plays a part very important to the healing of inflammatory diseases and wound.As everyone knows, some disease and associated angiogenesis out of control, for example eye neovascularization, retinopathy (comprising diabetic retinopathy), the macular degeneration relevant with the age, psoriasis, hemangioblastoma, vascular tumor, arteriosclerosis, inflammatory diseases, for example rheumatoid or rheumatic inflammatory disease, sacroiliitis (rheumatoid arthritis) particularly, perhaps other chronic inflammatory diseases, chronic asthma for example, artery or transplanting artery are atherosis, endometriosis and proliferative disease, for example common described noumenal tumour and liquid tumors (for example leukemia).Noumenal tumour, depend on especially vasculogenesis and supply with nutrition, nutrient, reach the refuse processing to it.In addition, vasculogenesis can promote the growth of cell or other position transfer tumours equally.
New vasculogenesis is the process of a high complexity and hight coordinate, and its requirement has a large amount of factors stimulated growth, but vascular endothelial growth factor (VEGFR) signal response represents critical rate-limiting step usually in physiology and pathology vasculogenesis.VEGF combination activated receptor type tyrosine kinase.The VEGFR hypotype of having been confirmed by the mankind has three kinds: VEGFR-1(Flt-1), VEGFR-2(KDR/Flk-1) and VEGFR-3(Flt-4).The main cell of VEGFR-2 mediation VEGF is replied, especially mitotic division and vasculogenesis.VEGFR-1 regulates the conduction of VEGFR-2 signal or isolates VEGF and VEGFR-2 as virtual/decoy receptor.The expression of VEGFR-1 is regulated by the anoxic forward, and it is similar that its mechanism and VEGF are regulated by HIF-1; The type of its function based on cell and developmental stage and change.（Stuttfeld?E,Ballmer-Hofer?K(September?2009),"Structure?and?function?of?VEGF?receptors".IUBMB?Life?61(9):915-22.）
VEGFR-2 is mitotic division and the survival that mainly mediates vascular endothelial cell (EC), keeps vasculogenesis and microvascular perviousness simultaneously.Therefore, the activity that directly suppresses kinases VEGFR-2 will reduce the growth of vasculogenesis and tumour, and suppress VEGFR-2 targeting more stable epithelial activity of host on genetics, but not suppress variable tumor tissues, will reduce the probability of resistance development.
Some drug targetings act on the VEGFR signal response; no matter be individually dosed; or with other chemotherapeutic agent coupling; all to patients with advanced malignant tumor effectively (" VEGF-targeted therapy:mechanisms of anti-tumor activity; " Nature Reviews Cancer; 2008,8,579; " Molecular basis for sunitinib efficacy and future clinical development, " Nature Reviews Drug Discovery, 2007,6,734; And " Angiogenesis:an organizing principle for drug discovery " Nature Reviews Drug Discovery, 2007,6,273).
C-Met, i.e. hepatocyte growth factor receptor (HGFR), its main point of application is at endotheliocyte, and has confirmed that it is at endotheliocyte, myogenous cells, all have expression in hematopoietic cell and motor neuron.The natural part of c-Met is pHGF (HGF), and it is a multi-functional somatomedin, i.e. dispersion factor (SF).In fetus and adult; activate the formation that c-Met can promote some form; for example, invasive growth will cause the Fast Growth of cell, intercellular division; move (" From Tpr-Met to Met; tumorigenesis and tubes, " Oncogene, 2007 with cell on every side to it; 26,1276; And " Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target, " Cancer Letter, 2009,280,1-14).
The human malignancies extensively existed exists lasting c-Met to stimulate, cross and express or variation, comprises mammary cancer, liver cancer, lung cancer, ovarian cancer, kidney, thyroid carcinoma, colorectal carcinoma, glioblastoma, prostate cancer etc.C-Met involves atherosclerosis and pulmonary fibrosis equally.By the interaction of mesenchyma stroma of tumors, comprise the HGF/c-Met approach, the invasive growth speed of these cancer cells has thoroughly been improved.Therefore, a large amount of evidences show that the c-Met signal response is relevant with certain cancers advancing of disease speed, and improved its with take role status in the cancer drug exploitation that c-Met is main target spot (" Molecular cancer therapy:can our expectation be MET, " Euro.J.Cancer, 2008, 44,641-651, and " Targeting the c-Met Signaling Pathway in Cancer, " Clin.Cancer Res., 2006, 12, 3657) .Agents targeting c-Met signaling pathway are now under clinical investigation. (" Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer, " Clinical Cancer Research, 2009, 15, 2207), and " Drug development of MET inhibitors:targeting oncogene addiction and expedience, " Nature Review Drug Discovery, 2008, 7, 504).
Axl belongs to the subfamily of tyrosine kinase receptor (RTKs), comprises Tyro3 and Mer (TAM).Wherein the TAM acceptor is by being characterized in 2 similar object areas of immunoglobulin (Ig) of extracellular region and tenuigenin kinases district associating and binary fibronectin III type.The part of TAM acceptor is Gas6 (growth arrest-specific 6) and Protein S; there is 43% aminoacid sequence in two kinds of vitamin k-dependent proteins; and there are similar domain structure (" The anticoagulation factor protein S and its relative; Gas6; are ligands for the Tyro 3/Axl family of receptor tyrosine kinases, " Cell, 1995; 80,661-670; And " Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6, " Nature, 1995,373,623-626).
Ample evidence show the Gas6/Axl system in advancing normal cell and growth of cancer cells and survival, playing the part of important role (" TAM receptor tyrosine kinases:biologic functions; signaling; and potential therapeutic targeting in human cancer; " Adv Cancer Res, 2008,100,35 – 83).Axl crosses expression and signal response involves several human malignancies, as colorectal carcinoma, mammary cancer, neurospongioma, thyroid carcinoma, cancer of the stomach, melanoma, lung cancer and renal cell carcinoma (RCC).Axl effect more specifically in biology is confirmed in gliomatous research, the signal response that reduces Axl will reduce the growth of neurospongioma and breast tumor, and wherein Axl will promote that cell migration, pipeline form, new vessel forms and tumor growth.Axl has been proved in tumour generates and has played the part of multiple player, and antibody therapy suppresses Axl and not only can block the function of Axl in malignant cell, also can block its function in the mesenchymal neoplasm cell simultaneously.The function that the restraining effect of Axl and the additive effect of anti-VEGF show to block Axl will be to improve effective way (" Axl as a potential therapeutic target in cancer:role of Axl in tumor growth; metastasis and angiogenesis. " Oncogene of angiogenesis inhibitor treatment; 2009; 28,3442-3455; And " TAM Receptor Tyrosine Kinases:Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer, " Adv Cancer Res, and 2008,100,35-83).
As everyone knows, cancer cells tends to adopt number of mechanisms to avoid the tight regulate process of cell, as cell proliferation, apoptosis and aging.Therefore, a lot of tumours can flee from out from single kinase inhibitory activity.By the systems analysis wide to tumour, show, tyrosine kinase receptor (RTK) coactivation completes chemoresistance by cancer cells, and as important biomechanism.One of them method is, overcomes the RTK coactivation, may be involved in the upper targeting for the treatment of in multiple RTKs simultaneously, thereby block carcinogenic RTK signal response, and overcome compensatory mechanism.(“Receptor?Tyrosine?Kinase?Coactivation?Networks?in?Cancer,”Cancer?Research,2010,70,3857)。Targeting is in VEGFR, and the anti-tumor method of c-Met and Axl signal response can prevent that tumour cell from overcoming VEGFR, the independent restraining effect of c-Met (HGFR) and/or Axl, thereby the result for the treatment of of raising cancer.
Abstract of invention
The present invention relates to the method for quinoline compound and the treatment cell proliferation disorders of new replacement.Compound of the present invention has restraining effect to protein tyrosine kinase activity.More satisfactory, compound of the present invention has multiple inhibitor function, can suppress as VEGF HGF or the response of Axl receptor signal.Correspondingly, the present invention also provides the inhibitor of some new protein tyrosine kinase receptor signal responses, as the vegf receptor signal response, and the response of HGF receptor signal, or the response of Axl receptor signal.
Especially, compound involved in the present invention, and pharmaceutically acceptable composition, can be effective as the tyrosine kinase receptor inhibitor, as c-Met, and VEGFR, or the inhibitor of Axl.
On the one hand, the present invention relates to a kind of suc as formula the compound shown in (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein, R
1, R
2, R
3, R
4, Q
1, Q
2, X, shown in Y and Z are defined as follows.
In some embodiments, each R
1, R
2, R
3And R
4Be H independently, D, F, Cl or Br, work as R
1(or R
2), R
3And R
4While being H simultaneously, R
2(or R
1) be not F;
Each Q
1And Q
2Be H independently, D, F, Cl, Br, N
3, CN, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl or C
2-6Alkynyl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl and C
2-6Alkynyl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, CN, N
3, SR
a, NR
aR
bOr-C (=O) NR
aR
bWork as Q
1And Q
2Be methoxyl group simultaneously, R
3(or R
4), R
1And R
2While being H simultaneously, R
4(or R
3) be not Cl;
Each X and Z are H independently, D, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, NO
2, N
3, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
a, SR
a, NR
aR
bOr-C (=O) NR
aR
b
Y is H, D, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, NO
2, N
3, C
2-6Thiazolinyl, C
2-6Alkynyl, SR
a, NR
aR
bOr-C (=O) NR
aR
bWith
Each R
aAnd R
bBe H independently, C
1-6Aliphatics, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Heterocyclic radical-C
1-4Alkylidene group, C
6-10Aryl-C
1-4Alkylidene group, (5-10 former molecular heteroaryl)-C
1-4Alkylidene group, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, or, work as R
aAnd R
bWhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted.
In the other embodiment, each R
1, R
2, R
3And R
4Be H independently, D, F or Cl, work as R
1(or R
2), R
3And R
4While being H simultaneously, R
2(or R
1) be not F.
In the other embodiment, each X and Z are H independently, D, C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, OR
aOr NR
aR
b.
In the other embodiment, Y is H independently, D, C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F or NR
aR
b.
In the other embodiment, each X and Z are methyl independently, ethyl, n-propyl, sec.-propyl or phenyl, wherein, described methyl, ethyl, n-propyl, sec.-propyl and phenyl are not substituted independently or are replaced by 1,2 or 3 substituting group, and described substituting group is independently selected from D or F.
In the other embodiment, Y is methyl, ethyl or n-propyl, wherein, and described methyl, ethyl and n-propyl are not substituted independently or are replaced by 1,2 or 3 substituting group, and described substituting group is independently selected from D or F.
In the other embodiment, each Q
1And Q
2Be H, D, Cl or OCH independently
3, work as Q
1And Q
2Be methoxyl group simultaneously, R
3(or R
4), R
1And R
2While being H simultaneously, R
4(or R
3) be not Cl.
In the other embodiment, each R
aAnd R
bBe H independently, C
1-3Aliphatics, C
1-3Haloalkyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Heterocyclic radical-C
1-2Alkylidene group, C
6-10Aryl-C
1-2Alkylidene group, (5-10 former molecular heteroaryl)-C
1-2Alkylidene group, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, or, work as R
aAnd R
bWhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises (1) the compounds of this invention and (2) pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.
In some embodiments, pharmaceutical composition of the present invention, further comprise the additional treatment agent, these additional treatment agent are selected from chemotherapeutic agent, and antiproliferative is used for the treatment of atherosclerotic medicine, the medicine that is used for the treatment of pulmonary fibrosis, or their combination.
In the other embodiment, pharmaceutical composition of the present invention, wherein related 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 (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), 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, fork clip is for Buddhist nun (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), brentuximab vedotin, 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, can be with the compounds of this invention or pharmaceutical composition for the preparation of the purposes of protecting, process, treat or alleviate the medicine of 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, head and neck cancer, prostate cancer, carcinoma of the pancreas, CNS(central nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, the present invention relates to come for the preparation of suppress or regulate the purposes of protein kinase activity in biological sample with the compounds of this invention or pharmaceutical composition, described purposes comprises uses the compounds of this invention to contact with described biological sample.
Some embodiments therein, kinases of the present invention is tyrosine kinase receptor.
In the other embodiment, tyrosine kinase receptor of the present invention is VEGFR or c-Met.
On the other hand, the invention provides some pharmaceutical compositions, it comprises the compound of the present invention as the tyrosine kinase receptor inhibitor, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.In some embodiments, pharmaceutical composition provided by the present invention comprises and can be used as the vegf receptor signal response, the compound of the response of HGF receptor signal or the agent of Axl receptor signal response suppression, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, or pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.In the other embodiment, pharmaceutical composition of the present invention further comprises the additional treatment agent.
On the other hand, the present invention relates to a kind of method of arrestin tyrosine kinase 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 suppress the vegf receptor signal response, the response of HGF receptor signal, or the method for Axl receptor signal response, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described acceptor.Suppress receptor protein kinase activity, particularly VEGF, HGF or the response of Axl receptor signal, can carry out in unicellular or multi-cell organism.If be present in multi-cell organism, method described in the invention comprises uses compound of the present invention or composition to carry out administration to organism.Some of them embodiment is, described organism is Mammals, and other embodiment is that described organism is the mankind.Other embodiment is, described method further comprises contacting of kinases and additional treatment agent.
On the other hand, the present invention relates to a kind of method that suppresses cell-proliferation activity, described method comprises the compounds of this invention or its pharmaceutical composition effectively dosage and the cells contacting of inhibition of cell proliferation.In some embodiments, the method for the invention further comprises contacting of additional treatment agent and cell.
On the other hand, the present invention relates to a kind of method of the patient's for the treatment of cell proliferation disorders, described method comprises needs of patients and effectively treats the dosage of required compound of the present invention or its composition administration.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 a kind of method that suppresses the patient tumors growth, described method comprises needs of patients and effectively treats the dosage of required compound of the present invention or its composition administration.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 method for preparation, separation and the purifying of the compound that formula (I) comprises.
Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.
Circumstantial letter of the present invention
Definition and general terms
The present invention will list the corresponding document of specific content of determining in detail, and embodiment is 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 is defined.The those skilled in the art will identify many similar or be equal to method described herein and material, and these can be applied to go in practice of the present invention.The present invention is limited to absolutely not the description of method and material.Have a lot of documents distinguish or conflict with similar material and the present patent application, comprising but never be limited to the definition of term, the usage of term, the technology of description, or the scope of controlling as the present patent application.
Unless applying other aspects of following definition, the present invention shows.According to purpose of the present invention, chemical element is according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, and 75,
ThEd, 1994 define.In addition; the organic chemistry General Principle is shown in " Organic Chemistry "; Thomas Sorrell; University Science Books; Sausalito:1999; and " March's Advanced Organic Chemistry, " by Michael B.Smith and Jerry March, John Wiley& Sons, New York:2007, therefore all contents have all merged reference.
Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as top general formula compound, or the special example in picture embodiment the inside, and subclass, and the compounds that comprises of the present invention.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " optionally ", no matter whether be positioned at term " replacement " before, all means that the one or more hydrogen atoms in given structure are replaced by concrete substituting group.Unless other aspects show, an optional substituted radical can be replaced in each commutable position of group.One or more substituting group that not only position can be selected from concrete group in given structural formula replaces, and substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to D, F, Cl, Br, N
3, NO
2, CN, OR
a, SR
a, NR
aR
b,-C (=O) NR
aR
b, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, phenyl, C
1-6Alkyl, C
1-6Aliphatics, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Cycloalkyl-C
1-4Alkylidene group, C
3-6Heterocyclic radical-C
1-4Alkylidene group, C
6-10Aryl-C
1-4Alkylidene group, (5-10 former molecular heteroaryl)-C
1-4Alkylidene group, C
6-10Aryl, or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, R
aAnd R
bThere is definition as described herein.
Term " aliphatic " or " aliphatic group " that the present invention uses, mean straight chain (being non-side chain) or side chain, the substituted or non-substituted complete saturated or hydrocarbon chain that contains one or more degrees of unsaturation.Unless otherwise detailed instructions, aliphatic group contains 1-20 carbon atom, some of them embodiment is, aliphatic group contains 1-10 carbon atom, and other embodiment is that aliphatic group contains 1-8 carbon atom, other embodiment is, aliphatic group contains 1-6 carbon atom, and other embodiment is that aliphatic group contains 1-3 carbon atom.Suitable aliphatic group comprises, but is not limited to, straight or branched, and substituted or non-substituted alkyl, the alkenyl or alkynyl group, as (C
1-C
6) aliphatic group, comprise straight or branched, substituted or non-substituted (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, or (C
2-C
6) alkynyl group.Such example comprises, but is not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, ethene, propylene, butylene, 2-butylene, acetylene, propine, butine, 2-butyne, etc., and described aliphatic group can not be substituted independently or be replaced by one or more substituting groups described in the invention.
Term " alkyl " or " alkyl group " that the present invention uses, mean containing the saturated straight chain of 1-20 carbon atom or the monovalence hydrocarbon polymer atomic group of side chain.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them embodiment is that alkyl group contains 1-10 carbon atom, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is that alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom, and other embodiment is that alkyl group contains 1-3 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 ,-CH (CH
3)
2), normal-butyl (n-Bu ,-CH
2CH
2CH
2CH
3), isobutyl-(i-Bu ,-CH
2CH (CH
3)
2), sec-butyl (s-Bu ,-CH (CH
3) CH
2CH
3), the tertiary butyl (t-Bu ,-C (CH
3)
3), 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., wherein said alkyl group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term used in the present invention " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.
Term " alkylidene group " means to remove two resulting saturated bivalent hydrocarbon radical groups of hydrogen atom from the saturated hydrocarbyl of straight or branched.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and other embodiment is, alkylidene group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, other embodiment is that alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (CH
2-), ethylidene (CH
2CH
2-), isopropylidene (CH (CH
3) CH
2-) etc., wherein said alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " alkenyl " means 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, and wherein at least one position is undersaturated condition, and a C-C is sp
2Two keys, wherein the group of alkenyl can not be substituted independently or replaced by one or more substituting groups described in the invention, comprises that group has the location of negation " just " or " E " " Z ", and wherein concrete example comprises, but be not limited to vinyl (CH=CH
2), allyl group (CH
2CH=CH
2) etc.
Term " alkynyl " means 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, wherein at least one position is undersaturated condition, a C-C is the sp triple bond, wherein alkynyl group can not be substituted independently or replaced by one or more substituting groups described in the invention, and concrete example comprises, but is not limited to, ethynyl (C ≡ CH), propargyl (CH
2C ≡ CH) ,-C ≡ C-CH
3Etc..
Term " alkoxyl group " means that alkyl group is connected with the 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 that alkoxy base contains 1-10 carbon atom, other embodiment is, alkoxy base contains 1-8 carbon atom, and other embodiment is that alkoxy base contains 1-6 carbon atom, other embodiment is, alkoxy base contains 1-4 carbon atom, and other embodiment is that 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., wherein said alkoxy base can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " hydroxy alkoxy base " means that the straight or branched alkoxy base is replaced by one or more oh group, and wherein alkoxy base has implication as described in the present invention.Unless otherwise detailed instructions, described hydroxy alkoxy base group contains 1-20 carbon atom, and some of them embodiment is that hydroxy alkoxy base group contains 1-10 carbon atom, other embodiment is, hydroxy alkoxy base group contains 1-8 carbon atom, and other embodiment is that hydroxy alkoxy base group contains 1-6 carbon atom, other embodiment is, hydroxy alkoxy base group contains 1-4 carbon atom, and other embodiment is that hydroxy alkoxy base group contains 1-3 carbon atom.In some embodiments, hydroxy alkoxy base group comprises 4 oh groups.In the other embodiment, hydroxy alkoxy base group comprises 3 oh groups.In the other embodiment, hydroxy alkoxy base group comprises 2 oh groups.In the other embodiment, hydroxy alkoxy base group comprises 1 oh group.
The example of hydroxy alkoxy base group comprises, but is not limited to, hydroxyl-oxethyl (OCH
2CH
2OH), 2-hydroxyl propoxy-(OCH
2CH (OH) CH
3), 3-hydroxyl propoxy-(OCH
2CH
2CH
2OH), 2-hydroxy-2-methyl propoxy-(OCH
2C (OH) (CH
3)
2), (R)-2-hydroxyl propoxy-((R)-OCH
2CH (OH) CH
3), or (S)-2-hydroxyl propoxy-((S)-OCH
2CH (OH) CH
3) ,-OCH
2CH (OH) CH
2OH ,-OCH (CH
3) (CH
2OH) ,-OCH
2CH (OH) CH
2CH
3,-OCH
2CH
2CH (OH) CH
3,-OCH
2CH
2CH
2CH
2OH ,-OCH
2C (OH) (CH
3)
2,-OCH
2CH (CH
2OH)
2,-OCH
2CH (CH
3) (CH
2OH) ,-OCH
2C (OH) (CH
3) (CH
2OH) ,-OCH (CH
3) CH (OH) CH
3,-OCH (CH
2OH) CH
2CH
3,-OC (CH
3)
2(CH
2OH) ,-OC (CH
3) (CH
2OH)
2, etc., wherein said hydroxy alkoxy base group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " means alkyl, and thiazolinyl or alkoxy base are replaced by one or more halogen atom, and such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc.
Term " carbocyclic ring ", " carbocylic radical " or " annular aliphatic " refer to that one or more tie points are connected to the rest part of molecule, non-aromatic, saturated or part is undersaturated, comprise 3-12 carbon atom, or 3-10 carbon atom, or 3-8 carbon atom, or the monocycle of 3-6 carbon atom, dicyclo and three-ring system.Suitable cyclic aliphatic group comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but never is 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, suberyl, the ring octyl group, ring nonyl, ring decyl, the ring undecyl, cyclo-dodecyl, etc.
Term " cycloalkyl " refers to that one or more tie points are connected to the rest part of molecule, saturated, containing monocycle, dicyclo or the three-ring system of 3-12 carbon atom.Its bicyclic system comprises spiral shell dicyclo and condensed-bicyclic.Some of them embodiment is the member ring systems containing 3-10 carbon atom, other embodiment is the member ring systems containing 3-8 carbon atom, other embodiment is the member ring systems containing 3-6 carbon atom, other embodiment is the member ring systems containing 5-6 carbon atom, and described group of naphthene base can not be substituted independently or be replaced by one or more substituting groups described in the invention.
Term " cycloalkyl alkylidene group " means that alkyl group can be replaced by one or more group of naphthene base, and wherein alkyl and group of naphthene base have implication as described in the present invention.Some of them embodiment is, the cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, and 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
1-3Alkyl 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 cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.Described cycloalkyl alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein the upper one or more atoms of ring are independent is optionally replaced by heteroatoms, ring can be fully saturated or comprise one or more degrees of unsaturation, but is never the fragrant same clan, only has a tie point to be connected to the rest part of molecule.Its bicyclic system comprises spiral shell dicyclo and condensed-bicyclic, and one of them ring can be monocyclic carbocyclic ring or single heterocycle.Wherein one or more ring hydrogen atoms are independent optionally to be replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle " " heterocyclic radical " or " heterocycle " group be 3-7 former molecular monocycle (2-6 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain picture SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2Group), other embodiment is, 3-6 former molecular monocycle (2-5 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain looking like S=O, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2Group, when described ring is triatomic ring, wherein only have a heteroatoms), or 7-10 former molecular dicyclo (4-9 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain picture SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2Group).
Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and saturated or the unsaturated ring of part or heterocyclic fused formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, the thioxane base, piperazinyl, the homopiperazine base, azelidinyl, the oxa-cyclobutyl, the thia cyclobutyl, homopiperidinyl, epoxypropyl, the nitrogen heterocyclic heptyl, the oxepane base, the thia suberyl, oxygen azatropylidene base, the diazepine base, sulphur azatropylidene base, the 2-pyrrolinyl, the 3-pyrrolinyl, indolinyl, the 2H-pyranyl, the 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, the dithiane base, the dithiode alkyl, the dihydro-thiophene base, the pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, the 4-tetrahydro isoquinolyl.The example of heterocyclic group also comprises, 1,1-dioxy thio-morpholinyl, and wherein encircle two carbon atoms by the Sauerstoffatom replacement as the pyrimidine dione base.
Term " heterocyclic radical alkylidene group " means that alkyl group can be replaced by one or more heterocyclic radical groups, and wherein alkyl and heterocyclic radical group have implication as described in the present invention.Some of them embodiment is, the heterocyclic radical alkylidene group refers to " more rudimentary heterocyclic radical alkylidene group " group, and the heterocyclic radical group is connected to C
1-6Alkyl group on.Other embodiment is that the heterocyclic radical group is connected to C
1-4Alkyl group on.Other embodiment is that the heterocyclic radical group is connected to C
1-2Alkyl group on.Such example comprises, but is not limited to 2-tetramethyleneimine ethyl, 3-azetidine methyl etc.Described heterocyclic radical alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heteroatoms " refers to O, S, and N, P and Si, comprise N, the form of S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; The perhaps substituted form of the hydrogen on nitrogen-atoms in heterocycle, for example, 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 " means single hydrogen atom.Such atomic group can be connected with other groups, for example with Sauerstoffatom, is connected, and forms oh group.
Term " D " or "
2H " mean single D atom.Such atomic group is connected with a methyl, forms list-deuterium for methyl (CDH
2), two D atoms are connected with a methyl, form two-deuterium for methyl (CD
2H), and three D atoms are connected with a methyl, form three-deuterium for methyl (CD
3).
Term " N
3" mean a nitrine structure.This group can be connected with other groups, for example, can be connected to form triazonmethane (MeN with a methyl
3), or be connected to form phenylazide (PhN with a phenyl
3).
Term " aryl " can be used separately or as most of " aralkyl ", " aralkoxy " or " aryloxy alkyl ", mean to contain altogether 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, dicyclo, and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 former molecular ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use, as aromatic nucleus can comprise phenyl, naphthyl and anthracene.Described aromatic yl group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " aryl alkylene " means that alkyl group can be replaced 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, the aryl alkylene group refers to " more rudimentary aryl alkylene " group, and aromatic yl group is connected to C
1-6Alkyl group on.Other embodiment is that the aryl alkylene group refers to containing C
1-4" the benzene alkylene " of alkyl.Other embodiment is that the aryl alkylene group refers to that aromatic yl group is connected to C
1-2Alkyl group on.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Described aryl alkylene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heteroaryl " can be used separately or as most of " heteroarylalkyl " or " heteroaryl alkoxyl group ", mean to contain altogether 5-14 annular atoms, or 5-12 annular atoms, or the monocycle of 5-10 annular atoms, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 5-7 former molecular ring, and only has an attachment point to be connected with the molecule rest part.Term " heteroaryl " can be used with term " fragrant heterocycle " or " heteroaromatics " exchange.
Other embodiment is, the virtue heterocycle comprises following monocycle, but be not limited to these monocycles: the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the N-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (as the 3-pyridazinyl), the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, tetrazyl (as the 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), the 2-thienyl, the 3-thienyl, pyrazolyl (as the 2-pyrazolyl), isothiazolyl, 1, 2, the 3-oxadiazolyl, 1, 2, the 5-oxadiazolyl, 1, 2, the 4-oxadiazolyl, 1, 2, the 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, the 5-triazinyl, also comprise following dicyclo, but never be limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as the 2-indyl), purine radicals, quinolyl (as the 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (as the 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).Described heteroaryl groups can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heteroaryl alkylidene group " means that alkyl group can be replaced by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, some of them embodiment is, the heteroaryl alkylidene group refers to " more rudimentary heteroaryl alkylidene group " group, and 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 the 2-picolyl, 3-furans ethyl etc.Described heteroaryl alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
No matter term " carboxyl " is use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO
2H; No matter term " carbonyl ", be use separately or be used in conjunction with other terms,, as " aminocarboxyl " or " acyloxy ", mean-(C=O)-.
Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", and wherein amino group is replaced by one or two alkyl group respectively independently.Some of them embodiment is that alkylamino is one or two C
1-6Alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is that 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 is amino " means that amino group is replaced by one or two aromatic yl group, and such example comprises, but is not limited to the N-phenylamino.Some of them embodiment is that the aromatic ring on fragrant amino can further be substituted.
Term " aminoalkyl group " comprises the C replaced by one or more amino
1-10The straight or branched alkyl group.Some of them embodiment is, aminoalkyl group is by C that one or more amino group replaced
1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
The term that used in the present invention " undersaturated " means to contain one or more degrees of unsaturation in group.
Term " comprises " for open language, comprises the content that the present invention is specified, but does not get rid of otherwise content.
Picture is described in the invention, and key of substituting group picture is connected to the member ring systems (shown in a and formula b) formed on the ring at center and represents that substituting group can replace any commutable position on ring.For example, formula a represents the substituted position of any possibility on the B ring, shown in b.
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo ", mean that a ring originates from the upper special ring-type carbon of another ring, for example, described suc as formula c, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", yet ring A and ring B share a carbon atom in two saturated member ring systems, are 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.Wherein said volution base group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer, and (Z), the conformer of (E).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 " expression have the structure isomeride of different-energy can cross low energy barrier, thereby transforms mutually.For example, proton tautomerism body (being prototropy) comprises by proton shifting and carries out change, as the change of keto-enol formula and imines-enamine isomerization.Valence tautomers comprises by some bonding electrons restructuring carries out change.
Unless other aspects show, within all tautomeric forms of compound of the present invention are included in 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 atoms.
Term used in the present invention " prodrug ", represent that a compound is converted into the compound shown in formula (I) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C
1-24) the ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises hydroxyl, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, as these phosphate compounds are that hydroxyl phosphorylation on parent obtains.About prodrug, complete discussion can be with reference to Publication about Document: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al., Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
" meta-bolites " refers to that concrete compound or its salt is in vivo by the resulting product of metabolism.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by the method that adopts test as described in the invention.Such product can be by the oxidation of drug compound process, reduces, and hydrolysis, amidated, the desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.
The definition of neutral body chemistry of the present invention and the use of convention be usually with reference to Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley& Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore have different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, and enantiomer, atropisomer, and their mixture, as racemic mixture, formed a part of the present invention.A lot of organic compound all exist with the optical activity form, 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 meaning the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, 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 in chemical reaction process there is no stereoselectivity or stereospecificity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can transform mutually by low energy barrier.For example proton tautomerism body (being prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-acid-enol form and imines-enamine.Valence (valency) tautomer comprises the change that reassembles into bonding electron.
" 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 is for we are known in affiliated field, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. puts down in writing.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that react formation with amino group has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by the additive method of putting down in writing on the books document as ion exchange method.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, the 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, the 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 present invention also intends having conceived the formed quaternary ammonium salt of compound of the group of any comprised N.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and 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 one or more solvent molecules and the formed associated complex of compound of the present invention.The solvent that forms 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 formed associated complex of water.
When term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes methylene oxygen carbonyl (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 " refer to the substituting group of carboxyl be used for the blocking-up or the protection carboxyl functional, comprise-CH of general carboxyl-protecting group
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.But the general description reference for blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley& Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
The description of compound of the present invention
The present invention relates to the quinolines replaced, its pharmacy acceptable salt, and pharmaceutical preparation, to tyrosine kinase receptor, VEGFR especially, the treatment of the receptor-mediated disease of c-Met acceptor or Axl or illness has potential purposes.Particularly, the present invention relates to a kind of suc as formula the compound shown in (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein R
1, R
2, R
3, R
4, Q
1, Q
2, X, shown in Y and Z are defined as follows.
In some embodiments, each R
1, R
2, R
3And R
4Be H independently, D, F, Cl or Br, work as R
1(or R
2), R
3And R
4While being H simultaneously, R
2(or R
1) be not F;
Each Q
1And Q
2Be H independently, D, F, Cl, Br, N
3, CN, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl or C
2-6Alkynyl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl and C
2-6Alkynyl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, CN, N
3, SR
a, NR
aR
bOr-C (=O) NR
aR
bWork as Q
1And Q
2Be methoxyl group simultaneously, R
3(or R
4), R
1And R
2While being H simultaneously, R
4(or R
3) be not Cl;
Each X and Z are H independently, D, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, NO
2, N
3, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
a, SR
a, NR
aR
bOr-C (=O) NR
aR
b
Y is H, D, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, NO
2, N
3, C
2-6Thiazolinyl, C
2-6Alkynyl, SR
a, NR
aR
bOr-C (=O) NR
aR
bWith
Each R
aAnd R
bBe H independently, C
1-6Aliphatics, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Heterocyclic radical-C
1-4Alkylidene group, C
6-10Aryl-C
1-4Alkylidene group, (5-10 former molecular heteroaryl)-C
1-4Alkylidene group, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, or, work as R
aAnd R
bWhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted.
In the other embodiment, each R
1, R
2, R
3And R
4Be H independently, D, F or Cl, work as R
1(or R
2), R
3And R
4While being H simultaneously, R
2(or R
1) be not F.
In the other embodiment, each X and Z are H independently, D, C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, OR
aOr NR
aR
b.
In the other embodiment, Y is H independently, D, C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F or NR
aR
b.
In the other embodiment, each X and Z are methyl independently, ethyl, n-propyl, sec.-propyl or phenyl, wherein, described methyl, ethyl, n-propyl, sec.-propyl and phenyl are not substituted independently or are replaced by 1,2 or 3 substituting group, and described substituting group is independently selected from D or F.
In the other embodiment, Y is methyl, ethyl or n-propyl, wherein, and described methyl, ethyl and n-propyl are not substituted independently or are replaced by 1,2 or 3 substituting group, and described substituting group is independently selected from D or F.
In the other embodiment, each Q
1And Q
2Be H, D, Cl or OCH independently
3, work as Q
1And Q
2Be methoxyl group simultaneously, R
3(or R
4), R
1And R
2While being H simultaneously, R
4(or R
3) be not Cl.
In the other embodiment, each R
aAnd R
bBe H independently, C
1-3Aliphatics, C
1-3Haloalkyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Heterocyclic radical-C
1-2Alkylidene group, C
6-10Aryl-C
1-2Alkylidene group, (5-10 former molecular heteroaryl)-C
1-2Alkylidene group, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, or, work as R
aAnd R
bWhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted.
In the other embodiment, the present invention relates to following one of them compound or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, but never be limited to these compounds:
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment acute and chronic hyperproliferative disease and/or blood vessel, the disease mediated occurs, and comprises that those are described in the invention.The application of compound of the present invention in producing cancer therapy drug.Compound of the present invention alleviates by the arrestin kinase activity for the production of a kind of medical supplies equally, stops, and controls or the treatment disease.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound and at least one pharmaceutically acceptable carrier of formula (I) representative, assistant agent or thinner in conjunction with required effective treatment consumption.
The present invention comprises the disease that mediation occurs the treatment patient vessel equally, or, to the method for this illness sensitivity, the treatment significant quantity that the method comprises use formula (I) representative compound is treated the patient.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises that material or composition must be to be applicable to chemistry or toxicologically, relevant with other components that form 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 pharmacy acceptable salt not necessarily.
If compound of the present invention is alkaline, conceivable salt can prepare by any suitable method provided on document, for example, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Perhaps use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; The 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, conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, the organic salt obtained from amino acid, and as glycine and arginine, ammonia, as uncle's ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The composition of compound of the present invention, preparation and administration
According on the other hand, the characteristics of pharmaceutical composition of the present invention comprise the compound of formula (I), the particular compound that the present invention is listed, or the compound of embodiment 1-17, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound can suppress the protein kinase in biological sample or patient body effectively detectablely.
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, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can be directly or indirectly according to other any adducts or derivatives of needing administration of patient, other aspects of the present invention described compound, its meta-bolites or his residue.
Picture is described in the invention, and the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carrier, 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 described with Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams& Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the comprehensive content of document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Carrier medium and the inconsistent scope of compound of the present invention except any routine, the any bad biological effect that for example produced or the interaction produced in the mode be harmful to 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 be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as the human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, the derivative of Mierocrystalline cellulose and it is as Xylo-Mucine, ethyl cellulose and rhodia, the 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, the glycols compound, as propylene glycol and polyoxyethylene glycol, the ester class is as ethyl oleic acid ester and ethyl laurate, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, dressing dress material, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, and the spraying inhalation, topical, the per rectum administration, nose administration, containing taking administration, vagina administration or by the administration of the property implanted medicine box.Term as used herein " through what inject " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to intraperitoneal administration or intravenous injection.The injection system of composition sterile of the present invention can be suspension water or oleaginous.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 nontoxic acceptable thinner or solvent of injection, 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 can be used as solvent or suspension medium by convention.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG synthesized.Lipid acid, as the glyceride derivative of oleic acid and it can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, their polyoxyethylene deriv particularly.These oil solutions or suspension can comprise long-chain alcohol thinner or dispersion agent, and as carboxymethyl cellulose or similar dispersion agent, the pharmaceutical preparation that is generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.The tensio-active agent that other are commonly used, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, be generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of drug target preparation.
The pharmaceutically acceptable composition of the present invention can be to carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to capsule, tablet, water suspension processed or solution.About tablet, orally use, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, all typically be added.For the capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension processed, its effective constituent is comprised 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 be with the form rectal administration of suppository.These can be by reagent and suitable non-perfusion adjuvant are mixed with and form, this adjuvant be at room temperature solid but next in the temperature of rectum be liquid, thereby melt and discharge medicine in rectum.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 that relates to zone or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable local application's preparation can prepare and be applied to these fields or organ.
Rectal suppository (seeing above content) or suitable enema can be applied to the local application of lower intestine.The local skin spot is medication so also.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 carriers 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 carriers.Suitable carrier comprises, but is not limited to mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
Can be prepared into preparation for composition eye use, pharmaceutically acceptable; as waited micronize suspension oozed, 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, for eye use, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by gaseous solvents or the inhalation of nose.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, with phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent, improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise known general inert diluent, for example, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (cottonseed particularly, 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 through acceptable thinner or solvent are made parenterally aseptic parenteral solution, suspension or emulsion, for example, 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 synthetic list or DG.In addition, lipid acid can be applied to injection as oleic acid.
Injection can be aseptic, filters as defended strainer 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 aseptic injection media before use.In order to extend the effect of compound of the present invention, usually need to slow down by subcutaneous injection or intramuscularly the absorption of compound.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 its dissolution rate, depends on successively grain size and crystal shape.In addition, can by compound, in the oils vehicle, dissolve or disperse the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and as many lactic acid-polyglycolide forms, the microcapsule matrix of 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 gather (acid anhydrides).Injection storage form also can embed liposome or the microemulsion compatible with bodily tissue by compound and prepare.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can be by mixing compound of the present invention to prepare with auxiliary material or the carrier of suitable non-perfusion, as cocoa butter, polyoxyethylene glycol, or the suppository wax, they are solid but next for liquid at body temperature in room 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 with at least one pharmaceutically acceptable inert excipient or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is 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 be by dressings, add shell prepares as known coating method on enteric coating and other drug preparation.They can optionally comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the unique activeconstituents in the method release composition postponed.As implant compositions can comprise polymer material and wax.
Active compound can form microcapsule formulations with together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula can or add shell by dressing, 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, and lactose or starch.Such formulation also can comprise the substance except inert diluent as general application, as compressing tablet lubricant and other compression aids as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They can optionally comprise tranquilizer, or preferably, in certain part of enteron aisle, with the unique activeconstituents in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but be not limited to polymer and wax.
Compound of the present invention by part or comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster through the formulation of percutaneous drug delivery.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any essential sanitas or essential buffer reagent under aseptic condition.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 has more advantage aspect the control compound is delivered in body, and such formulation can prepare by dissolving or decentralized compound in suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate is controlled film or compound is scattered in to polymer matrix or gelatin is controlled its speed.
Compound of the present invention preferably is prepared into the dose unit type to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit's type " refer to that herein the patient obtains suitably treating the physical dispersion unit of required medicine.Yet, should be appreciated that compound of the present invention or composition total usage every day will be next definite according to reliable medical science scope judgement by the doctor in charge.The patient that concrete effective dose level is special for any one or organism will depend on that many factors comprise the illness that is treated and the seriousness of illness, the activity of particular compound, concrete composition used, patient's age, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the 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 of consumption that can produce 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 that composition can be prepared into the inhibitor of dosage in the 0.01-200mg/kg body weight/day by formulation method, accepts the amount of composition by the patient and carries out administration.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with one or more other additional treatment (pharmacy) agent, wherein drug combination causes acceptable untoward reaction, and this has special meaning for high proliferative disease as the treatment of cancer.In this case, compound of the present invention can be in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.Picture is used in the present invention, the disease that the normal drug treatment of additional treatment agent is special, known exactly " treating suitably disease "." additional treatment agent " used in the present invention comprises that chemotherapeutic agent or other antiproliferative medicines can be in conjunction with compounds for treating proliferative disease of the present invention or cancers.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and the described compound of those following patents: WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/030705, WO 2005/092899, with demethylation reagent, comprise, but be not limited to, 5-mix nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the described compound of Publication about Document: US 6, 268137, US 5, 578, 716, US5, 919, 772, US 6, 054, 439, US 6, 184, 211, US 6, 020, 318, US 6, 066, 625, US 6, 506, 735, US 6, 221, 849, US 6, 953, 783, US 11/393, 380.
Other embodiment is that chemotherapeutic agent or other anti-proliferative drugs can be in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutic agent comprises, but be not limited to, other therapies or carcinostatic agent can be combined carcinostatic agent of the present invention and be comprised surgery, (a little example is as gamma-radiation for radiotherapy, the neutron beam radiotherapy, the electron beam radiotherapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, biological response modifier (Interferon, rabbit, interleukin, tumour necrosis factor (TNF), the effect of TRAIL receptor target and vehicle), overheated and psychrotherapy, dilute the reagent (as antiemetic) of any untoward reaction, chemotherapeutic agent with other approvals, include, but are not limited to, alkanisation medicine (mustargen, Chlorambucil, endoxan, melphalan, ifosfamide), metabolic antagonist (methotrexate, pemetrexed (Pemetrexed) etc.), purine antagonist and pyrimidine antagonist (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Dx (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), mineral ion (cis-platinum, carboplatin), (KSP passes through mitotic kinesin inhibitors to the cell division cycle inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol)), imatinib mesylate
Zorubicin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other).The monoclonal antibody class (Baily wood monoclonal antibody (Belimumab,
Brentuximab
Cetuximab (Cetuximab,
WAY-CMA 676 (Gemtuzumab,
Her monoclonal antibody (Ipilimumab,
Method wood monoclonal antibody difficult to understand (Ofatumumab,
Victibix (Panitumumab,
Lucentis (Ranibizumab,
Rituximab (Rituximab,
Tositumomab (Tositumomab,
Herceptin (Trastuzumab,
.Kinase inhibitor (imatinib (Imatinib,
Sutent (Sunitinib,
Xarelto (Sorafenib,
Cetuximab (Cetuximab,
, Herceptin (Trastuzumab,
Tarceva (Erlotinib,
Dasatinib (Dasatinib,
Tivozanib, dovitinib, axitinib, motesanib, pazopanib (pazopanib), Gefitinib (gefitinib,
Cediranib, brivanib, Telatinib (telatinib), masitinib, HKI-272 (neratinib), lenvatinib, ruxolitinib, linifanib, linsitinib, crizotinib, regorafenib, ponatinib, bosutinib (bosutinib), fork clip is for Buddhist nun (saracatinib), afatinib, amuvatinib, ponatinib, quizartinib, Wei Luofeini (vemurafenib
ZD6474 (Vandetanib,
Olaparib, veliparib, iniparib, Iressa (Iressa) and other).Medicine suppress or the approach that activates cancer as mTOR, the HIF(hypoxia inducible factor) approach and other.Cancer therapy forum more widely is shown in
Http:// www.nci.nih.gov/, the oncology list of medications of FDA approval is shown in
Http:// www.fda.gov/cder/cancer/druglist-rame.htm, and the Merck handbook, the 18 edition .2006, all contents are all to combine reference.
Other embodiment is that compound of the present invention can be in conjunction with the cytotoxin carcinostatic agent.Such carcinostatic agent can be inner the finding of the 13 edition the Merck index (2001).These carcinostatic agents comprise, but never be limited to, Asparaginase (Asparaginase), bleomycin (Bleomycin), carboplatin, carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytosine arabinoside (Cytarabine), Dacarbazine (Dacarbazine), dactinomycin (Dactinomycin), daunorubicin (Daunorubicin), Zorubicin (Dx), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, the hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), methotrexate (Methotrexate), ametycin (MitomycinC), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), Procarbazine (Procarbazine), raloxifene (Raloxifen), streptozocin (Streptozocin), tamoxifen (Tamoxifen), Tioguanine (Thioguanine), Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), vindesine.
With other suitable cytotoxic drugs of compound drug combination of the present invention, comprise, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but never be 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, the 5 FU 5 fluorouracil deoxynucleoside, the floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (Idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (Melphalan), mitotane (Mitotane), taxol, pentostatin (Pentostatin), N-phosphoric acid ethanoyl-L-Aspartic acid (PALA), Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide), Uniteston, phosphinothioylidynetrisaziridine (Thiotepa), the trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
Other suitable and cytotoxin class carcinostatic agents compound combined utilization of the present invention comprise newfound cytotoxic substance, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and natural or synthetic derivative thereof, Temozolomide (Temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab (tositumomab
Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001,1,370-377).
Other embodiment is that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is that signal transduction inhibitor is using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) with their parts separately.Such reagent comprises, but never is limited to, and antibody therapy is as Trastuzumab (trastuzumab), Cetuximab (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but never be limited to, the small molecules kinase inhibitor is as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004,64,4931-4941).
Other embodiment is, compound of the present invention in conjunction with other signal transduction inhibitor targetings in the receptor kinase of division kinases field family (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.), and their parts separately.Such reagent comprises, but is not limited to, and antibody is as rhuMAb-VEGF (Avastin).Such reagent comprises, but never be limited to, micromolecular inhibitor is as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res.2000, 60 (8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequin et al., 92nd AACR Meeting, New Orleans, Mar.24-28, 2001, abstract 3152), KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, abstract2575), CP-547, 632 (Beebe et al., Cancer Res.2003, 63, 7301-7309), CP-673, 451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract3989), CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract476).
Other embodiment is that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is that signal transduction inhibitor is using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) with their parts separately.Such reagent comprises, but never is limited to, antibody therapy as Herceptin (Trastuzumab,
Cetuximab (Cetuximab,
Her monoclonal antibody (Ipilimumab,
With handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but never is limited to, the small molecules kinase inhibitor as imatinib (Imatinib,
Sutent (Sunitinib,
Xarelto (Sorafenib,
Tarceva (Erlotinib,
Gefitinib (Gefitinib,
Dasatinib (Dasatinib,
AMN107 (Nilotinib,
lapatinibditosylate (Lapatinib,
Ke Zhuo for the Buddhist nun (Crizotinib,
Ruxolitinib
Vemurafenib
Vandetanib
Pazopanib
Ah method is for Buddhist nun (Afatinib), alisertib, 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, fork clip is for Buddhist nun (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941(Folkes, et al., J.Med.Chem., 2008, 51, 5522), BZE235, etc..
Other embodiment is that compound of the present invention can the bonding histone deacetylase inhibitors.Such reagent comprises, but never be limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3028) and MGCDOI 03 (US 6, 897, 220).
Other embodiment is that compound of the present invention can be in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but never be limited to Velcade (Bortezomib) (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004,23, Abstract 3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract 3849).Compound of the present invention can also, in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition that comprises compound of the present invention, as the part of many dosage regimens.Perhaps, those therapeutical agents can be the parts of one-pack type, form single composition together with compound of the present invention.If administration is as the part of many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thereby obtain the destination agent activity.
The change that can produce the compound of one-pack type and the consumption of additional treatment agent (those compositions that comprise an additional treatment agent are as described in the invention) 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 will be no more than composition and comprise the amount of therapeutical agent as the normal administration of unique promoting agent.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 unique active therapeutic agent.In the composition that comprises the additional treatment agent at those, the additional treatment agent will play synergy with compound of the present invention.
The purposes of compound of the present invention and composition
The feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I) or the listed compound of the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention the amount of compound effectively detectablely the arrestin kinases as VEGFR, the activity of c-Met or Axl.VEGFR, the deleterious effect of c-Met and Axl signal response will be treated or be reduced to the compounds of this invention to the patient as antitumor drug.
Compound of the present invention will be applied to, but never be limited to, and by the significant quantity of compound of the present invention or composition, patient's administration be prevented or treats patient's proliferative disease.Such disease comprises cancer, metastatic carcinoma especially, atherosclerosis, and pulmonary fibrosis.
The treatment that compound of the present invention will be applied to knurl comprises cancer and metastatic carcinoma, further includes, but are not limited to, and cancer is 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 hematopoiesis tumour (comprises leukemia, acute lymphoblastic tumour leukemia, 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 hematopoiesis tumour (comprising the acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocyte leukemia); The tumour of mesenchymal cell origin (comprise fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage); Maincenter peripheral nervous system knurl (comprising astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention also can be used for treating for example corneal graft rejection of eye disease, and the new vessel of eye forms, and retinal neovascularization forms and comprises that damage or metainfective new vessel form; Diabetic retinopathy; Terry's sign disease, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds equally also are used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention can be for the treatment of the situation relevant to diabetes as diabetic retinopathy and microangiopathy.The situation that compound of the present invention reduces for cancer patients's volume of blood flow equally.Compound of the present invention shifts to reduce to patient tumors also beneficial effect.
Compound of the present invention, except useful to the human treatment, also can be applicable to the animal of veterinary treatment pet, introduced variety and the animal on farm, comprises 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 in the situation of salt etc., it also means single compound, salt etc.
The methods for the treatment of that comprises compound of the present invention or composition administration, further comprise the administration to patient's additional treatment agent (combination therapy), wherein the additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein the additional treatment agent is applicable to treated disease, and the additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition be as single formulation, or the compound separated or composition are as the part of multi-form.The additional treatment agent can from compound of the present invention administration simultaneously or administration when different.The latter's situation, 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 equally to expressing VEGFR, the cytostatic method of c-Met or Axl, 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, the 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 and suppress VEGFR in biological sample, the method for c-Met or Axl kinase activity, this method comprises compound of the present invention or composition is contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of live body outside, include, but not limited to cell cultures or cell extraction; The examination of living tissue material obtained from Mammals or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly VEGFR in biological sample, c-Met or Axl kinase activity, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but never is limited to hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to the significant quantity of processing or alleviating the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential amount accurately will change according to patient's situation, and this depends on the race, the age, and patient's general condition, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as the present invention discusses.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.For example, the vascular stem, be used to overcome restenosis (after damage, vessel wall shrinks again).Yet the patient uses stem or other implantable devices will have the risk of clot formation or platelet activation.The pharmaceutically acceptable composition precoating device that these disadvantageous effects can comprise compound of the present invention by use stops or alleviates.
The general preparation method of suitable dressing and the dressing of implantable device is at document US 6,099,562, US 5,886, and 026 and US 5, in 304,121, describe to some extent, dressing be typically biocompatible polymer material as hydrogel polymer, poly-methyl two silicon ethers, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester, and composition thereof.Dressing can optionally further be covered by suitable dressing, as the fluoro Simethicone, and polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, come the performance group compound to control the feature discharged.Another aspect of the present invention comprises the implantable device that uses compound coating of the present invention.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or " medicine storage institute " is provided with polymkeric substance or other molecular mixing, and therefore with the pharmaceutical aqueous solution administering mode, compare, allow drug release that longer time limit is arranged.
General building-up process
Usually, compound of the present invention can prepare by method described in the invention, unless further instruction arranged, wherein substituent definition is suc as formula shown in (I).Following reaction scheme and embodiment are for further illustrating content of the present invention.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and all is contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by the those skilled in the art; disturb group as suitable protection, by utilizing other known reagent except described in the invention, or reaction conditions is made to the modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions also are applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, be decided to be degree centigrade unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, and Arco Chemical Company and Alfa Chemical Company does not have during use through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, the Tianjin space chemical company limited of residing well, Tianjin good fortune chemical reagent factory in morning, the prosperous China in Wuhan development in science and technology far away company limited, imperial chemical reagent company limited is risen in Qingdao, and Haiyang Chemical Plant, Qingdao buys and obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to obtain through sodium Metal 99.5 backflow drying.Anhydrous methylene chloride and chloroform are to obtain through hydrolith backflow drying.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reaction be generally nitrogen or argon gas direct draught or on anhydrous solvent cover one drying tube (unless showing aspect other), reaction flask is suitable soft rubber ball beyond the Great Wall all, substrate is squeezed into by syringe.Glassware is all dry the mistake.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDCl
3, DMSO-d
6, CD
3OD or acetone-d
6For solvent (take ppm as unit), use TMS (0ppm) or chloroform (7.25ppm) as reference standard.When multiplet occurring, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, two triplets).Coupling constant, mean with hertz (Hz).
The condition of Algorithm (MS) data is: and Agilent 1200 Series LCMS (Zorbax SB-C18,2.1 * 30mm, 4 microns, 10min, flow velocity is 0.6mL/min, (0.1% is dissolved in H to 5-95%
2The formic acid of O) in (0.1% is dissolved in CH
3The formic acid of CN)), at 210/254nm, with UV, detect, by low-response EFI pattern (ESI).
The characteristic manner of pure compound is: Agilent 1100 Series high speed liquid chromatographies (HPLC), detect with UV at 210nm and 254nm.Post operates under 40 ° of C.
The use of following brief word runs through the present invention:
The ATP adenosine triphosphate
BBr
3Boron tribromide
BINAP 2, and 2'-pair-(diphenyl phosphine)-1, the 1'-dinaphthalene
The BSA bovine serum albumin
BOC, the Boc tert-butoxycarbonyl
Ca (SO
3CF
3)
2Trifluoromethyl calcium sulfate
Cs
2CO
3Cesium carbonate
CHCl
3Chloroform
CDCl
3Deuterochloroform
CH
2Cl
2, the DCM methylene dichloride
Cu copper
The CuI cuprous iodide
Et
2The O ether
EtOH ethanol
DBU 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene
D
2Deuterium gas
The DIBAL diisobutyl aluminium hydride
The DIAD diisopropyl azodiformate
DIEA, DIPEA, iPr
2The Net DIPEA
The DEAD diethyl azodiformate
The DMF DMF
The DMAP DMAP
The DMSO dimethyl sulfoxide (DMSO)
The DPPA diphenyl phosphate azide
The DTT DTT
EDC, EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
The EDTA ethylenediamine tetraacetic acid (EDTA)
EtOAc, the EA ethyl acetate
Et
3N, the TEA triethylamine
The FBS foetal calf serum
The g gram
H hour
HATU 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
The HBr Hydrogen bromide
HCl hydrochloric acid
HOAc acetic acid
HOAT N-hydroxyl-7-azepine benzotriazole
HOBt I-hydroxybenzotriazole hydrate
H
2Hydrogen
H
2O water
H
2O
2Hydrogen peroxide
H
3PO
4Phosphoric acid
H
2SO
4Sulfuric acid
HNO
3Nitric acid
The HCOOK potassium formiate
Fe iron
The silica-based base lithium of LiHMDS hexamethyl two
The LDA lithium diisopropyl amido
The MBP myelin basic protein
The MCPBA metachloroperbenzoic acid
MeCN, CH
3The CN acetonitrile
MgSO
4Sal epsom
Mg ATP adenosine triphosphate magnesium
MeOH, CH
3OH methyl alcohol
The MeI methyl iodide
MOPS 3-(N-morpholino) propanesulfonic acid
ML, the ml milliliter
N
2Nitrogen
The NMP N-Methyl pyrrolidone
NaHCO
3Sodium bicarbonate
NaBH
4Sodium borohydride
NaBH
3The CN sodium cyanoborohydride
The NaOtBu sodium tert-butoxide
NaOH sodium hydroxide
NaClO
2Textone
NaCl sodium-chlor
NaH
2PO
4SODIUM PHOSPHATE, MONOBASIC
The NaH sodium hydride
The NaI sodium iodide
Na
2SO
4Sodium sulfate
The NBS N-bromo-succinimide
The Nonidet promise is lotion
NH
3Ammonia
NH
4The Cl ammonia chloride
Pd/C drapes over one's shoulders palladium/carbon
Pd
2(dba)
3Three (dibenzalacetone) two palladiums
Pd (OAc)
2Palladium
Pd (OH)
2Palladium hydroxide
Pd (PPh
3)
4Tetrakis triphenylphosphine palladium
Pd (dppf) Cl
21,1 '-bis-(diphenylphosphino) ferrocene palladium chloride
P (t-Bu)
3Three (tertiary butyl) phosphine
PE sherwood oil (60-90 ° of C)
The PBS phosphate buffered saline (PBS)
POCl
3Phosphorus oxychloride
K
2CO
3Salt of wormwood
KOH potassium hydroxide
RT, rt, r.t. room temperature
The Rt retention time
SOCl
2Sulfur oxychloride
The t-BuOK potassium tert.-butoxide
TBTU O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester
The THF tetrahydrofuran (THF)
The TFA trifluoroacetic acid
The TBAI tetrabutylammonium iodide
The TBS TBS
TEAC bis-(tetraethyl ammonium) carbonate
The Tris Tutofusin tris
Synthetic method 1-3 has listed in preparation the present invention the experimental procedure of the compound of coming into the open.Wherein, Q
1, Q
2, R
1, R
2, R
3, R
4, X, Y and Z have definition as described in the present invention.
Synthetic method 1
Target kinase inhibitor quinolines (
11) can prepare by synthetic method 1.Compound (
1), (
2) and (
3) add thermal condensation, obtain compound (
4).Compound (
4) at the high boiling point non-polar solvent, as dimethylbenzene, in orthodichlorobenzene, high temperature reflux, generation cyclization product (
5).Afterwards, compound (
5) at suitable chlorination reagent, as, SOCl
2, POCl
3Deng the effect under, change into compound (
6).Compound (
6) and the optional p-NP replaced (
7) carry out coupling, and by the nitryl group reduction obtain amino benzenes derivates (
9).Finally, compound (
9) condensing agent (EDCI or HATU) exist lower and carboxylic acid compound (
10) condensation obtain the target kinase inhibitor (
11).
Synthetic method 2
Target kinase inhibitor quinolines (
11) can also prepare by synthetic method 2.Compound (
12) at alkali, as potassium tert.-butoxide, under the existence of sodium hydride, with compound (
6) microwave reaction generation amino benzenes derivates (
9).Compound (
9) condensing agent (EDCI or HATU) exist lower and carboxylic acid compound (
10) condensation obtain the target kinase inhibitor (
11).
Synthetic method 3
Target kinase inhibitor quinolines (
11) also can prepare by synthetic method 3.Amino benzenes compounds (
12) condensing agent (EDCI or HATU) exist lower and carboxylic acid compound (
10) condensation obtain amides (
13), compound (
13) at alkali, as potassium tert.-butoxide, under sodium hydrides etc. exist, with compound (
6) reaction generate final target kinase inhibitor (
11).
Embodiment
Embodiment 1N-(4-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-
Carboxylic acid amides
Step 1) 5-(((3,4-Dimethoxyphenyl) amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone
By 3,4-dimethoxyaniline (50g, 0.33mol) and 2,2-dimethyl-1,3-diox-4,6-diketone (56.5g, 0.39mol) be dissolved in dehydrated alcohol (100mL), and add wherein triethyl orthoformate (53.2g, 0.36mol).After reaction solution reflux 1 hour, be cooled to-20 ° of C, and continue to stir 2 hours, filter afterwards.The gained solid is through dehydrated alcohol (100mL) washing, and obtaining title compound is gray solid (91.5g, 91.5%).
MS(ESI,neg.ion)m/z:306.2[M-H]
-；
1H?NMR(400MHz,CDCl
3):δ1.76(s,6H),3.90(s,3H),3.93(s,3H),6.76(d,J=2.5Hz,1H),6.81(dd,J=2.5Hz,7.0Hz,1H),6.89(d,J=8.2Hz,1H),8.55(d,J=14.4Hz,1H),11.24(d,J=14.3Hz,1H)。
Step 2) 6,7-dimethoxy-quinoline-4-alcohol
By 5-(((3,4-Dimethoxyphenyl) amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone (100g, 0.33mol) is dissolved in 1,2-dichlorobenzene (1.2L, Aladdin).After reaction solution reflux 5 hours, be cooled to-20 ° of C, and continue to stir 2 hours.Reaction mixture is filtered, and obtaining title compound is pale solid (45.8g, 68.6%).
MS(ESI,pos.ion)m/z:206.1[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ3.88(s,3H),3.92(s,3H),6.26(d,J=7.2Hz,1H),6.99(s,1H),7.64(d,J=7.2Hz,1H),7.70(s,1H),11.86(s,1H)。
Step 3) 4-is chloro-6, the 7-dimethoxy-quinoline
6,7-dimethoxy-quinoline-4-alcohol (45g, 0.22mol) is suspended in toluene (100mL), and slowly adds wherein phosphorus oxychloride (60mL, 0.66mol).Reaction solution, after 115 ° of C stir 1 hour, naturally cools to room temperature.By after ethyl acetate for mixture (400mL) dilution, regulate the pH value to 7-8 with 3M NaOH solution, and extract by ethyl acetate (150mLx2).The salt solution for organic phase (150mL) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure, obtaining title compound is faint yellow solid (40.5g, 82.7%).
MS(ESI,pos.ion)m/z:224.0[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ4.05(s,3H),4.06(s,3H),7.27(s,1H),7.35(d,J=4.8Hz,1H),7.41(s,1H),7.42(s,1H),8.57(d,J=4.8Hz,1H)。
Step 4) 6,7-dimethoxy-4 '-(4-nitrophenoxy) quinoline
4-is chloro-6, and 7-dimethoxy-quinoline (40g, 0.18mol) and 4-nitrophenol (26.2g, 0.19mol) are suspended in toluene (60mL), and add wherein DIPEA (27.8g, 0.22mol).Reaction solution after 115 ° of C stir 24 hours, concentrating under reduced pressure.Residue is washed through ethanol (40mL), and obtaining title compound is faint yellow solid (28g, 47.8%).
MS(ESI,pos.ion)m/z:327.1[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ4.00(s,3H),4.07(s,3H),6.69(d,J=5.1Hz,1H),7.27(d,J=9.0Hz,2H),7.37(s,1H),7.47(s,1H),8.32(d,J=9.1Hz,2H),8.62(d,J=5.1Hz,1H)。
Step 5) 4-((6,7-dimethoxy-quinoline-4-yl) oxygen base) aniline
By 6,7-dimethoxy-4 '-(4-nitrophenoxy) quinoline (28g, 85.8mmol) and potassium formiate (50.5g, 601.1mmol) are suspended in tetrahydrofuran (THF) (150mL) and water (40mL), and add wherein Pd/C (2.8g, 10%).Reaction solution, after 73 ° of C stir 12 hours, is cooled to room temperature, separates organic phase, and concentrating under reduced pressure.The mixing solutions of ethanol for residue (90mL) and water (30mL) is washed, and obtaining title compound is faint yellow solid (5.7g, 22.4%).
MS(ESI,pos.ion)m/z:297.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ3.92(s,3H),3.93(s,3H),5.16(s,2H),6.36(d,J=5.2Hz,1H),6.65-6.68(m,2H),6.91-6.93(m,2H),7.36(s,1H),7.50(s,1H),8.42(d,J=5.3Hz,1H)。
Step 6) N-(4-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-
Carboxylic acid amides
By 4-((6,7-dimethoxy-quinoline-4-yl) oxygen base) aniline (2g, 6.7mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (1.58g, 6.8mmol) is dissolved in methylene dichloride (28mL), and adds wherein EDCI (1.53g, 8mmol) and HOAT (0.18g, 1.3mmol).Reaction solution refluxes and spends the night, and then water (50mLx2) is washed.Gained solution anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.By residue recrystallization (PE/DCM (v/v)=5/1) in the mixing solutions of methylene dichloride and sherwood oil, obtaining title compound is white solid (1.9g, 87%).
MS(ESI,pos.ion)m/z:511.1[M+H]
+；
1H?NNR(400MHz,CDCl
3):δ10.78(s,1H),8.48(d,J=5.3Hz,1H),7.77-7.75(m,2H),7.58-7.55(m,3H),7.49-7.47(m,1H),7.42(s,1H),7.39-7.36(m,2H),7.15-7.13(m,2H),6.49(d,J=5.3Hz,1H),4.05(s,6H),3.37(s,3H),3.04(s,3H)。
Embodiment 2N-(4-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic
Acid amides
Step 1) 7-methoxyl group-4-(4-nitrophenoxy) quinoline
The chloro-7-methoxy quinoline of 4-(15g, 77.7mmol) and 4-nitrophenol (11.89g, 85.5mmol) are dissolved in toluene (39mL), and add wherein DIPEA (11.03g, 85.5mmol).Reaction solution, after 115 ° of C stir 4 hours, is cooled to room temperature.Reaction mixture NaHCO
3(0.6M, 40mL) aqueous solution is processed, and stirring at room 1 hour.The gained mixture is filtered, filter cake water (60mL) and ethanol (50mL) washing, obtaining title compound is light yellow solid (16g, 69.6%).
MS(ESI,pos,ion)m/z:297.0[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ3.98(s,3H),6.67(d,J=5.1Hz,1H),7.21-7.24(m,2H),7.24-7.25(m,1H),7.46(d,J=2.5Hz,1H),8.06(d,J=9.2Hz,1H),8.31(dd,J=2.1Hz,7.0Hz,2H),8.72(d,J=5.1Hz,1H)。
Step 2) 4-((7-methoxy quinoline-4-yl) oxygen base) aniline
7-methoxyl group-4-(4-nitrophenoxy) quinoline (8g, 27mmol) is dissolved in to tetrahydrofuran (THF) (42mL), and adds wherein the potassium formiate aqueous solution (16.33g, 14mL water) and Pd/C (0.48g, 10%) under 40 ° of C.Reaction solution is after 45 ° of C stir 4 hours, with 14mL tetrahydrofuran (THF) and the dilution of 12mL water.The gained mixture continued to stir after 15 minutes, filtered.The organic phase anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is suspended in the mixing solutions of ethanol (5mL) and water (25mL), after stirring 3 hours, filters, obtaining title compound is gray solid (6.25g, 86.9%).
MS(ESI,pos,ion)m/z:267.0[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ3.71(s,2H),3.96(s,1H),6.39(d,J=5.3Hz,1H),6.75(dd,J=2.2Hz,5.8Hz,2H),6.97(dd,J=2.2Hz,6.6Hz,2H),7.19(dd,J=2.6Hz,9.2Hz,1H),7.39(d,J=2.5Hz,1H),8.25(d,J=9.2Hz,1H),8.55(d,J=5.3Hz,1H)。
Step 3) N-(4-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acyl
Amine
By 4-((7-methoxy quinoline-4-yl) oxygen base) aniline (4g, 15mmol) He 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (3.56g, 18mmol) be dissolved in methylene dichloride (42mL), and add wherein HOAT (0.41g, 3mmol) under 43 ° of C.Reaction solution stirs and spends the night at 43 ° of C, is cooled to room temperature, then uses methylene dichloride (42mL) dilution.Organic phase water (42mLx2) is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is suspended in the mixing solutions of ethanol (20mL) and water (20mL), after stirring 3 hours, filters, obtaining title compound is light yellow solid (5.6g, 77.6%).
MS(ESI,pos,ion)m/z:481.0[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ2.80(s,3H),3.36(s,3H),3.96(s,3H),6.45(d,J=5.3Hz,1H),7.11-7.13(m,2H),7.20(dd,J=2.5Hz,9.2Hz,1H),7.35(t,J=1.1Hz,2.2Hz,1H),7.38(d,J=1.4Hz,1H),7.41(d,J=2.5Hz,1H),7.46-7.49(m,1H),7.55(t,J=7.3Hz,15.2Hz,2H),7.75(dd,J=2.1Hz,6.8Hz,2H),8.24(d,J=9.2Hz,1H),8.57(d,J=5.3Hz,1H),10.77(s,1H)。
Embodiment 3N-(the chloro-4-of 2-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole
-4-carboxylic acid amides
Step 1) the chloro-4-of 2-((7-methoxy quinoline-4-yl) oxygen base) aniline
4-amino-3-chlorophenol (158mg, 1.1mmol) is dissolved in methyl-sulphoxide (2mL), and at room temperature adds wherein NaH (60% is dissolved in mineral oil for 88mg, 2.2mmol).After reaction solution at room temperature stirs 15 minutes, add the chloro-7-methoxy quinoline of 4-(194mg, 1.0mmol).Reaction solution is placed under microwave, and 150 ° of C heat 2 hours, after being cooled to room temperature, and water (10mL) cancellation reaction, and extract by ethyl acetate (30mL).Salt solution for organic phase (30mLx3) is washed, through 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 pink solid (0.19g, 63%).
MS(ESI,pos.ion)m/z:301.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ3.93(s,3H),5.44(s,2H),6.41(d,J=5.2Hz,1H),6.91(d,J=8.7Hz,1H),6.99(m,1H),7.21(d,J=2.6Hz,1H),7.26(m,1H),7.38(d,J=2.6Hz,1H),8.17(d,J=8.7Hz,1H),8.57(d,J=5.2Hz,1H)。
Step 2) N-(the chloro-4-of 2-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole
-4-carboxylic acid amides
By the chloro-4-of 2-((7-methoxy quinoline-4-yl) oxygen base) aniline (190mg, 0.63mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (161mg, 0.69mmol) be suspended in methylene dichloride (6mL), and add wherein EDCI (145mg, 0.75mmol) and HOAT (24mg, 0.17mmol).Reaction solution, after 46 ° of C stir 17 hours, adds 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (30mg, 0.13mmol) and EDCI (24mg, 0.13mmol).Reaction solution continues to stir 5 hours at 46 ° of C, after being cooled to room temperature, and water (10mL) cancellation reaction, and with dichloromethane extraction (10mL).Salt solution for organic phase (20mLx3) is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH (v/v)=60/1) purifying, and obtaining title compound is lightpink solid (0.15g, 46%).
MS(ESI,pos.ion)m/z:515.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ2.72(s,3H),3.35(s,3H),3.94(s,3H),5.76(s,1H),6.56(d,J=5.2Hz,1H),7.29(m,2H),7.41(d,J=2.5Hz,1H),7.46(m,2H),7.54(m,2H),7.60(t,J=7.5Hz,2H),8.19(d,J=9.2Hz,1H),8.63(t,J=7.0Hz,1H),11.19(s,1H)。
Embodiment 4N-(the fluoro-4-of 2,3-bis-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
Step 1) 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 3-bis-
The mixing solutions of 2,3,4-trifluoronitrobenzene (5g, 28.2mmol) and phenylcarbinol (3.07g, 28.4mmol) is dissolved in to DMF (10mL), and adds wherein salt of wormwood (5.87g, 42.5mmol).Reaction solution is in stirring at room after 72 hours, and under 4 ° of C, water (35mL) dilutes, and stirs and spend the night.Reaction mixture is filtered, and gained solid water (30mL) is washed.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=20/1) purifying, and obtaining title compound is faint yellow solid (2.15g, 28.7%).
1H?NMR(400MHz,CDCl
3):δ7.90(m,1H),7.43(s,2H),7.42(s,2H),7.39(m,1H),6.86(m,1H),5.27(s,2H)。
Step 2) 4-amino-2, the 3-difluorophenol
By 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 3-bis-(1.93g, 0.73mmol) is suspended in the mixing solutions of methyl alcohol (45mL) and tetrahydrofuran (THF) (9mL), and adds wherein Pd/C (333mg, 10%).At H
2Under condition, reaction solution stirs 13 hours at 32 ° of C, then passes through diatomite filtration.Filtrate extracts by ethyl acetate (30mL), and gained organic phase water (30mL) is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is suspended in methylene dichloride (4mL), after stirring latter 1 hour, filters, obtaining title compound is Vandyke brown solid (0.89g, 84%).
MS(ESI,pos.ion)m/z:146.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ6.49(m,1H),6.38(m,1H),4.71(s,2H)。
Step 3) 2, the fluoro-4-of 3-bis-((7-methoxy quinoline-4-yl) oxygen base) aniline
By 4-amino-2,3-difluorophenol (208mg, 1.43mmol) is dissolved in DMF (4mL), and adds wherein potassium tert.-butoxide (257mg, 2.29mmol).Reaction mixture after 30 minutes, adds the chloro-7-methoxy quinoline of 4-(308mg, 1.59mmol) in stirring at room.Reaction solution is placed under microwave, and 120 ° of C stirred after 2 hours, were cooled to room temperature, with the 25mL shrend reaction of going out, and extracted by ethyl acetate (30mLx3).The salt solution for organic phase (30mLx3) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying, and obtaining title compound is faint yellow solid (0.11g, 25.4%).
MS(ESI,pos.ion)m/z:303.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ8.60(d,J=5.2Hz,1H),8.21(d,J=9.2Hz,1H),7.40(d,J=2.4Hz,1H),7.29(dd,J=2.4Hz,9.2Hz,1H),6.99(m,1H),6.66(m,1H),6.48(d,J=5.0Hz,1H),5.60(s,2H),3.93(s,3H)。
Step 4) N-(the fluoro-4-of 2,3-bis-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
By 2, the fluoro-4-of 3-bis-((7-methoxy quinoline-4-yl) oxygen base) aniline (110mg, 0.36mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (86mg, 0.37mmol) is suspended in methylene dichloride (3mL), and adds wherein EDCI (84mg, 0.44mmol) and HOAT (10mg, 0.07mmol).Reaction solution, after 46 ° of C stir 14.5 hours, adds 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (28mg, 0.12mmol) and EDCI (28mg, 0.15mmol).Reaction solution continues to stir 5 hours at 46 ° of C, then is cooled to room temperature, with the 5mL shrend, goes out after reaction, and ethyl acetate (10mLx3) extracts.The salt solution for organic phase (10mLx3) merged is washed, through 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 beige solid (162mg, 87.1%).
MS(ESI,pos.ion)m/z:517.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ11.19(s,1H),8.63(d,J=5.7Hz,1H),8.37(m,1H),8.23(d,J=9.2Hz,1H),7.61(t,J=7.2Hz,2H),7.54(m,1H),7.44(m,3H),7.32(dd,J=2.3Hz,9.1Hz,2H),6.62(d,J=5.1Hz,1H),3.95(s,3H),3.38(s,3H),2.72(s,3H)。
Embodiment 5N-(the fluoro-4-of 2,5-bis-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
Pyrazole-4-carboxamide
Step poly-1) amino-2,5 difluorophenols of 4-
By 1-(benzyloxy)-2, the fluoro-4-oil of mirbane of 5-bis-(1.06g, 4mmol) is suspended in the mixing solutions of methyl alcohol (25mL) and tetrahydrofuran (THF) (5mL), and adds wherein Pd/C (185mg, 17%).At H
2Under condition, reaction solution, after 32 ° of C stir 10 hours, passes through diatomite filtration.Methyl alcohol for organic phase (10mL) is washed, and concentrating under reduced pressure.Residue is suspended in methylene dichloride (15mL), after stirring 1 hour, filters, filter cake is washed through methylene dichloride (20mL), and obtaining title compound is Vandyke brown solid (0.5g, 86%).
MS(ESI,pos.ion)m/z:146.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ4.68(s,2H),6.53-6.65(m,2H),9.06(br?s,1H)。
Step 2) 2, the fluoro-4-of 5-bis-((7-methoxy quinoline-4-yl) oxygen base) aniline
By 4-amino-2, the chloro-7-methoxy quinoline of 5-difluorophenol (100mg, 0.51mmol) and 4-(114mg, 0.72mmol) mixture be dissolved in methyl-sulphoxide (2mL), and add wherein sodium hydride (60% is dissolved in mineral oil for 62mg, 1.02mmol).Reaction solution is placed under microwave, and 150 ° of C heating, after 2 hours, are cooled to room temperature, water (20mL) cancellation reaction, and extract by ethyl acetate (50mLx3).The salt solution for organic phase (80mL) merged is washed, through 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 orange solids (45mg, 40%).
MS(ESI,pos.ion)m/z:303.1[M+H]
+。
Step 3) N-(the fluoro-4-of 2,5-bis-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
By 2, the fluoro-4-of 5-bis-((7-methoxy quinoline-4-yl) oxygen base) aniline (0.25g, 0.83mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2, the mixing solutions of 3-dihydro-1 h-pyrazole-4-carboxylic acid (211mg, 0.93mmol) is dissolved in methylene dichloride (10mL), and adds wherein EDCI (0.19g, 0.98mmol) and HOAT (25mg, 0.21mmol).Reaction solution is after 45 ° of C stir 16 hours, and water (20mL) cancellation is reacted, and extracts with methylene dichloride (50mLx2).The salt solution for organic phase (80mL) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying, and obtaining title compound is white solid (0.21g, 49%).
MS(ESI,pos.ion)m/z:517.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ11.11(s,1H),8.56-8.62(m,2H),8.23(d,J=9.2Hz,1H),7.52-7.57(m,2H),7.45-7.49(m,1H),7.41(d,J=2.3Hz,1H),7.36-7.38(m,2H),7.21-7.24(m,1H),7.03(dd,J=7.0Hz,10.3Hz,1H),6.44(d,J=5.2Hz,1H),3.97(s,3H),3.38(s,3H),2.80(s,3H)。
Embodiment 6N-(the chloro-4-of 2-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
Pyrazole-4-carboxamide
Step poly-1) the chloro-4-of 2-((6,7-dimethoxy-quinoline-4-yl) oxygen base) aniline
Compound 4-amino-2-chlorophenol (474mg, 3.3mmol) is suspended in methyl-sulphoxide (7mL), and adds wherein sodium hydride (60% is dissolved in mineral oil for 264mg, 6.6mmol).Reaction mixture is in stirring at room after 15 minutes, adds 4-chloro-6,7-dimethoxy-quinoline (671mg, 3.0mmol).Reaction solution is placed under microwave, and 160 ° of C heating is after 2 hours, after being cooled to room temperature, and water (20mL) cancellation reaction, and be extracted with ethyl acetate (60mL).Salt solution for organic phase (60mLx3) is washed, through 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 purple solid (0.49g, 49%).
MS(ESI,pos.ion)m/z:331.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ3.93(d,J=3.3Hz,6H),5.42(s,2H),6.42(d,J=5.2Hz,1H),6.91(d,J=8.8Hz,1H),6.98-7.01(m,1H),7.20-7.21(m,1H),7.37(s,1H),7.49(s,1H),8.45(d,J=5.2Hz,1H)。
Step 2) N-(the chloro-4-of 2-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
By the chloro-4-((6 of 2-, 7-dimethoxy-quinoline-4-yl) oxygen base) aniline (0.49g, 1.48mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (414mg, 1.78mmol) is suspended in methylene dichloride (10mL), and adds wherein EDCI (342mg, 1.78mmol) and HOAT (41mg, 0.30mmol).Reaction solution, after 45 ° of C stir 24 hours, is cooled to room temperature, water (30mL) cancellation reaction, and extract with methylene dichloride (30mL).Salt solution for organic phase (30mLx3) is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH (v/v)=80/1) purifying, and obtaining title compound is red solid (0.37g, 45%).
MS(ESI,pos.ion)m/z:545.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ2.72(s,3H),3.40(s,3H),3.94(d,J=7.2Hz,6H),6.56(d,J=5.2Hz,1H),7.26-7.29(m,1H),7.40(s,1H),7.45(d,J=7.2Hz,2H),7.50-7.54(m,3H),7.60(t,J=7.5Hz,2H),8.49(d,J=5.2Hz,1H),8.65(d,J=9.0Hz,1H),11.19(s,1H)。
Embodiment 7N-(4-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro
-1H-pyrazole-4-carboxamide
Step 1) 4-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-2,3 difluoroanilines
By 4-amino-2,3-difluorophenol (208mg, 1.43mmol) is dissolved in DMF (4mL), and adds wherein potassium tert.-butoxide (257mg, 2.29mmol).Reaction mixture is in stirring at room after 30 minutes, adds 4-chloro-6,7-dimethoxy-quinoline (356mg, 1.59mmol).Reaction solution is placed under microwave, and 120 ° of C heating, after 2 hours, are cooled to room temperature, water (25mL) cancellation reaction, and extract by ethyl acetate (30mLx3).The salt solution for organic phase (30mLx3) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/3) purifying, and obtaining title compound is faint yellow solid (75mg, 15.8%).
MS(ESI,pos.ion)m/z:333.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ8.47(d,J=5.1Hz,1H),7.51(s,1H),7.40(s,1H),6.99(m,1H),6.76(m,1H),6.47(d,J=4.9Hz,1H),5.90(s,2H),3.94(s,6H)。
Step 2) N-(4-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro
-1H-pyrazole-4-carboxamide
By 2, the fluoro-4-of 3-bis-((7-methoxy quinoline-4-yl) oxygen base) aniline (0.14g, 0.42mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (204mg, 0.88mmol) is suspended in methylene dichloride (6mL), and adds wherein EDCI (0.1g, 0.52mmol) and HOAT (12mg, 0.09mmol).Reaction solution, after 45 ° of C stir 35 hours, is cooled to room temperature, water (5mL) cancellation reaction, and extract by ethyl acetate (10mLx3).The salt solution for organic phase (10mLx3) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/8) purifying, and obtaining title compound is beige solid (60mg, 26.1%).
MS(ESI,pos.ion)m/z:547.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ11.18(s,1H),8.49(d,J=5.1Hz,1H),8.34(m,1H),7.68(m,2H),7.61(m,2H),7.45(d,J=7.3Hz,2H),7.42(s,1H),7.29(m,1H),6.61(d,J=4.6Hz,1H),3.95(s,6H),3.34(s,3H),2.71(s,3H)。
Embodiment 8N-(4-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro
-1H-pyrazole-4-carboxamide
Step 1) 4-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-2, the 5-difluoroaniline
4-is chloro-6, and 7-dimethoxy-quinoline (0.57g, 2.55mmol) and 4-amino-2,5-difluorophenol (0.39g, 2.60mmol) is suspended in methyl-sulphoxide (5mL), and adds wherein sodium hydride (244mg, 5.10mmol 60% is dissolved in mineral oil).Reaction solution is placed under microwave, and 150 ° of C heating, after 2 hours, are cooled to room temperature, water (40mL) cancellation reaction, and extract by ethyl acetate (70mLx3).The salt solution for organic phase (100mL) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying, and obtaining title compound is orange solids (0.21g, 25%).
MS(ESI,pos.ion)m/z:333.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ8.49(d,J=5.2Hz,1H),7.55(s,1H),7.42(s,1H),6.96(dd,J=7.1Hz,10.6Hz,1H),6.67(dd,J=8.1Hz,11.0Hz,1H),6.42(d,J=5.2Hz,1H),4.04-4.06(m,6H)。
Step 2) N-(4-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro
-1H-pyrazole-4-carboxamide
By 2, the fluoro-4-of 5-bis-((7-methoxy quinoline-4-yl) oxygen base) aniline (170mg, 0.51mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2, the mixing solutions of 3-dihydro-1 h-pyrazole-4-carboxylic acid (145mg, 0.61mmol) is dissolved in methylene dichloride (10mL), and adds wherein EDCI (120mg, 0.61mmol) and HOAT (18mg, 0.11mmol).Reaction solution, after 45 ° of C stir 20 hours, is cooled to room temperature, water (20mL) cancellation reaction, and extract with methylene dichloride (50mLx2).The salt solution for organic phase (80mL) merged is washed, through anhydrous Na
2SO
4Drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/8) purifying, and obtaining title compound is white solid (218mg, 87%).
MS(ESI,pos.ion)m/z:547.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ11.12(s,1H),8.57-8.62(m,1H),8.52(d,J=5.4Hz,1H),7.52-7.57(m,3H),7.45-7.48(m,2H),7.38(d,J=5.9Hz,2H),7.04(dd,J=7.0Hz,10.3Hz,1H),6.48(d,J=5.2Hz,1H),4.05-4.06(m,6H),3.38(s,3H),2.80(s,3H)。
Embodiment 91-ethyl-N-(4-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-
Carboxylic acid amides
Step 1) 1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formaldehyde
Solvent DMF is cooled to 0 ° of C, then in DMF, dropwise adds POCl
3(1.40g, 9.2mmol), after dropwising, stir 30 minutes, then add 1-ethyl-5-methyl-2-phenyl-1H-pyrazoles-3 (2H)-one (0.56g in reaction solution, 2.8mmol), reaction solution is heated to 84 ° of C, and stirring reaction, after 4 hours, is cooled to room temperature, then reaction solution is poured in frozen water (100mL), in the mixture obtained, add the NaOH aqueous solution (2M) that it is adjusted to pH=11.Mixture CHCl
3(100mLx3) extraction, the salt solution for organic phase (100mLx3) of merging is washed, and uses anhydrous Na
2SO
4Drying, concentrating under reduced pressure then, it is yellow solid (438mg, 67.9%) that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=3/1) purifying.
MS(ESI,pos.ion)m/z:231.2[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ9.89(s,1H),7.52(t,J=7.3Hz,2H),7.44(d,J=7.3Hz,1H),7.32(d,J=7.2Hz,2H),3.79(m,2H),2.66(s,3H),1.08(t,J=7.1Hz,3H)。
Step 2) 1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid
By compound 1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formaldehyde (0.53g, 2.3mmol) is dissolved in DCM (6mL), then in reaction solution, adds successively DMSO (1.80g, 23mmol), H
3PO
4(0.75M, 3mL) and Textone (0.52g, 5.7mmol), the stirring at room reaction, after 30 minutes, adds saturated NaHCO in reaction solution
3The aqueous solution is adjusted to pH=5-6 by it, the mixture CHCl obtained
3(100mLx2) extraction, the salt solution for organic phase (50mLx3) of merging is washed, and uses anhydrous Na
2SO
4Drying, concentrating under reduced pressure then, it is yellow solid (280mg, 49.5%) that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purifying.
MS(ESI,pos.ion)m/z:247.2[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ7.56(t,J=7.1Hz,2H),7.49(m,1H),7.35(m,2H),3.84(m,2H),2.71(s,3H),1.08(t,J=7.1Hz,3H)。
Step 3) 1-ethyl-N-(4-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic
Acid amides
By compound 4-((7-methoxy quinoline-4-yl) oxygen base) aniline (296mg, 1.11mmol) and 1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (279mg, 1.13mmol) be suspended in DCM (5mL), then add EDCI (255mg in reaction solution, 1.33mmol) and HOAT (30mg, 0.22mmol), be heated to 43 ° of C, after stirring reaction 14.5 hours, be cooled to room temperature, add water (10mL) cancellation reaction, the mixture CH obtained
2Cl
2(20mLx3) extraction, the salt solution for organic phase (20mLx3) of merging is washed, and uses anhydrous Na
2SO
4Drying, concentrating under reduced pressure then, it is beige solid (260mg, 47.4%) that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purifying.
MS(ESI,pos.ion)m/z:495.2[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ10.78(s,1H),8.57(d,J=5.3Hz,1H),8.24(d,J=9.2Hz,1H),7.75(m,2H),7.56(m,2H),7.46(m,1H),7.40(m,3H),7.20(dd,J=2.5Hz,9.1Hz,1H),7.12(m,2H),6.45(d,J=5.3Hz,1H),3.97(s,3H),3.85(m,2H),2.82(s,3H),1.07(t,J=7.1Hz,3H)。
Embodiment 10N-(2-deuterium-4-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
By compound N-(the chloro-4-of 2-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (480mg, 0.93mmol) and triethylamine (0.20mL, 1.40mmol) be suspended in methyl alcohol (20mL), then add Pd/C (96mg in reaction solution, 20%), reaction solution is under deuterium compression ring border, be heated to 62 ° of C, and stirring reaction 20 hours, then be cooled to room temperature, suction filtration, filtrate decompression is concentrated, the residue obtained is after silica gel column chromatography (MeOH/EtOAc (v/v)=1/50) purifying, use respectively again EtOAc (10mL) and DCM (5mL) to wash, obtaining title compound after drying is white solid (340mg, 76%).
MS(ESI,pos.ion)m/z:482.2[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ2.71(s,3H),3.37(s,3H),3.94(s,3H),6.48(d,J=5.2Hz,1H),7.25(d,J=8.9Hz,2H),7.27-7.30(m,1H),7.41(d,J=2.4Hz,1H),7.45(d,J=7.2Hz,2H),7.50-7.53(m,1H),7.58-7.62(m,2H),7.74(d,J=8.9Hz,2H),8.21(d,J=9.2Hz,1H),8.61(d,J=5.2Hz,1H),10.84(s,1H)。
Embodiment 11N-(2-deuterium-4-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro
-1H-pyrazole-4-carboxamide
By compound N-(chloro-4-((6 of 2-, 7 dimethoxy-quinolines-4-yl) oxygen base) phenyl)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3 dihydro-1 h-pyrazoles-4-carboxylic acid amides (190mg, 0.35mmol) and triethylamine (0.07mL, 0.50mmol) be suspended in methyl alcohol (8mL), then add Pd/C (38mg in reaction solution, 20%), reaction solution is under deuterium compression ring border, be heated to 62 ° of C, and stirring reaction 12 hours, then be cooled to room temperature, suction filtration, filtrate decompression is concentrated, it is deep yellow solid (20mg that the residue obtained obtains title compound through silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifying, 11%).
MS(ESI,pos.ion)m/z:512.0[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ2.81(s,3H),3.37(s,3H),4.05(s,6H),6.49(m,1H),7.14(d,J=8.3Hz,2H),7.38(d,J=7.6Hz,2H),7.44(m,1H),7.48(m,1H),7.57(m,3H),7.77(m,2H),10.78(s,1H)。
Embodiment 12N-(the fluoro-4-of the chloro-5-of 2-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro
-1H-pyrazole-4-carboxamide
Step 1) 1-is chloro-4, the fluoro-2-oil of mirbane of 5-bis-
To adding in reaction flask 4-chloro-1,2-difluorobenzene (8.97g, 60.4mmol), be cooled to 0 ° of C, and then to the dense H that adds successively 98% in reaction flask
2SO
4(16.1mL, 302mmol) and 65% dense HNO
3(5.0mL, 66.4mmol),, pour in frozen water after 5 hours in the stirring at room reaction, EtOAc for mixture (50mLx2) extraction obtained, and the organic phase of merging is used saturated NaHCO successively
3The aqueous solution (0.6M, 50mL) and salt solution (50mL) are washed, and use anhydrous Na
2SO
4Drying, it is yellow oil (11.31g, 96.7%) that concentrating under reduced pressure obtains title compound.
1H?NMR(400MHz,CDCl
3):δ7.41-7.45(m,1H),7.86-7.90(m,1H)。
Step 2) the chloro-2-fluoro-4-nitrophenol of 5-potassium
Compound 1-is chloro-4, the fluoro-2-oil of mirbane of 5-bis-(5.12g, 26.5mmol) and 15% KOH (19.9g, 0.35mol) the mixture stirring and refluxing of the aqueous solution is after 3 hours, is cooled to room temperature, suction filtration, obtaining title compound is yellow solid (5.67g, 93.3%).
1H?NMR(400MHz,DMSO-d
6):δ6.20(d,J=13.2Hz,1H),7.70(d,J=8.6Hz,1H)。
Step 3) the chloro-2-fluorophenol of 4-amino-5-
Compound 5-chloro-2-fluoro-4-nitrophenol potassium (1.0g, 4.35mmol) is dissolved in to EtOH (22mL, 95%) and H
2In the mixed solvent of O (8mL), then in reaction solution, add iron powder (0.97g, 17.4mmol) and NH
4Cl (1.86g, 34.8mmol), the stirring at room reaction is after 10 hours, add methyl alcohol (25mL) and ethyl acetate (25mL) dilute reaction solution, suction filtration, filtrate decompression is concentrated, ethyl acetate for residue (40mL) dilution, wash with salt solution (25mL), uses anhydrous Na
2SO
4Drying, it is pale solid (0.6g, 85.3%) that concentrating under reduced pressure obtains title compound.
1H?NMR(400MHz,DMSO-d
6):δ4.90(s,2H),6.60(d,J=12.9Hz,1H),6.79(d,J=8.8Hz,1H),9.11(s,1H)。
Step 4) N-(the fluoro-4-hydroxy phenyl of the chloro-5-of 2-)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides
By the compound 4-chloro-2-fluorophenol of amino-5-(0.97g, 6mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (1.42g, 6.12mmol) is suspended in DMF (20mL), then in reaction solution, adds EDCI (0.38mg, 7.2mmol) and HOAT (0.16g, 1.2mmol), being heated to 80 ° of C, stirring reaction is after 24 hours, be cooled to 0 ° of C, then add H
2O (200mL) and EtOAc (2mL) dilute reaction solution, suction filtration, vacuum-drying, obtaining title compound is light brown solid (1.2g, 53.2%).
MS(ESI,pos.ion)m/z:376.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ2.68(s,3H),3.34(s,3H),7.03(d,J=8.8Hz,1H),7.41-7.43(m,2H),7.48-7.52(m,1H),7.56-7.60(m,2H),8.31(d,J=13.8Hz,1H),10.08(s,1H),10.95(s,1H)。
Step 5) N-(the fluoro-4-of the chloro-5-of 2-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
Pyrazole-4-carboxamide
To compound N-(fluoro-4-hydroxy phenyl of the chloro-5-of 2-)-2,5-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (225.5mg, 0.6mmol), t-BuOK (101mg, 0.9mmol) and the mixture of DMF (1.2mL) in add the chloro-7-methoxy quinoline of 4-(116mg, 0.6mmol), being heated to 100 ° of C, stirring reaction is after 25 hours, be cooled to room temperature, add EtOAc (0.5mL) and H
2O (12mL) dilution, the mixture obtained stirs and spends the night at ambient temperature, and then suction filtration, concentrated by filtrate decompression, it is light yellow solid (110mg, 34.5%) that the residue obtained obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purifying.
MS(ESI,pos.ion)m/z:533.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ2.71(s,3H),3.40(s,3H),3.94(s,3H),6.57(d,J=5.1Hz,1H),7.31(dd,J=2.5Hz,9.1Hz,1H),7.42-7.46(m,3H),7.51-7.55(m,1H),7.58-7.62(m,2H),7.80(d,J=8.2Hz,1H),8.21(d,J=9.2Hz,1H),8.62(d,J=5.2Hz,1H),8.68(d,J=13.4Hz,1H),11.37(s,1H)。
Embodiment 13N-(the chloro-4-of 2-((6,7-dimethoxy-quinoline-4-yl) oxygen base)-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-bis-
Hydrogen-1H-pyrazole-4-carboxamide
To compound N-(fluoro-4-hydroxy phenyl of the chloro-5-of 2-)-2,5-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (225.5mg, 0.6mmol), t-BuOK (101mg, 0.9mmol) and the mixture of DMF (1.2mL) in add 4-chloro-6,7-dimethoxy-quinoline (134mg, 0.6mmol), be heated to 100 ° of C, after stirring reaction 25 hours, be cooled to room temperature, add EtOAc (0.5mL) and H
2O (12mL) dilution, the mixture obtained stirs and spends the night at ambient temperature, and then suction filtration, concentrated by filtrate decompression, it is light yellow solid (55mg, 16.5%) that the residue obtained obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying.
MS(ESI,pos.ion)m/z:563.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ2.71(s,3H),3.40(s,3H),3.93(s,3H),3.94(s,3H),6.56(d,J=5.1Hz,1H),7.41-7.46(m,3H),7.51-7.55(m,1H),7.58-7.62(m,2H),7.78(d,J=8.1Hz,1H),8.48(d,J=5.2Hz,1H),8.68(d,J=13.4Hz,1H),11.37(s,1H)。
Embodiment 14N-(the chloro-4-of 3-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
Pyrazole-4-carboxamide
Step 1) N-(3-chloro-4-hydroxyl phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides
By compound 4-amino-2-chlorophenol (4.0g, 28.00mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (7.4g, 30.11mmol) be suspended in DCM (70mL), then add EDCI (6.65g, 30.11mmol) and HOAT (0.76g, 5.68mmol) in reaction solution, be heated to 45 ° of C, after stirring reaction 20 hours, be cooled to room temperature, suction filtration, DCM for filter cake (20mLx3) washes, vacuum-drying, obtaining title compound is gray solid (7.1g, 72.1%).
MS(ESI,pos.ion)m/z:358.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ10.56(s,1H),9.92(s,1H),7.83(d,J=2.5Hz,1H),7.59(m,2H),7.50(m,1H),7.42(m,2H),6.90(d,J=8.7Hz,1H),6.88(dd,J=9.6Hz,8.8Hz,1H),3.33(s,3H),2.68(s,3H)。
Step 2) N-(the chloro-4-of 3-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
By compound N-(3-chloro-4-hydroxyl phenyl)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (716mg, 2.0mmol) be suspended in DMF (8mL), then add t-BuOK (359mg in reaction solution, 3.2mmol), after stirring at room 30 minutes, add 4-chloro-6 again in reaction solution, 7-dimethoxy-quinoline (492mg, 2.2mmol), be heated to 120 ° of C, after stirring reaction 36 hours, be cooled to room temperature, add water (25mL) cancellation reaction, EtOAC for mixture (50mLx3) extraction, the salt solution for organic phase (50mLx3) merged is washed, use anhydrous Na
2SO
4drying, concentrating under reduced pressure, it is faint yellow solid (250mg, 22.9%) that the residue obtained obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=6/1) purifying.
MS(ESI,pos.ion)m/z:545.2[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ10.87(s,1H),8.48(d,J=5.3Hz,1H),8.10(d,J=2.5Hz,1H),7.53(m,5H),7.44(s,1H),7.37(m,2H),7.17(d,J=8.8Hz,1H),6.35(d,J=5.3Hz,1H),4.06(d,J=6.2Hz,6H),3.38(s,3H),2.81(s,3H)。
Embodiment 15N-(3-deuterium-4-((6,7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
Pyrazole-4-carboxamide
By compound N-(chloro-4-((6 of 3-, 7-dimethoxy-quinoline-4-yl) oxygen base) phenyl)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (350mg, 0.64mmol) and triethylamine (0.135mL, 0.96mmol) be suspended in methyl alcohol (15mL), then add Pd/C (70mg in reaction solution, 20%), reaction solution is under deuterium compression ring border, be heated to 62 ° of C, and stirring reaction 21 hours, then be cooled to room temperature, use the diatomite suction filtration, filtrate decompression is concentrated, it is orange solids (200mg that the residue obtained obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=8/1) purifying, 61.2%).
MS(ESI,pos.ion)m/z:512.2[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ10.78(s,1H),8.47(d,J=5.3Hz,1H),7.76(d,J=8.9Hz,2H),7.57(m,3H),7.48(m,1H),7.44(s,1H),7.38(m,2H),7.13(d,J=8.9Hz,2H),6.35(t,J=2.9Hz,1H),4.05(s,6H),3.37(s,3H),2.81(s,3H)。
Embodiment 16N-(the chloro-4-of 3-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
Step 1) the chloro-4-of 3-((7-methoxy quinoline-4-yl) oxygen base) aniline
To compound 4-amino-2-chlorophenol (500mg, 3.48mmol), the chloro-7-methoxy quinoline of 4-(675mg, 3.51mmol) and the mixture of DMSO (5mL) in add NaH (335mg in batches, 7.12mmol, 60% is dissolved in mineral oil), mixture under microwave condition in 150 ° of C stirring reactions after 2 hours, be cooled to room temperature, add water (50mL) cancellation reaction, EtOAc for mixture (100mLx3) extraction obtained, the salt solution for organic phase (80mL) of merging is washed, and uses anhydrous Na
2SO
4Drying, concentrating under reduced pressure, it is orange solids (345mg, 42%) that the residue obtained obtains title compound through purification by silica gel column chromatography (EtOAc/PE (v/v)=2/1).MS(ESI,pos.ion)m/z:301.0[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ8.56(d,J=5.2Hz,1H),8.21(d,J=9.2Hz,1H),7.38(d,J=2.5Hz,1H),7.26-7.29(m,1H),7.09(d,J=8.7Hz,1H),6.77(d,J=2.5Hz,1H),6.62(dd,J=2.6Hz,8.7Hz,1H),6.28(d,J=2.5Hz,1H),5.48(s,2H),3.92(s,3H)。
Step 2) N-(the chloro-4-of 3-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole
-4-carboxylic acid amides
By compound 3-chlorin-4-((7-methoxy quinoline-4-yl) oxygen base) aniline (345mg, 1.16mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (325mg, 1.37mmol) be dissolved in DCM (10mL), then add EDCI (270mg in reaction solution, 1.37mmol) and HOAT (35mg, 0.23mmol), being heated to 45 ℃, stirring reaction is after 16 hours, add water (20mL) cancellation reaction, DCM for mixture (50mLx2) extraction obtained, the salt solution for organic phase (80mL) of merging is washed, and uses anhydrous Na
2SO
4Drying, concentrating under reduced pressure, it is white solid (540mg, 91%) that residue obtains title compound through purification by silica gel column chromatography (EtOAc/PE (v/v)=2/1).
MS(ESI,pos.ion)m/z:515.1[M+H]
+；
1H?NMR(400MHz,DMSO-d
6):δ10.95(s,1H),8.59(d,J=5.2Hz,1H),8.23(d,J=9.2Hz,1H),8.17(d,J=2.4Hz,1H),7.57-7.61(m,2H),7.49-7.53(m,2H),7.41-7.45(m,4H),7.30(dd,J=2.5Hz,9.2Hz,1H),6.37-6.38(m,1H),3.93(s,3H),3.36(s,3H),2.70(s,3H)。
Embodiment 17N-(3-deuterium-4-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrrole
Azoles-4-carboxylic acid amides
By compound N-(the chloro-4-of 3-((7-methoxy quinoline-4-yl) oxygen base) phenyl)-1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (400mg, 0.78mmol) and triethylamine (0.16mL, 1.19mmol) be suspended in methyl alcohol (15mL), then add Pd/C (80mg in reaction solution, 20%), reaction solution is under deuterium compression ring border, be heated to 62 ° of C, and stirring reaction 24 hours, then be cooled to room temperature, suction filtration, filtrate decompression is concentrated, it is faint yellow solid (50mg that the residue obtained obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=10/1) purifying, 13%).
MS(ESI,pos.ion)m/z:482.0[M+H]
+；
1H?NMR(400MHz,CDCl
3):δ10.77(s,1H),8.56(d,J=5.2Hz,1H),8.24(d,J=9.2Hz,1H),7.75(d,J=8.8Hz,2H),7.54-7.57(m,2H),7.36-7.48(m,4H),7.20(dd,J=2.5Hz,9.2Hz,1H),7.11-7.13(m,2H),6.44-6.45(m,1H),3.96(s,3H),3.36(s,3H),2.80(s,3H)。
Biological test
The LC/MS/MS system of analyzing use comprises the serial vacuum degassing furnace of Agilent 1200, binary syringe pump, orifice plate automatic sampler, post thermostat container, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis is carried out under the MRM pattern, and the parameter of MRM conversion is as shown in Table A:
Table A
| Many reaction detection scanning | 490.2→383.1 |
| Cracked voltage | 230V |
| Capillary voltage | 55V |
| Dryer temperature | 350°C |
| Spraying gun | 40psi |
| The moisture eliminator flow velocity | 10L/min |
Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μ M posts, inject 5 μ L samples.Analysis condition: the aqueous formic acid that moving phase is 0.1% (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is as shown in table B:
Table B
| Time | The gradient of Mobile phase B |
| 0.5min | 5% |
| 1.0min | 95% |
| 2.2min | 95% |
| 2.3min | 5% |
| 5.0min | stop |
In addition, the serial LC/MS/MS spectrograph of Agilent 6330 in addition for analyzing, be equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; The LC/MS/MS spectrograph adopts the ESI radioactive source.Each analyte is carried out to suitable positively charged ion models treated to Application standard liquid and best analysis is carried out in the MRM conversion.Use Capcell MP-C18 post during analyzing, specification is: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA).Moving phase is the 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); Flow velocity is 0.6mL/min; Column temperature remains on room temperature; Inject 20 μ L samples.
Pharmacokinetic Evaluation after the oral quantitative the compounds of this invention of mouse, rat, dog and monkey
The present invention to the compounds of this invention the pharmacokinetic in mouse, rat, dog or monkey body assess.The compounds of this invention is with the aqueous solution of the aqueous solution or 2%HPMC+1% tween-80,
Salt brine solution, 4%MC suspension or capsule form are carried out administration.For intravenous administration, animal gives 1 or the dosage of 2mg/kg.For oral dosage (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.At time point, be 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hours or be 0.083,0.25,0.5,1.0,2.0 at time point, 4.0, within 6.0,8.0 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 2 to 10 minutes.Collect plasma solutions, and preserve until carry out above-mentioned LC/MS/MS analysis under-20 ° of C or-70 ° of C.
During by the quiet notes of compound or oral administration, compound of the present invention shows good pharmacokinetic property, comprises desirable clearance rate (Cl), transformation period (T
1/2) oral administration biaavailability of becoming reconciled.
Pharmacokinetics assessment data in table C rat body
The compounds of this invention suppresses the tyrosine kinase receptor activity, particularly suppresses c-Met, and VEGFR and Axl are active and test to be estimated by following animal heteroplastic transplantation model as the effect of antitumor drug.Result of study shows that the compounds of this invention can suppress c-Met effectively, and VEGF-R2 and Axl are in intracellular autophosphorylation effect, and the propagation of the inhibition transplanted tumor in nude mice of dose-dependently.
Kinase assay
The kinase inhibiting activity of the compounds of this invention is all to pass through KINOMEscan
TMTest, it mainly is based on quantitative assay sample and part fixing, that active-site directed is arranged and the test of kinases competitive binding ability.Completing of this test need to be in conjunction with following three elements: the kinases of DNA-mark, fixing part and testing sample.The kinase whose ability of the competitive binding of testing sample and fixed ligands can be determined by the amount of measuring the PCR in DNA marker.
For great majority tests, the T7 phage strains of kinases-mark is that the escherichia coli host that origin comes from the BL21 bacterial strain prepares.First intestinal bacteria are cultivated to logarithmic phase, then with the T7 phage, it are infected, and by its under continuous concussion in 32 ° of C hatchings until cracking, lysate is centrifugal, suction filtration, remove cell debris.And then the remaining kinases produced in the HEK-293 cell carrys out mark with DNA, for the detection of qPCR.The magnetic bead that is coated with Streptavidin, with after biotinylated small molecules part at room temperature reacts 30 minutes, generates the affine resin for kinase assay.The magnetic bead that coordination is good is stopped up by excessive vitamin H, with sealing buffered soln (SEABLOCK
TM(Pierce), 1%BSA, 0.05% tween 20,1mM DTT) wash and remove free part, to reduce non-specific binding.Association reaction is all at 1x binding buffer liquid (20% SEABLOCK by the magnetic bead of kinases, affinity that coordination is good and testing sample
TM, 0.17xPBS, 0.05% tween 20,6mM DTT) in complete.Carry out in 96 orifice plates of the polystyrene that is all 0.135mL in final volume of responding.The orifice plate of test is all being hatched 1 hour in room temperature condition under concussion continuously, the magnetic bead of affinity is all used lavation buffer solution (1xPBS, 0.05% tween 20) washing, then be resuspended to elution buffer (1xPBS, 0.05% tween 20,0.5 the abiotic elementization affinity ligands of μ M), and hatching 30 minutes in room temperature condition under concussion continuously.Kinases concentration in elutriant is measured by qPCR.
Kinase assay in the present invention is the KINOMEscan by DiscoveRx company
TM(42501 Albrae St.Fremont, CA94538, the USA) that Analysis Service completes, the test result of the embodiment of the present invention is listed in table D.
The Kds data of the table D embodiment of the present invention
Kds-binding constant (Binding Constants)
The xenotransplantation tumor model
The drug effect of the compounds of this invention is estimated by the standard muroid model of transplantation tumor.Human tumor cells (U87MG glioma cell, the MKN45 gastric adenocarcinoma cells, the Caki-1 kidney cancer cell, HUH7 liver cancer cell, NCI-H441 adenocarcinoma of lung epithelial cell, the MDA-MB-231 breast cancer cell, the SMMC-7721 liver cancer cell, after ATCC) cultivating, collecting, (the BALB/cA nu/nu in the female nude mouse body in age in week in rear veutro subcutaneous vaccination in 6-7, Shanghai SLAC Animal Lab.) (for group of solvents n=10, for each dosage group n=8).When gross tumor volume reaches 100-250mm
3The time, animal is divided into solvent control group (aqueous solution of 2%HPMC+1% tween-80) and compound group randomly.The following adopted compound carries out gastric infusion (3-50mpk/dose is dissolved in the aqueous solution of 2%HPMC+1% tween-80) to animal, starting Anywhere in 0 to 15 day from tumor cell inoculation, and usually carry out once every day in test.In the present invention, the test of xenogenesis inhibition animal model for tumour is to complete by institute of materia medica, Chinese science research institute Shanghai (No. 555, Zu Chongzhi road, Shanghai City, China Pudong Zhangjiang Hi-tech Park, postcode 201203).
Tumor growth suppresses (TGI) and analyzes
The crystallization growth of tumour is estimated by the relation of gross tumor volume and time.The major axis of Subcutaneous tumor (L) and minor axis (W) measure weekly twice by calipers, and the volume of tumour (TV) is by formula (LxW
2)/2) calculated.TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume intermediate value, with the percentage of solvent control group gross tumor volume intermediate value, recently means, by following formula, is calculated:
Primary statistics is analyzed by repeating variance determination and analysis (RMANOVA) and is completed.Next carry out multiple comparisons by Scheffe psot hoc test method.Separate solvent (the 2%HPMC+1% tween-80, etc.) negative contrast.
Table E
Finally it should be noted that alternate manner can be implemented the present invention in addition.Correspondingly, embodiments of the invention are to describe as illustration, but are not limited to content described in the invention, may be also the modification done within the scope of the present invention or the equivalents added in the claims.All publications that the present invention quotes or patent all will be as reference of the present invention.
Claims (17)
1. one kind suc as formula the compound shown in (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein:
Each R
1, R
2, R
3And R
4Be H independently, D, F, Cl or Br, work as R
1(or R
2), R
3And R
4While being H simultaneously, R
2(or R
1) be not F;
Each Q
1And Q
2Be H independently, D, F, Cl, Br, N
3, CN, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl or C
2-6Alkynyl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl and C
2-6Alkynyl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, CN, N
3, SR
a, NR
aR
bOr-C (=O) NR
aR
bWork as Q
1And Q
2Be methoxyl group simultaneously, R
3(or R
4), R
1And R
2While being H simultaneously, R
4(or R
3) be not Cl;
Each X and Z are H independently, D, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, NO
2, N
3, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
a, SR
a, NR
aR
bOr-C (=O) NR
aR
b
Y is H, D, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, NO
2, N
3, C
2-6Thiazolinyl, C
2-6Alkynyl, SR
a, NR
aR
bOr-C (=O) NR
aR
bWith
Each R
aAnd R
bBe H independently, C
1-6Aliphatics, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Heterocyclic radical-C
1-4Alkylidene group, C
6-10Aryl-C
1-4Alkylidene group, (5-10 former molecular heteroaryl)-C
1-4Alkylidene group, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, or, work as R
aAnd R
bWhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted.
2. compound according to claim 1, wherein, each R
1, R
2, R
3And R
4Be H independently, D, F or Cl, work as R
1(or R
2), R
3And R
4While being H simultaneously, R
2(or R
1) be not F.
3. compound according to claim 1, wherein, each X and Z are H independently, D, C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, OR
aOr NR
aR
b.
4. compound according to claim 1, wherein, Y is H independently, D, C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, wherein, described C
1-3Alkyl, C
2-6Alkynyl, C
6-10Aryl and 5-10 former molecular heteroaryl is not substituted independently or, by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F or NR
aR
b.
5. compound according to claim 1, wherein, each X and Z are methyl independently, ethyl, n-propyl, sec.-propyl or phenyl, wherein, described methyl, ethyl, n-propyl, sec.-propyl and phenyl are not substituted or independently by 1,2 or 3 substituting groups replace, and described substituting group is independently selected from D or F.
6. compound according to claim 1, wherein, Y is methyl, ethyl or n-propyl, wherein, and described methyl, ethyl and n-propyl are not substituted independently or are replaced by 1,2 or 3 substituting group, and described substituting group is independently selected from D or F.
7. compound according to claim 1, wherein, each Q
1And Q
2Be H, D, Cl or OCH independently
3, work as Q
1And Q
2Be methoxyl group simultaneously, R
3(or R
4), R
1And R
2While being H simultaneously, R
4(or R
3) be not Cl.
8. compound according to claim 1, wherein, each R
aAnd R
bBe H independently, C
1-3Aliphatics, C
1-3Haloalkyl, C
3-6Cycloalkyl, C
3-6Heterocyclic radical, C
3-6Heterocyclic radical-C
1-2Alkylidene group, C
6-10Aryl-C
1-2Alkylidene group, (5-10 former molecular heteroaryl)-C
1-2Alkylidene group, C
6-10Aryl or comprise 1,2,3 or 4 and independently be selected from O, S, the heteroatomic 5-10 of N former molecular heteroaryl, or, work as R
aAnd R
bWhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted.
9. compound according to claim 1 has following one of them structure:
10. a pharmaceutical composition comprises the described compound of claim 1-9 any one, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.
11. pharmaceutical composition according to claim 10, wherein further comprise the additional treatment agent, these additional treatment agent are selected from chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, be used for the treatment of the medicine of pulmonary fibrosis, or their combination.
12. pharmaceutical composition according to claim 11, wherein said 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 (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), 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, fork clip is for Buddhist nun (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), brentuximab vedotin, 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.
13. a right to use requires the described compound of 1-9 any one or the described pharmaceutical composition of claim 10-12 any one for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.
14., according to the purposes of the described compound of claim 13 or pharmaceutical composition, wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, head and neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
15. a right to use requires the described compound of 1-9 any one or the described pharmaceutical composition of claim 10-12 any one to come for the preparation of suppress or regulate the purposes of protein kinase activity in biological sample, described purposes comprises right to use and requires the described compound of 1-9 any one or right to use to require the described pharmaceutical composition of 10-12 any one to contact with described biological sample.
16. purposes according to claim 15, wherein said protein kinase is tyrosine kinase receptor.
17. purposes according to claim 16, wherein tyrosine kinase receptor is VEGFR or c-Met.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| US9133162B2 (en) | 2011-02-28 | 2015-09-15 | Sunshine Lake Pharma Co., Ltd. | Substituted quinoline compounds and methods of use |
| US9598400B2 (en) | 2011-02-28 | 2017-03-21 | Calitor Sciences, Llc | Substituted quinoline compounds and methods of use |
| CN104974162A (en) * | 2014-04-09 | 2015-10-14 | 广东东阳光药业有限公司 | Bicyclic pyrazolone compound, and use method and applications thereof |
| CN104119317B (en) * | 2014-07-25 | 2016-08-17 | 沈阳药科大学 | Quinolines containing 1,2,3-triazole and its preparation method and application |
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| CN104817497A (en) * | 2015-03-20 | 2015-08-05 | 南京众睿缘生物科技有限公司 | Alkynylquinoline derivatives, and preparation method and application thereof |
| CN104817497B (en) * | 2015-03-20 | 2017-03-08 | 南京众睿缘生物科技有限公司 | A kind of alkynes is for quinoline and its production and use |
| CN104926789A (en) * | 2015-05-20 | 2015-09-23 | 沈阳药科大学 | 4-phenoxyl substituted quinoline compound containing imidazolone and application thereof |
| CN105111141A (en) * | 2015-09-02 | 2015-12-02 | 苏州摩尔医药有限公司 | Cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and preparation method thereof |
| CN105503749A (en) * | 2016-01-04 | 2016-04-20 | 南京亚东启天药业有限公司 | Synthetic method of 4-(3-chlorine-4-fluorophenyl)-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline |
| CN107641099A (en) * | 2016-07-20 | 2018-01-30 | 广东东阳光药业有限公司 | The preparation method of 4 oxinoid compounds of substitution |
| WO2023134145A1 (en) * | 2022-01-17 | 2023-07-20 | 上海天慈生物谷生物工程有限公司 | Preparation method for tivozanib key intermediate |
| CN114573553A (en) * | 2022-01-27 | 2022-06-03 | 广州六顺生物科技股份有限公司 | Heteroaromatic ring derivative and preparation method and application thereof |
| CN114573553B (en) * | 2022-01-27 | 2023-11-10 | 广州六顺生物科技有限公司 | Heteroaromatic ring derivative and preparation method and application thereof |
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