TWI640518B - Fused tricyclic compounds as raf kinase inhibitors - Google Patents
Fused tricyclic compounds as raf kinase inhibitors Download PDFInfo
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Abstract
本發明提供某些稠合三環化合物及其鹽類、組合物和使用方法。 The present invention provides certain fused tricyclic compounds and salts, compositions and methods of use thereof.
Description
本說明書揭示了稠合三環化合物、包含至少一個所述稠合三環化合物的藥物組合物、其製備工藝以及其在治療中的用途。本說明書所揭示的某些三環化合物可以有助於抑制Raf激酶和治療由其介導的病症。 The present specification discloses fused tricyclic compounds, pharmaceutical compositions comprising at least one of the fused tricyclic compounds, processes for their preparation, and their use in therapy. Certain tricyclic compounds disclosed in the present specification may be useful for inhibiting Raf kinase and treating disorders mediated thereby.
Raf/MEK/ERK通路對於細胞的存活，生長，增殖和腫瘤的形成有積極性作用(Zebisch等人，Curr Med Chem.14(5)：601-623，2007；Roberts和Der，Oncogene 26(22)：3291-3310，2007；Montagut和Settleman,Cancer Lett.283(2)：125-134，2009)。Raf/MEK/ERK信號轉導通道的激發可以在配體連接到與膜結合的受體酪氨酸激酶後產生。GTP結合的RAS被啟動後，可以促進Raf家族蛋白(A-Raf、B-Raf和Raf1，以前被稱作C-Raf)的活化(Wellbrock等人，Nat.Rev.Mol.Cell Biol.5：875-885，2004)。 The Raf/MEK/ERK pathway has a positive effect on cell survival, growth, proliferation and tumor formation (Zebisch et al., Curr Med Chem. 14(5): 601-623, 2007; Roberts and Der, Oncogene 26 (22) : 3291-3310, 2007; Montagut and Settleman, Cancer Lett. 283(2): 125-134, 2009). Excitation of the Raf/MEK/ERK signal transduction pathway can be produced after the ligand is attached to a membrane-bound receptor tyrosine kinase. Activation of the Raf family proteins (A-Raf, B-Raf and Raf1, formerly known as C-Raf) can be promoted by GTP-bound RAS (Wellbrock et al., Nat. Rev. Mol. Cell Biol. 5: 875-885, 2004).
據報導，Raf/MEK/ERK信號通道中各種RAS GTP酶和B-Raf激酶的突變都可組成性啟動MAPK通道，從而導 致細胞分化和存活量的增加(Bos,Cancer Res.49：4682-4689，1989；Hoshino等人，Oncogene.18(3)：813-822，1999)。例如，據報導，在很大比例的人黑色素瘤和甲狀腺瘤中發現了B-Raf突變(Davies等人，Nature417：949-954，2002)(Cohen等人，J.Nat.Cancer Inst.95(8)：625-627，2003；Kimura等人，Cancer Res.63(7)：1454-1457，2003；Pollock和Meltzer,Cancer Cell2：5-7，2002)。而且，據報導，在Barret腺癌(Garnett等人，Cancer Cell6：313-319，2004；Sommerer等人，Oncogene 23(2)：554-558，2004)、乳腺癌(Davies等人，Nature 417：949-954，2002)、宮頸癌(Moreno-Bueno等人，Clin.Cancer Res.12(12)：365-3866，2006)、膽管癌(Tannapfel等人，Gut.52(5)：706-712，2003)、惡性膠質癌(Knobbe等人，Acta Neuropathol.(Berl.).108(6)：467-470，2004)、直腸癌(Yuen等人，Cancer Res.62(22)：6451-6455，2002；Davies等人，Nature417：949-954，2002)、胃癌(Lee等人，Oncogene22(44)：6942-6945)，肺癌(Brose等人，Cancer Res.62(23)：6997-7000，2002)、卵巢癌(Russell和McCluggage，J.Pathol.203(2)：617-619，2004；Davies等人，Nature417：949-954,2002)、胰腺癌(Ishimura等人，Cancer Lett.199(2)：169-173，2003)、***癌(Cho等人，Int.J.Cancer.119(8)：1858-1862，2006)和血液癌症(Garnett和Marais，Cancer Cell6：313-319，2004)中發現了頻率低但仍顯著的B-Raf突變。這些報導表明，B-Raf是人體癌症中最經常出現的突變基因之一。基於臨床前靶標確認、流行病學和成藥性，B-Raf激酶可以代表一類 很好的可以治療癌症的靶標。 It has been reported that mutations in various RAS GTPases and B-Raf kinases in the Raf/MEK/ERK signaling pathway can constitutively initiate MAPK channels, resulting in increased cell differentiation and survival (Bos, Cancer Res. 49:4682-4689). , 1989; Hoshino et al., Oncogene. 18(3): 813-822, 1999). For example, it has been reported that B-Raf mutations are found in a large proportion of human melanoma and thyroid tumors (Davies et al, Nature 417: 949-954, 2002) (Cohen et al, J. Nat . Cancer Inst. 95 ( 8): 625-627, 2003; Kimura et al., Cancer Res. 63(7): 1454-1457, 2003; Pollock and Meltzer, Cancer Cell 2: 5-7, 2002). Moreover, it has been reported that in Barret adenocarcinoma (Garnett et al, Cancer Cell 6: 313-319, 2004; Sommerer et al, Oncogene 23 (2): 554-558, 2004), breast cancer (Davies et al, Nature 417: 949-954, 2002), cervical cancer (Moreno-Bueno et al, Clin. Cancer Res. 12 (12): 365-3866, 2006), cholangiocarcinoma (Tannapfel et al, Gut. 52 (5): 706-712 , 2003), malignant glial carcinoma (Knobbe et al, Acta Neuropathol. (Berl.). 108 (6): 467-470, 2004), rectal cancer (Yuen et al, Cancer Res. 62 (22): 6451-6455 , 2002; Davies et al, Nature 417: 949-954, 2002), gastric cancer (Lee et al, Oncogene 22 (44): 6942-6945), lung cancer (Brose et al, Cancer Res. 62 (23): 6997-7000, 2002), ovarian cancer (Russell and McCluggage, J. Pathol. 203 (2): 617-619, 2004; Davies et al, Nature 417: 949-954, 2002), pancreatic cancer (Ishimura et al, Cancer Lett. 199 ( 2): 169-173, 2003), prostate cancer (Cho et al, Int. J. Cancer. 119 (8): 1858-1862, 2006) and hematological cancer (Garnett and Marais, Cancer Cell 6: 313-319, 2004) A low frequency but still significant B-Raf mutation was found. These reports indicate that B-Raf is one of the most frequently occurring mutations in human cancer. Based on preclinical target confirmation, epidemiology and drug-making properties, B-Raf kinase can represent a good class of targets for treating cancer.
已經討論了RAF激酶抑制劑在破壞腫瘤細胞生長中的用途，以及治療癌症如黑色素瘤，結腸直腸癌包括大腸結腸癌、組織細胞性淋巴瘤、肺腺癌、小細胞肺癌、胰腺癌和乳腺癌(Crump，Current Pharmaceutical Design 8：2243-2248，2002；Sebastien等人，Current Pharmaceutical Design 8：2249-2253，2002)，及/或治療或者預防與由缺血事件造成的神經元退化相關的疾病，包括在心搏停止後的腦缺血、中風和血管性癡呆。還討論了Raf激酶抑制劑在缺血性事件後的用途，主要來自於頭部受傷、外科手術及/或分娩期(York等人，Mol.and Cell.Biol.20(21)：8069-8083，2000；Chin等人，Neurochem.90：595-608，2004)和多囊性腎病(Nagao等人，Kidney Int.63(2)：427-437，2003)。 The use of RAF kinase inhibitors to disrupt tumor cell growth has also been discussed, as well as the treatment of cancers such as melanoma, including colorectal cancer, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer and breast cancer. (Crump, Current Pharmaceutical Design 8: 2243-2248, 2002; Sebastien et al, Current Pharmaceutical Design 8: 2249-2253, 2002), and/or treating or preventing diseases associated with neuronal degeneration caused by ischemic events, Includes cerebral ischemia, stroke, and vascular dementia after cardiac arrest. The use of Raf kinase inhibitors after ischemic events is also discussed, mainly from head injuries, surgery, and/or childbirth (York et al., Mol. and Cell. Biol. 20(21): 8069-8083 , 2000; Chin et al, Neurochem. 90: 595-608, 2004) and polycystic kidney disease (Nagao et al, Kidney Int. 63 (2): 427-437, 2003).
此外，某些高增生疾病的特徵是Raf激酶功能的過度活化，比如，這種活化來自於蛋白質的突變或過度表達。因此，Raf激酶抑制劑在高增生疾病如癌症的治療中是非常有用的。 In addition, certain hyperproliferative diseases are characterized by excessive activation of Raf kinase function, for example, such activation is due to mutation or overexpression of the protein. Therefore, Raf kinase inhibitors are very useful in the treatment of highly proliferative diseases such as cancer.
一些小分子的B-Raf激酶抑制劑正在被開發用於抗癌治療。Nexavar®(索拉菲尼的甲苯磺酸鹽)是一種多重激酶抑制劑，其中包括抑制B-Raf激酶，Nexavar®已被批准用於治療患有晚期腎癌和不可手術切除的肝癌病人。其它的Raf抑制劑也已經被揭示或進入了臨床試驗，例如SB-590885、RAF-265、PLX-4032、GSK2118436和XL-281。 Some small molecule B-Raf kinase inhibitors are being developed for anti-cancer treatment. Nexavar® (solafenib tosylate) is a multi-kinase inhibitor that includes inhibition of B-Raf kinase, and Nexavar® has been approved for the treatment of patients with advanced kidney cancer and unresectable liver cancer. Other Raf inhibitors have also been disclosed or entered into clinical trials such as SB-590885, RAF-265, PLX-4032, GSK2118436 and XL-281.
還有一些其他的B-Raf抑制劑。參見如美國專利申 請公開第2006/0189627號、美國專利申請公開第2006/0281751號、美國專利申請公開第2007/0049603號、國際專利申請公開第WO 2007/002325號、國際專利申請公開第WO 2007/002433號、國際專利申請公開第WO 03/068773號、國際專利申請公開第WO 03/068773號和國際專利申請公開第WO 2007/013896號。 There are also other B-Raf inhibitors. See, for example, US patent application Please disclose the publication No. 2006/0189627, US Patent Application Publication No. 2006/0281751, US Patent Application Publication No. 2007/0049603, International Patent Application Publication No. WO 2007/002325, and International Patent Application Publication No. WO 2007/002433, International Patent Application Publication No. WO 03/068773, International Patent Application Publication No. WO 03/068773, and International Patent Application Publication No. WO 2007/013896.
某些含氮雜環取代的芳香基雙環化合物已經被確定為Raf抑制劑。參見如國際專利申請公開第WO 2007/067444號和美國專利申請公開第2010/0197924號。 Certain nitrogen-containing heterocyclic substituted aryl bicyclic compounds have been identified as Raf inhibitors. See, for example, International Patent Application Publication No. WO 2007/067444 and U.S. Patent Application Publication No. 2010/0197924.
還確定了某些Raf激酶抑制劑。參見如國際專利申請公開第WO 2005/062795號、國際專利申請公開第WO 2008/079906號、國際專利申請公開第WO 2008/079909號、國際專利申請公開第WO 2006/066913號、國際專利申請公開第2008/028617號和國際專利申請公開第WO 2009/012283號。 Certain Raf kinase inhibitors have also been identified. See, for example, International Patent Application Publication No. WO 2005/062795, International Patent Application Publication No. WO 2008/079906, International Patent Application Publication No. WO 2008/079909, International Patent Application Publication No. WO 2006/066913, International Patent Application Publication No. 2008/028617 and International Patent Application Publication No. WO 2009/012283.
本說明書中揭示的化合物可以抑制Raf激酶如B-Raf激酶。茲提供選自式I之化合物中之至少一個化合物、其立體異構體和其藥學上可接受的鹽類，
其中：Q選自C和N； W選自C和N；X選自CH2和O；Y選自NR12、O和S；Z選自O、S、NR13、CO、SO、SO2和CR13R14；R1、R2、R3、R4、R5和R6，它們可以相同或不同，其各自選自氫、鹵素、鹵烷基、烷基、烯基、環烷基、芳基、雜環基、雜芳基、炔基、氰基、-NR13R14、-OR13、-COR13、-CO2R13、-CONR13R14、-C(=NR13)NR14R15、-NR13COR14、-NR13CONR14R15、-NR13CO2R14、-SO2R13、-NR13SO2NR14R15、-NR13SO2R14和-NR13SO2芳基，其中烷基、烯基、炔基、環烷基、雜芳基、芳基和雜環基可以被至少一個取代基R16任意取代，或(R1和R2)及/或(R3和R4)及/或(R5和R6)可與它們所連接的環一起形成稠環，此稠環可選自可被至少一個取代基R16任意取代的雜環和雜芳環；假設當Q是N時R1不存在，並假設W是N時R5不存在；R7選自氫、鹵素、烷基、烷氧基和烷硫基；R12選自氫和烷基；R13、R14和R15，它們可以相同或不同，各自選自氫、鹵烷基、烷基、烯基、炔基、環烷基、雜環、芳基和雜芳基；或(R13和R14)及/或(R14和R15)各與它們所連接的一或多個原子一起形成環，該環選自可被至少一個取代基R16任意取代的雜環和雜芳環；R16選自鹵素、鹵烷基、烷基、烯基、環烷基、芳基、雜芳基、雜環基、炔基、氧基、氰基、-OR'、-NR'R"、-COR'、 -CO2R'、-CONR'R"、-C(=NR')NR"R'''、-NR'COR"、-NR'CONR'R"、-NR'CO2R"、-SO2R'、-SO2芳基、-NR'SO2NR"R'''和NR'SO2R"，此處R'、R"和R'''獨立地選自氫、鹵烷基、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或(R'和R")及/或(R"和R''')與它們所連接的原子一起形成選自雜環基和雜芳環的環。 Wherein: Q is selected from C and N; W is selected from C and N; X is selected from CH 2 and O; Y is selected from NR 12 , O and S; and Z is selected from O, S, NR 13 , CO, SO, SO 2 And CR 13 R 14 ; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , which may be the same or different, each selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, alkenyl, cycloalkane Base, aryl, heterocyclic, heteroaryl, alkynyl, cyano, -NR 13 R 14 , -OR 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -C(=NR 13 ) NR 14 R 15 , -NR 13 COR 14 , -NR 13 CONR 14 R 15 , -NR 13 CO 2 R 14 , -SO 2 R 13 , -NR 13 SO 2 NR 14 R 15 , -NR 13 SO 2 R 14 and —NR 13 SO 2 aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl and heterocyclyl are optionally substituted by at least one substituent R 16 , or (R 1 And R 2 ) and/or (R 3 and R 4 ) and/or (R 5 and R 6 ) may form a fused ring together with the ring to which they are attached, and the fused ring may be selected from at least one substituent R 16 Any substituted heterocyclic ring and heteroaromatic ring; assume that R 1 is absent when Q is N, and that R 5 is absent if W is N; R 7 is selected from hydrogen, halogen, alkyl, alkoxy and alkylthio ;R 12 election From hydrogen and alkyl; R 13 , R 14 and R 15 , which may be the same or different, each selected from the group consisting of hydrogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and hetero An aryl group; or (R 13 and R 14 ) and/or (R 14 and R 15 ) each together with one or more atoms to which they are attached form a ring selected from the group which may be optionally substituted by at least one substituent R 16 Heterocyclic and heteroaryl rings; R 16 is selected from halo, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxy, cyano, -OR ', -NR'R", -COR', -CO 2 R', -CONR'R", -C(=NR')NR"R''', -NR'COR", -NR'CONR'R ", -NR'CO 2 R", -SO 2 R', -SO 2 aryl, -NR'SO 2 NR"R''' and NR'SO 2 R", where R', R" and R ''' is independently selected from the group consisting of hydrogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R' and R") and/or (R) "And R'"' together with the atoms to which they are attached form a ring selected from the group consisting of a heterocyclic group and a heteroaryl ring.
還提供了一種藥物組合物，所述藥物組合物包括至少一種藥學上可接受的載體和至少一個選自式(I)的化合物，及其立體異構體和本說明書中所描述的藥學上可接受的鹽。 Also provided is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound selected from formula (I), and stereoisomers thereof, and pharmaceutically acceptable as described in the specification Accepted salt.
還提供了一種治療對Raf激酶抑制劑有反應的癌症的方法，所述方法包括給需要治療這種癌症的受試者一定量的至少一個選自式(I)的化合物，及本文中所述的可有效治療所述癌症的該化合物的立體異構體和該化合物藥學上可接受的鹽類。 Also provided is a method of treating a cancer responsive to a Raf kinase inhibitor, the method comprising administering to a subject in need of treatment of the cancer an amount of at least one compound selected from Formula (I), and as described herein Stereoisomers of the compound and pharmaceutically acceptable salts of the compound effective to treat the cancer.
還提供了至少一種所述化合物在生產Raf激酶抑制劑藥物中的用途，所述化合物選自本文所述的式(I)化合物，及該化合物的立體異構體和該化合物藥學上可接受的鹽類。 Also provided is the use of at least one of said compounds in the manufacture of a Raf kinase inhibitor drug selected from the group consisting of a compound of formula (I) as described herein, and a stereoisomer of the compound and a pharmaceutically acceptable compound of the compound Salt.
還提供了至少一種所述化合物在生產治療癌症藥物中的用途，所述化合物選自於式(I)化合物及該化合物的立體異構體和該化合物藥學上可接受的鹽類。 Also provided is the use of at least one of said compounds in the manufacture of a medicament for the treatment of cancer selected from the group consisting of a compound of formula (I) and a stereoisomer of the compound and a pharmaceutically acceptable salt of the compound.
除根據上下文內容表明外，本說明書中所用的字、片語和符號通常是指具有如下含義。本文中的下述縮寫和術語是指：這裡的術語「烷基」是指烴基，所述烴基選自飽和 的直鏈的和支鏈烴基，所述飽和烴基包括1到18個碳原子，例如1到12個碳原子，進一步包括1到6碳原子。烷基的例子可以選自甲基、乙基、1-丙基或正丙基("n-Pr")、2-丙基或異丙基("i-Pr")、1-丁基或正丁基("n-Bu")、2-甲基-1-丙基或異丁基("i-Bu")、1-甲基丙基或仲丁基("s-Bu")、1,1-二甲基乙基或叔丁基("t-Bu")。烷基的其它例子可以選自於1-戊基(n-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)、1-己基(--CH2CH2CH2CH2CH2CH3)、2-己基(--CH(CH3)CH2CH2CH2CH3)、3-己基(--CH(CH2CH3)(CH2CH2CH3))、2-甲基1-2-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)和3,3-二甲基-2-丁基(--CH(CH3)C(CH3)3基團。 Words, phrases and symbols used in the specification generally have the following meanings, unless otherwise indicated by the context. The following abbreviations and terms herein mean that the term "alkyl" as used herein refers to a hydrocarbon group selected from saturated straight-chain and branched hydrocarbon groups, the saturated hydrocarbon group comprising from 1 to 18 carbon atoms, for example 1 to 12 carbon atoms, further including 1 to 6 carbon atoms. Examples of the alkyl group may be selected from methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-Butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"). Other examples of the alkyl group may be selected from the group consisting of 1-pentyl (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 ), 1-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-methyl1-2-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 ) and 3,3- Dimethyl-2-butyl (--CH(CH 3 )C(CH 3 ) 3 group.
這裡的術語「烯基」指的是選自直鏈的和支鏈的烴基，所述烴基包括至少一個C=C雙鍵和2到18個如2到6個碳原子。烯基的例子可以選自於亞乙基或乙烯基(--CH=CH2)、1-丙烯基(--CH=CHCH3)、2-丙烯基 (--CH2CH=CH2)、2-甲基-1-丙烯基，1-丁烯基、2-丁烯基、3-丁烯基、1,3-丁二烯基、2-甲基-1,3-丁二烯基、1-正丁烯基、2-正丁烯基、3-正丁烯基、4-正丁烯基和1,3-正己二烯基基團。 The term "alkenyl" as used herein refers to a hydrocarbon group selected from the group consisting of a straight chain and a branched chain, the hydrocarbon group comprising at least one C=C double bond and 2 to 18, such as 2 to 6 carbon atoms. Examples of the alkenyl group may be selected from ethylene or vinyl (--CH = CH 2), 1- propenyl group (--CH = CHCH 3), 2- propenyl (--CH 2 CH = CH 2) , 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadiene a group, a 1-n-butenyl group, a 2-n-butenyl group, a 3-n-butenyl group, a 4-n-butenyl group, and a 1,3-n-hexadienyl group.
這裡的術語「炔基」指的是選自直鏈的和支鏈的烴基，所述烴基包括至少一個C≡C三鍵和2到18個如2到6碳原子。炔基的例子包括乙炔基(--C≡CH)、1-丙炔基(-C≡CCH3)、2-丙炔基(炔丙基、-CH2C≡CH)、1-丁炔基、2-丁炔基和3-丁炔基基團。 The term "alkynyl" as used herein refers to a hydrocarbon group selected from the group consisting of linear and branched hydrocarbons including at least one C≡C triple bond and 2 to 18, such as 2 to 6 carbon atoms. Examples alkynyl groups include ethynyl (--C≡CH), 1- propynyl (-C≡CCH 3), 2- propynyl (propargyl, -CH 2 C≡CH), 1- butyne a base, a 2-butynyl group and a 3-butynyl group.
這裡的術語「環烷基」指的是選自飽和和部分不飽和環烴基的烴基，所述烴基包括單環的和多環(例如，雙環的和三環的)基團。例如，所述環烷基可以包括3到12碳原子，如3到8個碳原子，進一步如3到6個、3到5或3到4個碳原子。更進一步如所述環烷烴基可以選自於碳原子數為3到12，如3到8、3到6的單環基。單環環烷基的例子包括環丙基、環丁基、環戊基、1-環戊烷-1-烯基、1-環戊烷-2-烯基、1-環戊烷-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、環十一烷基和環十二烷基。雙環環烷基的例子包括由7到12個環原子組成的雙環基或橋雙環基，該雙環選自[4,4]、[4,5]、[5,5]、[5,6]和[6,6]環系，該橋雙環選自雙環[2.2.1]庚烷、雙環[2.2.2]辛烷和雙環[3.2.2]壬烷。該環可以是飽和的或具有至少一個雙鍵(比如，部分不飽和)，但不是完全共軛的，且不是芳香族的，如本文所定義的芳香族。 The term "cycloalkyl" as used herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups. For example, the cycloalkyl group may include 3 to 12 carbon atoms, such as 3 to 8 carbon atoms, further such as 3 to 6, 3 to 5 or 3 to 4 carbon atoms. Still further, the cycloalkane group may be selected from a monocyclic group having 3 to 12 carbon atoms, such as 3 to 8, 3 to 6. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentan-1-enyl, 1-cyclopentan-2-enyl, 1-cyclopentane-3- Alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, Cyclodecyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of the bicyclic cycloalkyl group include a bicyclic group or a bridged bicyclic group composed of 7 to 12 ring atoms selected from [4, 4], [4, 5], [5, 5], [5, 6] And the [6,6] ring system, the bridge bicyclic ring is selected from the group consisting of bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] decane. The ring may be saturated or have at least one double bond (eg, partially unsaturated), but is not fully conjugated and is not aromatic, as defined herein.
這裡的術語「芳香基」選自： 5元和6元的碳環芳香環，例如，苯基；雙環體系如7元到12元的雙環系，其中至少有一個環是碳環和芳香環，如所述雙環體系選自例如萘、茚和1,2,3,4-四氫喹啉；和三環體系如10到15元三環體系，其中至少有一個環是碳環和芳香環，如芴。 The term "aromatic group" as used herein is selected from: 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic systems such as 7- to 12-membered bicyclic systems, wherein at least one of the rings is a carbocyclic ring and an aromatic ring, such as, for example, naphthalene, Anthracene and 1,2,3,4-tetrahydroquinoline; and a tricyclic system such as a 10- to 15-membered tricyclic system wherein at least one of the rings is a carbocyclic ring and an aromatic ring such as hydrazine.
例如，該芳基是選自於將5元和6元碳環芳香環並到5元到7元環烷基或雜環上形成的芳基，該5元到7元環烷基或雜環包含至少一個選自N、O和S的雜原子，如果該碳芳香環並一個雜環那麼連接點在碳芳香環上，如果該碳芳香環與環烷基並環那麼連接點可以在碳芳香環或環烷基上。形成於取代的苯基衍生物而且在環原子中具有自由價的二價基被稱為取代的亞苯基自由基。單價多環烴基的二價自由基的命名是通過在相應的單價自由基的名稱中加入「-亞基"，如將有兩個連接點的萘基稱作亞二氫萘基，該單價多環烴基的名稱通過從自由價的碳原子上去除一個氫原子以「-基」結束。然而，無論如何芳基都不包括或與雜芳基重疊，下面將分別定義。因此，如果一或多個碳芳香環與雜環芳香環稠合，所得的環系統為本說明書中定義的雜芳基，而非芳基。 For example, the aryl group is an aryl group selected from the group consisting of a 5- and 6-membered carbocyclic aromatic ring and a 5- to 7-membered cycloalkyl or heterocyclic ring, the 5- to 7-membered cycloalkyl or heterocyclic ring. Containing at least one hetero atom selected from N, O and S, if the carbon aromatic ring and a heterocyclic ring are attached to the carbon aromatic ring, if the carbon aromatic ring is bonded to the cycloalkyl ring, the point of attachment may be in the carbon aromatic Ring or cycloalkyl. A divalent group formed on a substituted phenyl derivative and having a free valence in a ring atom is referred to as a substituted phenylene radical. The name of the divalent radical of the monovalent polycyclic hydrocarbon group is defined by adding a "-subunit" to the name of the corresponding monovalent radical, such as a naphthyl group having two points of attachment, which is called a dihydronaphthyl group. The name of a cycloalkyl group ends with a "-base" by removing a hydrogen atom from a free valence carbon atom. However, in any case, the aryl group does not include or overlap with the heteroaryl group, which will be defined separately below. Thus, if one or more carbon aromatic rings are fused to a heterocyclic aromatic ring, the resulting ring system is a heteroaryl group as defined in the specification, rather than an aryl group.
這裡的術語「鹵素」或「鹵」指的是F、Cl、Br或I。 The term "halogen" or "halo" as used herein refers to F, Cl, Br or I.
這裡的術語「雜芳基」選自於：5到7元芳香的單環包含至少一個雜原子，例如，該雜原子為1到4個，或者，在一些實施方案中，1到3個， 該等雜原子選自N、O和S，其餘的環原子為碳；8元到12元雙環包括至少一個雜原子，如1-4個，或在某些實施方案中，為1-3個或在其他的實施方案中，為1或2個，該等雜原子選自N、O和S，其餘的環原子為碳，並且其中至少一個環是芳香族的，並且芳香環上至少有一個雜原子；並且11到14元三環包括至少一個雜原子，例如，從1到4，或，在一些實施例中，從1到3，或在其它實施例中，1到2，雜原子選自N、O和S，其餘的環原子是碳並且至少一個環是芳香族的，並且芳香環上至少有一個雜原子。 The term "heteroaryl" as used herein is selected from the group consisting of: a 5- to 7-membered aromatic monocyclic ring comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, The heteroatoms are selected from N, O and S, the remaining ring atoms are carbon; the 8- to 12-membered bicyclic ring comprises at least one heteroatom, such as from 1 to 4, or in certain embodiments, from 1 to 3 Or in other embodiments, 1 or 2, the heteroatoms are selected from N, O and S, the remaining ring atoms are carbon, and at least one of the rings is aromatic and at least one of the aromatic rings Heteroatom; and the 11 to 14 membered tricyclic ring includes at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or in other embodiments, 1 to 2, heteroatoms. From N, O and S, the remaining ring atoms are carbon and at least one ring is aromatic and there is at least one heteroatom on the aromatic ring.
例如，雜芳基包括5到7元雜芳環並上5到7元環烷基環。對於這樣的並環，雙雜芳環體系中只是其中的一個環包含至少一個雜原子，連接點可以在雜芳環或環烷基環。 For example, a heteroaryl group includes a 5 to 7 membered heteroaryl ring and a 5 to 7 membered cycloalkyl ring. For such a bicyclic ring, only one of the rings in the biheteroaromatic ring system contains at least one hetero atom, and the point of attachment may be in a heteroaryl ring or a cycloalkyl ring.
當雜芳基上的S和O原子的總數超過1，這些雜原子就不會相鄰。在一些實施例中，雜芳基上的S和O的總數不超過2。在一些實施例中，雜芳環上S和O的總數不超過1. When the total number of S and O atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent. In some embodiments, the total number of S and O on the heteroaryl group does not exceed two. In some embodiments, the total number of S and O on the heteroaryl ring does not exceed 1.
雜芳基的例子包括，但是不僅僅限於(從優先指定的連接位置編碼1)吡啶基(比如2-吡啶基、3-吡啶基、4-吡啶基)、噌啉基、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、咪唑並吡啶基、異惡唑基、惡唑基、噻唑基、異噻唑基、噻二唑、四唑基、噻吩基、三嗪基、苯並噻吩基、呋喃基、苯並呋喃基、苯並咪唑基、吲哚基、異吲哚基、二氫吲哚基、酞嗪基、吡嗪基、噠嗪基、吡咯基、***基、喹啉 基、異喹啉基、吡唑基、吡咯並吡啶基(比如1H-吡咯並[2,3-b]吡啶-5-基)、吡唑並吡啶基(比如1H-吡唑並[3,4-b]吡啶-5-基)、苯並惡唑基(比如苯並[d]惡唑-6-基)，蝶啶基、嘌呤基、1-氧雜-2,3-二唑基、1-氧雜-2,4-二唑基、1-氧雜-2,5-二唑基、1-氧雜-3,4-二唑基、1-硫代-2,3-二唑基、1-硫代-2,4-二唑基、1-硫代-2,5-二唑基、1-硫代-3,4-二唑基、呋吖基、苯並呋吖基，苯並噻吩基、苯並噻唑基，苯並惡唑基、喹唑啉基、喹惡啉基、萘啶基、呋喃並吡啶基、苯並噻唑基(比如苯並[d]噻唑-6-基)、吲哚基(比如1H-吲唑-5-基)和5,6,7,8-四氫異喹啉。 Examples of heteroaryl groups include, but are not limited to, (encoded from a preferentially specified position 1) pyridyl groups (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), porphyrinyl, pyrazinyl, 2 , 4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazole, tetrazolyl, thiophene , triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, fluorenyl, isodecyl, indanyl, pyridazinyl, pyrazinyl, pyridazinyl Pyrrolyl, triazolyl, quinoline Alkyl, isoquinolyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (such as 1H-pyrazolo[3, 4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazole-6-yl), pteridinyl, fluorenyl, 1-oxa-2,3-diazolyl , 1-oxa-2,4-oxadiazole, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazole, 1-thio-2,3-di Azyl, 1-thio-2,4-oxadiyl, 1-thio-2,5-oxadiazolyl, 1-thio-3,4-oxadiazole, furazan, benzofurazan Benzo, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazole- 6-yl), fluorenyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.
這裡的術語「雜環的」或「雜環」或「雜環基」指的是選自4到12元的單環、雙環、三環的一類環，該等雜環是飽和和部分不飽和環，包括除至少一個雜原子外的至少一個碳原子，比如雜原子從1到4，進一步從1到3，或更進一步比如1或2個雜原子，該等雜原子選自氧、氮和硫。這裡的「雜環」也指一類5到7元雜環，該雜環由至少包括一個選自N、O和S中的雜原子，且與5-、6-及/或7元的環烷基，碳環芳香族或雜芳環並環，當該雜環與一個碳環芳香環或一個雜芳環並環時連接點在雜環上，而且當該雜環與環烷基並環時連接點可以是在環烷基或雜環上。 The term "heterocyclic" or "heterocyclic" or "heterocyclyl" as used herein refers to a monocyclic, bicyclic or tricyclic ring selected from 4 to 12 members, which are saturated and partially unsaturated. a ring comprising at least one carbon atom other than at least one hetero atom, such as a hetero atom from 1 to 4, further from 1 to 3, or further such as 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur. The term "heterocycle" as used herein also refers to a class of 5- to 7-membered heterocyclic rings consisting of at least one hetero atom selected from N, O and S, and 5-, 6- and/or 7-membered naphthenes. a carbocyclic aromatic or heteroaryl ring-and-ring, when the heterocyclic ring is ring-bonded to a carbocyclic aromatic ring or a heteroaromatic ring, the point of attachment is on the heterocyclic ring, and when the heterocyclic ring is ring-bonded to the cycloalkyl group The point of attachment can be on a cycloalkyl or heterocycle.
這裡的「雜環」也指一類脂肪族的螺環，該螺環包括至少一個選自N、O和S的雜原子，連接點在該雜環上。上述的這些環可能是飽和的或含有至少一個雙鍵(也就是部分不飽和)。上述這些環可能被氧取代。連接點可能是雜環上的碳原子或雜原子。雜環不是這裡所定義的雜芳環。 The "heterocyclic ring" herein also refers to a class of aliphatic spiro rings including at least one hetero atom selected from N, O and S, to which the point of attachment is. These rings may be saturated or contain at least one double bond (ie, partially unsaturated). These rings may be replaced by oxygen. The point of attachment may be a carbon atom or a hetero atom on the heterocycle. A heterocyclic ring is not a heteroaryl ring as defined herein.
雜環的例子包括，但不僅局限于(從優先指定的連接位置編碼1)1-吡咯烷基、2-吡咯烷基、2,4-咪唑烷基、2,3-吡唑烷基、1-呱啶基、2-呱啶基、3-呱啶基、4-呱啶基、2,5-呱嗪基、吡喃基、2-嗎啉基、3-嗎啉基、環氧乙烷基、氮雜環丙烯基、環硫乙烷基、氮雜環丁基、氧雜環丁烷基，硫雜環丁基、1,2-二硫雜環丁基、1,3-二硫雜環丁基、二氫吡啶、四氫吡啶、硫代嗎啉、氧硫雜環己烷基、呱嗪基、高呱嗪基、高呱啶基、氮雜環庚烷基、氧雜環庚烷基、硫雜環庚烷基、1,4-氧硫雜環己烷基、1,4-二氧雜環庚烷基、1,4-氧硫雜環庚烷基、1,4-氮氧雜環庚烷基、1,4-二硫雜環庚烷基、1,4-氮硫雜環庚烷基和1,4-二氮雜環庚烷、1-1,4-二噻烷基、1,4-氮硫雜環己烷基、氧氮雜卓、二氮雜卓、硫氮雜卓、二氫噻吩基、二氫吡喃基、二氫呋喃基、四氫呋喃基、四氫噻吩基、四氫吡喃基、四氫噻喃基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、1,4-二氧雜環己烷基、1,3-二氧環戊基、吡唑啉基、吡唑烷基、二噻烷基、二噻環戊基、吡唑烷基、咪唑啉基(pyrazolidinylimidazolinyl)、嘧啶酮基、1,1-二氧代-硫代嗎啉基、3-氮雜雙環[3.1.0]己基、3-氮雜雙環[4.1.0]庚烷基、氮雜雙環[2.2.2]己基。取代的雜環基還包括一或多個氧代基團取代的環體系，比如N-氧化呱啶基、N-氧化嗎啉基、1-氧代-1-硫代嗎啉基和1,1-二氧代-1-硫代嗎啉基。 Examples of heterocycles include, but are not limited to, (encoded from a preferentially specified position 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1 - aridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 2,5-pyridazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, epoxy Alkyl, azacyclopropenyl, cyclohexylethane, azetidinyl, oxetanyl, thioheterobutyl, 1,2-dithiot-butyl, 1,3-di Thiolyl, dihydropyridine, tetrahydropyridine, thiomorpholine, oxathiolanyl, pyridazinyl, oxazinyl, homoacridinyl, azepanyl, oxa Cycloheptyl, thiaheptanyl, 1,4-oxathiane, 1,4-dioxanyl, 1,4-oxathiamethylene, 1, 4-azacycloheptane, 1,4-dithiaheptanyl, 1,4-azetidinyl and 1,4-diazepane, 1-1, 4 -dithiaalkyl, 1,4-azetidinyl, oxazepine, diazepine, thiazepine, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuran Base, tetrahydrothiophenyl, tetrahydropyranyl, Hydrothiopyranyl, 1-pyrroline, 2-pyrolinyl, 3-pyrroline, porphyrin, 2H-pyranyl, 4H-pyranyl, 1,4-dioxane , 1,3-dioxocyclopentyl, pyrazolinyl, pyrazolidinyl, dithiaalkyl, dithiacyclopentyl, pyrazolidinyl, pyrazolidinyllimidazolinyl, pyrimidinone, 1 , 1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl. Substituted heterocyclic groups also include one or more oxo group substituted ring systems such as N-oxaridinyl, N-oxymorpholinyl, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
這裡的術語「稠環」指的是一類多環體系，例如，雙環或三環體系，其中兩個環僅共用兩個環原子和一個化學鍵。稠環的例子可以包括稠合的雙環烷基環，該雙環烷基環 由7到12個環原子排列成的雙環，該雙環選自如上所述的[4,4]、[4,5]、[5,5]、[5,6]和[6,6]環體系；稠合雙芳香環，例如如上所述的7到12元雙芳香環體系，稠合三芳香環，例如如上所述的10到15元三芳香環體系；稠合的雙雜芳環，例如如上所述的8-到12-元雙雜芳香環體系，稠合的三雜芳環，例如如上所述的11-到14-元三雜芳香環體系；以及如上所述的稠合雙環或三環雜芳環。 The term "fused ring" as used herein refers to a class of polycyclic systems, for example, bicyclic or tricyclic systems in which two rings share only two ring atoms and one chemical bond. Examples of the fused ring may include a fused bicycloalkyl ring, which is a bicycloalkyl ring. a bicyclic ring consisting of 7 to 12 ring atoms selected from the group consisting of [4, 4], [4, 5], [5, 5], [5, 6] and [6, 6] rings as described above. a system; a fused biaryl ring, such as a 7 to 12 membered biaromatic ring system as described above, a fused triaromatic ring, such as a 10 to 15 membered triaromatic ring system as described above; a fused biheteroaryl ring, For example, an 8- to 12-membered biheteroaromatic ring system as described above, a fused triheteroaryl ring, such as the 11- to 14-membered triheteroaromatic ring system as described above; and a fused bicyclic ring as described above Or a tricyclic heteroaryl ring.
這裡所述的化合物可以含有一個不對稱中心，因而可以作為對映異構體存在。這裡所述的化合物具有兩個或兩個以上的不對稱中心，該等不對稱中心另外可以作為非對映異構體存在。對映異構體和非對映異構體屬於廣泛的一類立體異構體。所有這些可能的立體異構體包括大體上純的拆分的對映異構體，外消旋混合物，和非對映體混合物。本文所揭示的該等化合物的全部立體異構體及/或其中的藥學上可接受的鹽類都包括在內。除非另外的特別提到，否則提到的一個異構體適用於任何一個合理的異構體。無論何時同分異構組分未指明的，所有可能的同分異構體都包括在內。 The compounds described herein may contain an asymmetric center and thus may exist as enantiomers. The compounds described herein have two or more asymmetric centers which may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broad class of stereoisomers. All such possible stereoisomers include substantially pure resolved enantiomers, racemic mixtures, and diastereomeric mixtures. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are included. Unless otherwise specifically mentioned, one of the isomers mentioned applies to any reasonable isomer. All possible isomers are included whenever the isomeric component is not indicated.
本發明中使用的術語"大體上純的"意思是目標立體異構體所包含其它的立體異構體的重量不超過35%，比如不超過30%，更進一步不超過25%，甚至不超過20%。在一些實施例中，術語"大體上純的"意思是目標立體異構體所包含其它立體異構體的重量不超過10%，例如不超過5%，比如不超過1%。 The term "substantially pure" as used in the present invention means that the other stereoisomers contained in the target stereoisomer have a weight of no more than 35%, such as no more than 30%, further no more than 25%, or even no more than 20%. In some embodiments, the term "substantially pure" means that the other stereoisomers contained in the target stereoisomer have a weight of no more than 10%, such as no more than 5%, such as no more than 1%.
當本發明所述的化合物包含烯族雙鍵時，除非另外 詳細的說明，否則這些雙鍵包括E和Z式幾何異構體。 When the compound of the present invention contains an olefinic double bond, unless otherwise Detailed description, otherwise these double bonds include E and Z geometric isomers.
本發明所述的一些化合物可以存在不同的氫原子連接點，被稱為互變異構體。例如，包括羰基-CH2C(O)-基團(酮式)的化合物可以經歷互變異構形成羥基-CH=C(OH)-基團(烯醇式)。酮式和烯醇式在使用時，單一形式以及混合物也包括在內。 Some of the compounds described in the present invention may have different hydrogen atom attachment points and are referred to as tautomers. For example, a compound comprising a carbonyl-CH 2 C(O)- group (keto form) can undergo tautomerization to form a hydroxy-CH=C(OH)- group (enol form). The keto and enol forms, when used, are also included in a single form as well as mixtures.
將反應產物彼此分離，或者跟原料分開是有利的。每一步或一連串幾步的目標物被分離及/或純化(下文中使用分離)通過本領域中常用的技術達到渴望的均勻度。代表性的分離技術包括多相提取，用一種溶劑或混合溶劑重結晶、蒸餾、昇華或色譜法。色譜法可以涉及到許多方法，包括例如：反相和正相；分子篩；離子交換；高，中，低壓液相色譜法和設備；小型分析(small scale analytical)；模擬化移動床("SMB")和製備薄層或厚層層析法，和小型薄層和快速色譜技術一樣。可以使用一些在本領域常用的技術來達到所希望的分離度。 It is advantageous to separate the reaction products from each other or separately from the starting materials. Each step or series of steps of the target is isolated and/or purified (using separations hereinafter) to achieve the desired uniformity by techniques commonly employed in the art. Representative separation techniques include multiphase extraction, recrystallization, distillation, sublimation or chromatography with a solvent or mixed solvent. Chromatography can involve a number of methods including, for example, reversed phase and normal phase; molecular sieves; ion exchange; high, medium, low pressure liquid chromatography and equipment; small scale analytical; simulated moving bed ("SMB") And preparation of thin layer or thick layer chromatography, as well as small thin layer and flash chromatography techniques. Some techniques commonly used in the art can be used to achieve the desired resolution.
非對映異構體的混合物可以利用它們在物理化學上的差異通過本領域公知的技術被分離成各自的非對映異構體，比如通過色譜法及/或分步結晶法。對映異構體能夠通過將對映異構體混合物與合適的光學活性化合物(例如，掌性助劑如掌性醇或Mosher醯氯)反應轉化為非對映異構體的混合物，然後將非對映異構體的混合物分離，並將各個非對映異構體轉化(如水解)為相應的純對映異構體。對映異構體還能夠用掌性HPLC柱分離。 Mixtures of diastereomers can be separated into the individual diastereomers by physicochemical differences using techniques well known in the art, such as by chromatography and/or fractional crystallization. An enantiomer can be converted to a mixture of diastereomers by reaction of a mixture of enantiomers with a suitable optically active compound (for example, a palmitic auxiliary such as palmitol or Mosher® chlorine) and then The mixture of diastereomers is separated and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. The enantiomers can also be separated using a palm HPLC column.
單一的立體異構體(例如大體上純的對映異構體)可以通過拆分外消旋混合物的方法獲得，比如利用光學活性的拆分劑形成非對映體的方法(Eliel,E.和Wilen,S.Stereochemistry of Organic Compounds.New York：John Wiley & Sons,Inc.，1994；Lochmuller,C.H.等人，"Chromatographic resolution of enantiomers：Selective review." J.Chromatogr.,113(3)(1975)：pp.283-302)。本發明的掌性化合物的外消旋混合物可以通過任何適合的方法來分離，包括：(1)與掌性化合物形成離子的，非對映異構的鹽，然後通過分步結晶或其它方法分離，(2)與掌性衍生試劑形成非對映異構化合物，分離形成的非對映異構體以及轉化成純的立體異構體，(3)直接在掌性條件下分離大體上純或富含的立體異構體。參見：Wainer,Irving W.,Ed.Drug Stereochemistry：Analytical Methods and Pharmacology.New York：Marcel Dekker,Inc.,1993。 Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture, such as by the use of optically active resolving agents to form diastereomers (Eliel, E. and Wilen, S.Stereochemistry of Organic Compounds.New York: J ohn Wiley & Sons, Inc., 1994; Lochmuller, CH et al., "Chromatographic resolution of enantiomers:. Selective review" J .Chromatogr, 113 (3) (. 1975): pp.283-302). The racemic mixture of the palm compound of the present invention can be isolated by any suitable method, including: (1) forming an ionic, diastereomeric salt with the palm compound, and then separating by fractional crystallization or other methods. (2) forming a diastereomeric compound with a palmitic derivatizing reagent, separating the diastereomer formed and converting into a pure stereoisomer, and (3) separating substantially pure under palmar conditions or Enriched stereoisomers. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
「藥學中可接受的鹽」包括但不僅限於無機酸鹽，選自比如，鹽酸鹽、磷酸鹽、磷酸氫鹽、氫溴酸鹽、硫酸鹽、亞硫酸鹽和硝酸鹽；也包括有機鹽，選自例如蘋果酸鹽、馬來酸鹽、延胡索酸鹽、酒石酸鹽、琥珀酸鹽、檸檬酸鹽、乳酸鹽、甲磺酸鹽、對甲苯磺酸鹽、2-羥基乙基磺酸鹽、苯甲酸鹽、水楊酸鹽、硬脂酸鹽、鏈烷酸鹽比如乙酸鹽，和HOOC-(CH2)n-COOH的鹽，這裡的n選自0到4。類似地，藥學中可接受的陽離子的例子包括但不限於鈉鹽、鉀鹽、鈣鹽、鋁鹽、鋰鹽和銨鹽。 "Pharmaceutically acceptable salts" include, but are not limited to, mineral acid salts selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfates, sulfites, and nitrates; , selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, a salt of a benzoate, a salicylate, a stearate, an alkanoate such as an acetate, and HOOC-(CH 2 ) n -COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium salts.
另外，如果得到本文中所述的一個化合物的酸加成 鹽，則可以通過鹼化該酸鹽之溶液來得到其游離鹼。相反地，如果這個化合物是游離鹼，加成鹽(例如藥學可接受的加成鹽)可以通過將游離鹼溶於一種合適的有機溶劑並且用酸處理該溶液的方法製作，與由鹼性化合物製備酸加成鹽的常規程式一致。所屬領域技術人員會識別各種合成方法，該等合成方法不需過度的實驗就可以用於製備無毒的藥學可接受的加成鹽。 In addition, if an acid addition of a compound described herein is obtained For the salt, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the compound is a free base, an addition salt (eg, a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, with a basic compound The conventional procedure for preparing acid addition salts is consistent. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.
這裡定義「藥學可接受的鹽」包括式I、II、III、IV及/或V中至少一個化合物的鹽，以及式I、II、III、IV及/或V中至少一個化合物的立體異構體的鹽，比如對映異構體的鹽，及/或非對映異構體的鹽。 A "pharmaceutically acceptable salt" as defined herein includes a salt of at least one compound of formula I, II, III, IV and/or V, and a stereoisomer of at least one compound of formula I, II, III, IV and/or V. Salts of the body, such as salts of enantiomers, and/or salts of diastereomers.
「治療(Treating)」、「治療(treat)」、「治療(treatment)」或者「緩解」指的是施用至少一個化合物及/或其中至少一個立體異構體，及/或至少一個本文揭示的藥學可接受的鹽給確認需要其的受試者，例如，該受試者患有癌症。 "Treating", "treat", "treatment" or "alleviation" refers to the administration of at least one compound and/or at least one of its stereoisomers, and/or at least one disclosed herein. A pharmaceutically acceptable salt is given to a subject who is in need of confirmation, for example, the subject has cancer.
術語「有效量」指的是至少一個化合物及/或其中至少一個立體異構體，及/或至少一個本文揭示的藥學可接受的鹽，如上所定義的，「治療」相同疾病或機能紊亂的受試者有效時的總量。 The term "effective amount" refers to at least one compound and/or at least one of its stereoisomers, and/or at least one pharmaceutically acceptable salt as disclosed herein, as defined above, "treating" the same disease or disorder. The total amount of time when the subject is active.
本文所述的術語「至少一個取代基」包括，例如，從1到4，比如從1到3，進一步比如從1到2個取代基。例如本文所述「至少一個取代基R16」包括從1到4，比如從1到3，進一步比如從1到2個選自本文所述R16列表中的取代基。 The term "at least one substituent" as used herein includes, for example, from 1 to 4, such as from 1 to 3, and further such as from 1 to 2 substituents. For example, "at least one substituent R 16 " as used herein includes from 1 to 4, such as from 1 to 3, and further such as from 1 to 2 substituents selected from the list of R 16 described herein.
提供了至少一種選自於式I中的化合物：
在一些實施例中，X是CH2。 In some embodiments, X is CH 2 .
在一些實施例中，X是O。 In some embodiments, X is O.
在一些實施例中，Y是NH且W是C。 In some embodiments, Y is NH and W is C.
在一些實施例中，Y是S且W是C。 In some embodiments, Y is S and W is C.
在一些實施例中，Q是C。 In some embodiments, Q is C.
在一些實施例中，Q是N且R1是不存在的。 In some embodiments, Q is N and R 1 is absent.
在一些實施例中，Z是O。 In some embodiments, Z is O.
在一些實施例中，每個R1和R2是氫原子。 In some embodiments, each of R 1 and R 2 is a hydrogen atom.
在一些實施例中，R3和R4與R3和R4連接的環一起形成一個選自雜環或雜芳環的稠環，比如萘啶基(例如，二 氫萘啶基)、吡咯吡啶基(例如，吡咯[2,3-b]吡啶-4-基)和嘌呤基，該環可以被至少一種取代基R16隨意取代，例如氧雜。 In some embodiments, R 3 and R 4 together with the ring to which R 3 and R 4 are joined form a fused ring selected from a heterocyclic or heteroaryl ring, such as a naphthyridinyl group (eg, dihydronaphthyridinyl), pyrrole pyridyl (e.g., pyrrolo [2,3-b] pyridin-4-yl) and purinyl, which ring may be substituted with at least one R 16 group optionally substituted, e.g. oxa.
在一些實施例中，R3和R4可以相同或者不同，各自選自氫、-CONR13R14，比如-CONHCH3，和雜芳基(例如，咪唑)可以被至少一個取代基R16任意取代，比如至少一個鹵代烷基，例如其中鹵代烷基是-CF3。 In some embodiments, R 3 and R 4 may be the same or different, each selected from the group consisting of hydrogen, —CONR 13 R 14 , such as —CONHCH 3 , and a heteroaryl group (eg, imidazole) may be optionally substituted with at least one substituent R 16 . substituted, such as at least a haloalkyl group, wherein haloalkyl e.g. -CF 3.
在一些實施例中，R5和R6與R5和R6連接的環一起形成一個稠環，該稠環為雜芳環，比如苯並咪唑基(例如，1H-苯並[d]咪唑-2-基)，和咪唑並吡啶基(比如3H-咪唑並[4,5-c]吡啶-2-基)，該雜芳環可以被至少一個取代基R16任意取代，比如鹵代烷基(例如，-CF3)、烷基(例如，甲基、叔丁基)、鹵素、氰基、鹵代烷氧基(例如，OCF3)、烷氧基(例如，甲氧基)、羥基和苯基。 In some embodiments, R 5 and R 6 together with the ring to which R 5 and R 6 are joined form a fused ring which is a heteroaryl ring such as benzimidazolyl (eg, 1H-benzo[d]imidazole 2-yl), and imidazolyl and pyridyl (such as 3H- imidazo [4,5-c] pyridin-2-yl), the heteroaryl ring may be substituted with at least one R 16 substituted by any group, such as haloalkyl ( For example, -CF 3 ), alkyl (eg, methyl, tert-butyl), halogen, cyano, haloalkoxy (eg, OCF 3 ), alkoxy (eg, methoxy), hydroxy, and phenyl .
在一些實施例中，R5和R6可以相同或不同，各自選自於氫、芳基比如苯基和雜芳基(例如吡啶基)，且可以被至少一個取代基R16任意取代，比如鹵代烷基(例如，-CF3)、烷基(例如，甲基、叔丁基)、鹵素、氰基、鹵代烷氧基(例如，OCF3)、烷氧基(例如，甲氧基)、羥基和苯基。 In some embodiments, R 5 and R 6 may be the same or different, each selected from hydrogen, an aryl group such as a phenyl group and a heteroaryl group (eg, pyridyl), and may be optionally substituted with at least one substituent R 16 , such as haloalkyl (e.g., -CF 3), alkyl (e.g., methyl, t-butyl), halo, cyano, haloalkoxy (e.g., OCF 3), alkoxy (e.g., methoxy), hydroxy And phenyl.
在一些實施例中，至少一個選自式(I)的化合物包括立體異構體及藥學可接受的鹽是選自下列式(II)中的化合物：
在一些實施例中，式(II)中X是O。 In some embodiments, X in formula (II) is O.
在一些實施例中，式(II)中X是CH2。 In some embodiments, Formula (II), X is CH 2.
在一些實施例中，式(II)中Y是S。 In some embodiments, Y in formula (II) is S.
在一些實施例中，式(II)中Z是O。 In some embodiments, Z in the formula (II) is O.
在一些實施例中，式(II)中Q是C。 In some embodiments, Q in formula (II) is C.
在一些實施例中，式(II)中Q是N且式(II)中R1不存在。 In some embodiments, Q in the formula (II) is N and R 1 in formula (II) is absent.
在一些實施例中，R3和R4與R3和R4連接的環一起形成一個選自雜環或雜芳環的稠環，比如萘啶基(例如，二氫萘啶基)、吡咯吡啶基(例如，吡咯[2,3-b]吡啶-4-基)，和嘌呤基，該環可以被至少一種取代基R16隨意取代，例如氧雜的。 In some embodiments, R 3 and R 4 together with the ring to which R 3 and R 4 are joined form a fused ring selected from a heterocyclic or heteroaryl ring, such as a naphthyridinyl group (eg, dihydronaphthyridinyl), pyrrole pyridyl (e.g., pyrrolo [2,3-b] pyridin-4-yl), purinyl, and which ring may be substituted with at least one R 16 group optionally substituted, for example, the oxa.
在一些實施例中，每個R1和R2是氫。 In some embodiments, each of R 1 and R 2 is hydrogen.
在一些實施例中，R3和R4可以相同或者不同，各自選自氫、-CONR13R14，比如-CONHCH3，和雜芳基(例如，咪唑)可以被至少一個取代基R16任意取代，比如至少一個鹵代 烷基，例如其中鹵代烷基是-CF3。 In some embodiments, R 3 and R 4 may be the same or different, each selected from the group consisting of hydrogen, —CONR 13 R 14 , such as —CONHCH 3 , and a heteroaryl group (eg, imidazole) may be optionally substituted with at least one substituent R 16 . substituted, such as at least a haloalkyl group, wherein haloalkyl e.g. -CF 3.
在一些實施例中，式(II)中R8、R9、R10和R11可以相同或不同，各自選自烷基(例如，甲基、叔丁基)、氫、鹵代烷基(例如，-CF3)、鹵素、羥基、氰基、烷氧基(例如，甲氧基)、鹵代烷氧基(例如，OCF3)和芳香基(例如，苯基)。 In some embodiments, Formula (II), R 8, R 9, R 10 and R 11 may be the same or different, are each selected from alkyl (e.g., methyl, t-butyl), hydrogen, haloalkyl (e.g., -CF 3 ), halogen, hydroxy, cyano, alkoxy (for example, methoxy), haloalkoxy (for example, OCF 3 ), and aryl (for example, phenyl).
在一些實施例中，至少一個選自式(I)的化合物包括其立體異構體及藥學可接受的鹽是選自式(III)中的化合物：
在一些實施例中，式(III)中A-M是-CH2-CH2-C(O)-。 In some embodiments, Formula (III), AM is -CH 2 -CH 2 -C (O) -.
在一些實施例中，式(III)中A-M是-CH=CH-。 In some embodiments, A-M in formula (III) is -CH=CH-.
在一些實施例中，式(III)中A-M是-CH2-O-C(O)-。 In some embodiments, Formula (III), AM is -CH 2 -OC (O) -.
在一些實施例中，式(III)中R12是H。 In some embodiments, R 12 in formula (III) is H.
在一些實施例中，式(III)中X是O。 In some embodiments, X in formula (III) is O.
在一些實施例中，式(III)中X是CH2。 In some embodiments, Formula (III) wherein X is CH 2.
在一些實施例中，式(III)中Z是O。 In some embodiments, Z in the formula (III) is O.
在一些實施例中，式(III)中R8、R9、R10和R11可以相同或不同，各自選自烷基(例如，甲基、叔丁基)、氫、鹵代烷基(例如，-CF3)、鹵素、羥基、氰基、烷氧基(例如，甲氧基)、鹵代烷氧基(例如，OCF3)和芳香基(例如，苯基)。 In some embodiments, R 8 , R 9 , R 10 and R 11 in formula (III) may be the same or different, each selected from alkyl (eg, methyl, tert-butyl), hydrogen, haloalkyl (eg, -CF 3 ), halogen, hydroxy, cyano, alkoxy (for example, methoxy), haloalkoxy (for example, OCF 3 ), and aryl (for example, phenyl).
在一些實施例中，至少一個選自式(I)的化合物，其立體異構體及其藥學可接受的鹽是選自式(IV)中的化合物：
在一些實施例中，R1和R2可以相同或不同，各自選自氫、烷基和鹵素。 In some embodiments, R 1 and R 2 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, and halogen.
在一些實施例中，式(IV)中R12是H。 In some embodiments, R 12 in formula (IV) is H.
在一些實施例中，式(IV)中X是O。 In some embodiments, X in formula (IV) is O.
在一些實施例中，式(IV)中X是CH2。 In some embodiments, Formula (IV), X is CH 2.
在一些實施例中，式(III)中R8、R9、R10和R11可以相同或不同，各自選自烷基(例如，甲基、叔丁基)、氫、 鹵代烷基(例如，-CF3)、鹵素、羥基、氰基、烷氧基(例如，甲氧基)、鹵代烷氧基(例如，OCF3)和芳香基(例如，苯基)。 In some embodiments, R 8 , R 9 , R 10 and R 11 in formula (III) may be the same or different, each selected from alkyl (eg, methyl, tert-butyl), hydrogen, haloalkyl (eg, -CF 3 ), halogen, hydroxy, cyano, alkoxy (for example, methoxy), haloalkoxy (for example, OCF 3 ), and aryl (for example, phenyl).
在一些實施例中，至少一個選自式(I)的化合物，其立體異構體及其藥學可接受的鹽是選自式(V)中的化合物：
R8、R9、R10和R11，可以相同或不同，各自選自氫、鹵素、烷基、烯基、環烷基、芳基、雜環基、雜芳基、炔基、氰基、-NR13R14、-OR13、-COR13、-CO2R13、-CONR13R14、-C(=NR13)NR14R15、-NR13COR14、-NR13CONR14R15、-NR13CO2R14、-SO2R13、-SO2芳基、-NR13SO2NR14R15和-NR13SO2R14，其中，烷基、烯基、炔基、環烷基、雜芳基、芳基和雜環基可以被至少一個取代基R16任意取代，或(R8和R9)及/或(R9和R10)及/或(R10和R11)與它們所連接的環一起形成稠環，該稠環選自可被至少一個取代基R16任意取代的雜環和雜芳環；R13、R14和R15，各者可以相同或不同，各自選自氫、鹵烷基、烷基、烯基、炔基、環烷基、雜環、芳基和雜芳基； 或(R13和R14)及/或(R14和R15)各與它們所連接的一或多個原子一起形成環，該環選自可被至少一個取代基R16任意取代的雜環和雜芳環；R16選自鹵素、鹵烷基、烷基、烯基、環烷基、芳基、雜芳基、雜環基、炔基、氧基、氰基、-OR'、-NR'R"、-COR'、-CO2R'、-CONR'R"、-C(=NR')NR"R'''、-NR'COR"、-NR'CONR'R"、-NR'CO2R"、-SO2R'、-SO2芳基、-NR'SO2NR"R'''、NR'SO2R"和NR'SO2芳基，此處R'、R"和R'''獨立地選自氫、鹵烷基、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或(R'和R")及/或(R"和R''')與它們所連接的原子一起形成選自雜環基和雜芳環的環。 R 8 , R 9 , R 10 and R 11 , which may be the same or different, each selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkynyl, cyano -NR 13 R 14 , -OR 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -C(=NR 13 )NR 14 R 15 , -NR 13 COR 14 , -NR 13 CONR 14 R 15 , -NR 13 CO 2 R 14 , -SO 2 R 13 , -SO 2 aryl, -NR 13 SO 2 NR 14 R 15 and -NR 13 SO 2 R 14 , wherein alkyl, alkenyl, alkyne The group, cycloalkyl, heteroaryl, aryl and heterocyclic group may be optionally substituted by at least one substituent R 16 , or (R 8 and R 9 ) and/or (R 9 and R 10 ) and/or (R) 10 and R 11 ) together with the ring to which they are attached form a fused ring selected from heterocyclic and heteroaryl rings which may be optionally substituted by at least one substituent R 16 ; R 13 , R 14 and R 15 , each They may be the same or different and are each selected from the group consisting of hydrogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; or (R 13 and R 14 ) and/or (R) 14 and R 15) each form a ring one or more atoms to which they are attached, which ring is selected from at least one substituent which may be any of R 16 taken Heterocyclic and heteroaromatic ring; R 16 is selected from halo, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, a heterocyclic group, an alkynyl group, an oxo group, a cyano group, -OR ', -NR'R", -COR', -CO 2 R', -CONR'R", -C(=NR')NR"R''', -NR'COR", -NR'CONR'R ", -NR'CO 2 R", -SO 2 R', -SO 2 aryl, -NR'SO 2 NR"R'", NR'SO 2 R" and NR'SO 2 aryl, here R', R" and R''' are independently selected from hydrogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R' and R ") and/or (R" and R'"' together with the atom to which they are attached form a ring selected from the group consisting of a heterocyclic group and a heteroaryl ring.
在一些實施例中，式(V)中的至少一個化合物是光學純的。 In some embodiments, at least one compound of formula (V) is optically pure.
在一些實施例中，式(V)中的X時O。 In some embodiments, X in the formula (V) is O.
在一些實施例中，式(V)中的X時CH2。 In some embodiments, X in the formula (V) is CH 2 .
在一些實施例中，式(III)中的R8、R9、R10和R11可以相同或者不同，各自選自烷基(例如，甲基、叔丁基)、氫、鹵代烷基(例如，-CF3)、鹵素、羥基、氰基、烷氧基(例如，甲氧基)、鹵代烷氧基(例如，OCF3)和芳香基(例如，苯基)。 In some embodiments, R 8 , R 9 , R 10 and R 11 in formula (III) may be the same or different, each selected from alkyl (eg, methyl, tert-butyl), hydrogen, haloalkyl (eg, , -CF 3 ), halogen, hydroxy, cyano, alkoxy (eg, methoxy), haloalkoxy (eg, OCF 3 ), and aryl (eg, phenyl).
本文也提供了至少一個選自下列化合物中的化合物，其立體異構體，及其藥學接受的鹽：
本文也提供了選自以下列出的立體化學化合物中的至少一個化合物：
本發明所揭示的化合物，及/或該等化合物藥學上可接受的鹽，可以從市售的起始原料與揭示內容一起合成。下面的方案說明了本文所揭示的一些化合物的製備方法。 The compounds disclosed herein, and/or the pharmaceutically acceptable salts of such compounds, can be synthesized from commercially available starting materials with the disclosure. The following scheme illustrates the preparation of some of the compounds disclosed herein.
方案I
還提供了一種治療與抑制raf激酶活性相關的癌症的方法。該方法包括給予有治療所述癌症需要的患者如哺乳動物或人類，有效劑量的至少一種化合物，該化合物選自通式(I)(例如通式(II)、(III)、(IV)和(V))的化合物，及其立體異構體和本文所述的其藥學上可接受的鹽。 Also provided is a method of treating cancer associated with inhibition of raf kinase activity. The method comprises administering to a patient, such as a mammal or a human, in need of treatment of said cancer, an effective amount of at least one compound selected from the group consisting of Formula (I) (eg, Formulas (II), (III), (IV) and (V)) a compound, and stereoisomers thereof, and pharmaceutically acceptable salts thereof as described herein.
選自通式(I)(例如通式(II)、(III)、(IV)和(V))中的至少一種化合物，及其立體異構體，和本文所述的其藥學上可接受的鹽，在治療中可以採用單獨給藥，或者與至少一種其他治療藥物聯合給藥。在一些實施例中，選自式(I)(例如通式(II)、(III)、(IV)和(V))的化合物，其立體異構體，以及藥學上可接受的鹽可以與至少一種額外的治療試劑組合使用。至少一種另外的治療試劑比如可以選自於抗增殖、抗癌症和化療試劑。本專利揭示的化合物及/或藥學上可以接受的鹽可以和至少一種其它的治療試劑以單一或者不同的劑型聯用。當給予不同劑型時，可以先給予至少一種其它的治療試劑，同時或者接下來給藥本發明中揭示的化合物及/或藥學上可以接受的鹽。 At least one compound selected from the group consisting of the general formula (I) (for example, the general formulae (II), (III), (IV), and (V)), and stereoisomers thereof, and pharmaceutically acceptable as described herein The salt may be administered alone or in combination with at least one other therapeutic agent. In some embodiments, a compound selected from formula (I) (eg, formula (II), (III), (IV), and (V)), a stereoisomer thereof, and a pharmaceutically acceptable salt can be At least one additional therapeutic agent is used in combination. The at least one additional therapeutic agent can be selected, for example, from anti-proliferative, anti-cancer, and chemotherapeutic agents. The compounds and/or pharmaceutically acceptable salts disclosed herein may be combined with at least one other therapeutic agent in a single or different dosage form. When different dosage forms are administered, at least one other therapeutic agent can be administered first, or the compound disclosed in the present invention and/or a pharmaceutically acceptable salt can be administered next.
「化療試劑」是一種不考慮作用機制，用於治療癌症的化合物。化療試劑可以是在「靶向治療」和常規化療中使用的化合物。合適的化療試劑可以選自比如引起細胞凋亡的試劑；多聚核苷酸(如，核酶)；多肽(如，酶)；藥物；生物 模擬物；生物鹼；烷基化試劑；抗腫瘤的抗生素；抗代謝物；激素；鉑化合物；與抗癌藥物，毒素，及/或者放射性核素連用的單克隆抗體；生物應答調節劑(干擾素，比如IFN-a和白細胞介素，比如IL-2)；過繼免疫治療劑；造血生長因數；引起腫瘤細胞分化的試劑(如全反式-維甲酸)；基因治療試劑；反義治療試劑和核苷；腫瘤疫苗；和一些血管再生抑制劑。 "Chemotherapy Reagent" is a compound that does not consider the mechanism of action and is used to treat cancer. The chemotherapeutic agent can be a compound used in "targeted therapy" and conventional chemotherapy. Suitable chemotherapeutic agents can be selected, for example, from agents that cause apoptosis; polynucleotides (eg, ribozymes); polypeptides (eg, enzymes); drugs; Mimetic; alkaloid; alkylating agent; antitumor antibiotic; antimetabolite; hormone; platinum compound; monoclonal antibody used in combination with anticancer drugs, toxins, and/or radionuclides; biological response modifier (interference) , such as IFN-a and interleukins, such as IL-2); adoptive immunotherapeutic agents; hematopoietic growth factors; agents that cause tumor cell differentiation (eg, all-trans-retinoic acid); gene therapy agents; antisense therapeutic agents And nucleosides; tumor vaccines; and some angiogenesis inhibitors.
化療試劑的例子包括厄洛替尼(特羅凱®，Genentech/OSI Pharm.)；硼替佐米(萬珂®，Millennium Pharm.)，氟維司群(FASLODEX®，阿斯利康)，舒尼替尼(索坦®，輝瑞)，來曲唑(弗隆®，諾華)；伊馬替尼甲磺酸鹽(格列衛®，諾華)；PTK787/ZK 222584(諾華)，奧沙利鉑(樂沙定®，賽諾菲)；5-FU(5-氟尿嘧啶)；亞葉酸鈣；雷帕黴素(西羅莫司，RAPAMUNE®，惠氏公司)；拉帕替尼(TYKERB ®，GSK572016，葛蘭素史克)；洛那法尼(SCH 66336)，索拉非尼(多吉美®，拜耳)；伊立替康(CAMPTOSAR®，輝瑞)和吉非替尼(易瑞沙®，阿斯利康)；AG1478，AG1571(SU 5271，Sugen)；烷基化試劑，如噻替派和CYTOXAN®環磷醯胺，烷基磺酸鹽，例如白消安，improsulfan和呱泊舒凡；氮雜環丙烷，如benzodopa，carboquone，meturedopa和uredopa；ethylenimines和methylamelamines如六甲蜜胺，triethylenemelamine，三亞乙基磷醯胺，三亞乙基硫代磷醯胺和三羥甲蜜胺；內酯(如bullatacin和bullatacinone)；喜樹鹼(比如托泊替康的合成類似物)，苔蘚抑素；callystatin；CC-1065和CC-1065的阿多來 新、卡折來新、比折來新的合成類似物；cryptophycins(如cryptophycin 1和cryptophycin 8)；朵拉司他汀；duocarmycin和其合成類似物，如KW-2189和CB1-TM1；eleutherobin；pancratistatin；a sarcodictyin；spongistatin；氮芥，如苯丁酸氮芥，chlomaphazine，chlorophosphamide，雌氮芥，異環磷醯胺，氮芥，氧化氮芥鹽酸鹽，馬法蘭，新恩比興(novembichin)，苯芥膽甾醇(phenesterine)，潑尼氮芥(prednimustine)，三芥環磷醯胺，尿嘧啶氮芥；亞硝基脲如卡莫司汀，氯脲黴素，福莫司汀，洛莫司汀，尼莫司汀和ranimnustine，抗生素如烯二炔類抗生素(如卡裡奇黴素gammalI和卡裡奇黴素omegaI1(Angew Chem.Intl.Ed.Engl.(1994)33：183-186))；dynemicin，比如dynemicin A；二膦酸鹽，如氯膦酸鹽；埃斯培拉黴素；和新制癌菌素髮色團，以及相關的生色烯二炔類抗生素的發色團、aclacinomysins、放線菌素(actinomycin)、authramycin、重氮絲氨酸、博萊黴素、放線菌素C(cactinomycin)、carabicin、caminomycin、carzinophilin、chromomycinis、放線菌素D(dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、阿黴素®(多柔比星，doxorubicin)、嗎啉基-阿黴素、氰基嗎啉基-阿黴素、2-pyrrolino-doxorubicin和去氧阿黴素)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素如絲裂黴素C、黴酚酸、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素、泊非黴素(porfiromycin)、嘌呤黴 素、quelamycin、羅多比星(rodorubicin)、鏈黑菌素、鏈脲菌素、殺結核菌素(tubercidin)、烏苯美司、淨司他丁(zinostatin)、佐柔比星(zorubicin)、抗代謝產物如氨甲喋呤和5-氟尿嘧啶(5-FU)；葉酸類似物如二甲葉酸(denopterin)，氨甲喋呤，蝶羅呤，三甲曲沙；嘌呤類似物如氟達拉濱、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤；嘧啶類似物如環胞苷、阿紮胞苷，6-氮雜尿苷(6-azauridine)、卡莫氟、阿糖胞苷、二去氧尿苷、去氧氟尿苷、依諾他濱、氟尿苷；雄激素，如卡普睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、環硫雄醇、美雄烷(mepitiostane)、睾內酯；抗腎上腺素如氨魯米特、米托坦、曲洛司坦；葉酸補充劑如frolinic acid；醋葡醛內酯；醛磷醯胺苷；氨基酮戊酸；eniluracil；安吖啶；bestrabucil；比生群(bisantrene)；edatraxate；defofamine；脫羰秋水仙鹼(demecolcine)；地吖醌(diaziquone)；elformithine；依利醋銨(elliptinium acetate)；埃博黴素；依託格魯(etoglucid)；硝酸鎵；羥基脲；香菇多糖；lonidainine；美登木素生物鹼(maytansinoids)，如美登素(maytansine)和安絲菌素(ansamitocins)；米托胍腙(mitoguazone)；米托蒽醌；mopidanmol；nitraerine；噴司他丁；苯來美特(phenamet)；吡柔比星；洛索蒽醌(losoxantrone)；podophyllinic acid；2-乙基醯肼；甲基苄肼；PSK®多糖複合物(JHS Natural Products,Eugene,Oreg.)；雷佐生(razoxane)；根黴素(rhizoxin)；sizofuran；鍺螺胺(spirogermanium)，細交鏈孢菌酮酸(tenuazonic acid)；三亞胺醌(triaziquone)；三(2-氯乙基)胺； 單端孢素(如T-2毒素，verracurin A，漆斑菌素A(roridin A)和anguidine)；氨基甲酸乙酯；長春地辛；氮烯咪胺，甘露醇氮芥；二溴甘露醇(mitobronitol)；二溴衛矛醇(mitolactol)；胍血生(pipobroman)；gacytosine；***糖苷("Ara-C")；環磷醯胺；塞替派；紫杉烷類，例如，TAXOL®(紫杉醇；Bristol-Myers Squibb Oncology、Princeton、N.J.)，ABRAXANE®(Cremophor-free)，白蛋白工程紫杉醇納米顆粒製劑(American Pharmaceutical Partners、Schaumberg、Ill.)，和泰索帝®(doxetaxel；Rhone-Poulenc Rorer,Antony,France)；chloranmbucil；健擇®(吉西他濱)，6-硫代鳥嘌呤；巰基嘌呤，氨甲喋呤，鉑類似物，如順鉑，卡鉑；長春花鹼；依託泊苷(etoposide)(VP-16)；異環磷醯胺；米托蒽醌；長春新鹼；諾維本®(長春瑞濱)；米托蒽醌(novantrone)；替尼泊苷；依達曲沙(edatrexate)；道諾黴素；氨基蝶呤；卡培他濱(XELODA®)；伊班膦酸鈉；CPT-11；拓撲異構酶抑制劑RFS 2000；二氟甲基鳥氨酸(DMFO)；類視色素如視黃酸；藥學上可接受的鹽、酸和任何上述的衍生物。 Examples of chemotherapeutic agents include erlotinib (Terroy®, Genentech/OSI Pharm.); bortezomib (Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), Shuni Tini (Soltan®, Pfizer), Letrozole (Fron®, Novartis); Imatinib mesylate (Gleevec®, Novartis); PTK787/ZK 222584 (Nova), oxaliplatin Leshadine®, Sanofi); 5-FU (5-fluorouracil); calcium leucovorin; rapamycin (sirolimus, RAPAMUNE®, Wyeth); lapartini ® (GSK572016, GlaxoSmithKline; Lonofani (SCH 66336), Sorafenib (Nexavar®, Bayer); Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (Iressa®, AstraZeneca) AG1478, AG1571 (SU 5271, Sugen); alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide, alkyl sulfonates such as busulfan, improsulfan and oxime sulpho; nitrogen heterocycle Propane, such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines such as hexamethylene melamine, triethylenemelamine, triethylenephosphonium, triethylene thiophosphonamide and tris Melamine; lactones (e.g. bullatacin and bullatacinone); camptothecin (topotecan such as synthetic analogs), bryostatin; callystatin; CC-1065 and a plurality of CC-1065 to A New, card-new, new synthetic analogues; cryptophycins (such as cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin and its synthetic analogues such as KW-2189 and CB1-TM1; eleutherobin; pancratistatin a sarcodictyin;spongistatin; nitrogen mustard, such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, nitrogen mustard, nitrogen oxide mustard hydrochloride, melphalan, neombibic, Phenostere, prednimustine, tri-salt cyclophosphamide, uracil mustard; nitrosourea such as carmustine, chloramphenicol, formoterol, lomo Statin, nimustine and ramininustine, antibiotics such as enediyne antibiotics (such as calicheamicin gammalI and calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186 )); dynemicin, such as dynemicin A; bisphosphonates such as clodronate; espermati; and new carotenoid chromophores, and related chromophores of chromogenic diacetylene antibiotics , aclacinomysins, actinomycin, authramycin, azaserine , bleomycin, cactinomycin, caracricin, caminomycin, carzinophilin, chromomycinis, actinin D, daunorubicin, detorubicin, 6-diazonium 5--5-oxo-L-norleucine, doxorubicin® (doxorubicin), morpholinyl-doxorubicin, cyanomorpholinyl-doxorubicin, 2-pyrrolino-doxorubicin And deoxytetracycline), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C , mycophenolic acid, nogalamycin, olivomycins, pilomycin, porfiromycin, fungus , quelamycin, rodorubicin, streptavidin, streptozotocin, tubercidin, ubexem, zinostatin, zorubicin , antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethyl phthalate (denopterin), methotrexate, pteroquinone, trimethoate; purine analogs such as fludarabine, 6-mercaptopurine , thiamiprine, thioguanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, di-deoxyuridine Glycosides, deoxyfluorouridine, enesitabine, fluorouridine; androgens such as calustronone, dromostanolone propionate, thiosulphate, mepitiostane , testosterone; anti-adrenalin such as aminoglutethimide, mitoxantrone, tromethamine; folic acid supplements such as frolinic acid; acetaldehyde lactone; aldoxime; amino ketovalerate; eniluracil; Acridine; bestrabucil; bisantrene; edatraxate; defofamine; decarbonylation; Diziquone; elformithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as beauty Maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentastatin; phenamet; pirarubicin; Losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin ; sizofuran; spirogermanium, tenuazonic acid; triaziquone; tris(2-chloroethyl)amine; Trichosporine (such as T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; nitromethamine, mannitol mustard; dibromomannitol (mitobronitol); mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, for example, TAXOL® (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor-free), Albumin Engineering Paclitaxel Nanoparticle Formulation (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® (doxetaxel; Rhone- Poulenc Rorer, Antony, France); chloranmbucil; Gemcitabine® (Gemcitabine), 6-thioguanine; guanidinium, methotrexate, platinum analogues such as cisplatin, carboplatin; vinblastine; etoposide (VP-16); Isocyclophosphamide; Mitoxantrone; Vincristine; Novec® (vinorelbine); Noventrone; Teniposide; Edatrexate ); daunorubicin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; Topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.
「化療試劑」也可以選自於，比如：(i)能夠調控或者抑制激素作用於腫瘤的抗激素類試劑，比如抗***和選擇性***受體調控劑(SERMs)，包括，比如它莫昔芬(包括NOLVADEX®；它莫昔芬檸檬酸鹽)、雷洛昔芬、屈洛昔芬、4-羥基他莫昔芬、曲沃昔芬、keoxifene、LY117018、奧那司酮和FARESTON®(toremifine檸檬酸鹽)；(ii)能夠抑制芳香酶的芳香酶抑制劑，能夠調節***在腎上腺中的產生，比如， 4(5)-咪唑、氨魯米特、MEGASE®(甲地孕酮醋酸鹽)、AROMASIN®(依西美坦；輝瑞)、formestanie、法倔唑、RIVISOR®(伏氯唑)、FEMARA®(來曲唑；諾華)和ARIMIDEX®(anastrozole；阿斯利康)；(iii)抗雄激素比如氟他胺、尼魯米特、比卡魯胺、亮丙瑞林(leuprolide)和戈舍瑞林；和曲沙他濱(troxacitabine，1,3-二惡茂烷核苷胞嘧啶類似物)；(iv)蛋白激酶抑制劑；(v)脂質激酶抑制劑；(vi)反義寡核苷酸，該等反義寡核苷酸能抑制信號傳導通路中基因的表達，這些基因引起一些變異細胞的增值，比如PKC-alpha、Ralf和H-Ras；(vii)核酶比如VEGF表達抑制劑(如，ANGIOZYME®)和HER2表達抑制劑；(viii)疫苗如基因治療疫苗，如ALLOVECTIN®，LEUVECTIN®，和VAXID®；PROLEUKIN® rIL-2；拓撲異構酶I抑制劑，如LURTOTECAN®；ABARELIX® rmRH；(ix)抗血管生成試劑比如(AVASTIN®，Genentech)；和(x)藥學上可接受的鹽，酸及上面提到的類似物。 "Chemotherapeutic agents" may also be selected, for example, from (i) anti-hormonal agents that modulate or inhibit the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, Tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trevoxifen, keoxifene, LY117018, ol's ketone and FARESTON ® (toremifine citrate); (ii) an aromatase inhibitor capable of inhibiting aromatase, which regulates the production of estrogen in the adrenal gland, for example, 4(5)-Imidazole, aminoglutethimide, MEGASE® (Megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (voltazole), FEMARA® (Letrozole; Novartis) and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and gosere Lin; and troxacitabine (troxacitabine, 1,3-dioxanine cytosine analog); (iv) protein kinase inhibitor; (v) lipid kinase inhibitor; (vi) antisense oligonucleoside Acids, these antisense oligonucleotides can inhibit the expression of genes in signaling pathways that cause proliferation of some variant cells, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (eg, ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase I inhibitors such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and similar to those mentioned above .
「化療試劑」也可以選自於，比如，有療效的抗體比如阿侖單抗(Campath)、貝伐單抗(AVASTIN®，Genentech)；西妥昔單抗(ERBITUX®，Imclone)；帕尼單抗(VECTIBIX®，Amgen)、利妥昔單抗(RITUXAN®，Genentech/Biogen Idec)、帕妥珠單抗(OMNITARG®,2C4,Genentech)、曲妥珠單抗(HERCEPTIN®，Genentech)、托西莫單抗(Bexxar,Corixia)，和抗體藥物結合物，吉妥珠單抗奧唑米星(MYLOTARG®，Wyeth)。 "Chemotherapeutic agents" may also be selected from, for example, therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); Pani Monoclonal antibody (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), Toximozumab (Bexxar, Corixia), and antibody drug conjugate, gemtuzumab MYZOLARG® (Wyeth).
有潛在療效的人源化單克隆抗體作為化療試劑可以 和至少一種來自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽聯合用藥，比如，可以選自於：阿侖單抗、阿泊珠單抗、阿塞珠單抗、atlizumab、bapineuzumab、貝伐單抗、bivatuzumab mertansine、cantuzumab mertansine、cedelizumab、賽妥珠單抗注射液、cidfusituzumab、cidtuzumab、達利珠單抗、依庫麗單抗(eculizumab)、依法利珠單抗、依帕珠單抗(epratuzumab)、erlizumab(厄利珠單抗)、felvizumab(泛維珠單抗)、fontolizumab、吉妥珠單抗奧唑米星、inotuzumab ozogamicin、易普利姆瑪(ipilimumab)、labetuzumab、林妥珠單抗、馬妥珠單抗(matuzumab)、美泊利單抗、motavizumab、motovizumab、那他珠單抗、尼妥珠單抗、nolovizumab、numavizumab、ocrelizumab、奧馬珠單抗、帕利珠單抗、帕考珠單抗(pascolizumab)、pecfusituzumab、pectuzumab、帕妥珠單抗、pexelizumab、ralivizumab、雷珠單抗、reslivizumab、reslizumab、resyvizumab、羅維珠單抗(rovelizumab)、盧利珠單抗(ruplizumab)、西羅珠單抗(sibrotuzumab)、希普利珠單抗(siplizumab)、索土珠單抗、替他珠單抗、tacatuzumab tetraxetan、他度珠單抗(tadocizumab)、他利珠單抗、tefibazumab、托珠單抗、toralizumab、曲妥珠單抗、tucotuzumab celmoleukin、tucusituzumab、umavizumab、urtoxazumab和維西珠單抗(visilizumab)。 Potentially potent humanized monoclonal antibodies can be used as chemotherapeutic agents And at least one compound derived from the formula (I) (such as (II), (III), (IV) and (V)), and an isomer thereof, and a pharmaceutically acceptable salt, for example, may be selected From: alemtuzumab, apocilizumab, acezumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab injection, cidfusituzumab, cidtuzumab, Dali Chemuzumab, eculizumab, ezetuzumab, epratuzumab, erlizumab (ehelizumab), felvizumab (panvizumab), fontolizumab, geudo Zolbiza oxazoic acid, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, nata beads Monoclonal antibody, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, lei Zumuzumab, reslivizumab, re Slizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sotoxazumab, telizumab, tacatuzumab Tetraxetan, tadocizumab, talibizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab and visilizumab.
也提供了一種藥物組合包含至少一種來自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，其異構體，和藥學 上可以接受的鹽，和至少一種藥學上可以接受的載體。 Also provided is a pharmaceutical composition comprising at least one compound from the formula (I) (such as (II), (III), (IV) and (V)), isomers thereof, and pharmacy An acceptable salt, and at least one pharmaceutically acceptable carrier.
該藥物組合物包含一種來自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽，可以用各種已知的方式給藥，比如口服、外塗、直腸給藥、非腸道給藥、吸入噴霧或者通過植入型藥盒，儘管在某種假定的情況下最適合的給藥途徑取決於特定的宿主，和活性成分給藥時的自然條件和疾病的嚴重程度。這裡使用的「非腸道給藥」包括皮下、皮內、靜脈注射、肌肉、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內和顱內注射或者輸液技術。本文所揭示的組合物可方便地以單位劑量的形式，並且由任何在本領域中公知的方法製備。 The pharmaceutical composition comprises a compound derived from the formula (I) (such as (II), (III), (IV) and (V)), and isomers thereof, and a pharmaceutically acceptable salt, which can be used in various Administration in a known manner, such as oral, topical, rectal, parenteral, inhalation spray or via an implantable kit, although in some hypothetical situations the most suitable route of administration depends on the particular The host, and the natural conditions of the active ingredient when administered and the severity of the disease. "Parenteral administration" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein are conveniently prepared in unit dosage form and by any methods known in the art.
選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽能夠以固體劑型進行口服，比如膠囊、藥片、片劑、糖衣片、顆粒和粉末，或者以液體劑型進行口服，比如酏劑、糖漿、乳劑、分散液和懸浮液。本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽也可以非腸道給藥，用無菌的液體劑型，比如分散液、懸浮液或者溶液。選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽也可以用其它的劑型來給藥比如：軟膏、乳霜、滴劑、局部用藥的透皮貼劑或者粉末、以眼用溶液或懸浮液的形式比如滴眼液進行眼部用藥、用噴霧或者粉末組合物的形式吸入或者鼻腔給藥，或者以乳膏、軟膏、噴劑、栓劑的形式進行直腸或***給藥。 A compound selected from the group consisting of formula (I) (such as (II), (III), (IV), and (V)), and isomers thereof, and a pharmaceutically acceptable salt can be orally administered in a solid dosage form, such as a capsule. , tablets, tablets, dragees, granules and powders, or orally in liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. The compounds disclosed in the patents selected from formula (I) (such as (II), (III), (IV) and (V)) and isomers thereof, and pharmaceutically acceptable salts may also be administered parenterally The drug is in a sterile liquid dosage form such as a dispersion, suspension or solution. Compounds selected from formula (I) (such as (II), (III), (IV), and (V)), and isomers thereof, and pharmaceutically acceptable salts can also be administered in other dosage forms, such as : ointment, cream, drops, topical transdermal patches or powders, in the form of ophthalmic solutions or suspensions such as eye drops for ocular administration, inhalation by spray or powder composition or nasal administration Or rectal or vaginal administration in the form of a cream, ointment, spray, or suppository.
明膠膠囊包含本專利揭示的至少一種化合物及/或者至少一種化合物藥學上可以接受的鹽和粉末狀載體，比如乳糖、澱粉、纖維素衍生物、硬脂酸鎂、硬脂酸和相似物也可以使用。相似的稀釋劑可以用來壓片。藥片和膠囊都可以製成緩釋產品用於在一段時間裡持續給藥。壓縮的藥片可以用糖包衣或者薄膜包衣以除去令人不愉快的味道，同時保護藥片隔絕空氣，或者腸溶包衣可以選擇性地在胃腸道裡溶解。 Gelatin capsules comprising at least one compound disclosed in the patent and/or at least one compound pharmaceutically acceptable salt and powder carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like use. A similar diluent can be used for tableting. Both tablets and capsules can be formulated as sustained release products for continued administration over a period of time. The compressed tablet can be coated with sugar or film to remove an unpleasant taste while protecting the tablet from air, or the enteric coating can be selectively dissolved in the gastrointestinal tract.
用於口服的液體劑型進一步包括至少一種選自於著色劑和矯味劑的試劑，用來提升患者的接受度。 Liquid dosage forms for oral administration further comprise at least one agent selected from the group consisting of coloring agents and flavoring agents for enhancing patient acceptance.
通常，水、合適的油、鹽溶液、葡萄糖水溶液(葡萄糖)，及相關的糖溶液和二醇類物質比如丙二醇或者聚乙二醇都可以是非腸道給藥溶液的合適載體。非腸道給藥的溶液包含本專利所述的至少一個化合物的水溶性鹽，至少一個合適的穩定劑，及在必要情況下至少一種緩衝物。一些抗氧化劑比如亞硫酸氫鈉、亞硫酸鈉，或者抗壞血酸，單獨或者連用，都可以作為合適的穩定劑。檸檬酸及其鹽和乙二胺四乙酸鈉也可以作為合適的穩定劑。除此之外，非腸道給藥溶液可以進一步包含至少一種防腐劑，選自於，比如，苯紮氯胺、甲基-和丙基對羥基苯甲酸酯和氯丁醇。 In general, water, a suitable oil, a saline solution, an aqueous dextrose solution (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol may be suitable carriers for parenteral solutions. Solutions for parenteral administration comprise a water soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer. Some antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, can be used as suitable stabilizers. Citric acid and its salts and sodium edetate can also be used as suitable stabilizers. In addition to this, the parenteral administration solution may further comprise at least one preservative selected from, for example, benzalkonium chloride, methyl- and propyl-p-hydroxybenzoate and chlorobutanol.
藥學上可以接受的載體可以選自於，比如能和藥物組合中的活性成分相容(在一些具體的實例中，可以穩定活性成分)和不會對受試者有害的載體。一些增溶劑比如環糊精(能夠和本專利揭示的的至少一種化合物及/或者至少一種藥學上可接受的鹽形成特定的，更易溶的複合物)可以用作藥用輔料 來傳輸活性成分。其它載體包括膠狀二氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉，和一些色素比如D&C黃色10號。一些合適的藥學上可接受的載體在Remington's Pharmaceutical Sciences,A.Osol中已有描述，可以用作本技術領域的標準文本。 The pharmaceutically acceptable carrier can be selected, for example, from a carrier which is compatible with the active ingredient in the pharmaceutical combination (in some specific examples, the active ingredient can be stabilized) and which is not deleterious to the subject. Some solubilizing agents such as cyclodextrins (which are capable of forming a specific, more soluble complex with at least one compound disclosed herein and/or at least one pharmaceutically acceptable salt) can be used as a pharmaceutical excipient to deliver the active ingredient. Other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and some pigments such as D&C Yellow No. 10. Some suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences , A. Osol and can be used as standard text in the art.
本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽可以進一步用於檢驗在體內對癌症治療的療效。比如，本專利揭示的至少一種化合物及/或者至少一種藥學上可接受的鹽可以對患有癌症的動物(比如小鼠模型)給藥，進而評價該至少一種化合物及/或者至少一種藥學上可接受的鹽的治療效果。在一或多個這種試驗中得到陽性結果可以有效地增強科學知識寶庫，進而有效地顯示這些化合物及/或者鹽的實用性。基於這些結論，可以確定對動物和人的給藥劑量和給藥途徑。 The compounds disclosed in the patents selected from formula (I) (such as (II), (III), (IV) and (V)) and isomers thereof, and pharmaceutically acceptable salts can be further used for testing The efficacy of in vivo treatment of cancer. For example, at least one compound and/or at least one pharmaceutically acceptable salt disclosed in the present patent can be administered to an animal (eg, a mouse model) having cancer, thereby evaluating the at least one compound and/or at least one pharmaceutically acceptable The therapeutic effect of the accepted salt. A positive result in one or more of these tests can effectively enhance the treasure trove of scientific knowledge, thereby effectively demonstrating the utility of these compounds and/or salts. Based on these conclusions, the dosage and route of administration to animals and humans can be determined.
對於吸入式給藥方式，本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽可以方便地從壓縮器或者噴霧器中以氣溶膠噴霧的形式傳輸。本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽也可以以一定劑型的粉末或者在噴射乾粉吸入器裝置輔助下吸入粉末組合物的形式傳輸。定量劑量吸入噴霧器(MDI)是典型的吸入式傳輸系統，可以將本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽製成在至少一種推進物比如選自碳氟化合物和烴類化合物 中的懸濁液或者溶液。 For inhaled administration, the compounds disclosed in the patents selected from formula (I) (such as (II), (III), (IV), and (V)), and isomers thereof, and pharmaceutically acceptable The salt can be conveniently delivered as an aerosol spray from a compressor or sprayer. The compounds disclosed in the patents selected from the formula (I) (such as (II), (III), (IV) and (V)) and isomers thereof, and pharmaceutically acceptable salts may also be in a certain dosage form. The powder is delivered as a powdered composition with the aid of a spray dry powder inhaler device. A metered dose inhalation nebulizer (MDI) is a typical inhalation delivery system, and the compounds disclosed in the patents selected from formula (I) (such as (II), (III), (IV) and (V)) and Isomers, and pharmaceutically acceptable salts, are made in at least one propellant such as a fluorocarbon and a hydrocarbon compound Suspension or solution in the medium.
對於眼部給藥，眼用製劑可以通過將適量重量百分比的本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽的溶液或者懸浮液，製成一種合適的眼用載體，使得比如本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽與眼球表面保持足夠時間的接觸，從而能讓化合物滲透到眼睛的角膜和內部區域。 For ocular administration, ophthalmic preparations may be prepared by applying an appropriate amount by weight of a compound selected from the formula (I) (e.g., (II), (III), (IV), and (V)) disclosed herein. A suitable ophthalmic carrier, such as (II), (III), (IV), is prepared in a solution or suspension of the pharmaceutically acceptable salt, such as disclosed herein. The compound of (V)), and its isomers, and the pharmaceutically acceptable salt remain in contact with the surface of the eye for a sufficient period of time to allow penetration of the compound into the cornea and internal regions of the eye.
本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽有用的的藥用劑型包括但不限於，硬和軟明膠膠囊、藥片、腸外注射劑，和口服懸浮液。 Medicinal compounds selected from the formula (I) (such as (II), (III), (IV) and (V)), and isomers thereof, and pharmaceutically acceptable salts useful medicinal use Dosage forms include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.
服藥劑量和許多因素相關，比如年齡、受試者的健康程度和體重、疾病的程度、同時治療的種類，若有的話，治療的頻率和期望的效果。總的來說，活性成分的日用劑量是可以變化的，比如，可以從0.1到2000毫克每天。例如，10-500毫克一天一次或者多次可能達到期望的效果。 The dose is related to a number of factors, such as age, subject's health and weight, degree of disease, type of concurrent treatment, if any, frequency of treatment and desired effect. In general, the daily dosage of the active ingredient can vary, for example, from 0.1 to 2000 mg per day. For example, 10-500 mg once or more times a day may achieve the desired effect.
在一些實施例中，大量的單位膠囊可以每個填充標準的兩片硬明膠膠囊製備，例如，比如100毫克粉末形式的本專利揭示的選自式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽，150毫克乳糖，50毫克纖維素，和6毫克硬脂酸鎂。 In some embodiments, a plurality of unit capsules can be prepared in two standard hard gelatin capsules filled with standard, for example, in the form of a 100 mg powder, disclosed in this patent, selected from formula (I) (eg, (II), (III) , (IV) and (V)) compounds and isomers thereof, and pharmaceutically acceptable salts, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
在一些實施例中，混合物選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的 鹽和可消化的油，比如大豆油、棉花籽油或者橄欖油，可以通過主動取代泵入明膠的方式製備或者注入來形成包含100毫克活性成分的軟明膠膠囊。該膠囊清被洗和乾燥。 In some embodiments, the mixture is selected from the group consisting of compounds of formula (I) (such as (II), (III), (IV), and (V)), and isomers thereof, and pharmaceutically acceptable Salts and digestible oils, such as soybean oil, cottonseed oil or olive oil, can be prepared or injected by actively replacing the pumped gelatin to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsule is washed and dried.
在一些實施例中，大量的藥片可以通過常規程式製備，每個劑量單位包含，比如，100毫克選來自於式(I)(比如(II)、(III)、(IV)和(V))的化合物及其異構體，和藥學上可以接受的鹽，0.2毫克膠體二氧化矽，5毫克硬脂酸鎂，275毫克微晶纖維素，11毫克澱粉和98.8毫克硬脂酸鎂。合適的包衣可以用於提高適口性或者延遲吸收。 In some embodiments, a plurality of tablets can be prepared by conventional procedures, each dosage unit comprising, for example, 100 mg from formula (I) (eg, (II), (III), (IV), and (V)) Compounds and isomers thereof, and pharmaceutically acceptable salts, 0.2 mg colloidal cerium oxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg magnesium stearate. A suitable coating can be used to increase palatability or delay absorption.
在一些實施例中，適用於注射給藥的胃腸外組合物，可以通過攪拌1.5%重量比的本專利揭示的至少一種化合物及/或至少一個對映體，非對映異構體，或者前述各者的藥學上可接受的鹽，在10%體積比的丙二醇中製備。該溶液加入用注射用水到預期體積，再滅菌。 In some embodiments, a parenteral composition suitable for administration by injection may be stirred by stirring 1.5% by weight of at least one compound disclosed in the patent and/or at least one enantiomer, diastereomer, or the foregoing The pharmaceutically acceptable salts of each were prepared in 10% by volume of propylene glycol. The solution is added to the intended volume with water for injection and sterilized.
在一些實施例中，可製備用於口服給藥的水溶性懸浮液。例如，每一個5毫升的水懸浮液中含有100毫克細碎的式(I)(比如(II)、(III)、(IV)和(V))的一種化合物，其立體異構體，及其藥學上可接受的鹽，100毫克羧甲基纖維素鈉，5毫克苯甲酸鈉，1克山梨醇溶液，U.S.P.和0.025毫升香草醛。 In some embodiments, a water soluble suspension for oral administration can be prepared. For example, each 5 ml of aqueous suspension contains 100 mg of a finely divided compound of formula (I) (such as (II), (III), (IV) and (V)), its stereoisomers, and A pharmaceutically acceptable salt, 100 mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1 gram sorbitol solution, USP and 0.025 ml vanillin.
當選自於式(I)(比如(II)、(III)、(IV)和(V))的化合物，及其異構體，和藥學上可以接受的鹽與至少一種其它的治療試劑逐步或者一起給藥時，可以使用同樣的劑型。當藥物在物理組合給藥時，劑型和給藥途徑的選擇取決於組合藥物的相容性。因此這一術語同時給藥可以理解為包含兩種試 劑同時或者按順序給藥，或者以固定劑量的至少兩種活性成分的組合物給藥。 a compound selected from the group consisting of formula (I) (such as (II), (III), (IV) and (V)), and isomers thereof, and a pharmaceutically acceptable salt with at least one other therapeutic agent stepwise or The same dosage form can be used when administered together. When the drug is administered in a physical combination, the choice of dosage form and route of administration will depend on the compatibility of the combination drug. Therefore, the simultaneous administration of this term can be understood to include both tests. The agents are administered simultaneously or sequentially, or in a fixed dose of a combination of at least two active ingredients.
本專利揭示的選自於式(I)(比如(II)、(III)、(IV)和(V))的至少一個化合物，及其異構體，和藥學上可以接受的鹽可以以單一活性成分或者和至少一種第二種活性成分，比如，選自公知的用於治療癌症的其他活性成分聯用。 At least one compound selected from the formula (I) (such as (II), (III), (IV) and (V)), and an isomer thereof, and a pharmaceutically acceptable salt may be singly The active ingredient is either in combination with at least one second active ingredient, for example selected from other known active ingredients for the treatment of cancer.
下面的例子純粹用於示範，不應以任何方式限制。已作出努力來確保使用資料的準確性(比如，數量、溫度等)，但仍然會有一些實驗方面的誤差和偏差。如果沒有其它說明，溫度是指攝氏度。試劑從Sigma-Aldrich，Alfa Aesar，或者TCI等供應商處獲得，如無說明，並沒有作進一步的純化。 The following examples are purely exemplary and should not be limited in any way. Efforts have been made to ensure the accuracy of the data used (eg, quantity, temperature, etc.), but there will still be some experimental errors and deviations. If there is no other explanation, the temperature is in degrees Celsius. Reagents were obtained from suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and, if not stated, were not further purified.
如果沒有其它說明，如下反應一般在氮氣或者氬氣的條件下或者乾燥管的情況下于無水溶劑中反應；反應燒瓶帶有橡膠塞以方便通過注射器加入底物和試劑；玻璃器皿通過烘乾及/或者加熱乾燥。 If not otherwise stated, the following reaction is generally carried out in an anhydrous solvent under nitrogen or argon or in the presence of a drying tube; the reaction flask is provided with a rubber stopper to facilitate the addition of the substrate and reagents via a syringe; the glassware is dried and / or heat dry.
如無其它說明，柱層析純化在Biotage系統(製造商：Dyax Corporation)上加入矽膠或者通過矽膠SepPak盒(Waters)，或者使用用帶矽膠盒的Teledyne Isco Combiflash純化系統。 Unless otherwise stated, column chromatography purification was carried out on a Biotage system (manufacturer: Dyax Corporation) by adding silicone or via a silicone SepPak box (Waters) or using a Teledyne Isco Combiflash purification system with a cassette.
氫譜使用400MHz的Varian系統得到。氫譜用CDCl3、CD2Cl2、CD3OD、D2O、d 6-DMSO、d 6-丙酮或(CD3)2CO
作溶劑，四甲基矽或者溶劑殘餘(CDCl3：7.25ppm；CD3OD：3.31ppm；D2O：4.79ppm；d 6-DMSO：2.50ppm；d 6-丙酮：2.05；(CD3)2CO：2.05)為內標。當峰的多重性報導時，可以使用如下的簡寫：s(單峰)、d(雙峰)、t(三重峰)、q(四重峰)、qn(五重峰)、sx(六重峰)、m(多重峰)、br(寬峰)、dd(兩個雙峰)、dt(兩三重峰)。給出的耦合常數用赫茲(Hz)表示。除一些試劑外所有的化合物都使用ChemDraw12.0版本來得到。在下文的實施例中，下列縮寫被用到：
實例1：化合物1.1-1.3的合成 Example 1: Synthesis of Compound 1.1-1.3
化合物1.1 Compound 1.1
步驟A：6-(苄氧基)-2，3-二氫茚-1-酮 Step A: 6-(Benzyloxy)-2,3-dihydroindole-1-one
向6-羥基-1，3-二氫茚-1-酮(30g，0.203mol)的300mL DMF溶液中攪拌下加入K2CO3(70g，0.507mol)，然後在0℃下滴加BnBr(38.2g，0.225mol)。該混合物升至室溫並攪拌20小時。用乙酸乙酯(500mL)稀釋該混合物，然後過濾以除去固體。將濾液用飽和食鹽水(200mL×5)洗滌，用無水硫酸鈉乾燥，並在真空下濃縮。所得的固體在***中重結晶得到白色固體狀目標化合物(44.5g，92%)。1H-NMR(600MHz,CDCl3)δ 7.47-7.46(m,2H),7.44-7.39(m,3H),7.38-7.35(m,1H),7.31-7.30(m,2H),5.12(s,2H),3.11-3.09(m,2H),2.76-2.74(m,2H)ppm。 To a solution of 6-hydroxy-1,3-dihydroindole-1-one (30 g, 0.203 mol) in 300 mL of DMF was added K 2 CO 3 (70 g, 0.507 mol) with stirring, and then BnBr was added dropwise at 0 ° C ( 38.2 g, 0.225 mol). The mixture was warmed to room temperature and stirred for 20 hours. The mixture was diluted with ethyl acetate (500 mL) then filtered to remove solid. The filtrate was washed with brine (200 mL×5), dried over anhydrous The obtained solid was recrystallized from EtOAc (EtOAc) 1 H-NMR (600MHz, CDCl 3 ) δ 7.47-7.46 (m, 2H), 7.44-7.39 (m, 3H), 7.38-7.35 (m, 1H), 7.31-7.30 (m, 2H), 5.12 (s , 2H), 3.11-3.09 (m, 2H), 2.76-2.74 (m, 2H) ppm.
步驟B：6-(苄氧基)-2,3-二氫-1氫-茚-1-醇 Step B: 6-(Benzyloxy)-2,3-dihydro-1hydro-inden-1-ol
在0℃下攪拌下，向步驟A的產品(44g，0.185mol)的500mL甲醇中分批加入硼氫化鈉(7.1g，0.186mol)，該混合物升至室溫並攪拌20小時。將反應混合物濃縮，並加入到200mL NaOH(20%)水溶液中，將所得到的混合物用乙酸乙酯(200mL×3)萃取。將合併的有機萃取液用飽和食鹽水(200mL×3)洗滌，乾燥，並濃縮得到白色固體狀目標化合物(32.0g，72%)。1H-NMR(600MHz,CDCl3)δ 7.46-7.42(m,2H),7.41-7.36(m,2H),7.34-7.30(m,1H),7.15(d,J=8.2Hz,1H),7.04(d,J=2.4Hz,1H),6.90(dd,J=8.2,2.5Hz,1H),5.20(t,J=6.2Hz,1H),5.07(s,2H),3.01-2.95(m,1H),2.79-2.72(m,1H),2.55-2.47(m,1H),2.01-1.87(m,1H)ppm。 Sodium borohydride (7.1 g, 0.186 mol) was added portionwise to a solution of the product from step A (44 g, 0.185 mol) in 500 mL of MeOH, and the mixture was stirred at room temperature and stirred for 20 hours. The reaction mixture was concentrated and added to aq. EtOAc (20%) EtOAc. The combined organic extracts were washed with EtOAc EtOAc. 1 H-NMR (600MHz, CDCl 3 ) δ 7.46-7.42 (m, 2H), 7.41-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.2, 2.5 Hz, 1H), 5.20 (t, J = 6.2 Hz, 1H), 5.07 (s, 2H), 3.01-2.95 (m) , 1H), 2.79-2.72 (m, 1H), 2.55-2.47 (m, 1H), 2.01-1.87 (m, 1H) ppm.
步驟C：5-(苄氧基)-1氫-茚 Step C: 5-(Benzyloxy)-1hydrogen-oxime
室溫攪拌下，向步驟B的產物(15.0g，62.5mmol)的甲苯(200mL)溶液中加入p-TsOH(1.0g，6.25mmol)，將混合物加熱到80℃反應1.5小時。將該混合物濃縮，並用柱色譜法純化(用石油醚：乙酸乙酯=30：1洗脫)，得到白色固體狀目標化合物(12.3g，89%)。1H-NMR(600MHz,CDCl3)δ 7.47-7.46(m,2H),7.41-7.33(m,5H),7.06-7.05(m,1H),6.85-6.84(m,1H),6.60-6.58(m,1H),5.11(s,2H),3.35(m,2H)ppm。 To a solution of the product from Step B (15.0 g, 62.5 mmol) in toluene (200 mL), EtOAc (EtOAc) The mixture was concentrated and purified with EtOAc EtOAc EtOAc EtOAc 1 H-NMR (600MHz, CDCl 3 ) δ 7.47-7.46 (m, 2H), 7.41-7.33 (m, 5H), 7.06-7.05 (m, 1H), 6.85-6.84 (m, 1H), 6.60-6.58 (m, 1H), 5.11 (s, 2H), 3.35 (m, 2H) ppm.
步驟D：(±)-exo-乙基3-(苄氧基)-1,1a,6,6a-四氫環丙烷[α]茚-1-羧酸乙酯 Step D: (±)-exo-ethyl 3-(benzyloxy)-1,1a,6,6a-tetrahydrocyclopropane[α]indole-1-carboxylic acid ethyl ester
室溫下，向步驟C的產物(10g，45mmol)和銅(I)三氟甲磺酸酯(用甲苯2：1配合物，0.23g，4.5mmol)的二氯甲烷(200mL)溶液中通過注射泵於10小時內加入重氮基乙酸乙酯(47mL，450mol)的二氯甲烷(50mL)溶液，該混合物在室溫下再攪拌2小時。過濾該反應物，將濾液在減壓下濃縮。殘餘物通過矽膠色譜法(用石油醚洗脫)純化，得到黃色油狀目標化合物(5.5g，40%)。1H-NMR(600MHz,DMSO-d 6)δ 7.39-7.36(m,2H),7.33-7.29(m,2H),7.27-7.23(m,1H),6.99(d,J=8.3Hz,1H),6.95(d,J=2.4Hz,1H),6.72(dd,J=8.3,2.3Hz,1H),4.98(s,2H),4.09(q,J=7.0Hz, 2H),3.11(dd,J=17.2,6.3Hz,1H),2.90(d,J=17.2Hz,1H),2.82(d,J=6.5Hz,1H),2.35(td,J=6.4,3.3Hz,1H),1.24-1.17(m,3H),1.13-1.05(m,1H)ppm。 By injection of the product of step C (10 g, 45 mmol) and copper (I) triflate (with toluene 2:1 complex, 0.23 g, 4.5 mmol) in dichloromethane (200 mL) A solution of diazoacetic acid ethyl acetate (47 mL, 450 mol) in dichloromethane (50 mL) was then evaporated. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcEtOAcEtOAc 1 H-NMR (600MHz, DMSO- d 6 ) δ 7.39-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.23 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H) ), 6.95 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 8.3, 2.3 Hz, 1H), 4.98 (s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.11 (dd , J =17.2, 6.3 Hz, 1H), 2.90 (d, J = 17.2 Hz, 1H), 2.82 (d, J = 6.5 Hz, 1H), 2.35 (td, J = 6.4, 3.3 Hz, 1H), 1.24 -1.17 (m, 3H), 1.13-1.05 (m, 1 H) ppm.
步驟E：(±)-exo-乙基-3-羥基-1,1a,6,6a-四氫環丙烷[α]茚-1-羧酸乙酯 Step E: (±)-exo-ethyl-3-hydroxy-1,1a,6,6a-tetrahydrocyclopropane[α]indole-1-carboxylic acid ethyl ester
在室溫下，向Pd/C(0.4g)與MeOH(20mL)的混合物中加入步驟D的產物(4g，0.013mol)的MeOH(20mL)溶液。室溫下，該混合物在氫氣中攪拌2小時。將該混合物過濾，將濾液濃縮。該殘餘物通過矽膠色譜法(用乙酸乙酯：石油醚=1：10洗脫)純化，得到無色油狀目標化合物(2.3g，82%)。1H-NMR(600MHz,CD3OD)δ 6.91(d,J=8.1Hz,1H),6.75(d,J=2.3Hz,1H),6.54(dd,J=8.2,2.2Hz,1H),4.08(q,J=7.0Hz,2H),3.09(dd,J=17.0,6.3Hz,1H),2.87(d,J=17.0Hz,1H),2.78(d,J=6.4Hz,1H),2.33(td,J=6.4,3.2Hz,1H),1.21(t,J=6.9Hz,3H),1.09-1.06(m,1H)ppm。 A solution of the product of Step D (4 g, 0.013 mol) in MeOH (20 mL). The mixture was stirred under hydrogen for 2 hours at room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc 1H-NMR (600MHz, CD3OD) δ 6.91 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.54 (dd, J = 8.2, 2.2 Hz, 1H), 4.08 (q) , J = 7.0 Hz, 2H), 3.09 (dd, J = 17.0, 6.3 Hz, 1H), 2.87 (d, J = 17.0 Hz, 1H), 2.78 (d, J = 6.4 Hz, 1H), 2.33 (td , J = 6.4, 3.2 Hz, 1H), 1.21 (t, J = 6.9 Hz, 3H), 1.09 - 1.06 (m, 1 H) ppm.
步驟F：(±)-exo-乙基3-((7-氧代-5-5,6,7,8-四氫-1-1,8-萘啶-4-基氧基)-1,1a,6,6a-四氫環丙烷[氫環茚-1-羧酸乙酯 Step F: (±)-exo-ethyl 3-((7-oxo-5-5,6,7,8-tetrahydro-1-1,8-naphthyridin-4-yloxy)-1 ,1a,6,6a-tetrahydrocyclopropane[hydrocyclodecan-1-carboxylic acid ethyl ester
步驟E的產品(2.0g，9mmol)，5-氟-3,4-二氫-1,8- 萘啶-2(1H)-酮(1.5g，9mmol)和碳酸銫(6g，18mmol)的DMF(30mL)混合物，在120物下攪拌2小時。用水(30mL)稀釋該反應物，並用乙酸乙酯(2×40mL)萃取。合併的有機相，用飽和食鹽水(50mL)洗滌，無水硫酸鈉乾燥，減壓濃縮乾燥。殘餘物通過矽膠色譜法(用乙酸乙酯：石油醚=1：5~1：1洗脫)純化，得到白色固體狀目標化合物(1.4g，42%)。 Product of Step E (2.0 g, 9 mmol), 5-fluoro-3,4-dihydro-1,8- A mixture of naphthyridin-2 (1H)-one (1.5 g, 9 mmol) and EtOAc (EtOAc,EtOAc) The reaction was diluted with water (30 mL) The combined organic layers were washed with brine sat. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)
步驟G：(±)-exo-3-((7-氧代-5-5,6,7,8-四氫-1-1,8-萘啶-4-基氧基)-1,1a,6,6a-四氫環丙烷[氫環茚-1-羧酸(中間體I) Step G: (±)-exo-3-((7-oxo-5-5,6,7,8-tetrahydro-1-1,8-naphthyridin-4-yloxy)-1,1a ,6,6a-tetrahydrocyclopropane [hydrocyclodecan-1-carboxylic acid ( intermediate I )
在室溫攪拌下，將氫氧化鈉溶液(7.7mL，2M，15mmol)加入到含步驟F產物(1.4g，3.8mmol)的THF(24mL)和甲醇(24mL)的溶液中。該混合物在60℃下攪拌2小時。在減壓下除去溶劑，將殘餘物溶解于水(20mL)中。該溶液用HCl(1mol/L)中和至pH=7，白色固體從溶液中沉澱出來。通過過濾收集白色固體，並在空氣中乾燥，得到目標化合物(0.9g，70%)。1H-NMR(600MHz,DMSO-d 6)δ 10.47(s,1H),7.97(d,J=5.7Hz,1H),7.28-7.14(m,3H),6.88(d,J=8.1Hz,1H),6.29(d,J=5.8Hz,1H),3.19(dd,J=17.6,6.4Hz,1H),3.00(d,J=17.6Hz,1H),2.92(t,J=7.7Hz,2H),2.81(d,J=6.3Hz,1H),2.54(t,J=7.7Hz,2H),2.37-2.31(m,1H),1.08-1.05(m,1H)ppm。 A solution of the product of Step F (1.4 g, 3.8 mmol) in THF (24 mL) and methanol (24 mL) The mixture was stirred at 60 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was crystallised from water The solution was neutralized with HCl (1 mol/L) to pH = 7, and a white solid precipitated from the solution. The white solid was collected by filtration and dried in vacuo to give the title compound (0.9 g, 70%). 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.47 (s, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.28-7.14 (m, 3H), 6.88 (d, J = 8.1 Hz, 1H), 6.29 (d, J = 5.8 Hz, 1H), 3.19 (dd, J = 17.6, 6.4 Hz, 1H), 3.00 (d, J = 17.6 Hz, 1H), 2.92 (t, J = 7.7 Hz, 2H), 2.81 (d, J = 6.3 Hz, 1H), 2.54 (t, J = 7.7 Hz, 2H), 2.37 - 2.31 (m, 1H), 1.08 - 1.05 (m, 1 H) ppm.
步驟H：(±)-exo-N-(2-氨基苯)-3-((7-oxo-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1,1a,6,6a-四氫環丙烷[a]茚-1-甲醯胺 Step H: (±)-exo-N-(2-aminophenyl)-3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy )-1,1a,6,6a-tetrahydrocyclopropane [a]non-1-carboxamide
室溫下，往含中間體I(30mg，0.089mmol)，苯-1,2-二胺(9.6mg，0.089mmol)和HATU(37mg，0.101mmol)的DMF(1mL)溶液中加入DIPEA(0.1mL)。該混合物在室溫下攪拌過夜。用水(5mL)稀釋該反應物，並用乙酸乙酯(2×10mL)萃取。合併的有機相用鹽水洗滌，用無水硫酸鈉乾燥，並在減壓下濃縮。殘留物不經進一步純化直接用於下一步驟。MS：M/e 427(M+1)+。 DIPEA (0.1) was added to a solution of intermediate I (30 mg, 0.089 mmol), benzene-1,2-diamine (9.6 mg, 0.089 mmol) and HATU (37 mg, 0.101 mmol) in DMF (1 mL) mL). The mixture was stirred at room temperature overnight. The reaction was diluted with water (5 mL) andEtOAcEtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was used in the next step without further purification. MS: M/e 427 (M+1) + .
步驟I：(±)-exo-5-((1-(1H-苯並[d]咪唑-2-基)-1,1a,6,6a-四氫環丙烷[a]茚-1-3-基)-氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物1.1) Step I: (±)-exo-5-((1-(1H-benzo[d]imidazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropane [a]茚-1-3 -yl)-oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 1.1 )
將步驟H的產物(38mg，0.089mmol)與冰醋酸(2mL)的混合物在80℃下攪拌3小時。除去溶劑，將氫氧化鈉(2mL，2mol/L)的溶液加入到殘餘物中。用EtOAc(2×10mL)萃取該混合物。合併有機相，用飽和食鹽水(20mL)洗滌，無 水硫酸鈉乾燥並減壓濃縮。將殘餘物用製備高效液相色譜法純化，得到白色固體狀目標化合物。1H-NMR(600MHz,DMSO-d 6)δ 10.52(s,1H),8.01(d,J=5.7Hz,1H),7.75(dd,J=6.1,3.2Hz,2H),7.51(dd,J=6.1,3.1Hz,2H),7.39(d,J=8.3Hz,1H),7.23(d,J=2.3Hz,1H),7.02(dd,J=8.2,2.3Hz,1H),6.34(d,J=5.8Hz,1H),3.48-3.41(m,2H),3.25(d,J=17.9Hz,1H),3.01-2.95(m,1H),2.92(t,J=7.7Hz,2H),2.55(t,J=7.7Hz,2H),2.02(t,J=3.1Hz,1H)ppm。MS：M/e 409(M+1)+。 A mixture of the product of Step H (38 mg, 0.089 mmol) and EtOAc (2 mL) was stirred at <RTIgt; The solvent was removed and a solution of sodium hydroxide (2 mL, 2 mol/L) was added to the residue. The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine sat. The residue was purified by preparative high-purity chromatography to afford title compound. 1 H-NMR (600 MHz, DMSO- d 6 ) δ 10.52 (s, 1H), 8.1 (d, J = 5.7 Hz, 1H), 7.75 (dd, J = 6.1, 3.2 Hz, 2H), 7.51 (dd, J = 6.1, 3.1 Hz, 2H), 7.39 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.2, 2.3 Hz, 1H), 6.34 ( d, J = 5.8 Hz, 1H), 3.48-3.41 (m, 2H), 3.25 (d, J = 17.9 Hz, 1H), 3.01-2.95 (m, 1H), 2.92 (t, J = 7.7 Hz, 2H) ), 2.55 (t, J = 7.7 Hz, 2H), 2.02 (t, J = 3.1 Hz, 1 H) ppm. MS: M/e 409 (M+1) + .
化合物1.2：(±)-exo-5-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1,1a,6,6a-四氫環丙烷[a]茚-3-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 1.2 : (±)-exo-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1,1a,6,6a-tetrahydrocyclohexane Propane [a] indol-3-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
室溫下，向中間體I(338mg，1.0mmol)、4-(三氟甲基)苯-1,2-二胺(190mg，1.1mmol)和DIPEA(500mg，3.9mmol)的DMF(10mL)溶液中加入HATU(405mg，1.1mmol)。該混合物在室溫下攪拌20小時。將該反應物用乙酸乙酯(50mL)稀釋，並用鹽水(3×20mL)洗滌，乾燥，無水硫酸鈉乾燥並減壓濃縮。 Intermediate D (338 mg, 1.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (190 mg, 1.1 mmol) and DIPEA (500 mg, 3.9 mmol) in DMF (10 mL) HATU (405 mg, 1.1 mmol) was added to the solution. The mixture was stirred at room temperature for 20 hours. The reaction was diluted with EtOAc (EtOAc)EtOAc.
將殘餘物溶解在乙酸(10mL)中，並將該混合物在 90℃下攪拌5小時。除去溶劑。用EtOAc(50mL)稀釋殘留物。將有機相用飽和碳酸氫鈉溶液(2×20mL)洗滌，鹽水(2×20mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。該殘餘物用矽膠色譜法純化(用二氯甲烷：甲醇=50：1~20：1洗脫)，得到白色固體狀目標化合物(245mg，51%)。1H-NMR(600MHz,DMSO-d 6)δ 10.50(s,1H),8.00(d,J=5.7Hz,1H),7.87(s,1H),7.71(d,J=8.2Hz,1H),7.58-7.48(m,1H),7.35(d,J=8.2Hz,1H),7.23(d,J=2.3Hz,1H),6.96(dd,J=8.2,2.4Hz,1H),6.33(d,J=5.8Hz,1H),3.38(dd,J=17.9,6.5Hz,1H),3.24-3.15(m,2H),2.98-2.89(m,2H),2.81-2.73(m,1H),2.58-2.52(m,2H),1.87-1.80(m,1H)ppm。MS：M/e 477(M+1)+。 The residue was dissolved in acetic acid (10 mL) and the mixture was stirred at <RTIgt; Remove the solvent. The residue was diluted with EtOAc (50 mL). The organic phase was washed with EtOAc EtOAc EtOAc m. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.50 (s, 1H), 8.00 (d, J = 5.7 Hz, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H) , 7.58-7.48 (m, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 6.96 (dd, J = 8.2, 2.4 Hz, 1H), 6.33 ( d, J = 5.8 Hz, 1H), 3.38 (dd, J = 17.9, 6.5 Hz, 1H), 3.24-3.15 (m, 2H), 2.98-2.89 (m, 2H), 2.81-2.73 (m, 1H) , 2.58-2.52 (m, 2H), 1.87-1.80 (m, 1 H) ppm. MS: M/e 477 (M+1) + .
化合物1.2通過掌性製備高效液相色譜被分離成兩個對映立體異構體(化合物1.2a，先出的峰和化合物1.2b，後出的峰)。下列是掌性分離的條件。 Compound 1.2 was separated into two enantiomeric stereoisomers by a palm-form preparative high performance liquid chromatography ( compound 1.2a , first-out peak and compound 1.2b , followed by a peak). The following are the conditions for palm separation.
化合物1.3Compound 1.3
步驟A：(±)-exo-N-(2-巰苯基)-3-((7-oxo-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1,1a,6,6a-四氫環丙烷[a]茚-1-甲醯胺 Step A: (±)-exo-N-(2-indolyl)-3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy -1,1a,6,6a-tetrahydrocyclopropane [a]pyridin-1-carboxamide
在室溫，氮氣保護下，向中間體I(34mg，0.1mmol)的二氯甲烷(3.0mL)溶液中加入草醯氯(0.03mL，0.4mmol)和DMF(催化量)。將混合物攪拌1.5小時。然後除去溶劑，殘餘物溶於二氯甲烷(3.0mL)中，然後在0℃氮氣保護下加入DIPEA(0.07mL，0.4mmol)和2-氨基苯硫醇(14mg，0.11mmol)。該混合物在室溫下攪拌2小時。用二氯甲烷萃取該混 合物，用飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾並濃縮。殘餘物通過製備薄層色譜法純化(二氯甲烷：甲醇=10：1)，得到粗產物(20mg)，為黃色固體，將粗產物直接用於在下一步驟中。 To a solution of Intermediate I (34 mg, 0.1 mmol) in dichloromethane (3.sub.3 mL), EtOAc (EtOAc) The mixture was stirred for 1.5 hours. The solvent was then removed and the residue was taken in dichloromethane <RTI ID=0.0>(</RTI><RTIID=0.0></RTI></RTI><RTIgt; The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative EtOAc (EtOAc:EtOAc)
步驟B：(±)-exo-5-((1-(苯並[d]噻唑-2-基)-1,1a,6,6a-四氫環丙烷[a]茚-3-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物1.3) Step B: (±)-exo-5-((1-(benzo[d]thiazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropane[a]indol-3-yl)oxy -3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 1.3 )
向步驟A的產物(20mg，粗品)的甲苯(4.0mL)溶液中加入PPA(200mg)。該混合物在140℃攪拌3小時。將反應液降至室溫並除去溶劑。將殘留物溶於二氯甲烷(10mL)，用飽和碳酸氫鈉溶液洗並用二氯甲烷(2×15mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，減壓濃縮。將殘留物通過製備高效液相色譜法純化得到黃色固體狀目標化合物(3.8mg，9%，兩步)。1H-NMR(400MHz,CD3OD)δ 7.94-7.83(m,3H),7.47-7.43(m,1H),7.35-7.29(m,2H),7.16(d,J=2.4Hz,1H),6.92(d,J=2.4Hz,1H),6.34(d,J=6.0Hz,1H),3.42-3.36(m,1H),3.29-3.26(m,1H),3.22-3.19(m,1H),3.04(t,J=8.0Hz,2H),2.77-2.72(m,1H),2.66-2.62(m,2H),2.05-2.03(m,1H)ppm。MS：M/e 426(M+1)+。 To a solution of the product from Step A (20 mg, EtOAc) The mixture was stirred at 140 ° C for 3 hours. The reaction solution was cooled to room temperature and the solvent was removed. The residue was dissolved in dichloromethane (10 mL)EtOAcEtOAcEtOAc The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (400MHz, CD 3 OD) δ 7.94-7.83 (m, 3H), 7.47-7.43 (m, 1H), 7.35-7.29 (m, 2H), 7.16 (d, J = 2.4 Hz, 1H) , 6.92 (d, J = 2.4 Hz, 1H), 6.34 (d, J = 6.0 Hz, 1H), 3.42-3.36 (m, 1H), 3.29-3.26 (m, 1H), 3.22-3.19 (m, 1H) ), 3.04 (t, J = 8.0 Hz, 2H), 2.77-2.72 (m, 1H), 2.66-2.62 (m, 2H), 2.05 - 2.03 (m, 1 H) ppm. MS: M/e 426 (M+1) + .
例2：化合物2.1-2.37的合成 Example 2: Synthesis of Compound 2.1-2.37
化合物2.1 Compound 2.1
步驟A：(苯並呋喃-5-基氧基)(叔丁基)二甲基矽烷 Step A: (benzofuran-5-yloxy)(tert-butyl)dimethyl decane
室溫攪拌下，向苯並呋喃-5-醇(5.2g，0.039mol)的DMF(50mL)溶液加入咪唑(5.3g，0.078mol)和叔丁基二甲基氯矽烷(6.1g，0.041mol)。該混合物在室溫下攪拌20小時。然後將飽和碳酸氫鈉溶液(150mL)加入到反應液中，該混合物用乙酸乙酯(3×100mL)萃取。將合併的有機相用飽和食鹽水 (3×100mL)洗滌，無水硫酸鈉乾燥，減壓濃縮。殘留物通過矽膠柱層析法(石油醚洗脫)純化，得到無色油狀目標化合物(7.8g，81%)。1H-NMR(600MHz,DMSO-d 6)δ 7.94(d,J=2.1Hz,1H),7.46(d,J=8.7Hz,1H),7.08(d,J=2.5Hz,1H),6.89-6.84(m,1H),6.81(dd,J=8.8,2.5Hz,1H),0.98(s,9H),0.19(s,6H)ppm。 To a solution of benzofuran-5-ol (5.2 g, 0.039 mol) in DMF (50 mL), EtOAc (EtOAc, EtOAc. ). The mixture was stirred at room temperature for 20 hours. Saturated sodium hydrogen carbonate solution (150 mL) was then added to the mixture and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with EtOAcq. The residue was purified by silica gel chromatography eluting elut elut elut 1 H-NMR (600MHz, DMSO- d 6 ) δ 7.94 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.89 - 6.84 (m, 1 H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 0.98 (s, 9H), 0.19 (s, 6H) ppm.
步驟B：(±)-exo-5-((叔丁基二甲基矽烷基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step B: (±)-exo-5-((tert-butyldimethylmethylalkyl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester
向步驟A的產品(9.25g，0.037mol)和三氟甲磺酸銅(I)(2：1混合於甲苯中，1.9g，3.7mmol)的二氯甲烷(200mL)中通過注射泵經過10小時加入重氮乙酸乙酯(38.7mL，0.37mol)的二氯甲烷(50mL)溶液。然後該混合物在室溫下攪拌2小時。過濾反應液，濾液減壓濃縮。殘留物通過矽膠柱層析(石油醚洗脫)得到目標化合物。該產品不需進一步純化直接用於下一步反應。 To the product of Step A (9.25 g, 0.037 mol) and copper (I) triflate (2:1 in toluene, 1.9 g, 3.7 mmol) in dichloromethane (200 mL) A solution of ethyl diazoacetate (38.7 mL, 0.37 mol) in dichloromethane (50 mL) was then evaporated. The mixture was then stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography eluting with petroleum ether. This product was used in the next step without further purification.
步驟C：(±)-exo-5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step C: (±)-exo-5-hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester
在0℃下，向步驟B的產品(10g，0.030mol)的THF(25mL)溶液中滴加四丁基氟化銨的THF(15mL，1M， 0.015mol)。然後該混合物在室溫下攪拌1小時。反應液用水(30mL)稀釋並用乙酸乙酯(2×50mL)萃取。將合併的有機相用飽和氯化鈉溶液(2×50mL)洗滌，無水硫酸鈉乾燥，減壓濃縮。殘留物通過矽膠柱層析法純化得到無色油狀目標化合物(3.8g，兩步產率46%)。1H-NMR(600MHz,CDCl3)δ 7.01(s,1H),6.89(d,J=2.6Hz,1H),6.68(d,J=8.6Hz,1H),6.63(dd,J=8.6,2.6Hz,1H),5.02(dd,J=5.5,1.1Hz,1H),4.15(q,J=7.1Hz,2H),3.19(dd,J=5.4,3.1Hz,1H),1.26(dd,J=3.1,1.1Hz,1H),1.26-1.23(m,3H)ppm。 To a solution of the product of Step B (10 g, 0.030 mol) in THF (25 mL), THF (15 mL, 1 M, 0.015 mol) was added dropwise. The mixture was then stirred at room temperature for 1 hour. The reaction was diluted with water (30 mL) andEtOAc. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by silica gel chromatography eluting elut elut elut elut elut 1 H-NMR (600MHz, CDCl 3) δ 7.01 (s, 1H), 6.89 (d, J = 2.6Hz, 1H), 6.68 (d, J = 8.6Hz, 1H), 6.63 (dd, J = 8.6, 2.6 Hz, 1H), 5.02 (dd, J = 5.5, 1.1 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.19 (dd, J = 5.4, 3.1 Hz, 1H), 1.26 (dd, J = 3.1, 1.1 Hz, 1H), 1.26-1.23 (m, 3H) ppm.
步驟D：(±)-exo-5-((7-氧代-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step D: (±)-exo-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro -1H-cyclopropane [b]benzofuran-1-carboxylic acid ethyl ester
將步驟C的產品(3.8g，0.017mol)，5-氟-3,4-二氫-1,8-萘啶-2(1H)-酮(2.85g，0.017mol)和碳酸銫(11.2g，0.034mol)的DMF(50mL)混合物在120℃下攪拌2小時。該反應液用水(20mL)稀釋並用乙酸乙酯(2×30mL)萃取。將合併的有機相用飽和食鹽水(50mL)洗滌，無水硫酸鈉乾燥，減壓濃縮。殘留物通過矽膠柱層析法純化(EtOAc：PE=1：5~1：1洗脫)得到白色固體狀目標化合物(2.8g，44%)。1H-NMR(400MHz,CDCl3)δ 9.99(s,1H),8.06(d,J=5.8Hz,1H),7.10(s,1H),6.90-6.82(m,2H),6.23(d,J=5.8Hz,1H),5.10(d,J=5.4Hz,1H),4.22-4.07(m,2H),3.24(s,1H),3.03(t,J=7.8Hz,2H),2.67(t, J=7.9Hz,2H),1.36-1.30(m,1H),1.29-1.17(m,3H)ppm。MS：M/e 367(M+1)+。 The product of Step C (3.8 g, 0.017 mol), 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2.85 g, 0.017 mol) and cesium carbonate (11.2 g) A mixture of 0.034 mol) of DMF (50 mL) was stirred at 120 ° C for 2 hours. The reaction was diluted with water (20 mL) andEtOAc. The combined organic layers were washed with EtOAcq. The residue was purified by EtOAc EtOAc EtOAc EtOAc. 1 H-NMR (400MHz, CDCl 3 ) δ 9.99 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.10 (s, 1H), 6.90-6.82 (m, 2H), 6.23 (d, J = 5.8 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.22-4.07 (m, 2H), 3.24 (s, 1H), 3.03 (t, J = 7.8 Hz, 2H), 2.67 ( t, J = 7.9 Hz, 2H), 1.36-1.30 (m, 1H), 1.29-1.17 (m, 3H) ppm. MS: M/e 367 (M+1) + .
步驟E：(±)-exo-5-((7-氧代-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸(中間體II) Step E: (±)-exo-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro -1H-cyclopropane [b]benzofuran-1-carboxylic acid ( Intermediate II )
室溫攪拌下，將氫氧化鈉的水溶液加入到步驟D的產品(2.8g，7.7mmol)的THF(54mL)和甲醇(54mL)溶液中。該混合物在60℃下攪拌2小時。減壓除去溶劑並將殘留物溶于水(20mL)中。該溶液用HCl(1mol/L)中和至pH=7時溶液中析出白色沉澱。通過過濾得到白色固體並在空氣中乾燥得到目標化合物(2.4g，92.7%)。1H-NMR(600MHz,DMSO-d 6)δ 12.74(s,1H),10.46(s,1H),7.96(d,J=5.4Hz,1H),7.33(d,J=2.4Hz,1H),7.00(d,J=8.6Hz,1H),6.97(d,J=2.4Hz,1H),6.26(d,J=5.4Hz,1H),5.24-5.21(m,1H),3.32-3.27(m,1H),2.94(t,J=7.8Hz,2H),2.55(t,J=7.8Hz,2H),1.23-1.21(m,1H)ppm。MS：M/e 339(M+1)+。 An aqueous solution of sodium hydroxide was added to a solution of the product from step D (2.8 g, 7.7 mmol) in THF (54 mL) and methanol (54 mL). The mixture was stirred at 60 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was crystalljjjjjjjjj When the solution was neutralized with HCl (1 mol/L) to pH = 7, a white precipitate precipitated from the solution. The title compound (2.4 g, 92.7%) was obtained. 1 H-NMR (600MHz, DMSO- d 6) δ 12.74 (s, 1H), 10.46 (s, 1H), 7.96 (d, J = 5.4Hz, 1H), 7.33 (d, J = 2.4Hz, 1H) , 7.00 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 5.4 Hz, 1H), 5.24 - 5.21 (m, 1H), 3.32-3.27 ( m, 1H), 2.94 (t, J = 7.8 Hz, 2H), 2.55 (t, J = 7.8 Hz, 2H), 1.23-1.21 (m, 1 H) ppm. MS: M/e 339 (M+1) + .
步驟F：(±)-exo-N-(2-氨基苯基)-5-((7-oxo-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-甲醯胺 Step F: (±)-exo-N-(2-aminophenyl)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy -1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxamide
將步驟E的產品(30mg，0.088mmol)，1,2-二氨基苯(9.6mg，0.088mmol)，DIPEA(17.2mg，0.130mmol)和HATU(37mg，0.101mmol)的DMF(1mL)混合物在室溫下攪拌過夜。該反應液用水(5mL)稀釋並用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥，減壓濃縮。殘留物不經進一步純化直接用於下一步驟。 The product of Step E (30 mg, 0.088 mmol), 1,2-diaminobenzene (9.6 mg, 0.088 mmol), DIPEA (17.2 mg, 0.130 mmol) and HATU (37 mg, 0.101 mmol) in DMF (1 mL) Stir at room temperature overnight. The reaction was diluted with water (5 mL) andEtOAc. The combined organic layer was washed with brine brine The residue was used in the next step without further purification.
步驟G：(±)-exo-5-((1-(1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.1) Step G: (±)-exo-5-((1-(1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-5- Ethyl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.1 )
將步驟F的產品(37mg，0.088mmol)的醋酸(1mL)的混合物在80℃下攪拌3小時。除去溶劑並將NaOH溶液(2mL，2mol/L)加入到殘留物中。該混合物用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥，減壓濃縮。殘留物通過製備高效液相色譜法純化得到白色固體狀目標化合物(10mg，41%)。1H-NMR(600MHz,CD3OD)δ 7.97(d,J=5.9Hz,1H),7.51(dd,J=6.0,3.2Hz,2H), 7.31(d,J=2.4Hz,1H),7.23(dd,J=6.0,3.2Hz,2H),7.03(d,J=8.7Hz,1H),7.00(dd,J=8.7,2.4Hz,1H),6.36(d,J=5.9Hz,1H),5.35(dd,J=5.5,1.3Hz,1H),3.52(dd,J=5.4,3.4Hz,1H),3.09(t,J=7.8Hz,2H),2.69(t,J=7.5Hz,2H),1.91(dd,J=3.3,1.3Hz,1H)ppm。MS：M/e 411(M+1)+。 A mixture of the product of Step F (37 mg, 0.088 mmol) inEtOAc (1 mL). The solvent was removed and a NaOH solution (2 mL, 2 mol/L) was added to the residue. The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (600MHz, CD 3 OD) δ 7.97 (d, J = 5.9 Hz, 1H), 7.51 (dd, J = 6.0, 3.2 Hz, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 6.0, 3.2 Hz, 2H), 7.03 (d, J = 8.7 Hz, 1H), 7.00 (dd, J = 8.7, 2.4 Hz, 1H), 6.36 (d, J = 5.9 Hz, 1H) ), 5.35 (dd, J = 5.5, 1.3 Hz, 1H), 3.52 (dd, J = 5.4, 3.4 Hz, 1H), 3.09 (t, J = 7.8 Hz, 2H), 2.69 (t, J = 7.5 Hz) , 2H), 1.91 (dd, J = 3.3, 1.3 Hz, 1H) ppm. MS: M/e 411 (M+1) + .
(1S,1aS,6bR)-5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯的立體選擇性合成(中間體III) Stereoselective Synthesis of (1S,1aS,6bR)-5-Hydroxy-1a,6b-Dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic Acid Ethyl Ester ( Intermediate III )
步驟A：(1S,1aS,6bR)-5-((叔丁基二甲基矽烷基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (1S,1aS,6bR)-5-((tert-Butyldimethylmethylalkyl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid Ethyl ester
室溫下，將三氟甲磺酸銅(I)(2：1混合於甲苯中，250mg，2.4%)和(S,S)-(+)-2,2-異丙叉雙(4-叔丁基)-2-噁唑啉(205mg，3.4%)的二氯甲烷(15mL)溶液在氮氣保護下攪拌1小時。加入(苯並呋喃-5-基氧基)(叔丁基)二甲基矽烷(5.0g，20.2mmol)的二氯甲烷(85mL)溶液，隨後用注射泵在十小時內緩慢加入重氮乙酸乙酯(40mL，380mmol)。濃縮該混合物，用柱層析法純化得到粗產品(7.3g)，粗產品不需任何進一步純化直接用於下一步反應。 Copper (I) triflate (2:1 mixed in toluene, 250 mg, 2.4%) and (S,S)-(+)-2,2-isopropylidene bis(4- at room temperature A solution of tert-butyl)-2-oxazoline (205 mg, 3.4%) in dichloromethane (15 mL). A solution of (benzofuran-5-yloxy)(tert-butyl)dimethyl decane (5.0 g, 20.2 mmol) in dichloromethane (85 mL) was added, followed by slow addition of diazoacetic acid over ten hours using a syringe pump Ethyl ester (40 mL, 380 mmol). The mixture was concentrated and purified by EtOAc EtOAc EtOAc:
步驟B：(1S,1aS,6bR)-5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(中間體III) Step B: (1S,1aS,6bR)-5-Hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester ( Intermediate III )
在0℃下，將四正丁基氟化銨(TBAF，1M THF，4mmol)滴加到步驟A的產品(7.3g，粗品)的THF(100mL)溶液中。該反應在室溫下攪拌30分鐘。濃縮該混合物，用柱層析法純化得到固體狀目標化合物(2.52g，兩步收率為57%，72% ee)。 Tetra-n-butylammonium fluoride (TBAF, 1 M THF, 4 mmol) was added dropwise to a solution of the product from Step A (7.3 g, crude) in THF (100 mL). The reaction was stirred at room temperature for 30 minutes. The mixture was concentrated and purified by column chromatography to afford titled compound (2.52 g,yield: 57%, ee).
化合物2.2：(±)-exo-5-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.2: (±)-exo-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
將中間體II(1g，2.96mmol)、4-(三氟甲基)-1,2-二氨基苯(0.52g，2.96mmol)、DIPEA(1.15g，8.88mmol)和HATU(1.69g，4.44mmol)的DMF(5mL)混合物在室溫下攪拌過夜。該反應液用水(10mL)稀釋並用乙酸乙酯(2×30mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗，無水硫酸鈉乾燥，並減壓濃縮。 Intermediate II (1 g, 2.96 mmol), 4-(trifluoromethyl)-1,2-diaminobenzene (0.52 g, 2.96 mmol), DIPEA (1.15 g, 8.88 mmol) and HATU (1.69 g, 4.44) A mixture of mmol of DMF (5 mL) was stirred at room temperature overnight. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq.
將所得殘留物溶於醋酸(10mL)。該混合物在80℃攪拌3小時。除去溶劑，向殘留物中加入NaOH溶液(20mL，2mol/L)。該混合物用乙酸乙酯(2×30mL)萃取。將合併的有機 相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。殘留物通過製備高效液相色譜法純化得到白色固體狀目標化合物(330mg，23.6%)。1H-NMR(600MHz,DMSO-d 6)δ 12.84(s,1H),10.47(s,1H),7.98(d,J=5.8Hz,1H),7.86(d,J=1.2Hz,1H),7.69(m,1H),7.48(t,J=6.2Hz,1H),7.38(d,J=2.6Hz,1H),7.08(d,J=8.7Hz,1H),7.02(dd,J=8.7,2.6Hz,1H),6.29(d,J=5.8Hz,1H),5.43(dd,J=5.4,1.2Hz,1H),3.55(dd,J=5.3,3.3Hz,1H),2.95(t,J=7.7Hz,2H),2.55(t,J=7.7Hz,2H),1.97(d,J=1.3Hz,1H)ppm。MS：M/e 479(M+1)+。 The residue obtained was dissolved in acetic acid (10 mL). The mixture was stirred at 80 ° C for 3 hours. The solvent was removed, and a NaOH solution (20 mL, 2 mol/L) was added to the residue. The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (600MHz, DMSO- d 6) δ 12.84 (s, 1H), 10.47 (s, 1H), 7.98 (d, J = 5.8Hz, 1H), 7.86 (d, J = 1.2Hz, 1H) , 7.69 (m, 1H), 7.48 (t, J = 6.2 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 7.02 (dd, J = 8.7, 2.6 Hz, 1H), 6.29 (d, J = 5.8 Hz, 1H), 5.43 (dd, J = 5.4, 1.2 Hz, 1H), 3.55 (dd, J = 5.3, 3.3 Hz, 1H), 2.95 ( t, J = 7.7 Hz, 2H), 2.55 (t, J = 7.7 Hz, 2H), 1.97 (d, J = 1.3 Hz, 1 H) ppm. MS: M/e 479 (M+1) + .
化合物2.2通過掌性製備高效液相色譜被分離成兩個對映立體異構體(化合物2.2a，先出的峰和化合物2.2b，後出的峰)。下列是掌性分離條件：
化合物2.2b：5-(((1R,1aS,6bR)-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.2b : 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H -cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：(1S,1aS,6bR)-5-((7-氧代-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (1S,1aS,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b- Ethyl dihydro-1H-cyclopropane [b]benzofuran-1-carboxylate
將中間體III(400mg，1.8mmol)，5-氟-3,4-二氫-1,8-萘啶-2(1H)-酮(250mg，1.5mmol)和碳酸銫(801mg，2.3mol)的DMF(20mL)混合物在120℃下攪拌2小時。該反應液用水(10mL)稀釋並用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。殘留物通過矽膠柱層析法(EtOAc：PE=3：1洗脫)純化得到白色 固體狀目標化合物(360mg，54.6%)。 Intermediate III (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) The mixture of DMF (20 mL) was stirred at 120 ° C for 2 h. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:
步驟B：(1S,1aS,6bR)-5-((7-氧代-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step B: (1S, 1aS, 6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b- Dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
在室溫攪拌下，向步驟A的產品(360mg，0.98mmol)的THF(3mL)和甲醇(3mL)溶液中加入氫氧化鈉溶液(1mL，2M，2mmol)。該混合物在60℃攪拌2小時。減壓除去溶劑並將殘留物溶于水(5mL)。該溶液用HCl(2mol/L)中和至pH=7，溶液中析出白色沉澱。通過過濾收集白色固體並在空氣中乾燥得到目標化合物(230mg，69.3%)。 To a solution of the product from step A (360 mg, 0.98 mmol) elute The mixture was stirred at 60 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was crystalljjjjd The solution was neutralized with HCl (2 mol/L) to pH = 7, and a white precipitate precipitated from the solution. The title compound (230 mg, 69.3%) was obtained.
步驟C：5-(((1R,1aS,6bR)-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Step C: 5-(((1R,1aS,6bR)-1-(6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H- Cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
將步驟B的產品(50mg，0.15mmol)，4-(三氟甲基)-1,2-二氨基苯(26mg，0.15mmol)，DIPEA(0.1mL)和HATU(84mg，0.22mmol)的DMF(1mL)混合物在室溫下攪拌過夜。該反應液用水(10mL)稀釋並用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉 乾燥，過濾並減壓濃縮。 The product of Step B (50 mg, 0.15 mmol), 4-(trifluoromethyl)-1,2-diaminobenzene (26 mg, 0.15 mmol), DIPEA (0.1 mL) and HATU (84 mg, 0.22 mmol) DMF (1 mL) The mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic phases were washed with saturated brine (10 mL) Dry, filter and concentrate under reduced pressure.
將所得殘留物溶於醋酸(1mL)。該混合物在80℃攪拌3小時。除去溶劑，向殘留物中加入NaOH溶液(2mL，2mol/L)。該混合物用乙酸乙酯(2×5mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。殘留物通過製備高效液相色譜法純化得到目標化合物(10mg，14.1%產率；69.6% ee)，為白色固體。 The resulting residue was dissolved in acetic acid (1 mL). The mixture was stirred at 80 ° C for 3 hours. The solvent was removed, and a NaOH solution (2 mL, 2 mol/L) was added to the residue. The mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc EtOAc (EtOAc)
化合物2.3：(±)-exo-5-((1-(5,6-二氯-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.3: (±)-exo-5-((1-(5,6-Dichloro-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b Benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
室溫下，將中間體II(600mg，1.8mmol)，4,5-二氯-1,2-二氨基苯(312mg，1.8mmol)，DIPEA(0.69g，5.4mmol)和HATU(1.01g，2.7mmol)的DMF(10mL)混合物在氮氣保護下攪拌過夜。該反應液用水(10mL)稀釋並用乙酸乙酯(2×30mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。 Intermediate II (600 mg, 1.8 mmol), 4,5-dichloro-1,2-diaminobenzene (312 mg, 1.8 mmol), DIPEA (0.69 g, 5.4 mmol) and HATU (1.01 g, A mixture of 2.7 mmol) of DMF (10 mL) was stirred overnight under nitrogen. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq.
將所得殘留物溶於醋酸(10mL)。該混合物在80℃攪拌3小時。除去溶劑，向殘留物中加入NaOH溶液(10mL，2mol/L)。該混合物用乙酸乙酯(2×30mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥，並減壓濃 縮。殘留物通過製備高效液相色譜法純化得到目標化合物(320mg，37.6%)，為白色固體。1H-NMR(600MHz,DMSO-d 6)δ 10.44(s,1H),7.93(d,J=5.8Hz,1H),7.74(s,2H),7.32(d,J=2.6Hz,1H),7.03(d,J=8.7Hz,1H),6.97(dd,J=8.6,2.5Hz,1H),6.24(d,J=5.8Hz,1H),5.39-5.36(m,1H),3.52-3.46(m,1H),2.90(t,J=7.7Hz,2H),2.50(t,J=7.7Hz,2H),1.91-1.87(m,1H)ppm。MS：M/e 479(M+1)+。 The residue obtained was dissolved in acetic acid (10 mL). The mixture was stirred at 80 ° C for 3 hours. The solvent was removed, and a NaOH solution (10 mL, 2 mol/L) was added to the residue. The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.44 (s, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7.74 (s, 2H), 7.32 (d, J = 2.6 Hz, 1H) , 7.03 (d, J = 8.7 Hz, 1H), 6.97 (dd, J = 8.6, 2.5 Hz, 1H), 6.24 (d, J = 5.8 Hz, 1H), 5.39-5.36 (m, 1H), 3.52- 3.46 (m, 1H), 2.90 (t, J = 7.7 Hz, 2H), 2.50 (t, J = 7.7 Hz, 2H), 1.91-1.87 (m, 1 H) ppm. MS: M/e 479 (M+1) + .
化合物2.3通過掌性製備高效液相色譜被分離成兩個對映立體異構體(化合物2.3a，先出的峰和化合物2.3b，後出的峰)。下列是掌性分離條件：
化合物2.4：(±)-exo-5-((1-(5-氟-6-甲基-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.4 : (±)-exo-5-((1-(5-fluoro-6-methyl-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
室溫下，向中間體II(338mg，1.0mmol)、4-氟-5-甲基-1,2-二氨基苯(169mg，1.2mmol)和三乙胺(300mg，3.0mmol)的DMF(7mL)溶液中加入HATU(420mg，1.1mmol)。該混合物在室溫下攪拌16小時。反應液用水(30mL)稀釋，白色固體析出。過濾該混合物並減壓充分乾燥得到的固體。將上述固體溶於醋酸(7mL)，該混合物在85℃攪拌8小時。除去溶劑。殘留物用DCM(20mL)稀釋並用NaOH溶液(2mol/L，5mL)洗。另用DCM(50mL)萃取水相。將合併的有機相用飽和食鹽水(2×20mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。殘留物通過矽膠柱層析法(DCM：MeOH=50：1~20：1洗脫)純化得到目標化合物(230mg，52%)，為棕色固體。1H-NMR(600MHz,CD3OD)δ 7.94(d,J=6.0Hz,1H),7.53(d,J=6.2Hz,1H),7.38(d,J=9.0Hz,1H),7.34(d,J=2.4Hz,1H),7.08(d,J=8.7Hz,1H),7.05(dd,J=8.8,2.4Hz,1H),6.35(d,J=6.0Hz,1H),5.55(dd,J=5.5,1.3Hz,1H),3.78(dd,J=5.5,3.4Hz,1H),3.06(t,J=7.8Hz,2H),2.65(t,J=7.8Hz,2H), 2.40(d,J=2.0Hz,3H),2.09(dd,J=3.4,1.3Hz,1H)ppm。MS：M/e 443(M+1)+。 To intermediate D (338 mg, 1.0 mmol), 4-fluoro-5-methyl-1,2-diaminobenzene (169 mg, 1.2 mmol) and triethylamine (300 mg, 3.0 mmol) in DMF HATU (420 mg, 1.1 mmol) was added to the solution of 7 mL). The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (30 mL) and evaporated. The mixture was filtered and the resulting solid was sufficiently dried under reduced pressure. The above solid was dissolved in acetic acid (7 mL), and the mixture was stirred at 85 ° C for 8 hr. Remove the solvent. The residue was diluted with DCM (20 mL) and washed with EtOAc. The aqueous phase was extracted with additional DCM (50 mL). The combined organic phases were washed with EtOAcq. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1 H-NMR (600MHz, CD 3 OD) δ 7.94 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 6.2 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.34 ( d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 7.05 (dd, J = 8.8, 2.4 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 5.55 ( Dd, J = 5.5, 1.3 Hz, 1H), 3.78 (dd, J = 5.5, 3.4 Hz, 1H), 3.06 (t, J = 7.8 Hz, 2H), 2.65 (t, J = 7.8 Hz, 2H), 2.40 (d, J = 2.0 Hz, 3H), 2.09 (dd, J = 3.4, 1.3 Hz, 1 H) ppm. MS: M/e 443 (M+1) + .
化合物2.4通過掌性製備高效液相色譜被分離成兩個對映立體異構體(化合物2.4a，先出的峰和化合物2.4b，後出的峰)。下列是掌性分離條件：
化合物2.5：(±)-exo-5-((1-(5-氯-6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.5: (±)-exo-5-((1-(5-chloro-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
在0℃下，向中間體II(300mg，0.887mmol)和三乙胺(500mg，3.0mmol)的DMF(5mL)溶液中加入HATU(370mg，0.97mmol)。該混合物攪拌15分鐘後，將4-氯-5-(三氟甲基)-1,2-二氨基苯(228mg，1.09mmol)的DMF(1mL)溶液加入到反應液中。該混合物在室溫下攪拌20小時。反應液用水(50mL)稀釋，白色固體析出。過濾該混合物並減壓充分乾燥得到的固體。 To a solution of the intermediate II (300 mg, 0.887 mmol) and triethylamine (500 mg, 3.0 mmol) in DMF (5 mL) After the mixture was stirred for 15 minutes, a solution of 4-chloro-5-(trifluoromethyl)-1,2-diaminobenzene (228 mg, 1.09 mmol) in DMF (1 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with water (50 mL) and evaporated. The mixture was filtered and the resulting solid was sufficiently dried under reduced pressure.
將上述固體溶於醋酸(5mL)中，該混合物在85℃攪拌5小時。除去溶劑。殘留物通過矽膠柱層析法(DCM：MeOH=50：1~20：1洗脫)純化得到目標化合物(205mg，45%)，為淺黃色固體。1H-NMR(400MHz,DMSO-d 6)δ 10.48(s,1H),7.96(d,J=4.1Hz,2H),7.82(s,1H),7.37(d,J=2.6Hz,1H),7.07(d,J=8.7Hz,1H),7.01(dd,J=8.7,2.6Hz,1H),6.26(d,J=5.8Hz,1H),5.42(d,J=5.3Hz,1H),3.57-3.51(m,1H),2.93(t,J=7.7Hz,2H),2.58-2.50(m,2H),1.98(d,J=2.1Hz,1H)ppm。MS：M/e 513(M+1)+。 The above solid was dissolved in acetic acid (5 mL) and the mixture was stirred at <RTIgt; Remove the solvent. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1 H-NMR (400MHz, DMSO- d 6) δ 10.48 (s, 1H), 7.96 (d, J = 4.1Hz, 2H), 7.82 (s, 1H), 7.37 (d, J = 2.6Hz, 1H) , 7.07 (d, J = 8.7 Hz, 1H), 7.01 (dd, J = 8.7, 2.6 Hz, 1H), 6.26 (d, J = 5.8 Hz, 1H), 5.42 (d, J = 5.3 Hz, 1H) , 3.57-3.51 (m, 1H), 2.93 (t, J = 7.7 Hz, 2H), 2.58-2.50 (m, 2H), 1.98 (d, J = 2.1 Hz, 1H) ppm. MS: M/e 513 (M+1) + .
化合物2.5通過掌性製備高效液相色譜被分離成兩個對映立體異構體(化合物2.5a，先出的峰和化合物2.5b，後出的峰)。下列是掌性分離條件：
化合物2.6 Compound 2.6
1H-NMR(600MHz,DMSO-d 6)δ 12.97(s,1H),10.45(s,1H),8.02(d,J=24.7Hz,1H),7.96(d,J=5.8Hz,1H), 7.65(dd,J=27.5,8.3Hz,1H),7.57-7.51(m,1H),7.36(d,J=2.6Hz,1H),7.07(d,J=8.7Hz,1H),7.01(dd,J=8.7,2.5Hz,1H),6.27(d,J=5.8Hz,1H),5.45-5.40(m,1H),3.57-3.53(m,1H),2.93(t,J=7.7Hz,2H),2.54(t,J=7.7Hz,2H),1.97-1.93(m,1H)ppm。MS：M/e 436(M+1)+。 1 H-NMR (600MHz, DMSO- d 6) δ 12.97 (s, 1H), 10.45 (s, 1H), 8.02 (d, J = 24.7Hz, 1H), 7.96 (d, J = 5.8Hz, 1H) , 7.65 (dd, J = 27.5, 8.3 Hz, 1H), 7.57-7.51 (m, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.01 ( Dd, J = 8.7, 2.5 Hz, 1H), 6.27 (d, J = 5.8 Hz, 1H), 5.45-5.40 (m, 1H), 3.57-3.53 (m, 1H), 2.93 (t, J = 7.7 Hz) , 2H), 2.54 (t, J = 7.7 Hz, 2H), 1.97-1.93 (m, 1 H) ppm. MS: M/e 436 (M+1) + .
化合物2.7 Compound 2.7
1H-NMR(600MHz,CD3OD)δ 7.94(d,J=5.4Hz,1H),7.64(d,J=6.6Hz,1H),7.42(s,1H),7.34(s,1H),7.26(s,1H),7.06(d,J=6.6Hz,2H),6.35(d,J=4.8Hz,1H),5.53(d,J=4.8Hz,1H),3.76(s,1H),3.09-3.02(m,2H),2.68-2.63(m,2H),2.08(s,1H)ppm。MS：M/e 429(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 7.94 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 6.6 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.26(s,1H),7.06(d, J =6.6Hz,2H), 6.35(d, J =4.8Hz,1H),5.53(d, J =4.8Hz,1H), 3.76(s,1H), 3.09-3.02 (m, 2H), 2.68-2.63 (m, 2H), 2.08 (s, 1 H) ppm. MS: M/e 429 (M+1) + .
化合物2.8 Compound 2.8
1H-NMR(600MHz,CD3OD)δ 7.99(d,J=6.0Hz,1H),7.61(d,J=8.4Hz,1H),7.53(s,1H),7.45-7.38(m,2H),7.15-7.08(m,2H),6.39(d,J=6.0Hz,1H),5.63(d,J=5.4Hz,1H),3.87-3.85(m,1H),3.10(t,J=7.8Hz,2H),2.70(t,J=7.8Hz, 2H),2.55(s,3H),2.19-2.15(m,1H)ppm。MS：M/e 425(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 7.99 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.45-7.38 (m, 2H) ), 7.15-7.08 (m, 2H), 6.39 (d , J = 6.0 Hz, 1H), 5.63 (d, J = 5.4 Hz, 1H), 3.87-3.85 (m, 1H), 3.10 (t, J = 7.8 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.55 (s, 3H), 2.19-2.15 (m, 1 H) ppm. MS: M/e 425 (M+1) + .
化合物2.9 Compound 2.9
1H-NMR(600MHz,CD3OD)δ 9.50(s,1H),8.63(s,1H),8.20(s,1H),7.99(s,1H),7.37(d,J=1.8Hz,1H),7.24(d,J=6.6Hz,1H),7.06(dd,J=8.5,2.3Hz,1H),7.01(d,J=8.7Hz,1H),6.39(d,J=6.0Hz,1H),5.21-5.05(m,1H),3.91(dd,J=18.4,8.9Hz,1H),3.61-3.53(m,1H),3.09(t,J=7.8Hz,2H),2.70(t,J=7.8Hz,2H)ppm。MS：M/e 412(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 9.50 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H) ), 7.24 (d, J = 6.6 Hz, 1H), 7.06 (dd, J = 8.5, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.39 (d, J = 6.0 Hz, 1H) ), 5.21-5.05 (m, 1H), 3.91 (dd, J = 18.4, 8.9 Hz, 1H), 3.61-3.53 (m, 1H), 3.09 (t, J = 7.8 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H) ppm. MS: M/e 412 (M+1) + .
化合物2.10 Compound 2.10
1H-NMR(600MHz,CD3OD)δ 8.03(d,J=6.3Hz,1H),7.78(s,1H),7.56(d,J=1.0Hz,1H),7.38(d,J=2.3Hz,1H),7.10-6.99(m,2H),6.51(d,J=6.4Hz,1H),5.47(dd,J=5.4,1.3Hz,1H),3.69-3.65(m,1H),3.15(t,J=7.8Hz,1H),2.79-2.70(m,2H),2.01-1.93(m,1H)ppm。MS：M/e 513(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 8.03 (d, J = 6.3 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 1.0 Hz, 1H), 7.38 (d, J = 2.3) Hz, 1H), 7.10-6.99 (m, 2H), 6.51 (d, J = 6.4 Hz, 1H), 5.47 (dd, J = 5.4, 1.3 Hz, 1H), 3.69-3.65 (m, 1H), 3.15 (t, J = 7.8 Hz, 1H), 2.79-2.70 (m, 2H), 2.01-1.93 (m, 1 H) ppm. MS: M/e 513 (M+1) + .
化合物2.11 Compound 2.11
1H-NMR(600MHz,CD3OD)δ 8.00(d,J=6.1Hz,1H),7.58(t,J=8.4Hz,2H),7.37(d,J=2.3Hz,1H),7.13-7.04(m,2H),6.43(d,J=6.1Hz,1H),5.51(dd,J=5.5,1.2Hz,1H),3.72(dd,J=5.4,3.4Hz,1H),3.12(t,J=7.8Hz,2H),2.75-2.69(m,2H),2.06(dd,J=3.4,1.2Hz,1H)ppm。MS：M/e 447(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 8.00 (d, J = 6.1 Hz, 1H), 7.58 (t, J = 8.4 Hz, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.13 7.04 (m, 2H), 6.43 (d, J = 6.1 Hz, 1H), 5.51 (dd, J = 5.5, 1.2 Hz, 1H), 3.72 (dd, J = 5.4, 3.4 Hz, 1H), 3.12 (t , J = 7.8 Hz, 2H), 2.75-2.69 (m, 2H), 2.06 (dd, J = 3.4, 1.2 Hz, 1H) ppm. MS: M/e 447 (M+1) + .
化合物2.12 Compound 2.12
1H-NMR(600MHz,CD3OD)δ 8.00(d,J=6.1Hz,1H),7.75-7.63(m,2H),7.49(dd,J=8.7,1.9Hz,1H),7.39(d,J=2.3Hz,1H),7.14-7.07(m,2H),6.42(d,J=6.0Hz,1H),5.57(dd,J=5.5,1.3Hz,1H),3.80(dd,J=5.4,3.4Hz,1H),3.11(t,J=7.8Hz,2H),2.73-2.67(m,2H),2.11(dd,J=3.4,1.3Hz,1H)ppm。MS：M/e 445(M+1)+。 1 H-NMR (600 MHz, CD 3 OD) δ 8.00 (d, J = 6.1 Hz, 1H), 7.75-7.63 (m, 2H), 7.49 (dd, J = 8.7, 1.9 Hz, 1H), 7.39 (d) , J = 2.3 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.42 (d, J = 6.0 Hz, 1H), 5.57 (dd, J = 5.5, 1.3 Hz, 1H), 3.80 (dd, J = 5.4, 3.4 Hz, 1H), 3.11 (t, J = 7.8 Hz, 2H), 2.73 - 2.67 (m, 2H), 2.11 (dd, J = 3.4, 1.3 Hz, 1 H) ppm. MS: M/e 445 (M+1) + .
化合物2.13 Compound 2.13
1H-NMR(600MHz,CD3OD)δ 7.99(d,J=6.0Hz,1H),7.83(s,1H),7.58(s,2H),7.38(d,J=2.4Hz,1H),7.14-7.04(m,2H),6.40(d,J=6.0Hz,1H),5.54(dd,J=5.5,1.3Hz,1H),3.76(dd,J=5.4,3.4Hz,1H),3.11(t,J=7.8Hz,2H),2.73-2.67(m,2H),2.08(dd,J=3.4,1.3Hz,1H)ppm。MS：M/e 489(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 7.99 (d, J = 6.0Hz, 1H), 7.83 (s, 1H), 7.58 (s, 2H), 7.38 (d, J = 2.4Hz, 1H), 7.14-7.04 (m, 2H), 6.40 (d, J = 6.0 Hz, 1H), 5.54 (dd, J = 5.5, 1.3 Hz, 1H), 3.76 (dd, J = 5.4, 3.4 Hz, 1H), 3.11 (t, J = 7.8 Hz, 2H), 2.73 - 2.67 (m, 2H), 2.08 (dd, J = 3.4, 1.3 Hz, 1 H) ppm. MS: M/e 489 (M+1) + .
化合物2.14 Compound 2.14
1H-NMR(600MHz,DMSO-d 6)δ 10.51(s,1H),7.99(d,J=5.8Hz,1H),7.64(d,J=8.7Hz,1H),7.58(s,1H),7.39(d,J=2.6Hz,1H),7.23(d,J=8.6Hz,1H),7.10(d,J=8.7Hz,1H),7.04(dd,J=8.7,2.6Hz,1H),6.30(d,J=5.8Hz,1H),5.48(d,J=5.3Hz,1H),3.61(s,1H),2.95(t,J=7.7Hz,2H),2.56(t,J=7.7Hz,2H),2.01(s,1H)ppm。MS：M/e 495(M+1)+。 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.51 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H) , 7.39 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.04 (dd, J = 8.7, 2.6 Hz, 1H) , 6.30 (d, J = 5.8 Hz, 1H), 5.48 (d, J = 5.3 Hz, 1H), 3.61 (s, 1H), 2.95 (t, J = 7.7 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.01 (s, 1 H) ppm. MS: M/e 495 (M+1) + .
化合物2.15 Compound 2.15
1H-NMR(600MHz,CD3OD)δ 8.00(d,J=6.0Hz,1H),7.88-7.85(m,1H),7.77-7.73(m,1H),7.66-7.60(m,2H),7.42(d,J=2.4Hz,1H),7.18-7.09(m,2H),6.43(d,J=6.0Hz,1H),5.64(dd,J=5.5,1.4Hz,1H),4.12(d,J=5.6Hz,3H),3.90(dd,J=5.5,3.5Hz,1H),3.12(t,J=7.8Hz,2H),2.71(t,J=7.8Hz,2H),2.46(dd,J=3.5,1.5Hz,1H)ppm。MS：M/e 425(M+1)+。 1 H-NMR (600MHz, CD 3 OD) δ 8.00 (d, J = 6.0 Hz, 1H), 7.88-7.85 (m, 1H), 7.77-7.73 (m, 1H), 7.66-7.60 (m, 2H) , 7.42 (d, J = 2.4 Hz, 1H), 7.18-7.09 (m, 2H), 6.43 (d, J = 6.0 Hz, 1H), 5.64 (dd, J = 5.5, 1.4 Hz, 1H), 4.12 ( d, J = 5.6 Hz, 3H), 3.90 (dd, J = 5.5, 3.5 Hz, 1H), 3.12 (t, J = 7.8 Hz, 2H), 2.71 (t, J = 7.8 Hz, 2H), 2.46 ( Dd, J = 3.5, 1.5 Hz, 1 H) ppm. MS: M/e 425 (M+1) + .
化合物2.16 Compound 2.16
1H-NMR(600MHz,DMSO-d 6)δ 10.49(s,1H),7.99(d,J=5.8Hz,1H),7.61(d,J=8.9Hz,1H),7.40(d,J=2.6Hz,1H),7.18(d,J=2.1Hz,1H),7.14(d,J=8.7Hz,1H),7.09-7.05(m,2H),6.30(d,J=5.8Hz,1H),5.67(d,J=5.5Hz,1H),3.85(s,3H),3.84-3.79(m,1H),2.95(t,J=7.7Hz,2H),2.56(t,J=7.7Hz,2H),2.21-2.08(m,1H)ppm。MS：M/e 441(M+1)+。 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.49 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.09-7.05 (m, 2H), 6.30 (d, J = 5.8 Hz, 1H) , 5.67 (d, J = 5.5 Hz, 1H), 3.85 (s, 3H), 3.84 - 3.79 (m, 1H), 2.95 (t, J = 7.7 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.21-2.08 (m, 1H) ppm. MS: M/e 441 (M+1) + .
化合物2.17 Compound 2.17
1H-NMR(600MHz,DMSO-d 6)δ 10.48(s,1H),7.98(d,J=5.8Hz,1H),7.71(d,J=6.7Hz,1H),7.56(d,J=9.7Hz,1H),7.36(d,J=2.5Hz,1H),7.06(d,J=8.7Hz,1H),7.01(dd,J=8.7,2.6Hz,1H),6.28(d,J=5.8Hz,1H),5.40(dd,J=5.3,1.0Hz,1H),3.54-3.50(m,1H),2.95(t,J=7.7Hz,2H),2.55(t,J=7.7Hz,2H),1.97-1.89(m,1H)ppm。MS：M/e 463(M+1)+。 1 H-NMR (600 MHz, DMSO- d 6 ) δ 10.48 (s, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 6.7 Hz, 1H), 7.56 (d, J = 9.7 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.01 (dd, J = 8.7, 2.6 Hz, 1H), 6.28 (d, J = 5.8 Hz, 1H), 5.40 (dd, J = 5.3, 1.0 Hz, 1H), 3.54-3.50 (m, 1H), 2.95 (t, J = 7.7 Hz, 2H), 2.55 (t, J = 7.7 Hz, 2H), 1.97-1.89 (m, 1H) ppm. MS: M/e 463 (M+1) + .
化合物2.18 Compound 2.18
1H-NMR(600MHz,CD3OD)δ 8.02(d,J=6.2Hz,1H),7.87(d,J=8.2Hz,1H),7.66(d,J=7.6Hz,1H),7.50(t,J=7.9Hz,1H),7.38(d,J=2.3Hz,1H),7.15-7.03(m,2H),6.46(d,J=6.2Hz,1H),5.53(dd,J=5.5,1.3Hz,1H),3.75-3.71(m,1H),3.14(t,J=7.8Hz,2H),2.73(t,J=7.8Hz,2H),2.08(dd,J=3.4,1.3Hz,1H)ppm。M/e 479(M+1)+。 1 H-NMR (600 MHz, CD 3 OD) δ 8.02 (d, J = 6.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.50 ( t, J = 7.9 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.15-7.03 (m, 2H), 6.46 (d, J = 6.2 Hz, 1H), 5.53 (dd, J = 5.5 , 1.3 Hz, 1H), 3.75-3.71 (m, 1H), 3.14 (t, J = 7.8 Hz, 2H), 2.73 (t, J = 7.8 Hz, 2H), 2.08 (dd, J = 3.4, 1.3 Hz) , 1H) ppm. M/e 479 (M+1) + .
化合物2.19 Compound 2.19
1H-NMR(400MHz,CD3OD)δ 7.96(d,J=6.2Hz,1H),7.41(d,J=8.2Hz,1H),7.38-7.35(m,1H),7.35-7.33(m,1H),7.14(dd,J=10.1,8.3Hz,1H),7.06(d,J=8.5Hz,1H),7.03(dd,J=8.7,2.3Hz,1H),6.38(d,J=6.1Hz,1H),5.50(dd,J=5.5,1.3Hz,1H),3.72(dd,J=5.5,3.4Hz,1H),3.07(t,J=7.7Hz,2H),2.67(t,J=7.7Hz,2H),2.01(dd,J=3.4,1.4Hz,1H)ppm。MS：M/e 429(M+1)+。 1 H-NMR (400MHz, CD 3 OD) δ 7.96 (d, J = 6.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.38-7.35 (m, 1H), 7.35-7.33 (m) , 1H), 7.14 (dd, J = 10.1, 8.3 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.03 (dd, J = 8.7, 2.3 Hz, 1H), 6.38 (d, J = 6.1 Hz, 1H), 5.50 (dd, J = 5.5, 1.3 Hz, 1H), 3.72 (dd, J = 5.5, 3.4 Hz, 1H), 3.07 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 2.01 (dd, J = 3.4, 1.4 Hz, 1 H) ppm. MS: M/e 429 (M+1) + .
化合物2.20 Compound 2.20
1H-NMR(400MHz,CD3OD)δ 7.94(d,J=5.8Hz,1H),7.49(s,1H),7.40(d,J=8.6Hz,1H),7.31(dd,J=8.6,1.7Hz,1H),7.28(d,J=2.2Hz,1H),7.00(d,J=8.6Hz,1H),6.96(dd,J=8.7,2.3Hz,1H),6.33(d,J=5.9Hz,1H),5.32-5.29(m,1H),3.51-3.43(m,1H),3.07(t,J=7.8Hz,2H),2.66(t,J=7.8Hz,2H),1.84-1.87(m,1H),1.37(s,9H)ppm。MS：M/e 467(M+1)+。 1 H-NMR (400 MHz, CD 3 OD) δ 7.94 (d, J = 5.8 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6 , 1.7 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.96 (dd, J = 8.7, 2.3 Hz, 1H), 6.33 (d, J = 5.9 Hz, 1H), 5.32 - 5.29 (m, 1H), 3.51-3.43 (m, 1H), 3.07 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 1.84 -1.87 (m, 1H), 1.37 (s, 9H) ppm. MS: M/e 467 (M+1) + .
化合物2.21 Compound 2.21.
1H-NMR(400MHz,DMSO-d 6)δ 12.18(s,1H),10.46(s,1H),7.96(d,J=5.6Hz,1H),7.35(d,J=2.4Hz,1H),7.27(s,2H),7.04(d,J=8.8Hz,1H),6.98(dd,J=2.4,8.4Hz,1H),6.27(d,J=5.6Hz,1H),5.33(dd,J=1.2,5.6Hz,1H),3.43(dd,J=3.2,5.2Hz,1H),2.95-2.88(m,6H),2.54(t,J=6.4Hz,2H),2.07-2.00(m,2H),1.83(dd,J=0.8,3.2Hz,1H)ppm。MS：M/e 451(M+1)+。 1 H-NMR (400MHz, DMSO- d 6) δ 12.18 (s, 1H), 10.46 (s, 1H), 7.96 (d, J = 5.6Hz, 1H), 7.35 (d, J = 2.4Hz, 1H) , 7.27(s, 2H), 7.04 (d, J = 8.8 Hz, 1H), 6.98 (dd, J = 2.4, 8.4 Hz, 1H), 6.27 (d, J = 5.6 Hz, 1H), 5.33 (dd, J = 1.2, 5.6 Hz, 1H), 3.43 (dd, J = 3.2, 5.2 Hz, 1H), 2.95-2.88 (m, 6H), 2.54 (t, J = 6.4 Hz, 2H), 2.07-2.00 (m , 2H), 1.83 (dd, J = 0.8, 3.2 Hz, 1H) ppm. MS: M/e 451 (M+1) + .
化合物2.22 Compound 2.22
1H-NMR(600MHz,DMSO-d 6)δ 12.66-12.59(m,1H),10.45(s,1H),8.10-7.95(m,2H),7.94-7.89(m,1H),7.75-7.70(m,1H),7.55-7.45(m,1H),7.36(d,J=2.4Hz,1H),7.25-7.19(m,1H),7.06(dd,J=1.8,9.0Hz,1H),7.00(d,J=8.4Hz,1H),6.27(dd,J=1.2,6.0Hz,1H),5.42-5.39(m,1H),3.53-3.51(m,1H),2.94(t,J=7.2Hz,2H),2.54(t,J=7.2Hz,2H),1.90(dd,J=1.2,3.0Hz,1H)。MS：M/e 454(M+1)+。 1 H-NMR (600MHz, DMSO- d 6 ) δ 12.66-12.59 (m, 1H), 10.45 (s, 1H), 8.10-7.95 (m, 2H), 7.94-7.89 (m, 1H), 7.75-7.70 (m, 1H), 7.55-7.45 (m, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.25-7.19 (m, 1H), 7.06 (dd, J = 1.8, 9.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.27 (dd, J = 1.2, 6.0 Hz, 1H), 5.42-5.39 (m, 1H), 3.53-3.51 (m, 1H), 2.94 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 1.90 (dd, J = 1.2, 3.0 Hz, 1H). MS: M/e 454 (M+1) + .
化合物2.23 Compound 2.23
1H-NMR(400MHz,CD3OD)δ 7.93(d,J=5.5Hz,1H),7.83(s,1H),7.68(d,J=8.5Hz,1H),7.50(d,J=8.4Hz,1H),7.30(d,J=2.4Hz,1H),7.04-6.95(m,2H),6.34(d,J=5.9Hz,1H),5.35(dd,J=5.4,1.3Hz,1H),3.91(s,3H),3.59-3.56(m,1H),3.06(t,J=7.8Hz,2H),2.68-2.61(m,2H),2.10(dd,J=3.3,1.3Hz,1H)ppm。MS：M/e 493(M+1)+。 1 H-NMR (400 MHz, CD 3 OD) δ 7.93 (d, J = 5.5 Hz, 1H), 7.83 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.4) Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.04-6.95 (m, 2H), 6.34 (d, J = 5.9 Hz, 1H), 5.35 (dd, J = 5.4, 1.3 Hz, 1H) ), 3.91 (s, 3H), 3.59-3.56 (m, 1H), 3.06 (t, J = 7.8 Hz, 2H), 2.68-2.61 (m, 2H), 2.10 (dd, J = 3.3, 1.3 Hz, 1H) ppm. MS: M/e 493 (M+1) + .
化合物2.24 Compound 2.24
1H-NMR(600MHz,DMSO-d 6)δ 10.46(s,1H),7.97(d,J=6.0Hz,1H),7.88(s,1H),7.73(d,J=9.0Hz,1H),7.54(d,J=8.4Hz,1H),7.38(d,J=2.4Hz,1H),7.07(d,J=8.4Hz,1H),7.01(dd,J=2.4,8.4Hz,1H),6.29(d,J=6.0Hz,1H),5.37(dd,J=1.2,5.4Hz,1H),3.90(s,3H),3.58-3.54(m,1H),2.94(t,J=7.2Hz,2H),2.54(t,J=7.2Hz,2H),2.26(dd,J=1.2,3.0Hz,1H)ppm。MS：M/e 493(M+1)+。 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.46 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H) , 7.54 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 2.4, 8.4 Hz, 1H) , 6.29 (d, J = 6.0 Hz, 1H), 5.37 (dd, J = 1.2, 5.4 Hz, 1H), 3.90 (s, 3H), 3.58-3.54 (m, 1H), 2.94 (t, J = 7.2) Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.26 (dd, J = 1.2, 3.0 Hz, 1H) ppm. MS: M/e 493 (M+1) + .
化合物2.25 Compound 2.25
1H-NMR(400MHz,DMSO-d 6)δ 12.87(br.s,1H),10.51(s,1H),7.96(d,J=6.0Hz,1H),7.84(s,1H),7.67(d,J=8.4Hz,1H),7.50-7.45(m,2H),7.11-7.04(m,2H),6.24(d,J=5.6Hz,1H),5.42(dd,J=1.2,5.2Hz,1H),3.62(dd,J=2.8,4.8Hz,1H),2.96(t,J=8.0Hz,2H),2.55(t,J=8.0Hz,2H),2.02(d,J=1.6,3.2Hz,1H)ppm。MS：M/e 479(M+1)+。 1 H-NMR (400 MHz, DMSO- d 6 ) δ 12.87 (br.s, 1H), 10.51 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.84 (s, 1H), 7.67 ( d, J = 8.4 Hz, 1H), 7.50-7.45 (m, 2H), 7.11 - 7.04 (m, 2H), 6.24 (d, J = 5.6 Hz, 1H), 5.42 (dd, J = 1.2, 5.2 Hz , 1H), 3.62 (dd, J = 2.8, 4.8 Hz, 1H), 2.96 (t, J = 8.0 Hz, 2H), 2.55 (t, J = 8.0 Hz, 2H), 2.02 (d, J = 1.6, 3.2 Hz, 1 H) ppm. MS: M/e 479 (M+1) + .
化合物2.26：(±)-exo-5-((1-(7-氯-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.26: (±)-exo-5-((1-(7-chloro-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzo Furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
室溫下，向中間體II(30mg，0.09mmol)和3-氯-2-硝基苯胺(15.3mg，0.09mmol)的吡啶(1mL)溶液中加入三氯氧磷(2滴)。該混合物在室溫下攪拌30分鐘。反應液用水(10mL)稀釋並用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽 和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。將殘留物溶於醋酸(2mL)並將鐵粉(15mg，0.27mmol)加入到反應液中。該混合物在70℃攪拌2小時。殘留物用甲醇(20mL)稀釋並通過矽藻土層過濾。將濾液減壓濃縮。殘留物通過製備高效液相色譜法純化得到目標化合物(6mg，15%)，為白色固體。1H-NMR(600MHz,CD3OD)δ 7.97(d,J=5.6Hz,1H),7.56(d,J=8.0Hz,1H),7.44(d,J=7.8Hz,1H),7.38(t,J=8.0Hz,1H),7.35(d,J=2.3Hz,1H),7.07(d,J=8.7Hz,1H),7.05(dd,J=8.7,2.3Hz,1H),6.40(d,J=6.1Hz,1H),5.55(dd,J=5.5,0.9Hz,1H),3.78(dd,J=5.4,3.4Hz,1H),3.08(t,J=7.8Hz,2H),2.68(t,J=7.8Hz,2H),2.05(d,J=2.8Hz,1H)ppm。MS：M/e 445(M+1)+。 Phosphorus oxychloride (2 drops) was added to a solution of intermediate II (30 mg, 0.09 mmol) and 3-chloro-2-nitroaniline (15.3 mg, 0.09 mmol) in pyridine (1 mL). The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq. The residue was dissolved in acetic acid (2 mL) and iron powder (15 mg, 0.27 mmol) was added to the mixture. The mixture was stirred at 70 ° C for 2 hours. The residue was diluted with MeOH (20 mL) and filtered over EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (600MHz, CD 3 OD) δ 7.97 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.38 ( t, J = 8.0 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.05 (dd, J = 8.7, 2.3 Hz, 1H), 6.40 ( d, J = 6.1 Hz, 1H), 5.55 (dd, J = 5.5, 0.9 Hz, 1H), 3.78 (dd, J = 5.4, 3.4 Hz, 1H), 3.08 (t, J = 7.8 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 2.05 (d, J = 2.8 Hz, 1 H) ppm. MS: M/e 445 (M+1) + .
化合物2.27：(±)-exo-5-((1-(6-羥基-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.27: (±)-exo-5-((1-(6-Hydroxy-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzo Furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：4-((叔丁基二甲基矽烷基)氧基)-2-硝基苯胺 Step A: 4-((tert-Butyldimethylmethylalkyl)oxy)-2-nitroaniline
室溫下，向4-氨基-3-硝基苯酚(1.0g，6.5mmol)和叔丁基二甲基氯矽烷(1.32g，8.8mmol)的DMF(10mL)溶液中加入咪唑(0.88g，13.0mmol)。該混合物在室溫下攪拌過夜。反應液用乙酸乙酯(300mL)稀釋並用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥並濃縮。殘留物通過矽膠柱層析法(石油醚：乙酸乙酯=2：1洗脫)純化得到目標化合物(1.85g，100%)，為灰色固體。1HNMR(600MHz,CDCl3)δ 7.54(d,J=2.7Hz,1H),6.96(dd,J=8.9,2.7Hz,1H),6.70(d,J=8.9Hz,1H),0.96(s,9H),0.18(s,6H)。 To a solution of 4-amino-3-nitrophenol (1.0 g, 6.5 mmol) and tert-butyldimethylchloromethane (1.32 g, 8.8 mmol) in DMF (10 mL) 13.0 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: 1H NMR (600MHz, CDCl 3 ) δ 7.54 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 8.9, 2.7 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 0.96 (s, 9H), 0.18 (s, 6H).
步驟B：4-((叔丁基二甲基矽烷基)氧基)-1,2-二氨基苯 Step B: 4-((tert-Butyldimethylmethylalkyl)oxy)-1,2-diaminobenzene
將4-(叔丁基二甲基矽氧基)-2-硝基苯胺(0.5g，1.9mmol)，鐵粉(1.1g，19mmol)和冰醋酸(1.0mL，18mmol)的乙醇(10mL)混合物回流攪拌4小時。該反應液通過矽藻土層過濾並濃縮濾液。然後將殘留物用乙酸乙酯(100mL)稀釋，用飽和碳酸氫鈉溶液(3×30mL)和飽和食鹽水(30mL)洗滌，無水硫酸鈉乾燥並濃縮。殘留物通過快速矽膠柱層析法(石油醚：乙酸乙酯=2：1洗脫)純化得到目標化合物(0.34g，77%)，為灰色固體。1HNMR(600MHz,DMSO-d 6)δ 6.31(d,J=8.2Hz,1H),6.06(d,J=2.7Hz,1H),5.84(dd,J=8.2,2.6Hz,1H),0.88(s,9H),0.07(s,6H)。 4-(tert-Butyldimethylamyloxy)-2-nitroaniline (0.5 g, 1.9 mmol), iron powder (1.1 g, 19 mmol) and glacial acetic acid (1.0 mL, 18 mmol) in ethanol (10 mL) The mixture was stirred at reflux for 4 hours. The reaction solution was filtered through a pad of celite and concentrated. The residue was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc EtOAc 1H NMR (600MHz, DMSO- d 6 ) δ 6.31 (d, J = 8.2 Hz, 1H), 6.06 (d, J = 2.7 Hz, 1H), 5.84 (dd, J = 8.2, 2.6 Hz, 1H), 0.88 ( s, 9H), 0.07 (s, 6H).
步驟C：(±)-exo-5-((1-(6-((叔丁基二甲基矽烷基)氧基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Step C: (±)-exo-5-((1-(6-((tert-butyldimethyl)alkyl)oxy)-1H-benzo[d]imidazol-2-yl)-1a,6b -dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
將中間體II(30mg，0.09mmol)，4-(叔丁基二甲基矽氧基)-1,2-二氨基苯(9.6mg，0.089mmol)，DIPEA(0.5mL)和HATU(37mg，0.101mmol)的DMF(2mL)混合物在室溫下攪拌過夜。將該反應液用乙酸乙酯(20mL)稀釋，飽和食鹽水洗滌，無水硫酸鈉乾燥並減壓濃縮。殘留物無需進一步純化直接用於下一步反應。 Intermediate II (30 mg, 0.09 mmol), 4-(tert-butyldimethylamyloxy)-1,2-diaminobenzene (9.6 mg, 0.089 mmol), DIPEA (0.5 mL) A mixture of 0.101 mmol of DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc EtOAc. The residue was used in the next reaction without further purification.
將上述產品在醋酸(2mL)中的混合物在85℃攪拌3小時。除去溶劑。殘留物用水稀釋並用2N NaOH溶液調pH 至7-8。將該混合物用DCM(2×10mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。殘留物通過製備高效液相色譜法純化得到目標化合物(20mg，40%)，為白色固體。 A mixture of the above product in acetic acid (2 mL) was stirred at 85 ° C for 3 hr. Remove the solvent. The residue was diluted with water and adjusted to pH with 2N NaOH solution To 7-8. The mixture was extracted with DCM (2×10 mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc)
步驟D：(±)-exo-5-((1-(6-羥基-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.27) Step D: (±)-exo-5-((1-(6-hydroxy-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzo Furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( Compound 2.2 7)
在0℃下，向上述產品(30mg，0.037mmol)的THF(2mL)溶液中滴加TBAF的THF(0.01mL，1M，0.01mmol)溶液。然後將該混合物在室溫下攪拌30分鐘。反應液用水(10mL)稀釋並用乙酸乙酯(20mL×2)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。殘留物通過製備高效液相色譜法純化得到目標化合物(10mg，63%)，為白色固體。1H-NMR(400MHz,CD3OD)δ 7.92(d,J=5.9Hz,1H),7.27(d,J=6.2Hz,1H),7.26(s,1H),6.97(d,J=8.6Hz,1H),6.94(dd,J=8.7,2.3Hz,1H),6.84(d,J=2.1Hz,1H),6.70(dd,J=8.6,2.3Hz,1H),6.31(d,J=5.9Hz,1H),5.26(dd,J=5.5,1.4Hz,1H),3.41(dd,J=5.5,3.4Hz,1H),3.05(t,J=7.7Hz,3H),2.64(t,J=7.7Hz,3H),1.80(dd,J=3.4,1.4Hz,1H)ppm。MS：M/e 427(M+1)+。 A solution of TBAF in THF (0.01 mL, 1 M, 0.01 mmol) was added dropwise to THF (2 mL). The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (10 mL) andEtOAc The combined organic layers were washed with EtOAcq. The residue was purified by EtOAc (EtOAc) 1 H-NMR (400 MHz, CD 3 OD) δ 7.92 (d, J = 5.9 Hz, 1H), 7.27 (d, J = 6.2 Hz, 1H), 7.26 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.7, 2.3 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.6, 2.3 Hz, 1H), 6.31 (d, J = 5.9 Hz, 1H), 5.26 (dd, J = 5.5, 1.4 Hz, 1H), 3.41 (dd, J = 5.5, 3.4 Hz, 1H), 3.05 (t, J = 7.7 Hz, 3H), 2.64 (t , J = 7.7 Hz, 3H), 1.80 (dd, J = 3.4, 1.4 Hz, 1H) ppm. MS: M/e 427 (M+1) + .
化合物2.28：(±)-exo-5-((1-(6-苯基-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.28: (±)-exo-5-((1-(6-phenyl-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzene And furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
將5-((1-(6-溴-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(22mg，0.045mmol)，苯硼酸(16.5mg，0.135mmol)，Pd(PPh3)4(20mg，0.017mmol)和K2CO3(21mg，0.15mmol)的二氧六環和水(2mL，4/1)的混合溶劑混合物在氮氣保護下回流攪拌5小時。該混合物用飽和食鹽水(2mL)稀釋並用乙酸乙酯(2mL×3)萃取，將合併的有機相用飽和食鹽水(2mL×3)洗滌，無水硫酸鈉乾燥並濃縮，所得殘留物通過製備高效液相色譜法純化得到目標化合物(12mg，55%)，為白色固體。1H-NMR(600MHz,CD3OD)δ 8.00(d,J=5.9Hz,1H),7.90(s,1H),7.84(dd,J=8.5,1.5Hz,1H),7.79(d,J=8.6Hz,1H),7.73-7.68(m,2H),7.52(t,J=7.7Hz,2H),7.46-7.40(m,2H),7.17-7.10(m,2H),6.40(d,J=6.0Hz,1H),5.67(dd,J=5.5,1.2Hz,1H),3.93-3.88(m,1H),3.11(t,J=7.8Hz,2H),2.72-2.68(m, 2H),2.23-2.18(m,1H)ppm。MS：M/e 487(M+1)+。 5-((1-(6-Bromo-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-5-yl)oxy -3,4-Dihydro-1,8-naphthyridin-2(1H)-one (22 mg, 0.045 mmol), phenylboronic acid (16.5 mg, 0.135 mmol), Pd(PPh 3 ) 4 (20 mg, 0.017 mmol) And a mixed solvent mixture of K 2 CO 3 (21 mg, 0.15 mmol) in dioxane and water (2 mL, 4/1) was stirred under nitrogen for 5 hr. The mixture was diluted with saturated brine (2 mL) and EtOAc (EtOAc m. Purification by liquid chromatography gave the title compound (12 mg, 55%) 1 H-NMR (600MHz, CD 3 OD) δ 8.00 (d, J = 5.9 Hz, 1H), 7.90 (s, 1H), 7.84 (dd, J = 8.5, 1.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.46-7.40 (m, 2H), 7.17-7.10 (m, 2H), 6.40 (d, J = 6.0 Hz, 1H), 5.67 (dd, J = 5.5, 1.2 Hz, 1H), 3.93 - 3.88 (m, 1H), 3.11 (t, J = 7.8 Hz, 2H), 2.72 - 2.68 (m, 2H) ), 2.23-2.18 (m, 1H) ppm. MS: M/e 487 (M+1) + .
化合物2.29：(±)-exo-5-((1-(3-苯基-1,2,4-二唑-5-yl)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-yl)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.29: (±)-exo-5-((1-(3-phenyl-1,2,4-oxadiazol-5-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzene And furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：(±)-exo-N-((肟基)(苯基)甲基)-5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-甲醯胺 Step A: (±)-exo-N-((indenyl)(phenyl)methyl)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine- 4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxamide
將中間體II(30mg，0.088mmol)，N-羥基苯甲醯胺 (12mg，0.088mol)，HATU(37mg，0.1mmol)和DIEPA(17mg，0.13mmol)的DMF(1mL)混合物在室溫下攪拌過夜。該反應液用水(10mL)稀釋並用乙酸乙酯(2×15mL)萃取。將合併的有機相用飽和食鹽水(2×5mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物(50mg)無需進一步純化直接用於下一步反應。 Mixture of intermediate II (30 mg, 0.088 mmol), N-hydroxybenzamide (12 mg, 0.088 mol), HATU (37 mg, 0.1 mmol) and DIEPA (17 mg, 0.13 mmol) in DMF (1 mL) at room temperature Stir overnight. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic phases were washed with EtOAc EtOAc m. The residue obtained (50 mg) was used in the next step without further purification.
步驟B：(±)-exo-5-((1-(3-苯基-1,2,4-二唑-5-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.29) Step B: (±)-exo-5-((1-(3-phenyl-1,2,4-oxadiazol-5-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzene And furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.29 )
將步驟A的產品(50mg，粗品)和吡啶(1mL)的混合物在100℃下攪拌2小時。將反應液冷卻至室溫並減壓濃縮。所得殘留物通過製備高效液相色譜法純化得到目標化合物(10mg，26%)，為白色固體。1H-NMR(400MHz,DMSO-d 6)δ 10.47(s,1H),8.00-7.96(m,3H),7.59-7.57(m,3H),7.39(d,J=2.8Hz,1H),7.10(d,J=9.2Hz,1H),7.04(dd,J=2.4,8.4Hz,1H),6.28(d,J=6.0Hz,1H),5.63(dd,J=1.2,5.2Hz,1H),3.74(dd,J=3.2,5.6Hz,1H),2.94(t,J=7.6Hz,2H),2.54(t,J=8.4Hz,2H),2.36(dd,J=1.2,3.2Hz,1H)ppm。MS：M/e 439(M+1)+。 A mixture of the product of Step A (50 mg, crude) and pyridine (1 mL) was stirred at 100 ° C for 2 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (400MHz, DMSO- d 6) δ 10.47 (s, 1H), 8.00-7.96 (m, 3H), 7.59-7.57 (m, 3H), 7.39 (d, J = 2.8Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 7.04 (dd, J = 2.4, 8.4 Hz, 1H), 6.28 (d, J = 6.0 Hz, 1H), 5.63 (dd, J = 1.2, 5.2 Hz, 1H) ), 3.74 (dd, J = 3.2, 5.6 Hz, 1H), 2.94 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 8.4 Hz, 2H), 2.36 (dd, J = 1.2, 3.2 Hz) , 1H) ppm. MS: M/e 439 (M+1) + .
化合物2.30：(±)-exo-5-((1-(4-苯基-1H-咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.30: (±)-exo-5-((1-(4-phenyl-1H-imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-5- Alkyloxy-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：(±)-exo-2-氧-2-苯基乙基-5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸酯 Step A: (±)-exo-2-oxo-2-phenylethyl-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl) Oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylate
將中間體II(30mg，0.088mmol)，2-溴-1-苯乙酮(35mg，0.176mol)和K2CO3(36mg，0.264mmol)的DMF(1mL)混合物在室溫下攪拌0.5小時。將反應液用水(10mL)稀釋並用乙酸乙酯(2×15mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物(50mg)無需進一步純化直接用於下一步反應。 The Intermediate II (30mg, 0.088mmol), 2- bromo-1-acetophenone (35mg, 0.176mol) and K DMF 2 CO 3 (36mg, 0.264mmol) in (1 mL) was stirred at room temperature for 0.5 hours . The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq. The residue obtained (50 mg) was used in the next step without further purification.
步驟B：(±)-exo-5-((1-(4-苯基-1H-咪唑-2-基)-1a,6b- 二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.30) Step B: (±)-exo-5-((1-(4-phenyl-1H-imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-5- Alkyloxy-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.30 )
將步驟A的產品(50mg，粗品)和NH4OAc的AcOH(1mL)混合物在120℃下攪拌10小時。將反應液冷卻至室溫，該混合物用飽和NaHCO3溶液(30mL)稀釋並用乙酸乙酯(2×15mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。所得殘留物通過製備高效液相色譜法純化得到目標化合物(7mg，18%)，為白色固體。1H-NMR(400MHz,DMSO-d 6)δ 12.08(s,1H),10.46(s,1H),7.96(d,J=6.0Hz,1H),7.73-7.70(m,2H),7.56-7.55(m,1H),7.36-7.30(m,3H),7.20-7.17(m,1H),7.01(d,J=8.4Hz,1H),6.95(dd,J=2.4,8.8Hz,1H),6.26(d,J=6.0Hz,1H),5.26(dd,J=1.6,5.6Hz,1H),3.31(s,1H),2.94(t,J=7.2Hz,2H),2.54(t,J=6.4Hz,2H),1.75(dd,J=1.2,3.2Hz,1H)ppm。MS：M/e 437(M+1)+。 A mixture of the product of Step A (50 mg, crude) and EtOAc (1 mL) of NH 4 OAc was stirred at 120 ° C for 10 hours. The reaction was cooled to room temperature, the mixture was diluted with saturated NaHCO 3 solution (30mL) and extracted with ethyl acetate (2 × 15mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (400MHz, DMSO- d 6) δ 12.08 (s, 1H), 10.46 (s, 1H), 7.96 (d, J = 6.0Hz, 1H), 7.73-7.70 (m, 2H), 7.56- 7.55 (m, 1H), 7.36-7.30 (m, 3H), 7.20-7.17 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H) , 6.26 (d, J = 6.0 Hz, 1H), 5.26 (dd, J = 1.6, 5.6 Hz, 1H), 3.31 (s, 1H), 2.94 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 6.4 Hz, 2H), 1.75 (dd, J = 1.2, 3.2 Hz, 1 H) ppm. MS: M/e 437 (M+1) + .
化合物2.31 Compound 2.31
化合物2.31是根據所述化合物2.30的製備過程，使 用2-溴-1-(吡啶-4-基)乙酮為原料製備的。 Compound 2.31 was prepared according to the preparation of the compound 2.30 using 2-bromo-1-(pyridin-4-yl)ethanone as a starting material.
1H-NMR(400MHz,CD3OD)δ 8.54-8.45(m,2H),7.95(d,J=6.0Hz,1H),7.78-7.73(m,2H),7.70(s,1H),7.27(d,J=2.4Hz,1H),6.99-9.64(m,2H),6.33(d,J=6.0Hz,1H),5.27(dd,J=1.6,5.6Hz,1H),3.38(dd,J=3.6,5.6Hz,1H),3.08(t,J=7.6Hz,2H),2.69-2.65(m,2H),1.81(dd,J=1.6,3.6Hz,1H)ppm。MS：M/e 438(M+1)+。 1 H-NMR (400 MHz, CD 3 OD) δ 8.54-8.45 (m, 2H), 7.95 (d, J = 6.0 Hz, 1H), 7.78-7.73 (m, 2H), 7.70 (s, 1H), 7.27 (d, J = 2.4 Hz, 1H), 6.99-9.64 (m, 2H), 6.33 (d, J = 6.0 Hz, 1H), 5.27 (dd, J = 1.6, 5.6 Hz, 1H), 3.38 (dd, J = 3.6, 5.6 Hz, 1H), 3.08 (t, J = 7.6 Hz, 2H), 2.69-2.65 (m, 2H), 1.81 (dd, J = 1.6, 3.6 Hz, 1H) ppm. MS: M/e 438 (M+1) + .
化合物2.32 Compound 2.32
化合物2.32是根據所述化合物2.30的製備過程，使用2-溴-1-(2-氯苯基)乙酮為原料製備的。 Compound 2.32 was prepared according to the preparation of the compound 2.30 using 2-bromo-1-(2-chlorophenyl)ethanone as a starting material.
1H-NMR(400MHz,DMSO-d 6)δ 12.25(br.s,1H),10.43(s,1H),8.22-8.21(m,1H),8.10-8.00(m,1H),7.94-7.93(m,1H),7.71-7.60(m,1H),7.43-7.42(m,1H),7.34-7.30(m,1H),7.25-7.15(m,1H),6.99-9.92(m,2H),6.23(d,J=4.4Hz,1H),5.25(s,1H),3.38-3.30(m,1H),3.08-2.89(m,2H),2.69-2.55(m,2H),1.76(s,1H)ppm。MS：M/e 471(M+1)+。 1 H-NMR (400 MHz, DMSO- d 6 ) δ 12.25 (br.s, 1H), 10.43 (s, 1H), 8.22-8.21 (m, 1H), 8.10-8.00 (m, 1H), 7.94-7.93 (m, 1H), 7.71-7.60 (m, 1H), 7.43-7.42 (m, 1H), 7.34-7.30 (m, 1H), 7.25-7.15 (m, 1H), 6.99-9.92 (m, 2H) , 6.23 (d, J = 4.4 Hz, 1H), 5.25 (s, 1H), 3.38-3.30 (m, 1H), 3.08-2.89 (m, 2H), 2.69-2.55 (m, 2H), 1.76 (s , 1H) ppm. MS: M/e 471 (M+1) + .
化合物2.33：(±)-exo-5-((1-(4-(三氟甲基)-1H-咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.33: (±)-exo-5-((1-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzo Furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：(±)-exo-5-((1-(羥甲基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Step A: (±)-exo-5-((1-(hydroxymethyl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-5-yl)oxy)-3,4 -dihydro-1,8-naphthyridin-2(1H)-one
向5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(中間體II，217mg，0.59mmol)的THF(10mL)溶液中加入LiAlH4(27mg，0.71mmol)。該反應在室溫下攪拌0.25小時。向反應液中滴加水(10mL)並用乙酸乙酯(2×15mL)萃取該混合物。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物(190mg)無需進一步純化直接用於下一步反應。 To 5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzene and furan-1-carboxylate (intermediate II, 217mg, 0.59mmol) in THF (10mL) was added LiAlH 4 (27mg, 0.71mmol). The reaction was stirred at room temperature for 0.25 hours. Water (10 mL) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with EtOAcq. The residue obtained (190 mg) was used in the next step without further purification.
步驟B：(±)-exo-5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-甲醛 Step B: (±)-exo-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-1-carbaldehyde
將步驟A的產品(190mg，粗品)和PCC(255mg，1.2mmol)的DCM(5mL)混合物在室溫下攪拌過夜。該混合物用水(30mL)稀釋並用二氯甲烷(2×15mL)萃取。將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，並減壓濃縮。所得殘留物通過製備薄層色譜法(DCM/MeOH=15/1)純化得到目標化合物(35mg，兩步產率17%)，為白色化合物。 A mixture of the product from Step A (190 mg, EtOAc) The mixture was diluted with water (30 mL) and EtOAc (EtOAc) The combined organic layers were washed with EtOAcq. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:
步驟C：(±)-exo-5-((1-(4-(三氟甲基)-1H-咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.33) Step C: (±)-exo-5-((1-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzo Furan-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.33 )
將3,3-二溴-1,1,1-三氟丙烷-2-酮(30mg，0.11mmol)和NaOAc(8mg，0.11mmol)溶于水(1mL)中並加熱至100℃攪拌1小時。將該混合物加入到步驟B的產品(35mg，0.1mmol)和氫氧化銨(0.5mL)的甲醇(3mL)溶液中。該混合物在室溫下攪拌40分鐘後加熱至回流攪拌1小時。冷卻後，減壓濃縮該混合物。所得殘留物通過製備高效液相色譜法純化得到目標化合物(8mg，19%)，為白色固體。1H-NMR(400MHz,DMSO-d 6)δ 12.60(s,1H),10.43(s,1H),7.92(d,J=6.0Hz,1H),7.68(s,1H),7.29(d,J=2.4Hz,1H),6.98(d,J=8.4Hz,1H),6.93(dd,J=2.4,8.4Hz,1H),6.22(d,J=5.2Hz,1H),5.21(dd,J=1.2,5.6Hz,1H),3.31-3.28(m,1H),2.90(t,J=7.6Hz,2H),2.51(t,J= 6.0Hz,2H),1.74(dd,J=1.6,3.2Hz,1H)ppm。MS：M/e 429(M+1)+。 3,3-Dibromo-1,1,1-trifluoropropan-2-one (30 mg, 0.11 mmol) and NaOAc (8 mg, 0.11 mmol) were dissolved in water (1 mL) and heated to 100 ° C for 1 hour. . This mixture was added to a solution of the product from Step B (35 mg, 0.1 mmol) and EtOAc (0.5 mL) in methanol (3 mL). The mixture was stirred at room temperature for 40 minutes and then heated to reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (400MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.43 (s, 1H), 7.92 (d, J = 6.0Hz, 1H), 7.68 (s, 1H), 7.29 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 2.4, 8.4 Hz, 1H), 6.22 (d, J = 5.2 Hz, 1H), 5.21 (dd, J = 1.2, 5.6 Hz, 1H), 3.31-3.28 (m, 1H), 2.90 (t, J = 7.6 Hz, 2H), 2.51 (t, J = 6.0 Hz, 2H), 1.74 (dd, J = 1.6) , 3.2 Hz, 1 H) ppm. MS: M/e 429 (M+1) + .
化合物2.34：(±)-exo-5-((1-(1-(2-羥乙基)-5-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.34: (±)-exo-5-((1-(1-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a ,6b-dihydro-1H-cyclopropane[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：2-((2-硝基-4-(三氟甲基)苯基)氨基)乙醇 Step A: 2-((2-Nitro-4-(trifluoromethyl)phenyl)amino)ethanol
在0℃下，向2-乙醇胺(1.76g，28.8mmol)的THF(10mL)溶液中加入1-氟-2-硝基-4-(三氟甲基)苯(2.0g，9.6mmol)。使該溶液升至室溫並在室溫下攪拌2小時。減壓除去溶劑，所得殘留物用乙酸乙酯(100mL)稀釋，飽和食鹽水(30mL×3)洗滌，無水硫酸鈉乾燥，過濾並濃縮得到目標化合物(2.4g，100%)，該化合物不需進一步純化直接用於下一步反應。1H NMR(600MHz,CDCl3)δ 8.59-8.44(m,2H), 7.65(dd,J=9.0,2.2Hz,1H),7.03(d,J=9.0Hz,1H),4.03-3.99(m,2H),3.60-3.56(m,2H)。 To a solution of 2-ethanolamine (1.76 g, 28.8 mmol) in THF (10 mL) EtOAc (EtOAc) The solution was allowed to warm to room temperature and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjjjj Further purification was used directly for the next reaction. 1 H NMR (600MHz, CDCl 3 ) δ 8.59-8.44 (m, 2H), 7.65 (dd, J = 9.0,2.2Hz, 1H), 7.03 (d, J = 9.0Hz, 1H), 4.03-3.99 (m , 2H), 3.60-3.56 (m, 2H).
步驟B：N-(2-((叔丁基二甲基矽烷基)氧基)乙基)-2-硝基-4-(三氟甲基)苯胺 Step B: N-(2-((tert-Butyldimethylmethyl)alkyl)oxy)ethyl)-2-nitro-4-(trifluoromethyl)aniline
室溫下，向步驟A的產品(2.4g，9.6mmol)和TBSCl(1.73g，11.5mmol)的DMF(15mL)溶液中加入咪唑(1.3g，19.2mmol)。該混合物在室溫下攪拌過夜。將該混合物稀釋於乙酸乙酯(100mL)中，飽和食鹽水(30mL×3)洗滌，無水硫酸鈉乾燥並濃縮。所得殘留物通過矽膠柱層析法(石油醚洗脫)純化得到目標化合物為(3.5g，100%)，為黃色固體。1H NMR(600MHz,CDCl3)δ 8.56(s,1H),8.50(d,J=1.2Hz,1H),7.63(dd,J=9.0,2.2Hz,1H),7.00(d,J=9.0Hz,1H),4.02-3.87(m,2H),3.52-3.48(m,2H),0.94(s,9H),0.13(s,6H)。 Imidazole (1.3 g, 19.2 mmol) was added to a solution of the product from Step A (2.4 g, 9.6 mmol) and TBSCl (1.73 g, 11.5 mmol) in DMF (15 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (EtOAc) (EtOAc) The residue obtained was purified by EtOAc EtOAc (EtOAc) 1 H NMR (600MHz, CDCl 3 ) δ 8.56 (s, 1H), 8.50 (d, J = 1.2Hz, 1H), 7.63 (dd, J = 9.0,2.2Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.52-3.48 (m, 2H), 0.94 (s, 9H), 0.13 (s, 6H).
步驟C：N1-(2-((叔丁基二甲基矽烷基)氧基)乙基)-4-(三氟甲基)-1,2-二氨基苯 Step C: N1-(2-((tert-Butyldimethylmethyl)alkyl)oxy)ethyl)-4-(trifluoromethyl)-1,2-diaminobenzene
將步驟B的產品(3.5g，9.6mmol)和Pd/C(0.3g)的MeOH(20mL)混合物在氫氣下室溫攪拌4小時。該混合物通過矽藻土層過濾並濃縮濾液。然後將所得殘留物稀釋於乙酸乙酯(100mL)中，飽和食鹽水(30mL×3)洗滌，無水硫酸鈉乾燥並濃縮得到目標化合物(3.1g，90%)，為紫色固體。1H NMR(600MHz,CDCl3)δ 7.10(dd,J=8.2,1.0Hz,1H),6.95(d, J=1.8Hz,1H),6.67(d,J=8.2Hz,1H),3.92(t,J=5.3Hz,2H),3.27(t,J=5.3Hz,2H),0.95(s,9H),0.12(s,6H)。 A mixture of the product of Step B (3.5 g, 9.6 mmol) and EtOAc (EtOAc) The mixture was filtered through a pad of celite and concentrated. The residue was diluted with EtOAc (EtOAc) (EtOAc) 1 H NMR (600MHz, CDCl 3 ) δ 7.10 (dd, J = 8.2,1.0Hz, 1H), 6.95 (d, J = 1.8Hz, 1H), 6.67 (d, J = 8.2Hz, 1H), 3.92 ( t, J = 5.3 Hz, 2H), 3.27 (t, J = 5.3 Hz, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
步驟D：(±)-exo-5-((1-(1-(2-羥乙基)-5-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.34) Step D: (±)-exo-5-((1-(1-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a ,6b-dihydro-1H-cyclopropane[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.34 )
將中間體II(300mg，0.9mmol)，步驟C的產品(440mg，1.45mmol)，DIPEA(1mL)，和HATU(551mg，1.45mmol)在DMF(5mL)中組成的混合物在室溫下攪拌過夜。該反應液用乙酸乙酯(20mL)稀釋，飽和食鹽水洗，無水硫酸鈉乾燥並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 A mixture of intermediate II (300 mg, 0.9 mmol), EtOAc (EtOAc (EtOAc,MeOHMeOHMeOH . The reaction mixture was diluted with EtOAc EtOAc. The residue obtained was used in the next reaction without further purification.
將上一步粗產品的醋酸(5mL)混合物在80℃下攪拌8小時。除去溶劑並將殘留物稀釋于水中。用2N NaOH將所得混合物的pH調至7-8。該混合物用二氯甲烷(2×10mL)萃取，將合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物快速矽膠色譜法(用PE：EtOAc 1：3洗脫)純化得到粗品化合物，該粗品進一步通過製備高效液相色譜法純化得到目標化合物(61mg，13%)，為白色固體。1H-NMR(400MHz,DMSO-d 6)δ 10.45(s,1H),7.94(d,J=5.8Hz,1H),7.86(s,1H),7.72(d,J=8.4Hz,1H),7.51-7.47(m,1H),7.33(d,J=2.5Hz,1H),7.04(d,J=8.7Hz,1H),6.97(dd,J =8.7,2.6Hz,1H),6.26(d,J=5.8Hz,1H),5.34(dd,J=5.3,1.2Hz,1H),4.43-4.37(m,2H),3.68(t,J=5.3Hz,2H),3.53(dd,J=5.2,3.3Hz,1H),2.91(t,J=7.7Hz,2H),2.51(t,J=7.7Hz,2H),2.23(dd,J=3.2,1.2Hz,1H)。 The acetic acid (5 mL) mixture of the crude product from the previous step was stirred at 80 ° C for 8 hours. The solvent was removed and the residue was diluted in water. The pH of the resulting mixture was adjusted to 7-8 with 2N NaOH. The mixture was extracted with dichloromethane (2×10 mL). The residue was purified by flash chromatography eluting eluting elut elut elut elut elut elut eluting 1 H-NMR (400MHz, DMSO- d 6 ) δ 10.45 (s, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H) , 7.51-7.47 (m, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.97 (dd, J = 8.7, 2.6 Hz, 1H), 6.26 ( d, J = 5.8 Hz, 1H), 5.34 (dd, J = 5.3, 1.2 Hz, 1H), 4.43-4.37 (m, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.53 (dd, J = 5.2, 3.3 Hz, 1H), 2.91 (t, J = 7.7 Hz, 2H), 2.51 (t, J = 7.7 Hz, 2H), 2.23 (dd, J = 3.2, 1.2 Hz, 1H).
化合物2.35：(±)-exo-5-((3-甲基-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.35: (±)-exo-5-((3-methyl-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydrol -1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：2-溴-4-甲氧基苯酚 Step A: 2-bromo-4-methoxyphenol
在0℃下，向4-甲氧基苯酚(10g，81mmol)的CHCl3(50mL)中加入Br2(4mL，78mmol)。該混合物在0℃ 下攪拌1小時，然後將該混合物升至室溫並在室溫下攪拌1小時。將最終混合物稀釋於二氯甲烷(500mL)中並用飽和NaHSO3(3×100mL)和飽和食鹽水(200mL)洗滌，無水硫酸鈉乾燥，過濾並濃縮得到目標化合物(16.6g，100%)，為灰白色固體，直接用於下一步反應。 At 0 ℃, the 4-methoxyphenol (10g, 81mmol) in CHCl 3 (50mL) was added Br 2 (4mL, 78mmol). The mixture was stirred at 0 ° C for 1 hour, then the mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The final mixture was diluted in dichloromethane (500 mL) and washed with saturated NaHSO 3 (3 × 100mL) and saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (16.6g, 100%), as An off-white solid was used directly in the next step.
步驟B：2-溴-1-(2,2-二乙氧基乙氧基)-4-苯甲醚 Step B: 2-bromo-1-(2,2-diethoxyethoxy)-4-anisole
將步驟A的產品(1.01g，5mmol)，2-溴-1,1-二乙氧基乙烷(1.05g，5.25mmol)和Cs2CO3(2.04g，6mmol)的DMF(10mL)混合物在120℃下攪拌2小時。該反應液降至室溫。將混合物用乙酸乙酯(200mL)稀釋並用飽和食鹽水(50mL)洗滌，無水硫酸鈉乾燥並凝縮。所得殘留物通過柱色譜法(用PE：EtOAc=6：1洗脫)純化得到油狀目標化合物(2.7g，85%)。1H-NMR(600MHz,CDCl3)δ 7.12(d,J=3.0Hz,1H),6.89(d,J=9.0Hz,1H),6.81(dd,J=9.0,3.0Hz,1H),4.87(t,J=5.2Hz,1H),4.02(d,J=5.2Hz,2H),3.84-3.78(m,2H),3.77(s,3H),3.73-3.67(m,2H),1.27(t,J=7.1Hz,6H)ppm。 A mixture of the product of Step A (1.01 g, 5 mmol), 2-bromo-1,1-diethoxyethane (1.05 g, 5.25 mmol) and Cs 2 CO 3 (2.04 g, 6 mmol) in DMF (10 mL) Stir at 120 ° C for 2 hours. The reaction solution was cooled to room temperature. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by EtOAc EtOAcqqqqqq 1 H-NMR (600MHz, CDCl 3 ) δ 7.12 (d, J = 3.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.81 (dd, J = 9.0, 3.0 Hz, 1H), 4.87 (t, J = 5.2 Hz, 1H), 4.02 (d, J = 5.2 Hz, 2H), 3.84 - 3.78 (m, 2H), 3.77 (s, 3H), 3.73 - 3.67 (m, 2H), 1.27 ( t, J = 7.1 Hz, 6H) ppm.
步驟C：7-溴-5-甲氧基苯並呋喃 Step C: 7-Bromo-5-methoxybenzofuran
向步驟B的產品(2.7g，8.5mmol)在甲苯(10mL)中的混合物加入PPA(1.0mL)。該反應液加熱至70℃攪拌1小時。然後降至室溫。反應物用乙酸乙酯稀釋(200mL)，水層用 NaOH(2mol/L)調節pH為7-8。有機相用飽和食鹽水(50mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過矽膠柱層析法(石油醚洗脫)純化得到油狀目標化合物(0.27g，16%)。1H-NMR(600MHz,CDCl3)δ 7.68(d,J=2.1Hz,1H),7.13(d,J=2.2Hz,1H),7.04(d,J=2.3Hz,1H),6.79(d,J=2.1Hz,1H),3.86(s,3H)ppm。 To a mixture of the product of Step B (2.7 g, 8.5 mmol) in toluene (10 mL) was added PPA (1.0 mL). The reaction solution was heated to 70 ° C and stirred for 1 hour. Then it is cooled to room temperature. The reaction was diluted with ethyl acetate (200 mL) and the aqueous layer was adjusted to pH 7-8 with NaOH (2 mol/L). The organic layer was washed with brine (50 mL) The residue obtained was purified by silica gel chromatography eluting elut elut 1 H-NMR (600MHz, CDCl 3 ) δ 7.68 (d, J = 2.1 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.79 (d) , J = 2.1 Hz, 1H), 3.86 (s, 3H) ppm.
步驟D：5-甲氧基-7-甲基苯並呋喃 Step D: 5-methoxy-7-methylbenzofuran
將步驟C的產品(3.6g，16mmol)，甲基硼酸(1.4g，24mmol)，Pd(dppf)2Cl2(0.65g，0.8mmol)和Cs2CO3(13.0g，40mmol)的1,4-二氧六環(50mL)和H2O(10mL)混合物在N2保護下回流攪拌3小時。將反應液降至室溫並通過矽藻土層過濾。將濾液用乙酸乙酯(200mL)稀釋，用飽和食鹽水(50mL)洗滌，無水硫酸鈉乾燥，減壓濃縮。將所得的殘留物通過矽膠柱層析法(石油醚洗脫)純化得到油狀目標化合物(1.0g，38%)。1H-NMR(600MHz,CDCl3)δ 7.63(d,J=1.6Hz,1H),6.92(d,J=2.1Hz,1H),6.76(s,1H),6.73(d,J=1.8Hz,1H),3.86(s,3H),2.53(s,3H)ppm。 The product of step C (3.6 g, 16 mmol), methylboronic acid (1.4 g, 24 mmol), Pd(dppf) 2 Cl 2 (0.65 g, 0.8 mmol) and Cs 2 CO 3 (13.0 g, 40 mmol) 4- dioxane (50mL) and H 2 O (10mL) was stirred at reflux for 3 hours under N 2. The reaction solution was cooled to room temperature and filtered through a pad of Celite. The filtrate was diluted with EtOAc (EtOAc)EtOAc. The residue obtained was purified by EtOAc EtOAc (EtOAc) 1 H-NMR (600MHz, CDCl 3 ) δ 7.63 (d, J = 1.6 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.76 (s, 1H), 6.73 (d, J = 1.8 Hz) , 1H), 3.86 (s, 3H), 2.53 (s, 3H) ppm.
步驟E：7-甲基苯並呋喃-5-醇 Step E: 7-methylbenzofuran-5-ol
向步驟D的產品(850mg，5.2mmol)和K2CO3的乙腈(10mL)混合物中加入TMSI(1.1mL)。該混合物回流攪拌2 小時。將反應液降至室溫。用乙酸乙酯(100mL)稀釋，用飽和食鹽水(30mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過矽膠柱層析法(用PE：EtOAc=5：1洗脫)純化得到油狀目標化合物(200mg，25%)。 The product from Step D (850mg, 5.2mmol) and K 2 CO 3 in acetonitrile (10 mL) was added TMSI (1.1mL) mixture. The mixture was stirred at reflux for 2 hours. The reaction solution was cooled to room temperature. It was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc
步驟F：叔丁基二甲基((7-甲基苯並呋喃-5-基)氧基)矽烷 Step F: tert-Butyldimethyl((7-methylbenzofuran-5-yl)oxy)decane
將步驟E的產品(200mg，1.4mmol)，TBSCl(225mg，1.5mmol)和咪唑(190mg，2.8mmol)的DMF(5mL)溶液在室溫下攪拌1小時。將該混合物用乙酸乙酯(100mL)稀釋並用飽和食鹽水(30mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過矽膠柱層析法(石油醚洗脫)純化得到油狀目標化合物(260mg，71%)。 A solution of the product from Step E (200 mg, 1.4 mmol), EtOAc (EtOAc, EtOAc, EtOAc The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue obtained was purified by silica gel chromatography eluting elut elut elut
步驟G：(±)-exo-5-((叔丁基二甲基矽烷基)氧基)-3-甲基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step G: (±)-exo-5-((tert-Butyldimethylmethylalkyl)oxy)-3-methyl-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-1 -carboxylic acid ethyl ester
向步驟F的產品(260mg，1mmol)和銅(I)三氟甲磺酸鹽(2：1混合於甲苯中，1mg，0.03mmol)的二氯甲烷(2mL)溶液中通過注射泵經過10小時加入重氮乙酸乙酯(1.0mL，10mol)的二氯甲烷(10mL)溶液。減壓除去溶劑，所得殘留物通過矽膠柱層析法(石油醚洗脫)純化得到目標化合物(200mg，粗品)，該化合物無需進一步純化直接用於下一步反應。 Add to the product of step F (260 mg, 1 mmol) and copper (I) triflate (2:1 in toluene, 1 mg, 0.03 mmol) in dichloromethane (2 mL) A solution of ethyl diazoacetate (1.0 mL, 10 mol) in dichloromethane (10 mL). The solvent was removed under reduced pressure. EtOAcqqqqqm
步驟H：(±)-exo-5-羥基-3-甲基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step H: (±)-exo-5-hydroxy-3-methyl-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester
在0℃下，向步驟G的產品(200mg，0.6mmol)的THF(5mL)溶液中滴加TBAF的THF溶液(0.15mL，1M，0.15mmol)。然後該混合物在室溫下攪拌10分鐘。將反應液濃縮並通過矽膠柱層析法(用EtOAc：PE=1：10洗脫)純化得到目標化合物(100mg，兩步收率43%)，為無色油狀，該產品直接用於下一步反應。 To a solution of the product from Step G (200 mg, 0.6 mmol) in THF (5 mL), THF (EtOAc, EtOAc, The mixture was then stirred at room temperature for 10 minutes. The reaction was concentrated and purified by EtOAc EtOAc (EtOAc:EtOAc: reaction.
步驟I：(±)-exo-3-甲基-5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step I: (±)-exo-3-methyl-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a, 6b-dihydro-1H-cyclopropane [b]benzofuran-1-carboxylic acid ethyl ester
將步驟B的產品(90mg，0.38mmol)，5-氟-3,4-二氫-1,8-萘啶-2(1H)-酮(64mg，0.38mmol)和碳酸銫(188mg，0.58mmol)的DMF(5mL)混合物在120℃下攪拌2小時。該反應液用水(10mL)稀釋並用乙酸乙酯(2×20mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 The product of Step B (90 mg, 0.38 mmol), 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58 mmol) The mixture of DMF (5 mL) was stirred at 120 ° C for 2 hours. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq. The residue obtained was used in the next reaction without further purification.
步驟J：(±)-exo-3-甲基-5-((7-氧-5,6,7,8-四氫-1,8- 萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step J: (±)-exo-3-methyl-5-((7-oxo-5,6,7,8-tetrahydro-1,8- Naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
室溫攪拌下，將氫氧化鈉溶液(3mL，2M)加入到步驟I的產品(60mg，3.8mmol)的甲醇(9mL)溶液中。該混合物在室溫下攪拌過夜。減壓除去溶劑，所得殘留物溶于水(10mL)中。該溶液用HCl(2mol/L)中和至pH=7並用乙酸乙酯萃取(2×10mL)。將合併的有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。1H-NMR(600MHz,DMSO-d 6)δ 12.57(s,1H),10.45(s,1H),7.97-7.95(m,1H),7.15(d,J=2.5Hz,1H),6.85(d,J=2.0Hz,1H),6.27(d,J=5.8Hz,1H),5.25(dd,J=5.3,1.0Hz,1H),3.32-3.30(m,1H),2.93(t,J=7.7Hz,2H),2.54(t,J=7.7Hz,2H),2.17(s,3H),1.21(dd,J=3.0,1.0Hz,1H)。 A solution of the product of Step I (60 mg, 3.8 mmol) in methanol (9 mL) The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The solution was neutralized with HCl (2 mol/L) to pH = 7 and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue obtained was used in the next reaction without further purification. 1 H-NMR (600MHz, DMSO- d 6) δ 12.57 (s, 1H), 10.45 (s, 1H), 7.97-7.95 (m, 1H), 7.15 (d, J = 2.5Hz, 1H), 6.85 ( d, J = 2.0 Hz, 1H), 6.27 (d, J = 5.8 Hz, 1H), 5.25 (dd, J = 5.3, 1.0 Hz, 1H), 3.32-3.30 (m, 1H), 2.93 (t, J = 7.7 Hz, 2H), 2.54 (t, J = 7.7 Hz, 2H), 2.17 (s, 3H), 1.21. (dd, J = 3.0, 1.0 Hz, 1H).
步驟K：(±)-exo-5-((3-甲基-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.35) Step K: (±)-exo-5-((3-methyl-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydrol -1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.35 )
將步驟J的產品(45mg，0.13mmol)，4-(三氟甲基) -1,2-二氨基苯(25mg，0.14mmol)，DIPEA(0.5ml)和HATU(61mg，0.16mmol)的DMF(2mL)混合物在室溫下攪拌2小時。加入水(2mL)，收集析出的固體並用水(2mL)洗得到中間體氨基產品。 The product of step J (45 mg, 0.13 mmol), 4-(trifluoromethyl)-1,2-diaminobenzene (25 mg, 0.14 mmol), DIPEA (0.5 ml) and HATU (61 mg, 0.16 mmol) of DMF (2 mL) The mixture was stirred at room temperature for 2 hours. Water (2 mL) was added, and the precipitated solid was collected and washed with water (2mL) to give an intermediate amino product.
將中間體氨基化合物的醋酸(2mL)溶液在80℃下攪拌2小時。除去溶劑並將NaOH水溶液(2mL，2mol/L)加入到殘留物中。該混合物用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備高效液相色譜法純化得到目標化合物(6mg，9.5%)，為白色固體。1H-NMR(400MHz,CD3OD)δ 7.93(d,J=5.9Hz,1H),7.78(s,1H),7.62(s,1H),7.49(d,J=7.1Hz,1H),7.11(d,J=2.5Hz,1H),6.84(d,J=2.0Hz,1H),6.34(d,J=5.9Hz,1H),5.36(dd,J=5.4,1.3Hz,1H),3.53(dd,J=5.4,3.3Hz,1H),3.06(t,J=7.7Hz,2H),2.66(t,J=7.8Hz,2H),2.26(s,3H),1.88(dd,J=3.3,1.3Hz,1H)ppm。 A solution of the intermediate amino compound in acetic acid (2 mL) was stirred at 80 ° C for 2 hr. The solvent was removed and aqueous NaOH (2 mL, 2 mol/L) was added to the residue. The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (400 MHz, CD 3 OD) δ 7.93 (d, J = 5.9 Hz, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 7.49 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 5.9 Hz, 1H), 5.36 (dd, J = 5.4, 1.3 Hz, 1H), 3.53 (dd, J = 5.4, 3.3 Hz, 1H), 3.06 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.26 (s, 3H), 1.88 (dd, J = 3.3, 1.3 Hz, 1 H) ppm.
化合物2.36：(±)-exo-5-((4-氯-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.36: (±)-exo-5-((4-chloro-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
步驟A：(±)-exo-4-氯-5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (±)-exo-4-chloro-5-hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester
室溫下，向5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1合成中步驟C的產品，500mg，2.3mmol)的乙腈(10mL)溶液中加入NCS(302mg，2.3mmol)。該混合物在室溫下攪拌過夜。將反應液用水(20mL)稀釋並用乙酸乙酯(2×10mL)萃取。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。1H-NMR(600MHz,CDCl3)δ 7.06(s,1H),6.86(s,1H),5.81(s,1H),5.18-4.89(m,1H),4.23-4.15(m,2H),3.22(dd,J=5.4,3.1Hz,1H),1.31(dd,J=3.1,1.1Hz,1H),1.28(t,J=7.2Hz,3H)ppm。 To 5-hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester (product of step C in the synthesis of compound 2.1 , 500 mg, 2.3 mmol) of acetonitrile NCS (302 mg, 2.3 mmol) was added to a solution (10 mL). The mixture was stirred at room temperature overnight. The reaction was diluted with water (20 mL) andEtOAcEtOAc. The combined organic layers were washed with EtOAcq. The residue obtained was used in the next reaction without further purification. 1 H-NMR (600MHz, CDCl 3 ) δ 7.06 (s, 1H), 6.86 (s, 1H), 5.81 (s, 1H), 5.18 - 4.89 (m, 1H), 4.23-4.15 (m, 2H), 3.22 (dd, J = 5.4, 3.1 Hz, 1H), 1.31 (dd, J = 3.1, 1.1 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H) ppm.
步驟B：(±)-exo-4-氯-5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step B: (±)-exo-4-chloro-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b -Dihydro-1H-cyclopropane [b]benzofuran-1-carboxylic acid ethyl ester
將步驟A的產品(577mg，2.3mmol)，5-氟-3,4-二氫-1,8-萘啶-2(1H)-酮(377mg，2.3mmol)和碳酸銫(1.1g，3.4 mmol)的DMF(20mL)混合物在120℃攪拌2小時。該反應液用水(40mL)稀釋並用乙酸乙酯(2×30mL)萃取。將合併的有機相用飽和食鹽水(40mL)洗滌，無水硫酸鈉乾燥並減壓濃縮，所得殘留物通過矽膠柱層析法(用EtOAc：PE=1：5~1：1洗脫)純化得到目標化合物(320mg，80%)，為白色固體。 The product of Step A (577 mg, 2.3 mmol), 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4) A mixture of mmol of DMF (20 mL) was stirred at 120 ° C for 2 h. The reaction was diluted with water (40 mL) andEtOAc. The combined organic phases were washed with EtOAc EtOAc EtOAc. The title compound (320 mg, 80%) was obtained as white solid.
步驟C：(±)-exo-4-氯-5-((7-氧-5,6,7,8-四氫-1,8-萘啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step C: (±)-exo-4-chloro-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b -dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
室溫攪拌下，將氫氧化鈉溶液(1mL，2M)加入到步驟B的產品(320mg，0.8mmol)的甲醇(3mL)溶液中。該混合物在室溫下攪拌2小時。減壓除去溶劑，所得殘留物溶于水(10mL)中。該溶液用HCl(1mol/L)中和至pH=7時溶液中析出白色固體。過濾收集白色固體並在空氣中乾燥得到目標化合物(230mg，77.2%)。1H-NMR(600MHz,DMSO-d 6)δ 12.68(s,1H),10.50(s,1H),7.96(d,J=5.8Hz,1H),7.53(s,1H),7.30(s,1H),6.18(d,J=5.8Hz,1H),5.32(d,J=5.3Hz,1H),3.34-3.31(m,1H),2.98(t,J=7.7Hz,2H),2.57(t,J=7.7Hz,2H),1.38-1.33(m,1H)ppm。 A solution of the product of Step B (320 mg, 0.8 mmol) in methanol (3 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The solution was neutralized with HCl (1 mol/L) to pH = 7 to precipitate a white solid. The white solid was collected by suction <RTI ID=0.0> 1 H-NMR (600MHz, DMSO- d 6) δ 12.68 (s, 1H), 10.50 (s, 1H), 7.96 (d, J = 5.8Hz, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 6.18 (d, J = 5.8 Hz, 1H), 5.32 (d, J = 5.3 Hz, 1H), 3.34 - 3.31 (m, 1H), 2.98 (t, J = 7.7 Hz, 2H), 2.57 ( t, J = 7.7 Hz, 2H), 1.38-1.33 (m, 1 H) ppm.
步驟D：(±)-exo-5-((4-氯-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮(化合物2.36) Step D: (±)-exo-5-((4-chloro-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one ( compound 2.36 )
室溫下，向步驟C的產品(60mg，0.16mmol)，4-氟-5-甲基-1,2-二氨基苯(22.6mg，0.16mmol)和DIPEA(0.1mL)的DMF(2mL)溶液中加入HATU(92mg，0.24mmol)。該混合物在室溫下攪拌20小時。反應液用乙酸乙酯(5mL)稀釋，飽和食鹽水(3×5mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。 To the product of Step C (60 mg, 0.16 mmol), 4-fluoro-5-methyl-1,2-diaminobenzene (22.6 mg, 0.16 mmol) and DIPEA (0.1 mL) in DMF (2 mL) HATU (92 mg, 0.24 mmol) was added to the solution. The mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc EtOAc.
將所得殘留物溶於醋酸(5mL)中並在80℃下攪拌3小時。除去溶劑並將NaOH溶液(2mol/L，10mL)加入到殘留物中。用乙酸乙酯(2×20mL)萃取水相。將合併的有機相用飽和食鹽水(20mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備高效液相色譜法純化得到目標化合物(20mg，26.0%)，為白色固體。1H-NMR(600MHz,DMSO-d 6)δ 12.90(s,1H),10.51(s,1H),7.98(d,J=5.8Hz,1H),7.88(s,1H),7.67(s,1H),7.58(s,1H),7.48(s,1H),7.38(s,1H),6.21(d,J=5.8Hz,1H),5.50(d,J=5.0Hz,1H),3.61-3.52(m,1H),2.99(t,J=7.7Hz,2H),2.57(t,J=7.8Hz,2H),2.10-2.05(m,1H)ppm。MS：M/e 513(M+1)+。 The obtained residue was dissolved in acetic acid (5 mL) and stirred at 80 ° C for 3 hr. The solvent was removed and a NaOH solution (2 mol/L, 10 mL) was added to the residue. The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with EtOAcq. The residue was purified by preparative EtOAc (EtOAc) 1 H-NMR (600MHz, DMSO- d 6) δ 12.90 (s, 1H), 10.51 (s, 1H), 7.98 (d, J = 5.8Hz, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 6.21 (d, J = 5.8 Hz, 1H), 5.50 (d, J = 5.0 Hz, 1H), 3.61 3.52 (m, 1H), 2.99 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 2.10-2.05 (m, 1 H) ppm. MS: M/e 513 (M+1)+.
化合物2.37：(±)-exo-5-((4-氯-1-(6-氟-5-甲基-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 2.37 : (±)-exo-5-((4-chloro-1-(6-fluoro-5-methyl-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
化合物2.37的製備，從化合物2.36合成中步驟C的產品開始，根據化合物2.36所描述的程式，通過使用4-氟-5-甲基-1,2-二氨基苯為原料，由本領域技術人員在適當的條件下完成。1H-NMR(600MHz,DMSO-d6)δ 12.43(s,1H),10.50(s,1H),7.97(d,J=5.8Hz,1H),7.55(s,1H),7.43-7.21(m,3H),6.20(d,J=5.8Hz,1H),5.43(d,J=4.5Hz,1H),3.49-3.40(m,1H),2.98(t,J=7.7Hz,2H),2.57(t,J=7.8Hz,2H),2.31(s,3H),1.97(d,J=2.2Hz,1H)ppm。MS：M/e 477(M+1)+。 Preparation of the compound 2.37, compound 2.36 from a synthesis product of Step C begins, according to the program compound 2.36 described, by using 4-fluoro-5-methyl-1,2-diaminobenzene as raw materials, by those skilled in the art Completed under appropriate conditions. 1 H-NMR (600MHz, DMSO-d 6 ) δ 12.43 (s, 1H), 10.50 (s, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.55 (s, 1H), 7.43-7.21 ( m, 3H), 6.20 (d, J = 5.8 Hz, 1H), 5.43 (d, J = 4.5 Hz, 1H), 3.49-3.40 (m, 1H), 2.98 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 2.31 (s, 3H), 1.97 (d, J = 2.2 Hz, 1 H) ppm. MS: M/e 477 (M+1)+.
實施例3：化合物3.1-3.8的合成 Example 3: Synthesis of Compounds 3.1-3.8
化合物3.1：(±)-exo-N-甲基-4-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)吡啶醯胺 Compound 3.1: (±)-exo-N-methyl-4-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydrol -1H-cyclopropane [b]benzofuran-5-yl)oxy)pyridinium
步驟A：(±)-exo-5-((2-(甲氨基甲醯基)吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (±)-exo-5-((2-(methylaminomercapto)pyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran- Ethyl 1-carboxylate
將5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1合成中步驟C的化合物，50mg，0.23mmol)，4-氯-N-甲氨基甲醯胺(39mg，0.23mol)和碳酸銫(225mg，0.69mmol)的DMF(4mL)混合物在120℃下攪拌30分鐘。該反應液用水(10mL)稀釋並用乙酸乙酯(3×30mL)萃取。將合併的有機相用滷水(2×10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到目標化合物(40mg，50%)，為白色固體。1H-NMR(600MHz,CDCl3)δ 8.39(d,J=5.4Hz,1H),8.03(s,1H),7.68(d,J=1.8Hz,1H),7.16(d,J=1.8Hz,1H),6.96(dd,J=3.0,6.0Hz,1H),6.93-6.92(m,2H),5.16(dd,J=0.6,5.4Hz,1H),4.21(dd,J=7.2,14.4Hz,2H),3.29(dd,J=3.0,5.4Hz,1H),3.03(d,J=4.8Hz,3H),1.41(dd,J=1.2,3.0Hz, 1H),1.31(t,J=7.2Hz,3H)ppm。MS：M/e 355(M+1)+。 5-Hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester ( compound of step C in compound 2.1 synthesis, 50 mg, 0.23 mmol), 4-chloro-N A mixture of methylcarbamethamine (39 mg, 0.23 mol) and cesium carbonate (225 mg, 0.69 mmol) in DMF (4 mL) was stirred at 120 ° C for 30 min. The reaction was diluted with water (10 mL) andEtOAcEtOAc. The combined organic phases were washed with brine (2×10 mL) The residue obtained was purified by EtOAc EtOAcjjjj: 1 H-NMR (600MHz, CDCl 3 ) δ 8.39 (d, J = 5.4 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.16 (d, J = 1.8 Hz) , 1H), 6.96 (dd, J = 3.0, 6.0 Hz, 1H), 6.93-6.92 (m, 2H), 5.16 (dd, J = 0.6, 5.4 Hz, 1H), 4.21 (dd, J = 7.2, 14.4) Hz, 2H), 3.29 (dd, J = 3.0, 5.4 Hz, 1H), 3.03 (d, J = 4.8 Hz, 3H), 1.41 (dd, J = 1.2, 3.0 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H) ppm. MS: M/e 355 (M+1)+.
步驟B：(±)-exo-5-((2-(甲基氨基甲醯胺)吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step B: (±)-exo-5-((2-(methylaminocarbamamine)pyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran 1-carboxylic acid
將步驟A的產品(60mg，0.17mmol)，氫氧化鈉水溶液(0.34mL，2M，0.68mmol)，THF(2mL)和甲醇(2mL)的混合物在60℃下攪拌1小時。該溶液用HCl(2mol/L)中和至pH=7並除去溶劑。將所得殘留物溶於乙酸乙酯(3×30mL)，水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮得到目標化合物(57mg，100%)，該化合物直接用於下一步。MS：M/e 327(M+1)+。 A mixture of the product of Step A (60 mg, 0.17 mmol), EtOAc (EtOAc (EtOAc) This solution was neutralized with HCl (2 mol/L) to pH = 7 and the solvent was removed. The residue was dissolved in ethyl acetate (3×30 mL)EtOAc. . MS: M/e 327 (M+1) + .
步驟C：(±)-exo-N-甲基-4-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)吡啶醯胺(化合物3.1) Step C: (±)-exo-N-methyl-4-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydrol -1H-cyclopropane [b]benzofuran-5-yl)oxy)pyridiniumamine ( Compound 3.1 )
將步驟B的產品(57mg，0.17mmol)，4-(三氟甲基)-1,2-二氨基苯(34mg，0.19mmol)，DIPEA(0.035mL，0.20mmol)和HATU(72mg，0.19mmol)的DMF(3mL)混合物在室溫下攪拌過夜。該反應液用乙酸乙酯(3×20mL)萃取，飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。 所得殘留物無需進一步純化直接用於下一步反應。 The product of Step B (57 mg, 0.17 mmol), 4- (trifluoromethyl)-1,2-diaminobenzene (34 mg, 0.19 mmol), DIPEA (0.035 mL, 0.20 mmol) and HATU (72 mg, 0.19 mmol) The mixture of DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc EtOAc EtOAc. The residue obtained was used in the next reaction without further purification.
將所得粗產品溶於醋酸(3mL)中並在60℃下攪拌6小時。該混合物用乙酸乙酯(50mL萃取，用碳酸氫鈉水溶液鹼化，飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到目標化合物(50mg，63%)，為白色固體。1H-NMR(400MHz,CDCl3)δ 8.35(d,J=5.6Hz,1H),7.75(s,1H),7.54(d,J=8.4Hz,1H),7.44-7.39(m,2H),7.12(d,J=2.4Hz,1H),7.02(dd,J=2.8,5.6Hz,1H),6.94-6.88(m,2H),5.38(dd,J=1.2,5.2Hz,1H),3.50(dd,J=3.6,5.6Hz,1H),2.94(s,3H),1.85(dd,J=1.6,3.6Hz,1H)ppm。MS：M/e 467(M+1)+。 The obtained crude product was dissolved in acetic acid (3 mL) and stirred at 60 ° C for 6 hr. The mixture was extracted with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. : petroleum ether = 1: 2) to give the title compound (50mg, 63%), as a white solid 1 H-NMR (400MHz, CDCl 3) δ 8.35 (d, J = 5.6Hz, 1H), 7.75 (s,. 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 2.8, 5.6 Hz, 1H), 6.94-6.88 (m, 2H), 5.38 (dd, J = 1.2, 5.2 Hz, 1H), 3.50 (dd, J = 3.6, 5.6 Hz, 1H), 2.94 (s, 3H), 1.85 (dd, J = 1.6, 3.6 Hz, 1 H) ppm. MS: M/e 467 (M+1) + .
化合物3.2：(±)-exo-2-(5-(嘧啶-4-基氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-6-(三氟甲基)-1H-苯並[d]咪唑 Compound 3.2 : (±)-exo-2-(5-(pyrimidin-4-yloxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-6-( Trifluoromethyl)-1H-benzo[d]imidazole
步驟A：(±)-exo-5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step A: (±)-exo-5-hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
室溫下，向5-((叔丁基二甲基矽烷基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1合成中步驟B的產品，1.5g，4.5mmol)的甲醇(13.5mL)溶液中加入氫氧化鈉水溶液(4.5mL，2M，9.0mmol)。該混合物在60℃下攪拌2小時。減壓除去溶劑並將殘留物溶于水(30mL)中。該溶液用HCl(2mol/L)中和至pH=7時溶液中析出白色沉澱。過濾收集白色固體並在空氣中乾燥得到目標化合物(450mg，52%)，該化合物直接用於下一步反應。1H-NMR(600MHz,DMSO-d 6)δ 9.03(s,1H),6.90(d,J=2.4Hz,1H),6.72(d,J=8.4Hz,1H),6.55(dd,J=3.0,9.0Hz,1H),5.08(dd,J=1.2,5.4Hz,1H),3.22(d,J=2.4Hz,1H),1.07(d,J=3.0Hz,1H)ppm。MS：M/e 193(M+1)+。 Ethyl 5-((tert-butyldimethylmethyl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylate ( Compound 2.1) A solution of the product of Step B, 1.5 g, 4.5 mmol of MeOH (13.5 mL) The mixture was stirred at 60 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was crystallisjjjjjjjj When the solution was neutralized with HCl (2 mol/L) to pH = 7, a white precipitate precipitated from the solution. The white solid was collected by filtration and dried in vacuo to give the title compound (450 mg, 52%). 1 H-NMR (600MHz, DMSO- d 6 ) δ 9.03 (s, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 3.0, 9.0 Hz, 1H), 5.08 (dd, J = 1.2, 5.4 Hz, 1H), 3.22 (d, J = 2.4 Hz, 1H), 1.07 (d, J = 3.0 Hz, 1 H) ppm. MS: M/e 193 (M + 1) + .
步驟B：(±)-exo-1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-醇 Step B: (±)-exo-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane[b]benzene Furan-5-ol
將步驟A的產品(100mg，0.52mmol)，4-(三氟甲基)-1,2-二氨基苯(101mg，0.57mmol)，DIPEA(0.11mL，0.62mmol)和HATU(217mg，0.57mmol)的DMF(5mL)混合物室溫攪拌過夜。該反應液用二氯甲烷(3×30mL)萃取，飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 The product of Step A (100 mg, 0.52 mmol), 4-(trifluoromethyl)-1,2-diaminobenzene (101 mg, 0.57 mmol), DIPEA (0.11 mL, 0.62 mmol) and HATU (217 mg, 0.57 mmol) The mixture of DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane (3×30 mL). The residue obtained was used in the next reaction without further purification.
將粗產品溶於醋酸(3mL)中並在60℃下攪拌1.5小時。該混合物用碳酸氫鈉水溶液鹼化，乙酸乙酯(3×30mL)萃取，飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到到目標化合物(30mg，17%)，為棕色油狀。1H-NMR(400MHz,CDCl3)δ 7.79(s,1H),7.63-7.61(m,1H),7.49-7.48(m,1H),6.94-6.93(m,1H),6.76-6.74(m,1H),6.65-6.63(m,1H),5.22-5.21(m,1H),3.43-3.42(m,1H),1.79(d,J=1.8Hz,1H)ppm。MS：M/e 333(M+1)+。 The crude product was dissolved in acetic acid (3 mL) and stirred at 60 ° C for 1.5 h. The mixture was basified with EtOAc (EtOAc) (EtOAc m. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc: 1 H-NMR (400 MHz, CDCl 3 ) δ 7.79 (s, 1H), 7.63-7.61 (m, 1H), 7.49-7.48 (m, 1H), 6.94-6.93 (m, 1H), 6.76-6.74 (m) , 1H), 6.65-6.63 (m, 1H), 5.22-5.21 (m, 1H), 3.43-3.42 (m, 1H), 1.79 (d, J = 1.8 Hz, 1H) ppm. MS: M/e 333 (M+1) + .
步驟C：(±)-exo-2-(5-(嘧啶-4-基氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-6-(三氟甲基)-1H-苯並[d]咪唑(化合物3.2) Step C : (±)-exo-2-(5-(pyrimidin-4-yloxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-6-( Trifluoromethyl)-1H-benzo[d]imidazole ( compound 3.2 )
將步驟B的產品(20mg，0.06mmol)，4-氯嘧啶(8mg，0.06mmol)和碳酸銫(60mg，0.18mmol)的DMF(2mL)混合物在100℃下攪拌2小時。該反應液用乙酸乙酯(3×30mL)萃取。將合併的有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到目標化合物(16mg)，為淺黃色固體，然後通過製備高效液相色譜法進一步純化得到標題化合物(5mg，24.6%)，為淺黃色固體。1H-NMR(600MHz,CDCl3)δ 8.73(s,1H),8.63(s,1H),7.82(s,1H),7.66(d,J=1.2Hz,1H),7.52(d,J=8.4Hz,1H),7.37(d,J=1.8Hz,1H),7.08- 7.02(m,3H),5.38(dd,J=1.2,5.4Hz,1H),3.57(dd,J=3.0,4.8Hz,1H),1.94(d,J=2.4Hz,1H)ppm。MS：M/e 411(M+1)+。 The product of Step B (20 mg, 0.06 mmol), 4-chloropyrimidine (8 mg, 0.06 mmol) and EtOAc (EtOAc) The reaction was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with EtOAc EtOAc m. The residue was purified by EtOAc (EtOAc:EtOAcHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 24.6%), as a pale yellow solid. 1 H-NMR (600MHz, CDCl 3 ) δ 8.73 (s, 1H), 8.63 (s, 1H), 7.82 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.08-7.02 (m, 3H), 5.38 (dd, J = 1.2, 5.4 Hz, 1H), 3.57 (dd, J = 3.0, 4.8 Hz, 1H), 1.94 (d, J = 2.4 Hz, 1 H) ppm. MS: M/e 411 (M+1) + .
化合物3.3：(±)-exo-2-(5-((1H-吡咯並[2,3-b]吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-6-(三氟甲基)-1H-苯並[d]咪唑 Compound 3.3: (±) -exo-2- (5 - ((1H- pyrrolo [2,3-b] pyridin-4-yl) oxy) -1a, 6b- cyclopropane dihydro -1H- [b Benzofuran-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
步驟A：(±)-exo-5-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (±)-exo-5-((1-((2-(trimethyldecyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl Ethyl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester
將5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1的合成中步驟C的產品，100mg，0.46mmol)，4-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶(180mg，0.46mol)，K2CO3(158mg，1.15mmol)， Pd2(dba)3(cat.)，X-PHOS(22mg，0.046mmol)的甲苯(5mL)混合物脫氣並在130℃微波下攪拌60分鐘。過濾該混合物並將濾液減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：4)純化得到目標化合物(120mg，56%)，為黃色油狀。 5-Hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester (product of step C in the synthesis of compound 2.1 , 100 mg, 0.46 mmol), 4-bromo- 1-((2-(Trimethyldecyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.46 mol), K 2 CO 3 (158 mg, 1.15 mmol) , Pd 2 (dba) 3 (cat.), a mixture of X-PHOS (22 mg, 0.046 mmol) in toluene (5 mL) was degassed and stirred under microwaves at 130 ° C for 60 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc
步驟B：(±)-exo-5-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step B: (±)-exo-5-((1-((2-(trimethyldecyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
室溫攪拌下，將氫氧化鈉水溶液(0.54mL，2M，1.08mmol)加入到步驟A的產品(125mg，0.27mmol)的THF(4mL)和甲醇(4mL)溶液中。該混合物在60℃下攪拌10分鐘。減壓除去溶劑並將殘留物溶于水(5mL)中。該溶液用HCl(2mol/L)中和至pH=7並用乙酸乙酯(3×30mL)萃取。將合併的有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮得到目標化合物(120mg，100%)，該化合物直接用於下一步反應。 Aqueous sodium hydroxide (0.54 mL, 2M, 1.08 mmol) was added to EtOAc (EtOAc) The mixture was stirred at 60 ° C for 10 minutes. The solvent was removed under reduced pressure and the residue was crystallised from water The solution was neutralized with HCl (2 mol/L) to pH = 7 and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with EtOAc EtOAc m.
步驟C：(±)-exo-6-(三氟甲基)-2-(5-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-1H-苯並[d]咪唑 Step C: (±)-exo-6-(trifluoromethyl)-2-(5-((1-((2-(trimethyl)alkyl)ethoxy)methyl)-1H-pyrrole [2,3-b]pyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-1H-benzo[d]imidazole
室溫下，向步驟B的產品(120mg，0.28mmol)的DMF(5mL)溶液中加入DIPEA(0.049mL，0.33mmol)和HATU(115mg，0.31mmol)。攪拌30分鐘後，加入4-(三氟甲基)-1,2-二氨基苯(53.4mg，0.31mmol)，該混合物攪拌過夜。該反應液用乙酸乙酯(3×20mL)萃取，飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 DIPEA (0.049 mL, 0.33 mmol) and HATU (115 mg, 0.31 mmol) were added to aq. After stirring for 30 minutes, 4-(trifluoromethyl)-1,2-diaminobenzene (53.4 mg, 0.31 mmol) was added and the mixture was stirred overnight. The reaction mixture was extracted with EtOAc EtOAc EtOAc. The residue obtained was used in the next reaction without further purification.
將粗產品溶於醋酸(5mL)中並在60℃下攪拌6小時。該混合物用乙酸乙酯(3×20mL)萃取，碳酸氫鈉水溶液鹼化，飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到到目標化合物(100mg，63%)，為白色固體。MS：M/e 579(M+1)+。 The crude product was dissolved in acetic acid (5 mL) and stirred at 60 ° C for 6 h. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue obtained was purified by EtOAc EtOAc EtOAc:EtOAc MS: M/e 579 (M+1) + .
步驟D：(±)-exo-2-(5-((1H-吡咯並[2,3-b]吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-6-(三氟甲基)-1H-苯並[d]咪唑(化合物3.3) Step D: (±)-exo-2-(5-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane [b Benzofuran-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (Compound 3.3)
化合物3.4：(±)-exo-6-(t三氟甲基)-2-(5-((2-(4-(三氟甲基)-1H-咪唑-2-基)吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-1H-苯並[d]咪唑 Compound 3.4 : (±)-exo-6-(t-trifluoromethyl)-2-(5-((2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine-4- Ethyl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-1H-benzo[d]imidazole
步驟A：(±)-exo-5-((2-氰基吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (±)-exo-5-((2-cyanopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ester
將5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1的合成中步驟C的產品，100mg，0.46mmol)，4-氯-2-氰基吡啶(64mg，0.46mmol)和碳酸銫(450mg，1.3mmol)的DMF(6mL)混合物在100℃下攪拌120分鐘。該反應液用乙酸乙酯(3×30mL)萃取。將合併的有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備薄層色譜法純化得到目標化合物(100mg，67.5%)，為白色固體。1H-NMR(600MHz,CDCl3)δ 8.51(d,J=5.4Hz,1H),7.16(d,J=2.4Hz,1H),7.12(d,J=2.4Hz,1H),6.98(dd,J=3.0,6.0Hz,1H),6.93(d,J=9.0Hz,1H),6.88(dd,J=2.4,8.4Hz,1H),5.14(d,J=5.4Hz,1H),4.18(dd,J=7.2,11.8Hz,2H),3.27(dd,J=3.0,5.4Hz,1H),1.37(d,J=3.0Hz,1H),1.28(t,J=7.2Hz,3H)ppm。MS：M/e 323(M+1)+。 5-Hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester (product of step C in the synthesis of compound 2.1 , 100 mg, 0.46 mmol), 4-chloro- A mixture of 2-cyanopyridine (64 mg, 0.46 mmol) and cesium carbonate (450 mg, 1.3 mmol) in DMF (6 mL) was stirred at 100 ° C for 120 min. The reaction was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with EtOAc EtOAc m. The residue obtained was purified by preparative EtOAc (EtOAc) 1 H-NMR (600MHz, CDCl 3 ) δ 8.51 (d, J = 5.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.98 (dd , J = 3.0, 6.0 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.88 (dd, J = 2.4, 8.4 Hz, 1H), 5.14 (d, J = 5.4 Hz, 1H), 4.18 (dd, J = 7.2, 11.8 Hz, 2H), 3.27 (dd, J = 3.0, 5.4 Hz, 1H), 1.37 (d, J = 3.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H) Ppm. MS: M/e 323 (M+1) + .
步驟B：(±)-exo-5-((2-甲脒基吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸甲酯 Step B: (±)-exo-5-((2-methylpyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid Methyl ester
室溫下，向步驟A的產品(45mg，0.14mmol)的甲 醇(3mL)溶液中加入甲醇鈉(15mg，0.28mmol)。該混合物在室溫下攪拌3小時。然後在室溫下加入NH4Cl(12mg，0.21mmol)並將混合物在室溫下攪拌1小時，然後在60℃下攪拌1.5小時。除去溶劑，所得殘留物無需進一步純化直接用於下一步反應。 Sodium methoxide (15 mg, 0.28 mmol) was added to a solution of EtOAc (EtOAc m. The mixture was stirred at room temperature for 3 hours. NH 4 Cl (12 mg, 0.21 mmol) was then added at room temperature and the mixture was stirred at room temperature for 1 hour and then at 60 ° C for 1.5 hours. The solvent was removed and the residue obtained was used directly to the next step without further purification.
步驟C：(±)-exo-5-((2-(4-(三氟甲基)-1H-咪唑-2-基)吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸甲酯 Step C: (±)-exo-5-((2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-1-carboxylic acid methyl ester
室溫下，向步驟B的產品的CH3CN(3mL)溶液中加入K2CO3(78mg，0.56mmol)和3-溴-1,1,1-三氟丙烷-2-酮(32mg，0.17mmol)。該混合物在60℃下攪拌2小時。減壓除去溶劑並將所得殘留物溶於乙酸乙酯(100mL)中。有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到目標化合物(10mg，17%)，為黃色固體。1H-NMR(600MHz,CDCl3)δ 8.35(d,J=5.4Hz,1H),7.71(d,J=3.0Hz,1H),7.44(s,1H),7.14(s,1H),6.91(s,2H),6.83(dd,J=3.0,6.6Hz,1H),5.14(d,J=5.4Hz,1H),3.72(s,3H),3.27(dd,J=3.0,5.4Hz,1H),1.40(d,J=2.4Hz,1H)ppm。MS：M/e 418(M+1)+。 At room temperature, CH product of Step B 3 CN (3mL) was added K 2 CO 3 (78mg, 0.56mmol ) and 3-bromo-1,1,1-trifluoro-2-one (32mg, 0.17 mmol). The mixture was stirred at 60 ° C for 2 hours. The solvent was removed under reduced pressure. The organic phase was washed with brine (2×10 mL) The residue obtained was purified by EtOAc EtOAcjjjj: 1 H-NMR (600MHz, CDCl 3 ) δ 8.35 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.44 (s, 1H), 7.14 (s, 1H), 6.91 (s, 2H), 6.83 (dd, J = 3.0, 6.6 Hz, 1H), 5.14 (d, J = 5.4 Hz, 1H), 3.72 (s, 3H), 3.27 (dd, J = 3.0, 5.4 Hz, 1H), 1.40 (d, J = 2.4 Hz, 1 H) ppm. MS: M/e 418 (M + 1) + .
步驟D：(±)-exo-5-((2-(4-(三氟甲基)-1H-咪唑-2-基) 吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step D: (±)-exo-5-((2-(4-(trifluoromethyl)-1H-imidazol-2-yl) Pyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
室溫攪拌下，將氫氧化鈉溶液(0.28mL，2M，0.56mmol)加入到步驟C產品(60mg，0.14mmol)的THF(1mL)和甲醇(1mL)溶液中。將該混合物在50℃下攪拌1小時。減壓除去溶劑並將所得殘留物溶於二氯甲烷(20mL)和水(5mL)中。將溶液用HCl(2mol/L)中和至pH=7並用二氯甲烷(3×30mL)萃取，無水硫酸鈉乾燥，過濾並減壓濃縮得到目標化合物為黃色固體(40mg，72%)，該產品無需進一步純化直接用於下一步反應。MS：M/e 404(M+1)+。 A solution of the product of Step C (60 mg, 0.14 mmol) in THF (1 mL) and methanol (1 mL). The mixture was stirred at 50 ° C for 1 hour. The solvent was removed under reduced pressure and the residue was evaporatedjjjjjjjjjj The solution was neutralized with HCl (2 mol / L) to EtOAc (EtOAc) (EtOAc (EtOAc) The product was used in the next step without further purification. MS: M/e 404 (M+1) + .
步驟E：(±)-exo-6-(三氟甲基)-2-(5-((2-(4-(三氟甲基)-1H-咪唑-2-基)吡啶-4-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-1H-苯並[d]咪唑(化合物3.4) Step E: (±)-exo-6-(trifluoromethyl)-2-(5-((2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl) )oxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-1H-benzo[d]imidazole (compound 3.4)
向步驟D的產品(40mg，0.1mmol)，4-(三氟甲基)-1,2-二氨基苯(19mg，0.11mmol)，DIPEA(0.02mL，0.12mmol)的DMF(2mL)溶液中加入HATU(42mg，0.11mmol)。該混合物室溫攪拌8小時。將該反應液用乙酸乙酯(3×30mL)萃取，飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾 並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 To the product of Step D (40 mg, 0.1 mmol), 4-(trifluoromethyl)-1,2-diaminobenzene (19 mg, 0.11 mmol), DIPEA (0.02 mL, 0.12 mmol) in DMF (2 mL) HATU (42 mg, 0.11 mmol) was added. The mixture was stirred at room temperature for 8 hours. The reaction mixture was extracted with ethyl acetate (3×30 mL), brine (2×10 mL) It was concentrated under reduced pressure. The residue obtained was used in the next reaction without further purification.
將粗產品溶於醋酸(2mL)中並在60℃下攪拌2小時。除去溶劑並將所得殘留物通過製備高效液相色譜法純化得到到目標化合物(5.1mg，10%)，為白色固體。1H-NMR(400MHz,CDCl3)δ 8.55-8.43(m,1H),7.77(s,1H),7.63-7.60(m,2H),7.56-7.55(m,1H),7.48-7.46(m,1H),7.33(s,1H),7.03-6.96(m,3H),5.37-5.36(m,1H),3.55-3.53(m,1H),1.94-1.92(m,1H)ppm。MS：M/e 544(M+1)+。 The crude product was dissolved in acetic acid (2 mL) and stirred at 60 ° C for 2 h. The solvent was removed and the residue obtained was purified mjjjlililili 1 H-NMR (400MHz, CDCl 3 ) δ 8.55-8.43 (m, 1H), 7.77 (s, 1H), 7.63-7.60 (m, 2H), 7.56-7.55 (m, 1H), 7.48-7.46 (m , 1H), 7.33 (s, 1H), 7.03-6.96 (m, 3H), 5.37-5.36 (m, 1H), 3.55-3.53 (m, 1H), 1.94-1.92 (m, 1H) ppm. MS: M/e 544 (M+1) + .
化合物3.5：(±)-exo-6-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-9H-嘌呤 Compound 3.5 : (±)-exo-6-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-9H-oxime
步驟A：(±)-exo-5-((9-((2-(三甲基矽烷基)乙氧基)甲基)-9H-嘌呤-6-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (±)-exo-5-((9-((2-(trimethyldecyl)ethoxy)methyl)-9H-indol-6-yl)oxy)-1a,6b- Ethyl dihydro-1H-cyclopropane [b]benzofuran-1-carboxylate
將5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1的合成中步驟C的產品，61mg，0.28mmol)，6-氯-9-((2-(三甲基矽烷基)乙氧基)甲基)-9H-嘌呤(80mg，0.28mmol)，K2CO3(96.6mg，0.70mmol)，Pd2(dba)3(cat.)，X-PHOS(13.3mg，0.028mmol)的甲苯(5mL)混合物脫氣並在130℃微波下攪拌2.5小時。過濾該混合物並將濾液減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到標題化合物(73mg，56%)，為無色油狀。MS：M/e 469(M+1)+。 5-Hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester (product of step C in the synthesis of compound 2.1 , 61 mg, 0.28 mmol), 6-chloro- 9-((2-(Trimethyldecyl)ethoxy)methyl)-9H-indole (80 mg, 0.28 mmol), K 2 CO 3 (96.6 mg, 0.70 mmol), Pd 2 (dba) 3 ( Cat.), a mixture of X-PHOS (13.3 mg, 0.028 mmol) in toluene (5 mL) was degassed and stirred at 130 ° C for 2.5 hours under microwave. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj MS: M/e 469 (M+1) + .
步驟B：(±)-exo-5-((9-((2-(三甲基矽烷基)乙氧基)甲基)-9H-嘌呤-6-基)氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step B: (±)-exo-5-((9-((2-(trimethyldecyl)ethoxy)methyl)-9H-indol-6-yl)oxy)-1a,6b- Dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
將步驟A的產品(65mg，0.14mmol)，氫氧化鈉水溶液(0.28mL，2M，0.56mmol)和THF(4mL)溶液回流攪拌6小時。減壓除去溶劑並將殘留物用HCl(2mol/L)中和至pH=4-5並用乙酸乙酯(3×30mL)萃取。將合併的有機相用飽和食 鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮得到目標化合物(62mg，100%)，該化合物直接用於下一步反應。 The product of Step A (65 mg, 0.14 mmol), EtOAc (EtOAc) The solvent was removed under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~ The combined organic phase is saturated with food The organic layer was washed with EtOAc (EtOAc m.
步驟C：(±)-exo-6-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-9-((2-(三甲基矽烷基)乙氧基)甲基)-9H-嘌呤 Step C: (±)-exo-6-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-9-((2-(trimethyldecyl)ethoxy)methyl)-9H-indole
室溫下，向步驟B的產品(62mg，0.14mmol)的DMF(5mL)溶液中加入DIPEA(21.7mg，0.188mmol)和HATU(58.5mg，0.154mmol)。攪拌0.5小時後，加入4-(三氟甲基)-1,2-二氨基苯(27.1mg，0.15mmol)，將該混合物攪拌過夜。向該反應液中加入水並用乙酸乙酯(3×20mL)萃取，將合併的有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 DIPEA (21.7 mg, 0.188 mmol) and HATU (58.5 mg, 0.154 mmol) were added to aq. After stirring for 0.5 hours, 4-(trifluoromethyl)-1,2-diaminobenzene (27.1 mg, 0.15 mmol) was added and the mixture was stirred overnight. Water was added to the mixture and the mixture was evaporated. The residue obtained was used in the next reaction without further purification.
將粗產品溶於醋酸(5mL)中並在60℃下攪拌5小時。該混合物用乙酸乙酯(3×20mL)萃取，將合併的有機相用Na2CO3溶液和飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯)純化得到到目標化合物(50mg，61.4%)，為白色固體。MS：M/e 581(M+1)+。 The crude product was dissolved in acetic acid (5 mL) and stirred at 60 ° C for 5 hr. The mixture (3 × 20mL) and extracted with ethyl acetate, and the combined organic phases with Na 2 CO 3 solution and saturated saline water (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: MS: M/e 581 (M+1) + .
步驟D：(±)-exo-6-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-9H- 嘌呤(化合物3.5) Step D: (±)-exo-6-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-9H- 嘌呤 (Compound 3.5)
在氮氣保護下，向步驟C的產品(50mg，0.086mmol)，1,2-二氨基乙烷(0.5mL)的THF(10mL)溶液中加入四丁基氟化銨的THF溶液(0.3mL，1.0M)。該混合物在60℃下攪拌5小時。向該反應混合物中加入乙酸乙酯(20mL)並用飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾並濃縮，所得殘留物通過製備薄層色譜法(二氯甲烷：甲醇=10：1)純化得到目標化合物(10mg，26%)，為白色固體。1H-NMR(600MHz,CD3OD)δ 8.46(s,2H),7.83(br.s,1H),7.67(br.s,1H),7.54(d,J=8.5Hz,1H),7.50(d,J=2.4Hz,1H),7.17(dd,J=2.4,9.0Hz,1H),7.07(d,J=8.4Hz,1H),5.43(dd,J=1.2,3.0Hz,1H),3.62(dd,J=3.0,5.4Hz,1H),2.01(dd,J=1.2,3.0Hz,1H)ppm。MS：M/e 451(M+1)+。 To a solution of the product from Step C (50 mg, 0.086 mmol), EtOAc (EtOAc) 1.0M). The mixture was stirred at 60 ° C for 5 hours. Ethyl acetate (20 mL) was added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated Compound (10 mg, 26%) was obtained as a white solid. 1 H-NMR (600MHz, CD 3 OD) δ 8.46 (s, 2H), 7.83 (br.s, 1H), 7.67 (br.s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 2.4, 9.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 5.43 (dd, J = 1.2, 3.0 Hz, 1H) , 3.62 (dd, J = 3.0, 5.4 Hz, 1H), 2.01 (dd, J = 1.2, 3.0 Hz, 1H) ppm. MS: M/e 451 (M+1) + .
化合物3.6：(±)-exo-2-(5-(吡啶-4-基氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-6-(三氟甲基)-1H-苯並[d]咪唑 Compound 3.6 : (±)-exo-2-(5-(pyridin-4-yloxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-6-( Trifluoromethyl)-1H-benzo[d]imidazole
步驟A：(±)-exo-5-(吡啶-4-基氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯 Step A: (±)-exo-5-(pyridin-4-yloxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester
將5-羥基-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸乙酯(化合物2.1的合成中步驟C的產品，150mg，0.69mmol)，4-溴吡啶鹽酸鹽(134mg，0.69mol)，碳酸銫(681mg，2.07mmol)，銅粉(cat.)的DMF(5mL)混合物在微波150℃下攪拌30分鐘。過濾該混合物並將濾液稀釋于水(20mL)中，乙酸乙酯(5×10mL)萃取。將合併的有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備薄層色譜法(乙酸乙酯：石油醚=1：2)純化得到目標化合物(20mg，10%)，為無色油狀。MS：M/e 298(M+1)+。 5-Hydroxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid ethyl ester (product of step C in the synthesis of compound 2.1 , 150 mg, 0.69 mmol), 4-bromopyridine The hydrochloride (134 mg, 0.69 mol), cesium carbonate (681 mg, 2.07 mmol), and a mixture of copper powder (cat.) in DMF (5 mL) was stirred at 150 ° C for 30 min. The mixture was filtered and the filtrate diluted with water (20 mL) The combined organic phases were washed with EtOAc EtOAc m. The residue obtained was purified by EtOAc (EtOAc:EtOAc:EtOAc MS: M/e 298 (M+1) + .
步驟B：(±)-exo-5-(吡啶-4-基氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-羧酸 Step B: (±)-exo-5-(pyridin-4-yloxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-carboxylic acid
將步驟A的產品(20mg，0.077mmol)和氫氧化鈉水 溶液(0.15mL，2M，0.30mmol)的THF(4mL)溶液60℃下攪拌5小時。減壓除去溶劑並將殘留物用HCl(2mol/L)中和至pH=7並減壓濃縮得到粗品化合物，該化合物直接用於下一步反應。 The product of step A (20 mg, 0.077 mmol) and sodium hydroxide water A solution of the solution (0.15 mL, 2M, 0.30 mmol) in THF (4 mL) The solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjj
步驟C：(±)-exo-2-(5-(吡啶-4-基氧基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-1-基)-6-(三氟甲基)-1H-苯並[d]咪唑(化合物3.6) Step C: (±)-exo-2-(5-(pyridin-4-yloxy)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-1-yl)-6-( Trifluoromethyl)-1H-benzo[d]imidazole (compound 3.6)
室溫下，向步驟B的產品(0.077mmol)的DMF(3mL)溶液中加入DIPEA(20mg，0.155mmol)和HATU(32.4mg，0.0853mmol)。攪拌30分鐘後，加入4-(三氟甲基)-1,2-二氨基苯(15mg，0.0853mmol)，將該混合物攪拌過夜。向該反應液中加入水並用乙酸乙酯(3×20mL)萃取，將合併的有機相用飽和食鹽水(2×10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物無需進一步純化直接用於下一步反應。 DIPEA (20 mg, 0.155 mmol) and HATU (32.4 mg, 0.0853 mmol) were added to a solution of the product from step B (0.077 mmol) in DMF (3 mL). After stirring for 30 minutes, 4-(trifluoromethyl)-1,2-diaminobenzene (15 mg, 0.0853 mmol) was added and the mixture was stirred overnight. Water was added to the mixture and the mixture was evaporated. The residue obtained was used in the next reaction without further purification.
將粗產品溶於醋酸(4mL)中並在60℃下攪拌6小時。該混合物用乙酸乙酯(3×20mL)萃取，將合併的有機相用Na2CO3溶液和飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮。所得殘留物通過製備高效液相色譜法純化得到到目標化合物(10mg，三步31.6%)，為白色固體。1H-NMR(400MHz,CD3OD)δ 8.39(br.s,2H),7.77(s,1H),7.62(d,J=8.4Hz,1H),7.47(dd,J=1.2,8.8Hz,1H),7.31(d,J=2.4Hz,1H),7.03-6.91(m,4H),5.35(dd,J=1.2,5.6Hz,1H), 3.53(dd,J=3.6,5.6Hz,1H),1.90(dd,J=1.6,3.6Hz,1H)ppm。MS：M/e 410(M+1)+。 The crude product was dissolved in acetic acid (4 mL) and stirred at 60 ° C for 6 hr. The mixture (3 × 20mL) and extracted with ethyl acetate, and the combined organic phases with Na 2 CO 3 solution and saturated saline water (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by preparative high-purity chromatography to give the title compound (10 mg, three step 31.6%) as white solid. 1 H-NMR (400 MHz, CD 3 OD) δ 8.39 (br.s, 2H), 7.77 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 1.2, 8.8 Hz , 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.03-6.91 (m, 4H), 5.35 (dd, J = 1.2, 5.6 Hz, 1H), 3.53 (dd, J = 3.6, 5.6 Hz, 1H), 1.90 (dd, J = 1.6, 3.6 Hz, 1H) ppm. MS: M/e 410 (M+1) + .
化合物3.7：(±)-exo-5-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-H-環丙烷[b]苯並呋喃-5-基)氧基)-1H-吡啶並[2,3-d][1,3]惡嗪-2(4H)-酮 Compound 3.7 : (±)-exo-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-H-cyclopropane [b]benzofuran-5-yl)oxy)-1H-pyrido[2,3-d][1,3]oxazine-2(4H)-one
步驟A：(4-氟-3-甲醯基吡啶-2-基)氨基叔丁酯 Step A: (4-Fluoro-3-carboxyridin-2-yl)amino-tert-butyl ester
在-78℃攪拌下，向4-氟吡啶-2-基氨基叔丁酯(1g，4.72mmol)的THF(20mL)溶液中滴加n-BuLi(4.7mL，11.8mmol)。攪拌0.5小時後，在-78℃下滴加DMF(2mL)的THF(2mL)溶液。TLC顯示反應完全。該反應在-78℃下用1N HCl淬滅至pH=4。然後加入水(20mL)並用乙酸乙酯(3×20mL)萃取。將合併的有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥 並減壓濃縮。所得殘留物通過柱層析法(乙酸乙酯：石油醚=1：2)純化得到目標化合物(0.65g，57%)，為白色固體。1H-NMR(600MHz,DMSO-d 6)δ 10.35(s,1H),9.99(s,1H),8.58-8.56(m,1H),7.23-7.21(m,1H),1.46(s,9H)ppm。 To a solution of 4-fluoropyridin-2-ylamino-tert-butyl ester (1 g, 4.72 mmol) in THF (20 mL), EtOAc (EtOAc) After stirring for 0.5 hours, a solution of DMF (2 mL) in THF (2 mL). TLC showed the reaction was complete. The reaction was quenched to pH = 4 with 1N HCl at -78. Water (20 mL) was then added and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjj 1 H-NMR (600MHz, DMSO- d 6 ) δ 10.35 (s, 1H), 9.99 (s, 1H), 8.58-8.56 (m, 1H), 7.23-7.21 (m, 1H), 1.46 (s, 9H) )ppm.
步驟B：4-氟-3-(羥甲基)吡啶-2-基氨基叔丁酯 Step B: 4-Fluoro-3-(hydroxymethyl)pyridin-2-ylamino tert-butyl ester
在0℃下，向步驟A的產品(480mg，2mmol)的甲醇(3mL)溶液加入NaBH4(76mg，2mmol)。該反應液在0℃下攪拌30分鐘。將反應液用飽和NH4Cl溶液(1mL)和水(5mL)淬滅，乙酸乙酯(2×15mL)萃取。將合併的有機相用無水硫酸鈉乾燥，過濾並減壓濃縮，得到目標化合物(460mg，95%)，為白色固體，該產品直接用於下一步反應。1H-NMR(600MHz,DMSO-d 6)δ 9.20(s,1H),8.31-8.28(m,1H),7.11-7.09(m,1H),5.26(t,J=6.0Hz,1H),4.48(d,J=6.0Hz,2H),1.45(s,9H)ppm。MS：M/e 243(M+1)+。 To a solution of the product from step A (480 mg, 2 <RTI ID=0.0></RTI><RTIgt; The reaction solution was stirred at 0 ° C for 30 minutes. The reaction was quenched with saturated NH 4 Cl solution (1 mL) and water (5mL), ethyl acetate (2 × 15mL) and extracted. The combined organic phases were dried with EtOAc EtOAc m. 1 H-NMR (600MHz, DMSO- d 6) δ 9.20 (s, 1H), 8.31-8.28 (m, 1H), 7.11-7.09 (m, 1H), 5.26 (t, J = 6.0Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 1.45 (s, 9H) ppm. MS: M/e 243 (M+1) + .
步驟C：3-(溴甲基)-4-氟吡啶-2-基氨基叔丁酯 Step C: 3-(Bromomethyl)-4-fluoropyridin-2-ylamino tert-butyl ester
將CBr4(531mg，1.6mmol)加入到步驟B的產品(242mg，1mmol)的THF(3mL)溶液中。然後將三苯基膦的THF(1mL)溶液滴入並將該混合物在室溫下攪拌3小時。該混合物被裝入矽膠柱。用(乙酸乙酯：石油醚=1：3)洗脫得到目標化合物(160mg，52%)，為白色固體。1H-NMR(400MHz,CDCl3)δ 8.38-8.35(m,1H),7.09(s,1H),6.90-6.86(m,1H),4.61(s,2H),1.54(s,9H)ppm。MS：M/e 305(M+1)+。 The CBr 4 (531mg, 1.6mmol) was added to the product from Step B (242mg, 1mmol) in THF (3mL). Then a solution of triphenylphosphine in THF (1 mL) was added dropwise and the mixture was stirred at room temperature for 3 hr. The mixture was loaded onto a silicone column. The title compound (160 mg, 52%) eluted 1 H-NMR (400 MHz, CDCl 3 ) δ 8.38-8.35 (m, 1H), 7.09 (s, 1H), 6.90-6.86 (m, 1H), 4.61 (s, 2H), 1.54 (s, 9H) ppm . MS: M/e 305 (M+1) + .
步驟D：5-氟-1H-吡啶並[2,3-d][1,3]惡嗪-2(4H)-酮 Step D: 5-Fluoro-1H-pyrido[2,3-d][1,3]oxazine-2(4H)-one
在氮氣保護下，將步驟C的產品(120mg，0.4mmol)的DMSO(1mL)溶液在60℃下攪拌4小時。然後加入水(10mL)並用乙酸乙酯(3×15mL)萃取。將合併的有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備薄層色譜(乙酸乙酯：石油醚=1：1)純化得到目標化合物(20mg，30%)，為固體。1H-NMR(600MHz,DMSO-d 6)δ 10.95(s,1H),8.21-8.18(m,1H),6.97-6.94(m,1H),5.37(s,2H)ppm。MS：M/e 169(M+1)+。 The product of step C (120 mg, 0.4 mmol) in DMSO (1 mL) was stirred at <RTIgt; Water (10 mL) was then added and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue obtained was purified by EtOAc EtOAcjjjjjjj 1 H-NMR (600 MHz, DMSO- d 6 ) δ 10.95 (s, 1H), 8.21 - 8.18 (m, 1H), 6.97 - 6.94 (m, 1H), 5.37 (s, 2H) ppm. MS: M/e 169 (M+1) + .
步驟E：(±)-exo-5-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-1H-吡啶並[2,3-d][1,3]惡嗪-2(4H)-酮 Step E: (±)-exo-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropane [b]benzofuran-5-yl)oxy)-1H-pyrido[2,3-d][1,3]oxazine-2(4H)-one
將化合物3.2的步驟B的產品(16mg，0.1mmol)，步驟D的產品(33mg，0.1mmol)和Cs2CO3(98mg，0.3mmol)的DMF(2mL)混合物在110℃下攪拌3小時。將該混合物降至室溫，加入水(10mL)並用乙酸乙酯(3×15mL)萃取。將合 併的有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥並減壓濃縮。所得殘留物通過製備高效液相色譜法純化得到標題化合物(7mg，15%)，為白色固體。1H-NMR(400MHz,DMSO-d 6)δ 12.85(s,1H),10.73(s,1H),8.03(d,J=6.0Hz,1H),7.85(s,1H),7.67(d,J=8.4Hz,1H),7.46(d,J=8.0Hz,1H),7.41(d,J=2.4Hz,1H),7.10-7.06(m,2H),6.30(d,J=6.0Hz,1H),5.44-5.42(m,3H),3.55(dd,J=3.6,5.2Hz,1H),1.97(d,J=2.8Hz,1H)ppm。MS：M/e 481(M+1)+。 Step 3.2 The compound B product (16mg, 0.1mmol), the product of Step D (33mg, 0.1mmol), and Cs 2 CO 3 (98mg, 0.3mmol ) in DMF (2mL) was stirred at 110 ℃ 3 hours. The mixture was cooled to room temperature, water (10 mL) was evaporated andEtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAcqqqqqq 1 H-NMR (400MHz, DMSO- d 6) δ 12.85 (s, 1H), 10.73 (s, 1H), 8.03 (d, J = 6.0Hz, 1H), 7.85 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.46 (d, J = 8.0Hz, 1H), 7.41 (d, J = 2.4Hz, 1H), 7.10-7.06 (m, 2H), 6.30 (d, J = 6.0Hz, 1H), 5.44 - 5.42 (m, 3H), 3.55 (dd, J = 3.6, 5.2 Hz, 1H), 1.97 (d, J = 2.8 Hz, 1H) ppm. MS: M/e 481 (M+1) + .
化合物3.8：(±)-exo-6-氯-5-((1-(6-(三氟甲基)-1H-苯並[d]咪唑-2-基)-1a,6b-二氫-1H-環丙烷[b]苯並呋喃-5-基)氧基)-3,4-二氫-1,8-萘啶-2(1H)-酮 Compound 3.8: (±)-exo-6-chloro-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro- 1H-cyclopropane [b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one
室溫攪拌下，向化合物2.2(70mg，0.15mmol)的AcOH(2mL)溶液中加入NCS(19mg，0.15mmol)並將該混合物加熱到60℃攪拌3小時。減壓濃縮該混合物並向殘留物中加入2N NaOH溶液(2mL)，乙酸乙酯(2mL×3)萃取。將合併的有機相用飽和食鹽水(2mL×3)洗滌，無水硫酸鈉乾燥並 減壓濃縮。所得殘留物通過製備薄層色譜法純化得到目標化合物(9mg，12%)，為白色固體。1H-NMR(600MHz,DMSO-d 6)δ 12.85(s,1H),10.76(s,1H),8.29(s,1H),7.83(s,1H),7.66(d,J=8.4Hz,1H),7.45(d,J=8.3Hz,1H),7.14(d,J=2.8Hz,1H),6.95(d,J=8.8Hz,1H),6.77(dd,J=8.8,2.8Hz,1H),5.36(dd,J=5.4,1.2Hz,1H),3.48(dd,J=5.3,3.3Hz,1H),2.74(t,J=7.8Hz,2H),2.48(t,J=7.8Hz,2H),1.91(s,1H)ppm。MS：M/e 513(M+1)+。 NCS (19 mg, 0.15 mmol) was added to a solution of Compound EtOAc (EtOAc,EtOAc. The mixture was concentrated under reduced pressure and dichloromethane (2 mL) The combined organic layers were washed with EtOAc EtOAc m. The residue obtained was purified by EtOAcqqqqqqq 1 H-NMR (600MHz, DMSO- d 6) δ 12.85 (s, 1H), 10.76 (s, 1H), 8.29 (s, 1H), 7.83 (s, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8, 2.8 Hz, 1H), 5.36 (dd, J = 5.4, 1.2 Hz, 1H), 3.48 (dd, J = 5.3, 3.3 Hz, 1H), 2.74 (t, J = 7.8 Hz, 2H), 2.48 (t, J = 7.8) Hz, 2H), 1.91 (s, 1 H) ppm. MS: M/e 513 (M+1) + .
Raf IC50實驗方案 Raf IC 50 protocol
本文揭示的化合物使用時間-分辨螢光能量轉移方法測試了針對B-Raf(V600E)(PV3849，來自Invitrogen)或C-Raf(Y340D/Y341D)(PV3805，來自Invitrogen)的活性。該試驗是在含有0.0625nM B-Raf或0.5nM C-Raf、25mM Tris pH7.4、10mM MgCl2、0.5mM EGTA、0.5mM Na3BO4、5mM β-磷酸甘油、0.01% Triton X-100、2.5mM DTT、0.1% BSA、0.1mM ATP、13.7nM GST標籤的MEK1(帶有K97R突變全長蛋白，從細菌表達系統中提純的重組蛋白)和0-5μM本文中揭示的化合物(最終濃度含1% DMSO)的反應(10μL)中進行的。將酶和該化合物在室溫下溫育60分鐘，加入ATP和GST-MEK1起始反應。室溫下溫育60分鐘後，加入等體積含有25mM Tris pH7.4、400mM KF、50mM EDTA、0.01% BSA、0.01% Triton X-100、1反應的偶聯Eu3+ cryptate的抗磷酸化MEK1/2(Ser217/221)兔多抗和1反應的偶聯d2的抗谷胱甘肽轉移酶鼠單抗，以停止反應。板子封閉起來，並在室溫下溫 育2小時，然後在BMG PHERA star FS儀器上讀取TR-FRET信號。用Graphpad Prism軟體通過非線性回歸計算出每個化合物的IC50。 The compounds disclosed herein were tested for activity against B-Raf (V600E) (PV3849 from Invitrogen) or C-Raf (Y340D/Y341D) (PV3805 from Invitrogen) using a time-resolved fluorescence energy transfer method. The assay was performed with 0.0625 nM B-Raf or 0.5 nM C-Raf, 25 mM Tris pH 7.4, 10 mM MgCl 2 , 0.5 mM EGTA, 0.5 mM Na 3 BO 4 , 5 mM β-glycerophosphate, 0.01% Triton X-100. , 2.5 mM DTT, 0.1% BSA, 0.1 mM ATP, 13.7 nM GST-tagged MEK1 (with K97R mutant full-length protein, recombinant protein purified from bacterial expression system) and 0-5 μM of the compounds disclosed herein (final concentration included) 1% DMSO) was carried out in a reaction (10 μL). The enzyme and the compound were incubated for 60 minutes at room temperature, and ATP and GST-MEK1 were added to initiate the reaction. After incubation for 60 minutes at room temperature, an equal volume of anti-phosphorylated MEK1 coupled with Eu 3+ cryptate containing 25 mM Tris pH 7.4, 400 mM KF, 50 mM EDTA, 0.01% BSA, 0.01% Triton X-100, 1 reaction was added. /2 (Ser217/221) rabbit polyclonal antibody and 1 reaction coupled with d2 anti-glutathione transferase murine mAb to stop the reaction. The plates were closed and incubated for 2 hours at room temperature and then the TR-FRET signal was read on a BMG PHERA star FS instrument. Using Graphpad Prism software to calculate the IC 50 for each compound by nonlinear regression.
化合物1.1-1.3、2.1-2.37和3.1-3.8抑制了B-Raf(V600E)/C-Raf，IC50值在0.1nM-10μM範圍內。 Compounds 1.1-1.3 , 2.1-2.37 and 3.1-3.8 inhibited B-Raf (V600E)/C-Raf with IC 50 values ranging from 0.1 nM to 10 μM.
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