TW201406751A - Substituted pyrazolone compounds and methods of use - Google Patents

Substituted pyrazolone compounds and methods of use Download PDF

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TW201406751A
TW201406751A TW102127914A TW102127914A TW201406751A TW 201406751 A TW201406751 A TW 201406751A TW 102127914 A TW102127914 A TW 102127914A TW 102127914 A TW102127914 A TW 102127914A TW 201406751 A TW201406751 A TW 201406751A
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Ning Xi
yan-jun Wu
Min Liao
yan-ming Feng
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Ning Xi
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Abstract

The present invention provides novel substituted pyrazolone compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

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取代的吡唑酮化合物及其使用方法 Substituted pyrazolone compounds and methods of use thereof

本發明是關於新的取代的吡唑酮化合物及其鹽,用於治療高增殖性的疾病,例如與哺乳動物有關的癌症。本發明尤其是關於抑制蛋白酪氨酸激酶活性的化合物,通過使用本發明化合物抑制蛋白酪氨酸激酶的活性,從而抑制細胞間或細胞內的信號回應。本發明同樣是關於使用本發明的化合物或藥學上包含本發明化合物的組合物來治療哺乳動物,尤其是人類高增殖性疾病的方法。 This invention relates to novel substituted pyrazolone compounds and salts thereof for use in the treatment of highly proliferative diseases, such as cancers associated with mammals. In particular, the present invention relates to a compound which inhibits the activity of a protein tyrosine kinase by inhibiting the activity of a protein tyrosine kinase by using the compound of the present invention, thereby inhibiting an intercellular or intracellular signal response. The invention is also directed to a method of treating a mammal, especially a human hyperproliferative disorder, using a compound of the invention or a composition comprising a compound of the invention.

蛋白激酶代表了一大類在對細胞功能保持控制和各種細胞病變的調控中起重要作用的蛋白質。通過調節信號回應途徑,蛋白激酶掌控著細胞的代謝,細胞***週期的進行,細胞增殖及細胞凋亡、分化和存活。目前已有500種人類激酶組,其中達150種之多與人類各種疾病相關,如炎性疾病,心血管疾病,代謝類疾病,神經退行性疾病和癌症。 Protein kinases represent a large class of proteins that play an important role in the maintenance of cellular function and the regulation of various cytopathic effects. By regulating the signaling pathway, protein kinases control cell metabolism, cell division cycle progression, cell proliferation and apoptosis, differentiation and survival. There are currently 500 human kinase groups, of which up to 150 are associated with various human diseases, such as inflammatory diseases, cardiovascular diseases, metabolic diseases, neurodegenerative diseases and cancer.

其中所述激酶部分清單包括abl、AATK、ALK、Akt、axl、bmx、bcr-abl、Blk、Brk、Btk、csk、c-kit、c-Met、c-src、c-tins、CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、CDK10、cRafl、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、TFX14、 TNK1、TNK2、TNNI3K、TXK、TYK2、TYRO3、tie、tie2、TRK、Yes和Zap70。 The list of kinases includes abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-tins, CDK1, CDK2 , CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, 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, TFX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes, and Zap70.

蛋白酪氨酸激酶為蛋白激酶的亞科,亦可以歸類於生長因數受體(如:Axl、VEGFR、c-Met(HGFR)、Ron、EGFR、PDGFR和FGFR)或非受體(如:c-src和bcr-abl)激酶。受體酪氨酸激酶為跨膜蛋白,能使生長因數跨越細胞膜保持細胞外結合區域,跨膜區和細胞內部分作為具有激酶的功能,磷酸化作用於一個具體蛋白酪氨酸殘基,從而影響細胞增殖。異常的表達或蛋白激酶活性會直接牽涉眾多人類癌症的發病機理。 Protein tyrosine kinases are subfamilies of protein kinases and can also be classified as growth factor receptors (eg, Axl, VEGFR, c-Met (HGFR), Ron, EGFR, PDGFR, and FGFR) or non-receptors (eg, C-src and bcr-abl) kinases. The receptor tyrosine kinase is a transmembrane protein that enables the growth factor to maintain the extracellular binding region across the cell membrane. The transmembrane region and the intracellular portion function as kinases, phosphorylating a specific protein tyrosine residue, thereby Affects cell proliferation. Abnormal expression or protein kinase activity is directly involved in the pathogenesis of many human cancers.

血管生成是從預存血脈形成新的毛細血管的過程,這對於女性/雌性動物生殖循環系統中胚胎的器官發育起著關鍵性的作用,同時也對炎性疾病和創傷的癒合也起著很重要的作用。眾所周知,某些疾病與失控的血管生成有關,例如眼新血管形成,視網膜病(包括糖尿病性視網膜病),與年齡有關的黃斑變性,牛皮癬,成血管細胞瘤,血管瘤,動脈硬化,炎性疾病,例如類風濕性或風濕性炎性疾病,特別是關節炎(類風濕性關節炎),或者其它慢性炎症,例如慢性哮喘,動脈或移植後動脈粥樣硬化,子宮內膜異位和增生性疾病,例如通常所述的實體腫瘤和液體腫瘤(例如白血病)。實體腫瘤,特別依賴於血管生成來給其供給營養、養分、及廢物處理。另外,血管生成同樣會促進細胞或其他位置轉移腫瘤的生長。 Angiogenesis is the process of forming new capillaries from pre-existing blood vessels, which plays a key role in the development of embryonic organs in the reproductive circulatory system of female/female animals, and also plays an important role in the healing of inflammatory diseases and wounds. The role. It is well known that certain diseases are associated with uncontrolled angiogenesis, such as ocular neovascularization, retinopathy (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory Diseases such as rheumatoid or rheumatic inflammatory diseases, especially arthritis (rheumatoid arthritis), or other chronic inflammations such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis and hyperplasia Sexual diseases such as solid tumors and liquid tumors (such as leukemia) as generally described. Solid tumors rely in particular on angiogenesis to supply nutrients, nutrients, and waste treatment. In addition, angiogenesis also promotes the growth of tumors in cells or other locations.

新的血管生成是一個高度複雜且高度協調的過程,其要求有大量的生長因數刺激,但血管內皮生長因數(VEGFR)信號回應通常在生理學和病理學血管生成中代表關鍵性的限速階段。VEGF結合並活化受體型酪氨酸激酶。已經被人類確認的VEGFR亞型有三種:VEGFR-1(Flt-1),VEGFR-2(KDR/Flk-1)和VEGFR-3(Flt-4)。VEGFR-2介導VEGF的主要細胞應答,尤其是有絲***和血管生成。VEGFR-1調節VEGFR-2信號傳導或是作為虛擬/誘捕受體隔離VEGF與VEGFR-2。VEGFR-1的表達受缺氧正向調節,其機理與VEGF受HIF-1調節類似;它的功能基於細胞的類型和發展階段而變化。(Stuttfeld E,Ballmer-Hofer K(September 2009),"Structure and function of VEGF receptors".IUBMB Life 61(9):915-22.) New angiogenesis is a highly complex and highly coordinated process that requires large amounts of growth factor stimulation, but vascular endothelial growth factor (VEGFR) signaling responses typically represent a critical rate-limiting phase in physiological and pathological angiogenesis. . VEGF binds to and activates receptor tyrosine kinases. There are three VEGFR subtypes that have been confirmed by humans: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4). VEGFR-2 mediates the major cellular responses of VEGF, particularly mitosis and angiogenesis. VEGFR-1 regulates VEGFR-2 signaling or isolates VEGF and VEGFR-2 as a virtual/trapping receptor. The expression of VEGFR-1 is positively regulated by hypoxia, and its mechanism is similar to that of VEGF regulated by HIF-1; its function varies depending on the type and stage of development of the cell. (Stuttfeld E, Ballmer-Hofer K (September 2009), "Structure and function of VEGF receptors". IUBMB Life 61(9): 915-22.)

VEGFR-2是主要介導血管內皮細胞(EC)的有絲***和存活,同時保持血管生成和微血管的滲透性。因此,直接抑制激酶VEGFR-2的活性將會減少血管生成和腫瘤的生長,並且抑制VEGFR-2靶向作用於遺傳學上較穩定的宿主上皮細胞的活性,而非抑制易變的腫瘤組織,將會減少耐藥性發展的幾率。 VEGFR-2 is primarily responsible for mitosis and survival of vascular endothelial cells (EC) while maintaining angiogenesis and microvascular permeability. Thus, direct inhibition of the activity of the kinase VEGFR-2 will reduce angiogenesis and tumor growth, and inhibit VEGFR-2 targeting to the activity of genetically more stable host epithelial cells, rather than inhibiting variable tumor tissue, Will reduce the chances of drug resistance development.

一些藥物靶向作用於VEGFR信號回應,無論是單獨給藥,抑或與其它化學治療藥物聯用,均對晚期惡性腫瘤患者有效(“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)。 Some drugs are targeted for VEGFR signaling, either alone or in combination with other chemotherapeutic drugs, and are effective in patients with advanced malignancies ("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,即肝細胞生長因數受體(HGFR),其主要的作用點是在內皮細胞,並已證實其在內皮細胞,肌原細胞,造血細胞和運動神經元內均有表達。c-Met天然的配體為肝細胞生長因數(HGF),其為一個多功能生長因數,即分散因數(SF)。在胎兒和成人中,啟動c-Met可促進某些形態的形成,譬如,侵襲性生長將會導致細胞的快速生長,細胞間的***,和細胞向其周圍遷移(“From Tpr-Met to Met,tumorigenesis and tubes,”Oncogene,2007,26,1276;and“Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target,”Cancer Letter,2009,280,1-14)。 c-Met, the hepatocyte growth factor receptor (HGFR), whose main site of action is in endothelial cells, has been shown to be expressed in endothelial cells, myogenic cells, hematopoietic cells and motor neurons. The natural ligand for c-Met is hepatocyte growth factor (HGF), which is a multifunctional growth factor, the dispersion factor (SF). In fetuses and adults, initiation of c-Met promotes the formation of certain forms. For example, invasive growth leads to rapid cell growth, intercellular division, and migration of cells to its surroundings ("From Tpr-Met to Met , tumorigenesis and tubes, "Oncogene, 2007 , 26 , 1276; and "Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target," Cancer Letter, 2009 , 280 , 1-14).

廣泛存在的人類惡性腫瘤存在持久的c-Met刺激、過表達或變異,包括乳腺癌、肝癌、肺癌、卵巢癌、腎癌、甲狀腺癌、結腸癌、惡性膠質瘤、***癌等。c-Met同樣牽涉動脈粥樣硬化和肺纖維化。通過腫瘤間質的相互作用,包括HGF/c-Met途徑,使這些癌細胞的侵襲性生長速度徹底提高了。因此,大量證據顯示c-Met信號回應與一些癌症疾病的發展速度有關,並提高了其在與以c-Met為主要靶點的癌症藥物開發中的角色地位(“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)。 Extensive human malignancies have persistent c-Met stimulation, overexpression or mutation, including breast cancer, liver cancer, lung cancer, ovarian cancer, kidney cancer, thyroid cancer, colon cancer, glioblastoma, prostate cancer and the like. c-Met is also involved in atherosclerosis and pulmonary fibrosis. Through the interaction of tumor stroma, including the HGF/c-Met pathway, the aggressive growth rate of these cancer cells is completely increased. Therefore, a large body of evidence indicates that c-Met signaling response is associated with the development of some cancer diseases and enhances its role in the development of cancer drugs with c-Met as its main target ("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屬於酪氨酸激酶受體(RTKs)的亞科,包括Tyro3和Mer(TAM)。 其中TAM受體通過在胞外區和細胞質激酶區聯合2個免疫球蛋白類似物區域和二元纖連蛋白III型來進行表徵的。TAM受體的配體是Gas6(growth arrest-specific 6)和蛋白S,兩種維生素K依賴性蛋白存在43%的氨基酸序列,並具有相似的區域結構(“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)。 Axl belongs to the subfamily of tyrosine kinase receptors (RTKs), including Tyro3 and Mer (TAM). The TAM receptor is characterized by combining two immunoglobulin analog regions and a binary fibronectin type III in the extracellular region and the cytoplasmic kinase region. The ligand for the TAM receptor is Gas6 (growth arrest-specific 6) and protein S. The two vitamin K-dependent proteins have a 43% amino acid sequence and have a similar regional 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).

充分的證據顯示Gas6/Axl體系在推進正常細胞和癌細胞生長和存活中扮演著重要的角色(“TAM receptor tyrosine kinases:biologic functions,signaling,and potential therapeutic targeting in human cancer,”Adv Cancer Res,2008,100,35-83)。Axl過表達和信號響應牽涉幾種人類惡性腫瘤,如結腸癌、乳腺癌、神經膠質瘤、甲狀腺癌、胃癌、黑色素瘤、肺癌、和腎細胞癌(RCC)。Axl在生物學中更具體的作用已在神經膠質瘤的研究中得到證實,即降低Axl的信號回應將會減少神經膠質瘤和乳腺腫瘤的生長,其中Axl將會促進細胞遷移、管道形成、新生血管形成及腫瘤生長。Axl已被證實在腫瘤生成中扮演著多重角色,而抗體療法來抑制Axl不僅會阻斷Axl在惡性腫瘤細胞中的功能,同時也會阻斷其在間質腫瘤細胞中的功能。Axl的抑制作用和抗VEGF的附加效應表明阻斷Axl的功能將會是提高抗血管生成治療的有效途徑(“Axl as a potential therapeutic target in cancer:role of Axl in tumor growth,metastasis and angiogenesis.” Oncogene,2009,28,3442-3455;and“TAM Receptor Tyrosine Kinases:Biologic Functions,Signaling,and Potential Therapeutic Targeting in Human Cancer,”Adv Cancer Res,2008,100,35-83)。 There is ample evidence that the Gas6/Axl system plays an important role in advancing the growth and survival of normal cells and cancer cells ("TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer," Adv Cancer Res, 2008 , 100, 35-83). Axl overexpression and signaling are involved in several human malignancies such as colon cancer, breast cancer, glioma, thyroid cancer, gastric cancer, melanoma, lung cancer, and renal cell carcinoma (RCC). The more specific role of Axl in biology has been confirmed in studies of gliomas, that is, reducing the signal response of Axl will reduce the growth of gliomas and breast tumors, where Axl will promote cell migration, pipeline formation, and regeneration. Angiogenesis and tumor growth. Axl has been shown to play multiple roles in tumorigenesis, and antibody therapy to inhibit Axl not only blocks Axl function in malignant cells, but also blocks its function in mesenchymal tumor cells. The inhibitory effect of Axl and the additional effect of anti-VEGF suggest that blocking the function of Axl will be an effective way to improve anti-angiogenesis therapy ("Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis." Oncogene, 2009, 28, 3442-3455; and "TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer," Adv Cancer Res, 2008, 100, 35-83).

RON(MST1R,recepteur d'origine nantais)是MET家族的另一成員,是配體巨噬細胞刺激蛋白(MSP,也被稱為MST1或類肝細胞生長因數(HGFL))的一種受體酪氨酸激酶,它與體外和體內的細胞分化、遷移和基質侵襲相關一所有這些過程都是具有轉移潛能的侵襲性生長腫瘤表型的替代標記物。RON主要調節在肺、甲狀腺、胰腺、***癌、結腸和乳腺癌細胞中的腫瘤表型並且能預測人類乳腺癌的不良預後。RON和MET的共表達和通過HGF-MET信號誘導的RON表達都在肝細胞癌的研究中描述過。此外,RON和MET在卵巢癌、乳腺癌和膀胱癌中的共表達預示著一種更壞的預後。考慮到RON和MET的信號冗長,最可能的方式是抑制MET的信號回應,而主要由RON信號回應來調節(“RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma.”Cancer Biol Ther.2011 July 1;12(1):9-46.)。 RON ( MST1R , recepteur d'origine nantais ) is another member of the MET family and is a receptor tyrosine for ligand macrophage stimulating protein (MSP, also known as MST1 or hepatocyte growth factor (HGFL)). Acid kinase, which is involved in cell differentiation, migration, and stromal invasion in vitro and in vivo, is a surrogate marker for invasive growth tumor phenotypes with metastatic potential. RON primarily regulates tumor phenotypes in lung, thyroid, pancreas, prostate cancer, colon and breast cancer cells and predicts poor prognosis in human breast cancer. Co-expression of RON and MET and RON expression induced by HGF-MET signaling have been described in the study of hepatocellular carcinoma. In addition, co-expression of RON and MET in ovarian, breast and bladder cancers predicts a worse prognosis. Considering the verbose length of RON and MET, the most likely way is to suppress the signal response of MET, and mainly by RON signal response ("RON( MST1R )is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma."Cancer Biol Ther .2011 July 1;12(1):9-46.).

MSP-RON信號軸在癌症發病機理中所起的作用在各種疾病模型系統中被廣泛研究過。體內和體外的研究結果都顯示MSP-RON信號回應在不同類型癌症的侵襲性生長中都是很重要的。由蛋白質的過度表達和致癌亞型的產生所誘導的以及多細胞內信號轉導的持續啟動所表明的異常的RON啟動作用存在於各種不同類型癌症中。RON信號回應對於癌症細胞的生長和生存也是必要的。這些特性使RON成為癌症治療的一個藥物靶點(“MSP-RON signalling in cancer:pathogenesis and therapeutic potential.”Nature Reviews Cancer,2013,13,466-481)。 The role of the MSP-RON signal axis in the pathogenesis of cancer has been extensively studied in various disease model systems. Both in vivo and in vitro studies have shown that MSP-RON signaling responses are important in the aggressive growth of different types of cancer. Abnormal RON priming, as evidenced by the overexpression of proteins and the production of oncogenic subtypes and the sustained initiation of multicellular signaling, is present in a variety of different types of cancer. The RON signal response is also necessary for the growth and survival of cancer cells. These properties make RON a drug target for cancer therapy ("MSP-RON signalling in cancer: pathogenesis and therapeutic potential." Nature Reviews Cancer, 2013, 13, 466-481).

眾所周知,癌細胞往往會採用多種機制來避免細胞緊密調節過程,如細胞增殖、凋亡及衰老。因此,很多腫瘤會從單個激酶抑制作用中逃離出來。通過對腫瘤廣闊的系統分析表明,酪氨酸激酶受體(RTK)共活化作用通過癌細胞完成化學抗性,並作為重要的生物機理。其中一個 方法是,克服RTK共活化作用,可能會同時牽涉在治療上靶向作用於多重RTKs,從而來阻斷致癌的RTK信號回應,並克服代償機制。(“Receptor Tyrosine Kinase Coactivation Networks in Cancer,”Cancer Research,2010,70,3857)。靶向作用於VEGFR,c-Met,Ron和Axl信號回應的抗腫瘤方法可以防止腫瘤細胞克服VEGFR,c-Met(HGFR),Ron和/或Axl的單獨抑制作用,從而提高癌症的治療效果。 It is well known that cancer cells often use a variety of mechanisms to avoid tight cell regulation processes such as cell proliferation, apoptosis and aging. Therefore, many tumors will escape from the inhibition of a single kinase. A broad systematic analysis of tumors indicates that tyrosine kinase receptor (RTK) co-activation works chemically through cancer cells and serves as an important biological mechanism. One of the The approach is to overcome the RTK co-activation, which may involve both therapeutic targeting of multiple RTKs, thereby blocking the oncogenic RTK signaling response and overcoming the compensatory mechanism. ("Receptor Tyrosine Kinase Coactivation Networks in Cancer," Cancer Research, 2010, 70, 3857). Anti-tumor methods that target VEGFR, c-Met, Ron and Axl signaling can prevent tumor cells from overcoming the independent inhibition of VEGFR, c-Met (HGFR), Ron and/or Axl, thereby improving the therapeutic effect of cancer.

本發明涉及新的取代的吡唑酮化合物和治療細胞增殖性疾病的方法。本發明的化合物對蛋白酪氨酸激酶活性有抑制作用。更讓人滿意的是,本發明的化合物具有多重的抑制劑功能,可以抑制像VEGFR,c-Met(HGFR),Ron和/或Axl信號回應。相應地,本發明還提供了一些新的蛋白酪氨酸激酶受體信號回應的抑制劑,如VEGF受體信號回應,HGF受體信號回應,Ron受體信號回應和/或Axl受體信號回應。 The present invention relates to novel substituted pyrazolone compounds and methods of treating cell proliferative disorders. The compounds of the invention have an inhibitory effect on protein tyrosine kinase activity. Even more satisfyingly, the compounds of the invention have multiple inhibitory functions that inhibit signal responses like VEGFR, c-Met (HGFR), Ron and/or Axl. Accordingly, the present invention also provides novel inhibitors of protein tyrosine kinase receptor signaling responses, such as VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling, and/or Axl receptor signaling. .

特別地,本發明所涉及的化合物,及其藥學上可接受的組合物,都可以有效地作為酪氨酸激酶受體抑制劑,如VEGFR,c-Met,Ron和/或Axl的抑制劑。 In particular, the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as tyrosine kinase receptor inhibitors, such as inhibitors of VEGFR, c-Met, Ron and/or Axl.

一方面,本發明涉及一種如式(I)所示的化合物: 或其立體異構體,幾何異構體,互變異構體,氮氧化物,水合物,溶劑化物,代謝產物,藥學上可接受的鹽或它的前藥,其中,式(I)中Q,R1,R2,R3,R4,R5,R6,W,X,Y和Z的定義如下所示。 In one aspect, the invention relates to a compound of formula (I): Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt thereof or a prodrug thereof, wherein Q in formula (I) The definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W, X, Y and Z are as follows.

在一些實施方案,式(I)中:Q為D,-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-C(=O)NRaRb, -N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb或-N(Rc)S(=O)2Ra;W為CR7或N;各X,Y和Z獨立地為H,D,C1-6烷基,C3-8環烷基,C3-8環烷基-C1-4亞烷基,C3-7雜環基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基或5-10個原子組成的雜芳基,其中,所述C1-6烷基,C3-8環烷基,C3-8環烷基-C1-4亞烷基,C3-7雜環基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基和5-10個原子組成的雜芳基可以任選地被1,2,3,4或5個獨立選自D,F,Cl,Br,CN,C2-6烯基,C2-6炔基,ORa,NRaRb,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代;各R1,R2,R3,R4,R5,R6和R7獨立地為H,D,F,Cl,Br,CN,N3,ORa,C1-6烷基,C1-6鹵代烷基,C2-6烯基或C2-6炔基;各Ra,Rb和Rc獨立地為H,C1-6脂肪族,C1-6鹵代烷基,C3-6環烷基,C3-6環烷基-C1-4亞烷基,C3-6雜環基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基或5-10個原子組成的雜芳基,其中,所述C1-6脂肪族,C1-6鹵代烷基,C3-6環烷基,C3-6環烷基-C1-4亞烷基,C3-6雜環基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代;和Rd為D,C3-8環烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基或5-10個原子組成的雜芳基,其中,所述C3-8環烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,Br,CN,ORa,NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代。 In some embodiments, in Formula (I): Q is D, -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d , -C(=O )NR a R b , -N(R c )S(=O)NR a R b , -N(R c )S(=O)R a , -N(R c )S(=O) 2 NR a R b or -N(R c )S(=O) 2 R a ;W is CR 7 or N; each X, Y and Z are independently H, D, C 1-6 alkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7 heterocyclyl, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl- a C 1-4 alkylene group, (a heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, a C 6-10 aryl group or a heteroaryl group of 5-10 atoms, wherein C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7 heterocyclic, C 3-7 heterocyclyl-C 1 -4 alkylene, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms) -C 1-4 alkylene group, C 6-10 aryl group and 5 A heteroaryl group of -10 atoms may optionally be 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, CN, C 2-6 alkenyl, C 2-6 alkynyl , OR a , NR a R b , R a OC 1-4 alkylene or R a R b NC 1-4 alkylene substituent; each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently H, D , F, Cl, Br, CN, N 3 , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; each R a , R b and R c is independently H, C 1-6 aliphatic, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 hetero Cyclic group, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1- a 4 alkylene group, a C 6-10 aryl group or a heteroaryl group of 5-10 atoms, wherein the C 1-6 aliphatic group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclic, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 An alkylene group, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, a C 6-10 aryl group and a heteroaryl group of 5-10 atoms may optionally be 1,2 , 3 or 4 substituents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino Substituted; and R d is D, C 3-8 cycloalkyl, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene a heteroaryl group consisting of 5-10 atoms, wherein the C 3-8 cycloalkyl, C 6-10 aryl-C 1 -4 alkylene, (heteroaryl group of 5-10 atoms) - C 1-4 alkylene group and 5-10 atoms The heteroaryl group may be optionally 1, 2, 3 or 4 independently selected from the group consisting of D, F, Cl, Br, CN, OR a , NR a R b , C 1-6 alkyl, C 2-6 alkenyl Substituted by a substituent of C 2-6 alkynyl, R a OC 1-4 alkylene or R a R b NC 1-4 alkylene.

在另外一些實施方案,式(I)中Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd或-C(=O)NRaRbIn still other embodiments, Q in the formula (I) is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d or -C(=O)NR a R b.

在另外一些實施方案,式(I)中各X,Y和Z獨立地為C1-4烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基,C3-6雜環基-C1-2亞烷基,苯基-C1-2亞烷基,(5-10個原子組成的雜芳基)-C1-2亞烷基,苯基或5-10個原子組成的雜芳基,其中,所述C1-4烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基,C3-6雜環基-C1-2亞烷基,苯基-C1-2亞烷基,(5-10個原子組成的雜芳基)-C1-2亞烷基,苯基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,C2-4烯基,C2-4炔基,ORa,NRaRb,RaO-C1-2亞烷基或RaRbN-C1-2亞烷基的取代基所取代。 In still other embodiments, each of X, Y and Z in formula (I) is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene , C 3-6 heterocyclyl, C 3-6 alkylene heterocyclyl -C 1-2 alkyl, phenyl -C 1-2 alkylene, (5-10 atoms heteroaryl) -C a 1-2 alkylene group, a phenyl group or a heteroaryl group of 5-10 atoms, wherein the C 1-4 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl-C 1 -2 alkylene, C 3-6 heterocyclic, C 3-6 heterocyclyl-C 1-2 alkylene, phenyl-C 1-2 alkylene, (5-10 atomic hetero An aryl)-C 1-2 alkylene group, a phenyl group and a heteroaryl group consisting of 5-10 atoms may optionally be 1, 2, 3 or 4 independently selected from D, F, Cl, CN, C. Substituents of 2-4 alkenyl, C 2-4 alkynyl, OR a , NR a R b , R a OC 1-2 alkylene or R a R b NC 1-2 alkylene.

在另外一些實施方案,式(I)中各R1,R2,R3,R4,R5,R6和R7獨立地為H,D,F或Cl。 In other embodiments, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 in formula (I) is independently H, D, F or Cl.

在另外一些實施方案,式(I)中各Ra,Rb和Rc獨立地為H,C1-4烷基,C1-4鹵代烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基或C3-6雜環基-C1-2亞烷基,其中,所述C1-4烷基,C1-4鹵代烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基和C3-6雜環基-C1-2亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-3鹵代烷基,C1-3烷氧基或C1-3烷基氨基的取代基所取代。 In still other embodiments, each of R a , R b and R c in formula (I) is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3- 6 cycloalkyl-C 1-2 alkylene, C 3-6 heterocyclic or C 3-6 heterocyclyl-C 1-2 alkylene, wherein said C 1-4 alkyl, C 1 -4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C 1-2 The alkyl group may be optionally 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-3 haloalkyl, C 1-3 alkoxy or C Substituted by a substituent of 1-3 alkylamino.

在另外一些實施方案,式(I)中Rd為C3-6環烷基,其中,所述C3-6環烷基可以任選地被1,2,3或4個獨立選自D,F,CN,ORa,NRaRb,C1-3烷基,C2-4烯基,C2-4炔基,RaO-C1-2亞烷基或RaRbN-C1-2亞烷基的取代基所取代。 In still other embodiments, R d in formula (I) is C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl can be optionally 1, 2, 3 or 4 independently selected from D , F, CN, OR a , NR a R b , C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, R a OC 1-2 alkylene or R a R b NC 1 Substituted by a substituent of -2 alkylene.

在另外一些實施方案,式(I)中各X,Y和Z獨立地為H,D,CH3,被1,2或3個氘原子所取代的甲基基團,乙基,丙基,異丙基,苯基或被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代的苯基基團。 In other embodiments, the formula (I) each of X, Y and Z are independently H, D, CH 3, 1, 2 or 3 deuterium atoms substituted with a methyl group, an ethyl group, a propyl group, Isopropyl, phenyl or a phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

在另外一些實施方案,式(I)中Q為: In still other embodiments, Q in formula (I) is:

在另外一些實施方案,本發明化合物具有式(II)所示結構: 其中,式(II)中Q,X,Y和Z的定義如下所示。 In still other embodiments, the compounds of the invention have the structure of formula (II): Among them, the definitions of Q, X, Y and Z in the formula (II) are as follows.

在一些實施方案,式(II)中:Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb,-N(Rc)S(=O)2Ra或-C(=O)NRaRb;各X,Y和Z獨立地為H,D,C1-6烷基,C3-8環烷基,C3-7雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基或(5-10個原子組成的雜芳基)-C1-4 亞烷基,其中,所述C1-6烷基,C3-8環烷基,C3-7雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基和(5-10個原子組成的雜芳基)-C1-4亞烷基可以任選地被1,2,3,4或5個獨立選自D,F,Cl,Br,CN,C2-6烯基,C2-6炔基,ORa,NRaRb,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代;各Ra,Rb和Rc獨立地為H,C1-6烷基,C3-6環烷基,C3-6雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-6環烷基-C1-4亞烷基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基或(5-10個原子組成的雜芳基)-C1-4亞烷基,其中,所述C1-6烷基,C3-6環烷基,C3-6雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-6環烷基-C1-4亞烷基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基和(5-10個原子組成的雜芳基)-C1-4亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代;和Rd為C3-8環烷基,其中,所述C3-8環烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,OH,NH2,C1-6烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代。 In some embodiments, in Formula (II): Q is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d , -N(R c )S (=O)NR a R b , -N(R c )S(=O)R a , -N(R c )S(=O) 2 NR a R b , -N(R c )S(=O 2 R a or -C(=O)NR a R b ; each X, Y and Z are independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-7 heterocycle Base, C 6-10 aryl, heteroaryl group of 5-10 atoms, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7 heterocyclyl-C 1-4 alkylene a C 6-10 aryl-C 1-4 alkylene group or a (5-10 atom heteroaryl group)-C 1-4 alkylene group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl, C 3-7 heterocyclic, C 6-10 aryl, heteroaryl of 5-10 atoms, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7heterocyclyl -C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene and (heteroaryl group of 5-10 atoms)-C 1-4 alkylene Optionally, 1, 2, 3, 4 or 5 are independently selected from the group consisting of D, F, Cl, Br, CN, C 2-6 alkenyl, C 2-6 alkynyl, OR a , NR a R b , Substituted by a substituent of R a OC 1-4 alkylene or R a R b NC 1-4 alkylene; each R a , R b and R c are independently H, C 1-6 alkyl, C 3 -6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, heteroaryl group of 5-10 atoms, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene or (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, wherein said C 1-6 alkyl group, C 3- 6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, heteroaryl consisting of 5-10 atoms, C 3-6 cycloalkyl-C 1-4 alkylene, C 3- 6 heterocyclyl -C 1-4 alkylene, C 6-10 aryl groups and -C 1-4 alkylene (5-10 atoms heteroaryl) -C 1-4 alkylene may be any Selectively 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkane Substituted by a substituent of the amino group; and R d is a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group may be optionally 1, 2, 3 or 4 independently selected from D, F Substituted by a substituent of Cl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino.

在另外一些實施方案,式(II)中Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd或-C(=O)NRaRbIn still other embodiments, Q in the formula (II) is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d or -C(=O)NR a R b .

在另外一些實施方案,式(II)中各X,Y和Z獨立地為H,D,C1-4烷基或苯基,其中,所述C1-4烷基和苯基可以任選地被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代。 In still other embodiments, each of X, Y and Z in formula (II) is independently H, D, C 1-4 alkyl or phenyl, wherein said C 1-4 alkyl and phenyl are optional The ground is replaced by 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

在另外一些實施方案,式(II)中各Ra,Rb和Rc獨立地為H,C1-4烷基,C3-6環烷基,C3-6雜環基,C3-6環烷基-C1-2亞烷基或C3-6雜環基-C1-2亞烷基,其中,所述C1-4烷基,C3-6環烷基,C3-6雜環基,C3-6環烷基-C1-2亞烷基和C3-6雜環基-C1-2亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基 的取代基所取代。 In still other embodiments, each R a , R b and R c in formula (II) is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 3 -6 cycloalkyl-C 1-2 alkylene or C 3-6 heterocyclyl-C 1-2 alkylene, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclyl, C 3-6 cycloalkyl-C 1-2 alkylene and C 3-6 heterocyclyl-C 1-2 alkylene may be optionally 1, 2, 3 or 4 Substituents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino are substituted.

在另外一些實施方案,式(II)中各X,Y和Z獨立地為H,D,Me,CH2D,CHD2,CD3,乙基,丙基,異丙基,苯基或被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代的苯基基團。 In still other embodiments, each of X, Y and Z in formula (II) is independently H, D, Me, CH 2 D, CHD 2 , CD 3 , ethyl, propyl, isopropyl, phenyl or 1, 2, 3, 4 or 5 phenyl groups independently substituted with substituents selected from D, F or Cl.

在另外一些實施方案,式(II)中Q為: In still other embodiments, Q in formula (II) is:

另一方面,本發明涉及一種藥物組合物,其包含(1)本發明化合物和(2)藥學上可接受的載體,賦形劑,稀釋劑,輔劑,媒介物,或它們的組合。 In another aspect, the invention relates to a pharmaceutical composition comprising (1) a compound of the invention and (2) a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

在一些實施方案,本發明所述的藥物組合物,更進一步地包含附加治療劑,這些附加治療劑選自化學治療藥物,抗增殖劑,用於治療動脈粥樣硬化的藥物,用於治療肺纖維化的藥物,或它們的組合。 In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic drug, an anti-proliferative agent, a drug for treating atherosclerosis, and a lung for treating Fibrotic drugs, or a combination thereof.

在另外一些實施方案,本發明所述的藥物組合物,其中所涉及的附加治療劑是阿黴素(Adriamycin),雷怕黴素(Rapamycin),Temsirolimus,依維莫司(Everolimus),Ixabepilone,吉西他濱(Gemcitabin),環磷醯胺(cyclophosphamide),***(dexamethasone),依託泊苷(etoposide),氟尿嘧啶(fluorouracil),阿法替尼(afatinib),alisertib,amuvatinib,阿西替尼(axitinib),波舒替尼(bosutinib),brivanib,cabozantinib,西地尼布(cediranib),crenolanib,克卓替尼(crizotinib),dabrafenib,dacomitinib,達沙替尼(dasatinib),danusertib,dovitinib,厄洛替尼(erlotinib),foretinib,ganetespib,吉非替尼(gefitinib),ibrutinib,伊馬替尼(imatinib),iniparib,拉帕替尼(lapatinib),lenvatinib,linifanib,linsitinib,馬賽替尼(masitinib),momelotinib,莫替沙尼(motesanib),來那替尼(neratinib),niraparib,尼洛替尼(nilotinib),oprozomib,olaparib,帕唑帕尼(pazopanib),pictilisib,ponatinib,quizartinib,regorafenib,rigosertib,rucaparib,ruxolitinib,塞卡替尼(saracatinib),saridegib,索拉非尼(sorafenib),舒尼替尼(sunitinib),tasocitinib,telatinib,tivantinib,tivozanib,tofacitinib,trametinib,凡德他尼(vandetanib),veliparib,vemurafenib,vismodegib,volasertib,干擾素(an interferon),卡鉑(carboplatin),托泊替康(topotecan),紫杉醇(taxol),長春堿(vinblastine),長春新堿(vincristine),替莫唑胺(temozolomide),托西莫單抗(tositumomab),trabedectin,belimumab,貝伐單抗(bevacizumab),brentuximab,cetuximab,gemtuzumab,ipilimumab,ofatumumab,panitumumab,ranibizumab,rituximab,tositumomab,曲妥單抗(trastuzumab)或它們的組合。 In still other embodiments, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent involved is Adriamycin, Rapamycin, Temsirolimus, Everolimus, Ixabepilone, Gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib ), bosutinib (brsutinib), brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotidine Erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib , motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilis Ib,ponatinib,quizartinib,regorafenib,rigosertib,rucaparib,ruxolitinib,sacatinib,saridegib,sorafenib,sunitinib,tasocitinib,telatinib,tivantinib,tivozanib,tofacitinib, Trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, Vincent (vincristine), temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab , trastuzumab or a combination thereof.

另一方面,可以使用本發明化合物或藥物組合物來製備用於防護、處理、治療或減輕患者增殖性疾病的藥品的用途。 In another aspect, the use of a compound or pharmaceutical composition of the invention to prepare a medicament for protecting, treating, treating or ameliorating a proliferative disorder in a patient can be used.

在一些實施方案,本發明所述的增殖性疾病是轉移癌、結腸癌,胃腺癌,膀胱癌,乳腺癌,腎癌,肝癌,肺癌,皮膚癌,甲狀腺癌,腦瘤,頸癌,***癌,胰腺癌,CNS(中樞神經系統)的癌症,惡性膠質瘤, 骨髓增生病,動脈粥樣硬化或肺纖維化。 In some embodiments, the proliferative diseases of the present invention are metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, brain tumor, cervical cancer, prostate cancer. , pancreatic cancer, CNS (central nervous system) cancer, malignant glioma, Myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

另一方面,本發明涉及使用本發明化合物或藥物組合物來製備用於在生物標本內抑制或調節蛋白激酶活性的用途,所述用途包含使用本發明化合物或藥物組合物與所述的生物標本接觸。 In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the preparation of a medicament for inhibiting or modulating protein kinase activity in a biological specimen, the use comprising the use of a compound or pharmaceutical composition of the invention and said biological specimen contact.

在其中一些實施方案,本發明所述蛋白激酶為受體酪氨酸激酶。 In some of these embodiments, the protein kinase of the invention is a receptor tyrosine kinase.

在另外一些實施方案,本發明所述受體酪氨酸激酶為VEGFR,c-Met,Ron,Axl或它們的組合。 In other embodiments, the receptor tyrosine kinase of the invention is VEGFR, c-Met, Ron, Axl or a combination thereof.

另一方面,本發明提供一些藥物組合物,其包含本發明作為酪氨酸激酶受體抑制劑的化合物,或其立體異構體,幾何異構體,互變異構體,溶劑化物,代謝產物,或其藥學上可接受的鹽,藥學上可接受的載體,賦形劑,稀釋劑,輔劑,媒介物,或它們的組合。在一些實施方案中,本發明所提供藥物組合物包含可作為VEGF受體信號回應,HGF受體信號回應,Ron受體信號回應和Axl受體信號回應抑制劑的化合物,或其立體異構體,幾何異構體,互變異構體,溶劑化物,代謝產物,或其藥學上可接受的鹽,或藥學上可接受的載體,賦形劑,稀釋劑,輔劑,媒介物,或它們的組合。在另外一些實施方案中,本發明藥物組合物更進一步地包含附加治療劑。 In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention as a tyrosine kinase receptor inhibitor, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite thereof Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. In some embodiments, the pharmaceutical compositions provided herein comprise a compound that is responsive to VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling, and Axl receptor signaling inhibitor, or a stereoisomer thereof , geometric isomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or their combination. In other embodiments, the pharmaceutical compositions of the present invention further comprise an additional therapeutic agent.

另一方面,本發明涉及一種抑制蛋白酪氨酸激酶活性的方法,該方法包含本發明化合物或其藥物組合物與所述激酶接觸。在其中一些實施方案中,本發明涉及抑制VEGF受體信號回應,HGF受體信號回應,Ron受體信號回應和Axl受體信號響應的方法,該方法包含本發明化合物或其藥物組合物與所述受體接觸。抑制受體蛋白激酶活性,特別是VEGF受體信號回應,HGF受體信號回應,Ron受體信號回應和/或Axl受體信號回應可以在單細胞或多細胞有機體中進行。如果存在於多細胞有機體,本發明所描述的方法包含使用本發明的化合物或組合物對有機體進行給藥。其中一些實施例是,所述有機體是哺乳動物,另外一些實施例是,所述有機體是人類。另外一些實施例是,所述方法更進一步地包含 蛋白激酶與附加治療劑的接觸。 In another aspect, the invention relates to a method of inhibiting protein tyrosine kinase activity comprising contacting a compound of the invention or a pharmaceutical composition thereof with said kinase. In some of these embodiments, the invention relates to a method of inhibiting VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling, and Axl receptor signaling, comprising a compound of the invention or a pharmaceutical composition thereof Receptor contact. Inhibition of receptor protein kinase activity, particularly VEGF receptor signaling, HGF receptor signaling, Ron receptor signaling and/or Axl receptor signaling can be performed in single or multicellular organisms. If present in a multicellular organism, the methods described herein comprise administering an organism using a compound or composition of the invention. In some embodiments, the organism is a mammal, and in other embodiments, the organism is a human. In still other embodiments, the method further includes Contact of protein kinases with additional therapeutic agents.

另一方面,本發明涉及一種抑制細胞增殖活性的方法,所述方法包含本發明化合物或其藥物組合物能有效抑制細胞增生的劑量與細胞接觸。在一些實施方案,本發明所述方法更進一步地包含附加治療劑與細胞的接觸。 In another aspect, the invention relates to a method of inhibiting cell proliferation activity comprising a dose of a compound of the invention or a pharmaceutical composition thereof effective to inhibit cell proliferation in contact with a cell. In some embodiments, the methods of the invention further comprise contacting the additional therapeutic agent with the cells.

另一方面,本發明涉及一種治療患者細胞增殖性疾病的方法,所述方法包含患者需要有效治療所需本發明的化合物或其組合物給藥的劑量。在一些實施方案,本發明所述方法更進一步包含附加治療劑的給藥。 In another aspect, the invention relates to a method of treating a cell proliferative disorder in a patient, the method comprising administering to a patient a dose effective to treat a compound of the invention or a composition thereof. In some embodiments, the methods of the invention further comprise administering an additional therapeutic agent.

另一方面,本發明涉及一種抑制患者腫瘤生長的方法,所述方法包含患者需要有效治療所需本發明的化合物或其組合物給藥的劑量。在一些實施方案,本發明所述方法更進一步地包含附加治療劑的給藥。 In another aspect, the invention features a method of inhibiting tumor growth in a patient, the method comprising administering to a patient a dose effective to treat a compound of the invention or a composition thereof. In some embodiments, the methods of the invention further comprise the administration of an additional therapeutic agent.

另一方面,本發明涉及式(I)或式(II)所包含的化合物的製備、分離和純化的方法。 In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I) or formula (II).

前面所述內容只概述了本發明的某些方面,但並不限於這些方面。這些方面及其他的方面的內容將在下面做更加具體完整的描述。 The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects will be described in more detail below.

定義和一般術語Definitions and general terms

本發明將會把確定的具體化的內容所對應的文獻詳細列出,實施例都伴隨有結構式和化學式的圖解。本發明有預期地涵蓋所有的選擇餘地、變體和同等物,這些可能像申請專利範圍所定義的那樣包含在現有發明領域。所屬領域的技術人員將識別許多類似或等同於在此所描述的方法和物質,這些可以應用於本發明的實踐中去。本發明絕非限於方法和物質的描述。有很多文獻和相似的物質與本發明申請相區別或抵觸,其中包括但絕不限於術語的定義,術語的用法,描述的技術,或像本發 明申請所控制的範圍。 The present invention will list the documents corresponding to the specific content of the determination, and the examples are accompanied by the diagrams of the structural formula and the chemical formula. The present invention is intended to cover all alternatives, modifications, and equivalents, which may be included in the field of the present invention as defined by the scope of the claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to those described herein, which can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials. There are many documents and similar substances that differ or contradict the application of the present invention, including but not limited to the definition of terms, the usage of terms, the techniques described, or like this. The scope controlled by the application.

本發明將應用以下定義除非其他方面表明。根據本發明的目的,化學元素根據元素週期表,CAS版本和化學藥品手冊,75,thEd,1994來定義。另外,有機化學一般原理見"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,因此所有的內容都融合了參考文獻。 The invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version and Handbook of Chemicals , 75, th Ed, 1994 . In addition, the general principles of organic chemistry can be found 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 The content is a fusion of references.

像本發明所描述的,本發明的化合物可以任選地被一個或多個取代基所取代,如上面的通式化合物,或者像實施例裡面特殊的例子,子類,和本發明所包含的一類化合物。應瞭解“任選取代的”這個術語與“取代或非取代的”這個術語可以交換使用。一般而言,術語“取代的”,表示所給結構中的一個或多個氫原子被具體取代基所取代。除非其他方面表明,一個任選的取代基團可以在基團各個可取代的位置進行取代。當所給出的結構式中不只一個位置能被選自具體基團的一個或多個取代基所取代,那麼取代基可以相同或不同地在各個位置取代。其中所述的取代基可以是,但並不限於,D,F,Cl,Br,N3,NO2,CN,OH,NH2,ORa,CH2D,CHD2,CD3,RaO-C1-4亞烷基,SRa,NRaRb,RaRbN-C1-4亞烷基,-C(=O)NRaRb,-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb,-N(Rc)S(=O)2Ra,甲基,乙基,正丙基,異丙基,甲氧基,苯基,苯基-C1-2亞烷基,C1-6烷基,C1-6脂肪族,C1-6鹵代烷基,C1-6烷氧基,C1-6烷基氨基,C2-6烯基,C2-6炔基,C3-8環烷基,C3-7雜環基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基,或5-10個原子組成的雜芳基,其中,Ra,Rb和Rc具有如本發明所述定義。 As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention. A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently. The substituents described therein may be, but are not limited to, D, F, Cl, Br, N 3 , NO 2 , CN, OH, NH 2 , OR a , CH 2 D, CHD 2 , CD 3 , R a OC 1-4 alkylene, SR a , NR a R b , R a RbN-C 1-4 alkylene, -C(=O)NR a R b , -N(R c )C(=O) NR a R b , -N(R c )C(=O)R d , -N(R c )S(=O)NR a R b , -N(R c )S(=O)R a ,- N(R c )S(=O) 2 NR a R b ,-N(R c )S(=O) 2 R a ,methyl,ethyl, n-propyl, isopropyl, methoxy, benzene Base, phenyl-C 1-2 alkylene, C 1-6 alkyl, C 1-6 aliphatic, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-7 heterocyclyl, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7 Heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, C 6 a -10 aryl group, or a heteroaryl group of 5-10 atoms, wherein R a , R b and R c have the definitions as defined in the present invention.

本發明使用的術語“脂肪族的”或“脂肪族基團”,表示直鏈(即非支鏈)或支鏈,取代或非取代的完全飽和或含有一個或多個不飽和度的烴鏈。除非另外詳細說明,脂肪族基團含有1-20個碳原子,其中一些實施例是,脂肪族基團含有1-10個碳原子,另外一些實施例是,脂肪族基團含有1-8 個碳原子,另外一些實施例是,脂肪族基團含有1-6個碳原子,另外一些實施例是,脂肪族基團含有1-3個碳原子。合適的脂肪族基團包括,但並不限於,直鏈或支鏈,取代或非取代的烷基,烯基或炔基基團,如C1-6脂肪族基團,包括直鏈或支鏈,取代或非取代的C1-6烷基,C2-6烯基,或C2-6炔基基團。這樣的實例包括,但並不限於,甲基,乙基,丙基,異丙基,丁基,異丁基,叔丁基,乙烯,丙烯,丁烯,2-丁烯,乙炔,丙炔,丁炔,2-丁炔,等等,並且所述脂肪族基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "aliphatic" or "aliphatic group" as used herein, denotes a straight-chain (ie unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturations. . Unless otherwise specified, the aliphatic group contains from 1 to 20 carbon atoms, some of which are, the aliphatic group contains from 1 to 10 carbon atoms, and in other embodiments, the aliphatic group contains from 1 to 8 A carbon atom, in other embodiments, the aliphatic group contains 1-6 carbon atoms, and in other embodiments, the aliphatic group contains 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups, such as C1-6 aliphatic groups, including straight chains or branches. A chain, a substituted or unsubstituted C 1-6 alkyl group, a C 2-6 alkenyl group, or a C 2-6 alkynyl group. Such examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethylene, propylene, butene, 2-butene, acetylene, propyne , butyne, 2-butyne, and the like, and the aliphatic group may be independently unsubstituted or substituted with one or more substituents described herein.

本發明使用的術語“烷基”或“烷基基團”,表示含1-20個碳原子的飽和直鏈或支鏈的一價碳氫化合物原子團。除非另外詳細說明,烷基基團含有1-20個碳原子,其中一些實施例是,烷基基團含有1-10個碳原子,另外一些實施例是,烷基基團含有1-8個碳原子,另外一些實施例是,烷基基團含有1-6個碳原子,另外一些實施例是,烷基基團含有1-4個碳原子,另外一些實施例是,烷基基團含有1-3個碳原子。 The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms, some of which are, wherein the alkyl group contains from 1 to 10 carbon atoms, and in other embodiments, the alkyl group contains from 1 to 8 A carbon atom, in other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, and in other embodiments, the alkyl group contains 1-3 carbon atoms.

烷基基團的實例包含,但並不限於,甲基(Me,-CH3),乙基(Et,-CH2CH3),正丙基(n-Pr,-CH2CH2CH3),異丙基(i-Pr,-CH(CH3)2),正丁基(n-Bu,-CH2CH2CH2CH3),異丁基(i-Bu,-CH2CH(CH3)2),仲丁基(s-Bu,-CH(CH3)CH2CH3),叔丁基(t-Bu,-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),正己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3),正庚基,正辛基,等等,其中所述烷 基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl ( n -Pr, -CH 2 CH 2 CH 3 ), isopropyl ( i- Pr, -CH(CH 3 ) 2 ), n-butyl ( n -Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl ( i -Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl ( s -Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl ( t -Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2), 2-methyl-3-pentyl (-CH (CH 2 CH 3) CH (CH 3) 2) 2,3-dimethyl-2-butyl (-C (CH 3) 2 CH (CH 3) 2), 3,3- dimethyl-2-butyl (-CH (CH 3) C ( CH 3 ) 3 ), n-heptyl, n-octyl, and the like, wherein the alkyl group may be independently unsubstituted or substituted with one or more substituents described herein.

本發明所使用的術語“烷基”和其首碼“烷”,都包含直鏈和支鏈的飽和碳鏈。 As used herein, the term "alkyl" and its first "alkane", both contain straight-chain and branched saturated carbon chains.

術語“亞烷基”表示從直鏈或支鏈的飽和烴基中去掉兩個氫原子所得到的飽和的二價烴基基團。除非另外詳細說明,亞烷基基團含有1-10個碳原子,另外一些實施例是,亞烷基基團含有1-6個碳原子,另外一些實施例是,亞烷基基團含有1-4個碳原子,另外一些實施例是,亞烷基基團含有1-2個碳原子。這樣的實例包括亞甲基(-CH2-),亞乙基(-CH2CH2-),亞異丙基(-CH(CH3)CH2-)等等,其中所述亞烷基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "alkylene" means a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 10 carbon atoms, and in other embodiments, an alkylene group contains from 1 to 6 carbon atoms. In still other embodiments, an alkylene group contains 1 - 4 carbon atoms, in other embodiments, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -), and the like, wherein the alkylene group The group may be independently unsubstituted or substituted by one or more substituents described herein.

術語“鏈烯基”表示2-12個碳原子,或2-8個碳原子,或2-6個碳原子,或2-4個碳原子的直鏈或支鏈的一價烴基,其中至少一個位置為不飽和狀態,即一個C-C為sp2雙鍵,其中鏈烯基的基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代,包括基團有“反”“正”或“E”“Z”的定位,其中具體的實例包括,但並不限於,乙烯基(-CH=CH2),烯丙基(-CH2CH=CH2)等等。 The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least One position is an unsaturated state, that is, one CC is a sp 2 double bond, wherein the alkenyl group may be independently unsubstituted or substituted by one or more substituents described herein, including a group having ""anti" positive "or" E "" Z "orientation, where specific examples include, but are not limited to, vinyl (-CH = CH 2), allyl (-CH 2 CH = CH 2), etc. .

術語“炔基”表示2-12個碳原子,或2-8個碳原子,或2-6個碳原子,或2-4個碳原子的直鏈或支鏈的一價烴基,其中至少一個位置為不飽和狀態,即一個C-C為sp三鍵,其中炔基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代,具體的實例包括,但並不限於,乙炔基(-C≡CH),炔丙基(-CH2C≡CH),1-丙炔基(-C≡C-CH3)等等。 The term "alkynyl" means a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one of which The position is an unsaturated state, that is, one CC is a sp triple bond, wherein the alkynyl group may be independently unsubstituted or substituted by one or more substituents described in the present invention, and specific examples include, but are not limited to, , ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 ) and the like.

術語“烷氧基”表示烷基基團通過氧原子與分子其餘部分相連,其中烷基基團具有如本發明所述的含義。除非另外詳細說明,所述烷氧基基團含有1-20個碳原子,其中一些實施例是,烷氧基基團含有1-10個碳原子,另外一些實施例是,烷氧基基團含有1-8個碳原子,另外一些實施例是, 烷氧基基團含有1-6個碳原子,另外一些實施例是,烷氧基基團含有1-4個碳原子,另外一些實施例是,烷氧基基團含有1-3個碳原子。 The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 20 carbon atoms, some of which are, the alkoxy group contains from 1 to 10 carbon atoms, and in other embodiments, the alkoxy group Containing 1-8 carbon atoms, in other embodiments, The alkoxy group contains from 1 to 6 carbon atoms. In still other embodiments, the alkoxy group contains from 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains from 1 to 3 carbon atoms. .

烷氧基基團的實例包含,但並不限於,甲氧基(MeO,-OCH3),乙氧基(EtO,-OCH2CH3),1-丙氧基(n-PrO,n-丙氧基,-OCH2CH2CH3),2-丙氧基(i-PrO,i-丙氧基,-OCH(CH3)2),1-丁氧基(n-BuO,n-丁氧基,-OCH2CH2CH2CH3),2-甲基-1-丙氧基(i-BuO,i-丁氧基,-OCH2CH(CH3)2),2-丁氧基(s-BuO,s-丁氧基,-OCH(CH3)CH2CH3),2-甲基-2-丙氧基(t-BuO,t-丁氧基,-OC(CH3)3),1-戊氧基(n-戊氧基,-OCH2CH2CH2CH2CH3),2-戊氧基(-OCH(CH3)CH2CH2CH3),3-戊氧基(-OCH(CH2CH3)2),2-甲基-2-丁氧基(-OC(CH3)2CH2CH3),3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2),3-甲基-1-丁氧基(-OCH2CH2CH(CH3)2),2-甲基-1-丁氧基(-OCH2CH(CH3)CH2CH3),等等,其中所述烷氧基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy ( n- PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy ( i- PrO, i -propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propoxy ( i- BuO, i -butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy ( t- BuO, t -butoxy, -OC(CH) 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), and the like, wherein the alkoxy group may be independently unsubstituted or substituted with one or more substituents described herein.

術語“鹵代烷基”,“鹵代烯基”或“鹵代烷氧基”表示烷基,烯基或烷氧基基團被一個或多個鹵素原子所取代,這樣的實例包含,但並不限於,三氟甲基,三氟甲氧基等。 The term "haloalkyl", "haloalkenyl" or "haloalkoxy" denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, and the like.

術語“碳環”、“碳環基”或“環狀脂肪族”是指有一個或多個連接點連接到分子的其餘部分,非芳香族的,飽和或部分不飽和的,包括3-12個碳原子,或3-10個碳原子,或3-8個碳原子,或3-6個碳原子的單環,雙環和三環體系。合適的環狀脂肪族基團包括,但並不限於,環烷基,環烯基和環炔基。環狀脂肪族基團的實例進一步包括,但絕不限於,環丙基,環丁基,環戊基,1-環戊基-1-烯基,1-環戊基-2-烯基,1-環戊基-3-烯基,環己基,1-環己基-1-烯基,1-環己基-2-烯基,1-環己基-3-烯基,環己二烯基,環庚基,環辛基,環壬基,環癸基,環十一烷基,環十二烷基,等等。 The term "carbocyclic", "carbocyclyl" or "cyclic aliphatic" means having one or more attachment points attached to the remainder of the molecule, non-aromatic, saturated or partially unsaturated, including 3-12 Monocyclic, bicyclic and tricyclic systems having one carbon atom, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of the cyclic aliphatic group further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, Cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

術語“環烷基”是指有一個或多個連接點連接到分子的其餘部分,飽和的,含3-12個碳原子的單環,雙環或三環體系。其雙環體系包含螺雙 環和稠合雙環。其中一些實施例是含3-10個碳原子的環體系,另外一些實施例是含3-8個碳原子的環體系,另外一些實施例是含3-6個碳原子的環體系,另外一些實施例是含5-6個碳原子的環體系,且所述環烷基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic ring system having one or more attachment points attached to the remainder of the molecule, saturated, having from 3 to 12 carbon atoms. Its double ring system contains a double screw Ring and fused bicyclic ring. Some of these examples are ring systems containing from 3 to 10 carbon atoms, others are ring systems containing from 3 to 8 carbon atoms, and other embodiments are ring systems containing from 3 to 6 carbon atoms, others Examples are ring systems containing from 5 to 6 carbon atoms, and the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

術語“環烷基亞烷基”表示烷基基團可以被一個或多個環烷基基團所取代,其中烷基和環烷基基團具有如本發明所述的含義。其中一些實施例是,環烷基亞烷基基團是指“較低級的環烷基亞烷基”基團,即環烷基基團連接到C1-6的烷基基團上。另外一些實施例是,環烷基基團連接到C1-4的烷基基團上。另外一些實施例是,環烷基基團連接到C1-3的烷基基團上。另外一些實施例是,環烷基基團連接到C1-2的烷基基團上。這樣的實例包括,但並不限於,環丙基乙基,環戊基甲基,環己基甲基等等。所述環烷基亞烷基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。這樣的實例包括,但並不限於,環丙基乙基,環戊基甲基,環己基甲基等等。 The term "cycloalkylalkylene" means that the alkyl group may be substituted by one or more cycloalkyl groups, wherein the alkyl and cycloalkyl groups have the meanings as described herein. In some of these embodiments, a cycloalkylalkylene group refers to a "lower cycloalkylalkylene" group, i.e., a cycloalkyl group attached to a C1-6 alkyl group. In other embodiments, a cycloalkyl group is attached to a C1-4 alkyl group. In other embodiments, a cycloalkyl group is attached to the C1-3 alkyl group. In other embodiments, a cycloalkyl group is attached to the C 1-2 alkyl group. Such examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. The cycloalkylalkylene group may be independently unsubstituted or substituted with one or more substituents described herein. Such examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

術語“雜環”、“雜環基”或“雜環的”在此處可交換使用,都是指單環,雙環,或三環體系,其中環上一個或多個原子獨立任選地被雜原子所替換,環可以是完全飽和的或包含一個或多個不飽和度,但絕不是芳香族類,只有一個連接點連接到分子的其餘部分。其雙環體系包含螺雙環和稠合雙環,並且其中一個環可以是單碳環或單雜環。其中一個或多個環上的氫原子獨立任選地被一個或多個本發明所描述的取代基所取代。其中一些實施例是,“雜環”“雜環基”或“雜環的”基團是3-7個原子組成的單環(2-6個碳原子和選自N,O,P,S的1-3個雜原子,在此S或P任選地被一個或多個氧原子所取代得到像SO,SO2,PO,PO2的基團),另外一些實施例是,3-6個原子組成的單環(2-5個碳原子和選自N,O,P,S的1-3個雜原子,在此S或P任選地被一個或多個氧原子所取代得到像S=O,SO2,PO,PO2的基團,當所述的環為三元環時,其中只有一個雜原子),或7-10個原子組成的雙環(4-9個碳原子和選自N,O,P,S的1-3個雜原子,在此S或P任選地被一個或多個氧原子所取代得到像SO, SO2,PO,PO2的基團)。 The terms "heterocycle", "heterocyclyl" or "heterocycle" are used interchangeably herein to refer to a monocyclic, bicyclic, or tricyclic ring system wherein one or more atoms on the ring are optionally independently Substituted by a heteroatom, the ring may be fully saturated or contain one or more degrees of unsaturation, but by no means an aromatic type, only one point of attachment is attached to the remainder of the molecule. Its bicyclic system comprises a spiro bicyclic ring and a fused bicyclic ring, and one of the rings may be a monocarbocyclic ring or a monoheterocyclic ring. Hydrogen atoms on one or more of the rings are independently, optionally, substituted by one or more substituents described herein. In some embodiments, a "heterocyclic""heterocyclyl" or "heterocyclic" group is a monocyclic ring of 3-7 atoms (2-6 carbon atoms and selected from N, O, P, S) 1-3 heteroatoms, where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 ), and in other embodiments, 3-6 a single ring composed of atoms (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give an image a group of S=O, SO 2 , PO, PO 2 , when the ring is a three-membered ring, wherein there is only one hetero atom), or a double ring of 7-10 atoms (4-9 carbon atoms and One to three heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 ).

雜環基可以是碳基或雜原子基。“雜環基”同樣也包括雜環基團與飽和或部分不飽和環或雜環稠合所形成的基團。雜環的實例包括,但並不限於,吡咯烷基,四氫呋喃基,二氫呋喃基,四氫噻吩基,四氫吡喃基,二氫吡喃基,四氫噻喃基,呱啶基,嗎啉基,硫代嗎啉基,噻噁烷基,呱嗪基,高呱嗪基,氮雜環丁基,氧雜環丁基,硫雜環丁基,高呱啶基,環氧丙基,氮雜環庚基,氧雜環庚基,硫雜環庚基,氧氮雜卓基,二氮雜卓基,硫氮雜卓基,2-吡咯啉基,3-吡咯啉基,二氫吲哚基,2H-吡喃基,4H-吡喃基,二氧雜環己基,1,3-二氧戊基,吡唑啉基,二噻烷基,二噻茂烷基,二氫噻吩基,吡唑烷基咪唑啉基,咪唑烷基,1,2,3,4-四氫異喹啉基。雜環基團的實例還包括,1,1-二氧硫代嗎啉基,和其中環上兩個碳原子被氧原子所取代如嘧啶二酮基。 The heterocyclic group may be a carbon group or a hetero atom group. "Heterocyclyl" also includes groups formed by the condensation of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, acridinyl, Morpholinyl, thiomorpholinyl, thiazolidine, pyridazinyl, oxazinyl, azetidinyl, oxetanyl, thioheterobutyl, homoacridinyl, propylene , azacycloheptyl, oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, 2-pyrroline, 3-pyrrolyl, Dihydroindenyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithianyl, di Hydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl. Examples of the heterocyclic group further include a 1,1-dioxothiomorpholinyl group, and wherein two carbon atoms in the ring are substituted with an oxygen atom such as a pyrimidinedione group.

術語“雜環基亞烷基”表示烷基基團可以被一個或多個雜環基基團所取代,其中烷基和雜環基基團具有如本發明所述的含義。其中一些實施例是,雜環基亞烷基基團是指“較低級的雜環基亞烷基”基團,即雜環基基團連接到C1-6的烷基基團上。另外一些實施例是,雜環基基團連接到C1-4的烷基基團上。另外一些實施例是,雜環基基團連接到C1-2的烷基基團上。這樣的實例包括,但並不限於,2-吡咯烷乙基,3-氮雜環丁烷甲基等等。所述雜環基亞烷基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "heterocyclylalkylene" means that the alkyl group may be substituted by one or more heterocyclyl groups, wherein the alkyl and heterocyclyl groups have the meanings as described herein. In some of these embodiments, a heterocyclylalkylene group refers to a "lower heterocyclylalkylene" group, i.e., a heterocyclyl group attached to a C1-6 alkyl group. In other embodiments, a heterocyclyl group is attached to a C1-4 alkyl group. In other embodiments, a heterocyclyl group is attached to the C 1-2 alkyl group. Such examples include, but are not limited to, 2-pyrrolidinoethyl, 3-azetidinylmethyl, and the like. The heterocyclylalkylene group may be independently unsubstituted or substituted with one or more substituents described herein.

術語“雜原子”是指O,S,N,P和Si,包括N,S和P任何氧化態的形式;伯、仲、叔胺和季銨鹽的形式;或者雜環中氮原子上的氫被取代的形式,例如,N(像3,4-二氫-2H-吡咯基中的N),NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。 The term "heteroatom" means O, S, N, P and Si, including the form of any oxidation state of N, S and P; in the form of primary, secondary, tertiary and quaternary ammonium salts; or on a nitrogen atom in a heterocycle a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).

術語“鹵素”是指F,Cl,Br或I。 The term "halogen" means F, Cl, Br or I.

術語“H”表示單個氫原子。這樣的原子團可以與其他基團連接,譬如與氧原子相連,形成羥基基團。 The term "H" denotes a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.

術語“D”或“2H”表示單個氘原子。一個這樣的原子團與一個甲基相連,形成單-氘代甲基(-CDH2),兩個氘原子與一個甲基相連,形成雙-氘代甲基(-CD2H),以及三個氘原子與一個甲基相連,形成三-氘代甲基(-CD3)。 The term "D" or "2 H" denotes a single deuterium atom. One such atomic group is bonded to a methyl group to form a mono-deuterated methyl group (-CDH 2 ), two deuterium atoms are bonded to one methyl group to form a bis-deuterated methyl group (-CD 2 H), and three The ruthenium atom is bonded to a methyl group to form a tri-deuterated methyl group (-CD 3 ).

術語“N3”表示一個疊氮結構。這種基團可以與其他基團相連接,例如,可與一個甲基相連形成疊氮甲烷(MeN3),或者與一個苯基相連形成疊氮苯(PhN3)。 The term "N 3 " means an azide structure. Such a group may be attached to other groups, for example, to a methyl group to form azide methane (MeN 3 ) or to a phenyl group to form azidobenzene (PhN 3 ).

術語“芳基”可以單獨使用或作為“芳烷基”、“芳烷氧基”或“芳氧基烷基”的一大部分,表示共含有6-14個環原子,或6-12個環原子,或6-10個環原子的單環,雙環,和三環的碳環體系,其中,至少一個環體系是芳香族的,其中每一個環體系包含3-7個原子組成的環,且只有一個附著點與分子的其餘部分相連。術語“芳基”可以和術語“芳香環”交換使用,如芳香環可以包括苯基,萘基和蒽。所述芳基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "aryl" may be used alone or as a large part of "aralkyl", "aralkyloxy" or "aryloxyalkyl", meaning a total of 6 to 14 ring atoms, or 6 to 12 a ring atom, or a monocyclic, bicyclic, and tricyclic carbocyclic ring system of 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3-7 atoms, And only one attachment point is connected to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", such as an aromatic ring which may include phenyl, naphthyl and anthracene. The aryl group may be independently unsubstituted or substituted with one or more substituents described herein.

術語“芳基亞烷基”表示烷基基團可以被一個或多個芳基基團所取代,其中烷基和芳基基團具有如本發明所述的含義,其中一些實施例是,芳基亞烷基基團是指“較低級的芳基亞烷基”基團,即芳基基團連接到C1-6的烷基基團上。另外一些實施例是,芳基亞烷基基團是指含C1-4的烷基的“苯烷撐”。另外一些實施例是,芳基亞烷基基團是指芳基基團連接到C1-2的烷基基團上。其中具體實例包括苄基,二苯基甲基,苯乙基等等。所述芳基亞烷基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "arylalkylene" means that the alkyl group may be substituted by one or more aryl groups, wherein the alkyl and aryl groups have the meanings as described herein, some of which are The alkylene group refers to a "lower arylalkylene" group, i.e., an aryl group attached to a C1-6 alkyl group. In other embodiments, an arylalkylene group refers to a "phenylene group" containing a C1-4 alkyl group. In other embodiments, an arylalkylene group refers to an aryl group attached to an alkyl group of C 1-2 . Specific examples thereof include a benzyl group, a diphenylmethyl group, a phenethyl group and the like. The arylalkylene group may be independently unsubstituted or substituted with one or more substituents described herein.

術語“雜芳基”可以單獨使用或作為“雜芳基烷基”或“雜芳基烷氧基”的一大部分,表示共含有5-14個環原子,或5-12個環原子,或5-10個環原子的單環,雙環,和三環體系,其中至少一個環體系是芳香族的,且至少一個環體系包含一個或多個雜原子,其中每一個環體系包含5-7個原子組成的環,且只有一個附著點與分子其餘部分相連。術語“雜芳基”可以與術語“芳雜環”或“雜芳族化合物”交換使用。 The term "heteroaryl" may be used alone or as a large part of "heteroarylalkyl" or "heteroarylalkoxy", meaning a total of 5 to 14 ring atoms, or 5 to 12 ring atoms, Or a monocyclic, bicyclic, and tricyclic ring system of 5-10 ring atoms, wherein at least one ring system is aromatic and at least one ring system comprises one or more heteroatoms, wherein each ring system comprises 5-7 A ring of atoms, and only one attachment point is attached to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic".

另外一些實施例是,芳雜環包括以下的單環,但並不限於這些單環:2-呋喃基,3-呋喃基,N-咪唑基,2-咪唑基,4-咪唑基,5-咪唑基,3-異噁唑基,4-異噁唑基,5-異噁唑基,2-噁唑基,4-噁唑基,5-噁唑基,N-吡咯基,2-吡咯基,3-吡咯基,2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,4-嘧啶基,5-嘧啶基,噠嗪基(如3-噠嗪基),2-噻唑基,4-噻唑基,5-噻唑基,四唑基(如5-四唑基),***基(如2-***基和5-***基),2-噻吩基,3-噻吩基,吡唑基(如2-吡唑基),異噻唑基,1,2,3-噁二唑基,1,2,5-噁二唑基,1,2,4-噁二唑基,1,2,3-***基,1,2,3-硫代二唑基,1,3,4-硫代二唑基,1,2,5-硫代二唑基,吡嗪基,1,3,5-三嗪基;也包括以下的雙環,但絕不限於這些雙環:苯並咪唑基,苯並呋喃基,苯並噻吩基,吲哚基(如2-吲哚基),嘌呤基,喹啉基(如2-喹啉基,3-喹啉基,4-喹啉基),和異喹啉基(如1-異喹啉基,3-異喹啉基或4-異喹啉基)。所述雜芳基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 In other embodiments, the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrole , 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2 -thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3 -Thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiyl Azyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyridyl Azinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl (eg 2-indole) Base, fluorenyl, quinolyl (eg 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and Quinoline (such as 1-isoquinolinyl, 3-isoquinolyl or 4-isoquinolinyl). The heteroaryl group can be independently unsubstituted or substituted with one or more substituents described herein.

術語“雜芳基亞烷基”表示烷基基團可以被一個或多個雜芳基基團所取代,其中烷基和雜芳基基團具有如本發明所述的含義,其中一些實施例是,雜芳基亞烷基基團是指“較低級的雜芳基亞烷基”基團,即雜芳基基團連接到C1-6的烷基基團上。另外一些實施例是,雜芳基基團連接到C1-4的烷基基團上。另外一些實施例是,雜芳基基團連接到C1-2的烷基基團上。其中具體實例包括2-吡啶甲基,3-呋喃乙基等等。所述雜芳基亞烷基基團可以獨立地未被取代或被一個或多個本發明所描述的取代基所取代。 The term "heteroarylalkylene" means that the alkyl group may be substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meanings as described herein, some of which are Yes, a heteroarylalkylene group refers to a "lower heteroarylalkylene" group, i.e., a heteroaryl group attached to a C1-6 alkyl group. In other embodiments, a heteroaryl group is attached to a C1-4 alkyl group. In other embodiments, a heteroaryl group is attached to the C 1-2 alkyl group. Specific examples thereof include 2-pyridylmethyl, 3-furanethyl and the like. The heteroarylalkylene group may be independently unsubstituted or substituted with one or more substituents described herein.

術語“羧基”,無論是單獨使用還是和其他術語連用,如“羧烷基”,表示-CO2H;術語“羰基”,無論是單獨使用還是和其他術語連用,如“氨基羰基”或“醯氧基”,表示-(C=O)-。 The term "carboxy", whether used alone or in conjunction with other terms, such as "carboxyalkyl", means -CO 2 H; the term "carbonyl", whether used alone or in conjunction with other terms, such as "aminocarbonyl" or ""醯oxy", which means -(C=O)-.

術語“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”,其中氨基基團分別獨立地被一個或兩個烷基基團所取代。其中一些實施例是,烷基氨基是一個或兩個C1-6烷基連接到氮原子上的較低級的烷基氨基基團。 另外一些實施例是,烷基氨基是C1-3的較低級的烷基氨基基團。合適的烷基氨基基團可以是單烷基氨基或二烷基氨基,這樣的實例包括,但並不限於,N-甲氨基,N-乙氨基,N,N-二甲氨基,N,N-二乙氨基等等。 The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is a lower alkylamino group having one or two C1-6 alkyl groups attached to the nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C1-3 . Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N, N - Diethylamino and the like.

術語“芳氨基”表示氨基基團被一個或兩個芳基基團所取代,這樣的實例包括,但並不限於N-苯氨基。其中一些實施例是,芳氨基上的芳環可以進一步被取代。 The term "arylamino" means that the amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some of these embodiments, the aromatic ring on the arylamino group can be further substituted.

術語“氨基烷基”包括被一個或多個氨基所取代的C1-10直鏈或支鏈烷基基團。其中一些實施例是,氨基烷基是被一個或多個氨基基團所取代的C1-6“較低級的氨基烷基”,這樣的實例包括,但並不限於,氨甲基,氨乙基,氨丙基,氨丁基和氨己基。 The term "aminoalkyl" includes C1-10 straight or branched alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a C1-6 "lower aminoalkyl group" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl.

在本發明中所使用的術語“不飽和的”表示基團中含有一個或多個不飽和度。 The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.

術語“包含”為開放式表達,即包括本發明所指明的內容,但並不排除其他方面的內容。 The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

除非其他方面表明,本發明所描述的結構式包括所有的同分異構形式(如對映異構,非對映異構,和幾何異構(或構象異構)):例如含有不對稱中心的R、S構型,雙鍵的(Z)、(E)異構體,和(Z)、(E)的構象異構體。因此,本發明的化合物的單個立體化學異構體或其對映異構體,非對映異構體,或幾何異構體(或構象異構體)的混合物都屬於本發明的範圍。 Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)): for example, containing asymmetric centers The R, S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers thereof, or mixtures of geometric isomers (or conformational isomers) are within the scope of the invention.

本發明所使用的術語“互變異構體”或“互變異構形式”表示具有不同能量的結構同分異構體可以越過低能壘,從而互相轉化。譬如,質子互變異構體(即質子移變)包括通過質子遷移進行互變,如酮-烯醇式互變和亞胺-烯胺同分異構化作用。化合價互變異構體包括通過一些成鍵電子重組而進行互變。 The term "tautomer" or "tautomeric form" as used in the present invention means that structural isomers having different energies can cross the low energy barrier and thereby transform each other. For example, proton tautomers (ie, proton shifts) include interconversions by proton transfer, such as keto-enol interconversion and imine-enamine isomerization. Valence tautomers include interconversion through some bonding electron recombination.

除非其他方面表明,本發明的化合物的所有互變異構形式都包含在本發明的範圍之內。另外,除非其他方面表明,本發明所描述的化合物 的結構式包括一個或多個不同的原子的富集同位素。 Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the compounds described herein The structural formula includes an enriched isotope of one or more different atoms.

本發明所使用的術語“前藥”,代表一個化合物在體內轉化為式(I)或式(II)所示的化合物。這樣的轉化受前體藥物在血液中水解或在血液或組織中經酶轉化為母體結構的影響。本發明前體藥物類化合物可以是酯,在現有的發明中酯可以作為前體藥物的有苯酯類,脂肪族(C1-24)酯類,醯氧基甲基酯類,碳酸酯,氨基甲酸酯類和氨基酸酯類。例如本發明裡的一個化合物包含羥基,即可以將其醯化得到前體藥物形式的化合物。其他的前體藥物形式包括磷酸酯,如這些磷酸酯類化合物是經母體上的羥基磷酸化得到的。關於前體藥物完整的討論可以參考以下文獻: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。 The term "prodrug" as used in the present invention denotes a compound which is converted in vivo to a compound of formula (I) or formula (II). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug of a phenyl ester, an aliphatic (C 1-24 ) ester, a decyloxymethyl ester, a carbonate, Carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be deuterated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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 SJ Hecker et al. , Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008 , 51, 2328-2345.

“代謝產物”是指具體的化合物或其鹽在體內通過代謝作用所得到的產物。一個化合物的代謝產物可以通過所屬領域公知的技術來進行鑒定,其活性可以通過如本發明所描述的那樣採用試驗的方法進行表徵。這樣的產物可以是通過給藥化合物經過氧化,還原,水解,醯氨化,脫醯氨作用,酯化,脫脂作用,酶裂解等等方法得到。相應地,本發明包括化合物的代謝產物,包括將本發明的化合物與哺乳動物充分接觸一段時間所產生的代謝產物。 "Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, hydrazine, deamination, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.

本發明中立體化學的定義和慣例的使用通常參考以下文獻: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.本發明的化合物可以包含不對稱中心或手性中心,因此存在 不同的立體異構體。本發明的化合物所有的立體異構形式,包括但絕不限於,非對映體,對映異構體,阻轉異構體,和它們的混合物,如外消旋混合物,組成了本發明的一部分。很多有機化合物都以光學活性形式存在,即它們有能力旋轉平面偏振光的平面。在描述光學活性化合物時,首碼D、L或R、S用來表示分子手性中心的絕對構型。首碼d、l或(+)、(-)用來命名化合物平面偏振光旋轉的符號,(-)或l是指化合物是左旋的,首碼(+)或d是指化合物是右旋的。這些立體異構體的化學結構是相同的,但是它們的立體結構不一樣。特定的立體異構體可以是對映體,異構體的混合物通常稱為對映異構體混合物。50:50的對映體混合物被稱為外消旋混合物或外消旋體,這可能導致化學反應過程中沒有立體選擇性或立體定向性。術語“外消旋混合物”和“外消旋體”是指等摩爾的兩個對映異構體的混合物,缺乏光學活性。 The use of the definitions and conventions of stereochemistry in the present invention is generally referred to the following documents: SP 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. The compounds of the invention may contain asymmetric centers or chiral centers, and thus different stereoisomers are present. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. portion. Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing an optically active compound, the first code D, L or R, S is used to indicate the absolute configuration of the molecular chiral center. The first code d, l or (+), (-) is used to name the symbol of the rotation of the plane polarized light of the compound, (-) or l means that the compound is left-handed, and the first code (+) or d means that the compound is right-handed. . The chemical structures of these stereoisomers are the same, but their stereostructures are different. A particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lack optical activity.

術語“互變異構體”或“互變異構的形式”是指不同能量的結構的同分異構體可以通過低能壘互相轉化。例如質子互變異構體(即質子移變的互變異構體)包括通過質子遷移的互變,如酮式-烯醇式和亞胺-烯胺的同分異構化作用。原子價(化合價)互變異構體包括重組成鍵電子的互變。 The term "tautomer" or "tautomeric form" means that the isomers of the structure of different energies can be converted into each other by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. The valence (valence) tautomer includes the interconversion of recombination bond electrons.

本發明所使用的“藥學上可接受的鹽”是指本發明的化合物的有機鹽和無機鹽。藥學上可接受的鹽在所屬領域是為我們所熟知的,如文獻:S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所記載的。藥學上可接受的無毒的酸形成的鹽包括,但並不限於,與氨基基團反應形成的無機酸鹽有鹽酸鹽,氫溴酸鹽,磷酸鹽,硫酸鹽,高氯酸鹽,和有機酸鹽如乙酸鹽,草酸鹽,馬來酸鹽,酒石酸鹽,檸檬酸鹽,琥珀酸鹽,丙二酸鹽,或通過書籍文獻上所記載的其他方法如離子交換法來得到這些鹽。其他藥學上可接受的鹽包括己二酸鹽,藻酸鹽,抗壞血酸鹽,天冬氨酸鹽,苯磺酸鹽,苯甲酸鹽,重硫酸鹽,硼酸鹽,丁酸鹽,樟腦酸鹽,樟腦磺酸鹽,環戊基丙酸鹽,二葡萄糖酸鹽,十二烷基硫酸鹽,乙磺酸鹽,甲酸鹽,反丁烯二酸鹽,葡庚糖酸鹽,甘油磷酸鹽,葡萄糖酸鹽,半硫酸鹽,庚 酸鹽,己酸鹽,氫碘酸鹽,2-羥基-乙磺酸鹽,乳糖醛酸鹽,乳酸鹽,月桂酸鹽,月桂基硫酸鹽,蘋果酸鹽,丙二酸鹽,甲磺酸鹽,2-萘磺酸鹽,煙酸鹽,硝酸鹽,油酸鹽,棕櫚酸鹽,撲酸鹽,果膠酸鹽,過硫酸鹽,3-苯基丙酸鹽,苦味酸鹽,特戊酸鹽,丙酸鹽,硬脂酸鹽,硫氰酸鹽,對甲苯磺酸鹽,十一酸鹽,戊酸鹽,等等。通過適當的堿得到的鹽包括鹼金屬,鹼土金屬,銨和N+(C1-4烷基)4的鹽。本發明也擬構思了任何所包含N的基團的化合物所形成的季銨鹽。水溶性或油溶性或分散產物可以通過季銨化作用得到。鹼金屬或鹼土金屬鹽包括鈉,鋰,鉀,鈣,鎂,等等。藥學上可接受的鹽進一步包括適當的、無毒的銨,季銨鹽和抗平衡離子形成的胺陽離子,如鹵化物,氫氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。 The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art and are described in the literature: SMBerge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977 , 66: 1-19. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and Organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods such as ion exchange methods described in the literature. . Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphorate , camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate , gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid Salt, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-benzene Propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by appropriate hydrazine include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4 . The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1- 8 sulfonate and aromatic sulfonate.

本發明的“溶劑化物”是指一個或多個溶劑分子與本發明的化合物所形成的締合物。形成溶劑化物的溶劑包括,但並不限於,水,異丙醇,乙醇,甲醇,二甲亞碸,乙酸乙酯,乙酸,氨基乙醇。術語“水合物”是指溶劑分子是水所形成的締合物。 "Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl hydrazine, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

術語“保護基團”或“Pg”是指一個取代基與別的官能團起反應的時候,通常用來阻斷或保護特殊的功能性。例如,“氨基的保護基團”是指一個取代基與氨基基團相連來阻斷或保護化合物中氨基的功能性,合適的氨基保護基團包括乙醯基,三氟乙醯基,叔丁氧羰基(BOC),苄氧羰基(CBZ)和9-芴亞甲氧羰基(Fmoc)。相似地,“羥基保護基團”是指羥基的取代基用來阻斷或保護羥基的功能性,合適的保護基團包括乙醯基和甲矽烷基。“羧基保護基團”是指羧基的取代基用來阻斷或保護羧基的功能性,一般的羧基保護基包括-CH2CH2SO2Ph,氰基乙基,2-(三甲基矽烷基)乙基,2-(三甲基矽烷基)乙氧基甲基,2-(對甲苯磺醯基)乙基,2-(對硝基苯磺醯基)乙基,2-(二苯基膦基)乙基,硝基乙基,等等。對於保護基團一般的描述可參考文獻:T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991;and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005. The term "protecting group" or "Pg" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "protecting group of an amino group" means a substituent which is bonded to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include ethenyl, trifluoroethylidene, tert-butyl Oxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group. Suitable protecting groups include ethenyl and carbaryl. "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylnonane) Ethyl, 2-(trimethyldecyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(di Phenylphosphino)ethyl, nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

本發明的化合物的描述Description of the compounds of the invention

本發明涉及取代的吡唑酮化合物,其藥學上可接受的鹽,及其藥物製劑,對酪氨酸激酶受體,尤其是VEGFR,c-Met,Ron和/或Axl受體介導的疾病或病症的治療有潛在的用途。特別是,本發明涉及一種如式(I)所示的化合物: 或其立體異構體,幾何異構體,互變異構體,氮氧化物,水合物,溶劑化物,代謝產物,藥學上可接受的鹽或它的前藥,其中,式(I)中Q,R1,R2,R3,R4,R5,R6,W,X,Y和Z的定義如下所示:在一些實施方案,式(I)中:Q為D,-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-C(=O)NRaRb,-N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb或-N(Rc)S(=O)2Ra;W為CR7或N;各X,Y和Z獨立地為H,D,C1-6烷基,C3-8環烷基,C3-8環烷基-C1-4亞烷基,C3-7雜環基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基或5-10個原子組成的雜芳基,其中,所述C1-6烷基,C3-8環烷基,C3-8環烷基-C1-4亞烷基,C3-7雜環基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基和5-10個原子組成的雜芳基可以任選地被1,2,3,4或5個獨立選自D,F,Cl,Br,CN,C2-6烯基,C2-6炔基,ORa,NRaRb,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代;各R1,R2,R3,R4,R5,R6和R7獨立地為H,D,F,Cl,Br,CN,N3,ORa,C1-6烷基,C1-6鹵代烷基,C2-6烯基或C2-6炔基; 各Ra,Rb和Rc獨立地為H,C1-6脂肪族,C1-6鹵代烷基,C3-6環烷基,C3-6環烷基-C1-4亞烷基,C3-6雜環基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基或5-10個原子組成的雜芳基,其中,所述C1-6脂肪族,C1-6鹵代烷基,C3-6環烷基,C3-6環烷基-C1-4亞烷基,C3-6雜環基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代;和Rd為D,C3-8環烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基或5-10個原子組成的雜芳基,其中,所述C3-8環烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,Br,CN,ORa,NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代。 The present invention relates to substituted pyrazolone compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof, mediated by tyrosine kinase receptors, particularly VEGFR, c-Met, Ron and/or Axl receptors Or the treatment of the condition has potential uses. In particular, the invention relates to a compound of formula (I): Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt thereof or a prodrug thereof, wherein Q in formula (I) , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W, X, Y and Z are as defined below: In some embodiments, in formula (I): Q is D, -N ( R c )C(=O)NR a R b , -N(R c )C(=O)R d , -C(=O)NR a R b , -N(R c )S(=O)NR a R b , -N(R c )S(=O)R a , -N(R c )S(=O) 2 NR a R b or -N(R c )S(=O) 2 R a ; W is CR 7 or N; each X, Y and Z are independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkylene , C 3-7 heterocyclyl, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene, (5-10 atomic heteroaryl) a C 1-4 alkylene group, a C 6-10 aryl group or a heteroaryl group of 5-10 atoms, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3 -8 cycloalkyl-C 1-4 alkylene, C 3-7 heterocyclyl, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkyl, (5-10 atoms heteroaryl) -C 1-4 alkylene heteroalkyl, C 6-10 aryl and 5 to 10 atoms Group may be optionally substituted with 1,2,3,4 or 5 substituents independently selected from D, F, Cl, Br, CN, C 2-6 alkenyl, C 2-6 alkynyl, OR a, NR a R b Substituted by a substituent of R a OC 1-4 alkylene or R a R b NC 1-4 alkylene; each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently The ground is H, D, F, Cl, Br, CN, N 3 , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; a , R b and R c are independently H, C 1-6 aliphatic, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclic group, C 3-6 heterocyclic group-C 1-4 alkylene group, C 6-10 aryl-C 1-4 alkylene group, (heteroaryl group of 5-10 atoms) a C 1-4 alkylene group, a C 6-10 aryl group or a heteroaryl group of 5-10 atoms, wherein the C 1-6 aliphatic group, a C 1-6 haloalkyl group, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclyl, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl -C 1-4 alkylene group, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, C 6-10 aryl group and heteroaryl group of 5-10 atoms may be optionally selected Ground cover 1, 2, 3 or 4 independently selected from D, F, Cl, CN, Substituted with a substituent of N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino; and R d is D, C 3-8 cycloalkyl, C 6-10 aryl -C 1-4 alkylene, (5-10 atoms heteroaryl) -C 1-4 alkylene of 5-10 atoms or a heteroaryl group, wherein the C 3-8 cycloalkyl, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group and 5-10 atoms The heteroaryl group may be optionally 1, 2, 3 or 4 independently selected from the group consisting of D, F, Cl, Br, CN, OR a , NR a R b , C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, R a OC 1-4 alkylene or R a R b NC 1-4 alkylene substituent.

在另外一些實施方案,式(I)中Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd或-C(=O)NRaRbIn still other embodiments, Q in the formula (I) is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d or -C(=O)NR a R b.

在另外一些實施方案,式(I)中各X,Y和Z獨立地為C1-4烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基,C3-6雜環基-C1-2亞烷基,苯基-C1-2亞烷基,(5-10個原子組成的雜芳基)-C1-2亞烷基,苯基或5-10個原子組成的雜芳基,其中,所述C1-4烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基,C3-6雜環基-C1-2亞烷基,苯基-C1-2亞烷基,(5-10個原子組成的雜芳基)-C1-2亞烷基,苯基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,C2-4烯基,C2-4炔基,ORa,NRaRb,RaO-C1-2亞烷基或RaRbN-C1-2亞烷基的取代基所取代。 In still other embodiments, each of X, Y and Z in formula (I) is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene , C 3-6 heterocyclyl, C 3-6 heterocyclyl-C 1-2 alkylene, phenyl-C 1-2 alkylene, (heteroaryl group of 5-10 atoms)-C a 1-2 alkylene group, a phenyl group or a heteroaryl group of 5-10 atoms, wherein the C 1-4 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl-C 1 -2 alkylene, C 3-6 heterocyclic, C 3-6 heterocyclyl-C 1-2 alkylene, phenyl-C 1-2 alkylene, (5-10 atomic hetero An aryl)-C 1-2 alkylene group, a phenyl group and a heteroaryl group consisting of 5-10 atoms may optionally be 1, 2, 3 or 4 independently selected from D, F, Cl, CN, C. Substituents of 2-4 alkenyl, C 2-4 alkynyl, OR a , NR a R b , R a OC 1-2 alkylene or R a R b NC 1-2 alkylene.

在另外一些實施方案,式(I)中各R1,R2,R3,R4,R5,R6和R7獨立地為H,D,F或Cl。 In other embodiments, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 in formula (I) is independently H, D, F or Cl.

在另外一些實施方案,式(I)中各Ra,Rb和Rc獨立地為H,C1-4烷基,C1-4鹵代烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基或C3-6雜環基-C1-2亞烷基,其中,所述C1-4烷基,C1-4鹵代烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基和C3-6雜環基-C1-2亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-3鹵代烷基,C1-3烷氧基或C1-3烷基氨基的取代基所取代。 In still other embodiments, each of R a , R b and R c in formula (I) is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3- 6 cycloalkyl-C 1-2 alkylene, C 3-6 heterocyclic or C 3-6 heterocyclyl-C 1-2 alkylene, wherein said C 1-4 alkyl, C 1 -4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C 1-2 The alkyl group may be optionally 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-3 haloalkyl, C 1-3 alkoxy or C Substituted by a substituent of 1-3 alkylamino.

在另外一些實施方案,式(I)中Rd為C3-6環烷基,其中,所述C3-6環烷基可以任選地被1,2,3或4個獨立選自D,F,CN,ORa,NRaRb,C1-3烷基,C2-4烯基,C2-4炔基,RaO-C1-2亞烷基或RaRbN-C1-2亞烷基的取代基所取代。 In still other embodiments, R d in formula (I) is C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl can be optionally 1, 2, 3 or 4 independently selected from D , F, CN, OR a , NR a R b , C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, R a OC 1-2 alkylene or R a R b NC 1 Substituted by a substituent of -2 alkylene.

在另外一些實施方案,式(I)中各X,Y和Z獨立地為H,D,CH3,被1,2或3個氘原子所取代的甲基基團,乙基,丙基,異丙基,苯基或被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代的苯基基團。 In other embodiments, the formula (I) each of X, Y and Z are independently H, D, CH 3, 1, 2 or 3 deuterium atoms substituted with a methyl group, an ethyl group, a propyl group, Isopropyl, phenyl or a phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

在另外一些實施方案,式(I)中Q為: In still other embodiments, Q in formula (I) is:

在另外一些實施方案,本發明化合物具有式(II)所示結構: 其中,式(II)中Q,X,Y和Z的定義如下所示:在一些實施方案,式(II)中:Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb,-N(Rc)S(=O)2Ra或-C(=O)NRaRb;各X,Y和Z獨立地為H,D,C1-6烷基,C3-8環烷基,C3-7雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基或(5-10個原子組成的雜芳基)-C1-4亞烷基,其中,所述C1-6烷基,C3-8環烷基,C3-7雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基和(5-10個原子組成的雜芳基)-C1-4亞烷基可以任選地被1,2,3,4或5個獨立選自D,F,Cl,Br,CN,C2-6烯基,C2-6炔基,ORa,NRaRb,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代;各Ra,Rb和Rc獨立地為H,C1-6烷基,C3-6環烷基,C3-6雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-6環烷基-C1-4亞烷基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基或(5-10個原子組成的雜芳基)-C1-4亞烷基,其中,所述C1-6烷基,C3-6環烷基,C3-6雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-6環烷基-C1-4亞烷基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基和(5-10個原子組成的雜芳基)-C1-4亞烷基可以任選 地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代;和Rd為C3-8環烷基,其中,所述C3-8環烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,OH,NH2,C1-6烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代。 In still other embodiments, the compounds of the invention have the structure of formula (II): Wherein, the definitions of Q, X, Y and Z in formula (II) are as follows: In some embodiments, in formula (II): Q is -N(R c )C(=O)NR a R b ,- N(R c )C(=O)R d , -N(R c )S(=O)NR a R b , -N(R c )S(=O)R a , -N(R c )S (=O) 2 NR a R b , -N(R c )S(=O) 2 R a or -C(=O)NR a R b ; each X, Y and Z are independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-7 heterocyclic, C 6-10 aryl, heteroaryl of 5-10 atoms, C 3-8 cycloalkyl-C 1 -4 alkylene, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene or (heteroaryl group of 5-10 atoms)- a C 1-4 alkylene group wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-7 heterocyclic group, C 6-10 aryl group, and 5-10 atomic hetero Aryl, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene and (5-10 atomic heteroaryl)-C 1-4 alkylene group may be optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, CN, C 2 -6 alkenyl, C 2-6 alkynyl, oR a, NR a R b , R a OC 1-4 alkylene group or a R a R b NC 1-4 alkylene substituents; each R a is , R b and R c are independently Is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, 5-10 atoms heteroaryl, C 3-6 cycloalkyl Benzyl-C 1-4 alkylene, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene or (5-10 atomic hetero Aryl)-C 1-4 alkylene, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, 5-10 Atomic composition of heteroaryl, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 The alkylene group and (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group may be optionally 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N 3 Substituted with a substituent of OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino; and R d is C 3-8 cycloalkyl, wherein said The C 3-8 cycloalkyl group may be optionally 1, 2, 3 or 4 independently selected from D, F, Cl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy or C Substituted by a substituent of the 1-6 alkylamino group.

在另外一些實施方案,式(II)中Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd或-C(=O)NRaRbIn still other embodiments, Q in the formula (II) is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d or -C(=O)NR a R b .

在另外一些實施方案,式(II)中各X,Y和Z獨立地為H,D,C1-4烷基或苯基,其中,所述C1-4烷基和苯基可以任選地被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代。 In still other embodiments, each of X, Y and Z in formula (II) is independently H, D, C 1-4 alkyl or phenyl, wherein said C 1-4 alkyl and phenyl are optional The ground is replaced by 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl.

在另外一些實施方案,式(II)中各Ra,Rb和Rc獨立地為H,C1-4烷基,C3-6環烷基,C3-6雜環基,C3-6環烷基-C1-2亞烷基或C3-6雜環基-C1-2亞烷基,其中,所述C1-4烷基,C3-6環烷基,C3-6雜環基,C3-6環烷基-C1-2亞烷基和C3-6雜環基-C1-2亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代。 In still other embodiments, each R a , R b and R c in formula (II) is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 3 -6 cycloalkyl-C 1-2 alkylene or C 3-6 heterocyclyl-C 1-2 alkylene, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclyl, C 3-6 cycloalkyl-C 1-2 alkylene and C 3-6 heterocyclyl-C 1-2 alkylene may be optionally 1, 2, 3 or 4 Substituents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino are substituted.

在另外一些實施方案,式(II)中各X,Y和Z獨立地為H,D,Me,CH2D,CHD2,CD3,乙基,丙基,異丙基,苯基或被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代的苯基基團。 In still other embodiments, each of X, Y and Z in formula (II) is independently H, D, Me, CH 2 D, CHD 2 , CD 3 , ethyl, propyl, isopropyl, phenyl or 1, 2, 3, 4 or 5 phenyl groups independently substituted with substituents selected from D, F or Cl.

在另外一些實施方案,式(II)中Q為: In still other embodiments, Q in formula (II) is:

在另外一些實施方案,本發明涉及到以下其中之一的化合物或其立體異構體,幾何異構體,互變異構體,氮氧化物,水合物,溶劑化物,代謝產物,藥學上可接受的鹽或它的前藥,但絕不限於這些化合物: In still other embodiments, the invention relates to a compound of any of the following, or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite thereof, pharmaceutically acceptable Salt or its prodrug, but by no means limited to these compounds:

本發明還包含本發明的化合物及其藥學上可接受的鹽的應用,即用於生產醫藥產品治療急慢性高增殖性疾病和/或血管發生介導的疾病,包括那些本發明所描述的。本發明的化合物在生產抗癌藥物中的應用。本發明的化合物同樣用於生產一種醫藥用品通過抑制蛋白激酶活性來減輕,阻止,控制或治療疾病。本發明包含藥物組合物,該藥物組合物包括式(I)或式(II)所代表的化合物與至少一個藥學上可接受的載體,輔劑或稀釋劑的結合所需的有效治療用量。 The invention further encompasses the use of a compound of the invention, and a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical product for the treatment of acute and chronic hyperproliferative diseases and/or angiogenesis-mediated diseases, including those described herein. Use of the compounds of the invention in the manufacture of anticancer drugs. The compounds of the invention are also useful in the manufacture of a medical article to alleviate, arrest, control or treat a disease by inhibiting protein kinase activity. The invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

本發明同樣包含治療患者血管發生介導的疾病,或對此病症敏感的方法,該方法包含使用式(I)或式(II)所代表化合物的治療有效量對患者進行治療。 The invention also encompasses a method of treating, or responsive to, a disease mediated by an angiogenesis in a patient, the method comprising treating a patient with a therapeutically effective amount of a compound represented by Formula (I) or Formula (II).

除非其他方面表明,本發明的化合物所有的立體異構體,幾何異構體,互變異構體,氮氧化物,水合物,溶劑化物,代謝產物,鹽和藥學 上可接受的前藥都屬於本發明的範圍。 All stereoisomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable compounds of the present invention, unless otherwise indicated Acceptable prodrugs are within the scope of the invention.

具體地說,鹽是藥學上可接受的鹽。術語“藥學上可接受的”包括物質或組合物必須是適合化學或毒理學地,與組成製劑的其他組分和用於治療的哺乳動物有關。 In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically relevant to the other components of the formulation and to the mammal being treated.

本發明的化合物的鹽還包括用於製備或純化式(I)或式(II)所示化合物的中間體或式(I)或式(II)所示化合物分離的對映異構體的鹽,但不一定是藥學上可接受的鹽。 Salts of the compounds of the invention also include intermediates useful in the preparation or purification of compounds of formula (I) or formula (II) or salts of enantiomers isolated from compounds of formula (I) or formula (II) , but not necessarily a pharmaceutically acceptable salt.

如果本發明的化合物是鹼性的,則想得到的鹽可以通過文獻上提供的任何合適的方法製備得到,例如,使用無機酸,如鹽酸,氫溴酸,硫酸,硝酸和磷酸等等。或者使用有機酸,如乙酸,馬來酸,琥珀酸,扁桃酸,富馬酸,丙二酸,丙酮酸,草酸,羥乙酸和水楊酸;吡喃糖酸,如葡萄糖醛酸和半乳糖醛酸;α-羥酸,如檸檬酸和酒石酸;氨基酸,如天門冬氨酸和谷氨酸;芳香族酸,如苯甲酸和肉桂酸;磺酸,如對甲苯磺酸,乙磺酸,等等。 If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranoic acid such as glucuronic acid and galactose Aldehydic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.

如果本發明的化合物是酸性的,則想得到的鹽可以通過合適的方法製備得到,如,使用無機堿或有機堿,如氨(伯氨,仲氨,叔氨),鹼金屬氫氧化物或鹼土金屬氫氧化物,等等。合適的鹽包括,但並不限於,從氨基酸得到的有機鹽,如甘氨酸和精氨酸,氨,如伯氨、仲氨和叔氨,和環狀氨,如呱啶,嗎啉和呱嗪等,和從鈉,鈣,鉀,鎂,錳,鐵,銅,鋅,鋁和鋰得到無機鹽。 If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic hydrazine or an organic hydrazine such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), an alkali metal hydroxide or an alkaline earth. Metal hydroxide, and so on. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as acridine, morpholine and pyridazine Etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

本發明的化合物的組合物,製劑和給藥Compositions, formulations and administration of the compounds of the invention

根據另一方面,本發明的藥物組合物的特點包括式(I)或式(II)的化合物,本發明所列出的具體化合物,或實施例1-30的化合物,和藥學上可接受的載體,輔劑,或媒介物。本發明的組合物中化合物的量能有效地可探測地抑制生物標本或患者體內的蛋白激酶。 According to another aspect, the pharmaceutical composition of the present invention comprises a compound of formula (I) or formula (II), a specific compound listed herein, or a compound of Examples 1-30, and a pharmaceutically acceptable Carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is effective to detectably inhibit protein kinases in biological specimens or patients.

本發明的化合物存在自由形態,或合適的、作為藥學上可接受的衍生物。根據本發明,藥學上可接受的衍生物包括,但並不限於,藥學上 可接受的前藥,鹽,酯,酯類的鹽,或能直接或間接地根據患者的需要給藥的其他任何加合物或衍生物,本發明其他方面所描述的化合物,其代謝產物或他的殘留物。 The compounds of the invention exist in free form or, as appropriate, as pharmaceutically acceptable derivatives. According to the invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically Acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered, directly or indirectly, according to the needs of the patient, a compound described in other aspects of the invention, a metabolite thereof or His residue.

像本發明所描述的,本發明藥學上可接受的組合物進一步包含藥學上可接受的載體,輔劑,或賦形劑,這些像本發明所應用的,包括任何溶劑,稀釋劑,或其他液體賦形劑,分散劑或懸浮劑,表面活性劑,等滲劑,增稠劑,乳化劑,防腐劑,固體黏合劑或潤滑劑,等等,適合於特有的目標劑型。如以下文獻所描述的: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,綜合此處文獻的內容,表明不同的載體可應用於藥學上可接受的組合物的製劑和它們公知的製備方法。除了任何常規的載體媒介與本發明的化合物不相容的範圍,例如所產生的任何不良的生物效應或與藥學上可接受的組合物的任何其他組分以有害的方式產生的相互作用,它們的用途也是本發明所考慮的範圍。 As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988- 1999, Marcel Dekker, New York, incorporating the contents of the literature, indicates that different carriers are useful in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to any conventional carrier medium that is incompatible with the compounds of the invention, such as any undesirable biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a detrimental manner, The use is also within the scope of the invention.

可作為藥學上可接受載體的物質包括,但並不限於,離子交換劑,鋁,硬脂酸鋁,卵磷脂,血清蛋白,如人血清蛋白,緩衝物質如磷酸鹽,甘氨酸,山梨酸,山梨酸鉀,飽和植物脂肪酸的部分甘油酯混合物,水,鹽或電解質,如硫酸魚精蛋白,磷酸氫二鈉,磷酸氫鉀,氯化鈉,鋅鹽,膠體矽,三矽酸鎂,聚乙烯吡咯烷酮,聚丙烯酸脂,蠟,聚乙烯-聚氧丙烯-阻斷聚合體,羊毛脂,糖,如乳糖,葡萄糖和蔗糖;澱粉如玉米澱粉和土豆澱粉;纖維素和它的衍生物如羧甲基纖維素鈉,乙基纖維素和乙酸纖維素;樹膠粉;麥芽;明膠;滑石粉;輔料如可哥豆脂和栓劑蠟狀物;油如花生油,棉子油,紅花油,麻油,橄欖油,玉米油和豆油;二醇類化合物,如丙二醇和聚乙二醇;酯類如乙基油酸酯和乙基月桂酸酯;瓊脂;緩衝劑如氫氧化鎂和氫氧化鋁;海藻酸;無熱原的水;等滲鹽;林格(氏)溶液;乙醇,磷酸緩衝溶液,和其他無毒的合適的潤滑劑如月桂 硫酸鈉和硬脂酸鎂,著色劑,釋放劑,包衣衣料,甜味劑,調味劑和香料,防腐劑和抗氧化劑。 Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbus Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal bismuth, magnesium tristearate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid Pyrogen-free water; isotonic saline; Ringer (s) solution; ethanol, phosphate buffer solution, and other suitable non-toxic lubricants such as lauryl Sodium sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and flavors, preservatives and antioxidants.

本發明的組合物可以是口服給藥,注射給藥,噴霧吸入法,局部給藥,經直腸給藥,經鼻給藥,含服給藥,***給藥或通過植入性藥盒給藥。此處所使用的術語“經注射的”包括皮下的,靜脈的,肌內的,關節內的,滑膜(腔)內的,胸骨內的,膜內的,眼內的,肝內的,病灶內的,和顱內的注射或輸注技術。優選的組合物為口服給藥,向腹膜內給藥或靜脈注射。本發明的組合物無菌的注射方式可以是水的或油脂性的懸浮液。這些懸浮液可以根據公知技術採用合適的分散劑、濕潤劑和懸浮劑按配方製造。無菌注射劑可以是無菌注射液或懸浮液,是注射無毒的可接受的稀釋劑或溶劑,如1,3-丁二醇溶液。這些可接受的賦形劑和溶劑可以是水,林格溶液和等滲氯化鈉溶液。更進一步地,無菌的非揮發性的油按照慣例可以作為溶劑或懸浮介質。 The composition of the present invention may be administered orally, by injection, by inhalation, topically, rectally, nasally, buccally, vaginally or by an implantable kit. . The term "injected" as used herein includes subcutaneous, venous, intramuscular, intra-articular, intrasynovial, intrasternal, intramembranous, intraocular, intrahepatic, focal Internal, and intracranial injection or infusion techniques. A preferred composition is for oral administration, either intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention may be a watery or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing, wetting and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension, or a non-toxic acceptable diluent or solvent, such as a solution of 1,3-butanediol. These acceptable excipients and solvents can be water, Ringer's solution and isotonic sodium chloride solution. Still further, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium.

以此為目的,任何溫和的非揮發性的油可以是合成的單或二葡基甘油二酯。脂肪酸,如油酸和它的甘油酯衍生物可用於血管注射劑的製備,作為天然的藥學上可接受的油脂,如橄欖油或蓖麻油,特別是它們的聚氧乙烯衍生物。這些油溶液或懸浮液可以包含長鏈醇稀釋劑或分散劑,如羧甲基纖維素或相似分散劑,一般用於藥學上可接受劑型的藥物製劑包括乳化液和懸浮液。其他常用的表面活性劑,如吐溫類,司盤類和其他乳化劑或生物藥效率的強化劑,一般用於藥學上可接受的固體,液體,或其他劑型,並可以應用於目標藥物製劑的製備。 For this purpose, any mild non-volatile oil can be a synthetic mono or di-glycosyl diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long-chain alcohol diluent or dispersing agent, such as carboxymethyl cellulose or similar dispersing agents, and pharmaceutical preparations which are generally used in pharmaceutically acceptable dosage forms include emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, are generally used in pharmaceutically acceptable solid, liquid, or other dosage forms and can be applied to targeted pharmaceutical preparations. Preparation.

本發明藥學上可接受的組合物可以是以任何可接受的口服劑型進行口服給藥,其中包括,但並不限於,膠囊,片劑,水製懸浮液或溶液。關於片劑口服使用,載體一般包括乳糖和玉米澱粉。潤滑劑,如硬脂酸鎂,都典型地被添加。對於膠囊口服給藥,合適的稀釋劑包括乳糖和幹的玉米澱粉。當口服給藥為水製懸浮液時,其有效成分由乳化劑和懸浮劑組成。如果想得到這些劑型,某些甜味劑、調味劑或著色劑也可以被添加。 The pharmaceutically acceptable compositions of this invention may be orally administered in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For oral administration to tablets, the carriers generally include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration to capsules, suitable diluents include lactose and dried corn starch. When the oral administration is an aqueous suspension, the active ingredient consists of an emulsifier and a suspending agent. If these dosage forms are desired, certain sweeteners, flavoring or coloring agents can also be added.

另外,本發明藥學上可接受的組合物可以以栓劑的形式直腸給藥。這些可以通過將試劑與合適的非灌注輔藥混合製備而成,這種輔藥在室溫下為固體但在直腸的溫度下則為液體,從而在直腸中熔化並釋放藥物。這樣的物質包括可哥豆脂,蜂蠟,和聚乙二醇類。本發明藥學上可接受的組合物可以是局部給藥,特別是局部用藥時,涉及到區域或器官的治療目標容易達到,如眼、皮膚或下腸道的疾病。合適的局部用藥製劑可以製備得到並應用於這些領域或器官。 Additionally, the pharmaceutically acceptable compositions of this invention may be administered rectally in the form of a suppository. These can be prepared by mixing the agent with a suitable non-perfused adjuvant which is solid at room temperature but liquid at the temperature of the rectum to melt and release the drug in the rectum. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may be administered topically, especially when applied topically, to areas where the therapeutic goals of the area or organ are readily attainable, such as diseases of the eye, skin or lower intestinal tract. Suitable topical formulations can be prepared and applied to these fields or organs.

直腸栓劑(見以上內容)或合適的灌腸劑可以應用於下部腸道的局部用藥。局部皮膚斑也可以這樣用藥。對於局部用藥,藥學上可接受的組合物可以按製劑方法製備成合適的軟膏,該軟膏包含活性成分懸浮於或溶解於一個或多個載體。本發明局部給藥的載體化合物包括,但並不限於礦物油,液體石蠟,白凡士林,丙二醇,聚氧乙烯,聚氧丙烯化合物,乳化蠟和水。另外,藥學上可接受的組合物可以製備成合適的洗劑或乳劑,該洗劑或乳劑包含活性成分懸浮於或溶於一個或多個藥學上可接受的載體。合適的載體包括,但並不限於,礦物油,司盤-60(脫水山梨醇單硬脂酸酯),吐溫60(聚山梨酯60),十六烷基酯蠟,棕櫚醇,2-辛基十二烷醇,苯甲醇和水。 Rectal suppositories (see above) or suitable enema agents can be applied topically to the lower intestinal tract. Local skin spots can also be used as such. For topical administration, the pharmaceutically acceptable compositions can be formulated into suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Additionally, the pharmaceutically acceptable compositions may be prepared as a suitable lotion or emulsion containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, Span-60 (sorbitan monostearate), Tween 60 (polysorbate 60), cetyl ester wax, palmitol, 2- Octyl dodecanol, benzyl alcohol and water.

對於眼用的、藥學上可接受的組合物可以製備成製劑,如等滲的微粒化懸浮液,pH調節的無菌鹽水或其他水溶液,優選地,等滲溶液和pH調節的無菌鹽水或其他水溶液,可以添加消毒防腐劑如苯紮氯銨。另外,對於眼用的,藥學上可接受的組合物可以按製劑配方製備成軟膏如凡士林油。本發明藥學上可接受的組合物可以通過鼻的氣溶劑或吸入劑進行給藥。這樣的組合物可以根據製劑配方的公知技術製備得到,或可以製備成鹽溶液,使用苯甲醇或其他合適的防腐劑、吸收促進劑、碳氟化合物或其他常規增溶劑或分散劑來提高生物利用度。 For ophthalmic, pharmaceutically acceptable compositions can be prepared as preparations, such as isotonic microparticulate suspensions, pH adjusted sterile saline or other aqueous solutions, preferably, isotonic solutions and pH adjusted sterile saline or other aqueous solutions. A disinfectant preservative such as benzalkonium chloride can be added. Alternatively, for ophthalmology, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum oil in a formulation. The pharmaceutically acceptable compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to well-known techniques of formulation formulations, or may be prepared as a salt solution, using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons or other conventional solubilizing or dispersing agents to enhance bioavailability. degree.

口服給藥的液體劑型包括,但並不限於,藥學上可接受的乳劑,微乳劑,溶液,懸浮液,糖漿劑和酏劑。除活性化合物外,液體劑型可以包含公知的一般的惰性稀釋劑,例如,水或其他溶劑,增溶劑和乳化劑, 如乙醇,異丙醇,碳酸乙酯,乙酸乙酯,苯甲醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,二甲基甲醯胺,油脂(特別是棉籽,落花生,玉米,微生物,橄欖,蓖麻和麻油),甘油,2-四氫呋喃甲醇,聚乙二醇,去水山梨糖醇脂肪酸酯,以及它們的混合物。除惰性的稀釋劑之外,口服組合物也可以包含輔劑如濕潤劑,乳化劑或懸浮劑,甜味劑,調味劑和芳香劑。 Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain a conventional inert diluent such as water or other solvents, solubilizers and emulsifiers. Such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, groundnut, corn, Microorganisms, olives, ramie and sesame oil), glycerin, 2-tetrahydrofuran methanol, polyethylene glycol, sorbitan fatty acid esters, and mixtures thereof. Besides the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening, flavoring and perfuming agents.

注射劑,如無菌注射液或油脂性的懸浮液可以根據公知技術採用合適的分散劑、濕潤劑和懸浮劑按製劑配方製備得到。無菌注射劑可以是無毒的經注射地可接受的稀釋劑或溶劑製成的無菌注射液、懸浮液或乳液,例如,1,3-丁二醇溶液。可接受的賦形劑和溶劑可以是水,林格(氏)溶液,U.S.P.和等滲氯化鈉溶液。另外,無菌的非揮發性的油按照慣例作為溶劑或懸浮介質。以此為目的任何溫和的非揮發性的油可以包括合成的單或二葡基甘油二酯。另外,脂肪酸如油酸可以應用於注射劑。 An injection, such as a sterile injectable solution or a oleaginous suspension, can be prepared according to the known formulation using suitable dispersing agents, wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in the form of a non-toxic injectable acceptable diluent or solvent, for example, a 1,3-butanediol solution. Acceptable excipients and solvents can be water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspension medium. Any mild non-volatile oil for this purpose may include synthetic mono- or di-glycosyl diglycerides. In addition, fatty acids such as oleic acid find use in injections.

注射劑可以是無菌的,如通過細菌防衛篩檢程式過濾,或以無菌固體組合物的形式摻入滅菌劑,在使用前滅菌劑可以溶解於或分散於消毒水或其他無菌注射介質中。為了延長本發明的化合物的效果,通常需要通過皮下注射或肌內注射來減緩化合物的吸收。這樣可以實現利用液體懸浮液解決晶體或非晶體物質水溶性差的問題。化合物的吸收率取決於它的溶出度,依次取決於晶粒大小和晶體形狀。另外,可以通過化合物在油類賦形劑中溶解或分散來完成化合物注射給藥的延遲吸收。 The injection may be sterile, such as by filtration through a bacterial defense screening procedure, or by incorporating a sterilizing agent in the form of a sterile solid composition which may be dissolved or dispersed in sterile water or other sterile injectable medium before use. In order to prolong the effects of the compounds of the invention, it is usually necessary to slow the absorption of the compound by subcutaneous or intramuscular injection. This makes it possible to solve the problem of poor water solubility of crystalline or amorphous materials by using a liquid suspension. The rate of absorption of a compound depends on its dissolution, which in turn depends on the grain size and crystal shape. In addition, delayed absorption of the compound injection administration can be accomplished by dissolving or dispersing the compound in an oil vehicle.

注射劑儲藏形式是通過可生物降解的聚合物,如多乳酸-聚乙醇酸交酯形成化合物的微膠囊基質完成的。化合物的控釋比例取決於化合物形成聚合物的比例和特殊聚合物的性質。其他可生物降解聚合物包括聚(正酯類)和聚(酸酐)。注射劑儲藏形式也可以通過化合物嵌入與身體組織相容的脂質體或微乳劑製備得到。 The injectable form of the preparation is accomplished by a biodegradable polymer, such as a microcapsule matrix of a polylactic acid-polyglycolide forming compound. The controlled release ratio of the compound depends on the ratio of the compound forming the polymer and the nature of the particular polymer. Other biodegradable polymers include poly(orthoesters) and poly(anhydrides). The injectable preparation form can also be prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

其中一些實施例是,直腸或***給藥的組合物為栓劑,栓劑可以通過將本發明的化合物與合適的非灌注的輔料或載體混合來製備得到,如可哥豆脂,聚乙二醇,或栓劑蠟狀物,它們在室溫為固體但在體溫下則為液體,因此在***或***內便熔化釋放活性化合物。 In some embodiments, the composition for rectal or vaginal administration is a suppository, and the suppository can be prepared by mixing a compound of the present invention with a suitable non-perfused adjuvant or carrier, such as cocoa butter, polyethylene glycol, Or suppository waxes which are solid at room temperature but liquid at body temperature and therefore melt in the vaginal or sheath lumen to release the active compound.

口服給藥的固體劑型包括膠囊,片劑,丸劑,粉劑和粒劑。在這些劑型中,活性化合物與至少一種藥學上可接受的惰性賦形劑或載體混合,如檸檬酸鈉或磷酸鈣或充填劑或a)填充劑如澱粉,乳糖,蔗糖,葡萄糖,甘露醇和矽酸,b)黏合劑如羧甲基纖維素,藻酸鹽,明膠,聚乙烯吡咯酮,蔗糖和***膠,c)保濕劑如甘油,d)崩解劑如瓊脂,碳酸鈣,土豆澱粉或木薯澱粉,海藻酸,某些矽酸鹽和碳酸鈉,e)阻滯劑溶液如石蠟,f)吸收促進劑如季胺類化合物,g)濕潤劑如十六醇和單硬脂酸甘油酯,h)吸收劑如白陶土和皂土,i)潤滑劑如滑石粉,硬脂酸鈣,硬脂酸鎂,固體聚乙二醇,月桂硫酸鈉,及它們的混合物。至於膠囊,片劑和丸劑,這些劑型可以包含緩衝劑。 Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or a filler or a) fillers such as starch, lactose, sucrose, glucose, mannitol and hydrazine Acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato starch or Tapioca starch, alginic acid, certain citrates and sodium carbonate, e) retarder solutions such as paraffin, f) absorption enhancers such as quaternary amines, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. As for capsules, tablets and pills, these dosage forms may contain a buffer.

相似類型的固體組合物可以是填充劑充滿於軟的或硬的膠囊,所使用的輔料有乳糖和高分子的聚乙二醇等等。固體劑型像片劑,錠劑,膠囊,丸劑和粒劑可以通過包衣、加殼如腸溶包衣和其他藥物製劑上公知的包衣方法製備得到。它們可以任選地包含遮光劑,或優選地,在腸道的某一部分,任意地,以延遲的方法釋放組合物中的唯一活性成分。如植入組合物可以包含多聚體物質和蠟狀物。 A solid composition of a similar type may be a filler filled with a soft or hard capsule, and the excipients used are lactose and high molecular weight polyethylene glycol and the like. The solid dosage forms like tablets, troches, capsules, pills and granules can be prepared by coating, encapsulation, such as enteric coating, and other pharmaceutical preparations. They may optionally contain opacifying agents or, preferably, the only active ingredient in the composition, in a certain portion of the intestinal tract, optionally, in a delayed manner. For example, the implant composition can comprise a multimeric substance and a wax.

活性化合物可以與本發明所描述的一個或多個賦形劑一起形成微膠囊劑型。固體劑型像片劑、錠劑、膠囊、丸劑和粒劑可以通過包衣或加殼,如腸溶包衣、控釋包衣和其他公知的藥物製劑方法。在這些固體劑型中,活性化合物可以與至少一種惰性稀釋劑混合,如蔗糖,乳糖或澱粉。這樣的劑型作為一般的應用也可以包含除惰性稀釋劑之外的添加物質,如壓片潤滑劑和其他壓片助劑如硬脂酸鎂和微晶纖維素。至於膠囊,片劑和丸劑,這些劑型可以包含緩衝劑。它們可以任選地包含鎮靜劑,或優選地,在腸道的某一部分,以任意延遲的方法釋放組合物中的唯一活性成分。可應用的植入組合物可以包括,但並不限於,多聚體和蠟狀物。 The active compound can be combined with one or more excipients described herein to form a microcapsule dosage form. Solid dosage forms like tablets, troches, capsules, pills, and granules can be coated or otherwise, such as enteric coatings, controlled release coatings, and other known pharmaceutical formulations. In these solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as a general application, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. As for capsules, tablets and pills, these dosage forms may contain a buffer. They may optionally contain a sedative, or preferably, in a certain portion of the intestinal tract, release the only active ingredient in the composition in any delayed manner. Applicable implant compositions can include, but are not limited to, multimers and waxes.

本發明的化合物通過局部的或經皮膚給藥的劑型包括軟膏,糊劑,乳劑,洗劑,凝膠劑,粉劑,溶液,噴霧劑,吸入劑,貼片。活性成分 在無菌的條件下與藥學上可接受的載體和任何必需的防腐劑或必需的緩衝劑相混合。眼科的藥物製劑,滴耳劑和滴眼劑都是本發明考慮的範圍。另外,本發明還考慮透皮貼劑的應用,它在控制化合物傳遞到體內方面有著更多的優點,這樣的劑型可以通過溶解或分散化合物到合適的介質中來製備得到。吸收促進劑可以增加化合物穿過皮膚的流量,通過速率控制薄膜或將化合物分散於聚合體基質或明膠來控制其速率。 The formulations of the present invention for topical or transdermal administration include ointments, pastes, emulsions, lotions, gels, powders, solutions, sprays, inhalants, patches. Active ingredient Mix under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or requisite buffers. Ophthalmic pharmaceutical preparations, ear drops and eye drops are all contemplated by the present invention. In addition, the present invention contemplates the use of transdermal patches which have additional advantages in controlling the delivery of the compound to the body, such dosage forms being prepared by dissolving or dispersing the compound into a suitable medium. Absorption enhancers can increase the flux of the compound across the skin, controlling its rate by rate controlling the film or dispersing the compound in a polymeric matrix or gelatin.

本發明的化合物優選地按製劑配方製備成劑量單位型以減輕給藥量和劑量的均勻性。術語“劑量單位型”在此處是指患者得到適當治療所需藥物的物理分散單位。然而,應瞭解本發明的化合物或組合物每日總的用法將通過主治醫生根據可靠的醫學範圍判斷來確定。具體的有效劑量水準對於任何一個特殊的患者或有機體將取決於許多因素包括被治療的病症和病症的嚴重性,具體化合物的活性,所用的具體組合物,患者的年齡、體重、健康狀況、性別和飲食習慣,給藥時間,給藥途徑和所用具體化合物的***速率,治療的持續時間,藥物應用於聯合用藥或與有特效的化合物聯用,以及其他一些藥學領域公知的因素。 The compounds of the present invention are preferably prepared in dosage unit form in a formulation to reduce the uniformity of administration and dosage. The term "dosage unit type" as used herein refers to the physically discrete unit of the drug required for the patient to receive appropriate treatment. However, it is to be understood that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on a reliable medical field judgment. The specific effective dosage level will depend on a number of factors for any particular patient or organism, including the severity of the condition and condition being treated, the activity of the particular compound, the particular composition employed, the patient's age, weight, health, sex And dietary habits, time of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, administration of the drug in combination or in combination with a compound having a specific effect, and other factors well known in the pharmaceutical arts.

可以結合載體物質產生單個劑型組合物的本發明的化合物的用量的改變取決於主治和特殊的給藥模式。其中一些實施例是,組合物可以按製劑方法製備成劑量在0.01-200mg/kg體重/天的抑制劑,通過患者接受組合物的量來進行給藥。 The amount of the compound of the invention which can be combined with the carrier material to produce a single dosage form composition will vary depending upon the attending and the particular mode of administration. In some of these embodiments, the composition can be prepared as an inhibitor at a dose of from 0.01 to 200 mg/kg body weight per day by formulation and administered by the patient receiving the amount of the composition.

本發明的化合物可以以僅有的藥學試劑或結合一個或多個其他附加治療(藥學的)劑來給藥,其中聯合用藥引起可接受的不良反應,這對於高增生性疾病如癌症的治療具有特殊的意義。在這種情況下,本發明的化合物可以結合已知的細胞毒素劑,單個轉導抑制劑或其他抗癌試劑,以及它們的混合物和組合。像本發明所使用的,附加治療劑正常給藥治療特殊的疾病,就是已知的“合適地治療疾病”。本發明所使用的“附加治療劑”包括化學治療藥物或其他抗增殖的藥物可以結合本發明的化合物治療增殖性疾病或癌症。 The compounds of the present invention may be administered as the sole pharmaceutical agent or in combination with one or more additional therapeutic (pharmaceutical) agents, wherein the combination induces an acceptable adverse reaction, which has a therapeutic effect on a hyperproliferative disease such as cancer. Special meaning. In this case, the compounds of the invention may be combined with known cytotoxic agents, single transduction inhibitors or other anti-cancer agents, as well as mixtures and combinations thereof. As used herein, the additional therapeutic agent is normally administered to treat a particular condition, known as "appropriate treatment of the disease." As used herein, "additional therapeutic agents", including chemotherapeutic drugs or other anti-proliferative drugs, can be combined with the compounds of the invention to treat proliferative diseases or cancer.

化學治療藥物或其他抗增殖藥物包括組蛋白去乙醯化酶(HDAC)抑 制劑,包括但並不限於,SAHA,MS-275,MGO103,以及那些以下專利所描述的化合物: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,和脫甲基化試劑包括,但並不限於,5-雜氮-2′-去氧胞苷(5-aza-dC)、阿紮胞苷(Vidaza)、地西他濱(Decitabine)和以下文獻所描述的化合物: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。 Chemotherapeutic drugs or other antiproliferative drugs including histone deacetylase (HDAC) Formulations, including, but not limited to, SAHA, MS-275, MGO 103, and those described in the 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, WO 2005/030705, WO 2005/092899, and demethylating agents including, but not limited to, 5-hetero Nitrogen-2'-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine (Decitabine) and the compounds described in the following documents: US 6,268,137, US 5,578,716, US 5, 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.

另外一些實施例是,化學治療藥物或其他抗增殖藥物可以結合本發明的化合物治療增殖性疾病和癌症。已知的化學治療藥物包括,但並不限於,其他療法或抗癌劑可以聯合本發明的抗癌劑與包括外科,放射療法(少許例子如γ輻射,中子束放射療法,電子束放射療法,質子療法,近距離放射療法和系統放射性同位素療法),內分泌療法,紫杉烷類(紫杉醇,多西紫杉醇等等),鉑的衍生物,生物反應調節劑(干擾素,白細胞間素,腫瘤壞死因數(TNF),TRAIL受體靶向作用和媒介物),過熱和冷凍療法,稀釋任何不良反應的試劑(如止吐藥),和其他認可的化學治療藥物,包括但並不限於,烷化藥物(氮芥,苯丁酸氮芥,環磷醯胺,苯丙氨酸氮芥,異環磷醯胺),抗代謝物(甲氨蝶呤,培美曲塞(Pemetrexed)等等),嘌呤拮抗劑和嘧啶拮抗劑(6-巰嘌呤(6-Mercaptopurine),5-氟尿嘧啶,Cytarabile,吉西他濱(Gemcitabine)),紡錘體抑制劑(長春堿,長春新堿,長春瑞濱,紫杉醇),鬼臼毒素(依託泊苷,伊立替康(Irinotecan),托泊替康(Topotecan)),抗生素(多柔比星(Doxorubicin),博萊黴素(Bleomycin),絲裂黴素(Mitomycin)),亞硝基脲(卡莫司汀(Carmustine),洛莫司汀(Lomustine)),無機離子(順鉑,卡鉑),細胞***週期抑制劑(KSP通過有絲***驅動蛋白抑制劑,CENP-E和CDK抑制劑),酵素(天門冬醯胺酶),荷爾蒙(它莫昔芬(Tamoxifen),亮丙瑞林(Leuprolide),氟他胺(Flutamide), 甲地孕酮(Megestrol)),格列衛(GLEEVEC®),阿黴素(Adriamycin),***(Dexamethasone),和環磷醯胺。抗血管生成因數(阿瓦斯丁(Avastin)及其他)。單抗類(貝利木單抗(Belimumab,BENLYSTA®),Brentuximab(ADCETRIS®),西妥昔單抗(Cetuximab,ERBITUX®),吉妥單抗(Gemtuzumab,MYLOTARG®),伊匹單抗(Ipilimumab,YERVOY®),奧法木單抗(Ofatumumab,ARZERR®),帕尼單抗(Panitumumab,VECTIBIX®),雷珠單抗(Ranibizumab,LUCENTIS®),利妥昔單抗(Rituximab,RITUXAN®),托西莫單抗(Tositumomab,BEXXAR®),曲妥珠單抗(Trastuzumab,HERCEPTIN®))。激酶抑制劑(伊馬替尼(Imatinib,GLEEVEC®),舒尼替尼(Sunitinib,SUTENT®),索拉非尼(Sorafenib,NEXAVAR®),西妥昔單抗(Cetuximab,ERBITUX®),曲妥珠單抗(Trastuzumab,HERCEPTIN®),厄洛替尼(Erlotinib,TARCEVA®)),達沙替尼(Dasatinib,SPRYCEL®),tivozanib,dovitinib,axitinib,motesanib,帕唑帕尼(pazopanib),吉非替尼(gefitinib,IRESSA®),cediranib,brivanib,替拉替尼(telatinib),masitinib,來那替尼(neratinib),lenvatinib,ruxolitinib,linifanib,linsitinib,crizotinib,regorafehib,ponatinib,博舒替尼(bosutinib),塞卡替尼(saracatinib),afatinib,amuvatinib,ponatinib,quizartinib,威羅菲尼(vemurafenib,ZELBORAF®),凡德他尼(Vandetanib,CAPRELSA®),olaparib,veliparib,iniparib,易瑞沙(Iressa)及其他)。藥物抑制或啟動癌症的途徑如mTOR,HIF(缺氧誘導因數)途徑及其他。癌症治療較廣泛的論壇見http://www.nci.nih.gov/,FDA認可的腫瘤學藥物清單見http://www.fda.gov/cder/cancer/druglist-rame.htm,和默克手冊,第十八版.2006,所有的內容都是結合了參考文獻。 In other embodiments, a chemotherapeutic drug or other anti-proliferative drug can be combined with a compound of the invention to treat proliferative diseases and cancer. Known chemotherapeutic drugs include, but are not limited to, other therapies or anticancer agents may be combined with the anticancer agents of the present invention and include surgical, radiation therapy (a few examples such as gamma radiation, neutron beam radiation therapy, electron beam radiation therapy) , proton therapy, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (paclitaxel, docetaxel, etc.), platinum derivatives, biological response modifiers (interferon, interleukin, tumor) Necrosis factor (TNF), TRAIL receptor targeting and vehicle), hyperthermia and cryotherapy, agents that dilute any adverse reactions (eg antiemetics), and other approved chemotherapeutics, including but not limited to, alkanes Chemical drugs (nitrogen mustard, chlorambucil, cyclophosphamide, phenylalanine mustard, ifosfamide), antimetabolites (methotrexate, Pemetrexed, etc.) , 嘌呤 antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-fluorouracil, Cytarabile, Gemcitabine), spindle inhibitors (Changchun, Changchun Xinyi, vinorelbine, paclitaxel), Podophyllotoxin Toposide, Irinotecan, Topotecan, Antibiotics (Doxorubicin, Bleomycin, Mitomycin), Nitroso Urea (Carmustine, Lomustine), inorganic ions (cisplatin, carboplatin), cell division cycle inhibitors (KSP through mitotic kinesin inhibitors, CENP-E and CDK inhibitors) ), enzyme (asparaginase), hormone (Tamoxifen, Leuprolide, Flutamide, Megestrol), Gleevec (GLEEVEC) ® ), Adriamycin, Dexamethasone, and Cyclophosphamide. Anti-angiogenic factors (Avastin and others). Monoclonal antibodies (Belimumab, BENLYSTA ® , Brentuximab (ADCETRIS ® ), Cetuximab (ERBITUX ® ), Gemtuzumab (MYLOTARG ® ), Ipilimumab ( ipilimumab, YERVOY ®), ofatumumab (ofatumumab, ARZERR ®), panitumumab (panitumumab, VECTIBIX ®), ranibizumab (ranibizumab, LUCENTIS ®), rituximab (rituximab, RITUXAN ® ), Tositumomab (BEXXAR ® ), Trastuzumab (HERCEPTIN ® ). Kinase inhibitors (imatinib (Imatinib, GLEEVEC ®), sunitinib (Sunitinib, SUTENT ®), sorafenib (Sorafenib, NEXAVAR ®), cetuximab (Cetuximab, ERBITUX ®), Trastuzumab Chemizumab (HERCEPTIN ® ), Erlotinib (TARCEVA ® ), Dasatinib (SPRYCEL ® ), tivozanib, dovitinib, axitinib, motesanib, pazopanib, Kyrgyzstan gefitinib (gefitinib, iRESSA ®), cediranib , brivanib, tipranavir erlotinib (telatinib), masitinib, neratinib (neratinib), lenvatinib, ruxolitinib, linifanib, linsitinib, crizotinib, regorafehib, ponatinib, bosutinib (bosutinib), sacatinib, afatinib, amuvatinib, ponatinib, quizartinib, vemurafenib (ZELBORAF ® ), vandetanib (CAPRELSA ® ), olaparib, veliparib, iniparib, irri Sand (Iressa) and others). Drugs inhibit or initiate cancer pathways such as mTOR, HIF (hypoxia-inducible factor) pathways and others. A broader forum for cancer treatment can be found at http://www.nci.nih.gov/, and a list of FDA-approved oncology drugs can be found at http://www.fda.gov/cder/cancer/druglist-rame.htm, and The gram manual, eighteenth edition. 2006, all of which incorporates references.

另外一些實施例是,本發明的化合物可以結合細胞毒素抗癌劑。這樣的抗癌劑可以在第十三版默克索引(2001)裡找到。這些抗癌劑包括,但絕不限於,門冬醯胺酶(Asparaginase),博來黴素(Bleomycin),卡鉑,卡莫司汀(Carmustine),苯丁酸氮芥(Chlorambucil),順鉑,L- 天冬醯胺酶(Colaspase),環磷醯胺,阿糖胞苷(Cytarabine),達卡巴嗪(Dacarbazine),放線菌素D(Dactinomycin),柔紅黴素(Daunorubicin),阿黴素(多柔比星),表柔比星(Epirubicin),依託泊苷(Etoposide),5-氟脲嘧啶,六甲基三聚氰胺,羥基脲,異環磷醯胺,伊立替康,亞葉酸,環己亞硝脲,氮芥,6-巰基嘌呤,美司鈉(Mesna),甲氨蝶呤(Methotrexate),絲裂黴素C(Mitomycin C),米托蒽醌(Mitoxantrone),潑尼松龍(Prednisolone),潑尼松(Prednisone),丙卡巴肼(Procarbazine),雷洛昔芬(Raloxifen),鏈唑黴素(Streptozocin),他莫昔芬(Tamoxifen),硫鳥嘌呤(Thioguanine),托泊替康,長春堿,長春新堿,長春地辛。 In other embodiments, the compounds of the invention may bind to a cytotoxic anticancer agent. Such anticancer agents can be found in the thirteenth edition of the Merck Index (2001). These anticancer agents include, but are in no way limited to, Asparaginase, Bleomycin, Carboplatin, Carmustine, Chlorambucil, Cisplatin , L- Colasase, cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Doxorubicin (multiple) (Ribibis), Epirubicin, Etoposide, 5-fluorouracil, hexamethyl melamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, cyclohexa Nitrourea, nitrogen mustard, 6-mercaptopurine, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Prednisolone ), Prednisone, Procarbazine, Raloxifen, Streptozocin, Tamoxifen, Thioguanine, Topotecan Kang, Changchun, Changchun Xinyi, Changchun Dixin.

與本發明的化合物聯合用藥的其他合適的細胞毒類藥物包括,但並不限於,這些公認地應用於腫瘤性疾病治療的化合物,如以下文獻中所描述的:Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.);這些抗癌劑包括,但絕不限於,氨魯米特(Aminoglutethimide),L-門冬醯胺酶,硫唑嘌呤,5-氮雜胞苷,克拉屈濱(Cladribine),白消安(Busulfan),己烯雌酚,2',2'-二氟去氧胞二磷膽鹼,多西紫杉醇,赤羥基壬烷基腺嘌呤(Erythrohydroxynonyladenine),乙炔***,5-氟尿嘧啶去氧核苷,5-氟去氧尿苷單磷酸,磷酸氟達拉濱(Fludarabine phosphate),氟***(Fluoxymesterone),氟他胺(Flutamide),己酸羥孕酮,伊達比星(Idarubicin),干擾素,醋酸甲羥孕酮,醋酸甲地孕酮,美法侖(Melphalan),米托坦(Mitotane),紫杉醇,噴司他丁(Pentostatin),N-磷酸乙醯基-L-天冬氨酸(PALA),普卡黴素(Plicamycin),甲基環己亞硝脲(Semustine),替尼泊苷(Teniposide),丙酸***,塞替派(Thiotepa),三甲基三聚氰胺,尿核苷和長春瑞濱。 Other suitable cytotoxic drugs for administration in combination with the compounds of the present invention include, but are not limited to, those compounds which are recognized for their use in the treatment of neoplastic diseases, as described in the following literature: Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.); these anticancer agents include, but are in no way limited to, Aminoglutethimide, L-aspartate, azathioprine, 5-azacytidine, Cladribine, Busulfan, diethylstilbestrol, 2',2'-difluorodeoxycyanocholine, docetaxel, Erythrohydroxynonyladenine, acetylene Alcohol, 5-fluorouracil deoxynucleoside, 5-fluorodeoxyuridine monophosphate, Fludarabine phosphate, Fluoxymesterone, Flutamide, Hydroxyprogesterone caproate, Idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, Melphalan, Mitotane, paclitaxel, pentastatin, N-phosphate Mercapto-L-aspartic acid (PALA), Puka Plicamycin, semustine, Teniposide, testosterone propionate, Thiotepa, trimethyl melamine, uridine and vinorelbine.

其他合適的與本發明的化合物聯合應用的細胞毒素類抗癌劑包括新發現的細胞毒素物質,其中包括,但並不限於,奧沙利鉑(Oxaliplatin),吉西他濱(Gemcitabine),卡培他濱(Capecitabine),大環內酯類抗腫瘤藥及其天然或合成的衍生物,替莫唑胺(Temozolomide)(Quinn et al., J.Clin.Oncology,2003,21(4),646-651),托西莫單抗(tositumomab,BEXXAR®),Trabedectin(Vidal et al.,Proceedings of the American Society for Clinical Oncology,2004,23,abstract 3181),和驅動蛋白紡錘體蛋白抑制劑Eg5(Wood et al.,Curr.Opin.Pharmacol. 2001,1,370-377)。 Other suitable cytotoxic anticancer agents for use in combination with the compounds of the present invention include newly discovered cytotoxic substances including, but not limited to, Oxaliplatin, Gemcitabine, Capecitabine (Capecitabine), a macrolide antitumor drug and its natural or synthetic derivative, Temozolomide (Quinn et al. , J. Clin . Oncology, 2003 , 21(4), 646-651) Simuzumab (BEXXAR ® ), Trabedectin (Vidal et al. , Proceedings of the American Society for Clinical Oncology , 2004 , 23, abstract 3181), and kinesin spindle protein inhibitor Eg5 (Wood et al. , Curr. Opin. Pharmacol . 2001 , 1, 370-377).

另外一些實施例是,本發明的化合物可以結合其他信號轉導抑制劑。有趣的是信號轉導抑制劑把EGFR家族作為目標,如EGFR,HER-2和HER-4(Raymond et al.,Drugs, 2000,60(Suppl.l),15-23;Harari et al.,Oncogene,2000,19(53),6102-6114)和它們各自的配體。這樣的試劑包括,但絕不限於,抗體療法如赫賽汀(曲妥單抗),西妥昔單抗(Erbitux),和帕妥珠單抗(Pertuzumab)。這樣的療法也包括,但絕不限於,小分子激酶抑制劑如易瑞沙(Gefitinib),它賽瓦(Erlotinib),Tykerb(Lapatinib),CANERTINIB(CI1033),AEE788(Traxler et al.,Cancer Research,2004,64,4931-4941)。 In other embodiments, the compounds of the invention may bind to other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such 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) and their respective ligands. Such agents include, but are not limited to, antibody therapies such as Herceptin (trastuzumab), cetuximab (Erbitux), and pertuzumab (Pertuzumab). Such therapies also include, but are in no way limited to, small molecule kinase inhibitors such as Gefitinib, Erlotinib, Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research). , 2004 , 64, 4931-4941).

另外一些實施例是,本發明的化合物結合其他信號轉導抑制劑靶向作用於***激酶領域家族的受體激酶(VEGFR,FGFR,PDGFR,flt-3,c-kit,c-fins,等等),和它們各自的配體。這樣的試劑包括,但並不限於,抗體如貝伐單抗(Avastin)。這樣的試劑包括,但絕不限於,小分子抑制劑如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,abstract 2575),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,abstract 3989),CHIR-258(Lee et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract 2130),MLN-518(Shen et al.,Blood,2003,102,11,abstract 476)。 In other embodiments, the compounds of the invention bind to other signal transduction inhibitors to target receptor kinases in the cleavage kinase domain family (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc. ), and their respective ligands. Such agents include, but are not limited to, antibodies such as bevacizumab (Avastin). Such agents include, but are in no way limited to, small molecule inhibitors such 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 , abstract 2575), 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, abstract 3989), CHIR-258 (Lee et al. Proceedings of the American Association of Cancer Research , 2004 , 45, abstract 2130), MLN-518 (Shen et al., Blood , 2003 , 102, 11, abstract 476).

另外一些實施例是,本發明的化合物可以結合其他信號轉導抑制劑。有趣的是信號轉導抑制劑把EGFR家族作為目標,如EGFR,HER-2和HER-4(Raymond et al.,Drugs, 2000,60(Suppl.l),15-23;Harari et al.,Oncogene,2000,19(53),6102-6114)和它們各自的配體。這樣的試劑包括,但絕不限於,抗體療法如曲妥珠單抗(Trastuzumab,HERCEPTIN®),西妥昔單抗(Cetuximab,ERBITUX®),伊匹單抗(Ipilimumab,YERVOY®)和帕妥珠單抗(Pertuzumab)。這樣的療法也包括,但絕不限於,小分子激酶抑制劑如伊馬替尼(Imatinib,GLEEVEC®),舒尼替尼(Sunitinib,SUTENT®),索拉非尼(Sorafenib,NEXAVAR®),厄洛替尼(Erlotinib,TARCEVA®),吉非替尼(Gefitinib,IRESSA®),達沙替尼(Dasatinib,SPRYCEL®),尼洛替尼(Nilotinib,TASIGNA®),拉帕替尼(Lapatinib,TYKERB®),克卓替尼(Crizotinib,XALKORI®),Ruxolitinib(JAKAFI®),Vemurafenib(ZELBORAF®),Vandetanib(CAPRELSA®),Pazopanib(VOTRIENT®),阿法替尼(Afatinib),alisertib,amuvatinib,阿西替尼(axitinib),波舒替尼(bosutinib),brivanib,canertinib,cabozantinib,西地尼布(cediranib),dabrafenib,dacomitinib,,danusertib,dovitinib,foretinib,ganetespib,ibrutinib,iniparib,lenvatinib,linifanib,linsitinib,馬賽替尼(masitinib),momelotinib,莫替沙尼(motesanib),來那替尼(neratinib),niraparib,oprozomib,olaparib,pictilisib,ponatinib,quizartinib,regorafenib,rigosertib,rucaparib,塞卡替尼(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,等等。 In other embodiments, the compounds of the invention may bind to other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such 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) and their respective ligands. Such agents include, but are not limited to, antibody therapies such as Herceptin (Trastuzumab, HERCEPTIN ®), cetuximab (Cetuximab, ERBITUX ®), ipilimumab (Ipilimumab, YERVOY ®) and pertuzumab Metuzumab (Pertuzumab). Such therapies include, but not limited to, small-molecule kinase inhibitors such as imatinib (Imatinib, GLEEVEC ®), sunitinib (Sunitinib, SUTENT ®), sorafenib (Sorafenib, NEXAVAR ®), Ecuador Erlotinib (TARCEVA ® ), Gefitinib (IRESSA ® ), Dasatinib (SPRYCEL ® ), Nilotinib (TASIGNA ® ), Lapatinib (Lapatinib, TYKERB ® ),Crizotinib (XALKORI ® ), Ruxolitinib (JAKAFI ® ), Vemurafenib (ZELBORAF ® ), Vandetanib (CAPRELSA ® ), Pazopanib (VOTRIENT ® ), Afatinib (Afatinib), alisertib, amuvatinib, Axitinib (axitinib), bosutinib (brsutinib), brivanib, canertinib, cabozantinib, cedaniib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib ,linsitinib,masitinib,momelotinib,motesanib,neratinib,niraparib,oprozomib,olaparib,pictilisib,ponatinib,quizartinib,regorafenib , rigosertib, rucaparib, sarkatinib, 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, and the like.

另外一些實施例是,本發明的化合物可以結合組蛋白脫乙醯基酶抑制劑。這樣的試劑包括,但絕不限於,辛二醯苯胺氧肟酸(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,abstract 3028)和MGCDOI 03(US 6,897,220)。 In other embodiments, the compounds of the invention may bind to a histone deacetylase inhibitor. Such agents include, but are in no way limited to, octyl benzalkonium 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, abstract 3028) and MGCDOI 03 (US 6,897, 220).

另外一些實施例是,本發明的化合物可以結合其他抗癌劑如蛋白酶體抑制劑和m-TOR抑制劑。這些包括,但絕不限於,硼替佐米(Bortezomib)(Mackay et al.,Proceedings of the American Society for Clinical Oncology,2004,23,Abstract 3109),和CCI-779(Wu et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract 3849)。本發明的化合物還可以結合其他抗癌劑如拓撲異構酶抑制劑,包括但絕不限於喜樹堿。 In other embodiments, the compounds of the invention may be combined with other anticancer agents such as proteasome inhibitors and m-TOR inhibitors. These include, but are in no way limited to, 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). The compounds of the invention may also incorporate other anticancer agents such as topoisomerase inhibitors, including but not limited to camptotheca acuminata.

那些附加治療劑可以與包含本發明的化合物的組合物分開給藥,作為多給藥方案的一部分。或者,那些治療劑可以是單劑型的一部分,與本發明的化合物混合在一起形成單個組合物。如果給藥作為多給藥方案的一部分,兩個活性劑可以同時連續地或在一段時間內互相傳遞,從而得到目標試劑活性。 Those additional therapeutic agents can be administered separately from the compositions comprising the compounds of the invention as part of a multiple dosing regimen. Alternatively, those therapeutic agents can be part of a single dosage form, mixed with the compounds of the invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents can be delivered to each other either continuously or over a period of time to provide the desired agent activity.

可以結合載體物質產生單劑型的化合物和附加治療劑的用量(那些包含一個附加治療劑的組合物像本發明所描述的)的改變取決於主治和特殊給藥模式。正常地,本發明的組合物附加治療劑的量將不超過組合物包含治療劑作為唯一的活性劑的正常給藥的量。另一方面,現公開的組合物附加治療劑的量的範圍大約是現有組合物正常量的50%-100%,包含的試劑作為唯一活性治療劑。在那些包含附加治療劑的組合物中,附加治療劑將與本發明的化合物起協同作用。 The amount of compound that can be combined with the carrier material to produce a single dosage form and the amount of additional therapeutic agent (such as those comprising an additional therapeutic agent as described herein) will vary depending upon the attending and particular mode of administration. Normally, the amount of additional therapeutic agent of the compositions of the present invention will not exceed the amount normally administered by the composition comprising the therapeutic agent as the sole active agent. In another aspect, the amount of the additional therapeutic agent of the presently disclosed compositions ranges from about 50% to about 100% of the normal amount of the existing compositions, and the included agent acts as the sole active therapeutic agent. In those compositions comprising additional therapeutic agents, the additional therapeutic agent will act synergistically with the compounds of the invention.

本發明的化合物和組合物的用途Use of the compounds and compositions of the invention

本發明的藥物組合物的特徵包括式(I)或式(II)所示的化合物或本發明 所列出的化合物,以及藥學上可接受的載體,輔劑或媒介物。本發明的組合物中化合物的量可以有效地可探測地抑制蛋白激酶如VEGFR,c-Met,Ron或Axl的活性。本發明化合物將作為抗腫瘤藥物對患者進行治療或減小VEGFR,c-Met,Ron和/或Axl受體信號回應的有害作用。 The pharmaceutical composition of the present invention is characterized by a compound represented by formula (I) or formula (II) or the present invention The compounds listed, as well as pharmaceutically acceptable carriers, adjuvants or vehicles. The amount of the compound in the composition of the present invention is effective to detectably inhibit the activity of a protein kinase such as VEGFR, c-Met, Ron or Axl. The compounds of the invention will treat patients as anti-tumor drugs or reduce the deleterious effects of VEGFR, c-Met, Ron and/or Axl receptor signaling.

本發明的化合物將應用於,但絕不限於,使用本發明的化合物或組合物的有效量對患者給藥來預防或治療患者增殖性疾病。這樣的疾病包括癌症,尤其是轉移癌,動脈粥樣硬化,和肺纖維化。 The compounds of the invention will be, but are not limited to, administered to a patient using an effective amount of a compound or composition of the invention to prevent or treat a proliferative disorder in a patient. Such diseases include cancer, especially metastatic cancer, atherosclerosis, and pulmonary fibrosis.

本發明的化合物將應用於瘤的治療包括癌症和轉移癌,進一步包括但並不限於,癌症如膀胱癌,乳腺癌,結腸癌,腎癌,肝癌,肺癌(包括小細胞肺癌),食道癌,膽囊癌,卵巢癌,胰腺癌,胃癌,宮頸癌,甲狀腺癌,***癌,和皮膚癌(包括鱗狀細胞癌);淋巴系統造血腫瘤(包括白血病,急性淋巴囊腫性白血病,急性成淋巴細胞性白血病,B細胞淋巴瘤,T細胞淋巴瘤,何傑金(氏)淋巴瘤,非何傑金(氏)淋巴瘤,多毛細胞白血病和伯基特淋巴瘤);骨髓系統造血腫瘤(包括急慢性骨髓性粒細胞性白血病,骨髓增生異常綜合症,和前髓細胞白血病);間充質細胞起源的腫瘤(包括纖維肉瘤和橫紋肌肉瘤,和其他肉瘤,如軟組織和軟骨);中樞末梢神經系統瘤(包括星形細胞瘤,成神經細胞瘤,神經膠質瘤,和神經鞘瘤);和其他腫瘤(包括黑素瘤,精原細胞瘤,畸胎癌,骨肉瘤,xenoderoma pigmentosum,keratoctanthoma,甲狀腺濾泡瘤和卡波濟(氏)肉瘤)。 The compounds of the present invention will be applied to the treatment of tumors including cancer and metastatic cancer, and further include, but are not limited to, cancers such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer, Gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); lymphoid hematopoietic tumors (including leukemia, acute lymphocytic leukemia, acute lymphoblastic Leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's lymphoma); Bone marrow system hematopoietic tumors (including acute and chronic) Myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas such as soft tissue and cartilage); central peripheral neuroma ( Including astrocytoma, neuroblastoma, glioma, and schwannomas; and other tumors (including melanoma, seminoma, teratoma) Cancer, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular tumor and Kaposi's sarcoma.

本發明的化合物還可用於治療眼科病症例如角膜移植排斥,眼的新生血管形成,視網膜新生血管形成包括損傷或感染後的新生血管形成;糖尿病性視網膜病;晶狀體後纖維組織增生症,和新生血管性青光眼;視網膜缺血;玻璃體出血;潰瘍性疾病如胃潰瘍;病理學的但非惡性狀況如血管瘤,包括嬰兒血管內皮細胞瘤,鼻咽和無血管性骨壞死的血管纖維瘤;雌性生殖系統紊亂如子宮內膜異位。這些化合物同樣也用於治療水腫和脈管通透性過高的狀況。 The compounds of the invention are also useful in the treatment of ophthalmic conditions such as corneal transplant rejection, neovascularization of the eye, neovascularization of the retina including neovascularization following injury or infection; diabetic retinopathy; posterior lens hyperplasia, and neovascularization Glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological but non-malignant conditions such as hemangioma, including infantile vascular endothelial cell tumor, aneurysm of nasopharyngeal and avascular necrosis; female reproductive system Disorders such as endometriosis. These compounds are also used to treat conditions of edema and vascular hyperpermeability.

本發明的化合物可以用於處理與糖尿病相關的情況如糖尿病性視網 ,病和微血管病。本發明的化合物同樣用於癌症患者血流量減少的情況。本發明的化合物對患者腫瘤轉移減少也有有益效果。 The compounds of the invention may be used to treat conditions associated with diabetes such as diabetic visual networks , disease and microvascular disease. The compounds of the invention are also useful in the reduction of blood flow in cancer patients. The compounds of the invention also have beneficial effects on the reduction of tumor metastasis in patients.

本發明的化合物除了對人類治療有益以外,還可應用於獸醫治療寵物、引進品種的動物和農場的動物,包括哺乳動物,齧齒類動物等等。另外一些動物的實例包括馬、狗和貓。在此,本發明的化合物包括其藥學上可接受的衍生物。 In addition to being useful for human therapy, the compounds of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and farm animals, including mammals, rodents, and the like. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the invention include pharmaceutically acceptable derivatives thereof.

在將複數形式應用於化合物,鹽等的情況下,其也意指單一的化合物,鹽等。 In the case where the plural form is applied to a compound, a salt or the like, it also means a single compound, a salt or the like.

包含本發明的化合物或組合物給藥的治療方法,進一步包括對患者附加治療劑(聯合治療)的給藥,其中附加治療劑選自:化學療法、抗增殖劑或抗炎劑,其中附加治療劑適用於所治療的疾病,且附加治療劑可以和本發明的化合物或組合物聯合給藥,本發明的化合物或組合物作為單個劑型,或分開的化合物或組合物作為多劑型的一部分。附加治療劑可以與本發明的化合物同時給藥或不同時給藥。後者的情況,給藥可以錯開進行如6小時,12小時,1天,2天,3天,1周,2周,3周,1個月或2個月進行。 The method of treatment comprising administration of a compound or composition of the invention further comprises the administration of an additional therapeutic agent (combination therapy) to the patient, wherein the additional therapeutic agent is selected from the group consisting of: chemotherapy, anti-proliferative or anti-inflammatory agents, wherein the additional treatment The agents are suitable for the condition to be treated, and the additional therapeutic agents can be administered in combination with the compounds or compositions of the invention, either as a single dosage form, or as a separate compound or composition as part of a multiple dosage form. The additional therapeutic agent can be administered simultaneously or not simultaneously with the compounds of the invention. In the latter case, administration can be carried out staggered as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.

本發明同樣包含對表達VEGFR或c-Met的細胞生長抑制的方法,此方法包括本發明的化合物或組合物與細胞接觸,從而抑制細胞生長。能被抑制生長的細胞包括:乳腺癌細胞,結腸直腸癌細胞,肺癌細胞,乳頭狀癌細胞,***癌細胞,淋巴瘤細胞,結腸癌細胞,胰腺癌細胞,卵巢癌細胞,子宮頸癌細胞,中樞神經系統癌細胞,成骨肉瘤細胞,腎癌細胞,肝細胞癌細胞,膀胱癌細胞,胃癌細胞,頭或頸鱗癌細胞,黑色素瘤細胞和白血病細胞。 The invention also encompasses a method of inhibiting growth of a cell expressing VEGFR or c-Met, the method comprising contacting a compound or composition of the invention with a cell to inhibit cell growth. Cells that can be inhibited from growth include: breast cancer cells, colorectal cancer cells, lung cancer cells, papillary cancer cells, prostate cancer cells, lymphoma cells, colon cancer cells, pancreatic cancer cells, ovarian cancer cells, cervical cancer cells, Central nervous system cancer cells, osteosarcoma cells, renal cancer cells, hepatocellular carcinoma cells, bladder cancer cells, gastric cancer cells, head or cervical squamous cell carcinoma cells, melanoma cells and leukemia cells.

本發明提供了在生物標本內抑制VEGFR或c-Met激酶活性的方法,此方法包括將本發明的化合物或組合物與生物標本接觸。本發明所使用的術語“生物標本”是指活體外部的標本,包括但絕不限於,細胞培養或細胞提取;從哺乳動物或其提取物得到的活組織檢查物質;血液,唾液, 尿液,糞便,***,眼淚,或其他活組織液體物質及其提取物。抑制生物標本中激酶活性,特別是VEGFR,c-Met,Ron或Axl激酶活性,可用於所屬領域技術人員公知的多種用途。這樣的用途包括,但絕不限於,輸血法,器官移植,生物標本儲藏和生物鑒定。 The invention provides a method of inhibiting VEGFR or c-Met kinase activity in a biological sample, the method comprising contacting a compound or composition of the invention with a biological sample. The term "biological specimen" as used in the present invention refers to a specimen external to a living body, including but not limited to, cell culture or cell extraction; biopsy material obtained from a mammal or an extract thereof; blood, saliva, Urine, feces, semen, tears, or other living tissue fluids and their extracts. Inhibition of kinase activity in a biological specimen, particularly VEGFR, c-Met, Ron or Axl kinase activity, can be used for a variety of uses well known to those skilled in the art. Such uses include, but are in no way limited to, transfusion methods, organ transplantation, biological specimen storage, and bioassay.

本發明的化合物或藥學上可接受的組合物的“有效量”或“有效劑量”是指處理或減輕一個或多個本發明所提到病症的嚴重度的有效量。根據本發明的方法,化合物和組合物可以是任何給藥量和任何給藥途徑來有效地用於處理或減輕疾病的嚴重程度。必需的準確的量將根據患者的情況而改變,這取決於種族,年齡,患者的一般條件,感染的嚴重程度,特殊的因素,給藥方式,等等。化合物或組合物可以和一個或多個其他治療劑聯合給藥,如本發明所討論的。 An "effective amount" or "effective amount" of a compound or pharmaceutically acceptable composition of the invention refers to an effective amount to treat or ameliorate the severity of one or more of the conditions mentioned herein. In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and in any route of administration effective to treat or reduce the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, specific factors, mode of administration, and the like. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.

本發明的化合物或其藥物組合物可以應用於可植入的內科裝置的包衣,如假體,人工瓣膜,人造血管,莖和導尿管。例如,脈管莖,已經被用於克服再狹窄(損傷後血管壁的再收縮)。然而,患者使用莖或其他可植入裝置將會有血塊形成或血小板啟動的風險。這些不利的作用可以通過使用包含本發明的化合物的藥學上可接受的組合物預塗漬裝置來阻止或減輕。 The compounds of the present invention or pharmaceutical compositions thereof can be applied to coatings of implantable medical devices such as prostheses, prosthetic valves, artificial blood vessels, stems and urinary catheters. For example, vascular stems have been used to overcome restenosis (recontraction of the vessel wall after injury). However, patients with stems or other implantable devices will be at risk of clot formation or platelet activation. These adverse effects can be prevented or alleviated by the use of a pharmaceutically acceptable composition pre-coating device comprising a compound of the invention.

合適的包衣和可植入裝置的包衣的一般製備方法在文獻US 6,099,562,US 5,886,026和US 5,304,121中有所描述,包衣是有代表性地生物相容的多聚體材料如水凝膠聚合體,聚甲基二矽醚,聚已酸內酯,聚乙二醇,聚乳酸,乙烯-乙酸乙烯酯,及其混合物。包衣可以任選地更進一步地被合適的包衣所覆蓋,如氟代二甲矽油,多糖酶,聚乙二醇,磷脂類,或它們的組合,來表現組合物控制釋放的特徵。本發明的另一方面包括使用本發明的化合物塗敷的可植入裝置。本發明的化合物也可以塗敷在可植入體內的醫療用具上,如珠狀物,或與聚合物或其他分子混合來提供“藥物儲藏所”,因此與藥物水溶液給藥方式比較,允許藥物釋放有更長的時間期限。 A general method for the preparation of suitable coatings and coatings for implantable devices is described in the documents US Pat. No. 6,099,562, US Pat. No. 5,886, 026, and US Pat. , polymethyl dimethyl ether, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a suitable coating, such as fluorodimethyl hydrazine oil, a polysaccharide enzyme, polyethylene glycol, phospholipids, or combinations thereof, to characterize the controlled release of the composition. Another aspect of the invention includes an implantable device coated with a compound of the invention. The compounds of the present invention may also be applied to medical devices implantable in the body, such as beads, or mixed with a polymer or other molecule to provide a "drug store", thus allowing the drug to be compared to the aqueous drug solution. Release has a longer period of time.

一般合成過程General synthetic process

一般地,本發明的化合物可以通過本發明所描述的方法製備得到,除非有進一步的說明,其中取代基的定義如式(I)或式(II)所示。下面的反應方案和實施例用於進一步舉例說明本發明的內容。 In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I) or formula (II). The following reaction schemes and examples are provided to further illustrate the contents of the present invention.

所屬領域的專業人員將認識到:本發明所描述的化學反應可以用來合適地製備許多本發明的其他化合物,且用於製備本發明的化合物的其它方法都被認為是在本發明的範圍之內。例如,根據本發明那些非例證的化合物的合成可以成功地被所屬領域的技術人員通過修飾方法完成,如適當的保護干擾基團,通過利用其他已知的試劑除了本發明所描述的,或將反應條件做一些常規的修改。另外,本發明所公開的反應或已知的反應條件也公認地適用於本發明其他化合物的製備。 Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

下面所描述的實施例,除非其他方面表明所有的溫度定為攝氏度。試劑購買於商品供應商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company,使用時都沒有經過進一步純化,除非其他方面表明。一般的試劑從汕頭西隴化工廠,廣東光華化學試劑廠,廣州化學試劑廠,天津好寓宇化學品有限公司,天津市福晨化學試劑廠,武漢鑫華遠科技發展有限公司,青島騰龍化學試劑有限公司,和青島海洋化工廠購買得到。 The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant purchased it.

無水四氫呋喃,二氧六環,甲苯,***是經過金屬鈉回流乾燥得到。無水二氯甲烷和氯仿是經過氫化鈣回流乾燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙醯胺和N,N-二甲基甲醯胺是經無水硫酸鈉事先乾燥使用。 Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.

以下反應一般是在氮氣或氬氣正壓下或在無水溶劑上套一乾燥管(除非其他方面表明),反應瓶都塞上合適的橡皮塞,底物通過注射器打入。玻璃器皿都是乾燥過的。 The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.

色譜柱是使用矽膠柱。矽膠(300-400目)購於青島海洋化工廠。核磁共振光譜以CDCl3、DMSO-d 6 、CD3OD或丙酮-d 6 為溶劑(以ppm為單位),用TMS(0ppm)或氯仿(7.25ppm)作為參照標準。當出現多重 峰的時候,將使用下面的縮寫:s(singlet,單峰)、d(doublet,雙峰)、t(triplet,三重峰)、m(multiplet,多重峰)、br(broadened,寬峰)、dd(doublet of doublets,雙二重峰)、dt(doublet of triplets,雙三重峰)。偶合常數,用赫茲(Hz)表示。 The column is a silicone column. Silicone rubber (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The nuclear magnetic resonance spectrum was measured by CDCl 3 , DMSO- d 6 , CD 3 OD or acetone- d 6 (in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, single peak), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).

低解析度質譜(MS)資料的條件是:Agilent 1200 Series LCMS(Zorbax SB-C18,2.1×30mm,4微米,10min,流速為0.6mL/min,5%-95%(0.1%溶於H2O的蟻酸)中的(0.1%溶於CH3CN的蟻酸)),在210/254nm用UV檢測,用低回應電噴模式(ESI)。 The conditions for the low-resolution mass spectrometry (MS) data were: Agilent 1200 Series LCMS (Zorbax SB-C18, 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min, 5%-95% (0.1% dissolved in H 2 ) (0.1% of formic acid in CH 3 CN) in the formic acid of O), UV detection at 210/254 nm, with low response electrospray mode (ESI).

純的化合物的表徵方式為:Agilent 1100 Series高性能液相色譜(HPLC),在210nm和254nm用UV檢測。柱在40℃下操作。 Pure compounds were characterized by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm. The column was operated at 40 °C.

下面簡寫詞的使用貫穿本發明:ATP 三磷酸腺甙 The following abbreviations are used throughout the invention: ATP adenosine triphosphate

BBr3 三溴化硼 BBr 3 boron tribromide

BINAP 2,2'-雙-(二苯膦基)-1,1'-聯萘 BINAP 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl

BSA 牛血清白蛋白 BSA bovine serum albumin

BOC,Boc 叔丁氧基羰基 BOC, Boc tert-butoxycarbonyl

Ca(SO3CF3)2 三氟甲基硫酸鈣 Ca(SO 3 CF 3 ) 2 trifluoromethyl sulfate

Cs2CO3 碳酸銫 Cs 2 CO 3 strontium carbonate

CHCl3 氯仿 CHCl 3 chloroform

CDCl3 氘代氯仿 CDCl 3 deuterated chloroform

CH2Cl2,DCM 二氯甲烷 CH 2 Cl 2 , DCM dichloromethane

Cu 銅 Cu copper

CuI 碘化亞銅 CuI cuprous iodide

Et2O *** Et 2 O ether

EtOH 乙醇 EtOH ethanol

DBU 1,8-二氮雜二環[5.4.0]十一碳-7-烯 DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

D2 氘氣 D 2 helium

DIBAL 二異丁基氫化鋁 DIBAL diisobutylaluminum hydride

DIAD 偶氮二甲酸二異丙酯 DIAD diisopropyl azodicarboxylate

DIEA,DIPEA,iPr2Net N,N-二異丙基乙胺 DIEA, DIPEA, iPr 2 Net N, N-diisopropylethylamine

DEAD 偶氮二甲酸二乙酯 DEAD diethyl azodicarboxylate

DMF N,N-二甲基甲醯胺,二甲基甲醯胺 DMF N,N-dimethylformamide, dimethylformamide

DMAP 4-二甲氨基吡啶 DMAP 4-dimethylaminopyridine

DMSO 二甲基亞碸 DMSO dimethyl sulfoxide

DPPA 疊氮磷酸二苯酯 DPPA diphenyl phosphate

DTT 二巰基蘇糖醇 DTT dimercaptosuitol

EDC,EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亞胺鹽酸鹽 EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EDTA 乙二胺四乙酸 EDTA ethylenediaminetetraacetic acid

EtOAc,EA 乙酸乙酯 EtOAc, EA ethyl acetate

Et3N,TEA 三乙胺 Et 3 N, TEA triethylamine

FBS 胎牛血清 FBS fetal bovine serum

g 克 g g

h 小時 h hours

HATU 2-(7-偶氮苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

HBr 氫溴酸 HBr hydrobromic acid

HCl 鹽酸 HCl hydrochloric acid

HOAc 乙酸 HOAc acetic acid

HOAT N-羥基-7-氮雜苯並三氮唑 HOAT N-hydroxy-7-azabenzotriazole

HOBt 1-羥基苯並***水合物 HOBt 1-hydroxybenzotriazole hydrate

H2 氫氣 H 2 hydrogen

H2O 水 H 2 O water

H2O2 過氧化氫 H 2 O 2 hydrogen peroxide

H3PO4 磷酸 H 3 PO 4 phosphate

H2SO4 硫酸 H 2 SO 4 sulfuric acid

HNO3 硝酸 HNO 3 nitric acid

HCOOK 甲酸鉀 HCOOK potassium formate

Fe 鐵 Fe iron

LiHMDS 六甲基二矽基基鋰 LiHMDS hexamethyldidecyl lithium

LDA 二異丙基胺基鋰 LDA diisopropylamino lithium

MBP 髓磷脂鹼性蛋白 MBP myelin basic protein

MCPBA 間氯過氧苯甲酸 MCPBA m-chloroperoxybenzoic acid

MeCN,CH3CN 乙腈 MeCN, CH 3 CN acetonitrile

MgSO4 硫酸鎂 MgSO 4 magnesium sulfate

Mg ATP 腺苷三磷酸鎂 Mg ATP magnesium adenosine triphosphate

MeOH,CH3OH 甲醇 MeOH, CH 3 OH methanol

MeI 碘甲烷 MeI methyl iodide

MOPS 3-(N-嗎啉代)丙磺酸 MOPS 3-(N-morpholino)propanesulfonic acid

mL,ml 毫升 mL, ml ml

N2 氮氣 N 2 nitrogen

NMP N-甲基吡咯烷酮 NMP N-methylpyrrolidone

NaHCO3 碳酸氫鈉 NaHCO 3 sodium bicarbonate

NaBH4 硼氫化鈉 NaBH 4 sodium borohydride

NaBH3CN 氰基硼氫化鈉 NaBH 3 CN sodium cyanoborohydride

NaOtBu 叔丁醇鈉 NaOtBu sodium tert-butoxide

NaOH 氫氧化鈉 NaOH sodium hydroxide

NaClO2 亞氯酸鈉 NaClO 2 sodium chlorite

NaCl 氯化鈉 NaCl sodium chloride

NaH2PO4 磷酸二氫鈉 NaH 2 PO 4 sodium dihydrogen phosphate

NaH 氫化鈉 NaH sodium hydride

NaI 碘化鈉 NaI sodium iodide

Na2SO4 硫酸鈉 Na 2 SO 4 sodium sulfate

NBS N-溴丁二醯亞胺 NBS N-bromobutanediimine

Nonidet 諾乃洗劑 Nonidet Norit lotion

NH3NH 3 ammonia

NH4Cl 氯化氨 NH 4 Cl ammonia chloride

Pd/C 披鈀/碳 Pd/C palladium/carbon

Pd2(dba)3 三(二亞苄基丙酮)二鈀 Pd 2 (dba) 3 tris(dibenzylideneacetone) dipalladium

Pd(OAc)2 醋酸鈀 Pd(OAc) 2 palladium acetate

Pd(OH)2 氫氧化鈀 Pd(OH) 2 palladium hydroxide

Pd(PPh3)4 四(三苯基膦)鈀 Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium

Pd(dppf)Cl2 1,1’-二(二苯基膦基)二茂鐵二氯化鈀 Pd(dppf)Cl 2 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride

P(t-Bu)3 三(叔丁基)膦 P(t-Bu) 3 tri(tert-butyl)phosphine

PE 石油醚(60-90℃) PE petroleum ether (60-90 ° C)

PBS 磷酸鹽緩衝鹽水 PBS phosphate buffered saline

POCl3 三氯氧磷 POCl 3 phosphorus oxychloride

PhI(OAc)2 二乙酸碘苯 PhI(OAc) 2 iodobenzene diacetate

K2CO3 碳酸鉀 K 2 CO 3 potassium carbonate

KOH 氫氧化鉀 KOH potassium hydroxide

RT,rt,r.t. 室溫 RT, rt, r.t. room temperature

Rt 保留時間 Rt retention time

SOCl2 氯化亞碸 SOCl 2

t-BuOK 叔丁醇鉀 t -BuOK potassium tert-butoxide

TBTU O-苯並三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯 TBTU O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate

THF 四氫呋喃 THF tetrahydrofuran

TFA 三氟乙酸 TFA trifluoroacetic acid

TBAI 四丁基碘化銨 TBAI tetrabutylammonium iodide

TBS 三羥甲基氨基甲烷緩衝鹽水 TBS Tris buffered saline

TEAC 二(四乙基銨)碳酸鹽 TEAC bis(tetraethylammonium) carbonate

Tris 三羥甲基氨基甲烷 Tris Tris

所述合成方案1-3是製備下述實施例化合物的典型合成方案。各X,Y,Z,W,R1,R2,R3,R4,R5,R6和Rd具有本發明所述的含義。 The synthetic schemes 1-3 are typical synthetic schemes for the preparation of the compounds of the following examples. Each of X, Y, Z, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R d has the meanings indicated in the present invention.

合成方案1Synthetic scheme 1

本發明的化合物可通過上述合成方案1製備得到,具體合成方案見實施例描述。在合成方案1中6-氨基吡啶-3-醇(1)首先和取代的吡唑酮化合物(2)發生縮合反應生成化合物(3)。在鹼性條件下(例如,使用t-叔丁醇鉀或氫化鈉),吡啶醯胺(4)與化合物(3)在升高溫度和極性溶劑(如DMF)的條件下反應得到醯胺化合物(5)。在氧化劑二乙酸碘苯或NaClO作用下醯胺化合物(5)發生重排反應得到氨基吡啶(6)。最後,氨基吡啶(6)與醯氯化合物(7)發生醯化反應生成目標激醇抑制劑(8)The compounds of the present invention can be prepared by the above synthesis scheme 1 , and the specific synthesis schemes are described in the examples. In Synthetic Scheme 1 , 6-aminopyridin-3-ol ( 1 ) is first condensed with a substituted pyrazolone compound ( 2 ) to form compound ( 3 ) . Under basic conditions (for example, using potassium t -tert-butoxide or sodium hydride), pyridinium ( 4 ) is reacted with compound ( 3 ) under elevated temperature and a polar solvent (such as DMF) to give the guanamine compound. ( 5 ) . The guanamine compound ( 5 ) undergoes a rearrangement reaction under the action of the oxidant iodobenzene diacetate or NaClO to obtain an aminopyridine ( 6 ) . Finally, aminopyridine (6) with the acyl chloride compound (7) the occurrence of certain acylation reaction inhibitor laser alcohol (8).

合成方案2Synthetic scheme 2

本發明的化合物也可以通過上述合成方案2製備得到,具體合成方案見實施例描述。在合成方案2中,芳基化合物(9)先與取代的吡啶化合物(10)在升高溫度的條件下發生耦合反應,得到二芳基醚化合物(11)。化合物(11)再和取代的吡唑酮化合物(2)發生縮合反應生成目標激酶抑制劑(12)The compounds of the present invention can also be prepared by the above Synthesis Scheme 2. The specific synthesis schemes are described in the examples. In the synthesis scheme 2 , the aryl compound ( 9 ) is first coupled with the substituted pyridine compound ( 10 ) under elevated temperature to obtain a diaryl ether compound ( 11 ) . Compound ( 11 ) is then condensed with a substituted pyrazolone compound ( 2 ) to form a target kinase inhibitor ( 12 ) .

合成方案3Synthetic scheme 3

目標激酶抑制劑(12)(15)也可以通過合成方案3製備得到,在合成方案3中,芳基化合物(9)在縮合劑(EDCI或HATU)存在下與 羧酸類化合物(2)縮合得到醯胺類化合物(13),化合物(13)在堿,如叔丁醇鉀,氫化鈉等存在下,與化合物(10)反應生成化合物(12)。醯胺吡啶化合物(12)在氧化劑二乙酸碘苯或NaClO作用下進一步發生重排反應得到氨基吡啶化合物(14),化合物(14)可進一步與化合物(7)在鹼性條件下發生醯化反應轉化目標激酶抑制劑(15)The target kinase inhibitors ( 12 ) and ( 15 ) can also be prepared by the synthesis scheme 3. In the synthesis scheme 3 , the aryl compound ( 9 ) is condensed with the carboxylic acid compound ( 2 ) in the presence of a condensing agent (EDCI or HATU). The guanamine compound ( 13 ) is obtained , and the compound ( 13 ) is reacted with the compound ( 10 ) in the presence of hydrazine such as potassium t-butoxide or sodium hydride to form a compound ( 12 ) . The indole pyridine compound ( 12 ) is further rearranged by the oxidant iodobenzene or NaClO to obtain an aminopyridine compound ( 14 ) , and the compound ( 14 ) can further undergo a oximation reaction with the compound ( 7 ) under alkaline conditions. Transformation of a target kinase inhibitor ( 15 ) .

實施例Example 實施例1 3-氯-4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺Example 1 3-Chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Phenoxy)pyridinium

步驟1)N-(4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 1) N- (4-Hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine

將4-氨基苯酚(1.09g,10mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(2.37g,10.2mmol)溶於二氯甲烷(30mL)中,然後加入EDCI(2.3g,12mmol)和HOAT(0.27g,2mmol)。反應混合物在46℃攪拌4小時後,冷卻至室溫,並用乙酸乙酯(10mL)和水(10mL)稀釋。反應混合物室溫攪拌1小時後,過濾,得到標題化合物為白色固體(1.7g,52.5%)。 4-Aminophenol (1.09 g, 10 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxylic acid (2.37 g , 10.2 mmol) was dissolved in dichloromethane (30 mL) then EDCI (2.3 g, 12 mmol) and HOAT (0.27 g, 2 mmol). The reaction mixture was stirred at 46 <0>C for 4 h then cooled to EtOAc EtOAc. After the reaction mixture was stirred at room temperature for 1 hr.

MS(ESI,pos.ion)m/z:324.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.68(s,3H),3.32(s,3H),6.72(d,J=8.8Hz,2H),7.36-7.42(m,4H),7.49(t,J=7.4Hz,1H),7.57(t,J=7.6Hz,2H),9.21(s,1H),10.46(s,1H)。 MS (ESI, pos.ion) m / z: 324.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.68 (s, 3H), 3.32 (s, 3H), 6.72 (d, J = 8.8 Hz, 2H), 7.36-7.42 (m, 4H), 7.49 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 9.21 (s, 1H) ), 10.46 (s, 1H).

步驟2)3,4-二氯-2吡啶醯胺 Step 2) 3,4-Dichloro-2pyridinium

將2,2,6,6-四甲基呱啶(6.2mL,37.2mmol)溶於二***(50mL),然後在0℃通過注射器在15分鐘內加入溶於己烷(2.5M,23mL,57.5mmol)的正丁基鋰。反應液在0℃攪拌0.5小時後,降至-78℃保持0.5 小時,然後通過注射器在15分鐘內向反應液中加入溶於***(20mL)的3,4-二氯吡啶(5.00g,33.8mmol)溶液。反應液在-78℃攪拌2小時後,加入異氰酸三甲基矽烷(94%純度,6.7mL,50.7mmol)。反應混合物升至室溫並攪拌2小時,然後用醋酸(6.76g,112.6mmol)和35mL水淬滅。繼續攪拌過夜,析出白色固體,過濾收集。濾液用乙酸乙酯(50mL x 3)萃取,合併的有機相用食鹽水(50mL)洗滌,並用無水硫酸鈉乾燥後真空濃縮。將所得固體合併並用35mL***洗滌得到標題化合物為淡黃色固體(2.20g,34.0%)。 2,2,6,6-Tetramethyl acridine (6.2 mL, 37.2 mmol) was dissolved in diethyl ether (50 mL) then taken in hexanes (2.5 M, 23 mL, 57.5 mmol) of n-butyllithium. The reaction solution was stirred at 0 ° C for 0.5 hour and then lowered to -78 ° C to maintain 0.5. An hour, then a solution of 3,4-dichloropyridine (5.00 g, 33.8 mmol) in diethyl ether (20 mL) was added to the reaction mixture over 15 min. After the reaction mixture was stirred at -78 ° C for 2 hours, trimethyl decane isocyanate (94% purity, 6.7 mL, 50.7 mmol). The reaction mixture was warmed to room rt and stirred for 2 h then quenched with EtOAc (EtOAc &lt Stirring was continued overnight, a white solid precipitated and collected by filtration. The filtrate was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained solids were combined and evaporated tolujjjjjjjjj

MS(ESI,pos.ion)m/z:191.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.48(d,J=5.2Hz,1H),8.09(br s,1H),7.82(s,1H),7.81(d,J=5.2Hz,1H)。 MS (ESI, pos.ion) m / z: 191.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 8.48 (d, J = 5.2Hz, 1H), 8.09 ( Br s, 1H), 7.82 (s, 1H), 7.81 (d, J = 5.2 Hz, 1H).

步驟3)3-氯-4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺 Step 3) 3-Chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Phenoxy)pyridinium

N-(4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(356mg,1.1mmol)溶於二甲亞碸(4mL),並置於一個微波小瓶內,然後室溫加入NaH(88mg,2.2mmol,60%分散於礦物油中)。反應液室溫攪拌30分鐘後加入3,4-二氯-2-吡啶醯胺(191mg,1.0mmol)。反應混合物置於微波下,160℃反應2小時後,冷卻至室溫,用水稀釋(10mL)。所得混合物用乙酸乙酯(30mL x 3)萃取。合併的有機相用食鹽水(30mL x 3)洗滌,用無水硫酸鈉乾燥後,真空濃縮。殘留物通過矽膠柱層析(DCM/MeOH(v/v)=50/1)純化得到標題化合物為淡黃色固體(140mg,29%)。 N- (4-Hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine (356 mg, 1.1 Methyl) was dissolved in dimethyl hydrazine (4 mL) and placed in a microwave vial, then NaH (88 mg, 2.2 mmol, 60% dispersion in mineral oil) was added at room temperature. After the reaction mixture was stirred at room temperature for 30 minutes, 3,4-dichloro-2-pyridinamine (191 mg, 1.0 mmol) was added. The reaction mixture was placed under microwave at 160 ° C for 2 hours, cooled to room temperature and diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (30 mL EtOAc) The residue was purified by EtOAc EtOAc EtOAc EtOAc

MS(ESI,pos.ion)m/z:478.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.71(s,3H),3.35(s,3H),6.82(d,J=5.4Hz,1H),7.19(d,J=9.0Hz,2H),7.44(d,J=7.5Hz,2H),7.53(m,1H),7.59(m,2H),7.74(m,3H),8.02(s,1H),8.33(d,J=5.4Hz,1H),10.84(s,1H)。 MS (ESI, pos.ion) m / z: 478.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.71 (s, 3H), 3.35 (s, 3H), 6.82 (d, J = 5.4 Hz, 1H), 7.19 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 7.53 (m, 1H), 7.59 (m, 2H), 7.74 (m, 3H), 8.02 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 10.84 (s, 1H).

實施例2 3-氯-4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺Example 2 3-Chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) 基)-2-氟苯氧基)吡啶醯胺2-fluorophenoxy)pyridinium

步驟1)4-(4-氨基-2-氟苯氧基)-3-氯吡啶醯胺 Step 1) 4-(4-Amino-2-fluorophenoxy)-3-chloropyridiniumamine

將4-氨基-2-氟苯酚(254mg,2.0mmol)溶於二甲基甲醯胺(5mL)中,加入叔丁醇鉀(359mg,3.2mmol)。反應液在室溫攪拌30分鐘,然後加入3,4-二氯-2-吡啶醯胺(420mg,2.2mmol)。將反應混合物置於微波下,120℃反應2小時,冷卻至室溫後,用25mL水稀釋。所得混合物用乙酸乙酯(30mL x 3)萃取,合併的有機相用食鹽水(30mL x 3)洗滌,用無水硫酸鈉乾燥後,真空濃縮。殘留物通過矽膠柱層析(EtOAc/PE(v/v)=2/1)純化得到標題化合物為淡黃色固體(306mg,54.4%)。 4-Amino-2-fluorophenol (254 mg, 2.0 mmol) was dissolved in dimethylformamide (5 mL) and potassium tert-butoxide (359 mg, 3.2 mmol). The reaction was stirred at room temperature for 30 min then 3,4-dichloro-2-pyridinamine (420 mg, 2.2 mmol). The reaction mixture was placed under microwave at 120 ° C for 2 hours, cooled to room temperature and diluted with 25 mL of water. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

MS(ESI,pos.ion)m/z:282.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.30(d,J=5.6Hz,1H),8.03(s,1H),7.73(s,1H),7.03(t,J=9.0Hz,1H),6.72(dd,J=0.8Hz,5.6Hz,1H),6.53(dd,J=2.4Hz,13.2Hz,1H),6.44(dd,J=1.8Hz,8.7Hz,1H),5.55(s,2H)。 MS (ESI, pos.ion) m / z: 282.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): (ppm) δ 8.30 (d, J = 5.6Hz, 1H), 8.03 ( s, 1H), 7.73 (s, 1H), 7.03 (t, J = 9.0 Hz, 1H), 6.72 (dd, J = 0.8 Hz, 5.6 Hz, 1H), 6.53 (dd, J = 2.4 Hz, 13.2 Hz , 1H), 6.44 (dd, J = 1.8 Hz, 8.7 Hz, 1H), 5.55 (s, 2H).

步驟2)3-氯-4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺 Step 2) 3-Chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) )-2-fluorophenoxy)pyridinium

將4-(4-氨基-2-氟苯氧基)-3-氯吡啶醯胺(306mg,1.40mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(390mg,1.68mmol)懸浮於二氯甲烷(6mL)中,然後加入EDCI(322mg,1.68mmol)和HOAT(38mg,0.28mmol)。反應混合物在45℃攪拌14.5小時後,冷卻至室溫,並用5mL水淬滅。反應混合物用乙酸乙酯(10mL x 3)萃取,合併的有機相用食鹽水(10mL x 3)洗滌,用無水硫酸鈉乾燥後,真空濃縮。殘留物通過矽膠柱層析(EtOAc/PE(v/v)=1/4)純化得到標題化合物為淡黃色固體(647mg,93.2%)。 4-(4-Amino-2-fluorophenoxy)-3-chloropyridiniumamine (306 mg, 1.40 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1 H -pyrazole-4-carboxylic acid (390 mg, 1.68 mmol) was suspended in dichloromethane (6 mL) then EDCI ( 322 g, 1.68 mmol) and HOAT (38 mg, 0.28 mmol). After the reaction mixture was stirred at 45 ° C for 14.5 hours, cooled to room temperature and quenched with 5 mL water. The reaction mixture was extracted with EtOAc EtOAc EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc

MS(ESI,pos.ion)m/z:496.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.98(s,1H),8.33(d,J=5.6Hz,1H),8.06(br s,1H),7.99(dd,J=2.2Hz,13.2Hz,1H),7.75(br s,1H),7.60(t,J=7.2Hz,2H),7.52(m,1H),7.45(d,J=5.6Hz,2H),7.35(m,2H),6.84(d,J=5.5Hz,1H),3.37(s,3H),2.71(s,3H)。 MS (ESI, pos.) m/z: 496.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 10.98 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.06 (br s, 1H), 7.99 (dd, J = 2.2 Hz, 13.2 Hz, 1H), 7.75 (br s, 1H), 7.60 (t, J = 7.2 Hz, 2H), 7.52 ( m, 1H), 7.45 (d, J = 5.6 Hz, 2H), 7.35 (m, 2H), 6.84 (d, J = 5.5 Hz, 1H), 3.37 (s, 3H), 2.71 (s, 3H).

實施例3 4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2,3-二氟苯氧基)吡啶醯胺Example 3 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2, 3-difluorophenoxy)pyridinium

步驟1)1-(苄氧基)-2,3-二氟-4-硝基苯 Step 1) 1-(Benzyloxy)-2,3-difluoro-4-nitrobenzene

將2,4,5-三氟硝基苯(5.00g,28.2mmol)和苯甲醇(3.07g,28.4mmol)溶於二甲基甲醯胺(10mL)中,然後加入碳酸鉀(5.87g,42.5mmol)。反應液在室溫攪拌72小時後,用水(35mL)稀釋,4℃繼續攪拌過夜。過濾,收集沉澱,用水(20mL)洗,然後通過矽膠柱層析(EtOAc/PE(v/v)=1/20)純化得到標題化合物為淡黃色固體(2.15g,28.7%)。 2,4,5-trifluoronitrobenzene (5.00 g, 28.2 mmol) and benzyl alcohol (3.07 g, 28.4 mmol) were dissolved in dimethylformamide (10 mL), then potassium carbonate (5.87 g, 42.5 mmol). After the reaction mixture was stirred at room temperature for 72 hr, diluted with water (35 mL) Filtration, EtOAc (EtOAc) (EtOAc:EtOAc.

1H NMR(400MHz,CDCl3):δ(ppm)7.90(m,1H),7.43(s,2H),7.42(s,2H),7.39(m,1H),6.86(m,1H),5.27(s,2H)。 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.90 (m, 1H), 7.43 (s, 2H), 7.42 (s, 2H), 7.39 (m, 1H), 6.86 (m, 1H), 5.27 (s, 2H).

步驟2)4-氨基-2,3-二氟苯酚 Step 2) 4-Amino-2,3-difluorophenol

將1-(苄氧基)-2,3-二氟-4-硝基苯(1.93g,0.73mmol)懸浮於甲醇(45mL)和四氫呋喃(9mL)的混合溶液中,然後加入Pd/C(333mg,6% Pd含量,53%~55%水含量)。反應混合物在H2條件下於32℃攪拌13小時後,通過矽藻土過濾,濾餅用50mL乙酸乙酯洗滌。濾液真空濃縮後,殘留物用30mL二氯甲烷洗滌得到標題化合物為深褐色固體(0.89g,84%)。 1-(Benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) was suspended in a mixed solution of methanol (45 mL) and tetrahydrofuran (9 mL), then Pd/C ( 333 mg, 6% Pd content, 53% to 55% water content). After the reaction mixture was stirred at 32 ° C for 13 hr under H 2 , filtered over Celite, and filtered. The filtrate was concentrated in vacuo.

MS(ESI,pos.ion)m/z:146.2[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)6.49(m,1H),6.38(m,1H),4.71(s,2H)。 MS (ESI, pos.ion) m / z: 146.2 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).

步驟3)4-(4-氨基-2,3-二氟苯氧基)吡啶醯胺 Step 3) 4-(4-Amino-2,3-difluorophenoxy)pyridinium

將4-氨基-2,3-二氟苯酚(208mg,1.43mmol)溶於二甲基甲醯胺(4mL)中,然後加入叔丁醇鉀(257mg,2.29mmol)。反應液在室溫攪拌30分鐘後,加入4-氯吡啶甲醯胺(249mg,1.59mmol)。將反應混合物置於微波下,120℃反應3小時後,冷卻至室溫,並用25mL水稀釋。所得到的混合物用乙酸乙酯(30mL x 3)萃取,合併的有機相用食鹽水(30mL x 3)洗滌,用無水硫酸鈉乾燥後真空濃縮。殘留物通過矽膠柱層析(PE/EtOAc(v/v)=1/2)純化得到標題化合物為橙色固體(110mg,41.5%)。 4-Amino-2,3-difluorophenol (208 mg, 1.43 mmol) was dissolved in dimethylformamide (4 mL) then potassium t-butoxide (257 mg, 2.29 mmol). After the reaction mixture was stirred at room temperature for 30 minutes, 4-chloropyridylcarbamide (249 mg, 1.59 mmol) was added. The reaction mixture was placed under microwave at 120 ° C for 3 hours, cooled to room temperature and diluted with 25 mL of water. The resulting mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

MS(ESI,pos.ion)m/z:266.0[M+H]+,283.2[M+NH4]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.42(d,J=5.6Hz,1H),7.84(br s,1H),7.65(d,J=2.5Hz,1H),7.03(m,1H),6.77(m,1H),6.56(m,1H),5.56(br s,1H),3.08(s,2H)。 MS (ESI, pos.) m/z: 266.0 [M+H] + , 283.2 [M+NH 4 ] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 8.42 (d, J = 5.6 Hz, 1H), 7.84 (br s, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.03 (m, 1H), 6.77 (m, 1H), 6.56 (m, 1H), 5.56 ( Br s, 1H), 3.08 (s, 2H).

步驟4)4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2,3-二氟苯氧基)吡啶醯胺 Step 4) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2, 3-difluorophenoxy)pyridinium

將4-(4-氨基-2,3-二氟苯氧基)吡啶醯胺(180mg,0.68mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(161mg,0.69mmol)懸浮於二氯甲烷(4mL),然後加入EDCI(157mg,0.82mmol)和HOAT(19mg,0.14mmol)。反應混合物在45℃攪拌反應12小時後,再加入1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(87mg,0.37mmol),反應混合物繼續在45℃攪拌反應5小時後,冷卻至室溫後,用5mL水淬滅反應,混合物用乙酸乙酯(10mL x 3)萃取。合併的有機相用食鹽水(10mL x 3)洗滌,用無水硫酸鈉乾燥並真空濃縮。殘留物通過矽膠柱層析(純EtOAc)純化得到標題化合物為橙色固體(108mg,33.2%)。 4-(4-Amino-2,3-difluorophenoxy)pyridiniumamine (180 mg, 0.68 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1 H -pyrazole-4-carboxylic acid (161 mg, 0.69 mmol) was suspended in dichloromethane (4 mL), then EDCI (157 mg, 0.82 mmol) and HOAT (19 mg, 0.14 mmol). After the reaction mixture was stirred at 45 ° C for 12 hours, 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxylic acid (87 mg was further added. After the reaction mixture was stirred at 45 ° C for 5 hours, cooled to room temperature and then quenched with 5 mL of water, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with EtOAcq. The residue was purified by EtOAc EtOAc EtOAc EtOAc

MS(ESI,pos.ion)m/z:480.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)11.2(s,1H),8.55(d,J=5.7Hz,1H),8.34(m,1H),8.16(br s,1H),7.76(br s,1H),7.64(m,3H),7.59(d,J=7.8Hz,1H),7.46(m,3H),7.28(m,1H),3.38(s,3H),2.71(s,3H)。 MS (ESI, pos.ion) m / z: 480.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 11.2 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.34 (m, 1H), 8.16 (br s, 1H), 7.76 (br s, 1H), 7.64 (m, 3H), 7.59 (d, J = 7.8 Hz, 1H), 7.46 (m) , 3H), 7.28 (m, 1H), 3.38 (s, 3H), 2.71 (s, 3H).

實施例4 4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2,5-二氟苯氧基)吡啶醯胺Example 4 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2, 5-difluorophenoxy)pyridiniumamine

步驟1)1-(苄氧基)-2,5-二氟-4-硝基苯 Step 1) 1-(Benzyloxy)-2,5-difluoro-4-nitrobenzene

將2,4,5-三氟硝基苯(5.4g,30.5mmol)和苯甲醇(3.2ml,30.5mmol)混合溶液溶於二甲基甲醯胺(20mL),然後加入碳酸鉀(6.33g,46.1mmol)。反應液在室溫攪拌反應72小時。在0℃下加入水(60mL)後,所得反應混合物繼續在4℃攪拌24小時。過濾,收集固體,並用30mL水洗滌,45℃真空乾燥得到標題化合物為淡黃色固體(6.0g,74%)。 A mixed solution of 2,4,5-trifluoronitrobenzene (5.4 g, 30.5 mmol) and benzyl alcohol (3.2 ml, 30.5 mmol) was dissolved in dimethylformamide (20 mL), then potassium carbonate (6.33 g) , 46.1 mmol). The reaction solution was stirred at room temperature for 72 hours. After adding water (60 mL) at 0 ° C, the resulting reaction mixture was stirred at 4 ° C for 24 hours. Filtration, EtOAc (EtOAc) (EtOAc)

1H NMR(400MHz,CDCl3):δ(ppm)5.22(s,2H),6.85-6.89(m,1H),7.40-7.43(m,5H),7.89-7.94(m,1H)。 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 5.22 (s, 2H), 6.85-6.89 (m, 1H), 7.40-7.43 (m, 5H), 7.89-7.94 (m, 1H).

步驟2)4-氨基-2,5-二氟苯酚 Step 2) 4-Amino-2,5-difluorophenol

將1-(苄氧基)-2,5-二氟-4-硝基苯(1.06g,4mmol)懸浮於甲醇(25mL)和四氫呋喃(5mL)的混合溶液中,然後加入Pd/C(50% Pd含量,185mg)。反應液在H2條件下於32℃攪拌反應10小時。反應混合物通過矽藻土過濾,濾液進行真空濃縮。所得殘留物用二氯甲烷(15mL)洗滌,得到標題化合物為深褐色固體(500mg,86%)。 1-(Benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) was suspended in a mixed solution of methanol (25 mL) and tetrahydrofuran (5 mL), then Pd/C (50) % Pd content, 185 mg). The reaction solution was stirred at 32 ° C for 10 hours under H 2 conditions. The reaction mixture was filtered through celite, and filtrate was concentrated in vacuo. The residue was washed with EtOAc (EtOAc)

MS(ESI,pos.ion)m/z:146.2[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)4.68(s,2H),6.53-6.65(m,2H),9.06(br,1H)。 MS (ESI, pos. ion) m/z: 146.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 4.68 (s, 2H), 6.53-6.65 (m, 2H) ), 9.06 (br, 1H).

步驟3)4-(4-氨基-2,5-二氟苯氧基)吡啶醯胺 Step 3) 4-(4-Amino-2,5-difluorophenoxy)pyridinium

將4-氨基-2,5-二氟苯酚(100mg,0.64mmol)和4-氯吡啶醯胺(110 mg,0.71mmol)溶於二甲基甲醯胺(2mL),然後加入NaH(80mg,1.3mmol,60%分散於礦物油中)。將反應液置於微波下,120℃反應1.5小時。反應混合物冷卻至室溫,用水(20mL)稀釋,用乙酸乙酯(30mL x 3)萃取。合併的有機相用食鹽水(80mL)洗滌,用無水硫酸鈉乾燥,並真空濃縮。殘留物通過快速柱層析(EtOAc/PE(v/v)=4/1)純化得到標題化合物為褐色固體(52mg,26%)。 4-Amino-2,5-difluorophenol (100 mg, 0.64 mmol) and 4-chloropyridiniumamine (110 Mg, 0.71 mmol) was dissolved in dimethylformamide (2 mL) then NaH (80 mg, 1.3 mmol, 60% disperse in mineral oil). The reaction solution was placed under microwave and reacted at 120 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL) The combined organic phases were washed with EtOAc EtOAc m. The residue was purified by flash chromatography eluting elut elut elut elut elut elut

MS(ESI,pos.ion)m/z:266.2[M+H]+MS (ESI, pos.) m/z: 266.2 [M+H] + .

步驟4)4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2,5-二氟苯氧基)吡啶醯胺 Step 4) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2, 5-difluorophenoxy)pyridiniumamine

將4-(4-氨基-2,5-二氟苯氧基)吡啶醯胺(200mg,0.76mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(165mg,0.75mmol)的混合溶液溶於二氯甲烷(10mL)中,然後加入EDCI(175mg,0.93mmol)和HOAT(26mg,0.15mmol)。反應液在45℃攪拌反應16小時後,冷卻至室溫,並用乙酸乙酯(20mL)稀釋。過濾,所得固體於45℃真空乾燥過夜,得到標題化合物為白色固體(230mg,63.7%)。 4-(4-Amino-2,5-difluorophenoxy)pyridiniumamine (200 mg, 0.76 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3- A mixed solution of dihydro-1 H -pyrazole-4-carboxylic acid (165 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), then EDCI (175 mg, 0.93 mmol) and HOAT (26 mg, 0.15 mmol). After the reaction mixture was stirred at 45 ° C for 16 hr, then cooled to room temperature and diluted with ethyl acetate (20 mL). Filtration and the resulting solid were dried in vacuo tolululu

MS(ESI,pos.ion)m/z:480.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)11.24(s,1H),8.53-8.57(m,2H),8.15(s,1H),7.75(s,1H),7.53-7.59(m,4H),7.44-7.45(m,3H),7.24-7.25(d,J=5.2Hz,1H),3.43(s,3H),2.70(s,3H)。 MS (ESI, pos. ion) m/z: 480.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 11.24 (s, 1H), 8.53 - 8.57 (m, 2H) ), 8.15 (s, 1H), 7.75 (s, 1H), 7.53 - 7.59 (m, 4H), 7.44 - 7.45 (m, 3H), 7.24 - 7.25 (d, J = 5.2 Hz, 1H), 3.43 ( s, 3H), 2.70 (s, 3H).

實施例5 3-氯-4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2,5-二氟苯氧基)吡啶醯胺Example 5 3-Chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido) )-2,5-difluorophenoxy)pyridinium

將化合物N-(2,5-二氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(395mg,1.1mmol)溶解在DMF(5.0mL)中,然後向反應液中加入t-BuOK(202mg,1.8mmol),室溫攪拌30分鐘後,加入3,4-二氯-2-吡啶甲醯胺(190mg,1.0mmol),混合物於微波條件下在120℃ 攪拌反應2小時後,冷卻至室溫,加入水(30mL)淬滅反應,混合物用EtOAc(50mL x 3)萃取,合併的有機相用食鹽水(50mL x 3)洗,用無水Na2SO4乾燥,然後減壓濃縮,得到的殘留物經矽膠柱層析(MeOH/DCM(v/v)=1/30)純化得到標題化合物為淡黃色固體(310mg,60%)。 The compound N -(2,5-difluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole- 4-decylamine (395 mg, 1.1 mmol) was dissolved in DMF (5.0 mL), then t- BuOK (202 mg, 1.8 mmol) was added to the reaction mixture, and stirred at room temperature for 30 minutes, then 3,4-dichloro- 2-Pyridylcaroxime (190 mg, 1.0 mmol), EtOAc (50 mL, EtOAc) the combined organic phase was washed with brine (50mL x 3) washed, dried over anhydrous Na 2 SO 4, then concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (MeOH / DCM (v / v ) = 1/30 The title compound was obtained as a pale-yellow solid (310 mg, 60%).

MS(ESI,pos.ion)m/z:514.2[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.70(s,3H),3.38(s,3H),6.96(d,J=5.5Hz,1H),7.45(d,J=7.0Hz,2H),7.51-7.55(m,1H),7.58-7.66(m,3H),7.75(s,1H),8.05(s,1H),8.34(d,J=5.5Hz,1H),8.53-8.58(m,1H),11.25(s,1H)。 MS (ESI, pos.ion) m / z: 514.2 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.70 (s, 3H), 3.38 (s, 3H), 6.96 (d, J = 5.5 Hz, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.51-7.55 (m, 1H), 7.58-7.66 (m, 3H), 7.75 (s, 1H), 8.05 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.53 - 8.58 (m, 1H), 11.25 (s, 1H).

實施例6 4-(3-氯-4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺Example 6 4-(3-Chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Phenoxy)pyridinium

步驟1)4-(4-氨基-3-氯苯氧基)吡啶醯胺 Step 1) 4-(4-Amino-3-chlorophenoxy)pyridinium

將4-氨基-2-氯苯酚鹽酸鹽(446mg,2.4mmol)溶於二甲亞碸(4mL)中,然後加入NaH(280mg,7.0mmol,60%分散於礦物油中)。反應液在室溫攪拌30分鐘後,加入4-氯吡啶甲醯胺(345mg,2.2mmol)。將反應液置於微波下,160℃反應2小時後,冷卻至室溫,用水(20mL)稀釋。所得混合物用乙酸乙酯(20mL x 3)萃取,合併的有機相用食鹽水(20mL)洗滌,用無水硫酸鈉乾燥,並真空濃縮。殘留物通過矽膠柱層析(EtOAc/PE(v/v)=1/1)純化得到標題化合物為橙色固體(170mg,29%)。 4-Amino-2-chlorophenol hydrochloride (446 mg, 2.4 mmol) was dissolved in dimethyl hydrazine (4 mL) then NaH (280 mg, 7.0 mmol, 60% dispersion in mineral oil). After the reaction mixture was stirred at room temperature for 30 minutes, 4-chloropyridylcarbamide (345 mg, 2.2 mmol) was added. The reaction solution was placed under microwave at 160 ° C for 2 hours, cooled to room temperature and diluted with water (20 mL). The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

MS(ESI,pos.ion)m/z:264.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)5.45(s,2H),6.89(d,J=8.7Hz,1H),6.92(m,1H),7.11(m,1H),7.16(d,J=2.6Hz,1H),7.34(d,J=2.6 Hz,1H),7.68(s,1H),8.10(s,1H),8.47(d,J=5.6Hz,1H)。 MS (ESI, pos.ion) m / z: 264.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 5.45 (s, 2H), 6.89 (d, J = 8.7 Hz, 1H), 6.92 (m, 1H), 7.11 (m, 1H), 7.16 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.68 (s, 1H), 8.10 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H).

步驟2)4-(3-氯-4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺 Step 2) 4-(3-Chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Phenoxy)pyridinium

將4-(4-氨基-3-氯苯氧基)吡啶醯胺(191mg,0.72mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(168mg,0.72mmol)懸浮於二氯甲烷(10mL)中,然後加入EDCI(166mg,0.86mmol)和HOAT(20mg,0.14mmol)。反應液在46℃攪拌6小時後,加入1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(32mg,0.14mmol)和EDCI(27mg,0.14mmol)。反應混合物在46℃繼續攪拌13小時,冷卻至室溫,並用水(10mL)稀釋。所得混合物用乙酸乙酯(10mL x 3)萃取,合併的有機相用食鹽水(10mL)洗滌,用無水硫酸鈉乾燥,並真空濃縮。殘留物通過矽膠柱層析(DCM/MeOH(v/v)=50/1)純化得到標題化合物為淡黃色固體(160mg,46.5%)。 4-(4-Amino-3-chlorophenoxy)pyridiniumamine (191 mg, 0.72 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1H -pyrazole-4-carboxylic acid (168 mg, 0.72 mmol) was suspended in dichloromethane (10 mL) then EDCI (166 mg, <RTIgt; After the reaction mixture was stirred at 46 ° C for 6 hours, 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxylic acid (32 mg, 0.14) was added. Methyl) and EDCI (27 mg, 0.14 mmol). The reaction mixture was stirred at 46 ° C for further 13 hours, cooled to room temperature and diluted with water (10 mL). The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

MS(ESI,pos.ion)m/z:478.2[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.71(s,3H),3.37(s,3H),7.19(m,1H),7.23(m,1H),7.43(m,3H),7.50(m,2H),7.60(m,2H),7.72(s,1H),8.13(s,1H),8.52(d,J=5.6Hz,1H),8.63(d,J=9.1Hz,1H),11.19(s,1H)。 MS (ESI, pos.ion) m / z: 478.2 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.71 (s, 3H), 3.37 (s, 3H), 7.19 (m, 1H), 7.23 (m, 1H), 7.43 (m, 3H), 7.50 (m, 2H), 7.60 (m, 2H), 7.72 (s, 1H), 8.13 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.63 (d, J = 9.1 Hz, 1H), 11.19 (s, 1H).

實施例7 4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺Example 7 4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)pyridine- 3-yl)oxy)pyridinium

步驟1)4-((6-氨基吡啶-3-基)氧基)吡啶醯胺 Step 1) 4-((6-Aminopyridin-3-yl)oxy)pyridinium

將6-氨基吡啶-3-醇(220mg,2mmol)和t-BuOK(225mg,2.16mmol)溶於二甲基甲醯胺(2.5mL)中,然後加入4-氯吡啶甲醯胺(315mg,2mmol)。反應液在80℃下加熱5小時後,冷卻至室溫,用乙酸乙酯(50mL)和水(50mL)稀釋。有機相真空濃縮,所得殘留物通過矽膠柱層析(DCM/CH3OH(v/v)=30/1)純化得到標題化合物為褐色固體(230mg,50 %)。 6-Aminopyridin-3-ol (220 mg, 2 mmol) and t- BuOK (225 mg, 2.16 mmol) were dissolved in dimethylformamide (2.5 mL), then 4-chloropyridylcarbamide (315 mg, 2mmol). The reaction mixture was heated at 80 ° C for 5 hr, then cooled to room temperature and diluted with ethyl acetate (50mL) and water (50mL). The organic phase was concentrated in vacuo, the resulting residue was purified by silica gel column chromatography (DCM / CH 3 OH (v / v) = 30/1) to give the title compound as a tan solid (230mg, 50%).

MS(ESI,pos.ion)m/z:231.1[M+H]+1H NMR(400MHz,CDCl3):δ(ppm)6.09(s,2H),6.53-6.56(d,J=8.88Hz,1H),7.12-7.14(dd,J=2.64Hz,5.6Hz,1H),7.31-7.34(dd,J=2.92Hz,8.88Hz,1H),7.35-7.36(d,J=2.48Hz,1H),7.70(s,1H),7.83-7.84(d,J=2.8Hz,1H),8.11(s,1H),8.46-8.49(d,J=5.6Hz,1H)。 MS (ESI, pos. ion) m/z: 231.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 6.09 (s, 2H), 6.53-6.56 (d, J = 8.88) Hz, 1H), 7.12-7.14 (dd, J = 2.64 Hz, 5.6 Hz, 1H), 7.31-7.34 (dd, J = 2.92 Hz, 8.88 Hz, 1H), 7.35-7.36 (d, J = 2.48 Hz, 1H), 7.70 (s, 1H), 7.83-7.84 (d, J = 2.8 Hz, 1H), 8.11 (s, 1H), 8.46-8.49 (d, J = 5.6 Hz, 1H).

步驟2)4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺 Step 2) 4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)pyridine- 3-yl)oxy)pyridinium

將4-((6-氨基吡啶-3-基)氧基)吡啶醯胺(230mg,1mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(237mg,1.02mmol)懸浮於二氯甲烷(5mL)中,然後加入EDCI(230mg,1.2mmol)和HOAT(27mg,0.2mmol)。反應液在45℃攪拌28小時,冷卻至室溫後,用水(10mL)和二氯甲烷(20mL)稀釋。有機相真空濃縮,所得殘留物通過矽膠柱層析純化(DCM/CH3OH(v/v)=40/1)得到標題化合物為淺灰色固體(111 mg,25%)。 4-((6-Aminopyridin-3-yl)oxy)pyridiniumamine (230 mg, 1 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro -1 H -pyrazole-4-carboxylic acid (237 mg, 1.02 mmol) was suspended in dichloromethane (5 mL) then EtOAc (230 <RTIgt; The reaction mixture was stirred at 45 ° C for 28 hours, cooled to room temperature and diluted with water (10 mL) and dichloromethane (20 mL). The organic phase was concentrated in vacuo, the resulting residue was purified by silica gel column chromatography the title compound (DCM / CH 3 OH (v / v) = 40/1) by a light gray solid (111 mg, 25%).

MS(ESI,pos.ion)m/z:445.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.72(s,3H),3.33(s,3H),7.20-7.22(dd,J=2.64Hz,5.64Hz,1H),7.43-7.46(m,3H),7.52-7.54(m,1H),7.58-7.62(m,2H),7.72(s,3H),7.75-7.78(dd,J=2.88Hz,8.96Hz,1H),8.13(s,1H),8.27-8.28(d,J=2.68Hz,1H),8.34-8.36(d,J=9.08Hz,1H),8.52-8.54(d,J=5.6Hz,1H)。 MS (ESI, pos.ion) m / z: 445.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.72 (s, 3H), 3.33 (s, 3H), 7.20-7.22 (dd, J = 2.64 Hz, 5.64 Hz, 1H), 7.43-7.46 (m, 3H), 7.52-7.54 (m, 1H), 7.58-7.62 (m, 2H), 7.72 (s, 3H) , 7.75-7.78 (dd, J = 2.88 Hz, 8.96 Hz, 1H), 8.13 (s, 1H), 8.27-8.28 (d, J = 2.68 Hz, 1H), 8.34 - 8.36 (d, J = 9.08 Hz, 1H), 8.52 - 8.54 (d, J = 5.6 Hz, 1H).

實施例8 N-(5-((2-(環丙烷甲醯胺基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 8 N- (5-((2-(cyclopropanecarbamimidyl)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine

步驟1)N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 1) N- (5-((2-Aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -dihydro-1 H -pyrazole-4-decylamine

將4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺(111mg,0.25mmol)溶於乙酸乙酯(2mL)、乙腈(2mL)和水(1mL)的混合溶液中,然後加入二乙酸碘苯(97mg,0.3mmol)。反應液在0℃攪拌反應30分鐘後,升至室溫,繼續攪拌12小時。反應混合物真空濃縮,所得殘留物通過矽膠柱層析(DCM/CH3OH(v/v)=40/1)純化得到標題化合物為淺米色固體(85mg,81.7%)。 4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)pyridine-3- Alkyloxy)pyridiniumamine (111 mg, 0.25 mmol) was dissolved in a mixed solution of ethyl acetate (2 mL), acetonitrile (2 mL) and water (1 mL), and then iodobenzene diacetate (97 mg, 0.3 mmol). After the reaction mixture was stirred at 0 ° C for 30 minutes, it was allowed to warm to room temperature and stirring was continued for 12 hours. The reaction mixture was concentrated in vacuo, the resulting residue was purified by silica gel column to give the title compound chromatography (DCM / CH 3 OH (v / v) = 40/1) was purified as a pale beige solid (85mg, 81.7%).

MS(ESI,pos.ion)m/z:417.2[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.71(s,3H),3.38(s,3H),5.83(s,1H),5.98(s,2H),6.17(s,1H),7.08-7.10(m,2H),7.42-7.81(m,6H),7.80-7.81(d,J=5.8Hz,1H),8.17(s,1H),8.29-8.31(d,J=8.56Hz,1H),11.19(s,1H)。 MS (ESI, pos.ion) m / z: 417.2 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.71 (s, 3H), 3.38 (s, 3H), 5.83 (s, 1H), 5.98 (s, 2H), 6.17 (s, 1H), 7.08-7.10 (m, 2H), 7.42-7.81 (m, 6H), 7.80-7.81 (d, J = 5.8 Hz, 1H), 8.17 (s, 1H), 8.29-8.31 (d, J = 8.56 Hz, 1H), 11.19 (s, 1H).

步驟2)N-(5-((2-(環丙烷甲醯胺基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N- (5-((2-(cyclopropanecarbamoyl)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine

將化合物N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(500mg,1.2mmol)懸浮在DCM(5mL)和三乙胺(1mL)中,冷卻至0℃,然後向反應液中緩慢加入環丙基甲醯氯(377mg,3.6mmol),升至室溫並攪拌反應4.5小時,然後加入DCM(10mL)和水(10mL)稀釋反應液,將分液得到的有機相減壓濃縮,得到的殘留物溶解在MeOH(30mL),然後加入飽和Na2CO3的水溶液(30mL),得到的混合物室溫攪拌2小時後,抽濾,並將濾液減壓濃縮,殘留物經矽膠柱層析(DCM/MeOH(v/v)=50/1)純化得到標題化合物為灰白色固體(350mg,60%)。 The compound N- (5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1 H -pyrazole-4-decylamine (500 mg, 1.2 mmol) was suspended in DCM (5 mL) and triethylamine (1 mL), cooled to 0 ° C, then slowly added to the reaction mixture. The mixture was stirred at room temperature and stirred for 4.5 hours. The reaction mixture was diluted with DCM (10 mL) and water (10 mL). after MeOH (30mL), then saturated aqueous Na 2 CO 3 in (30mL) was added, the resulting mixture was stirred at room temperature for 2 hours and filtered off with suction, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH (v/v) = 50/1).

MS(ESI,pos.ion)m/z:485.3[M+H]+;HPLC:99.7%;1H NMR(600MHz,CDCl3):δ(ppm)11.25(s,1H),9.42(s,1H),8.37(t,J=12.0Hz,1H),8.17(t,J=7.5Hz,1 H),8.10(t,J=9.8Hz,1 H),7.93(d,J=2.1Hz,1 H),7.60-7.51(m,2 H),7.51-7.42(m,2 H),7.41-7.36(m,2 H),6.64(dd,J=6.1,2.4Hz,1 H),5.32(s,1 H),3.39(s,3 H),2.81(s,3 H),1.14-1.05 (m,2 H),0.97-0.88(m,2 H)。 MS (ESI, pos.) m/z: 485.3 [M+H] + ; HPLC: 99.7%; 1 H NMR (600 MHz, CDCl 3 ): δ (ppm) 11.25 (s, 1H), 9.42 (s, 1H), 8.37 (t, J = 12.0 Hz, 1H), 8.17 (t, J = 7.5 Hz, 1 H), 8.10 (t, J = 9.8 Hz, 1 H), 7.93 (d, J = 2.1 Hz, 1 H), 7.60-7.51 (m, 2 H), 7.51-7.42 (m, 2 H), 7.41-7.36 (m, 2 H), 6.64 (dd, J = 6.1, 2.4 Hz, 1 H), 5.32 (s, 1 H), 3.39 (s, 3 H), 2.81 (s, 3 H), 1.14-1.05 (m, 2 H), 0.97-0.88 (m, 2 H).

實施例9 3-氯-4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺Example 9 3-Chloro-4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Pyridin-3-yl)oxy)pyridinium

步驟1)N-(5-羥基吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 1) N- (5-Hydroxypyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-indole amine

將6-氨基吡啶-3-醇(330mg,3mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(710mg,306mmol)懸浮於二甲基甲醯胺(10mL)中,然後加入EDCI(690mg,3.6mmol)和HOAT(80mg,0.6mmol)。反應液在60℃攪拌反應4小時後,冷卻至室溫,並用水(100mL)和乙酸乙酯(2mL)稀釋。反應混合物冷卻至0℃並攪拌過夜。過濾,收集固體,得到標題化合物為淺褐色固體(680mg,70%)。 6-Aminopyridin-3-ol (330 mg, 3 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxylic acid (710 mg, 306 mmol) was suspended in dimethylformamide (10 mL), then EDCI (690 mg, 3.6 mmol) and HOAT (80 mg, 0.6 mmol). After the reaction mixture was stirred at 60 ° C for 4 hours, it was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (2 mL). The reaction mixture was cooled to 0 ° C and stirred overnight. The title compound was obtained as a light brown solid (yield: 680mg, 70%).

MS(ESI,pos.ion)m/z:325.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.50(s,3H),3.33(s,3H),7.18-7.20(dd,J=2.3Hz,8.8Hz,1H),7.40-7.42(d,J=7.5Hz,2H),7.48-7.52(m,1H),7.56-7.60(m,2H),7.81-7.82(d,J=2.2Hz,1H),7.95(s,1H),8.04-8.06(d,J=8.8Hz,1H),9.61(s,1H),10.85(s,1H)。 MS (ESI, pos.ion) m / z: 325.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.50 (s, 3H), 3.33 (s, 3H), 7.18-7.20 (dd, J = 2.3 Hz, 8.8 Hz, 1H), 7.40-7.42 (d, J = 7.5 Hz, 2H), 7.48-7.52 (m, 1H), 7.56-7.60 (m, 2H), 7.81 - 7.82 (d, J = 2.2 Hz, 1H), 7.95 (s, 1H), 8.04-8.06 (d, J = 8.8 Hz, 1H), 9.61 (s, 1H), 10.85 (s, 1H).

步驟2)3-氯-4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺 Step 2) 3-Chloro-4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Pyridin-3-yl)oxy)pyridinium

將6-氨基吡啶-3-醇(324mg,1mmol)和t-BuOK(135mg,1.2mmol)溶於二甲基甲醯胺(2mL),然後加入3,4-二氯-2-吡啶甲醯胺(191mg,1mmol)。反應液在80℃攪拌反應15小時後,冷卻至室溫,用乙酸乙酯(1mL)和水(20mL)稀釋。反應混合物攪拌過夜,過濾,收集固體,得到標題化合物為褐色固體(290mg,60.5%)。 6-Aminopyridin-3-ol (324 mg, 1 mmol) and t- BuOK (135 mg, 1.2 mmol) were dissolved in dimethylformamide (2 mL) then 3,4-dichloro-2-pyridinecarboxamide Amine (191 mg, 1 mmol). After the reaction mixture was stirred at 80 ° C for 15 hours, it was cooled to room temperature and diluted with ethyl acetate (1 mL) and water (20 mL). The reaction mixture was stirred with EtOAc EtOAc m.

MS(ESI,pos.ion)m/z:479.2[M+H]+1H NMR(400MHz,CDCl3):δ(ppm)2.72(s,3H),3.35(s,3H),6.91-6.92(d, J=5.5Hz,1H),6.09(s,2H),7.43-7.45(m,2H),7.50-7.54(m,1H),7.58-7.62(m,2H),7.73-7.76(m,2H),8.03(s,1H),8.26-8.27(d,J=2.7Hz,1H),8.33-8.36(m,2H),11.26(s,1H)。 MS (ESI, pos.ion) m / z: 479.2 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ (ppm) 2.72 (s, 3H), 3.35 (s, 3H), 6.91- 6.92 (d, J = 5.5 Hz, 1H), 6.09 (s, 2H), 7.43-7.45 (m, 2H), 7.50-7.54 (m, 1H), 7.58-7.62 (m, 2H), 7.73-7.76 ( m, 2H), 8.03 (s, 1H), 8.26-8.27 (d, J = 2.7 Hz, 1H), 8.33 - 8.36 (m, 2H), 11.26 (s, 1H).

實施例10 4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺Example 10 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2- Fluorophenoxy)pyridinium

步驟1)N-(3-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 1) N- (3-Fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4- Guanamine

將4-氨基-2-氟苯酚(2.54g,20mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(4.74g,20.4mmol)懸浮於DCM(60mL)中,並向其中加入EDCI(4.6g,24mmol)和HOAT(0.54g,4mmol)。反應液在45℃攪拌12小時後,冷卻至室溫,並加水(10mL)淬滅。混合物繼續攪拌4小時,過濾,收集固體,所得固體用DCM(20mL x 3)洗,並於60℃真空乾燥12小時,得到標題化合物為土黃色固體(6.37g,93.4%)。 4-Amino-2-fluorophenol (2.54 g, 20 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxylate The acid (4.74 g, 20.4 mmol) was suspended in DCM (60 mL) and EDCI (4.6 g, 24 mmol) and HOAT (0.54 g, 4mmol). The reaction was stirred at 45 &lt;0&gt;C for 12 h then cooled to EtOAc EtOAc >EtOAc. The mixture was stirred for 4 hours, filtered, and EtOAc was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS(ESI,pos.ion)m/z:342.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.59(s,1H),9.58(s,1H),7.64(dd,J=2.4Hz,13.5Hz,1H),7.60(m,2H),7.50(m,1H),7.42(m,2H),6.97(m,1H),6.88(dd,J=9.6Hz,8.8Hz,1H),3.34(s,3H),2.70(s,3H)。 MS (ESI, pos.ion) m / z: 342.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 10.59 (s, 1H), 9.58 (s, 1H), 7.64 (dd, J = 2.4 Hz, 13.5 Hz, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.42 (m, 2H), 6.97 (m, 1H), 6.88 (dd, J = 9.6) Hz, 8.8 Hz, 1H), 3.34 (s, 3H), 2.70 (s, 3H).

步驟2)4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺 Step 2) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2- Fluorophenoxy)pyridinium

N-(3-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(2.2g,6.4mmol),4-氯吡啶甲醯胺(1g,6.39mmol)溶於DMSO(12mL)中,並向其中加入NaH(615mg,12.3mmol,50%分散於礦物油中),反應液在160℃攪拌反應20小時後,冷卻至室溫,加水(70mL)淬 滅反應。混合物用EtOAc(100mL x 3)萃取,合併的有機相用食鹽水(100mL)洗,用無水Na2SO4乾燥,並減壓濃縮。所得殘留物經矽膠柱層析(PE/EtOAc(v/v)=1/4)純化,得到標題化合物為白色固體(0.85g,29%)。 N- (3-Fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine (2.2 g, 6.4 mmol), 4-chloropyridinecarbamide (1 g, 6.39 mmol) was dissolved in DMSO (12 mL), and NaH (615 mg, 12.3 mmol, 50% dispersion in mineral oil) was added thereto. After the reaction was stirred at 160 ° C for 20 hours, it was cooled to room temperature and then quenched with water (70 mL). The mixture (100mL x 3) and extracted with EtOAc, and the combined organic phase was washed with brine (100 mL) wash, dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:

MS(ESI,pos.ion)m/z:462.1[M+H]+1H NMR(400MHz,CDCl3):δ(ppm)10.87(s,1H),8.40-8.41(d,J=5.6Hz,1H),7.88-7.92(dd,J=2.4Hz,12.6Hz,1H),7.82-7.83(d,J=3.9Hz,1H),7.71-7.71(d,J=2.5Hz,1H),7.54-7.58(m,2H),7.46-7.49(m,1H),7.35-7.37(d,J=8.6Hz,2H),7.07-7.11(m,1H),6.96-6.98(dd,J=2.5Hz,5.6Hz,1H),5.56(s,1H),3.37(s,3H),2.79(s,3H)。 MS (ESI, pos. ion) m/z: 4621. [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 10.87 (s, 1H), 8.40-8.41 (d, J = 5.6 Hz, 1H), 7.88-7.92 (dd, J = 2.4 Hz, 12.6 Hz, 1H), 7.82-7.83 (d, J = 3.9 Hz, 1H), 7.71-7.71 (d, J = 2.5 Hz, 1H), 7.54-7.58 (m, 2H), 7.46-7.49 (m, 1H), 7.35-7.37 (d, J = 8.6 Hz, 2H), 7.07-7.11 (m, 1H), 6.96-6.98 (dd, J = 2.5 Hz, 5.6 Hz, 1H), 5.56 (s, 1H), 3.37 (s, 3H), 2.79 (s, 3H).

實施例11 N-(4-((2-((環丙烷甲醯胺基)吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 11 N -(4-((2-((cyclopropanecarbamoyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo -2-phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine

步驟1)N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 1) N- (4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1 H -pyrazole-4-decylamine

將4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺(0.4g,0.86mmol)和PhI(OAc)2(419mg,1.5mmol)溶解在EtOAc(8mL),MeCN(8mL)和H2O(4mL)的混合液中,冷卻至0℃,攪拌30分鐘。將反應液升至室溫,繼續攪拌8小時。混合物用NaHCO3水溶液(60mL)稀釋,並用EtOAc(100mL x 3)萃取。合併的有機相用食鹽水(100mL)洗,無水Na2SO4乾燥,並減壓濃縮,所得殘留物經矽膠柱層析(DCM/MeOH(v/v)=10/1)純化,得到標題化合物為白色固體(0.21g,56%)。 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-2-fluorobenzene oxy) pyridin-acyl amine (0.4g, 0.86mmol) and PhI (OAc) 2 (419mg, 1.5mmol) was dissolved in EtOAc (8mL) MeCN (8mL) and H 2 O (4mL) the mixture was cooled to Stir at 0 ° C for 30 minutes. The reaction solution was warmed to room temperature and stirring was continued for 8 hours. The mixture was diluted with aqueous NaHCO 3 (60mL), and extracted with EtOAc (100mL x 3). The combined organic phase was washed with brine (100 mL) wash, dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure, the resulting residue (10/1 DCM / MeOH ( v / v) =) was purified by silica gel column chromatography to give the title The compound was a white solid (0.21 g, 56%).

MS(ESI,pos.ion)m/z:434.2[M+H]+1H NMR(400MHz,CDCl3):δ(ppm)10.83(s,1H),7.91-7.92(d,J=5.9Hz,1H),7.83-7.86(dd,J=2.4Hz,10.1Hz,1H),7.56-7.58(m,2H),7.46-7.52(d,J=5.9Hz,2H),7.35-7.37(d,J=8.6Hz,2H),7.04-7.09(m,1H),6.29-6.31 (m,1H),5.92-5.93(d,J=2.1Hz,1H),4.45(s,2H),3.37(s,3H),2.79(s,3H)。 MS (ESI, pos.) m/z: 434.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 10.83 (s, 1H), 7.91 - 7.92 (d, J = 5.9 Hz, 1H), 7.83-7.86 (dd, J = 2.4 Hz, 10.1 Hz, 1H), 7.56-7.58 (m, 2H), 7.46-7.52 (d, J = 5.9 Hz, 2H), 7.35-7.37 (d , J = 8.6 Hz, 2H), 7.04-7.09 (m, 1H), 6.29-6.31 (m, 1H), 5.92-5.93 (d, J = 2.1 Hz, 1H), 4.45 (s, 2H), 3.37 ( s, 3H), 2.79 (s, 3H).

步驟2)N-(4-((2-((環丙烷甲醯胺基)吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N- (4-((2-((cyclopropanecarbamoyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo -2-phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine

將化合物N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(217mg,0.5mmol)溶解在DCM(5mL)中,冷卻至0℃,然後向反應液中加入Et3N(253mg,2.5mmol)和環丙基甲醯氯(125mg,1.2mmol),室溫攪拌反應4小時後,加入H2O(10mL)淬滅反應,得到的混合物用DCM(50mL x 3)萃取,合併的有機相用食鹽水(50mL x 3)洗,用無水Na2SO4乾燥,然後減壓濃縮,得到的殘留物溶解在CH3OH(20mL)中,然後加入Na2CO3(106mg,1.0mmol)的水(1mL)溶液,得到的混合物室溫攪拌1小時後,減壓濃縮,得到的殘留物經矽膠柱層析(100% DCM)純化得到標題化合物為米黃色固體(158mg,63.2%)。 The compound N -(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1 H -pyrazole-4-decylamine (217 mg, 0.5 mmol) was dissolved in DCM (5 mL), cooled to 0 ° C, then Et 3 N (253 mg, 2.5 mmol) propyl methyl acyl chloride (125mg, 1.2mmol), stirred at room temperature for 4 hours, added H 2 O (10mL) was quenched reaction mixture was extracted with DCM (50mL x 3), the combined organic phase was washed with brine (50mL x 3) washing, Na 2 SO 4 dried over anhydrous, and then concentrated under reduced pressure, the resulting residue was dissolved in CH 3 OH (20mL), followed by addition of Na 2 CO 3 (106mg, 1.0mmol ) in water (1 mL The resulting mixture was stirred at room temperature for 1 hr then EtOAc EtOAc m.

1H NMR(600MHz,CDCl3):δ(ppm)10.93(s,1H),10.73(s,1H),8.03(d,J=6.0Hz,2H),7.96(dd,J=12.5,2.3Hz,1H),7.59(t,J=7.8Hz,2H),7.51(d,J=7.5Hz,1H),7.38(d,J=7.4Hz,2H),7.30(d,J=9.2Hz,1H),7.12(t,J=8.7Hz,1H),6.74(dd,J=6.3,1.9Hz,1H),3.40(s,3H),2.81(s,3H),1.79(m,1H),1.12(m,2H),0.97(m,2H)。 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 10.93 (s, 1H), 10.73 (s, 1H), 8.03 (d, J = 6.0Hz, 2H), 7.96 (dd, J = 12.5,2.3Hz , 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.51 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H) ), 7.12 (t, J = 8.7 Hz, 1H), 6.74 (dd, J = 6.3, 1.9 Hz, 1H), 3.40 (s, 3H), 2.81 (s, 3H), 1.79 (m, 1H), 1.12 (m, 2H), 0.97 (m, 2H).

實施例12 4-(5-氯-4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺Example 12 4-(5-Chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) )-2-fluorophenoxy)pyridinium

步驟1)1-氯-4,5-二氟-2-硝基苯 Step 1) 1-Chloro-4,5-difluoro-2-nitrobenzene

向反應瓶中加入4-氯-1,2-二氟苯(8.97g,60.4mmol),冷卻至0℃,然後再依次加入98%的濃H2SO4(16.1mL,302mmol)和65%的濃 HNO3(5.0mL,66.4mmol),在室溫攪拌反應5小時後,傾倒入冰水中,得到的混合物用EtOAc(200mL x 2)萃取,合併的有機相依次用飽和的NaHCO3水溶液(200mL x 2)和食鹽水(200mL)洗,用無水Na2SO4乾燥,減壓濃縮得到標題化合物為黃色液體(11.31g,96.7%)。 4-Chloro-1,2-difluorobenzene (8.97 g, 60.4 mmol) was added to the reaction flask, cooled to 0 ° C, then 98% concentrated H 2 SO 4 (16.1 mL, 302 mmol) and then 65%. after concentrated HNO 3 (5.0mL, 66.4mmol), stirred at room temperature for 5 hours, poured into ice water, and the mixture was extracted with EtOAc (200mL x 2), the combined organic phases are washed with saturated aqueous NaHCO 3 ( 200mL x 2) and brine (200mL) washed, dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure to give the title compound as a yellow liquid (11.31g, 96.7%).

1H NMR(400MHz,CDCl3):δ(ppm)7.41-7.45(m,1H),7.86-7.90(m,1H)。 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.41 - 7.45 (m, 1H), 7.86 - 7.90 (m, 1H).

步驟2)5-氯-2-氟-4-硝基苯酚鉀 Step 2) Potassium 5-chloro-2-fluoro-4-nitrophenolate

化合物1-氯-4,5-二氟-2-硝基苯(5.12g,26.5mmol)和15%的KOH(19.9g,0.35mol)水溶液的混合物攪拌回流3小時後,冷卻至室溫,抽濾,得到標題化合物為黃色固體(5.67g,93.3%)。 A mixture of the compound 1-chloro-4,5-difluoro-2-nitrobenzene (5.12 g, 26.5 mmol) and 15% KOH (19.9 g, 0.35 mol) was stirred and refluxed for 3 hr then cooled to room temperature. The title compound was obtained as a yellow solid (5.67 g, 93.3%).

1H NMR(400MHz,DMSO-d 6):δ(ppm)6.20(d,J=13.2Hz,1H),7.70(d,J=8.6Hz,1H)。 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 6.20 (d, J = 13.2 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H).

步驟3)4-氨基-5-氯-2-氟苯酚 Step 3) 4-Amino-5-chloro-2-fluorophenol

將化合物5-氯-2-氟-4-硝基苯酚鉀(1.0g,4.35mmol)溶解在EtOH(22mL,95%)和H2O(8mL)的混合溶劑中,然後向反應液中加入鐵粉(0.97g,17.4mmol)和NH4Cl(1.86g,34.8mmol),室溫攪拌反應10小時後,加入甲醇(25mL)和乙酸乙酯(25mL)稀釋反應液,抽濾,將濾液減壓濃縮,殘留物用乙酸乙酯(40mL)稀釋,用食鹽水(25mL)洗,用無水Na2SO4乾燥,減壓濃縮得到標題化合物為灰白色固體(0.6g,85.3%)。 The compound 5-chloro-2-fluoro-4-nitrophenol potassium (1.0 g, 4.35 mmol) was dissolved in a mixed solvent of EtOH (22 mL, 95%) and H 2 O (8 mL), and then added to the reaction mixture. Iron powder (0.97 g, 17.4 mmol) and NH 4 Cl (1.86 g, 34.8 mmol), the mixture was stirred at room temperature for 10 hours, then the mixture was diluted with methanol (25 mL) and ethyl acetate (25 mL) and filtered. concentrated under reduced pressure, diluted with ethyl acetate (40 mL) The residue was washed with brine (25 mL), dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure to give the title compound as an off-white solid (0.6g, 85.3%).

1H NMR(400MHz,DMSO-d 6):δ(ppm)4.90(s,2H),6.60(d,J=12.9Hz,1H),6.79(d,J=8.8Hz,1H),9.11(s,1H)。 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 4.90 (s, 2H), 6.60 (d, J = 12.9Hz, 1H), 6.79 (d, J = 8.8Hz, 1H), 9.11 (s , 1H).

步驟4)N-(2-氯-5-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 4) N- (2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyridyl Azole-4-decylamine

將化合物4-氨基-5-氯-2-氟苯酚(0.97g,6mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(1.42g,6.12mmol)懸浮在DMF(20mL)中,然後向反應液中加入EDCI(0.38mg,7.2mmol)和HOAT(0.16g,1.2mmol),加熱至80℃,攪拌反應24小時後,冷卻至0℃,然後加 入H2O(200mL)和EtOAc(2mL)稀釋反應液,抽濾,真空乾燥,得到標題化合物為淺棕色固體(1.2g,53.2%)。 The compound 4-amino-5-chloro-2-fluorophenol (0.97 g, 6 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyridyl The azole-4-carboxylic acid (1.42 g, 6.12 mmol) was suspended in DMF (20 mL), then EDCI (0.38 mg, 7.2 mmol) and HOAT (0.16 g, 1.2 mmol). after the reaction stirred for 24 hours, cooled to 0 deg.] C, then the mixture was diluted with H 2 O (200mL) and EtOAc (2mL), filtered off with suction, and dried in vacuo to give the title compound as a light brown solid (1.2g, 53.2%).

MS(ESI,pos.ion)m/z:376.1[M+H]+1H NMR(400MHz,DMSO-d 6):δ(ppm)2.68(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)。 MS (ESI, pos.ion) m / z: 376.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.68 (s, 3H), 3.34 (s, 3H), 7.03 (d, J = 8.8 Hz, 1H), 7.41-7.43 (m, 2H), 7.48-7.52 (m, 1H), 7.56-7.60 (m, 2H), 8.31 (d, J = 13.8 Hz, 1H) , 10.08 (s, 1H), 10.95 (s, 1H).

步驟5)4-(5-氯-4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺 Step 5) 4-(5-Chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) )-2-fluorophenoxy)pyridinium

將化合物N-(2-氯-5-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(751.6mg,2mmol)和t-BuOK(224.4mg,2mmol)懸浮在DMF(4mL)中,然後向反應液中4-氯吡啶甲醯胺(313.2mg,2mmol),加熱至120℃並攪拌反應15小時,然後冷卻至室溫,加入H2O(40mL),得到的混合物室溫攪拌過夜,抽濾,濾餅經矽膠柱層析(DCM/CH3OH(v/v)=50/1)純化得到標題化合物為淺黃色固體(290mg,60.5%)。 The compound N-(2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole -4-decylamine (751.6 mg, 2 mmol) and t- BuOK (224.4 mg, 2 mmol) were suspended in DMF (4 mL) and then evaporated to 4-chloropyridinecarbamide (313.2 mg, 2 mmol). 120 deg.] C and the reaction stirred for 15 hours then cooled to room temperature, H 2 O (40mL), the resulting mixture was stirred overnight at room temperature, filtered off with suction, the filter cake by silica gel column chromatography (DCM / CH 3 OH (v / v The title compound was obtained as a pale yellow solid (290 mg, 60.5%).

MS(ESI,pos.ion)m/z:496.2[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)11.37(s,1H),8.69-8.66(d,J=13.4Hz,1H),8.55-8.54(d,J=5.6Hz,1H),8.15(s,1H),7.78-7.75(m,2H),7.62-7.58(m,2H),7.55-7.51(m,1H),7.46-7.43(m,3H),7.26-7.24(dd,J=5.6Hz,2.6Hz,1H),3.38(s,3H),2.72(s,3H)。 MS (ESI, pos.) m/z: 496.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 11.37 (s, 1H), 8.69-8.66 (d, J =13.4 Hz, 1H), 8.55-8.54 (d, J = 5.6 Hz, 1H), 8.15 (s, 1H), 7.78-7.75 (m, 2H), 7.62-7.58 (m, 2H), 7.55-7.51 ( m, 1H), 7.46-7.43 (m, 3H), 7.26-7.24 (dd, J = 5.6 Hz, 2.6 Hz, 1H), 3.38 (s, 3H), 2.72 (s, 3H).

實施例13 4-(2-氯-4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺Example 13 4-(2-Chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamide) Phenoxy)pyridinium

步驟1)N-(3-氯-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 1) N- (3-Chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4- Guanamine

將化合物4-氨基-2-氯苯酚(4.0g,28.00mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(7.4g,30.11mmol)懸浮在DCM(70mL)中,然後向反應液中加入EDCI(6.65g,30.11mmol)和HOAT(0.76g,5.68mmol),加熱至45℃並攪拌反應20小時,然後冷卻至室溫,抽濾,濾餅用DCM(20mL x 3)洗,在真空乾燥箱50℃乾燥過夜,得到標題化合物為灰色固體(7.1g,72.1%)。 The compound 4-amino-2-chlorophenol (4.0 g, 28.00 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4 The carboxylic acid (7.4 g, 30.11 mmol) was suspended in DCM (70 mL), then EDCI (6.65 g, 30.11 mmol) and HOAT (0.76 g, 5.68 mmol) were added to the reaction mixture, heated to 45 ° C and stirred for reaction 20 After a few hours, it was cooled to room temperature, filtered, filtered, EtOAc EtOAcjjjjjj

MS(ESI,pos.ion)m/z:358.1[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.56(s,1H),9.92(s,1H),7.59(m,2H),7.50(m,1H),7.42(m,2H),7.83(dd,J=2.6Hz,8.7Hz,1H),6.90(d,J=8.7Hz,1H),6.88(dd,J=9.6Hz,8.8Hz,1H),3.33(s,3H),2.68(s,3H)。 MS (ESI, pos.ion) m / z: 358.1 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 10.56 (s, 1H), 9.92 (s, 1H), 7.59 (m, 2H), 7.50 (m, 1H), 7.42 (m, 2H), 7.83 (dd, J = 2.6 Hz, 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.88 ( Dd, J = 9.6 Hz, 8.8 Hz, 1H), 3.33 (s, 3H), 2.68 (s, 3H).

步驟2)4-(2-氯-4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺 Step 2) 4-(2-Chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido) Phenoxy)pyridinium

將化合物N-(3-氯-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(1.074g,3.0mmol)懸浮在DMF(12mL)中,然後向反應液中加入t-BuOK(539mg,4.8mmol),室溫攪拌30分鐘後,加入4-氯吡啶甲醯胺(517mg,3.3mmol),升溫至120℃並攪拌反應36小時,然後冷卻至室溫,加入水(50mL)淬滅反應,混合物用EtOAc(50mL x 3)萃取,合併的有機相用食鹽水(50mL x 3)洗,用無水Na2SO4乾燥,然後減壓濃縮,得到的殘留物經矽膠柱層析(EtOAc/PE(v/v)=3/1)純化得到標題化合物為白色固體(580mg,40.4%). The compound N-(3-chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine (1.074 g, 3.0 mmol) was suspended in DMF (12 mL), and then t- BuOK (539 mg, 4.8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, then 4-chloropyridinecarbamide (517 mg, 3.3) was added. (mmol), warmed to 120 ° C and stirred for 36 h, then cooled to rt then quenched with water (50 mL). EtOAc (50 mL EtOAc) , dried over anhydrous Na 2 SO 4, then concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v ) = 3/1) to give the title compound as a white solid (580mg, 40.4% ).

MS(ESI,pos.ion)m/z:478.0[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.95(s,1H),8.53(d,J=5.6Hz,1H),8.16(d,J=2.4Hz,1H),8.13(br s,1H),7.72(br s,1H),7.60(m,2H),7.51(m,2H),7.44(d,J=7.3Hz,2H),7.38(d,J=8.8Hz,1H),7.32(d,J=2.6Hz,1H),7.17(dd,J=2.6Hz,5.6Hz,1H),3.16(d,J=5.2Hz,3H),2.70(s,3H)。 MS (ESI, pos.) m/z: 478.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ (ppm) 10.95 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.13 (br s, 1H), 7.72 (br s, 1H), 7.60 (m, 2H), 7.51 (m, 2H), 7.44 (d) , J = 7.3 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 2.6 Hz, 5.6 Hz, 1H), 3.16 ( d, J = 5.2 Hz, 3H), 2.70 (s, 3H).

實施例14 4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-3-氟苯氧基)吡啶醯胺Example 14 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido)-3- Fluorophenoxy)pyridinium

步驟1)4-氨基-3-氟苯酚 Step 1) 4-Amino-3-fluorophenol

化合物3-氟-4-硝基苯酚(2.0g,12.73mmol),10% Pd/C(0.4g),HCOOK(8.75g,101.85mmol)和THF/H2O(70mL/20mL)的懸浮液在50℃攪拌反應5小時後,冷卻至室溫,用矽藻土抽濾,濾液用水(30mL)稀釋,混合物用THF(50mL)萃取,得到的有機相用無水Na2SO4乾燥,然後減壓濃縮,得到的殘留物用水(50mL)稀釋,混合物用DCM(50mL)萃取,得到的有機相用無水Na2SO4乾燥,然後減壓濃縮,得到標題化合物為棕色固體(1.17g,72.3%)。 Suspension of compound 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10% Pd/C (0.4 g), HCOOK (8.75 g, 101.85 mmol) and THF/H 2 O (70 mL / 20 mL) after stirring the reaction at 50 ℃ 5 hours, cooled to room temperature, the filtrate was washed with water (30mL) diluted with diatomaceous earth filtration, the mixture was extracted with THF (50mL), the organic phase obtained was dried over anhydrous Na 2 SO 4, then reduced Thickener, (50 mL) was diluted with water to give the residue, the mixture was extracted with DCM (50mL), the organic phase obtained was dried over anhydrous Na 2 SO 4, then concentrated under reduced pressure to give the title compound as a brown solid (1.17g, 72.3% ).

MS(ESI,pos,ion)m/z:128.1[M+H]+,Rt=0.204min。 MS (ESI, pos, ion) m / z: 128.1 [M + H] +, Rt = 0.204min.

步驟2)N-(2-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N- (2-Fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4- Guanamine

將化合物4-氨基-3-氟苯酚(1.0g,7.87mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(2.19g,9.44mmol)懸浮在CH2Cl2(20mL)中,然後向反應液中加入EDCI(3.02g,15.7mmol)和HOAT(0.21g,1.57mmol),加熱至回流並攪拌反應20小時,然後冷卻至室溫,加入水(10mL),並將得到的混合物在室溫條件攪拌過夜,抽濾,濾餅用水(5mL)洗,然後經矽膠柱層析(CH2Cl2/MeOH(v/v)=70/1)純化得到標題化合物為米白色固體(1.25g,46.6%)。 The compound 4-amino-3-fluorophenol (1.0 g, 7.87 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4 - carboxylic acid (2.19g, 9.44mmol) suspended in CH 2 Cl 2 (20mL), followed by addition of EDCI (3.02g, 15.7mmol) to the reaction mixture and HOAT (0.21g, 1.57mmol), was heated to reflux and stirred After reacting for 20 hours, it was cooled to room temperature, water (10 mL) was added, and the obtained mixture was stirred at room temperature overnight, filtered, filtered, washed with water (5mL), and then chromatographic column chromatography (CH 2 Cl 2 / MeOH (v/v) = 70/1).

MS(ESI,pos,ion)m/z:342.1[M+H]+,Rt=2.712min。 MS (ESI, pos, ion) m / z: 342.1 [M + H] +, Rt = 2.712min.

步驟3)4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-3-氟苯氧基)吡啶醯胺 Step 3) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluoro Phenoxy)pyridinium

向化合物N-(2-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(300mg,0.879mmol)和t-BuOK(118mg,1.05mmol)的混合物中加入DMF(2.5mL),室溫攪拌30分鐘後,加入4-氯吡啶甲醯 胺(165mg,1.05mmol),加熱至120℃並攪拌反應5小時,然後冷卻至室溫,加入H2O(50mL)和EtOAc(2mL),得到的混合物室溫攪拌過夜,抽濾,濾餅用水(5mL)洗,真空乾燥,得到標題化合物為深棕色固體(370mg,91.2%)。 To the compound N -(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-indole the mixture amine (300mg, 0.879mmol) and t -BuOK (118mg, 1.05mmol) was added DMF (2.5mL), stirred at room temperature for 30 minutes, 4-chloro-pyridine carboxylic acyl amine (165mg, 1.05mmol), was heated to 120 deg.] C and the reaction was stirred for 5 hours, then cooled to room temperature, H 2 O (50mL) and EtOAc (2mL), the resulting mixture was stirred overnight at room temperature, filtered off with suction, the filter cake was washed with water (5mL), dried in vacuo, The title compound was obtained as a dark brown solid (370 mg, 91.2%).

MS(ESI,pos,ion)m/z:462.2[M+H]+,Rt=3.012min。 MS (ESI, pos, ion) m / z: 462.2 [M + H] +, Rt = 3.012min.

實施例15 3-氯-4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-3-氟苯氧基)吡啶醯胺Example 15 3-Chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-carboxamido) )-3-fluorophenoxy)pyridinium

將化合物N-(2-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(300mg,0.879mmol),t-BuOK(118mg,1.05mmol)和DMF(3mL)的混合物室溫攪拌30分鐘後,加入3,4-二氯-2-吡啶醯胺(201mg,1.05mmol),加熱至120℃並攪拌反應12小時,然後加入EtOAc(1mL)和H2O(20mL),得到的混合物室溫攪拌過夜,抽濾,得到標題化合物為棕色固體(379mg,87.0%)。 The compound N -(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-indole amine (300mg, 0.879mmol), t -BuOK (118mg, 1.05mmol) and DMF (3mL) was stirred at rt for 30 minutes, 3,4-dichloro-2-pyridinyl Amides (201mg, 1.05mmol) and heated to 120 deg.] C and stirred for 12 hours, followed by addition of EtOAc (1mL) and H 2 O (20mL), the resulting mixture was stirred overnight at room temperature, suction filtration to give the title compound as a brown solid (379mg, 87.0%).

MS(ESI,pos,ion)m/z:496.0[M+H]+,Rt=2.642min。 MS (ESI, pos, ion) m / z: 496.0 [M + H] +, Rt = 2.642min.

實施例16 N-(4-((2-(環丙烷甲醯胺基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 16 N -(4-((2-(cyclopropanecarbamoyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1 H -pyrazole-4-decylamine

步驟1)4-氨基苯酚 Step 1) 4-Aminophenol

將4-硝基酚(7g,50.3mmol)和HCOOK(1.8g,21.48mmol)溶解在THF(210mL)和水(70mL)中,然後向其中加入Pd/C(110mg,10% Pd含量,53%~55%水含量)。反應液在50℃攪拌反應24小時後,真空濃縮。殘餘反應液用二氯甲烷(100mL)稀釋後通過矽藻土過濾。濾液通過 真空濃縮得到標題化合物為淡橙色固體(3.28g,60%)。 4-Nitrophenol (7g, 50.3mmol) and HCOOK (1.8g, 21.48mmol) were dissolved in THF (210mL) and water (70mL), then Pd/C (110mg, 10% Pd content, 53 %~55% water content). The reaction solution was stirred at 50 ° C for 24 hours and then concentrated in vacuo. The residual reaction solution was diluted with dichloromethane (100 mL) and filtered over Celite. Filtrate pass Concentration in vacuo gave the title compound as m.

MS(ESI,pos.ion)m/z:110.1[M+H]+MS (ESI, pos.) m/z: 110.1 [M+H] + .

步驟2)4-(4-氨基苯氧基)吡啶-2-胺 Step 2) 4-(4-Aminophenoxy)pyridin-2-amine

將4-氨基苯酚(218mg,2mmol)和4-氯吡啶-2-胺(256mg,2mmol)溶於二甲亞碸(2.5mL)中,然後加入固體甲醇鈉(216mg,4mmol)。將反應液置於微波下,180℃反應40分鐘後,冷卻至室溫,用水(10mL)淬滅反應。反應混合物用乙酸乙酯(10mL x 3)萃取,合併的有機相用無水硫酸鈉乾燥並真空濃縮。殘留物通過矽膠柱層析(DCM/CH3OH(v/v)=30/1)純化得到標題化合物為褐色固體(103mg,26%)。 4-Aminophenol (218 mg, 2 mmol) and 4-chloropyridin-2-amine (256 mg, 2 mmol) were dissolved in dimethyl hydrazine (2.5 mL), then solid sodium methoxide (216 mg, 4 mmol). The reaction solution was placed under microwave at 180 ° C for 40 minutes, then cooled to room temperature and then quenched with water (10 mL). The reaction mixture was extracted with EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (DCM / CH 3 OH (v / v) = 30/1) to give the title compound as a tan solid (103mg, 26%).

MS(ESI,pos.ion)m/z:202.2[M+H]+1H NMR(400MHz,CDCl3):δ(ppm)3.65(s,2H),4.37(s,1H),5.89-5.90(d,J=2.04Hz,1H),6.25-6.27(dd,J=2.08Hz,5.88Hz,1H),6.68-6.71(m,2H),6.86-6.89(m,2H),7.88-7.89(d,J=5.88Hz,1H)。 MS (ESI, pos.ion) m / z: 202.2 [M + H] +; 1 H NMR (400MHz, CDCl 3): δ (ppm) 3.65 (s, 2H), 4.37 (s, 1H), 5.89- 5.90 (d, J = 2.04 Hz, 1H), 6.25-6.27 (dd, J = 2.08 Hz, 5.88 Hz, 1H), 6.68-6.71 (m, 2H), 6.86-6.89 (m, 2H), 7.88-7.89 (d, J = 5.88 Hz, 1H).

步驟3)N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 3) N- (4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro -1 H -pyrazole-4-decylamine

將4-(4-氨基苯氧基)吡啶-2-胺(101mg,0.5mmol)和1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(118mg,0.51mmol)溶於二氯甲烷(5mL),然後加入EDCI(115mg,0.6mmol)和HOAT(13.6mg,0.1mmol)。反應液在45℃攪拌反應3小時後,用水(20mL)淬滅。有機相分離後真空濃縮。殘留物通過矽膠柱層析(DCM/CH3OH(v/v)=20/1)純化得到標題化合物為淺灰色固體(110mg,49.2%)。 4-(4-Aminophenoxy)pyridin-2-amine (101 mg, 0.5 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H Pyrazole-4-carboxylic acid (118 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL) then EDCI (l. After the reaction mixture was stirred at 45 ° C for 3 hr, then was then evaporated. The organic phase was separated and concentrated in vacuo. The residue was purified by silica gel column to give the title compound chromatography (DCM / CH 3 OH (v / v) = 20/1) as a light gray solid (110mg, 49.2%).

MS(ESI,pos.ion)m/z:416.4[M+H]+1H NMR(400MHz,DMSO-d 6 ):δ(ppm)2.71(s,3H),3.36(s,3H),5.80-5.81(d,J=2.16Hz,1H),5.92(s,2H),6.12-6.14(dd,J=2.24Hz,5.8Hz,1H),7.08-7.10(m,2H),7.42-7.45(m,2H),7.51-7.53(m,1H),7.57-7.61(m,2H),7.65-7.67(m,2H),7.77-7.79(d,J=5.8Hz,1H)。 MS (ESI, pos.ion) m / z: 416.4 [M + H] +; 1 H NMR (400MHz, DMSO- d 6): δ (ppm) 2.71 (s, 3H), 3.36 (s, 3H), 5.80-5.81 (d, J = 2.16 Hz, 1H), 5.92 (s, 2H), 6.12-6.14 (dd, J = 2.24 Hz, 5.8 Hz, 1H), 7.08-7.10 (m, 2H), 7.42-7.45 (m, 2H), 7.51-7.53 (m, 1H), 7.57-7.61 (m, 2H), 7.65-7.67 (m, 2H), 7.77-7.79 (d, J = 5.8 Hz, 1H).

步驟4)N-(4-((2-(環丙烷甲醯胺基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧 代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 4) N- (4-((2-(cyclopropanecarbamoyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1 H -pyrazole-4-decylamine

將化合物N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(200mg,0.48mmol)溶解在DCM(5mL),冷卻至0℃,然後向反應液中加入三乙胺(1mL),接下來再加入環丙基甲醯氯(104.5mg,0.96mmol),室溫攪拌反應3小時後,加入水(10mL)淬滅反應,分液,向得到的有機相加入飽和Na2CO3水溶液(10mL)和EtOH(30mL),得到的混合物室溫攪拌30分鐘後,減壓濃縮,得到的殘留物經矽膠柱層析(DCM/MeOH(v/v)=80/1)純化得到標題化合物為白色固體(130mg,56%)。 The compound N -(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1 H -pyrazole-4-decylamine (200 mg, 0.48 mmol) was dissolved in DCM (5 mL), cooled to 0 ° C, then triethylamine (1 mL) was added to the reaction mixture, followed by cyclopropylmethyl hydrazide after chloro (104.5mg, 0.96mmol), stirred at room temperature for 3 hours, was added water (10mL) quenched the reaction, liquid separation, the organic phase obtained was added saturated aqueous Na 2 CO 3 (10mL) and EtOH (30mL), The obtained mixture was stirred at room temperature for 30 min, EtOAc m. .

HPLC:99.5%;MS(ESI,pos.ion)m/z:484.3[M+H]+1H NMR(600MHz,CDCl3):δ(ppm)10.77(s,1H),9.45(s,1H),8.05(d,J=5.8Hz,1H),7.90(s,1H),7.74(d,J=8.9Hz,2H),7.57(t,J=7.8Hz,2H),7.48(t,J=7.5Hz,1H),7.38(d,J=7.4Hz,2H),7.05(d,J=8.9Hz,2H),6.62(dd,J=6.0Hz,2.0Hz,1H),3.37(s,3H),2.81(s,3H),1.65(td,J=7.7Hz,4.0Hz,1H),1.26(d,J=12.8Hz,2H),1.10(dt,J=7.9Hz,4.0Hz,2H)。 HPLC: 99.5%; MS (ESI, pos.) m/z: 484.3 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 ): δ (ppm) 10.77 (s, 1H), 9.45 (s, 1H), 8.05 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 6.62 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 3.37 (s) , 3H), 2.81 (s, 3H), 1.65 (td, J = 7.7 Hz, 4.0 Hz, 1H), 1.26 (d, J = 12.8 Hz, 2H), 1.10 (dt, J = 7.9 Hz, 4.0 Hz, 2H).

實施例17 N-(5-((2-(3-(2-羥基乙基)脲基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 17 N-(5-((2-(3-(2-hydroxyethyl))ureido)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3 -oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

步驟1)4-氯吡啶-2-甲醯胺 Step 1) 4-Chloropyridine-2-carboxamide

將4-氯吡啶甲酸(100mg,0.64mmol)溶解在二氯甲烷(10mL)中,向其中加入一滴N,N-二甲基甲醯胺和二氯亞碸(0.14mL,1.92 mmol)。反應液室溫攪拌過夜後,減壓濃縮。所得殘留物溶解在四氫呋喃(10mL)中,向其中加入三乙胺(0.2mL,0.13mmol),將混合物置於氨氣氛中攪拌1小時,減壓濃縮,加水(20mL)稀釋,並用乙酸乙酯(10mL x 3)萃取。合併的有機相用鹽水(20mL)洗,無水硫酸鈉乾燥,並減壓濃縮,殘留物經矽膠柱層析(PE/EtOAc(v/v)=5/1)純化,得到標題化合物為黃色固體(70mg70%)。 4-Chloropicolinic acid (100 mg, 0.64 mmol) was dissolved in dichloromethane (10 mL), and a drop of N,N-dimethylformamide and dichloromethane (0.14 mL, 1.92) Mm). The reaction mixture was stirred at room temperature overnight and then evaporated. The residue was dissolved in tetrahydrofuran (10 mL). EtOAc (EtOAc m. (10mL x 3) extraction. The combined organic phases were washed with EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (70mg70%).

MS(ESI,pos.ion)m/z:157[M+1]+1H NMR(300MHz,CD3OD):δ(ppm)8.48(d,J=5.15Hz,1H),8.22(d,J=2.10Hz,1H),7.79(brs,1H),7.46(dd,J=5.28,2.13Hz,1H),5.80(brs,1H)。 MS (ESI, pos.) m/z: 157 [M + 1] + ; 1 H NMR (300 MHz, CD 3 OD): δ (ppm) 8.48 (d, J = 5.15 Hz, 1H), 8.22 (d) , J = 2.10 Hz, 1H), 7.79 (brs, 1H), 7.46 (dd, J = 5.28, 2.13 Hz, 1H), 5.80 (brs, 1H).

步驟2)N-(5-羥基吡啶-2-基)-2,5-二甲基-3-氧代-1-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N-(5-Hydroxypyridin-2-yl)-2,5-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將2-氨基-5-羥基吡啶鹽酸鹽(500mg,3.41mmol)懸浮在N,N-二甲基甲醯胺(8mL)中,向其中加入三乙胺(0.77mL,5.5mmol),混合液室溫攪拌1小時,待用;與此同時,將1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲酸(0.64g,2.75mmol),HOAT(449mg,3.3mmol)和EDCI(0.63g,3.3mmol)溶解在N,N-二甲基甲醯胺(8mL)中,向其中滴加三乙胺(0.77mL,5.5mmol)。混合物室溫攪拌1小時後,向體系中加入上述製備的混合液。反應液升溫至60℃,攪拌5小時後,冷卻至室溫,加水(150mL)稀釋,並用1M鹽酸調節pH=6。將所得混合液用乙酸乙酯(20mL x 4)萃取,合併的有機相用鹽水(20mL)洗,無水硫酸鈉乾燥,並減壓濃縮,殘留物經矽膠柱層析純化(DCM/MeOH(v/v)=10/1)得到標題化合物為淺黃色固體(699mg,78%)。 2-Amino-5-hydroxypyridine hydrochloride (500 mg, 3.41 mmol) was suspended in N,N-dimethylformamide (8 mL), and triethylamine (0.77 mL, 5.5 mmol) was added and mixed. The solution was stirred at room temperature for 1 hour, and was used; at the same time, 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.64) g, 2.75 mmol), HOAT (449 mg, 3.3 mmol) and EDCI (0.63 g, 3.3 mmol) were dissolved in N,N-dimethylformamide (8 mL), and triethylamine (0.77 mL, 5.5 mmol). After the mixture was stirred at room temperature for 1 hour, the mixture prepared above was added to the system. The reaction solution was warmed to 60 ° C, stirred for 5 hours, cooled to room temperature, diluted with water (150 mL), and adjusted to pH = 6 with 1M hydrochloric acid. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The title compound was obtained as a pale-yellow solid ( 699 g, 78%).

MS(ESI,pos.ion)m/z:325.1[M+H]+MS (ESI, pos.) m/z: 325.1 [M+H] + .

步驟3)4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺 Step 3) 4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridine-3 -yl)oxy)pyridinium

將N-(5-羥基吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(468mg,1.4mmol)溶解在N,N-二甲基甲醯胺(30mL)中,並向其中加入叔丁醇鉀(486mg,4.33mmol),溶液室溫攪拌20分鐘後,向體 系內繼續加入4-氯吡啶-2-甲醯胺(293mg,1.87mmol)。反應液加熱至120℃,攪拌2小時。反應畢,冷卻至室溫,加水(15mL)稀釋,並用乙酸乙酯(20mL x 3)萃取。合併的有機相用鹽水(20mL)洗,減壓濃縮,所得殘留物經矽膠柱層析純化(DCM/MeOH(v/v)=50/1)得到標題化合物為類白色固體(285mg,44%)。 N-(5-Hydroxypyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazole-4-decylamine ( 468 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (30 mL), and potassium t-butoxide (486 mg, 4.33 mmol) was added thereto, and the solution was stirred at room temperature for 20 minutes, and then added to the system. 4-Chloropyridine-2-carboxamide (293 mg, 1.87 mmol). The reaction solution was heated to 120 ° C and stirred for 2 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (15 mL), and evaporated. The combined organic phases were washed with EtOAc EtOAc m. ).

MS(ESI,pos.ion)m/z:444.8[M+H]+MS (ESI, pos.) m/z: 444.8 [M+H] + .

步驟4)N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 4) N-(5-((2-Aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3 -dihydro-1H-pyrazole-4-decylamine

將4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶醯胺(60mg,0.13mmol)溶解在乙酸乙酯/乙腈/水(2mL/2mL/1mL)的混合液中,冷卻至0℃,向其中加入二乙酸碘苯(54mg,0.16mmol)。反應液室溫攪拌2小時後,加壓濃縮。將所得殘留物溶解在乙酸乙酯(10mL)中,用飽和碳酸鈉溶液(10mL)洗,無水硫酸鈉乾燥。郵寄溶液經減壓濃縮後,得到標題化合物為黃色固體(43mg,77%)。 4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl Ethyl pyridinamine (60 mg, 0.13 mmol) was dissolved in a mixture of ethyl acetate / acetonitrile / water (2 mL / 2 mL / 1 mL), cooled to 0 ° C, and iodobenzene diacetate (54 mg, 0.16) was added thereto. Mm). The reaction solution was stirred at room temperature for 2 hours and then concentrated under pressure. The residue was dissolved in ethyl acetate (10 mL). The title compound was obtained as a yellow solid (43 mg, 77%).

MS(ESI,pos.ion)m/z:416.9[M+H]+1H NMR(300MHz,CDCl3):11.21(s,1H),8.31(d,J=9.0Hz,1H),8.13(d,J=2.8Hz,1H),7.92(d,J=5.9Hz,1H),7.57-7.27(m,6H),6.29(dd,J=5.91,2.13Hz,1H),5.94(d,J=2.19Hz,1H),4.51(brs,2H),3.37(s,3H),2.79(s,3H)。 MS (ESI, pos.ion) m / z: 416.9 [M + H] +; 1 H NMR (300MHz, CDCl 3): 11.21 (s, 1H), 8.31 (d, J = 9.0Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 5.9 Hz, 1H), 7.57-7.27 (m, 6H), 6.29 (dd, J = 5.91, 2.13 Hz, 1H), 5.94 (d, J = 2.19 Hz, 1H), 4.51 (brs, 2H), 3.37 (s, 3H), 2.79 (s, 3H).

步驟5)(4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶-2-基)氨基甲酸苯基酯 Step 5) (4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridine- Phenyl 3-yl)oxy)pyridin-2-yl)carbamate

將N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(0.25g,0.6mmol)懸浮在二氯甲烷(20mL)中,並向其中加入吡啶(0.65mL,6mmol)。懸浮液冷卻至0℃後,向體系內緩慢加入氯甲酸苯酯(98mg,0.63mmol)的二氯甲烷(5mL)溶液。反應液室溫攪拌2小時,反應畢,加二氯甲烷(20mL)稀釋,依次 用水(25mL x 2)和鹽水(25mL)洗。將有機溶液用無水硫酸鈉乾燥,減壓濃縮,殘留物經矽膠柱層析純化(DCM/MeOH(v/v)=100/1)得到標題化合物為白色固體(134mg,42%)。 N-(5-((2-Aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-guanamine (0.25 g, 0.6 mmol) was suspended in dichloromethane (20 mL), and pyridine (0.65 mL, 6 mmol) was added. After the suspension was cooled to 0 ° C, a solution of phenyl chloroformate (98 mg, 0.63 mmol) in dichloromethane (5 mL) was slowly added to the mixture. The reaction solution was stirred at room temperature for 2 hours, and the reaction was completed, and diluted with dichloromethane (20 mL). Wash with water (25 mL x 2) and brine (25 mL). The organic solution was dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS(ESI,pos.ion)m/z:536.8[M+H]+MS (ESI, pos.) m/z: 536.8 [M+H] + .

步驟6)N-(5-((2-(3-(2-羥基乙基)脲基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 6) N-(5-((2-(3-(2-hydroxyethyl))ureido)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3 -oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將2-氨基乙醇(14mg,0.224mmol)加入到(4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺基)吡啶-3-基)氧基)吡啶-2-基)氨基甲酸苯基酯(0.1g,0.187mmol)和NMP(10mL)的混合物中。反應液加熱至40℃攪拌2小時後,將溶劑在40℃蒸發。向殘留物中加入乙酸乙酯(20mL),有固體析出,過濾,收集固體,並用乙酸乙酯(3mL)洗,得到標題化合物為白色固體(92mg,98%)。 2-Aminoethanol (14 mg, 0.224 mmol) was added to (4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole) A mixture of phenyl 4-aminoguanido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.1 g, 0.187 mmol) and NMP (10 mL). After the reaction mixture was heated to 40 ° C and stirred for 2 hours, the solvent was evaporated at 40 ° C. Ethyl acetate (20 mL) was evaporated.

MS(ESI,pos.ion)m/z:504.2[M+H]+1H NMR(300MHz,DMSO-d 6):11.23(s,1H),9.14(s,1H),8.33(d,J=9.0Hz,1H),8.21(d,J=2.9Hz,1H),8.08(d,J=5.8Hz,1H),8.04(brs,1H),7.69(dd,J=8.9,2.9Hz,1H),7.63-7.43(m,5H),6.97(d,J=2.19Hz,1H),6.58(d,J=5.8Hz,1H),4.73(t,J=5.2Hz,2H),3.43(q,J=5.7Hz,2H),3.37(s,3H),3.32(s,3H),3.18(q,J=5.6Hz,2H),2.72(s,3H)。 MS (ESI, pos.ion) m / z: 504.2 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 11.23 (s, 1H), 9.14 (s, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.08 (d, J = 5.8 Hz, 1H), 8.04 (brs, 1H), 7.69 (dd, J = 8.9, 2.9 Hz, 1H), 7.63-7.43 (m, 5H), 6.97 (d, J = 2.19 Hz, 1H), 6.58 (d, J = 5.8 Hz, 1H), 4.73 (t, J = 5.2 Hz, 2H), 3.43 ( q, J = 5.7 Hz, 2H), 3.37 (s, 3H), 3.32 (s, 3H), 3.18 (q, J = 5.6 Hz, 2H), 2.72 (s, 3H).

實施例18 N-(5-((2-(3-(2-羥基乙基)-3-甲基脲基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 18 N-(5-((2-(3-(2-hydroxyethyl))-3-methylureido)pyridin-4-yl)oxy)pyridin-2-yl)-1,5- Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將2-(甲基氨基)乙醇(5.0mg,0.06mmol)加入到(4-((6-(1,5-二甲基 -3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶-2-基)氨基甲酸苯基酯(30mg,0.05mmol)和NMP(5mL)的混合物中。反應液加熱到40℃攪拌1.5小時後,冷卻至室溫,加乙酸乙酯(15mL)和水(10mL)稀釋。分離的有機相依次用水(10mL x 3)、食鹽水(10mL)洗,無水硫酸鈉乾燥,並減壓濃縮。殘留物經矽膠柱層析純化(DCM/MeOH(v/v)=20/1)後,再用***(5mL)洗,得到標題化合物為白色固體(17mg,59%)。 2-(Methylamino)ethanol (5.0 mg, 0.06 mmol) was added to (4-((6-(1,5-dimethyl)) Phenyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (30 mg, 0.05 mmol) and a mixture of NMP (5 mL). The reaction mixture was heated to 40 ° C and stirred for 1.5 hr then cooled to room temperature and diluted with ethyl acetate (15 mL) and water (10 mL). The separated organic phase was washed with water (10 mL EtOAc) The residue was purified by EtOAc EtOAcjjjjjjjj

MS(ESI,pos.ion)m/z:518.2[M+H]+1H NMR(300MHz,CD3OD):8.44(d,J=9.0Hz,1H),8.24(d,J=2.85Hz,1H),8.20(d,J=7.14Hz,1H),7.73(dd,J=9.0,2.88Hz,1H),7.64-7.56(m,3H),7.46-7.43(m,2H),3.72(t,J=5.2Hz,2H),3.53(t,J=5.2Hz,2H),3.43(s,3H),3.08(s,3H),2.80(s,3H)。 MS (ESI, pos.) m/z: 518.2 [M+H] + ; 1 H NMR (300 MHz, CD 3 OD): 8.44 (d, J = 9.0 Hz, 1H), 8.24 (d, J = 2.85) Hz, 1H), 8.20 (d, J = 7.14 Hz, 1H), 7.73 (dd, J = 9.0, 2.88 Hz, 1H), 7.64 - 7.56 (m, 3H), 7.46 - 7.43 (m, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.53 (t, J = 5.2 Hz, 2H), 3.43 (s, 3H), 3.08 (s, 3H), 2.80 (s, 3H).

實施例19 N-(5-((2-(環丁烷甲醯胺基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 19 N-(5-((2-(cyclobutanecarbamoyl)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo- 2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(50mg,0.12mmol)懸浮在四氫呋喃(13mL)中,向其中加入三乙胺(0.034mL,0.24mmol)。懸浮液冷卻至0℃,向體系內緩慢加入環丁基甲醯氯(28.5mg,0.24mmol)的四氫呋喃(3mL)溶液。反應液室溫攪拌1.25小時後,加乙酸乙酯(15mL)稀釋,將混合液依次用水(15mL x 2)、食鹽水(15mL)洗,無水硫酸鈉乾燥,並減壓濃縮。所得殘留物經矽膠柱層析純化(DCM/MeOH(v/v)=60/1)得到標題化合物為白色固體(25mg,41%)。 N-(5-((2-Aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-guanamine (50 mg, 0.12 mmol) was suspended in tetrahydrofuran (13 mL), and triethylamine (0.034 mL, 0.24 mmol) was added. The suspension was cooled to 0.degree. C. and a solution of EtOAc (2. The reaction mixture was stirred at room temperature for 1.25 hr then EtOAc (EtOAc) The residue was purified with EtOAc EtOAc EtOAc EtOAc

MS(ESI,pos.ion)m/z:499.2[M+H]+1H NMR(300MHz,CDCl3):11.21(s,1H),8.35(d,J=9.0Hz,1H),8.14(d,J=2.6Hz,1H),8.13-8.08(m,2H),7.89-7.88(m,1H),7.55-7.35(m,1H),6.56(d,J=3.0Hz,1H),3.36(s,3H),3.22-3.11(m,1H),2.78(s,3H),2.43-2.29(m,2H),2.26-2.15(m,2H),2.04-1.87(m,2H)。 MS (ESI, pos.ion) m / z: 499.2 [M + H] +; 1 H NMR (300MHz, CDCl 3): 11.21 (s, 1H), 8.35 (d, J = 9.0Hz, 1H), 8.14 (d, J = 2.6 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.89-7.88 (m, 1H), 7.55-7.35 (m, 1H), 6.56 (d, J = 3.0 Hz, 1H), 3.36 (s, 3H), 3.22-3.11 (m, 1H), 2.78 (s, 3H), 2.43-2.29 (m, 2H), 2.26-2.15 (m, 2H), 2.04-1.87 (m, 2H).

實施例20 N-(5-((2-(3-羥基環丁基甲醯胺基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 20 N-(5-((2-(3-hydroxycyclobutylcarbamoyl)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo -2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

步驟1)3-乙醯氧基環丁烷羧酸 Step 1) 3-Ethyloxycyclobutanecarboxylic acid

將3-羥基環丁烷基羧酸(100mg,0.86mmol)溶解在二氯甲烷(10mL)中,向其中加入DMAP(1.0mg,0.086mmol),溶液冷卻至0℃,再向體系內加入乙醯氯(0.14mL,2.6mmol)。反應液加熱至45℃攪拌4小時後,冷卻至室溫,並加二氯甲烷DCM(20mL)稀釋。將混合物依次用水(10mL)、鹽水(10mL)洗,無水硫酸鈉乾燥,過濾,並減壓濃縮,得到的粗產品不經進一步純化,直接用於下一步反應。 3-Hydroxycyclobutanecarboxylic acid (100 mg, 0.86 mmol) was dissolved in dichloromethane (10 mL), DMAP (1.0 mg, 0.086 mmol) was added thereto, the solution was cooled to 0 ° C, and then B was added to the system. Chlorofluorene (0.14 mL, 2.6 mmol). The reaction was heated to 45.degree. C. and stirred for 4 h then cooled to EtOAc. The mixture was washed with EtOAc EtOAc EtOAc.

步驟2)3-((4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶-2-基)氨甲醯基)環丁基乙酯 Step 2) 3-((4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido) Pyridin-3-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutylethyl

將N-(5-((2-氨基吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(50mg,0.12mmol),HOAt(19mg,0.24mmol),EDCI(28mg,0.14mmol)和DIPEA(0.1mL,0.6mmol)溶解在N,N-二甲基甲醯胺(5mL)中,冷卻至0℃,向其中加入3-乙醯氧基環丁烷羧酸的N,N-二甲基甲醯胺(5mL)溶液。反應液加熱至120℃,攪拌5小時後,冷卻至室溫,加水(50mL)稀釋,並用乙酸乙酯(30mL x 3)萃取。將合併的有機相用鹽水(10mL)洗,無水硫酸鈉乾燥,過濾, 並減壓濃縮。所得殘留物經矽膠柱層析純化(DCM/EtOAc(v/v)=1/2)得到標題化合物為白色固體(20mg,30%)。 N-(5-((2-Aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-di Hydrogen-1H-pyrazole-4-decylamine (50 mg, 0.12 mmol), HOAt (19 mg, 0.24 mmol), EDCI (28 mg, 0.14 mmol) and DIPEA (0.1 mL, 0.6 mmol) dissolved in N, N-dimethyl In carbamide (5 mL), it was cooled to 0 ° C, and a solution of 3-ethyloxycyclobutanecarboxylic acid in N,N-dimethylformamide (5 mL) was added thereto. The reaction mixture was heated to 120 ° C, stirred for 5 hr, then cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (30mL). The combined organics were washed with brine (10 mL) dry It was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj

MS(ESI,pos.ion)m/z:556.9[M+H]+MS (ESI, pos.) m/z: 556.9 [M+H] + .

步驟3)N-(5-((2-(3-羥基環丁基甲醯胺基)吡啶-4-基)氧基)吡啶-2-基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 3) N-(5-((2-(3-hydroxycyclobutylcarbamimidyl)pyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo -2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將3-((4-((6-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)吡啶-3-基)氧基)吡啶-2-基)氨甲醯基)環丁基乙酯(40mg,0.072mmol)溶解在甲醇(2.5mL)中,冷卻至0℃,向其中加入氫氧化鈉(6mg,0.144mmol)。反應液室溫攪拌1小時後,減壓濃縮。所得殘留物依次用水(5mL)、***(5mL)洗,過濾,收集固體,得到標題化合物為白色固體(17mg,42%)。 3-((4-((6-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridine) -3-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutylethyl ester (40 mg, 0.072 mmol) was dissolved in methanol (2.5 mL), cooled to 0 ° C, and sodium hydroxide was added thereto. (6 mg, 0.144 mmol). The reaction solution was stirred at room temperature for 1 hour and then concentrated. The residue was washed with EtOAc EtOAc m.

MS(ESI,pos.ion)m/z:515.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):11.24(s,1H),10.48(s,1H),8.33(d,J=9.0Hz,1H),8.23(d,J=2.88Hz,1H),8.19(d,J=5.7Hz,1H),7.73-7.69(m,2H),7.63-7.5(m,3H),7.46-7.43(m,2H),6.72(dd,J=2.4,5.7Hz,1H),5.09(d,J=7.3Hz,1H),3.96(m,1H),3.37(s,3H),2.72(s,3H),2.77-2.66(m,1H),2.34-2.26(m,2H),2.04-1.91(m,2H)。 MS (ESI, pos.ion) m / z: 515.0 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 11.24 (s, 1H), 10.48 (s, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.23 (d, J = 2.88 Hz, 1H), 8.19 (d, J = 5.7 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.63 - 7.5 (m, 3H), 7.46-7.43 (m, 2H), 6.72 (dd, J = 2.4, 5.7 Hz, 1H), 5.09 (d, J = 7.3 Hz, 1H), 3.96 (m, 1H), 3.37 (s, 3H), 2.72 (s, 3H), 2.77-2.66 (m, 1H), 2.34 - 2.26 (m, 2H), 2.04-1.91 (m, 2H).

實施例21 N-(4-((2-(環丁基甲醯胺基)吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 21 N-(4-((2-(cyclobutylcarbamimidyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

步驟1)4-氨基-2-氟苯酚 Step 1) 4-Amino-2-fluorophenol

將2-氟-4-硝基苯酚(5.0g,31.8mmol)溶解在甲醇(200mL)中,向其中加入Pd/C(1.0g,10%)。反應液於H2氛中,室溫攪拌過夜。將混合物 用矽藻土過濾,並用甲醇(5mL)洗。合併的濾液減壓濃縮後,得到標題化合物為棕色固體(4.02g,>99%)。 2-Fluoro-4-nitrophenol (5.0 g, 31.8 mmol) was dissolved in methanol (200 mL), and Pd/C (1.0 g, 10%) was added. H 2 atmosphere reaction was stirred overnight at room temperature. The mixture was filtered through celite and washed with methanol (5 mL). The combined filtrate was concentrated under reduced EtOAcqqqqqqq

MS(ESI,pos.ion)m/z:128.1[M+H]+MS (ESI, pos.) m/z: 128.1 [M+H] + .

步驟2)N-(3-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N-(3-Fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-indole amine

將1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲酸(6.12g,26.3mmol),HOAT(4.3g,31.6mmol)和EDCI(6.03g,31.6mmol)溶解在N,N-二甲基甲醯胺(200mL)中,向其中緩慢滴加三乙胺(9.2mL,65.8mmol)。溶液室溫攪拌20分鐘,繼續向體系內加入4-氨基-2-氟苯酚(4.02g,31.6mmol)的N,N-二甲基甲醯胺(20mL)溶液。反應液加熱至70℃攪拌4小時,減壓濃縮至體積為2mL後,加水/乙酸乙酯(150mL/50mL)的混合液稀釋。過濾,收集析出的沉澱物,並用乙酸乙酯(10mL)洗,乾燥後得到棕色的產物(5.49g)。之後,將濾液分離,得到有機相,減壓濃縮,並經矽膠柱層析純化(DCM/EtOAc(v/v)=10/1)後得到黃色產物(1.692g)。將產物合併,得到標題化合物,總收率為80%。 1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (6.12 g, 26.3 mmol), HOAT (4.3 g, 31.6 mmol) And EDCI (6.03 g, 31.6 mmol) was dissolved in N,N-dimethylformamide (200 mL), and triethylamine (9.2 mL, 65.8 mmol) was slowly added dropwise thereto. The solution was stirred at room temperature for 20 minutes and a solution of 4-amino-2-fluorophenol (4.02 g, 31.6 mmol) in N,N-dimethylformamide (20 mL) was then added. The reaction solution was heated to 70 ° C for 4 hours, concentrated under reduced pressure to a volume of 2 mL, and then diluted with water and ethyl acetate (150mL / 50mL). After filtration, the precipitate was collected, washed with ethyl acetate (10 mL) and evaporated After that, the filtrate was separated to give crystals crystals. The products were combined to give the title compound.

MS(ESI,pos.ion)m/z:342.0[M+H]+1H NMR(300MHz,CDCl3):10.58(s,1H),7.72(dd,J=2.4,12.69Hz,1H),7.58-7.32(m,5H),7.09-7.04(m,1H),6.89(t,J=9.3Hz,1H),3.34(s,3H),2.78(s,3H)。 MS (ESI, pos.ion) m / z: 342.0 [M + H] +; 1 H NMR (300MHz, CDCl 3): 10.58 (s, 1H), 7.72 (dd, J = 2.4,12.69Hz, 1H) , 7.58-7.32 (m, 5H), 7.09-7.04 (m, 1H), 6.89 (t, J = 9.3 Hz, 1H), 3.34 (s, 3H), 2.78 (s, 3H).

步驟3)4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺 Step 3) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluoro Phenoxy)pyridinium

將N-(3-氟-4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(7.18g,21.1mmol)溶解在N,N-二甲基甲醯胺(200mL)中,向其中加入叔丁醇鉀(7.08g,63.2mmol),溶液室溫攪拌20分鐘後,繼續向體系內加入4-氯吡啶醯胺(4.27g,25.2mmol)。將反應液加熱至120℃,攪拌3小時,減壓濃縮至2mL後,加水稀釋(60mL)。過濾,收集析出的沉澱,並用水(10mL)洗。所得粗產品經矽膠柱層析純化 (DCM/EtOAc/MeOH(v/v/v)=1/1/0.05)後,得到標題化合物為黃色固體(4.15g,43% yield)。 N-(3-Fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine ( 7.18 g, 21.1 mmol) was dissolved in N,N-dimethylformamide (200 mL), and potassium t-butoxide (7.08 g, 63.2 mmol) was added thereto, and the solution was stirred at room temperature for 20 minutes, and then continued to the system. 4-Chloropyridiniumamine (4.27 g, 25.2 mmol) was added. The reaction solution was heated to 120 ° C, stirred for 3 hours, concentrated under reduced pressure to 2 mL, then diluted with water (60 mL). The precipitate was collected by filtration and washed with water (10 mL). The crude product obtained is purified by gel column chromatography. The title compound was obtained as a yellow solid (4.15 g, 43% yield).

MS(ESI,pos.ion)m/z:462.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.97(s,1H),8.53(d,J=6.0Hz,1H),8.12(brs,1H),7.97(dd,J=2.0,13.23Hz,1H),7.72(brs,1H),7.63-7.42(m,5H),7.42-7.32(m,3H),7.21(dd,J=2.7,5.7Hz,1H),3.37(s,3H),2.71(s,3H)。 MS (ESI, pos.ion) m / z: 462.0 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.97 (s, 1H), 8.53 (d, J = 6.0Hz, 1H) , 8.12 (brs, 1H), 7.97 (dd, J = 2.0, 13.23 Hz, 1H), 7.72 (brs, 1H), 7.63-7.42 (m, 5H), 7.42-7.32 (m, 3H), 7.21 (dd , J = 2.7, 5.7 Hz, 1H), 3.37 (s, 3H), 2.71 (s, 3H).

步驟4)N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 4) N-(4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazole-4-decylamine

將4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟苯氧基)吡啶醯胺(2.5g,6.0mmol)溶解在乙酸乙酯/乙腈/水(60mL/60mL/30mL)中,冷卻至0℃,向其中加入二乙酸碘苯(2.9g,9.0mmol)。反應液室溫攪拌2小時後,減壓濃縮。將所得殘留物溶解在乙酸乙酯(150mL)中,用碳酸氫鈉飽和溶液(80mL)洗,無水硫酸鈉乾燥,並減壓濃縮。殘留物經二氯甲烷/***(1/10,22mL)洗,得到標題化合物為黃色固體(2.09g,81% yield)。 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy The pyridylamine (2.5 g, 6.0 mmol) was dissolved in ethyl acetate / acetonitrile / water (60 mL / 60 mL / 30 mL), cooled to 0 ° C, and iodobenzene diacetate (2.9 g, 9.0 mmol) was added. The reaction solution was stirred at room temperature for 2 hr and then evaporated. The residue was dissolved in ethyl acetate (150 mL)EtOAc. The residue was washed with EtOAc EtOAc (EtOAc)

MS(ESI,pos.ion)m/z:434.0[M+H]+1H NMR(300MHz,CDCl3):10.83(s,1H),7.92(d,J=5.8Hz,1H),7.84(dd,J=2.4,12.5Hz,1H),7.60-7.33(m,5H),7.26-7.22(m,1H),7.06(t,J=8.7Hz,1H),6.29(dd,J=2.2,5.9Hz,1H),5.92(d,J=2.19Hz,1H),4.40(brs,2H),3.37(s,3H),2.79(s,3H)。 MS (ESI, pos.ion) m / z: 434.0 [M + H] +; 1 H NMR (300MHz, CDCl 3): 10.83 (s, 1H), 7.92 (d, J = 5.8Hz, 1H), 7.84 (dd, J = 2.4, 12.5 Hz, 1H), 7.60-7.33 (m, 5H), 7.26-7.22 (m, 1H), 7.06 (t, J = 8.7 Hz, 1H), 6.29 (dd, J = 2.2) , 5.9 Hz, 1H), 5.92 (d, J = 2.19 Hz, 1H), 4.40 (brs, 2H), 3.37 (s, 3H), 2.79 (s, 3H).

步驟5)N-(4-((2-(環丁基甲醯胺基)吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 5) N-(4-((2-(cyclobutylcarbamimidyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(100mg,0.231mmol)溶解在四氫呋喃/N,N-二甲基甲醯胺(15mL/0.5mL)的混合液中,向其中加入三乙胺(0.058mL,0.462mmol),懸浮液冷卻至0℃,在1小時內,向體系內繼續加入環丁基甲醯氯(30mg,0.254mmol)的四氫呋喃(5mL)溶液。反應液室溫攪拌2小時後,加乙酸乙酯(20mL)稀釋,所得混合物依次用水(25 mL x 3)、鹽水(25mL)洗,無水硫酸鈉乾燥,過濾,減壓濃縮,殘留物經矽膠柱層析純化(DCM/EtOAc/MeOH(v/v/v)=100/20/1)得到標題化合物為白色固體(51mg,44%)。 N-(4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3- Dihydro-1H-pyrazole-4-decylamine (100 mg, 0.231 mmol) was dissolved in a mixture of tetrahydrofuran/N,N-dimethylformamide (15 mL / 0.5 mL), and triethylamine was added thereto. 0.058 mL, 0.462 mmol), the suspension was cooled to 0 ° C, and a solution of <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; After the reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate (20 mL). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The title compound was obtained as a white solid (m.

MS(ESI,pos.ion)m/z:516.0[M+H]+1H NMR(300MHz,CDCl3):10.84(s,1H),8.06(d,J=5.8Hz,1H),7.91-7.86(m,3H),7.59-7.35(m,5H),7.28-7.24(m,1H),7.09(t,J=8.7Hz,1H),6.56(dd,J=2.9,5.8Hz,1H),3.68(s,3H),3.16(m,1H),2.79(s,3H),2.43-2.29(m,2H),2.26-2.15(m,2H),2.06-1.84(m,2H)。 MS (ESI, pos.ion) m / z: 516.0 [M + H] +; 1 H NMR (300MHz, CDCl 3): 10.84 (s, 1H), 8.06 (d, J = 5.8Hz, 1H), 7.91 -7.86 (m, 3H), 7.59-7.35 (m, 5H), 7.28-7.24 (m, 1H), 7.09 (t, J = 8.7 Hz, 1H), 6.56 (dd, J = 2.9, 5.8 Hz, 1H) ), 3.68 (s, 3H), 3.16 (m, 1H), 2.79 (s, 3H), 2.43-2.29 (m, 2H), 2.26-2.15 (m, 2H), 2.06-1.84 (m, 2H).

實施例22 N-(3-氟-4-((2-(3-(2-羥基乙基)脲基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 22 N-(3-Fluoro-4-((2-(3-(2-hydroxyethyl))ureido)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

步驟1)(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟代苯氧基)吡啶-2-基)氨基甲酸苯酯 Step 1) (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2- Phenyl phenoxy)pyridin-2-yl)carbamate

將N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(500mg,1.10mmol)懸浮在二氯甲烷/吡啶(50mL/25mL)的混合液中,冷卻至0℃,在半小時內,向其中加入氯甲酸苯酯(450mg,2.90mmol)的二氯甲烷(5mL)溶液。反應液室溫攪拌2小時後,加二氯甲烷(250mL)稀釋。將混合液依次用水(150mL x 3)、鹽水(150mL)洗,無水硫酸鈉乾燥,過濾,減壓濃縮。所得殘留物將矽膠柱層析純化(DCM/MeOH(v/v)=150/1)得到標題化合物為白色固體(352mg,46%)。 N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - Pyrazole-4-decylamine (500 mg, 1.10 mmol) was suspended in a mixture of dichloromethane / pyridine (50 mL / 25 mL), cooled to 0 ° C, and phenyl chloroformate (450 mg) was added thereto over half an hour. , 2.90 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature for 2 hr then diluted with dichloromethane (250 mL). The mixture was washed with water (150 mL EtOAc) The residue was purified by EtOAc EtOAc EtOAc EtOAc

MS(ESI,pos.ion)m/z:554.0[M+H]+MS (ESI, pos.) m/z: 554.0 [M+H] + .

步驟2)N-(3-氟-4-((2-(3-(2-羥基乙基)脲基)吡啶-4-基)氧基)苯基)-1,5-二甲 基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N-(3-Fluoro-4-((2-(3-(2-hydroxyethyl))))pyridin-4-yl)oxy)phenyl)-1,5-dimethyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟代苯氧基)吡啶-2-基)氨基甲酸苯酯(100mg,0.18mmol),NMP(5mL)和2-氨基乙醇(3.0mg,0.22mmol)的混合物加熱至40℃,攪拌2小時後,在40℃減壓蒸幹溶劑,並用乙酸乙酯(20mL)稀釋。過濾,收集固體,經乙酸乙酯(3mL)洗後,得到標題化合物為白色固體(65mg,69%)。 (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluoro A mixture of phenyloxy)pyridin-2-yl)carbamic acid phenyl ester (100 mg, 0.18 mmol), NMP (5 mL) and 2-aminoethanol (3.0 mg, 0.22 mmol) was warmed to 40 ° C and stirred for 2 hours The solvent was evaporated to dryness <RTI ID=0.0> Filtration and EtOAc (3 mL)

MS(ESI,pos.ion)m/z:521.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.94(s,1H),9.14(s,1H),8.06(d,J=5.9Hz,1H),8.00(brs,1H),7.94(dd,J=1.50,12.84Hz,1H),7.63-7.42(m,5H),7.31-7.29(m,2H),6.97(d,J=2.04Hz,1H),6.56(dd,J=2.4,5.9Hz,1H),4.72(t,J=5.1Hz,1H),3.42(q,J=5.4Hz,2H),3.37(s,3H),3.17(q,J=5.6Hz,2H),2.70(s,3H)。 MS (ESI, pos.ion) m / z: 521.0 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.94 (s, 1H), 9.14 (s, 1H), 8.06 (d, J = 5.9 Hz, 1H), 8.00 (brs, 1H), 7.94 (dd, J = 1.50, 12.84 Hz, 1H), 7.63-7.42 (m, 5H), 7.31-7.29 (m, 2H), 6.97 (d) , J = 2.04 Hz, 1H), 6.56 (dd, J = 2.4, 5.9 Hz, 1H), 4.72 (t, J = 5.1 Hz, 1H), 3.42 (q, J = 5.4 Hz, 2H), 3.37 (s , 3H), 3.17 (q, J = 5.6 Hz, 2H), 2.70 (s, 3H).

實施例23 N-(3-氟代-4-((2-(3-(2-羥基丙基)-3-甲基脲基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 23 N-(3-Fluoro-4-((2-(3-(2-hydroxypropyl)-3-methylureido)pyridin-4-yl)oxy)phenyl)-1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟代苯氧基)吡啶-2-基)氨基甲酸苯酯(100mg,0.18mmol),NMP(5mL)和1-氨基丙基-2-醇(16mg,0.2mmol)的混合物加熱至40℃,攪拌2小時後,在40℃減壓濃縮,並用乙酸乙酯(20mL)稀釋。過濾,收集固體,,得到標題化合物為白色固體(58mg,60%)。 (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluoro a mixture of phenyloxy)pyridin-2-yl)carbamic acid phenyl ester (100 mg, 0.18 mmol), NMP (5 mL) and 1-aminopropyl-2-ol (16 mg, 0.2 mmol) was heated to 40 ° C and stirred 2 After several hours, it was concentrated under reduced pressure at 40 ° C and diluted with ethyl acetate (20 mL). The title compound was obtained as a white solid (yield: 58 mg, 60%).

MS(ESI,pos.ion)m/z:535.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.94(s,1H),9.14(s,1H),8.06(d,J=5.8 Hz,1H),7.98(brs,1H),7.93(dd,J=1.5,12.8Hz,1H),7.63-7.42(m,5H),7.31-7.29(m,2H),6.97(d,J=2.1Hz,1H),6.56(dd,J=2.4,5.8Hz,1H),4.73(d,J=4.8Hz,1H),3.69-3.61(m,1H),3.37(s,3H),3.18-3.10(m,1H),3.00-2.92(m,1H),2.70(s,3H),1.02(d,J=6.2Hz,3H)。 MS (ESI, pos.ion) m / z: 535.0 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.94 (s, 1H), 9.14 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.98 (brs, 1H), 7.93 (dd, J = 1.5, 12.8 Hz, 1H), 7.63-7.42 (m, 5H), 7.31-7.29 (m, 2H), 6.97 (d) , J = 2.1 Hz, 1H), 6.56 (dd, J = 2.4, 5.8 Hz, 1H), 4.73 (d, J = 4.8 Hz, 1H), 3.69-3.61 (m, 1H), 3.37 (s, 3H) , 3.18-3.10 (m, 1H), 3.00-2.92 (m, 1H), 2.70 (s, 3H), 1.02 (d, J = 6.2 Hz, 3H).

實施例24 N-(4-((2-(3,3-二甲基脲基)吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 24 N-(4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3- Oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2-氟代苯氧基)吡啶-2-基)氨基甲酸苯酯(100mg,0.18mmol),NMP(5mL)和液態二甲胺(0.045mL,33%)的混合物加熱至40℃,攪拌2小時後,在40℃蒸幹溶劑,並加乙酸乙酯(20mL)稀釋。過濾,收集析出的沉澱,得到標題化合物為白色固體(25mg,27%)。 (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluoro A mixture of phenyloxy)pyridin-2-yl)carbamic acid phenyl ester (100 mg, 0.18 mmol), NMP (5 mL) and liquid dimethylamine (0.045 mL, 33%) was warmed to 40 ° C and stirred for 2 hours. The solvent was evaporated to dryness <RTI ID=0.0> Filtration and the precipitated residue were collected to give the title compound as a white solid (25 mg, 27%).

MS(ESI,pos.ion)m/z:505.0[M+H]+1H NMR(300MHz,CD3OD):8.07(d,J=5.8Hz,1H),7.88(dd,J=2.4,12.9Hz,1H),7.66-7.43(m,5H),7.31-7.27(m,1H),7.21(t,J=8.7Hz,1H),6.59(dd,J=2.4,5.8Hz,1H),4.84(s,3H),3.41(s,3H),3.00(s,6H),2.76(s,3H)。 MS (ESI, pos.) m/z: 505.0 [M+H] + ; 1 H NMR (300 MHz, CD 3 OD): 8.07 (d, J = 5.8 Hz, 1H), 7.88 (dd, J = 2.4 , 12.9 Hz, 1H), 7.66-7.43 (m, 5H), 7.31-7.27 (m, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.59 (dd, J = 2.4, 5.8 Hz, 1H) , 4.84 (s, 3H), 3.41 (s, 3H), 3.00 (s, 6H), 2.76 (s, 3H).

實施例25 N-(4-((2-(3-乙基-3-甲基脲基)吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 25 N-(4-((2-(3-ethyl-3-methylureido)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)-2- 氟苯氧基)吡啶-2-基)氨基甲酸苯酯(100mg,0.18mmol),NMP(5mL)和N-甲基乙基胺(12mg,0.2mmol)的混合物加熱至40℃,攪拌2小時後,在40℃蒸幹溶劑,並加水(10mL)稀釋。過濾,收集析出的沉澱,將其用矽膠柱層析純化(DCM/MeOH(v/v)=60/1),得到標題化合物為白色固體(55mg,62%)。 (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2- A mixture of phenylphenoxy)pyridin-2-yl)carbamate (100 mg, 0.18 mmol), NMP (5 mL) and N-methylethylamine (12 mg, 0.2 mmol) was warmed to 40 ° C and stirred for 2 hours Thereafter, the solvent was evaporated to dryness at 40 ° C, and diluted with water (10 mL). Filtration, the precipitated residue was purified and purified eluting elut elut elut elut elut elut elut

MS(ESI,pos.ion)m/z:519.3[M+H]+1H NMR(300MHz,CD3OD):8.07(d,J=5.8Hz,1H),7.88(dd,J=2.4,12.9Hz,1H),7.66-7.43(m,5H),7.31-7.27(m,1H),7.21(t,J=8.6Hz,1H),6.59(dd,J=2.4,5.8Hz,1H),3.41(s,3H),3.40(q,J=7.2Hz,2H),2.99(s,3H),1.76(s,3H),1.16(t,J=7.2,3H)。 MS (ESI, pos.) m/z: 519.3 [M+H] + ; 1 H NMR (300 MHz, CD 3 OD): 8.07 (d, J = 5.8 Hz, 1H), 7.88 (dd, J = 2.4 , 12.9 Hz, 1H), 7.66-7.43 (m, 5H), 7.31-7.27 (m, 1H), 7.21 (t, J = 8.6 Hz, 1H), 6.59 (dd, J = 2.4, 5.8 Hz, 1H) , 3.41 (s, 3H), 3.40 (q, J = 7.2 Hz, 2H), 2.99 (s, 3H), 1.76 (s, 3H), 1.16 (t, J = 7.2, 3H).

實施例26 N-(4-((2-(環丁基甲醯胺基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 26 N-(4-((2-(cyclobutylcarbamimidyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazole-4-decylamine

步驟1)4-氨基苯酚 Step 1) 4-Aminophenol

將4-硝基苯酚(2g,14.4 mmol)溶解在乙醇(80mL)中,並向其中加入Pd/C(10%,300mg)。反應液於氫氣氛中室溫攪拌5小時後,用矽藻土過濾,乙醇(10mL)洗濾餅,收集的濾液經減壓濃縮,得到標題化合物為棕色固體(1.58g,>99%)。 4-Nitrophenol (2 g, 14.4 mmol) was dissolved in ethanol (80 mL), and Pd/C (10%, 300 mg) was added thereto. After the reaction mixture was stirred at room temperature for 5 hr, EtOAc (EtOAc) (EtOAc)

MS(ESI,pos.ion)m/z:110.1[M+H]+MS (ESI, pos.) m/z: 110.1 [M+H] + .

步驟2)N-(4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-羧酸(1.70g,7.35mmol),HOAT(1.2g,8.82mmol),EDCI(1.68g,8.82mmol)溶解在N,N- 二甲基甲醯胺(40mL)中,並向其中滴加三乙胺(2.6mL,18.38mmol)。溶液室溫攪拌20分鐘,想反應體系內滴加4-氨基苯酚(994mg,9.11mmol)的N,N-二甲基甲醯胺(6mL)溶液。將反應液加熱至70℃,攪拌5小時後,減壓濃縮至2mL,並加水(50mL)稀釋。過濾,收集析出的沉澱,水(5mL)洗,乾燥後得到粗產品,再經二氯甲烷(20mL)洗,得到標題化合物為棕色固體(2.02g,85%)。 1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.70 g, 7.35 mmol), HOAT (1.2 g, 8.82 mmol) ), EDCI (1.68g, 8.82mmol) dissolved in N, N- Trimethylcarbamide (40 mL) was added dropwise triethylamine (2.6 mL, 18.38 mmol). The solution was stirred at room temperature for 20 minutes, and a solution of 4-aminophenol (994 mg, 9.11 mmol) in N,N-dimethylformamide (6 mL) was added dropwise. The reaction solution was heated to 70 ° C, stirred for 5 hours, then concentrated to 2 mL under reduced pressure and diluted with water (50 mL). Filtration, the precipitated crystals were evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS(ESI,pos.ion)m/z:324.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.46(s,1H),9.17(s,1H),7.61-7.55(m,2H),7.52-7.46(m,1H),7.43-7.34(m,4H),6.73-6.68(m,2H),3.33(s,3H),2.69(s,3H)。 MS (ESI, pos.) m/z: 324.0 [M+H] + ; 1 H NMR (300 MHz, DMSO- d 6 ): 10.46 (s, 1H), 9.17 (s, 1H), 7.61-7.55 ( m, 2H), 7.52-7.46 (m, 1H), 7.43-7.34 (m, 4H), 6.73-6.68 (m, 2H), 3.33 (s, 3H), 2.69 (s, 3H).

步驟3)4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺 Step 3) 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy) Pyridinamine

將N-(4-羥基苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(1.80g,5.57mmol)溶解在N,N-二甲基甲醯胺(35mL),並向其中加入叔丁醇鉀(1.87g,16.7mmol)。溶液室溫攪拌20分鐘後,繼續向體系內加入4-氯吡啶醯胺(1.046g,6.68mmol)。將反應液加熱至120℃,攪拌3小時後,減壓濃縮至2mL,並加水(60mL)稀釋。過濾,收集析出的沉澱,水(5mL)洗,乾燥後,得粗產品,再經二氯甲烷(20mL)洗,得到標題化合物為棕色固體(1.8g,73%)。 N-(4-Hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine (1.80 g, 5.57 Methyl) was dissolved in N,N-dimethylformamide (35 mL), and potassium t-butoxide (1.87 g, 16.7 mmol) was added. After the solution was stirred at room temperature for 20 minutes, 4-chloropyridiniumamine (1.046 g, 6.68 mmol) was then added to the system. The reaction solution was heated to 120 ° C, stirred for 3 hours, then concentrated to 2 mL under reduced pressure and diluted with water (60 mL). Filtration, the precipitated crystals were evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS(ESI,pos.ion)m/z:444.2[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.84(s,1H),8.51(d,J=5.64Hz,1H),8.11(d,J=2.64Hz,1H),7.75-7.69(m,3H),7.63-7.56(m,2H),7.54-7.48(m,1H),7.46-7.39(m,3H),7.22-7.15(m,3H),3.36(s,3H),2.71(s,3H)。 MS (ESI, pos.) m/z: 444.2 [M+H] + ; 1 H NMR (300 MHz, DMSO- d 6 ): 10.84 (s, 1H), 8.51 (d, J = 5.64 Hz, 1H) , 8.11 (d, J = 2.64 Hz, 1H), 7.75-7.69 (m, 3H), 7.63-7.56 (m, 2H), 7.54-7.48 (m, 1H), 7.46-7.39 (m, 3H), 7.22 -7.15 (m, 3H), 3.36 (s, 3H), 2.71 (s, 3H).

步驟4)N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 4) N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-decylamine

將4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶醯胺(1.773g,3.998mmol)溶解在乙酸乙酯/乙腈/水(20 mL/20mL/10mL)的混合液中,降溫至0℃,向其中加入二乙酸碘苯(1.6g,4.96mmol)。反應液室溫攪拌過夜後,減壓濃縮,並加乙酸乙酯(100mL)稀釋。將混合物用飽和的碳酸氫鈉溶液(60mL)洗,無水硫酸鈉乾燥,並減壓濃縮。殘留物經矽膠柱層析純化(DCM/MeOH(v/v)=30/1)得到標題化合物為黃色固體(799mg,48%)。 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridinium Amine (1.773 g, 3.998 mmol) dissolved in ethyl acetate / acetonitrile / water (20 In a mixed solution of mL/20 mL/10 mL), the temperature was lowered to 0 ° C, and iodobenzene diacetate (1.6 g, 4.96 mmol) was added thereto. The reaction mixture was stirred at rt EtOAc. The mixture was washed with aq. The residue was purified by EtOAc EtOAcjjjjjjj

MS(ESI,pos.ion)m/z:416.1[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.77(s,1H),7.78(d,J=9.8Hz,1H),7.68-7.63(m,2H),7.62-7.56(m,2H),7.54-7.48(m,1H),7.45-7.41(m,2H),6.13(dd,J=2.3,9.8Hz,1H),5.90(brs,2H),5.82(d,J=2.2Hz,1H),3.36(s,3H),2.71(s,3H)。 MS (ESI, pos.ion) m / z: 416.1 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.77 (s, 1H), 7.78 (d, J = 9.8Hz, 1H) , 7.68-7.63 (m, 2H), 7.62-7.56 (m, 2H), 7.54-7.48 (m, 1H), 7.45-7.41 (m, 2H), 6.13 (dd, J = 2.3, 9.8 Hz, 1H) , 5.90 (brs, 2H), 5.82 (d, J = 2.2 Hz, 1H), 3.36 (s, 3H), 2.71 (s, 3H).

步驟5)N-(4-((2-(環丁基甲醯胺基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 5) N-(4-((2-(cyclobutylcarbamimidyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazole-4-decylamine

將N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(100mg,0.241mmol)懸浮在四氫呋喃/N,N-二甲基甲醯胺(15mL/1mL)中,並向其中加入三乙胺(0.06mL,0.482mmol),懸浮液冷卻至0℃後,在1小時內,向反應體系內滴加環丁基醯氯(31.0mg,0.265mmol)的四氫呋喃(5mL)溶液。反應液室溫攪拌5小時,反應畢,加乙酸乙酯(20mL)稀釋。將所得的混合物依次用水(25mL x 3)、鹽水(25mL)洗,無水硫酸鈉乾燥,過濾並減壓濃縮。殘留物經矽膠柱層析純化(DCM/EA/MeOH(v/v)=100/25/1)得到標題化合物為白色固體(30mg,25%)。 N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H Pyrazole-4-decylamine (100 mg, 0.241 mmol) was suspended in tetrahydrofuran/N,N-dimethylformamide (15 mL / 1 mL), and triethylamine (0.06 mL, 0.482 mmol). After the suspension was cooled to 0 ° C, a solution of cyclobutylphosphonium chloride (31.0 mg, 0.265 mmol) in tetrahydrofuran (5 mL) was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 5 hr. The resulting mixture was washed with EtOAc EtOAc. The residue was purified by EtOAc EtOAcjjjjjjjj

MS(ESI,pos.ion)m/z:498.0[M+H]+1H NMR(300MHz,CDCl3):10.73(s,1H),8.05(d,J=5.8Hz,1H),7.87-7.86(m,2H),7.74-7.70(m,2H),7.58-7.36(m,5H),7.07-7.03(m,2H),6.54(dd,J=2.3,5.8Hz,1H),3.35(s,3H),3.22-3.10(m,1H),2.80(s,3H),2.43-2.31(m,2H),2.26-2.15(m,2H),2.08-1.86(m,2H)。 MS (ESI, pos.ion) m / z: 498.0 [M + H] +; 1 H NMR (300MHz, CDCl 3): 10.73 (s, 1H), 8.05 (d, J = 5.8Hz, 1H), 7.87 -7.86 (m, 2H), 7.74-7.70 (m, 2H), 7.58-7.36 (m, 5H), 7.07-7.03 (m, 2H), 6.54 (dd, J = 2.3, 5.8 Hz, 1H), 3.35 (s, 3H), 3.22-3.10 (m, 1H), 2.80 (s, 3H), 2.43-2.31 (m, 2H), 2.26-2.15 (m, 2H), 2.08-1.86 (m, 2H).

實施例27 N-(4-((2-(環戊基甲醯胺基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-Example 27 N-(4-((2-(cyclopentylamidomethyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3- 氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧基-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(100mg,0.241mmol)懸浮在四氫呋喃/N,N-二甲基甲醯胺(20mL/1mL)中,並向其中加入三乙胺(0.06mL,0.481mmol),懸浮液冷卻至0℃後,在2小時內,向其中滴加環戊基甲醯氯(64.0mg,0.481mmol)的四氫呋喃(5mL)溶液。反應液室溫攪拌1.5小時,反應畢,加乙酸乙酯(25mL)稀釋。將所得混合物依次用水(25mL x 3)、鹽水(25mL)洗,無水硫酸鈉乾燥,過濾,並減壓濃縮。殘留物經矽膠柱層析純化(DCM/EtOAc/MeOH(v/v)=80/15/1)得到標題化合物為白色固體(39mg,32%)。 N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxy-2-phenyl-2,3-dihydro-1H Pyrazole-4-decylamine (100 mg, 0.241 mmol) was suspended in tetrahydrofuran / N,N-dimethylformamide (20 mL / 1 mL), and triethylamine (0.06 mL, 0.481 mmol). After the suspension was cooled to 0 ° C, a solution of cyclopentylformamidine chloride (64.0 mg, 0.481 mmol) in tetrahydrofuran (5 mL) was added dropwise over 2 hr. The reaction solution was stirred at room temperature for 1.5 hr. The mixture was washed with EtOAc (EtOAc m. The residue was purified by EtOAc EtOAcjjjjjjj

MS(ESI,pos.ion)m/z:512.2[M+H]+1H NMR(300MHz,CDCl3):10.73(s,1H),8.05(d,J=5.7Hz,1H),8.01(brs,1H),7.73-7.68(m,2H),7.58-7.34(m,5H),7.06-7.01(m,2H),6.54(dd,J=2.4,5.7Hz,1H),3.35(s,3H),2.79(s,3H),2.71-2.63(m,1H),1.95-1.57(m,8H)。 MS (ESI, pos.ion) m / z: 512.2 [M + H] +; 1 H NMR (300MHz, CDCl 3): 10.73 (s, 1H), 8.05 (d, J = 5.7Hz, 1H), 8.01 (brs, 1H), 7.73-7.68 (m, 2H), 7.58-7.34 (m, 5H), 7.06-7.01 (m, 2H), 6.54 (dd, J = 2.4, 5.7 Hz, 1H), 3.35 (s , 3H), 2.79 (s, 3H), 2.71-2.63 (m, 1H), 1.95-1.57 (m, 8H).

實施例28 N-(4-((2-(3-(2-羥基乙基)-3-甲基脲基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 28 N-(4-((2-(3-(2-hydroxyethyl))-3-methylureido)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl -3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

步驟1)(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶-2-基)氨基甲酸苯酯 Step 1) (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy) Phenylpyridin-2-yl)carbamate

將N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺(600mg,1.44mmol)溶解在二氯甲烷/吡啶(30mL/20mL)的混合液中,冷卻至0℃,在1小時內,向其中緩慢加入氯甲酸苯酯(565mg,3.61mmol)的二氯甲烷(10mL)溶液。反應液室溫攪拌2小時後,加二氯甲烷(200mL)稀釋。將混合液依次用水(140mL x 4)、鹽水(150mL)洗,無水硫酸鈉乾燥,過濾,並減壓濃縮,殘留物經故交柱層析純化(DCM/EtOAc(v/v)=2/1)得到標題化合物為白色固體(327mg,42%)。 N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - Pyrazole-4-decylamine (600 mg, 1.44 mmol) was dissolved in a mixture of dichloromethane / pyridine (30 mL / 20 mL), cooled to 0 ° C, and phenyl chloroformate was slowly added thereto over 1 hour. A solution of 565 mg, 3.61 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature for 2 hr then diluted with dichloromethane (200 mL). The mixture was washed with EtOAc (EtOAc) (EtOAc)EtOAc. The title compound was obtained as a white solid (327 mg, 42%).

MS(ESI,pos.ion)m/z:536.0[M+H]+MS (ESI, pos.ion) m / z: 536.0 [M + H] +.

步驟2)N-(4-((2-(3-(2-羥基乙基1)-3-甲基脲基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺 Step 2) N-(4-((2-(3-(2-hydroxyethyl))-3-methylureido)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-decylamine

將(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶-2-基)氨基甲酸苯酯(50mg,0.093mmol),NMP(3mL)和2-(甲基氨基)乙醇(8.4mg,0.112mmol)的混合物加熱至40℃。攪拌2小時後,在40℃減壓蒸幹溶劑,並用乙酸乙酯(10mL)稀釋。所得混合物依次用水(7mL x 3)、鹽水(10mL)洗,無水硫酸鈉乾燥,過濾,並減壓濃縮。殘留物經乙酸乙酯(2mL)洗,得到標題化合物為白色固體(25mg,52%)。 (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridine A mixture of phenyl-2-carbamate (50 mg, 0.093 mmol), NMP (3 mL) and 2-(methylamino)ethanol (8.4 mg, 0.112 mmol) was then warmed to 40. After stirring for 2 hours, the solvent was evaporated to dryness <RTI ID=0.0> The resulting mixture was washed with EtOAc EtOAc m. The residue was washed with EtOAcqqqqqqqqq

MS(ESI,pos.ion)m/z:517.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.80(s,1H),9.04(s,1H),8.06(d,J=5.7Hz,1H),7.70-7.65(m,2H),7.62-7.41(m,5H),7.36(d,J=2.2Hz,1H),7.14-7.09(m,2H),6.54(dd,J=2.3,5.7Hz,1H),5.31(brs,1H),3.56(q,J=4.8Hz,2H),3.36(s,3H),3.36-3.33(m,2H),2.88(s,3H),2.71(s,3H)。 MS (ESI, pos.ion) m / z: 517.0 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.80 (s, 1H), 9.04 (s, 1H), 8.06 (d, J = 5.7 Hz, 1H), 7.70-7.65 (m, 2H), 7.62-7.41 (m, 5H), 7.36 (d, J = 2.2 Hz, 1H), 7.14-7.09 (m, 2H), 6.54 (dd , J = 2.3, 5.7 Hz, 1H), 5.31 (brs, 1H), 3.56 (q, J = 4.8 Hz, 2H), 3.36 (s, 3H), 3.36-3.33 (m, 2H), 2.88 (s, 3H), 2.71 (s, 3H).

實施例29 1,5-二甲基-N-(4-((2-(3-甲基脲基)吡啶-4-基)氧基)苯基)-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 29 1,5-Dimethyl-N-(4-((2-(3-methylureido)pyridin-4-yl)oxy)phenyl)-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-decylamine

將(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶-2-基)氨基甲酸苯酯(100mg,0.187mmol),NMP(3mL)和甲胺溶液(25%,0.2mL)的混合物加熱至40℃。攪拌過夜後,減壓蒸幹溶劑,並加水(10mL)稀釋。過濾,收集析出的沉澱,該沉澱經矽膠柱層析純化(DCM/EtOAc/MeOH(v/v/v)=1/1/0.01)得到標題化合物為白色固體(46mg,52%)。 (4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridine A mixture of phenyl-2-carbamate (100 mg, 0.187 mmol), NMP (3 mL) and methylamine solution (25%, 0.2 mL) was then warmed to 40. After stirring overnight, the solvent was evaporated to dryness and evaporated and evaporated. Filtration, the precipitated crystals were crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS(ESI,pos.ion)m/z:473.1[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.81(s,1H),9.13(s,1H),8.04(d,J=5.9Hz,1H),7.99-7.94(m,1H),7.71-7.65(m,2H),7.62-7.42(m,5H),7.15-7.09(m,2H),6.87(d,J=2.28Hz,1H),6.51(dd,J=2.3,5.9Hz,1H),3.36(s,3H),2.71(s,3H),2.68(d,J=4.6Hz,3H)。 MS (ESI, pos.ion) m / z: 473.1 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.81 (s, 1H), 9.13 (s, 1H), 8.04 (d, J = 5.9 Hz, 1H), 7.99-7.94 (m, 1H), 7.71-7.65 (m, 2H), 7.62-7.42 (m, 5H), 7.15-7.09 (m, 2H), 6.87 (d, J = 2.28 Hz, 1H), 6.51 (dd, J = 2.3, 5.9 Hz, 1H), 3.36 (s, 3H), 2.71 (s, 3H), 2.68 (d, J = 4.6 Hz, 3H).

實施例30 N-(4-((2-(3-乙基脲基)吡啶-4-基)氧基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-醯胺Example 30 N-(4-((2-(3-ethylureido)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-decylamine

將乙基氨基鹽酸鹽(29mg,0.356mmol)溶解在NMP(3mL)中,向其中加入三乙胺(0.1mL),溶液室溫攪拌10分鐘,繼續向體系內加入(4-(4-(1,5-二甲基-3-氧代-2-苯基-2,3-二氫-1H-吡唑-4-甲醯胺基)苯氧基)吡啶-2-基)氨基甲酸苯酯(100mg,0.187mmol)。反應液加熱至40℃,攪拌過夜後,在40℃減壓蒸幹溶劑,並加水(10mL)稀釋。過濾,收集析出的沉澱,該沉澱經矽膠柱層析純化(DCM/EtOAc/MeOH(v/v/v)=80/40/1)得到標題化合物為白色固體(46mg,50%)。 Ethylaminohydrochloride (29 mg, 0.356 mmol) was dissolved in NMP (3 mL), triethylamine (0.1 mL) was added, and the solution was stirred at room temperature for 10 min and then added to the system (4-(4- (1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamic acid Phenyl ester (100 mg, 0.187 mmol). The reaction solution was heated to 40 ° C, and after stirring overnight, the solvent was evaporated to dryness under vacuo, and then diluted with water (10 mL). Filtration, the precipitated crystals were crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS(ESI,pos.ion)m/z:487.0[M+H]+1H NMR(300MHz,DMSO-d 6 ):10.81(s,1H),9.13(s,1H),8.04(d,J=5.9Hz,1H),7.99-7.94(m,1H),7.71-7.65(m,2H),7.62-7.42(m,5H),7.15-7.09(m,2H),6.87(d,J=2.3Hz,1H),6.51(dd,J=2.3,5.9Hz,1H),3.36(s,3H),2.71(s,3H),2.68(d,J=4.6Hz,3H)。 MS (ESI, pos.ion) m / z: 487.0 [M + H] +; 1 H NMR (300MHz, DMSO- d 6): 10.81 (s, 1H), 9.13 (s, 1H), 8.04 (d, J = 5.9 Hz, 1H), 7.99-7.94 (m, 1H), 7.71-7.65 (m, 2H), 7.62-7.42 (m, 5H), 7.15-7.09 (m, 2H), 6.87 (d, J = 2.3 Hz, 1H), 6.51 (dd, J = 2.3, 5.9 Hz, 1H), 3.36 (s, 3H), 2.71 (s, 3H), 2.68 (d, J = 4.6 Hz, 3H).

生物試驗Biological test 生物分析方法 Biological analysis method

分析用的LC/MS/MS系統包括Agilent 1200系列真空脫氣爐,二元注射泵,孔板自動採樣器,柱恒溫箱,帶電噴霧電離(ESI)源的Agilent G6430三級四級杆質譜儀。定量分析在MRM模式下進行,MRM轉換的參數如表A所示: The LC/MS/MS system for analysis includes the Agilent 1200 Series vacuum degassing furnace, binary syringe pump, orifice autosampler, column incubator, and charged spray ionization (ESI) source for the Agilent G6430 three-stage quadrupole mass spectrometer . Quantitative analysis is performed in MRM mode. The parameters of MRM conversion are shown in Table A:

分析使用Agilent XDB-C18,2.1 x 30mm,3.5μM柱,注入5μL樣品。分析條件:流動相為0.1%的甲酸水溶液(A)和0.1%的甲酸甲醇溶液(B)。流速為0.4mL/min。流動相梯度如表B所示: Analysis Agilent XDB-C18, 2.1 x 30 mm, 3.5 μM column was used and 5 μL of sample was injected. Analytical conditions: The mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. The mobile phase gradient is shown in Table B:

此外,用於分析的還有Agilent 6330系列LC/MS/MS光譜儀,配備有G1312A二元注射泵,G1367A自動採樣器和G1314C UV檢測器;LC/MS/MS光譜儀採用ESI放射源。使用標準液對每一個分析物進行合適的陽離子模型處理和MRM轉換進行最佳的分析。在分析期間使用Capcell MP-C18柱,規格為:100 x 4.6mm I.D.,5μM(Phenomenex,Torrance,California,USA)。流動相是5mM醋酸銨,0.1%甲醇水溶液(A):5mM醋酸銨,0.1%甲醇乙腈溶液(B)(70:30,v/v);流速為0.6mL/min;柱溫保持在室溫;注入20μL樣品。 In addition, the Agilent 6330 Series LC/MS/MS spectrometer was equipped for analysis with a G1312A binary syringe pump, a G1367A autosampler and a G1314C UV detector; and an LC/MS/MS spectrometer with an ESI source. Each analyte was subjected to the best cation model processing and MRM conversion for optimal analysis using standard solutions. Capcell MP-C18 columns were used during the analysis and were: 100 x 4.6 mm I.D., 5 [mu]M (Phenomenex, Torrance, California, USA). The mobile phase was 5 mM ammonium acetate, 0.1% aqueous methanol (A): 5 mM ammonium acetate, 0.1% methanol in acetonitrile (B) (70:30, v/v); flow rate was 0.6 mL/min; column temperature was kept at room temperature ; Inject 20 μL of sample.

實施例A 人和大鼠肝微粒體中的穩定性 Example A Stability in Human and Rat Liver Microsomes

將人或大鼠肝微粒體置於聚丙烯試管中孵育,並引導其複製。典型的孵育混合液包括人或大鼠肝微粒體(0.5mg蛋白質/mL),目標化合物(5μM)和總體積為200μL的NADPH(1.0mM)磷酸鉀緩衝液(PBS,100mM,pH值為7.4),將化合物溶解在DMSO中,並使用PBS將其稀釋, 使其最終的DMSO溶液的濃度為0.05%。並在37℃下與空氣相通的水浴中進行孵育,預孵育3分鐘後向混合液中加入蛋白並開始反應。在不同的時間點(0,5,10,15,30和60min),加入同體積冰冷乙腈終止反應。樣品於-80℃下保存直到進行LC/MS/MS分析。 Human or rat liver microsomes were incubated in polypropylene tubes and guided for replication. A typical incubation mixture consists of human or rat liver microsomes (0.5 mg protein/mL), target compound (5 μM) and a total volume of 200 μL of NADPH (1.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4). ), dissolving the compound in DMSO and diluting it with PBS, The final concentration of the DMSO solution was 0.05%. The incubation was carried out in a water bath at 37 ° C in air, and after pre-incubation for 3 minutes, the protein was added to the mixture and the reaction was started. At different time points (0, 5, 10, 15, 30 and 60 min), the reaction was stopped by the addition of the same volume of ice-cold acetonitrile. Samples were stored at -80 °C until LC/MS/MS analysis.

化合物在人或大鼠肝微粒體孵育混合物中的濃度是通過LC/MS/MS的方法來測定的。濃度範圍的線性範圍是通過每一個受試化合物來確定的。 The concentration of the compound in the human or rat liver microsome incubation mixture was determined by LC/MS/MS. The linear range of concentration ranges is determined by each test compound.

平行孵育試驗使用變性的微粒體作為陰性對照,在37℃下孵化,反應在不同的時間點(0,15和60分鐘)終止。 The parallel incubation assay used denatured microsomes as a negative control, incubation at 37 ° C, and the reactions were terminated at different time points (0, 15 and 60 minutes).

右美沙芬(70μM)作為陽性對照,在37℃下孵化,反應在不同的時間點(0,5,10,15,30和60分鐘)終止。每一種測定方法中都包括陽性和陰性對照樣品,以保證微粒體孵化體系的完整性。此外,本發明所述化合物在人或大鼠肝微粒體中的穩定性資料也可由以下試驗得到。將人或大鼠肝微粒體置於聚丙烯試管中孵育,並引導其複製。典型的孵育混合物包括人或大鼠肝微粒體(最終濃度:0.5mg蛋白/mL),化合物(最終濃度:1.5μM)和總體積為30μL的K-緩衝溶液(含1.0mM EDTA,100mM,pH 7.4)。將化合物溶解在DMSO中,並用K-緩衝溶液稀釋,使DMSO的最終濃度為0.2%。預孵育10分鐘後,加入15μL NADPH(最終濃度:2mM)進行酶促反應,整個試驗在37℃的孵育管中進行。在不同的時間點(0,15,30和60分鐘),加入135μL乙腈(含IS)終止反應。以4000rpm離心10分鐘,除去蛋白,收集上層清液,用LC-MS/MS分析。 Dextromethorphan (70 μM) was used as a positive control and incubated at 37 ° C. The reaction was terminated at different time points (0, 5, 10, 15, 30 and 60 minutes). Positive and negative control samples are included in each assay to ensure the integrity of the microsomal incubation system. Furthermore, the stability data of the compounds of the present invention in human or rat liver microsomes can also be obtained from the following tests. Human or rat liver microsomes were incubated in polypropylene tubes and guided for replication. Typical incubation mixtures include human or rat liver microsomes (final concentration: 0.5 mg protein/mL), compound (final concentration: 1.5 μM) and a total volume of 30 μL of K-buffer solution (containing 1.0 mM EDTA, 100 mM, pH) 7.4). The compound was dissolved in DMSO and diluted with a K-buffer solution to give a final concentration of 0.2% DMSO. After pre-incubation for 10 minutes, 15 μL of NADPH (final concentration: 2 mM) was added for enzymatic reaction, and the entire experiment was carried out in an incubation tube at 37 °C. At various time points (0, 15, 30 and 60 minutes), the reaction was stopped by the addition of 135 μL of acetonitrile (containing IS). The protein was removed by centrifugation at 4000 rpm for 10 minutes, and the supernatant was collected and analyzed by LC-MS/MS.

在上述試驗中,酮色林(1μM)被選作陽性對照,在37℃下孵化,反應在不同的時間點(0,15,30和60分鐘)終止。每一種測定方法中都包括陽性對照樣品,以保證微粒體孵化體系的完整性。 In the above test, ketanserin (1 μM) was selected as a positive control, incubated at 37 ° C, and the reaction was terminated at different time points (0, 15, 30 and 60 minutes). Positive control samples are included in each assay to ensure the integrity of the microsomal incubation system.

資料分析 date analyzing

對於每一個反應,將化合物在人或大鼠肝微粒體孵育中的濃度(以百分比表示)按相對零時間點的百分比作圖,以此來推斷體內肝固有清除率 CLint(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.) For each reaction, the concentration of the compound in human or rat liver microsome incubation (expressed as a percentage) is plotted as a percentage of the relative zero time point to extrapolate the intrinsic clearance of liver CL int (ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Privacy of human hepatic clearance from in vivo animal experiments and in vitro metabolism studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29:1316- 1324.)

本發明化合物在大鼠肝微粒體中都非常穩定。例如,將實施例8,11和16在試驗條件下孵育在大鼠肝微粒體中時,幾乎沒有代謝,因此表現出延長的(T1/2)。 The compounds of the invention are very stable in rat liver microsomes. For example, when Examples 8, 11 and 16 were incubated in rat liver microsomes under the test conditions, there was almost no metabolism and thus exhibited an extended (T 1/2 ).

實施例B 小鼠、大鼠、犬和猴子口服定量本發明化合物後的藥代動力學評價 Example B Pharmacokinetic Evaluation of Oral Quantification of Compounds of the Invention in Mice, Rats, Dogs and Monkeys

本發明對本發明化合物在小鼠、大鼠、犬或猴子體內的藥代動力學研究進行了評估。本發明化合物以水溶液或2% HPMC+1%吐溫-80的水溶液,5% DMSO+5%的鹽水溶液,4% MC或膠囊形式進行給藥。對於靜脈注射給藥,動物給予1或2mg/kg的劑量。對於口服劑量(p.o.),大鼠和小鼠是5或10mg/kg,犬和猴子是10mg/kg。在時間點為0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12和24小時取血(0.3mL),並在3,000或4,000rpm下離心10分鐘。收集血漿溶液,並於-20℃或-70℃下保存直到進行上述的LC/MS/MS分析。 The present invention evaluates the pharmacokinetic study of the compounds of the invention in mice, rats, dogs or monkeys. The compounds of the invention are administered as an aqueous solution or as an aqueous solution of 2% HPMC + 1% Tween-80, 5% DMSO + 5% saline solution, 4% MC or capsule. For intravenous administration, animals are given a dose of 1 or 2 mg/kg. For oral doses (p.o.), rats and mice were 5 or 10 mg/kg, and dogs and monkeys were 10 mg/kg. Blood (0.3 mL) was taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000 rpm for 10 minutes. The plasma solution was collected and stored at -20 ° C or -70 ° C until the above LC/MS/MS analysis was performed.

表2本發明實施例在大鼠體內的藥代動力學資料 Table 2 Pharmacokinetic data of the examples of the present invention in rats

將化合物靜注或口服給藥時,本發明所述化合物表現出良好的藥代動力學性質,包括理想的清除率(Cl),半衰期(T1/2)和好的口服生物利用度。 When the compound is administered intravenously or orally, the compounds of the present invention exhibit good pharmacokinetic properties including desirable clearance (Cl), half-life (T 1/2 ) and good oral bioavailability.

本發明化合物抑制酪氨酸激酶受體活性,特別是抑制c-Met,VEGFR,Ron和Axl活性和作為抗腫瘤藥物的功效是通過下述動物異種移植模型試驗來進行評價的。研究結果表明本發明化合物可以有效地抑制c-Met,VEGF-R2,Ron和Axl的磷酸化作用,並且劑量依賴性的抑制裸鼠移植瘤的增殖。 The compounds of the present invention inhibit tyrosine kinase receptor activity, particularly inhibition of c-Met, VEGFR, Ron and Axl activities and efficacy as antitumor drugs are evaluated by the following animal xenograft model test. The results of the study indicate that the compounds of the present invention can effectively inhibit the phosphorylation of c-Met, VEGF-R2, Ron and Axl, and inhibit the proliferation of xenografts in nude mice in a dose-dependent manner.

激酶試驗Kinase assay

激酶試驗通過檢測摻入γ-33P-ATP的髓磷脂堿基蛋白(MBP)來完成的。製備20μg/mL的MBP(Sigma #M-1891)三羥甲基氨基甲烷緩衝鹽溶液(TBS;50mM Tris pH 8.0,138mM NaCl,2.7mM KCl),包被高結合性的白384孔板(Greiner),每孔60μL。4℃,孵育24小時。之後用100μL TBS洗板3次。激酶反應在總體積為34μL的激酶緩衝液(5mM Hepes pH 7.6,15mM NaCl,0.01%牛血清白蛋白(Sigma #I-5506),10mM MgCl2,1mM DTT,0.02% TritonX-100)中進行。將化合物溶解在DMSO中,加入各孔中,DMSO的最終濃度為1%。每個資料測定兩遍,每個化合物的測定至少進行兩次試驗。比如,酶的最終濃度為10nM或20nM。加入沒有標記的ATP(10μM)和γ-33P標記的ATP(每孔2×106 cpm,3000Ci/mmole)開始反應。反映在室溫下震盪進行1個小時。384孔板用7x的PBS清洗,然後加入每孔50μL的閃爍液。用Wallac Trilux計數器 檢測結果。對於所屬領域的技術人員來說,這僅是眾多檢測方法中的一種,其他的方法亦可。 Kinase Assay accomplished by detecting incorporation of γ- 33 P-ATP myelin alkali-protein (MBP). Preparation of 20 μg/mL MBP (Sigma #M-1891) Tris buffer (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl), coated with high binding white 384-well plates (Greiner) ), 60 μL per well. Incubate for 24 hours at 4 °C. The plate was then washed 3 times with 100 μL of TBS. The kinase reaction was carried out in a total volume of 34 μL of kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% Triton X-100). Compounds were dissolved in DMSO and added to each well with a final concentration of 1% DMSO. Each data was measured twice, and each compound was tested at least twice. For example, the final concentration of the enzyme is 10 nM or 20 nM. The reaction was started by adding unlabeled ATP (10 μM) and γ- 33 P-labeled ATP (2 × 10 6 cpm per well, 3000 Ci/mmole). Reflected at room temperature for 1 hour. The 384-well plates were washed with 7x PBS and then 50 μL of scintillation fluid per well was added. The results were measured using a Wallac Trilux counter. For those skilled in the art, this is only one of many detection methods, and other methods are also possible.

上述試驗方法可以得到抑制的IC50和/或抑制常數Ki。IC50定義為在試驗條件下,抑制50%酶活性時的化合物濃度。利用½ log的稀釋倍數做出包含10個濃度點的曲線,估算IC50值(例如,通過以下化合物濃度做出一條典型的曲線:100μM,30μM,10μM,3μM,1μM,0.3μM,0.1μM,0.03μM,0.01μM,0μM)。 The above test method can give an inhibitory IC 50 and/or an inhibition constant K i . IC 50 is defined as the concentration of a compound that inhibits 50% of the enzyme activity under the conditions of the test. A curve containing 10 concentration points was made using a dilution factor of 1⁄2 log to estimate the IC 50 value (for example, a typical curve was made by the following compound concentrations: 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0 μM).

c-Met(h)激酶測定 c-Met(h) kinase assay

人c-Met在8mM pH值為7.0的MOPS,0.2mM EDTA,250μM KKKSPGEYVNIEFG,10mM醋酸鎂和[γ-33P-ATP](比活性約500 cpm/pmol,濃度根據需求確定)存在的條件下進行孵育。加入MgATP混合物後開始反應。室溫下孵育40分鐘之後,向其中加入3%磷酸溶液來終止反應。將10μL的反應液呈斑點狀分佈於P30篩檢程式上,並用75mM磷酸在5分鐘內清洗3次,並在乾燥和閃爍計數之前立刻放入甲醇溶液中保存。 Human c-Met in the presence of 8 mM MOPS at pH 7.0, 0.2 mM EDTA, 250 μM KKKSPGEYVNIEFG, 10 mM magnesium acetate and [γ- 33 P-ATP] (specific activity about 500 cpm/pmol, concentration determined according to needs) Incubate. The reaction was started after the addition of the MgATP mixture. After incubating for 40 minutes at room temperature, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μL of the reaction solution was spotted on a P30 screening program and washed 3 times with 75 mM phosphoric acid in 5 minutes, and immediately placed in a methanol solution before drying and scintillation counting.

KDR(h)(VEGF-R2(h))激酶測定 KDR(h) (VEGF-R2(h)) kinase assay

人KDR在8mM pH值為7.0的MOPS,0.2mM EDTA,0.33mg/mL髓磷脂堿蛋白,10mM醋酸鎂和[γ-33P-ATP](比活性約500 cpm/pmol,濃度根據需求確定)存在的條件下進行孵育。加入MgATP混合物後開始反應。室溫下孵育40分鐘之後,向其中加入3%磷酸溶液終止反應。將10μL反應液呈斑點狀分佈於P30篩檢程式上,並用75mM磷酸在5分鐘內清洗3次,並在乾燥和閃爍計數之前立刻放入甲醇溶液中保存。 Human KDR at 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin 堿 protein, 10 mM magnesium acetate and [γ- 33 P-ATP] (specific activity about 500 cpm/pmol, concentration determined according to needs) Incubation is carried out under the conditions present. The reaction was started after the addition of the MgATP mixture. After incubating for 40 minutes at room temperature, the reaction was terminated by adding a 3% phosphoric acid solution thereto. 10 μL of the reaction solution was spotted on a P30 screening program and washed 3 times with 75 mM phosphoric acid in 5 minutes, and immediately placed in a methanol solution before drying and scintillation counting.

Axl(h)激酶測定 Axl (h) kinase assay

人Axl在8mM pH值為7.0的MOPS,0.2mM EDTA,0.33mg/mL髓磷脂堿蛋白,10mM醋酸鎂和[γ-33P-ATP](比活性約500 cpm/pmol,濃度根據需求確定)存在的條件下進行孵育。加入MgATP混合物後開始 反應。室溫下孵育40分鐘之後,加入3%磷酸溶液來終止反應。將10μL反應液呈斑點狀分佈於P30篩檢程式上,並用75mM磷酸在5分鐘內清洗3次,並在乾燥和閃爍計數之前立刻放入甲醇溶液中保存。 Human Axl at 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin 堿 protein, 10 mM magnesium acetate and [γ- 33 P-ATP] (specific activity about 500 cpm/pmol, concentration determined according to needs) Incubation is carried out under the conditions present. The reaction was started after the addition of the MgATP mixture. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of a 3% phosphoric acid solution. 10 μL of the reaction solution was spotted on a P30 screening program and washed 3 times with 75 mM phosphoric acid in 5 minutes, and immediately placed in a methanol solution before drying and scintillation counting.

本發明中的激酶試驗是由英國Millipore公司來完成的(Millipore UK Ltd,Dundee Technology Park,Dundee DD2 1SW,UK)。 The kinase assay in the present invention was performed by Millipore Corporation of the United Kingdom (Millipore UK Ltd, Dundee Technology Park, Dundee DD2 1SW, UK).

本發明化合物的激酶抑制活性也可以通過KINOMEscan TM測試,它主要是基於定量測定樣品和固定的、有活性位元點導向的配體與激酶競爭性結合能力的試驗。這個試驗的完成需要結合以下三要素:DNA-標記的激酶、固定的配體和待測樣品。待測樣品與固定配體的競爭性結合激酶的能力可以通過測定DNA標記中的PCR的量來確定。 Kinase inhibitory activity of compounds of the invention may be tested by KINOME scan TM, and it is mainly based on fixed, the test ligand competitive binding ability of quantitatively measuring kinase activity of a sample with a bit of the guide point. The completion of this test requires the combination of the following three elements: DNA-labeled kinase, immobilized ligand, and sample to be tested. The ability of a test sample to compete with a immobilized ligand for binding to a kinase can be determined by determining the amount of PCR in the DNA tag.

對於大多數試驗來說,激酶-標記的T7噬菌體菌株是由來源於BL21菌株的大腸桿菌宿主製備得到的。即先將大腸桿菌培養到對數生長期,然後用T7噬菌體將其感染,並將其在連續震盪下於32℃孵化直到裂解,將裂解液離心、抽濾,除去細胞碎片。剩餘的在HEK-293細胞內產生的激酶緊接著用DNA來標記,用於qPCR的檢測。包被有鏈黴親和素的磁珠與生物素化的小分子配體在室溫下反應30分鐘後,生成用於激酶試驗的親和樹脂。配位好的磁珠被過量的生物素堵塞,用封閉緩衝溶液(SEABLOCKTM(Pierce),1% BSA,0.05%吐溫-20,1mM DTT)洗滌除去游離的配體,以減少非特異性結合。結合反應都是通過激酶、配位好的親和性的磁珠和待測樣品在1x結合緩衝液(20% SEABLOCKTM,0.17x PBS,0.05%吐溫-20,6mM DTT)中完成的。所有反應均在終體積為0.135mL的聚苯乙烯的96孔板中進行。試驗的孔板均在連續震盪下於室溫條件孵化1小時,親和性的磁珠均用洗滌緩衝液(1x PBS,0.05%吐溫-20)洗滌,然後重懸浮於洗脫緩衝液(1x PBS,0.05%吐溫-20,0.5μM非生物素化親和性配體)中,並在連續震盪下於室溫條件孵化30分鐘。洗脫液中的激酶濃度通過qPCR測定。 For most of the assays, the kinase-tagged T7 phage strain was prepared from an E. coli host derived from the BL21 strain. E. coli was first cultured in logarithmic growth phase, then infected with T7 phage, and incubated at 32 ° C under continuous shaking until lysis, and the lysate was centrifuged and suction filtered to remove cell debris. The remaining kinase produced in HEK-293 cells was then labeled with DNA for detection of qPCR. The magnetic beads coated with streptavidin and the biotinylated small molecule ligand were reacted at room temperature for 30 minutes to form an affinity resin for the kinase assay. Good coordination excess biotin magnetic beads were blocked with blocking buffer (SEABLOCK TM (Pierce), 1 % BSA, 0.05% Tween 20, 1 mM DTT) free ligand is removed by washing to reduce non-specific Combine. Kinase reactions are bound by, a good affinity for the ligand and sample to be tested beads 1x binding buffer (20% SEABLOCK TM, 0.17x PBS , 0.05% Tween -20,6mM DTT) is completed. All reactions were carried out in 96-well plates of polystyrene in a final volume of 0.135 mL. The wells were incubated for 1 hour at room temperature under continuous shaking. The affinity beads were washed with washing buffer (1x PBS, 0.05% Tween-20) and resuspended in elution buffer (1x). PBS, 0.05% Tween-20, 0.5 μM non-biotinylated affinity ligand), and incubated for 30 minutes at room temperature under continuous shaking. The kinase concentration in the eluate was determined by qPCR.

本發明中的激酶試驗是由DiscoveRx公司的KINOMEscan TM分析服務來完成的(42501 Albrae St.Fremont,CA 94538,USA),本發明實施例 的測試結果列於表3中。 Kinase assay of the present invention is a DiscoveRx (TM) analysis company Scan service Kinome completed (42501 Albrae St.Fremont, CA 94538, USA), the test results of Examples of the present invention is shown in Table 3.

Kd-結合常數(Binding Constants) Kd-binding constants (Binding Constants)

本發明化合物在c-Met(h)和KDR(h)的試驗中顯示出很高的活性。 The compounds of the invention showed high activity in the tests of c-Met (h) and KDR (h).

細胞磷酸化試驗Cell phosphorylation test

通常,細胞與待測化合物預孵育,使其達到充分的靶標結合。利用夾心酶聯免疫分析(Sandwich-ELISA)技術檢測自磷酸化水準。利用½ log的稀釋倍數做出包含8個濃度點的曲線,估算IC50值(每個濃度測定2次)。本發明中細胞磷酸化試驗可以通過ProQinase GmbH公司(ProQinase GmbH,Breisacher Straße 117 D-79106,Freiburg,Germany)來完成的。 Typically, the cells are pre-incubated with the test compound to achieve sufficient target binding. The level of autophosphorylation was measured by sandwich enzyme-ELISA (Sandwich-ELISA). A curve containing 8 concentration points was made using a dilution factor of 1⁄2 log, and IC 50 values were estimated (2 determinations per concentration). The cell phosphorylation assay in the present invention can be carried out by ProQinase GmbH (ProQinase GmbH, Breisacher Straße 117 D-79106, Freiburg, Germany).

c-Met磷酸化試驗 c-Met phosphorylation test

眾所周知,人胃腺癌細胞株MKN45過表達c-Met。c-Met過表達導致組成型,配體非依賴的激酶自磷酸化。加入SU11274,磷酸化Met水準顯著降低,因此可以確定本發明化合物的抑制能力。通過夾心酶聯免疫分析(Sandwich-ELISA)技術可以對磷酸化Met信號進行定量。試驗設已知Met抑制劑組,以驗證試驗方法的可靠性。 It is well known that the human gastric adenocarcinoma cell line MKN45 overexpresses c-Met. Overexpression of c-Met leads to constitutive, ligand-independent kinase autophosphorylation. With the addition of SU11274, the level of phosphorylated Met is significantly reduced, so that the inhibitory ability of the compound of the present invention can be determined. Phosphorylated Met signals can be quantified by sandwich enzyme-ELISA. A set of known Met inhibitors was set up to verify the reliability of the test method.

VEGF-R2磷酸化試驗 VEGF-R2 phosphorylation test

已知永生化人臍靜脈內皮細胞(HUE)過表達VEGF-R2。用生理學的配體VEGF-A刺激這些細胞,可導致明顯的受體自磷酸化。細胞與待測 化合物預孵育,達到充分的靶標結合。優化刺激條件,達到劑量依賴性的抑制磷酸化VEGF-R2信號,並通過夾心酶聯免疫分析(Sandwich-ELISA)技術對磷酸化信號進行定量。試驗設已知VEGF-R2抑制劑組,以驗證試驗方法的可靠性。 It is known that immortalized human umbilical vein endothelial cells (HUE) overexpress VEGF-R2. Stimulation of these cells with the physiological ligand VEGF-A results in significant receptor autophosphorylation. Cell and test Compounds are pre-incubated to achieve sufficient target binding. Stimulation conditions were optimized to achieve dose-dependent inhibition of phosphorylated VEGF-R2 signaling, and phosphorylation signals were quantified by sandwich enzyme-ELISA. The VEGF-R2 inhibitor group was known to be tested to verify the reliability of the test method.

Axl磷酸化試驗 Axl phosphorylation test

通常利用小鼠胚胎成纖維細胞(MEF)進行細胞Axl磷酸化試驗。細胞通過轉染表達全長的Axl蛋白。之後通過克隆選擇獲得一個高度Axl自磷酸化的轉染細胞。然後加入星狀孢子素,磷酸化Axl水準顯著降低,因此可以確定化合物的抑制能力。並通過夾心酶聯免疫分析(Sandwich-ELISA)技術對磷酸化Axl水準進行定量。 Cellular Axl phosphorylation assays are typically performed using mouse embryonic fibroblasts (MEF). Cells express full length Axl protein by transfection. A highly Axl autophosphorylated transfected cell was then obtained by clonal selection. Then, with the addition of stellate spores, the level of phosphorylated Axl is significantly lowered, so that the inhibitory ability of the compound can be determined. Phosphorylated Axl levels were quantified by sandwich enzyme-ELISA.

異種移植腫瘤模型Xenograft tumor model

本發明化合物的藥效是通過移植腫瘤的標準鼠類模型來進行評價的。人腫瘤細胞(U87MG膠質瘤細胞,ATCC)培養、收集後,於後腹側皮下接種於6-7周齡的雌性裸小鼠體內(BALB/cA nu/nu,湖南SLAC動物實驗室)(對於溶劑組和每一個劑量組:n=6-10)。當腫瘤體積達到100-250mm3時,動物隨機地分為溶劑對照組(5% DMSO+70% Captisol®(30%),7% HCl(pH1),18% Captisol®(30%);或者7% DMSO,7% HCl(pH1),70% Captisol®(30%),16% Captisol®(30%))和化合物組。後續採用化合物對動物進行灌胃給藥,從腫瘤細胞接種後的0到15天中的任何地方開始,並且通常在試驗中每天進行一次。 The pharmacological effects of the compounds of the invention were evaluated by standard murine models of transplanted tumors. Human tumor cells (U87MG glioma cells, ATCC) were cultured, collected, and subcutaneously inoculated into 6-7 week old female nude mice (BALB/cA nu/nu, Hunan SLAC Animal Laboratory). Solvent group and each dose group: n = 6-10). When the tumor volume reached 100-250 mm 3 , the animals were randomly divided into a solvent control group (5% DMSO + 70% Captisol ® (30%), 7% HCl (pH 1), 18% Captisol ® (30%); or 7 % DMSO, 7% HCl (pH 1), 70% Captisol ® (30%), 16% Captisol ® (30%) and compound groups. Subsequent administration of the compound to the animals is carried out by gavage from anywhere in the 0 to 15 days after tumor cell inoculation, and usually once a day in the trial.

腫瘤生長抑制(TGI)分析 Tumor growth inhibition (TGI) analysis

腫瘤的演化生長是通過腫瘤體積與時間的關係來進行評價的。皮下腫瘤的長軸(L)和短軸(W)通過測徑器每週測定兩次,腫瘤的體積(TV)通過公式(L×W2)/2)進行計算。TGI由溶劑組小鼠腫瘤體積的中值和藥物組小鼠腫瘤體積中值的差值來進行計算,以溶劑對照組腫瘤體積中值的百分比來表示,通過下述公式進行計算: 原始統計分析是通過重複方差測定分析(RMANOVA)來完成的。接下來通過Scheffe psot hoc試驗方法進行多重比較。單獨溶劑(5% DMSO+70% Captisol®(30%),7% HCl(pHl),18% Captisol®(30%);或者7% DMSO,7% HCl(pH1),70% Captisol®(30%),16% Captisol®(30%))為陰性對照。 The evolution of tumors is evaluated by the relationship between tumor volume and time. The long axis (L) and the short axis (W) of the subcutaneous tumor were measured twice a week by a caliper, and the volume of the tumor (TV) was calculated by the formula (L × W 2 )/2). TGI was calculated from the median tumor volume of the solvent group and the median tumor volume of the drug group, expressed as a percentage of the median tumor volume of the solvent control group, and calculated by the following formula: The original statistical analysis was performed by repeated variance analysis (RMANOVA). Next, multiple comparisons were performed by the Scheffe psot hoc test method. Solvent alone (5% DMSO + 70% Captisol ® (30%), 7% HCl (pHl), 18% Captisol ® (30%); or 7% DMSO, 7% HCl (pH 1), 70% Captisol ® (30 %), 16% Captisol ® (30%)) was a negative control.

最後需要注意的是,還有其它方式可以實施本發明。相應地,本發明的實施例是將作為例證進行說明,但並不限於本發明所描述的內容,還可能是在本發明範圍內所作的修改或在申請專利範圍中所添加的等同內容。本發明所引用的所有出版物或專利都將作為本發明的參考文獻。 Finally, it should be noted that there are other ways in which the invention can be implemented. Accordingly, the embodiments of the present invention are intended to be illustrative, but not limited to the description of the present invention, and may be modified within the scope of the invention or equivalents added in the scope of the claims. All publications or patents cited herein are hereby incorporated by reference.

Claims (23)

一種如式(I)所示的化合物: 或其立體異構體,幾何異構體,互變異構體,氮氧化物,水合物,溶劑化物,代謝產物,藥學上可接受的鹽或它的前藥,其中:Q為D,-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-C(=O)NRaRb,-N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb或-N(Rc)S(=O)2Ra;W為CR7或N;各X,Y和Z獨立地為H,D,C1-6烷基,C3-8環烷基,C3-8環烷基-C1-4亞烷基,C3-7雜環基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基或5-10個原子組成的雜芳基,其中,所述C1-6烷基,C3-8環烷基,C3-8環烷基-C1-4亞烷基,C3-7雜環基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基和5-10個原子組成的雜芳基可以任選地被1,2,3,4或5個獨立選自D,F,Cl,Br,CN,C2-6烯基,C2-6炔基,ORa,NRaRb,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代;各R1,R2,R3,R4,R5,R6和R7獨立地為H,D,F,Cl,Br,CN,N3,ORa,C1-6烷基,C1-6鹵代烷基,C2-6烯基或C2-6炔基;各Ra,Rb和Rc獨立地為H,C1-6脂肪族,C1-6鹵代烷基,C3-6環烷基,C3-6環烷基-C1-4亞烷基,C3-6雜環基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基或5-10個原子組成的雜芳基,其中,所述C1-6脂肪族,C1-6鹵代烷基,C3-6環烷基,C3-6環烷基-C1-4亞烷基,C3-6雜環基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基,C6-10芳基和 5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代;和Rd為D,C3-8環烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基或5-10個原子組成的雜芳基,其中,所述C3-8環烷基,C6-10芳基-C1-4亞烷基,(5-10個原子組成的雜芳基)-C1-4亞烷基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,Br,CN,ORa,NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代。 a compound of formula (I): Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: Q is D, -N (R c )C(=O)NR a R b , -N(R c )C(=O)R d , -C(=O)NR a R b ,-N(R c )S(=O) NR a R b , -N(R c )S(=O)R a , -N(R c )S(=O) 2 NR a R b or -N(R c )S(=O) 2 R a W is CR 7 or N; each X, Y and Z are independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkylene , C 3-7 heterocyclyl, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene, (5-10 atomic hetero An aryl)-C 1-4 alkylene group, a C 6-10 aryl group or a heteroaryl group of 5-10 atoms, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl-C 1-4 alkylene, C 3-7 heterocyclic, C 3-7 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 An alkylene group, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, a C 6-10 aryl group and a heteroaryl group of 5-10 atoms may optionally be 1,2 , 3, 4 or 5 independently selected from D, F, Cl, Br, CN, C 2-6 alkenyl, C 2-6 alkynyl, OR a , NR a R b , R a OC 1-4 alkylene group or a R a R b NC 1-4 alkylene substituents; each R 1, R 2, R 3 , R 4, R 5, R 6 and R 7 are independently H, D, F, Cl, Br, CN, N 3 , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; each R a , R b and R c are independently H, C 1-6 aliphatic, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, C 3 -6 heterocyclyl, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)- a C 1-4 alkylene group, a C 6-10 aryl group or a heteroaryl group of 5-10 atoms, wherein the C 1-6 aliphatic group, a C 1-6 haloalkyl group, a C 3-6 cycloalkane Base, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclyl, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, C 6-10 aryl group and heteroaryl group of 5-10 atoms may optionally be 1, 2, 3 or 4 independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino Substituted by a substituent; and R d is D, C 3-8 cycloalkyl, C 6-10Aryl -C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene or heteroaryl group of 5-10 atoms, wherein C 3-8 cycloalkyl, C 6-10 aryl-C 1-4 alkylene, (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group and 5-10 atoms The heteroaryl group may be optionally 1, 2, 3 or 4 independently selected from the group consisting of D, F, Cl, Br, CN, OR a , NR a R b , C 1-6 alkyl, C 2-6 olefin Substituent, C 2-6 alkynyl, R a OC 1-4 alkylene or R a R b NC 1-4 alkylene substituent. 如申請專利範圍第1項所述的化合物,其中,Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd或-C(=O)NRaRbThe compound of claim 1, wherein Q is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d or -C(= O) NR a R b . 如申請專利範圍第1項所述的化合物,其中,各X,Y和Z獨立地為C1-4烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基,C3-6雜環基-C1-2亞烷基,苯基-C1-2亞烷基,(5-10個原子組成的雜芳基)-C1-2亞烷基,苯基或5-10個原子組成的雜芳基,其中,所述C1-4烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基,C3-6雜環基-C1-2亞烷基,苯基-C1-2亞烷基,(5-10個原子組成的雜芳基)-C1-2亞烷基,苯基和5-10個原子組成的雜芳基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,C2-4烯基,C2-4炔基,ORa,NRaRb,RaO-C1-2亞烷基或RaRbN-C1-2亞烷基的取代基所取代。 The compound of claim 1, wherein each of X, Y and Z is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, C 3-6 heterocyclyl, C 3-6 heterocyclyl-C 1-2 alkylene, phenyl-C 1-2 alkylene, (heteroaryl group of 5-10 atoms) a -C 1-2 alkylene group, a phenyl group or a heteroaryl group of 5-10 atoms, wherein the C 1-4 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyl group -C 1-2 alkylene, C 3-6 heterocyclyl, C 3-6 heterocyclyl-C 1-2 alkylene, phenyl-C 1-2 alkylene, (5-10 atoms The heteroaryl group-C 1-2 alkylene group, the phenyl group and the heteroaryl group consisting of 5-10 atoms may be optionally 1, 2, 3 or 4 independently selected from D, F, Cl, Substituted by a substituent of CN, C 2-4 alkenyl, C 2-4 alkynyl, OR a , NR a R b , R a OC 1-2 alkylene or R a R b NC 1-2 alkylene . 如申請專利範圍第1項所述的化合物,其中,各R1,R2,R3,R4,R5,R6和R7獨立地為H,D,F或Cl。 The compound of claim 1, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently H, D, F or Cl. 如申請專利範圍第1項所述的化合物,其中,各Ra,Rb和Rc獨立地為H,C1-4烷基,C1-4鹵代烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基或C3-6雜環基-C1-2亞烷基,其中,所述C1-4烷基,C1-4鹵代烷基,C3-6環烷基,C3-6環烷基-C1-2亞烷基,C3-6雜環基和C3-6雜環基-C1-2亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH, NH2,C1-3鹵代烷基,C1-3烷氧基或C1-3烷基氨基的取代基所取代。 The compound of claim 1, wherein each of R a , R b and R c is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, a C 3-6 cycloalkyl-C 1-2 alkylene group, a C 3-6 heterocyclic group or a C 3-6 heterocyclic group-C 1-2 alkylene group, wherein the C 1-4 alkyl group , C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C 1 The -2 alkylene group may be optionally 1, 2, 3 or 4 independently selected from the group consisting of D, F, Cl, CN, N 3 , OH, NH 2 , C 1-3 haloalkyl, C 1-3 alkoxy Substituted by a substituent of a C 1-3 alkylamino group. 如申請專利範圍第1項所述的化合物,其中Rd為C3-6環烷基,其中,所述C3-6環烷基可以任選地被1,2,3或4個獨立選自D,F,CN,ORa,NRaRb,C1-3烷基,C2-4烯基,C2-4炔基,RaO-C1-2亞烷基或RaRbN-C1-2亞烷基的取代基所取代。 The compound of claim 1, wherein R d is a C 3-6 cycloalkyl group, wherein the C 3-6 cycloalkyl group may be optionally selected by 1, 2, 3 or 4 independently. From D, F, CN, OR a , NR a R b , C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, R a OC 1-2 alkylene or R a R b Substituted by a substituent of NC 1-2 alkylene. 如申請專利範圍第1項所述的化合物,其中,各X,Y和Z獨立地為H,D,CH3,被1,2或3個氘原子所取代的甲基基團,乙基,丙基,異丙基,苯基或被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代的苯基基團。 The compound of claim 1, wherein each of X, Y and Z is independently H, D, CH 3 , a methyl group substituted by 1, 2 or 3 deuterium atoms, ethyl, A propyl group, an isopropyl group, a phenyl group or a phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl. 如申請專利範圍第1項所述的化合物,其中Q為: The compound of claim 1, wherein Q is: 如申請專利範圍第1項所述的化合物,具有式(II)所示結構: 其中:Q為-N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd,-N(Rc)S(=O)NRaRb,-N(Rc)S(=O)Ra,-N(Rc)S(=O)2NRaRb,-N(Rc)S(=O)2Ra或-C(=O)NRaRb;各X,Y和Z獨立地為H,D,C1-6烷基,C3-8環烷基,C3-7雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基或(5-10個原子組成的雜芳基)-C1-4亞烷基,其中,所述C1-6烷基,C3-8環烷基,C3-7雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-8環烷基-C1-4亞烷基,C3-7雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基和(5-10個原子組成的雜芳基)-C1-4亞烷基可以任選地被1,2,3,4或5個獨立選自D,F,Cl,Br,CN,C2-6烯基,C2-6炔基,ORa,NRaRb,RaO-C1-4亞烷基或RaRbN-C1-4亞烷基的取代基所取代;各Ra,Rb和Rc獨立地為H,C1-6烷基,C3-6環烷基,C3-6雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-6環烷基-C1-4亞烷基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基或(5-10個原子組成的雜芳基)-C1-4亞烷基,其中,所述C1-6烷基,C3-6環烷基,C3-6雜環基,C6-10芳基,5-10個原子組成的雜芳基,C3-6環烷基-C1-4亞烷基,C3-6雜環基-C1-4亞烷基,C6-10芳基-C1-4亞烷基和(5-10個原子組成的雜芳基)-C1-4亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代;和Rd為C3-8環烷基,其中,所述C3-8環烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,OH,NH2,C1-6烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代。 The compound of the above formula (1) has the structure represented by the formula (II): Where: Q is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d , -N(R c )S(=O)NR a R b , -N(R c )S(=O)R a , -N(R c )S(=O) 2 NR a R b , -N(R c )S(=O) 2 R a or -C(= O) NR a R b ; each X, Y and Z are independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-7 heterocyclyl, C 6-10 aryl, Heteroaryl group of 5-10 atoms, C 3-8 cycloalkyl-C 1-4 alkylene group, C 3-7 heterocyclic group - C 1-4 alkylene group, C 6-10 aryl group - C 1-4 alkylene or (heteroaryl group of 5-10 atoms)-C 1-4 alkylene group, wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3 -7 heterocyclic group, C 6-10 aryl group, heteroaryl group of 5-10 atoms, C 3-8 cycloalkyl-C 1-4 alkylene group, C 3-7 heterocyclic group - C 1 -4 alkylene, C 6-10 aryl-C 1-4 alkylene and (heteroaryl group of 5-10 atoms) -C 1-4 alkylene may be optionally 1,2, 3, 4 or 5 independently selected from D, F, Cl, Br, CN, C 2-6 alkenyl, C 2-6 alkynyl, OR a , NR a R b , R a OC 1-4 alkylene Or a substituent of R a R b NC 1-4 alkylene; each R a , R b and R c are independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- 6 heterocyclic group, C 6-10 aryl, 5-10 atoms Composition of heteroaryl, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclyl-C 1-4 alkylene, C 6-10 aryl-C 1-4 An alkyl group or a heteroaryl group of 5-10 atoms, a C 1-4 alkylene group, wherein the C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 heterocyclic group , C 6-10 aryl, heteroaryl group of 5-10 atoms, C 3-6 cycloalkyl-C 1-4 alkylene, C 3-6 heterocyclyl-C 1-4 alkylene , C 6-10 aryl-C 1-4 alkylene and (5-10 atomic heteroaryl)-C 1-4 alkylene may be optionally 1, 2, 3 or 4 independent Substituted from a substituent selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino; and R d is a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group may be optionally 1, 2, 3 or 4 independently selected from the group consisting of D, F, Cl, OH, NH 2 , C 1-6 Substituted by a substituent of an alkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group. 如申請專利範圍第9項所述的化合物,其中,Q為 -N(Rc)C(=O)NRaRb,-N(Rc)C(=O)Rd或-C(=O)NRaRbThe compound of claim 9, wherein Q is -N(R c )C(=O)NR a R b , -N(R c )C(=O)R d or -C(= O) NR a R b . 如申請專利範圍第9項所述的化合物,其中,各X,Y和Z獨立地為H,D,C1-4烷基,或苯基,其中,所述C1-4烷基和苯基可以任選地被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代。 The compound of claim 9, wherein each of X, Y and Z is independently H, D, C 1-4 alkyl, or phenyl, wherein said C 1-4 alkyl and benzene The group may be optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl. 如申請專利範圍第9項所述的化合物,其中,各Ra,Rb和Rc獨立地為H,C1-4烷基,C3-6環烷基,C3-6雜環基,C3-6環烷基-C1-2亞烷基或C3-6雜環基-C1-2亞烷基,其中,所述C1-4烷基,C3-6環烷基,C3-6雜環基,C3-6環烷基-C1-2亞烷基和C3-6雜環基-C1-2亞烷基可以任選地被1,2,3或4個獨立選自D,F,Cl,CN,N3,OH,NH2,C1-6鹵代烷基,C1-6烷氧基或C1-6烷基氨基的取代基所取代。 The compound according to claim 9, wherein each of R a , R b and R c is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclic group. a C 3-6 cycloalkyl-C 1-2 alkylene group or a C 3-6 heterocyclic group-C 1-2 alkylene group, wherein the C 1-4 alkyl group, C 3-6 cycloalkane a C 3-6 heterocyclyl group, a C 3-6 cycloalkyl-C 1-2 alkylene group and a C 3-6 heterocyclyl-C 1-2 alkylene group may optionally be 1,2, Substituting 3 or 4 substituents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino . 如申請專利範圍第9項所述的化合物,其中,各X,Y和Z獨立地為H,D,Me,CH2D,CHD2,CD3,乙基,丙基,異丙基,苯基或被1,2,3,4或5個獨立選自D,F或Cl的取代基所取代的苯基基團。 The compound of claim 9, wherein each of X, Y and Z is independently H, D, Me, CH 2 D, CHD 2 , CD 3 , ethyl, propyl, isopropyl, benzene A phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F or Cl. 如申請專利範圍第9項所述的化合物,其中Q為: The compound of claim 9, wherein Q is: 如申請專利範圍第1項所述的化合物,具有以下其中之一的結構: The compound of claim 1, wherein the compound has one of the following structures: 一種藥物組合物,其包含申請專利範圍第1項至第15項中任一項所述的化合物或藥學上可接受的載體,賦形劑,稀釋劑,輔劑,媒介物,或它們的組合。 A pharmaceutical composition comprising the compound of any one of claims 1 to 15 or a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof . 如申請專利範圍第16項所述的藥物組合物,其中更進一步地包含附加治療劑,這些附加治療劑選自化學治療藥物,抗增殖劑,用於治療動脈粥樣硬化的藥物,用於治療肺纖維化的藥物,或它們的組合。 The pharmaceutical composition according to claim 16, which further comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic drug, an anti-proliferative agent, a drug for treating atherosclerosis, and a therapeutic agent. Pulmonary fibrosis drugs, or a combination thereof. 如申請專利範圍第17項所述的藥物組合物,其中所述的附加治療劑是阿黴素(Adriamycin),雷怕黴素(Rapamycin),Temsirolimus,依維莫司(Everolimus),Ixabepilone,吉西他濱(Gemcitabin),環磷醯胺(cyclophosphamide),***(dexamethasone),依託泊苷(etoposide),氟尿嘧啶(fluorouracil),阿法替尼(afatinib),alisertib,amuvatinib,阿西替尼(axitinib),波舒替尼(bosutinib),brivanib,cabozantinib,西地尼布(cediranib),crenolanib,克卓替尼(crizotinib),dabrafenib,dacomitinib,達沙替尼(dasatinib),danusertib,dovitinib,厄洛替尼(erlotinib),foretinib,ganetespib,吉非替尼(gefitinib),ibrutinib,伊馬替尼(imatinib),iniparib,拉帕替尼(lapatinib),lenvatinib,linifanib,linsitinib,馬賽替尼(masitinib),momelotinib,莫替沙尼(motesanib),來那替尼(neratinib),niraparib,尼洛替尼(nilotinib),oprozomib,olaparib,帕唑帕尼(pazopanib),pictilisib,ponatinib,quizartinib,regorafenib,rigosertib, rucaparib,ruxolitinib,塞卡替尼(saracatinib),saridegib,索拉非尼(sorafenib),舒尼替尼(sunitinib),tasocitinib,telatinib,tivantinib,tivozanib,tofacitinib,trametinib,凡德他尼(vandetanib),veliparib,vemurafenib,vismodegib,volasertib,干擾素(an interferon),卡鉑(carboplatin),托泊替康(topotecan),紫杉醇(taxol),長春堿(vinblastine),長春新堿(vincristine),替莫唑胺(temozolomide),托西莫單抗(tositumomab),trabedectin,belimumab,貝伐單抗(bevacizumab),brentuximab,cetuximab,gemtuzumab,ipilimumab,ofatumumab,panitumumab,ranibizumab,rituximab,tositumomab,曲妥單抗(trastuzumab)或它們的組合。 The pharmaceutical composition according to claim 17, wherein the additional therapeutic agent is Adriamycin, Rapamycin, Temsirolimus, Everolimus, Ixabepilone, Gemcitabine (Gemcitabin), cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib , bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib (erlotinib), foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, Motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatini b,quizartinib,regorafenib,rigosertib, Rucaparib, ruxolitinib, sarkatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, vandetanib Veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide ), tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or their The combination. 一種使用如申請專利範圍第1項至第15項中任一項所述的化合物或申請專利範圍第16項至第18項中任一項所述的藥物組合物來製備用於防護、處理、治療或減輕患者增殖性疾病的藥品的用途。 A pharmaceutical composition according to any one of claims 1 to 15 or a pharmaceutical composition according to any one of claims 16 to 18, which is prepared for use in protection, treatment, The use of a drug to treat or alleviate a proliferative disease in a patient. 如申請專利範圍第19項所述的化合物或藥物組合物的用途,其中所述的增殖性疾病是轉移癌、結腸癌,胃腺癌,膀胱癌,乳腺癌,腎癌,肝癌,肺癌,皮膚癌,甲狀腺癌,腦瘤,頸癌,***癌,胰腺癌,CNS(中樞神經系統)的癌症,惡性膠質瘤,骨髓增生病,動脈粥樣硬化或肺纖維化。 The use of the compound or pharmaceutical composition according to claim 19, wherein the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer , thyroid cancer, brain tumor, cervical cancer, prostate cancer, pancreatic cancer, CNS (central nervous system) cancer, malignant glioma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis. 一種使用如申請專利範圍第1項至第15項中任一項所述的化合物或申請專利範圍第16項至第18項中任一項所述的藥物組合物來製備用於在生物標本內抑制或調節蛋白激酶活性的用途,所述用途包含使用申請專利範圍第1項至第15項中任一項所述的化合物或使用申請專利範圍第第16項至第18任一項所述的藥物組合物與所述的生物標本接觸。 A pharmaceutical composition according to any one of claims 1 to 15 or a pharmaceutical composition according to any one of claims 16 to 18, which is prepared for use in a biological specimen The use of inhibiting or modulating the activity of a protein kinase comprising the use of a compound according to any one of claims 1 to 15 or the use of any one of claims 16 to 18 The pharmaceutical composition is contacted with the biological specimen. 如申請專利範圍第21項所述的用途,其中所述蛋白激酶為受體酪氨酸激酶。 The use of claim 21, wherein the protein kinase is a receptor tyrosine kinase. 如申請專利範圍第22項所述的用途,其中所述受體酪氨酸激酶為VEGFR,c-Met,Ron,Axl或它們的組合。 The use of claim 22, wherein the receptor tyrosine kinase is VEGFR, c-Met, Ron, Axl or a combination thereof.
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