TWI633107B - Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors - Google Patents
Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors Download PDFInfo
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Abstract
本發明揭示的是一類稠合的四元或五元環的化合物及其鹽、其藥學組合物,及其使用方法。 The present invention discloses a fused four or five membered ring compound, and salts thereof, pharmaceutical compositions thereof, and methods of use thereof.
Description
本發明揭示的是稠合的四元或五元環化合物,該類化合物可以抑制聚(ADP-核糖)聚合酶(PARP)的活性,藥學成分中至少包括本發明揭示的一個化合物,用於治療特定的疾病。 The present invention discloses a fused quaternary or five-membered ring compound which inhibits the activity of poly(ADP-ribose) polymerase (PARP), which comprises at least one compound disclosed in the present invention for treatment. Specific disease.
聚(ADP-核糖)聚合酶(PARP),以前公認是聚(ADP-核糖)合酶或者聚(ADP-核糖)轉移酶,是含有PARP催化區域的一類蛋白質(BMC Genomics,2005年10月4日;6:139)。迄今為止發現了PARP家族中的大約17位成員,包括PARP-1、PARP-2、PARP-3、PARP-4(Vault-PARP)、PARP-5a(端錨聚合酶-1,Tankyrase-1)、PARP5b(端錨聚合酶-2,Tankyrase-2)、PARP-6、PARP-7(tiPARP)、PARP-8、PARP-9(BAL1)、PARP-10、PARP-11、PARP-12、PARP-13(ZAP)、PARP-14(CoaSt6)、PARP-15和PARP-16。各種PARP的催化活性是可以將ADP-核糖的部分從煙醯胺腺嘌呤二核苷酸(NAD+)轉移至很多靶蛋白質的谷氨酸殘基上,從而形成ADP-核糖聚合物的長鏈。然而,有報導稱,一些PARP 家族成員只能催化靶蛋白的單ADP-核糖基化,其他PARP家族成員這一活性還未見報道(Mol.Cell.2008年10月10日;32(1):57-69.)。研究表明,很多的PARP酶在很多方面有重要的功能性作用,例如,DNA修復、轉錄調控、有絲分裂進程、維持基因組的完整性、端粒穩定性、細胞死亡和Wnt信號通路。 Poly(ADP-ribose) polymerase (PARP), previously recognized as poly(ADP-ribose) synthase or poly(ADP-ribose) transferase, is a class of proteins containing PARP catalytic regions ( BMC Genomics , October 4, 2005) Day; 6:139). To date, approximately 17 members of the PARP family have been discovered, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5a (terminal anchorase-1, Tankyrase-1). , PARP5b (terminal anchorase-2, Tankyrase-2), PARP-6, PARP-7 (tiPARP), PARP-8, PARP-9 (BAL1), PARP-10, PARP-11, PARP-12, PARP -13 (ZAP), PARP-14 (CoaSt6), PARP-15 and PARP-16. The catalytic activity of various PARPs is such that a portion of the ADP-ribose can be transferred from the nicotinamide adenine dinucleotide (NAD + ) to the glutamate residue of many target proteins, thereby forming a long chain of the ADP-ribose polymer. . However, it has been reported that some members of the PARP family can only catalyze the single ADP-ribosylation of target proteins, and the activity of other PARP family members has not been reported ( Mol. Cell. October 10, 2008; 32(1) :57-69.). Studies have shown that many PARP enzymes have important functional roles in many aspects, such as DNA repair, transcriptional regulation, mitotic progression, maintenance of genomic integrity, telomere stability, cell death, and Wnt signaling pathways.
PARP-1可能是數量最大,研究最多的家族成員了,PARP-2可能是PARP-1最相近的成員。損壞的DNA片段可以啟動PARP,一旦啟動,會催化多聚ADP核糖單元,連接到多種核蛋白上,包括組蛋白和PARP自身。研究表明,聚(ADP-核糖)合成的重點是在DNA損壞的地方停止轉錄和增加修復酶。已有研究報導了PARP在斷裂DNA鏈修復中起到關鍵作用。敲除PARP-1使細胞對多種治療方式更敏感,如烷基化試劑,拓撲異構酶(topo)I抑制劑和γ-輻射。研究表明,PARP抑制劑可以增強腫瘤對放療的敏感度(包括電離輻射和其他破壞DNA的治療),也能增加對抗癌藥物的敏感度(包括鉑類藥物、替莫唑胺和拓撲異構酶I抑制劑)。還有研究表明,PARP抑制劑還對放射增敏(低氧)的腫瘤細胞有效果和阻止腫瘤細胞在放療後從潛在的致死性和亞致死性DNA損傷中恢復回來,可能是因為PARP抑制劑能夠抑制斷裂的DNA鏈重組,並且能夠影響一些DNA損傷的信號傳輸通道. PARP-1 is probably the largest and most studied family member, and PARP-2 may be the closest member of PARP-1. The damaged DNA fragment can initiate PARP, and once activated, catalyzes the poly ADP ribose unit, which is linked to a variety of nuclear proteins, including histones and PARP itself. Studies have shown that the focus of poly(ADP-ribose) synthesis is to stop transcription and increase repair enzymes where DNA is damaged. Studies have reported that PARP plays a key role in the repair of broken DNA strands. Knocking out PARP-1 makes cells more sensitive to a variety of therapeutic modalities, such as alkylating agents, topoisomerase (topo) I inhibitors, and gamma-irradiation. Studies have shown that PARP inhibitors can enhance the sensitivity of tumors to radiation therapy (including ionizing radiation and other DNA-damaging treatments), as well as increase the sensitivity of anticancer drugs (including platinum drugs, temozolomide and topoisomerase I inhibition). Agent). Studies have also shown that PARP inhibitors also have an effect on radiosensitized (hypoxic) tumor cells and prevent tumor cells from recovering from potentially lethal and sublethal DNA damage after radiotherapy, possibly because of PARP inhibitors. It can inhibit the DNA strand reorganization of rupture and can affect some signal transmission channels of DNA damage.
PARP抑制劑可以通過合成致死的概念有效的破壞有BRCA1或BRCA2基因缺陷的腫瘤。同時,野生型BRCA基因腫瘤對PARP抑制劑不敏感。BRCA1或者BRCA2的缺陷 會顯著提高這些基因對PARP抑制劑的敏感性。PARP抑制劑有可能增加DNA單鏈斷裂(SSB),在複製過程中,單鏈斷裂會轉化為有毒性的DNA雙鏈斷裂(DSB),而雙鏈斷裂無法在BRCA1/2有缺陷的細胞中的通過同源重組修復。有研究也表明,在ATM、ATR、RAD51缺陷,以及其他同源重組修復有缺陷時,PARP抑制劑也會導致合成致死。PARP抑制劑可以治療有DNA修復缺陷的癌症。 PARP inhibitors can effectively destroy tumors with BRCA1 or BRCA2 gene defects by synthesizing a lethal concept. At the same time, wild-type BRCA gene tumors are not sensitive to PARP inhibitors. Defects of BRCA1 or BRCA2 Significantly increase the sensitivity of these genes to PARP inhibitors. PARP inhibitors may increase DNA single-strand breaks (SSB), in which single-strand breaks are converted to toxic DNA double-strand breaks (DSB), while double-strand breaks are not possible in BRCA1/2 deficient cells. Repair by homologous recombination. Studies have also shown that PARP inhibitors can lead to synthetic lethality when ATM, ATR, RAD51 deficiency, and other homologous recombination repairs are defective. PARP inhibitors can treat cancers with DNA repair defects.
PARP的活化作用也可能用於治療細胞死亡。中風、外傷、帕金森疾病時發生的缺血再灌注損傷和神經損傷可能伴隨著PARP的過度啟動。PARP的過度啟動也可能使NAD+迅速消耗,形成ADP核糖多聚物。因為NAD+的生物合成會消耗ATP,細胞的ATP的水準會隨後耗盡,死於缺血性細胞壞死。抑制PARP很可能會因為能夠保持細胞的NAD+和ATP水準和阻止特定的炎症通路的啟動而降低細胞壞死的可能,該炎症通路會使細胞因為一種免疫反應而被進一步破壞。 Activation of PARP may also be used to treat cell death. Ischemia-reperfusion injury and nerve damage during stroke, trauma, and Parkinson's disease may be accompanied by excessive initiation of PARP. Excessive initiation of PARP may also cause rapid depletion of NAD + to form ADP ribose polymers. Because the biosynthesis of NAD + consumes ATP, the level of ATP in the cells is subsequently depleted, dying from ischemic cell necrosis. Inhibition of PARP is likely to reduce the possibility of cell necrosis by maintaining the NAD + and ATP levels of the cells and preventing the initiation of specific inflammatory pathways that cause the cells to be further destroyed by an immune response.
有報導稱,PARP的啟動對NMDA和NO-誘導的神經毒性有著很重要的作用。該報導基於皮質培養和海馬腦片,其中毒性的預防和PARP的抑制活性直接相關。可以假定PARP抑制劑在治療神經退行性疾病和頭部外傷中有潛在的作用。 It has been reported that the initiation of PARP plays an important role in NMDA and NO-induced neurotoxicity. This report is based on cortical culture and hippocampal slices, where prevention of toxicity is directly related to the inhibitory activity of PARP. It can be assumed that PARP inhibitors have a potential role in the treatment of neurodegenerative diseases and head trauma.
研究表明,PARP抑制劑可以用於治療和預防自身免疫疾病,例如,I型糖尿病和糖尿病併發症(Pharmaceutical Research(2005)52:60-71)。 Studies have shown that PARP inhibitors can be used to treat and prevent autoimmune diseases such as type I diabetes and diabetic complications (Pharmaceutical Research (2005) 52: 60-71).
PARP-3是PARP家族中有新特點的成員。最近有研 究表明,PARP-3在保持基因組的完整性和有絲分裂過程中都起到重要作用(PNAS 2011年2月15日|卷108 |編號7 | 2783-2788)。PARP-3不足會引發細胞對DNA雙鏈斷裂回應降低。PARP-3缺乏同時使用PARP-1/2抑制劑會使細胞經x-照射後存活率降低。PARP-3對保持有絲分裂紡錘體的完整性和端粒的穩定很有必要。因此PARP-3也可能有潛在的抗癌活性。 PARP-3 is a member of the PARP family with new features. Recently research Studies have shown that PARP-3 plays an important role in maintaining genomic integrity and mitosis (PNAS February 15, 2011 | Vol. 108 | No. 7 | 2783-2788). Insufficient PARP-3 causes a decrease in cellular response to DNA double-strand breaks. The lack of PARP-3 deficiency in the use of PARP-1/2 inhibitors results in a decrease in cell viability after x-irradiation. PARP-3 is necessary to maintain the integrity of the mitotic spindle and the stability of the telomeres. Therefore, PARP-3 may also have potential anticancer activity.
端錨聚合酶-1(Tankyrase-1)(與TRF1相互作用錨蛋白相關的ADP-核糖聚合酶1)開始被認為是一種人類端粒酶複合體的組分。端錨聚合酶-2(Tankyrase-2)與端錨聚合酶-1的序列同源性可能為83%,序列相似性可能為90%。小鼠遺傳學研究表明,端錨聚合酶-1和端錨聚合酶-2大量的功能相同。端錨聚合酶-1能夠正向調節端粒長度,使端粒延長。抑制端錨聚合酶可以使細胞對端粒酶抑制劑更敏感。端錨聚合酶-1對有絲分裂中的姊妹端粒分解很有必要。通過RNAi抑制端錨聚合酶-1可以誘導有絲分裂阻滯。端錨聚合酶的抑制作用可能有潛在抗癌活性。 Tankyrase-1 (ADP-ribose polymerase 1 associated with TRF1 interacting with ankyrin) was initially considered to be a component of the human telomerase complex. The sequence homology of Tankyrase-2 to tankyrase-1 may be 83% and the sequence similarity may be 90%. Mouse genetic studies have shown that tankyrase-1 and tankyrase-2 have a large number of functions. Tankyrase-1 is capable of positively regulating telomere length and prolonging telomeres. Inhibition of tankyrase can make cells more sensitive to telomerase inhibitors. Tankyrase-1 is necessary for sister telomere breakdown in mitosis. Mitotic arrest can be induced by RNAi inhibition of tankyrase-1. Inhibition of tankyrase may have potential anticancer activity.
有研究表明,端錨聚合酶與Wnt信號通路的調控有關。Wnt信號通路會由β-連環蛋白降解複合物通過對下游效應器β-連環蛋白水解產生負調節,該β-連環蛋白降解複合物包括腺瘤性息肉病(APC),軸蛋白(Axin)和糖原合酶激酶3α/β(GSK3α/β)。研究表明,多種癌症中都發現Wnt信號通路的不適當啟動。腫瘤抑制基因APC的截斷突變很明顯是結直腸癌中最常見的遺傳變異。APC突變可能會產生缺陷的β-連 環蛋白降解複合物,核β-連環蛋白的積累,及/或Wnt信號通路應答基因的活躍轉錄。也有報導表明端錨聚合酶抑制劑可以通過提高軸蛋白的水準,來穩定β-連環蛋白降解複合物。軸蛋白(Axin),是β-連環蛋白降解複合物的關鍵組分,可以通過聚腺苷二磷酸核醣聚合(PARylation)和泛素化來降解。抑制端錨聚合酶可以減少軸蛋白降解及/或增加軸蛋白水準。研究表明,端錨聚合酶抑制劑抑制來抑制APC缺陷的結腸癌細胞集落形成。因此,端錨聚合酶抑制劑可能對啟動的Wnt信號通路的癌症有潛在的療效。 Studies have shown that tankyrase is involved in the regulation of Wnt signaling. The Wnt signaling pathway is negatively regulated by the β-catenin degradation complex by hydrolysis of the downstream effector β-catenin, which includes adenomatous polyposis (APC), axin (Axin) and Glycogen synthase kinase 3α/β (GSK3α/β). Studies have shown that inappropriate initiation of the Wnt signaling pathway is found in a variety of cancers. The truncation mutation of the tumor suppressor gene APC is clearly the most common genetic variation in colorectal cancer. APC mutations may produce defective β-links Cyclin-degrading complexes, accumulation of nuclear β-catenin, and/or active transcription of Wnt signaling pathway-responsive genes. It has also been reported that a tankyrase inhibitor can stabilize the β-catenin degradation complex by increasing the level of the axon. Axin, a key component of the β-catenin degradation complex, can be degraded by polyadenylation, ribylation and ubiquitination. Inhibition of tankyrase can reduce axonal degradation and/or increase axon levels. Studies have shown that tankyrase inhibitors inhibit colony formation in colon cancer cells that inhibit APC deficiency. Therefore, tankyrase inhibitors may have potential therapeutic effects on cancers that initiate the Wnt signaling pathway.
本發明提供了化合物及/或其藥學上可以接受的鹽,藥學組合物包括至少這些化合物的一種和其藥學上可以接受的鹽,用來抑制PARP活性,從而治療疾病,例如癌症。例如,本發明描述的化合物和組合物可以用來治療有DNA修復通路缺陷的癌症,及/或用於增強化療和放射治療的療效。 The present invention provides a compound and/or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises at least one of these compounds and a pharmaceutically acceptable salt thereof for inhibiting PARP activity, thereby treating a disease such as cancer. For example, the compounds and compositions described herein can be used to treat cancers that are defective in DNA repair pathways, and/or to enhance the efficacy of chemotherapy and radiation therapy.
據報導,某些小分子化合物可以作為PARP抑制劑。例如:PCT公開號WO 2000/42040和2004/800713,報導了三環吲哚衍生物作為PARP抑制劑。PCT公開號WO 2002/44183和2004/105700,報導了三環二氮雜吲哚衍生物作為PARP抑制劑。PCT公開號WO 2011/130661和GB專利2462361,報導了二氫吡啶酞嗪酮衍生物作為PARP抑制劑。以下發明報導了其他環狀化合物作為PARP抑制劑,US 7,915,280;US 7,235,557;USRE041150;US 6,887,996和EP1339402B1。 It has been reported that certain small molecule compounds can be used as PARP inhibitors. For example, PCT Publication Nos. WO 2000/42040 and 2004/800713, reported tricyclic indole derivatives as PARP inhibitors. PCT Publication Nos. WO 2002/44183 and 2004/105700 report tricyclic diazepine derivatives as PARP inhibitors. PCT Publication No. WO 2011/130661 and GB Patent 2,462,361, reported dihydropyridazinone derivatives as PARP inhibitors. The following inventions report other cyclic compounds as PARP inhibitors, US 7,915,280; US 7,235,557; USRE041150; US 6,887,996 and EP1339402B1.
PCT公開號WO 2004/4014294,公開於2004年2月19日,報導了4,7-二取代吲哚衍生物作為PARP抑制劑。其 他環狀化合物作為PARP抑制劑也報導於US 6,906,096公開號WO 2009/063244,公開於2009年5月22日,揭示了噠嗪酮衍生物作為PARP抑制劑。GB專利號2462361,公開於2010年10月2日,揭示了二氫吡啶酞嗪酮衍生物作為PARP抑制劑。US 7,429,578,公開於2008年9月30日報導了三環衍生物作為PARP抑制劑。以下發明報導了其他環狀化合物作為PARP抑制劑:EP1140936B1;US 6,495,541;US 6,799,298。US 6,423,705,公開於2003年7月23日,報導了使用PARP抑制劑的聯合治療。以下發明報導了其他使用PARP抑制劑的聯合用藥治療:US 2009/0312280A1;WO 2007113647A1。US 6,967,198,公開於2005年11月22日,報導了三環化合物作為蛋白激酶抑制劑來增強抗腫瘤藥物和放射治療的藥效。US 7,462,713,公開於2008年12月9日,也報導了三環化合物作為蛋白激酶抑制劑來增強抗腫瘤藥物和放射治療的藥效。EP專利號1585749,公開於2008年8月13日,報導了二氮雜吲哚衍生物用來增強抗腫瘤藥物和放射治療的藥效。 PCT Publication No. WO 2004/4014294, published on Feb. 19, 2004, discloses 4,7-disubstituted indole derivatives as PARP inhibitors. its His cyclic compound as a PARP inhibitor is also reported in US Pat. No. 6,906,096, issued on May 22, 2009, which discloses a pyrazinozin derivative as a PARP inhibitor. GB Patent No. 2,462,361, published on October 2, 2010, discloses dihydropyridazinone derivatives as PARP inhibitors. US 7,429,578, published on September 30, 2008, discloses tricyclic derivatives as PARP inhibitors. The following invention reports other cyclic compounds as PARP inhibitors: EP1140936B1; US 6,495,541; US 6,799,298. US 6,423,705, published July 23, 2003, discloses a combination therapy using a PARP inhibitor. The following invention reports other combination therapies using PARP inhibitors: US 2009/0312280 A1; WO 2007113647 A1. US 6,967,198, published November 22, 2005, discloses tricyclic compounds as protein kinase inhibitors to enhance the efficacy of anti-tumor drugs and radiation therapy. US 7,462,713, published on December 9, 2008, also discloses tricyclic compounds as protein kinase inhibitors to enhance the efficacy of anti-tumor drugs and radiation therapy. EP Patent No. 1585749, published on August 13, 2008, reports the use of diazepine derivatives to enhance the efficacy of anti-tumor drugs and radiation therapy.
本發明揭示的化合物可以作為多聚(ADP-核糖基)轉移酶(PARPs)抑制劑,可以用於治療癌症、中風、腦外傷和神經退行性疾病等。用於治療癌症,本發明揭示的化合物及其藥學上可以接受的鹽類可以和DNA損傷的細胞毒素劑一起給藥,如順鉑、拓撲替康(topotecan)、伊立替康(irinotecan)、替莫唑胺(temozolomide),及/或放射治療。 The compounds disclosed in the present invention can be used as inhibitors of poly(ADP-ribosyl)transferases (PARPs), and can be used for the treatment of cancer, stroke, brain trauma, and neurodegenerative diseases. For use in the treatment of cancer, the compounds disclosed herein and their pharmaceutically acceptable salts can be administered with DNA-damaging cytotoxic agents such as cisplatin, topotecan, irinotecan, temozolomide (temozolomide), and / or radiation therapy.
本發明還提供了至少一種選自分子式(I)的化合物,其異構體,及其藥學上可以接受的鹽:
其中:RN選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基或者雜芳基均可獨立地被至少一個取代基R12任選取代;X選自由C、N、O和S所組成的群組;m和n,可以相同也可不同,可以分別是0、1、2或3之整數;t是0、1、2或3之整數;R 1 ,在每次出現時獨立地選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10、COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基;其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R2選自氫、COR9、CONR9R10、CO2R9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 3 、R 4 、R 5 、R 6 、R 7 和R 8 ,可以相同也可不同,分 別獨立地選自氫、鹵素、-NR9R10、-OR9、氧基、-COR9、-CO2R9、-CONR9R10、-NR9CONR10R11、-NR9CO2R10、-NR9SO2R10和-SO2R9、烷基、烯基、環烷基、芳基、雜環基、炔基和雜芳基;其中各烷基、烯基、炔基、環烷基、芳基、雜環基和雜芳基均可獨立地被至少一個取代基R12任選取代,或者(R3和R4)及/或(R4和R5)及/或(R5和R6)及/或(R6和R7)及/或(R7和R8),與它們所連接的一或多個原子,一起形成具有0、1或2個雜原子的3到8元飽和的、部分不飽和或全部不飽和的環,所述雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-,且該環可以被至少一個取代基R 12 任選取代,條件是:當X是O,R5和R6都不存在,當X是N,R6不存在,當X是S,R5和R6都不存在,或者R5和R6中至少一者是氧基,當R3和R4中的一者是氧基時,另外一者不存在,當R7和R8中的一者是氧基時,另外一者不存在,當X是C,R5和R6中的一者是氧基時,另外一者不存在;R 9 、R 10 和R 11 ,可以相同也可不同,分別選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 12 選自氰基、鹵素、鹵烷基、NO2、-NR'R"、-OR'、 氧基、-COR'、-CO2R'、-CONR'R"、-NR'CONR"R"'、-NR'CO2R"、-NR'SO2R"、-SO2R'、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中R'、R"和R'''獨立地選自氫、鹵烷基、烷基、芳烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,或者(R'和R")及/或(R"和R"'),與它們所連接的幾個碳原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和的、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-。 Wherein: R N is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl The aryl or heteroaryl group may be independently substituted with at least one substituent R 12 ; X is selected from the group consisting of C, N, O and S; m and n may be the same or different and may be respectively Is an integer of 0, 1, 2 or 3; t is an integer of 0, 1 , 2 or 3; R 1 is independently selected from halogen, cyano, NO 2 , OR 9 , NR 9 R 10 at each occurrence , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group may be independently optionally substituted with at least one substituent R 12 ; R 2 is selected from the group consisting of hydrogen, COR 9 , CONR 9 R 10 , CO 2 R 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring The alkyl group, the heterocyclic group, the aryl group and the heteroaryl group may each independently be taken by at least one Group optionally substituted by R 12; R 3, R 4, R 5, R 6, R 7 and R 8, may be the same or different, are independently selected from hydrogen, halogen, -NR 9 R 10, -OR 9 , Oxy, -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 CONR 10 R 11 , -NR 9 CO 2 R 10 , -NR 9 SO 2 R 10 and -SO 2 R 9 , alkane a base, an alkenyl group, a cycloalkyl group, an aryl group, a heterocyclic group, an alkynyl group and a heteroaryl group; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocyclic group and heteroaryl group may be Independently substituted by at least one substituent R 12 , or (R 3 and R 4 ) and/or (R 4 and R 5 ) and/or (R 5 and R 6 ) and/or (R 6 and R 7 ) and / or (R 7 and R 8), with one or more atoms to which they are attached, together form a saturated 3-8 yuan having 1 or 2 heteroatoms, partially unsaturated or fully unsaturated a ring, the hetero atom may be independently selected from -NR 13 -, -O-, -S-, -SO-, and -SO 2 -, and the ring may be optionally substituted with at least one substituent R 12 , provided that : when X is O, R 5 and R 6 are absent, when X is N, R 6 is not present when X is S, R 5 and R 6 do not exist, or R 5 and R 6 at least one of Group, where R 3 and R 4 is a group of one when the other one is absent, when R 7 and R 8 is a group when one of the other one does not exist, and when X is C, When one of R 5 and R 6 is an oxy group, the other one is absent; R 9 , R 10 and R 11 may be the same or different and are respectively selected from hydrogen, alkyl, alkenyl, alkynyl, and ring. An alkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may be independently substituted with at least one substituent R 12 Optionally substituted; R 12 is selected from cyano, halo, haloalkyl, NO 2 , -NR'R", -OR', oxy, -COR', -CO 2 R', -CONR'R", - NR'CONR"R"', -NR'CO 2 R", -NR'SO 2 R", -SO 2 R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and a heteroaryl group, wherein R', R" and R"' are independently selected from the group consisting of hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero An aryl group, or (R' and R") and/or (R" and R"'), together with several carbon atoms to which they are attached, form 3 to 8 having 0, 1 or 2 additional heteroatoms Saturated Partially unsaturated or fully unsaturated ring, the additional heteroatoms may be independently selected from -NR 13 -, - O -, - S -, - SO- and -SO 2 -.
R 13 選自氫、烷基、環烷基、芳基、雜芳基和雜環基。 R 13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
本發明還提供了一種藥物組合物,該藥物組合物至少包含一種藥學上可以接受的載體,和至少一種選自式(I)所示的化合物及其藥學上可以接受的鹽。 The present invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and at least one compound selected from the group consisting of the compound of the formula (I) and a pharmaceutically acceptable salt thereof.
本發明提供了一種抑制PARP的方法,是把PARP和一定量的至少一種這裡所示選自結構式(I)的化合物及其藥學上可以接受的鹽接觸,可以有效的抑制PARP的活性。 The present invention provides a method of inhibiting PARP by contacting PARP with an amount of at least one compound selected from the group consisting of structural formula (I) and a pharmaceutically acceptable salt thereof, which is effective for inhibiting the activity of PARP.
本發明同樣提供了一種可以治療至少一種與PARP抑制相關的疾病的辦法,包括對治療對象給藥,這些治療對象是確認需要治療至少一種相關疾病,而藥物則包括一定量的至少一種本發明所描述選自通式(I)的化合物及其藥學上可以接受的鹽。該藥物可以治療至少一種下述疾病,如癌症(如白血病、結腸癌、膠質母細胞瘤、淋巴瘤、黑色素瘤、乳腺癌和宮頸癌)、細胞毒性癌、缺血再灌注損傷(如那些相關聯的,但不限於心臟衰竭、心肌梗死、中風、其他神經損傷和器官移植等)、再灌注損傷(如眼睛、腎、腸管和骨 骼肌的再灌注)、炎症性疾病(如關節炎、痛風、炎症性腸道疾病、中樞神經系統炎症、多發性硬化症、過敏性腦炎、敗血症、敗血性休克、出血性休克、肺纖維化和葡萄膜炎)、免疫性疾病或紊亂(如類風濕性關節炎和感染性休克)、退行性疾病(如糖尿病、帕金森病)、低血糖症、逆轉錄病毒感染、對乙醯氨基酚過量引發的肝毒性、阿黴素及鉑為基礎的抗腫瘤藥物引發的心臟和腎臟的毒性,硫芥引發的皮膚繼發損傷。 The present invention also provides a method of treating at least one disease associated with PARP inhibition, comprising administering to a subject for confirming the need to treat at least one related disease, and the medicament comprising a quantity of at least one of the present invention A compound selected from the group consisting of the general formula (I) and a pharmaceutically acceptable salt thereof are described. The drug can treat at least one of the following diseases, such as cancer (such as leukemia, colon cancer, glioblastoma, lymphoma, melanoma, breast cancer and cervical cancer), cytotoxic cancer, ischemia-reperfusion injury (such as those related) Combined with, but not limited to, heart failure, myocardial infarction, stroke, other nerve damage and organ transplantation, etc., reperfusion injury (such as eyes, kidneys, intestines and bones) Reperfusion of skeletal muscle), inflammatory diseases (such as arthritis, gout, inflammatory bowel disease, central nervous system inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic shock, lung fiber And uveitis), immune diseases or disorders (such as rheumatoid arthritis and septic shock), degenerative diseases (such as diabetes, Parkinson's disease), hypoglycemia, retroviral infection, acetaminophen Hepatic toxicity induced by phenol excess, doxorubicin and platinum-based anti-tumor drugs, heart and kidney toxicity, secondary damage to skin caused by sulfur mustard.
本發明提供了至少一種本發明描述的選自通式(I)所示化合物及其藥學上可以接受的鹽在藥物生產的用途,該藥物可抑制PARP的活性。 The present invention provides at least one use of a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament which inhibits the activity of PARP.
本發明提供了至少一種本發明描述的選自通式(I)所示化合物及其藥學上可以接受的鹽在藥物生產的用途,該藥物可治療下列至少一種疾病,例如癌症(如白血病、結腸癌、膠質母細胞瘤、淋巴瘤、黑色素瘤、乳腺癌和宮頸癌)、細胞毒性癌、缺血再灌注損傷(如那些相關聯的,但又不限於心臟衰竭、心肌梗死、中風、其他神經損傷和器官移植等)、再灌注損傷(如眼睛、腎、腸管和骨骼肌的再灌注)、炎症性疾病(如關節炎、痛風、炎症性腸道疾病、中樞神經系統炎症、多發性硬化症、過敏性腦炎、敗血症、敗血性休克、出血性休克、肺纖維化和葡萄膜炎)、免疫性疾病或紊亂(如類風濕性關節炎和感染性休克)、退行性疾病(如糖尿病、帕金森病)、低血糖症、逆轉錄病毒感染、對乙醯氨基酚過量引發的肝毒性、阿黴素及鉑為基礎的抗腫瘤藥物引發的心 臟和腎臟的毒性、硫芥引發的皮膚繼發損傷。 The present invention provides at least one use of a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for the treatment of at least one of the following diseases, such as cancer (eg leukemia, colon) Cancer, glioblastoma, lymphoma, melanoma, breast and cervical cancer), cytotoxic cancer, ischemia-reperfusion injury (such as those associated with, but not limited to, heart failure, myocardial infarction, stroke, other nerves) Injury and organ transplantation, etc., reperfusion injury (such as reperfusion of eyes, kidneys, intestines and skeletal muscle), inflammatory diseases (such as arthritis, gout, inflammatory bowel disease, central nervous system inflammation, multiple sclerosis) , allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis), immune diseases or disorders (such as rheumatoid arthritis and septic shock), degenerative diseases (such as diabetes, Parkinson's disease), hypoglycemia, retroviral infection, hepatotoxicity caused by excessive acetaminophen, doxorubicin and platinum-based anti-tumor drugs Dirty and kidney toxicity, secondary damage to the skin caused by sulfur mustard.
在本發明中,除非上下文中另有所指,下面所要用到的單詞,短語和符號,要表達的含義有如下規定。以下縮寫和術語的含義貫穿整文:這裡的術語「烷基」是指烴基,該烴基選自飽和的直鏈的和帶支鏈的烴基,該烴基包括1到18,例如1到12,進一步比如1到6個碳原子。烷基的實例可以選自甲基、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-甲丙基或仲丁基("s-Bu"),以及1,1-二甲基乙基或叔丁基("t-Bu")。其他的烷基的例子可以選自1-戊基(n-pentyl,--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-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) 等。 In the present invention, unless otherwise indicated in the context, the meanings of the words, phrases and symbols to be used below are as follows. The following abbreviations and terms have the meaning throughout the text: The term "alkyl" as used herein refers to a hydrocarbyl group selected from saturated straight-chain and branched hydrocarbyl groups, including from 1 to 18, for example from 1 to 12, further For example, 1 to 6 carbon atoms. Examples of alkyl groups 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"), And 1,1-dimethylethyl or tert-butyl ("t-Bu"). Examples of other alkyl groups may be selected from the group consisting of 1-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-butene (--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-methyl-2-pentyl (--C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (--CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (--CH(CH) 3 ) CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (--C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-- CH (CH 2 CH 3) CH (CH 3) 2), 2,3- dimethyl-2-butyl (--C (CH 3) 2 CH (CH 3) 2) and 3,3-dimethyl -2-butyl (--CH (CH 3) C ( CH 3) 3) and the like.
這裡的術語「烯基」指的是選自直鏈的和帶支鏈的烴基,該烴基包括至少一個C=C雙鍵和2到18,例如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 linear and branched chains, which includes at least one C=C double bond and 2 to 18, for example 2 to 6 carbon atoms. Examples of alkenyl groups may be selected from ethylene or vinyl (--CH=CH2), 1-propenyl (--CH=CHCH3), 2-propenyl (--CH2CH=CH2), 2-methyl -1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl, 1-positive Butenyl, 2-n-butenyl, 3-n-butenyl, 4-n-butenyl and 1,3-n-hexadienyl groups.
這裡的術語「炔基」指的是選自直鏈的和帶支鏈的烴基,該烴基包括至少一個C≡C三鍵和2到18,例如2到6個碳原子。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 linear and branched chains comprising at least one C≡C triple bond and 2 to 18, for example 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl (-C≡CH), 1-propynyl (-C≡CCH 3 ), 2-propynyl (propargyl, -CH 2 C≡CH), 1-butynyl , 2-butynyl and 3-butynyl groups.
這裡的術語「環烷基」指的是選自飽和和部分不飽和的環烴基,該環烴基包括單環的和多環(例如,雙環的和三環的)基團。例如,該環烷基可以包括3到12,例如3到8,進一步比如3到6,3到5或者3到4個碳原子。進一步例如,環烷基可以選自3到12,例如3到8,3到6碳原子的單環基團。單環環烷烴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個環原子排列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 cyclic hydrocarbon group selected from the group consisting of saturated and partially unsaturated, including cyclocyclic and polycyclic (eg, bicyclic and tricyclic) groups. For example, the cycloalkyl group may include 3 to 12, such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from 3 to 12, for example, a monocyclic group of 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkane 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 consisting of 7 to 12 ring atoms, and the double ring is selected from [4, 4], [4, 5], [5, 5], [5,6] and [6,6] ring systems, 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」指一個基團選自: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 means a group selected from the group consisting of a 5-membered and 6-membered carbocyclic aromatic ring, for example, a phenyl group; a bicyclic system such as a 7- to 12-membered bicyclic ring system in which at least one ring is a carbocyclic ring. And an aromatic ring, such as said bicyclic ring system selected from, 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 ring is a carbocyclic ring And aromatic rings, such as 芴.
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。單價多環烴基命名以「-基」結尾,由單價多環烴基從具有自由價的碳原子上移去一個氫原子得到二價基,命名是在相應的單價基的名稱中加入「-亞基",如將有兩個連接點的萘基稱作亞二氫萘基。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,所得到的環體系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 monovalent polycyclic hydrocarbon group is named after a "- group", and a monovalent polycyclic hydrocarbon group is removed from a carbon atom having a free valence to obtain a divalent group, and a "subunit" is added to the name of the corresponding monovalent group. ", such as a naphthyl group having two points of attachment, is called a dihydronaphthyl group. 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"芳基烷基"指的是上文定義中的烷基被上文定義中的芳基取代。 The term "arylalkyl" as used herein refers to an alkyl group as defined above substituted with an aryl group as defined above.
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1個雜原子,例如,從1到4,在一些實施例中,為1到3個雜原子。雜原子選自N、O和S,其餘的環原子為碳;8元到12元雙環包含至少1個雜原子,例如,從1到4,在一些實施例中,為1到3個雜原子,或者,其他實施例中,為1或2個雜原子。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;11到14元三環包含至少1個雜原子,例如,從1到4,在一些實施例中,為1到3個雜原子,或者,其他實施例中,為1或2個雜原子。雜原子選自N、O和S,其餘的環原子是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。 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, and in some embodiments, from 1 to 3 heteroatoms. The heteroatoms are selected from N, O and S, the remaining ring atoms are carbon; the 8- to 12-membered bicyclic ring contains at least one heteroatom, for example, from 1 to 4, and in some embodiments, from 1 to 3 heteroatoms. Or, in other embodiments, 1 or 2 heteroatoms. The hetero atom is selected from N, O and S, the remaining ring atoms are carbon, and at least one of the rings is aromatic and has at least one hetero atom in the aromatic ring; the 11 to 14 membered tricyclic ring contains at least one hetero atom, For example, from 1 to 4, in some embodiments, 1 to 3 heteroatoms, or, in other embodiments, 1 or 2 heteroatoms. 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 the aromatic ring has at least one heteroatom.
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 one.
雜芳基的例子包括,但是不限於(從優先指定的連接位置編碼1)吡啶基(例如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、異噁唑基、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、三唑基、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 linkage position) pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), hydrazine Lolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thia Diazole, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isodecyl, indanyl, pyridazinyl , pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridine-5- , pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazole-6-yl), butterfly Pyridyl, fluorenyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazole, 1-oxa-2,5-oxadiazolyl, 1-oxa- 3,4-diazolyl, 1-thio-2,3-oxadiazolyl, 1-thio-2,4-oxadiazole, 1-thio-2,5-diazolyl, 1-sulfur 3,4-oxadiazolyl, furazanyl, benzofurazyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, Furopyridinyl, benzothiazolyl (such as benzo[d]thiazole-6-yl), fluorenyl (ratio Such as 1H-carbazol-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,該雜環是飽和和部分不飽和環,包括選自N、O和S中的至少1個雜原子,例如,從1到4,進一步比如,1到3個雜原子,或者,進一步比如,1或2個雜原子。雜原子外,至少一個碳原子。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的雜原子,且與5-、6-及/或7-元的環烷基環,碳環芳香環或雜芳環並環,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-membered rings which are saturated and partially unsubstituted. The saturated ring includes at least one hetero atom selected from N, O and S, for example, from 1 to 4, further, for example, 1 to 3 hetero atoms, or, further, for example, 1 or 2 hetero atoms. Outside the heteroatom, at least one carbon atom. 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 a cycloalkyl ring, a carbocyclic aromatic ring or a 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 bonded to the cycloalkyl group The ring-bonding point can be on a cycloalkyl or heterocyclic ring.
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)。上述雜環可能被氧取代。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). The above heterocyclic ring may be substituted 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,但不局限於(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-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、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、二氫吡啶基、四氫吡啶基、硫代嗎啉基、氧硫雜環己烷基、呱嗪基、高呱嗪基、高哌啶基、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、嘧啶酮基、1,1-二氧-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基基團取代的環 體系,比如N-氧化哌啶基、N-氧化嗎啉基、1-氧-1-硫代嗎啉基和1,1-二氧-1-硫代嗎啉基。 Examples of heterocycles include, but are not limited to, (encoded from a preferred position of the linkage 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1 - piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-pyridazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, epoxy B Alkyl, azacyclopropenyl, cyclohexylethane, azetidinyl, oxetanyl, thioheterobutyl, 1,2-dithiot-butyl, 1,3-di Thiopyletyl, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxathiolanyl, pyridazinyl, oxazinyl, homopiperidinyl, azepanyl , oxetanyl, thiaheptanyl, 1,4-oxathiolanyl, 1,4-dioxanyl, 1,4-oxathiaheptyl , 1,4-azacycloheptyl, 1,4-dithiaheptanyl, 1,4-azetidinyl and 1,4-diazepane, 1- 1,4-Dithiaalkyl, 1,4-azetidinyl, oxazepine, diazepine, thiazepine, dihydrothienyl, dihydropyranyl, dihydrofuran Base, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyran , tetrahydrothiopyranyl, 1-pyrroline, 2-pyrolinyl, 3-pyrroline, porphyrin, 2H-pyranyl, 4H-pyranyl, 1,4-dioxe Hexyl, 1,3-dioxocyclopentyl, pyrazolinyl, pyrazolidinyl, dithiaalkyl, dithiacyclopentyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, 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 oxy group substituted rings Systems such as N-oxypiperidinyl, N-oxymorpholinyl, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
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 compounds described herein contain olefinic double bonds, these double bonds include the E and Z geometric isomers unless otherwise specified.
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;小量分析;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。本領域技術人員使用這些技術達到所需分離度。 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 and low pressure liquid chromatography and equipment; small amount analysis; simulated moving bed ("SMB") and preparation of thin layers Or thick layer chromatography, as with small thin layers and flash chromatography. Those skilled in the art use these techniques to achieve the desired resolution.
非對映異構體的混合物可以利用該等非對映異構體混合物的物理化學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,手性助劑如手性醇或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手性HPLC柱分離。 Mixtures of diastereomers can be separated into the individual diastereomers by techniques well known in the art using physicochemical differences in mixtures of such diastereomers, such as by chromatography and/or fractionation. Step 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 chiral auxiliary such as a chiral alcohol or Mosher chloro), 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 by a chiral 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)。本發明的手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)與手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)與手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)直接在手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: John 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 chiral compound of the present invention can be isolated by any suitable method, including: (1) formation of an ionic, diastereomeric salt with a chiral compound, followed by separation by fractional crystallization or other methods. (2) forming a diastereomeric compound with a chiral derivatizing reagent, separating the diastereomer formed and converting into a pure stereoisomer, and (3) separating substantially pure or under chiral conditions. Enriched stereoisomers. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
「藥學上可接受的鹽」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。 Alternatively, if an acid addition salt of one of the compounds described herein is obtained, the free base can be obtained by basifying 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 additions without undue experimentation. salt.
如本文所定義的,「藥學上可接受的鹽」包括至少一種選自通式I、II(包括II-1、II-2,或Ⅱ-3)和III的化合物的鹽,和至少一種選自通式I、II(包括II-1、II-2,或Ⅱ-3)和III的立體異構體的鹽,例如對映異構體及/或非對映異構體的鹽。 As defined herein, a "pharmaceutically acceptable salt" includes at least one salt selected from the group consisting of compounds of Formulas I, II (including II-1, II-2, or II-3) and III, and at least one selected Salts of the stereoisomers of the formula I, II (including II-1, II-2, or II-3) and III, such as the salts of the enantiomers and/or diastereomers.
"治療"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前述各者的受試者,例如,該受試者患有癌症及/或炎症性疾病,或有一個症狀,例如,癌症及/或炎症性疾病,或有一個傾向,例如,癌症及/或炎症性疾病,以治癒、癒合、減輕、解除、轉變、補救、改善,或影響為目的,例如,癌症及/或炎症性疾病,該受試者的症狀,例如,癌症及/或炎症性疾病,或傾向,例如,癌症及/或炎症性疾病。 "Treatment" or "alleviation" refers to the administration of at least one compound and/or at least one of the stereoisomers thereof, and/or at least one pharmaceutically acceptable salt disclosed herein to a subject that confirms the need for each of the foregoing, for example The subject has cancer and/or inflammatory disease, or has a symptom, such as a cancer and/or an inflammatory disease, or has a tendency, for example, a cancer and/or an inflammatory disease, to heal, heal, Ameliorating, relieving, transforming, remedying, ameliorating, or influencing, for example, cancer and/or inflammatory diseases, symptoms of the subject, for example, cancer and/or inflammatory diseases, or predispositions, for example, cancer and/or Or an inflammatory disease.
術語「有效量」是指本發明中至少一種化合物的量及/或至少一種藥學上可以接受的鹽能夠有效「治療」上文所述的在的疾病或病症。就癌症而言,有效的量可能引起的任何變化觀察或測量的一個主題為「治療」和「緩和」。例如,有效的量降低癌症或腫瘤細胞的數量;腫瘤體積縮小;抑制或阻止腫瘤細胞浸潤周圍器官包括,例如,腫瘤向軟組織和骨的傳播;抑制和阻止腫瘤轉移;抑制和阻止腫瘤生長;在一定程度上緩解的一個或多個與癌症相關的症狀,降低發病率和死亡率;提高生活品質;或以上藥效的組合。一個有效的量可以是足以降低回應抑制PARP的疾病的症狀的量。為 癌症治療的效果,在體內可以,例如,可以通過評估的生存時間的測量、疾病進展時間(TTP)、反應率(RR)、回應時間,及/或生活品質。有效量可能會有所不同,如在這些技術技巧的認識,根據給藥途徑、輔料的使用,以及與其他藥物聯合使用。 The term "effective amount" means that the amount and/or at least one pharmaceutically acceptable salt of at least one compound of the invention is effective to "treat" a disease or condition as described above. In the case of cancer, a subject of any change that may be caused by an effective amount is "treatment" and "alleviation". For example, an effective amount reduces the number of cancer or tumor cells; the tumor shrinks; inhibits or prevents tumor cells from infiltrating surrounding organs including, for example, the spread of tumors to soft tissues and bones; inhibits and prevents tumor metastasis; inhibits and prevents tumor growth; To some extent alleviate one or more cancer-related symptoms, reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount sufficient to reduce the symptoms of a disease that responds to PARP inhibition. for The effects of cancer treatment can be, for example, measured by the estimated survival time, time to disease progression (TTP), response rate (RR), response time, and/or quality of life. The effective amount may vary, as recognized in these technical techniques, depending on the route of administration, the use of excipients, and in combination with other drugs.
術語「抑制」是指減少的生物學活性或過程中的基線活動。「抑制PARP」是指本發明中至少一種化合物的存在及/或至少一種藥學上可以接受的鹽直接或間接的使PARP活性減少,至少一種化合物及/或至少一種藥學上可以接受的鹽會引起PARP活性降低。活性降低是不受理論的約束,可能是由於本發明中至少一種化合物及/或至少一種藥學上可以接受的鹽與PARP的直接或相互作用,或由於的至少一種化合物及/或至少一種藥學上可以接受的鹽的相互作用,與一或多個的其他因素,反過來影響PARP活性。例如,至少一種化合物的存在及/或至少一個藥學上可接受的鹽,通過直接結合的PARP,可能會降低PARP活性,另一個因素是(直接或間接)減少PARP在細胞或組織中的量來降低PARP的活性。 The term "inhibition" refers to reduced biological activity or baseline activity in the process. By "inhibiting PARP" is meant that the presence and/or at least one pharmaceutically acceptable salt of at least one compound of the invention directly or indirectly reduces PARP activity, at least one compound and/or at least one pharmaceutically acceptable salt may cause PARP activity is reduced. The decrease in activity is not bound by theory, possibly due to the direct or interaction of at least one compound and/or at least one pharmaceutically acceptable salt of the invention with PARP, or due to at least one compound and/or at least one pharmaceutically acceptable Acceptable salt interactions, with one or more other factors, in turn affect PARP activity. For example, the presence of at least one compound and/or at least one pharmaceutically acceptable salt, by direct binding of PARP, may reduce PARP activity, and another factor (directly or indirectly) reduces the amount of PARP in cells or tissues. Reduce the activity of PARP.
這裡揭示的術語「至少有一個被取代」,例如從1到4,比如從1到3,進一步比如從1到2的取代。例如,這裡揭示的至少一個取代的R12包含從1到4,比如從1到3,更進一步比如從1到2的取代選自於R12中所列的基團。 The term "at least one is replaced" as disclosed herein, for example from 1 to 4, such as from 1 to 3, further such as from 1 to 2. For example, at least one substituted R 12 disclosed herein comprises from 1 to 4, such as from 1 to 3, and further such as from 1 to 2, the substituents are selected from the groups listed in R 12 .
在第一個態樣,本發明中提供至少一個化合物,其異構體及其藥學上可以接受的鹽選自分子式(I):
其中:RN選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;X選自由C、N、O和S所組成的群組;m和n,可以相同也可不同,可以分別是0、1、2或3之整數;t是0、1、2或3之整數;R 1 ,在每次出現時獨立地選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10、COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 2 選自由氫、COR9、CONR9R10、CO2R9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基所組成的群組,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 3 、R 4 、R 5 、R 6 、R 7 和R 8 可以相同也可不同,分別獨立地選自氫、鹵素、-NR9R10、-OR9、氧基、-COR9、-CO2R9、-CONR9R10、-NR9CONR10R11、-NR9CO2R10、-NR9SO2R10和 -SO2R9、烷基、烯基、環烷基、芳基、雜環基、炔基和雜芳基,其中各烷基、烯基、炔基、環烷基、芳基、雜環基和雜芳基均可獨立地被至少一個取代基R12任選取代,或者(R3和R4)及/或(R4和R5)及/或(R5和R6)及/或(R6和R7)及/或(R7和R8),與它們所連接的一或多個原子,一起形成具有0、1或2個雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-或-SO2-,且該環可被至少一個取代基R12任選取代,條件是:當X是O,R5和R6都不存在,當X是N,R6不存在,當X是S,R5和R6都不存在,或者R5和R6中至少一者是氧基,當R3和R4中的一者是氧基時,另外一者不存在,當R7和R8中的一者是氧基時,另外一者不存在,當X是C且R5和R6中的一者是氧基時,另外一者不存在;R 9 、R 10 和R 11 ,可以相同也可不同,分別選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基或者雜芳基均可獨立地被至少一個取代基R12任選取代;R 12 選自氰基、鹵素、鹵烷基、NO2、-NR'R"、-OR'、氧基、-COR'、-CO2R'、-CONR'R"、-NR'CONR"R"'、-NR'CO2R"、-NR'SO2R"、-SO2R'、烷基、烯基、炔基、環烷基、雜環基、 芳基和雜芳基,其中R'、R"和R'''獨立地選自氫、鹵烷基、烷基、芳烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,或者(R'和R")及/或(R"和R"'),與它們所連接的幾個原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-。 Wherein: R N is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl And aryl and heteroaryl may be independently substituted by at least one substituent R 12 ; X is selected from the group consisting of C, N, O and S; m and n may be the same or different and may be respectively Is an integer of 0, 1, 2 or 3; t is an integer of 0, 1 , 2 or 3; R 1 is independently selected from halogen, cyano, NO 2 , OR 9 , NR 9 R 10 at each occurrence , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group may be independently optionally substituted with at least one substituent R 12 ; R 2 is selected from hydrogen, COR 9 , CONR a group consisting of 9 R 10 , CO 2 R 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be independently Optionally substituted with at least one substituent R 12 ; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be the same or different and are each independently selected from hydrogen, halogen, -NR 9 R 10 , - OR 9 , oxy, -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 CONR 10 R 11 , -NR 9 CO 2 R 10 , -NR 9 SO 2 R 10 and -SO 2 R 9, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, a heterocyclic group, an alkynyl group, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group may independently be substituted with at least one R 12 group is optionally substituted, or (R 3 and R 4) and / or (R 4 and R 5) and / or (R 5 and R 6) and / or (R 6 And R 7 ) and/or (R 7 and R 8 ), together with one or more of the atoms to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or all of which has 0, 1 or 2 heteroatoms. a saturated ring, the hetero atom may be independently selected from -NR 13 -, -O-, -S-, -SO- or -SO 2 -, and the ring may be optionally substituted with at least one substituent R 12 , with the proviso that: when X is O, R 5 and R 6 are absent, when X is N, R 6 is not present when X is S, R 5 and R 6 do not exist, or R 5 and R 6 are to Is one group, when R 3 and R 4 is a group of one when the other one is absent, when R 7 and R 8 is a group when one of the other one does not exist, and when X Is C and one of R 5 and R 6 is an oxy group, the other one is absent; R 9 , R 10 and R 11 may be the same or different and are respectively selected from hydrogen, alkyl, alkenyl, alkyne a base, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group may be independently substituted by at least one The group R 12 is optionally substituted; R 12 is selected from the group consisting of cyano, halogen, haloalkyl, NO 2 , -NR'R", -OR', oxy, -COR', -CO 2 R', -CONR'R ", -NR'CONR"R"', -NR'CO 2 R", -NR'SO 2 R", -SO 2 R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, Aryl and heteroaryl, wherein R', R" and R" are independently selected from the group consisting of hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl And heteroaryl, or (R' and R") and/or (R" and R"'), together with the several atoms to which they are attached, form 3 with 0, 1 or 2 additional heteroatoms To 8 yuan full , Partially unsaturated or fully unsaturated ring, the additional heteroatoms may be independently selected from -NR 13 -, - O -, - S -, - SO- and -SO 2 -.
R 13 選自氫、烷基、環烷基、芳基、雜芳基和雜環基。 R 13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
在一些實施例中,分子式(I)中的X是C。在一些實施例中,分子式(I)中的X是N。 In some embodiments, X in formula (I) is C. In some embodiments, X in formula (I) is N.
在一些實施例中,分子式(I)中的m和n都是整數1。在一些實施例中,分子式(I)中的n是整數1,分子式(I)中的m是整數2;在其他一些實施例中,分子式(I)中的n是整數2,分子式(I)中的m是整數1。 In some embodiments, m and n in formula (I) are both integers 1. In some embodiments, formula (I) in which n is an integer of 1, formula (I) wherein m is an integer of 2; In some other embodiments of formula (I) wherein n is an integer of 2, of formula (I) m in is an integer 1.
在一些實施例中,分子式(I)中的t是整數0。在一些實施例中,分子式(I)中的t是整數1,分子式(I)中的R1選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10,COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個上述定義中的取代基R12任選取代。在一些進一步的實施例中,分子式(I)中的t是整數1,分子式(I)中的R1是鹵素(例如F、Cl和Br,進一步比如,F)或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)。在一些進一步的實施例中,分子式(I)中的t是整數1,分子式(I)中的R1是鹵素(例如F)。 In some embodiments, t in formula (I) is an integer zero. In some embodiments, t in formula (I) is an integer of 1, and R 1 in formula (I) is selected from the group consisting of halogen, cyano, NO 2 , OR 9 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, The alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R 12 as defined above. In some further embodiments, t in formula (I) is an integer of 1, and R 1 in formula (I) is halo (eg, F, Cl, and Br, further, for example, F) or alkyl (eg, 1- A 12 carbon alkyl group, further, for example, an alkyl group of 1 to 6 carbons). In some further embodiments, t in formula (I) is an integer of 1, and R 1 in formula (I) is a halogen (eg, F).
在一些實施例中,分子式(I)中的RN是羥基或者烷氧基任選取代的烷基。在一些進一步的實施例中,分子式(I)中的RN是羥基或者1-12個碳的烷氧基任選取代的1-12個碳的烷基。在一些進一步的實施例中,分子式(I)中的RN是羥基或者1-6個碳的烷氧基任選取代的1-6個碳的烷基。 In some embodiments, R N in formula (I) is hydroxy or alkoxy optionally substituted alkyl. In some further embodiments, R N in formula (I) is a hydroxy or an alkoxy group of 1 to 12 carbons optionally substituted with an alkyl group of 1 to 12 carbons. In some further embodiments, R N in formula (I) is hydroxy or an alkoxy group of 1-6 carbons, optionally substituted 1-6 carbon alkyl.
在一些實施例中,分子式(I)中的R2是氫或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個上述分子式(I)定義中的中取代基R12任選取代。在一些實施例中,分子式(I)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個取代基R 12 任選取代,這裡,R 12 選自-NR'R"、-OR'、雜環基和芳基,這裡R'和R'''獨立地選自氫、鹵烷基、烷基和芳烷基,或者R'和R",與它們所連接的原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-。在一些進一步的實施例中,分子式(I)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個取代基R 12 任選取代,這裡,R 12 選自-NR'R"、-OR'、雜環基和芳基(例如,苯基),這裡R'和R"獨立地選自氫、鹵烷基(例如,1-12個碳的鹵烷基,進一步比如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)、芳烷基(例如,苯基1-12個碳的烷基,進一步比如,苯基1-6個碳的烷基),或者R'和R",與它們所連接的原子,一起形成具有0、1或2個額外 的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-(例如,5或者6元飽和環上有0或者1個額外的雜原子,雜原子是氧原子,進一步比如,5元飽和環、6元飽和環,或者6元飽和環,環上有1個氧雜原子)。在一些進一步的實施例中,分子式(I)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個選自芳基(例如,苯基)的取代基,任選取代,3、4、5、6、7、8元的含有一個氮原子及/或一個氧原子的雜環,-OR'和-NR'R",這裡R’和R"獨立地選自氫、鹵烷基(例如,1-12個碳的鹵烷基,進一步比如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)、芳烷基(例如,苯基1-6個碳的烷基)。在一些進一步的實施例中,分子式(I)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個選自芳基(例如,苯基)的取代基任選取代;3、4、5、6、7、8元的含有一個氮原子及/或一個氧原子的雜環,雜環可以選自吡咯烷基、哌啶基、嗎啉基和環氧乙基;-OR';和-NR'R",這裡R’和R"獨立地選自氫、鹵烷基(例如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),和芳烷基(例如,苯基1-6個碳的烷基,進一步比如,苯甲基)。 In some embodiments, R 2 in formula (I) is hydrogen or alkyl (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be subjected to at least one of the above formulas. The intermediate substituent R 12 in the definition of (I) is optionally substituted. In some embodiments, R 2 in formula (I) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R 12 Optionally substituted, herein, R 12 is selected from the group consisting of -NR'R", -OR', heterocyclyl and aryl, wherein R' and R''' are independently selected from hydrogen, haloalkyl, alkyl and aralkyl. a radical, or R' and R", together with the atom to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, said additional The heteroatoms can be independently selected from the group consisting of -NR 13 -, -O-, -S-, -SO-, and -SO 2 -. In some further embodiments, R 2 in formula (I) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R 12 is optionally substituted, wherein R 12 is selected from -NR'R", -OR', heterocyclyl and aryl (eg, phenyl), where R' and R" are independently selected from hydrogen, haloalkyl (for example, a haloalkyl group of 1 to 12 carbons, further, for example, a haloalkyl group of 1 to 6 carbons), an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) An alkyl group, an aralkyl group (for example, an alkyl group of 1 to 12 carbons of a phenyl group, further, for example, an alkyl group of 1 to 6 carbons of a phenyl group), or R' and R", and an atom to which they are attached, Together, a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring having 0, 1 or 2 additional heteroatoms may be formed, which may be independently selected from -NR 13 -, -O-, -S-, -SO- and -SO 2 - (for example, there are 0 or 1 additional heteroatoms on a 5 or 6-membered saturated ring, the hetero atom is an oxygen atom, further, for example, a 5-membered saturated ring, a 6-membered saturated ring , or a 6-membered saturated ring with 1 oxygen heteroatom on the ring). Embodiment, formula (I) in R 2 is alkyl (e.g., 1 to 12 carbons, further such as 1 to 6 carbons), may be at least one selected from aryl ( For example, a substituent of phenyl), optionally substituted, a 3, 4, 5, 6, 7, 8-membered heterocyclic ring containing a nitrogen atom and/or an oxygen atom, -OR' and -NR'R", Here, R' and R" are independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 12 carbons, further, for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1 to 12) a carbon alkyl group, further, for example, an alkyl group of 1 to 6 carbons, an aralkyl group (for example, an alkyl group having 1 to 6 carbon atoms). In some further embodiments, in the formula (I) R 2 is an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be optionally substituted with at least one substituent selected from an aryl group (for example, a phenyl group). Substituted; 3, 4, 5, 6, 7, 8 yuan heterocyclic ring containing a nitrogen atom and/or an oxygen atom, the heterocyclic ring may be selected from pyrrolidinyl, piperidinyl, morpholinyl and epoxyethyl ;-OR'; and -NR'R", where R' and R" are independently selected from hydrogen, haloalkyl (eg, 1-6 carbons) An alkyl group, an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), and an aralkyl group (for example, an alkyl group having 1 to 6 carbon atoms), further For example, benzyl).
在一些實施例中,分子式(I)中的R5選自氫、烷基、環烷基、芳基、-COR9和-COOR9,其中各烷基、環烷基和芳基,均可獨立地被至少一個取代基R12任選取代,R9是烷基 或者環烷基,可以被至少一個取代基R12任選取代,R12的定義見分子式(I)。在一些實施例中,分子式(I)中的R5選自氫、烷基、環烷基、芳基、-COR9和-COOR9,其中各烷基、環烷基,或者芳基,均可獨立地被至少一個取代基R12任選取代,R9是烷基或者環烷基,可以被至少一個取代基R12任選取代,R12選自-NR'R"、芳基,和-NR'CO2R",其中R’和R"獨立地選自氫、鹵烷基和烷基。在一些進一步的實施例中,分子式(I)中的R5選自氫;烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個選自-NR'R"和芳基(例如,苯基)的取代基,任選取代;環烷基(例如,3、4、5、6、7、8個碳的環烷基);芳基(例如,苯基),可以被-NR'R"任選取代;-COR9,這裡,R9是環烷基(例如,3、4、5、6、7、8個碳的環烷基),或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),每個環烷基和烷基,可以被至少一個選自-NR'R",芳基(例如,苯基)和-NR'CO2R"的取代基任選取代,這裡,R’和R"獨立地選自氫,鹵烷基(例如,1-6個碳的鹵烷基),烷基(例如,1-6個碳的烷基)。在一些進一步的實施例中,分子式(I)中的R5選自氫;1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基、丁基,或者3,3-二甲基丁基),可以被取代基-NR'R"任選取代;環己基;被取代基-NR'R"任選取代的苯基;-COR9,這裡,R9是環丙基,或者1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基,或者丁基),每個環丙基和1-6個碳的烷基可以被至少一個選自-NR'R",芳基(例如,苯基)和-NR'CO2R"的取代基任選取代, 這裡R’和R"獨立地選自氫,和1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基、丁基,或者叔丁基)。 In some embodiments, R 5 in formula (I) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR 9 and -COOR 9 wherein each alkyl, cycloalkyl and aryl group may be independently substituted with at least one substituent group is optionally substituted with R 12, R 9 is an alkyl or cycloalkyl group may be substituted with at least one of R 12 is optionally substituted, R 12, see the definition of formula (I). In some embodiments, R 5 in formula (I) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR 9 and -COOR 9 wherein each alkyl, cycloalkyl, or aryl group is may be independently substituted with at least one substituent optionally substituted with R 12, R 9 is an alkyl or cycloalkyl group may be substituted with at least one of R 12 is optionally substituted, R 12 is selected from -NR'R ", aryl group, and -NR'CO 2 R", wherein R' and R" are independently selected from the group consisting of hydrogen, haloalkyl and alkyl. In some further embodiments, R 5 in formula (I) is selected from hydrogen; alkyl ( For example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons, may be substituted with at least one substituent selected from the group consisting of -NR'R" and an aryl group (for example, a phenyl group), optionally Substituted; cycloalkyl (eg, 3, 4, 5, 6, 7, 8 carbon cycloalkyl); aryl (eg, phenyl), optionally substituted by -NR'R"; -COR 9 Here, R 9 is a cycloalkyl group (for example, a cycloalkyl group of 3, 4, 5, 6, 7, 8 carbons), or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 a -6 carbon alkyl group, each of the cycloalkyl group and the alkyl group, may be at least one selected from the group consisting of -NR'R", an aryl group (for example, a phenyl group) And a substituent of -NR'CO 2 R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1-6 carbon alkyl groups). In some further embodiments, formula (I) in R 5 is selected from hydrogen; 1-6 carbon alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or 3, 3- dimethylbutyl), may be substituted -NR'R "optionally substituted; cyclohexyl; substituted group -NR'R" optionally substituted phenyl; -COR 9, where, R 9 is a cyclic a propyl group, or an alkyl group of 1 to 6 carbons (for example, methyl, ethyl, propyl, isopropyl, or butyl), each of which is a cyclopropyl group and a 1-6 carbon alkyl group may be at least A substituent selected from -NR'R", an aryl group (for example, phenyl) and -NR'CO 2 R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, and 1 to 6 carbons Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl).
在一些實施例中,分子式(I)中的R4和R5,與它們所連接的幾個碳原子,一起形成具有0、1或2個雜原子的3、4、5、6、7或8元飽和、部分不飽和或全部不飽和的環,所述雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-,且該環可被至少一個上述分子式(I)定義中的取代基R12任選取代。在一些實施例中,分子式(I)中的R4和R5,與它們所連接的幾個碳原子,一起形成含有一個氮雜原子的5元飽和環。 In some embodiments, R 4 and R 5 in formula (I) , together with several carbon atoms to which they are attached, form 3, 4, 5, 6, 7 or 0, 1 or 2 heteroatoms or An 8-membered saturated, partially unsaturated or fully unsaturated ring, said heteroatoms being independently selected from the group consisting of -NR 13 -, -O-, -S-, -SO-, and -SO 2 -, and the ring may be The substituent R 12 in the definition of at least one of the above formula (I) is optionally substituted. In some embodiments, R 4 and R 5 in formula (I) , together with the several carbon atoms to which they are attached, form a 5-membered saturated ring containing a nitrogen heteroatom.
在一些實施例中,分子式(I)中的至少一對(R3和R4)、(R5和R6)和(R7和R8)是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基,進一步比如,甲基)。在一些實施例中,分子式(I)中的R3和R4,可以相同也可不同,分別獨立地選自氫、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)和羥基。 In some embodiments, at least one pair (R 3 and R 4 ), (R 5 and R 6 ), and (R 7 and R 8 ) of formula (I ) are alkyl groups (eg, 1-12 carbons) An alkyl group, further, for example, an alkyl group of 1 to 6 carbons, further, for example, a methyl group. In some embodiments, R 3 and R 4 in formula (I) may be the same or different and are each independently selected from hydrogen, alkyl (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 - 6 carbon alkyl) and hydroxyl.
在第二個態樣,本發明中至少一個選自分子式(I)化合物,其立體異構體,及其藥學上可以接受的鹽,選自下列分子式(II):
其中:RN選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、 芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;m和n,可以相同也可不同,可以分別是0、1、2或3之整數;t是整數0、1、2或3之整數;R 1 ,在每次出現時獨立地選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10、COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 2 選自氫、COR9、CONR9R10、CO2R9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 3 、R 4 、R 5 、R 6 、R 7 和R 8 ,可以相同也可不同,分別獨立地選自氫、鹵素、-NR9R10、-OR9、氧基、-COR9、-CO2R9、-CONR9R10、-NR9CONR10R11、-NR9CO2R10、-NR9SO2R10和-SO2R9、烷基、烯基、環烷基、芳基、雜環基、炔基和雜芳基,其中各烷基、烯基、炔基、環烷基、芳基、雜環基和雜芳基均可獨立地被至少一個取代基R12任選取代;或者(R3和R4)及/或(R4和R5)及/或(R5和R6)及/或(R6和R7)及/或(R7和R8),與它們所連接的一或多個原子,一起形成具有0、1或2個雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-,且該環可被至少一個取代基R 12 任選取代,條件是: 當R3和R4中的一者是氧基時,另外一者不存在,當R7和R8中的一者是氧基時,另外一者不存在,當R5和R6中的一者是氧基時,另外一者不存在;R 9 、R 10 和R 11 ,可以相同也可不同,分別選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 12 選自氰基、鹵素、鹵烷基、NO2、-NR'R"、OR'、氧基、-COR'、-CO2R'、-CONR'R"、-NR'CONR"R"'、-NR'CO2R"、-NR'SO2R"、-SO2R'、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中R'、R"和R'''獨立地選自氫、鹵烷基、烷基、芳烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,或者(R'和R")及/或(R"和R"'),與它們所連接的幾個原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-或者-SO2-。 Wherein: R N is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl And aryl and heteroaryl may be independently substituted by at least one substituent R 12 ; m and n may be the same or different and may each be an integer of 0, 1, 2 or 3; t is an integer of 0, An integer of 1 , 2 or 3; R 1 , independently selected from the group consisting of halogen, cyano, NO 2 , OR 9 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 at each occurrence R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, The heterocyclic group, the aryl group and the heteroaryl group may each independently be optionally substituted with at least one substituent R 12 ; R 2 is selected from the group consisting of hydrogen, COR 9 , CONR 9 R 10 , CO 2 R 9 , SO 2 R 9 , alkane a base, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Independently substituted with at least one substituent R 12 ; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, -NR 9 R 10 , -OR 9 , oxy, -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 CONR 10 R 11 , -NR 9 CO 2 R 10 , -NR 9 SO 2 R 10 and -SO 2 R 9 , alkyl, alkenyl, cycloalkyl, aryl, hetero a cycloalkyl, alkynyl and heteroaryl group, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group is independently optionally substituted with at least one substituent R 12 ; or (R 3 and R 4) and / or (R 4 and R 5) and / or (R 5 and R 6) and / or (R 6 and R 7) and / or (R 7 and R 8), and The one or more atoms to which they are joined together form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 heteroatoms, which may be independently selected from -NR 13 -, -O-, -S-, -SO- and -SO 2 -, and the ring may be optionally substituted by at least one substituent R 12 , provided that: one of R 3 and R 4 is an oxy group when the other one does not exist, when the R 7 and R 8 is one group, the further one is absent, when R 5 and R 6 is one group, the further Does not exist; R 9, R 10 and R 11, may be the same or different, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R 12 ; R 12 is selected from cyano, halo, haloalkyl , NO 2 , -NR'R", OR', oxy, -COR', -CO 2 R', -CONR'R", -NR'CONR"R"', -NR'CO 2 R", - NR'SO 2 R", -SO 2 R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R', R" and R''' independently Selected from hydrogen, haloalkyl, alkyl, aralkyl, 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 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, said additional The atoms may be independently selected from -NR 13 -, -O-, -S-, -SO- or -SO 2 -.
R 13 選自氫、烷基、環烷基、芳基、雜芳基和雜環基。 R 13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
在一些實施例中,分子式(II)中的m和n都是整數1。在一些實施例中,分子式(II)中的n是1,分子式(II)中的m是2;在其他一些實施例中,分子式(II)中的n是2,分子式(II)中的m是1。 In some embodiments, m and n in formula (II) are both integers 1. In some embodiments, the formula (II) in which n is 1, the formula (II) wherein m is 2; in other embodiments, the formula (II) wherein n is 2, the formula (II) in m it's 1.
在一些實施例中,分子式(II)中的t是0。在一些實施例中,分子式(II)中的t是1,分子式(II)中的R1選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10、 COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個上述定義中的取代基R12任選取代;在一些進一步的實施例中,分子式(II)中的t是1,分子式(II)中的R1是鹵素(例如F、Cl和Br,進一步比如,F)或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)。在一些進一步的實施例中,分子式(II)中的t是1,分子式(II)中的R1是鹵素(例如F)。 In some embodiments, t in formula (II) is zero. In some embodiments, the formula (II) in t is 1, the formula (II), R 1 is selected from halogen, cyano, NO 2, OR 9, NR 9 R 10, NR 9 COR 10, NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkyne The base, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R 12 as defined above; in some further embodiments, t in formula (II) Is 1, R 1 in the formula (II) is a halogen (for example, F, Cl, and Br, further, for example, F) or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) alkyl). In some further embodiments, of formula (II) in t is 1, the formula (II), R 1 is halogen (e.g., F).
在一些實施例中,分子式(II)中的RN是至少一個選自羥基和烷氧基的取代基。在一些進一步的實施例中,分子式(II)中的RN是任選取代的1-12個碳的烷基,取代基至少是一個選自羥基和1-12個碳的烷氧基的取代基。在一些進一步的實施例中,分子式(II)中的RN是任選取代的1-6個碳的烷基,取代基至少是一個選自羥基或者1-6個碳的烷氧基的取代基。 In some embodiments, R N in formula (II) is at least one substituent selected from the group consisting of a hydroxyl group and an alkoxy group. In some further embodiments, R N in formula (II) is an optionally substituted alkyl group of 1 to 12 carbons, and the substituent is substituted with at least one alkoxy group selected from the group consisting of a hydroxyl group and 1 to 12 carbons. base. In some further embodiments, R N in formula (II) is an optionally substituted 1-6 carbon alkyl group, and the substituent is at least one substituent selected from a hydroxyl group or an alkoxy group of 1 to 6 carbons. base.
在一些實施例中,分子式(II)中的R2是氫或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個上述分子式(II)定義中的中取代基R12任選取代。在一些實施例中,分子式(II)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個取代基R12任選取代,這裡,R12選自-NR'R"、-OR'、雜環基和芳基,這裡R’和R'''獨立地選自氫、鹵烷基、烷基和芳烷基,或者R'和R",與它們所連接的幾個碳原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或 全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-。在一些進一步的實施例中,分子式(II)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個取代基R12任選取代,這裡,R12選自-NR'R"、-OR'、雜環基,和芳基(例如,苯基),這裡R’和R"獨立地選自氫、鹵烷基(例如,1-12個碳的鹵烷基,進一步比如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)、芳烷基(例如,苯基1-12個碳的烷基,進一步比如,苯基1-6個碳的烷基),或者R'和R",與它們所連接的原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-(例如,5或者6元飽和環上有0或者1個額外的雜原子,雜原子是氧原子,進一步比如,5元飽和環,6元飽和環,或者6元飽和環,環上有1個氧雜原子)。在一些進一步的實施例中,分子式(II)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個選自芳基(例如,苯基)的取代基,任選取代,3、4、5、6、7、8元的含有一個氮原子及/或一個氧原子的雜環,-OR’和-NR'R",這裡R’和R"獨立地選自氫、鹵烷基(例如,1-12個碳的鹵烷基,進一步比如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)、芳烷基(例如,苯基1-6個碳的烷基)。在一些進一步的實施例中,分子式(II)中的R2是烷基(例如,1-12個碳的烷基,進一步 比如,1-6個碳的烷基),可以被至少一個選自芳基(例如,苯基)的取代基,任選取代;3、4、5、6、7、8元的含有一個氮原子及/或一個氧原子的雜環,雜環可以選自吡咯烷基、哌啶基、嗎啉基和環氧乙基;-OR'和-NR'R",這裡R’和R"獨立地選自氫、鹵烷基(例如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),和芳烷基(例如,苯基1-6個碳的烷基,進一步比如,苯甲基)。 In some embodiments, R 2 in formula (II) is hydrogen or an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be subjected to at least one of the above formulas. The intermediate substituent R 12 in the definition of (II) is optionally substituted. In some embodiments, R 2 in formula (II) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R 12 Optionally substituted, here, R 12 is selected from -NR'R", -OR', heterocyclyl and aryl, wherein R' and R''' are independently selected from hydrogen, haloalkyl, alkyl and aralkyl a group, or R' and R", together with several carbon atoms to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring having 0, 1 or 2 additional heteroatoms. The additional heteroatoms can be independently selected from the group consisting of -NR 13 -, -O-, -S-, -SO-, and -SO 2 -. In some further embodiments, R 2 in formula (II) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R 12 is optionally substituted, wherein R 12 is selected from the group consisting of -NR'R", -OR', heterocyclyl, and aryl (for example, phenyl), wherein R' and R" are independently selected from hydrogen, haloalkane. a group (for example, a haloalkyl group of 1 to 12 carbons, further, for example, a haloalkyl group of 1 to 6 carbons), an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) Alkyl), aralkyl (eg, phenyl 1-12 carbon alkyl, further, for example, phenyl 1-6 carbon alkyl), or R' and R", with the atom to which they are attached Forming together a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, which may be independently selected from -NR 13 -, -O- , -S-, -SO-, and -SO 2 - (for example, there are 0 or 1 additional heteroatoms on a 5 or 6-membered saturated ring, the heteroatoms are oxygen atoms, further, for example, a 5-membered saturated ring, 6-membered saturated Ring, or a 6-membered saturated ring, with 1 oxygen atom on the ring). Step embodiment, of formula (II) in R 2 is alkyl (e.g., 1 to 12 carbons, further such as 1 to 6 carbons), may be at least one selected from aryl a substituent (for example, phenyl), optionally substituted, a 3, 4, 5, 6, 7, 8-membered heterocyclic ring containing a nitrogen atom and/or an oxygen atom, -OR' and -NR'R" Wherein R' and R" are independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 12 carbons, further, for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1- a 12 carbon alkyl group, further, for example, a 1-6 carbon alkyl group, an aralkyl group (eg, a phenyl group of 1 to 6 carbon alkyl groups). In some further embodiments, the formula (II) R 2 in the group is an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent selected from an aryl group (for example, a phenyl group). Optionally substituted; 3, 4, 5, 6, 7, 8 of a heterocyclic ring containing a nitrogen atom and/or an oxygen atom, the heterocyclic ring may be selected from pyrrolidinyl, piperidinyl, morpholinyl and epoxy Ethyl; -OR' and -NR'R", where R' and R" are independently selected from hydrogen, haloalkyl (eg, 1-6 Haloalkyl), alkyl (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), and an aralkyl group (for example, an alkyl group of 1 to 6 carbons) Further, for example, benzyl).
在一些實施例中,分子式(II)中的R5選自氫、烷基、環烷基、芳基、-COR9,和-COOR9,其中各烷基、環烷基和芳基,均可獨立地被至少一個取代基R12任選取代,R9是烷基或者環烷基,可以被至少一個取代基R12任選取代,R12的定義見分子式(II)。在一些實施例中,分子式(II)中的R5選自氫、烷基、環烷基、芳基、-COR9和-COOR9,其中各烷基、環烷基,或者芳基,均可獨立地被至少一個取代基R12任選取代,R9是烷基或者環烷基,可以被至少一個取代基R12任選取代,R12選自-NR'R"、芳基,和-NR'CO2R",這裡R’和R"獨立地選自氫、鹵烷基和烷基。在一些進一步的實施例中,分子式(II)中的R5選自氫;烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個選自-NR'R"和芳基(例如,苯基)的取代基,任選取代;環烷基(例如,3、4、5、6、7、8個碳的環烷基);芳基(例如,苯基),可以被-NR'R"任選取代;-COR9,這裡,R9是環烷基(例如,3、4、5、6、7、8個碳的環烷基),或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),其中各環烷基和烷基,可以被至 少一個選自-NR'R"、芳基(例如,苯基)和-NR'CO2R"的取代基任選取代,這裡R’和R"獨立地選自氫、鹵烷基(例如,1-6個碳的鹵烷基)、烷基(例如,1-6個碳的烷基)。在一些進一步的實施例中,分子式(II)中的R5選自氫;1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基、丁基,或者3,3-二甲基丁基),可以被取代基-NR'R"任選取代;環己基;苯基,被取代基-NR'R"任選取代;-COR9,這裡,R9是環丙基,或者1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基,或者丁基),每個環丙基或者1-6個碳的烷基可以被至少一個選自-NR'R"、芳基(例如,苯基)和-NR'CO2R"的取代基任選取代,這裡R’和R"獨立地選自氫,和1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基、丁基,或者叔丁基)。 In some embodiments, R 5 in formula (II) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR 9 , and -COOR 9 wherein each alkyl, cycloalkyl, and aryl group may be independently substituted with at least one substituent optionally substituted with R 12, R 9 is an alkyl or cycloalkyl group may be substituted with at least one R 12 group is optionally substituted, R 12, see the definition of formula (II). In some embodiments, R 5 in formula (II) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR 9 and -COOR 9 wherein each alkyl, cycloalkyl, or aryl group is may be independently substituted with at least one substituent optionally substituted with R 12, R 9 is an alkyl or cycloalkyl group may be substituted with at least one of R 12 is optionally substituted, R 12 is selected from -NR'R ", aryl group, and -NR'CO 2 R", where R' and R" are independently selected from the group consisting of hydrogen, haloalkyl and alkyl. In some further embodiments, R 5 in formula (II) is selected from hydrogen; alkyl ( For example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons, may be substituted with at least one substituent selected from the group consisting of -NR'R" and an aryl group (for example, a phenyl group), optionally Substituted; cycloalkyl (eg, 3, 4, 5, 6, 7, 8 carbon cycloalkyl); aryl (eg, phenyl), optionally substituted by -NR'R"; -COR 9 Here, R 9 is a cycloalkyl group (for example, a cycloalkyl group of 3, 4, 5, 6, 7, 8 carbons), or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 a -6 carbon alkyl group, wherein each cycloalkyl group and alkyl group may be selected from at least one selected from the group consisting of -NR'R" and an aryl group (for example, Yl) and -NR'CO 2 R "substituent optionally substituted, where R 'and R" are independently selected from hydrogen, haloalkyl (e.g., 1-6 carbon haloalkyl), alkyl (e.g. , 1-6 carbon alkyl). In some further embodiments, R 5 in formula (II) is selected from the group consisting of hydrogen; 1-6 carbon alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, or 3, 3-dimethylbutyl), which may be optionally substituted by a substituent -NR'R";cyclohexyl; phenyl, optionally substituted by a substituent -NR'R"; -COR 9 , where R 9 is a ring a propyl group, or an alkyl group of 1 to 6 carbons (for example, methyl, ethyl, propyl, isopropyl, or butyl), each of which is a cyclopropyl group or a 1-6 carbon alkyl group A substituent selected from the group consisting of -NR'R", aryl (for example, phenyl) and -NR'CO 2 R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, and 1-6 carbons Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl).
在一些實施例中,分子式(II)中的R4和R5,與它們所連接的原子,一起形成具有0、1或2個雜原子的3、4、5、6、7、8元飽和、部分不飽和或全部不飽和的環,所述雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-,且該環可被至少一個上述分子式(II)定義中的中取代基R12任選取代。在一些進一步的實施例中,分子式(II)中的R4和R5,與它們所連接的原子,一起形成有一個氮原子的5元飽和環。 In some embodiments, R 4 and R 5 in formula (II) , together with the atom to which they are attached, form a 3, 4, 5, 6, 7, 8 elementary saturation having 0, 1 or 2 heteroatoms. a partially unsaturated or fully unsaturated ring, said heteroatoms being independently selected from the group consisting of -NR 13 -, -O-, -S-, -SO-, and -SO 2 -, and the ring may be at least one of the above The intermediate substituent R 12 in the definition of formula (II) is optionally substituted. In some further embodiments, R 4 and R 5 in formula (II) , together with the atoms to which they are attached, form a 5-membered saturated ring having a nitrogen atom.
在一些實施例中,分子式(II)中的至少一對(R3和R4)、(R5和R6)和(R7和R8)是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基,進一步比如,甲基)。在一些實施例中,分子式(II)中的R3和R4,可以相同也可不同,分別獨立地選自氫、烷基(例如,1-12個碳的烷基,進一步比 如,1-6個碳的烷基)和羥基。 In some embodiments, the at least one pair of (R 3 and R 4) of formula (II) is, (R 5 and R 6) and (R 7 and R 8) is alkyl (e.g., 1 to 12 carbons An alkyl group, further, for example, an alkyl group of 1 to 6 carbons, further, for example, a methyl group. In some embodiments, the formula (II), R 3 and R 4, may be the same or different, are independently selected from hydrogen, alkyl (e.g., 1 to 12 carbons, further such as 1- 6 carbon alkyl) and hydroxyl.
在第三個態樣,本發明中至少一個選自分子式(I)化合物,其立體異構體,及其藥學上可以接受的鹽,選自下列分子式(III):
其中:RN選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;m和n,可以相同也可不同,可以分別是0、1、2或3之整數;t是整數0、1、2或3之整數;R 1 ,在每次出現時獨立地選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10、COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 2 選自氫、COR9、CONR9R10、CO2R9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代; R 3 、R 4 、R 5 、R 7 和R 8 ,可以相同也可不同,分別獨立地選自氫、鹵素、-NR9R10、-OR9、氧基、-COR9、-CO2R9、-CONR9R10、-NR9CONR10R11、-NR9CO2R10、-NR9SO2R10和-SO2R9、烷基、烯基、環烷基、芳基、雜環基、炔基和雜芳基,其中各烷基、烯基、炔基、環烷基、芳基、雜環基和雜芳基均可獨立地被至少一個取代基R12任選取代;或者(R3和R4)及/或(R4和R5)及/或(R5和R7)及/或(R7和R8),與它們所連接的一或多個原子,一起形成具有0、1或2個雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-,且該環可被至少一個取代基R 12 任選取代,當R3和R4中的一者是氧基時,另外一者不存在,當R7和R8中的一者是氧基時,另外一者不存在,R 9 、R 10 和R 11 ,可以相同也可不同,分別選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個取代基R12任選取代;R 12 選自氰基、鹵素、鹵烷基、NO2、-NR'R"、-OR'、氧基、-COR'、-CO2R'、-CONR'R"、-NR'CONR"R"'、-NR'CO2R"、-NR'SO2R"、-SO2R'、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中R'、R"和R'''獨立地選自氫、鹵烷基、烷基、芳烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,或者(R'和R")及/或(R"和R"'),與它們所連接的幾個原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分 不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-或者-SO2-;且R 13 選自氫、烷基、環烷基、芳基、雜芳基和雜環基。 Wherein: R N is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl The aryl and heteroaryl groups may each be independently substituted with at least one substituent R 12 ; m and n may be the same or different and may each be an integer of 0, 1, 2 or 3; t is an integer of 0, An integer of 1 , 2 or 3; R 1 , independently selected from the group consisting of halogen, cyano, NO 2 , OR 9 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 at each occurrence R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, The heterocyclic group, the aryl group and the heteroaryl group may each independently be optionally substituted with at least one substituent R 12 ; R 2 is selected from the group consisting of hydrogen, COR 9 , CONR 9 R 10 , CO 2 R 9 , SO 2 R 9 , alkane a base, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Independently substituted with at least one substituent R 12 ; R 3 , R 4 , R 5 , R 7 and R 8 may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, -NR 9 R 10 , -OR 9 , oxy, -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 CONR 10 R 11 , -NR 9 CO 2 R 10 , -NR 9 SO 2 R 10 and -SO 2 R 9 , alkyl, alkenyl, cycloalkyl, aryl, heterocyclic, Alkynyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group is independently optionally substituted with at least one substituent R 12 ; or (R 3 and R 4 ) and/or (R 4 and R 5 ) and/or (R 5 and R 7 ) and/or (R 7 and R 8 ) together with one or more of the atoms to which they are attached a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring of 0, 1 or 2 heteroatoms which may be independently selected from the group consisting of -NR 13 -, -O-, -S-, -SO- And -SO 2 -, and the ring may be optionally substituted by at least one substituent R 12 , when one of R 3 and R 4 is an oxy group, the other is absent, when in R 7 and R 8 When one is an oxy group, the other one is absent, and R 9 , R 10 and R 11 may be the same or different and are respectively selected from hydrogen, an alkyl group, an alkenyl group, An alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may be independently at least one Substituent R 12 is optionally substituted; R 12 is selected from cyano, halo, haloalkyl, NO 2 , -NR'R", -OR', oxy, -COR', -CO 2 R', -CONR'R",-NR'CONR"R"',-NR'CO 2 R", -NR'SO 2 R", -SO 2 R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic And aryl and heteroaryl, wherein R', R" and R" are independently selected from the group consisting of hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl, or (R' and R") and/or (R" and R"'), together with several atoms to which they are attached, form 0, 1 or 2 additional heteroatoms a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring, said additional heteroatoms being independently selected from -NR 13 -, -O-, -S-, -SO- or -SO 2 -; R 13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
在一些實施例中,分子式(III)中的m和n都是整數1。在一些實施例中,分子式(III)中的n是整數1,分子式(III)中的m是整數2;在其他一些實施例中,分子式(III)中的n是2,分子式(III)中的m是1。 In some embodiments, m and n in formula (III) are both integer 1. In some embodiments, formula (III) in which n is an integer of 1, of formula (III) wherein m is an integer of 2; In other embodiments, the formula (III) wherein n is 2, the formula (III), m is 1.
在一些實施例中,分子式(III)中的t是0。在一些實施例中,分子式(III)中的t是1,分子式(III)中的R1選自鹵素、氰基、NO2、OR9、NR9R10、NR9COR10、NR9SO2R10、CONR9R10、COOR9、SO2R9、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基均可獨立地被至少一個上述定義中的取代基R12任選取代。在一些進一步的實施例中,分子式(III)中的t是1,分子式(III)中的R1是鹵素(例如F、Cl和Br,進一步比如,F)或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)。在一些進一步的實施例中,分子式(III)中的t是1,分子式(III)中的R1是鹵素(例如F)。 In some embodiments, t in formula (III) is zero. In some embodiments, formula (III) in t is 1, the formula (III), R 1 is selected from halogen, cyano, NO 2, OR 9, NR 9 R 10, NR 9 COR 10, NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkyne The benzyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R 12 as defined above. In some further embodiments, the formula (III) in t is 1, the formula (III), R 1 is halogen (e.g. F, Cl and Br, further such as, F) or alkyl (e.g., 1-12 A carbon alkyl group, further, for example, an alkyl group of 1 to 6 carbons). In some further embodiments, the formula (III) in t is 1, the formula (III), R 1 is halogen (e.g., F).
在一些實施例中,分子式(III)中的RN是至少一個選自羥基和烷氧基的烷基取代基。在一些進一步的實施例中,分子式(III)中的RN是任選取代的1-12個碳的烷基,烷基至少是一個選自羥基和1-12個碳的烷氧基的取代基。在一些進一步的實施例中,分子式(III)中的RN是任選取代的1-6個碳的烷基,烷基至少是一個選自羥基或者1-6個碳的烷氧基的取代 基。 In some embodiments, R N in formula (III) is at least one alkyl substituent selected from the group consisting of a hydroxyl group and an alkoxy group. In some further embodiments, R N in formula (III) is an optionally substituted alkyl group of 1 to 12 carbons, and the alkyl group is substituted with at least one alkoxy group selected from the group consisting of a hydroxyl group and 1 to 12 carbons. base. In some further embodiments, R N in formula (III) is an optionally substituted 1-6 carbon alkyl group, and the alkyl group is at least one substituent selected from a hydroxyl group or an alkoxy group of 1 to 6 carbons. base.
在一些實施例中,分子式(III)中的R2是氫或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個上述分子式(III)定義中的中取代基R12任選取代。在一些實施例中,分子式(III)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個取代基R 12 任選取代,這裡,R 12 選自-NR'R"、-OR'、雜環基和芳基,這裡R’和R'''獨立地選自氫、鹵烷基、烷基和芳烷基,或者R'和R",與它們所連接的原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-和-SO2-。在一些進一步的實施例中,分子式(III)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個取代基R12任選取代,這裡,R12選自-NR'R"、-OR'、雜環基和芳基(例如,苯基),這裡R’和R"獨立地選自氫,鹵烷基(例如,1-12個碳的鹵烷基,進一步比如,1-6個碳的鹵烷基),烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),芳烷基(例如,苯基1-12個碳的烷基,進一步比如,苯基1-6個碳的烷基),或者R'和R",與它們所連接的原子,一起形成具有0、1或2個額外的雜原子的3到8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-或-SO2-(例如,5或者6元飽和環上有0或者1個額外的雜原子,雜原子是氧原子,進一步比如,5元飽和環、6元 飽和環,或者6元飽和環,環上有1個氧雜原子)。在一些進一步的實施例中,分子式(III)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個任選芳基(例如,苯基)的取代基;3、4、5、6、7和8元環的含有一個氮原子及/或一個氧原子的雜環,-OR’和-NR'R",這裡R’和R"獨立地選自氫、鹵烷基(例如,1-12個碳的鹵烷基,進一步比如,1-6個碳的鹵烷基)、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)、芳烷基(例如,苯基1-6個碳的烷基)。在一些進一步的實施例中,分子式(III)中的R2是烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個任選芳基(例如,苯基)的取代基;3、4、5、6、7和8元環的含有一個氮原子及/或一個氧原子的雜環,雜環可以選自吡咯烷基,哌啶基,嗎啉基和環氧乙基;-OR';和-NR'R",這裡R’和R"獨立地選自氫,鹵烷基(例如,1-6個碳的鹵烷基),烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),和芳烷基(例如,苯基1-6個碳的烷基,進一步比如,苯甲基)。 In some embodiments, R 2 in formula (III) is hydrogen or an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be subjected to at least one of the above formulas. The intermediate substituent R 12 in the definition of (III) is optionally substituted. In some embodiments, R 2 in formula (III) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R 12 Optionally substituted, herein, R 12 is selected from the group consisting of -NR'R", -OR', heterocyclyl and aryl, wherein R' and R''' are independently selected from hydrogen, haloalkyl, alkyl and aralkyl. a radical, or R' and R", together with the atom to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, said additional The heteroatoms can be independently selected from the group consisting of -NR 13 -, -O-, -S-, -SO-, and -SO 2 -. In some further embodiments, R 2 in formula (III) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R 12 is optionally substituted, wherein R 12 is selected from -NR'R", -OR', heterocyclyl and aryl (for example, phenyl), wherein R' and R" are independently selected from hydrogen, haloalkyl (for example, a haloalkyl group of 1 to 12 carbons, further, for example, a haloalkyl group of 1 to 6 carbons), an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) An alkyl group, an aralkyl group (for example, an alkyl group of 1 to 12 carbons of a phenyl group, further, for example, an alkyl group of 1 to 6 carbons of a phenyl group), or R' and R", and an atom to which they are attached, Together, a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring having 0, 1 or 2 additional heteroatoms may be formed, which may be independently selected from -NR 13 -, -O-, -S-, -SO- or -SO 2 - (for example, there are 0 or 1 additional heteroatoms on a 5 or 6-membered saturated ring, the hetero atom is an oxygen atom, further, for example, a 5-membered saturated ring, a 6-membered saturated ring , or a 6-membered saturated ring with 1 oxygen heteroatom on the ring). In an embodiment of the formula, R 2 in formula (III) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one optional aryl group (eg, a substituent of a phenyl group; a heterocyclic ring containing a nitrogen atom and/or an oxygen atom of the 3, 4, 5, 6, 7 and 8 membered rings, -OR' and -NR'R", where R' and R" is independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 12 carbons, further, for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1 to 12 carbons of alkane) Further, for example, an alkyl group of 1 to 6 carbons, an aralkyl group (for example, an alkyl group of 1 to 6 carbons). In some further embodiments, R 2 in the formula (III) is An alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), may be substituted with at least one optional aryl group (eg, phenyl); 3, 4, 5, 6 a 7- and 8-membered ring heterocyclic ring containing a nitrogen atom and/or an oxygen atom, the heterocyclic ring may be selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and epoxyethyl; -OR'; and -NR 'R', where R' and R" are independently selected from hydrogen, haloalkyl (eg, haloalkyl of 1 to 6 carbons), alkane (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), and an aralkyl group (for example, an alkyl group of a phenyl group of 1 to 6 carbons, further, for example, a benzyl group) .
在一些實施例中,分子式(III)中的R5選自氫、烷基、環烷基、芳基、-COR9和-COOR9,其中各烷基、環烷基和芳基,均可獨立地被至少一個取代基R12任選取代,R9是烷基或者環烷基,可以被至少一個取代基R12任選取代,R12的定義見分子式(III)。在一些實施例中,分子式(III)中的R5選自氫、烷基、環烷基、芳基、-COR9和-COOR9,其中各烷基、環烷基,或者芳基,均可獨立地被至少一個取代基R12任選取 代,R9是烷基或者環烷基,可以被至少一個取代基R12任選取代,R12選自-NR'R"、芳基,和-NR'CO2R",這裡R’和R"獨立地選自氫、鹵烷基,和烷基。在一些進一步的實施例中,分子式(III)中的R5選自氫;烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),可以被至少一個選自-NR'R"和芳基(例如,苯基)的取代基,任選取代;環烷基(例如,3、4、5、6、7、8個碳的環烷基);芳基(例如,苯基),可以被-NR'R"任選取代;-COR9,這裡,R9是環烷基(例如,3、4、5、6、7、8個碳的環烷基),或者烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基),其中各環烷基和烷基,可以被至少一個選自-NR'R"、芳基(例如,苯基)和-NR'CO2R"的取代基任選取代,這裡R’和R"獨立地選自氫、鹵烷基(例如,1-6個碳的鹵烷基)、烷基(例如,1-6個碳的烷基)。在一些進一步的實施例中,分子式(III)中的R5選自氫;1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基、丁基,或者3,3-二甲基丁基),可以被取代基-NR'R"任選取代;環己基;苯基,被取代基-NR'R"任選取代;-COR9,這裡,R9是環丙基,或者1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基,或者丁基),每個環丙基或者1-6個碳的烷基可以被至少一個選自-NR'R"、芳基(例如,苯基)和-NR'CO2R"的取代基任選取代,這裡R’和R"獨立地選自氫,和1-6個碳的烷基(例如,甲基、乙基、丙基、異丙基、丁基,或者叔丁基)。 In some embodiments, R 5 in formula (III) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR 9 and -COOR 9 wherein each alkyl, cycloalkyl and aryl group may be independently substituted with at least one substituent group is optionally substituted with R 12, R 9 is an alkyl or cycloalkyl group may be substituted with at least one of R 12 is optionally substituted, R 12, see the definition of the formula (III). In some embodiments, R 5 in formula (III) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR 9 and -COOR 9 wherein each alkyl, cycloalkyl, or aryl group is may be independently substituted with at least one substituent optionally substituted with R 12, R 9 is an alkyl or cycloalkyl group may be substituted with at least one of R 12 is optionally substituted, R 12 is selected from -NR'R ", aryl group, and -NR'CO 2 R", wherein R' and R" are independently selected from the group consisting of hydrogen, haloalkyl, and alkyl. In some further embodiments, R 5 in formula (III) is selected from hydrogen; alkyl (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), may be substituted with at least one substituent selected from the group consisting of -NR'R" and an aryl group (for example, a phenyl group) Alternative; cycloalkyl (eg, 3, 4, 5, 6, 7, 8 carbon cycloalkyl); aryl (eg, phenyl), optionally substituted by -NR'R"; -COR 9. Here, R 9 is a cycloalkyl group (for example, a cycloalkyl group of 3, 4, 5, 6, 7, 8 carbons), or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, a 1-6 carbon alkyl group, wherein each cycloalkyl group and alkyl group may be selected from at least one selected from the group consisting of -NR'R" and an aryl group (for example Substituents of phenyl) and -NR'CO 2 R" are optionally substituted, wherein R' and R" are independently selected from hydrogen, haloalkyl (eg haloalkyl of 1 to 6 carbons), alkyl (for example, an alkyl group of 1 to 6 carbons). In some further embodiments, R 5 in formula (III) is selected from the group consisting of hydrogen; 1-6 carbon alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, or 3, 3-dimethylbutyl), which may be optionally substituted by a substituent -NR'R";cyclohexyl; phenyl, optionally substituted by a substituent -NR'R"; -COR 9 , where R 9 is a ring a propyl group, or an alkyl group of 1 to 6 carbons (for example, methyl, ethyl, propyl, isopropyl, or butyl), each of which is a cyclopropyl group or a 1-6 carbon alkyl group A substituent selected from the group consisting of -NR'R", aryl (for example, phenyl) and -NR'CO 2 R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, and 1-6 carbons Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl).
在一些實施例中,分子式(III)中的R4和R5,與R4 和R5所連接的幾個原子,一起形成具有0、1或2個額外的雜原子的3、4、5、6、7或者8元飽和、部分不飽和或全部不飽和的環,所述額外的雜原子可以獨立地選自-NR13-、-O-、-S-、-SO-或-SO2-,且該環可被至少一個上述分子式(III)定義中的中取代基R12任選取代。在一些進一步的實施例中,分子式(III)中的R4和R5,與R4和R5所連接的一或多個原子,一起形成有一個氮原子的5元飽和環。 In some embodiments, R 4 and R 5 in formula (III) , together with several atoms to which R 4 and R 5 are attached, form 3, 4, 5 having 0, 1 or 2 additional heteroatoms. , 6, 7 or 8-membered saturated, partially unsaturated or fully unsaturated ring, the additional heteroatoms may be independently selected from -NR 13 -, - O -, - S -, - SO- or -SO 2 And, the ring may be optionally substituted by at least one of the above-mentioned intermediate substituents R 12 in the definition of formula (III) . In some further embodiments, R 4 and R 5 in formula (III) , together with one or more atoms to which R 4 and R 5 are attached, form a 5-membered saturated ring having a nitrogen atom.
一些實施例中,分子式(III)中的R3和R4,可以相同也可不同,分別獨立地選自氫、烷基(例如,1-12個碳的烷基,進一步比如,1-6個碳的烷基)和羥基。 In some embodiments, R 3 and R 4 in the formula (III) may be the same or different and are each independently selected from hydrogen, an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1-6 a carbon alkyl group) and a hydroxyl group.
本發明還提供了至少一種化合物選自下列化合物,其異構體,及其藥學上可以接受的鹽:
本發明還提供一種抑制PARP活性的方法。該方法包括使有效量的至少一種化合物、至少一種化合物的立體異構體及/或至少一種化合物藥學上可以接受的鹽與PARP接觸來抑制PARP活性。 The invention also provides a method of inhibiting PARP activity. The method comprises contacting an effective amount of at least one compound, a stereoisomer of at least one compound, and/or a pharmaceutically acceptable salt of at least one compound with PARP to inhibit PARP activity.
本發明提供了一種可以治療至少一種與PARP相關的疾病的辦法,包括對確認需要治療至少一種相關疾病的治療對象(如哺乳動物或人類)給藥,而藥物則是一定量的至少一種本發明所描述的化合物及其藥學上可以接受的鹽。 The present invention provides a method of treating at least one PARP-associated disease comprising administering to a subject (e.g., a mammal or a human) who is in need of treatment for at least one related disease, and wherein the drug is an amount of at least one of the present invention The compounds described and their pharmaceutically acceptable salts.
可以治療至少一種以下疾病,例如,卵巢癌、乳腺癌、結腸癌、白血病、惡性膠質瘤、淋巴瘤、黑色素瘤、宮 頸癌和其他細胞毒性的癌症。 It can treat at least one of the following diseases, for example, ovarian cancer, breast cancer, colon cancer, leukemia, glioblastoma, lymphoma, melanoma, palace Cervical cancer and other cytotoxic cancers.
本發明揭示的至少一個化合物、至少一種化合物的立體異構體及/或至少一種化合物藥學上可以接受的鹽可單獨使用或與放療和化療組合使用,例如,增加腫瘤細胞的凋亡、限制腫瘤的生長、降低轉移、延長荷瘤動物的生存。 The at least one compound disclosed in the present invention, the stereoisomer of at least one compound, and/or the pharmaceutically acceptable salt of at least one compound may be used alone or in combination with radiation therapy and chemotherapy, for example, increasing tumor cell apoptosis and limiting tumors. Growth, reduce metastasis, and prolong the survival of tumor-bearing animals.
在某些實施例中,本發明中揭示的至少一個化合物、至少一種化合物的立體異構體及/或至少一種藥學上可以接受的鹽可以與至少一個另外的治療劑組合使用,如至少一種額外的化療劑。 In certain embodiments, at least one compound disclosed in the present invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt can be used in combination with at least one additional therapeutic agent, such as at least one additional Chemotherapeutic agent.
「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例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; biomime; alkaloids; alkylating agents; Antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies used in combination with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (interferons 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 .
化療藥物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、英丙舒凡和呱泊舒凡;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和其阿多來新、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gamma1I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-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;阿拉伯糖苷("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 drugs include erlotinib (Terroy®, Genentech/OSI Pharm.); bortezomib (Millennium Pharm.); fulvestrant (FASLODEX®, AstraZeneca); 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; Lonafani (SCH 66336); Sorafenib (Nexaco®, 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, propylene buffalo and valprosone; Aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines such as hexamethylene melamine, triethylenemelamine, triethylenephosphonium, triethylene thiophosphonamide and tris Melamine; lactones (such as bullatacin and bullatacinone); camptothecin (such as synthetic analogs of topotecan); bryostatin; callistatin; CC-1065 and its adoline, card, new, discount 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; Such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, nitrogen mustard, nitrogen oxide mustard hydrochloride, melphalan, neombibic, phenesterine, splash Nidnane mustard (prednimustine), tricotine cyclophosphamide, uracil mustard; nitrosourea such as carmustine, chlorfluazuron, formoterol, lomustine, nimustine and raminnustine Antibiotics such as enediyne antibiotics (such as calicheamicin gamma1I and calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186)); dynemicin, such as dynemicin A; Bisphosphonates such as clodronate; espermati; and new A chromophore for carcinogens, and related chromophores of chromogenic diacetylene antibiotics, aclacinomysins, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, Carabicin, caminomycin, carzinophilin, chromomycinis, actinomycin D, daunorubicin; detorubicin, 6-diazo-5-oxo-L-norleucine, ® adriamycin (doxorubicin, doxorubicin), morpholino - doxorubicin, morpholino-cyano - doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin, epirubicin (epirubicin), Essoubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, oleomycin (olivomycins), pilomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptavidin, streptozotocin, tuberculin, uranium Benzis, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouridine Pyrimidine (5-FU); folic acid analogs such as dimethyl phthalate (denopterin), methotrexate, pteroquinone, trimethoate; guanidine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, sulfur Guanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, di-deoxyuridine, deoxyfluorouridine, Notitabine, fluorouridine; androgens, such as calpressone, dromostanolone propionate, cyclostrankrol, mepitiostane, testosterone; anti-adrenalin Aminoglutamine, mitoxantrone, and tromethamine; folic acid supplements such as frolinic acid; acetaldehyde lactone; aldoxime; aminolevulinic acid; eniluracil; amidine; bestrabucil; Bisantrene); defofamine; defolamine; demecolcine; diziquone; elformithine; elliptinium acetate; epothilone; etoglucid; Lentinus edodes; lonidainine; maytansinoids, such as maytansine 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; trichosporin (eg T-2 toxin, verracurin A, Roridin A and anguidine); urethane; vindesine; nitromethamine; mannitol mustard; mitobronitol; mitolactol; Pipobroman; gacytosine; arabinoside ("Ara-C");cyclophosphamide;thiotepa; taxanes, for example, TAXOL® (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor-free), albumin engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) Taxotere ® (doxetaxel; Rhone-Poulenc Rorer , Antony, France); chloranmbucil; GEMZAR ® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, carboplatin; Vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; noviben® (vinorelbine); novantrone; Nipaside; edatrexate; daunorubicin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; Fluoromethylornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids and any of the above derivatives.
「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,比如抗雌激素和選擇性雌激素受體調控劑(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,能夠調節雌激素在腎上腺中的產生,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)抗血管生成試劑例如貝伐單抗(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, Moxifene (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 ® Progesterone acetate), AROMASIN ® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR ® (voltazole), FEMARA ® (letrozole; Novartis) and ARIMIDEX ® (anastrozole; AstraZeneca) (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and troxacitabine (1,3-dioxine) (iv) protein kinase inhibitor; (v) lipid kinase inhibitor; (vi) antisense oligonucleoside 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 ( Such as 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) an anti-angiogenic agent such as bevacizumab (AVASTIN ® , Genentech); and (x) a pharmaceutically acceptable salt, an acid, and the analogs 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本發明中的至少一種化合物,及其異構體,及/或其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)。 The potentially potent humanized monoclonal antibody can be used as a chemotherapeutic agent in combination with at least one compound of the present invention, and an isomer thereof, and/or a pharmaceutically acceptable salt thereof, for example, can be selected from: Rumuzumab, apocilizumab, acezumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab injection, cidfusituzumab, cidtuzumab, daclizumab, Eculizumab, ezetuzumab, epratuzumab, erlizumab (ehelizumab), felvizumab (panvizumab), fontolizumab, gemtuzumab Zommidin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, meboli Monoclonal antibody, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pa Topuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siprilizumab ( Siplizumab), soxemumab, tacatuzumab tetraxetan, tadocizumab, talibizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab Celmoleukin, tucusituzumab, umavizumab, urtoxazumab and visilizumab.
也提供了一種組合物,該組合物包含至少一種本發明中的化合物、至少一種化合物的立體異構體及/或至少一種本發明揭示的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 composition comprising at least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein, and at least one pharmaceutically acceptable a.
該組合物包含至少一種本發明中的化合物、至少一種化合物的立體異構體,及/或至少一種本發明揭示的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 composition comprises at least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein, which may be administered in a variety of known manners, such as orally, Overcoat, rectal, parenteral, inhalation spray, or by implantable kit, although in some hypothetical situations the most appropriate route of administration depends on the particular host, and when the active ingredient is administered The natural conditions 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 cranial Internal injection or infusion technology. The compositions disclosed herein are conveniently prepared in unit dosage form and by any methods known in the art.
至少一種本發明中的化合物、至少一種化合物的立體異構體,及/或至少一種本發明揭示的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。至少一種本發明中的化合物、至少一種化合物的立體異構體,及/或至少一種本發明揭示的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。本發明中的化合物及其異構體,和其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陰道給藥。 At least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein, can be orally administered in a solid dosage form, such as a capsule, tablet, tablet, dragee Or granules and powders, or oral administration in liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. At least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein may also be administered parenterally, in a sterile liquid dosage form, such as a dispersion, Suspension or solution. The compounds of the present invention and isomers thereof, and pharmaceutically acceptable salts thereof, may also be administered in other dosage forms such as: ointments, creams, drops, topical transdermal patches or powders, to the eye. Ophthalmic administration in the form of a solution or suspension such as eye drops, inhalation or nasal administration in the form of a spray or a powder composition, or rectal or vaginal administration in the form of a cream, ointment, spray, or suppository.
明膠膠囊包含至少一種本發明揭示的化合物、至少一種化合物的立體異構體及/或者至少一種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掩蓋令人不愉快的味道,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 comprise at least one compound disclosed herein, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, Stearic acid and analogs can also be used. 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. Compressed tablets may be coated with sugar or film to mask an unpleasant taste while protecting the tablet from air, or the enteric coating may 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。 The liquid dosage form for oral administration further comprises at least one selected from the group consisting of A reagent for colorants and flavors to increase 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發明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 of the invention, 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。例如一些增溶劑環糊精(能夠和本發明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. For example, some solubilizing cyclodextrins (which are capable of forming a specific, more soluble complex with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) 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.
本發明揭示的至少一種化合物、至少一種化合物的立體異構體及/或至少一種藥學上可以接受的鹽,可以用於初步評估在體外實驗中,抑制PARP活性的療效。本發明揭示 的至少一個化合物、至少一種化合物的立體異構體及/或至少一種藥學上可以接受的鹽可進一步用於檢驗在體內實驗中對癌症的療效。例如,本發明揭示的至少一個化合物、至少一種化合物的立體異構體及/或至少一種藥學上可以接受的鹽可以對患有癌症的一個動物(例如,小鼠模型)給藥,進而評價該至少一個化合物、其異構體及/或至少一種藥學上可以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。基於這些實驗結果,可以確定對動物和人類的給藥劑量和給藥途徑。 The at least one compound, at least one stereoisomer of the compound, and/or at least one pharmaceutically acceptable salt disclosed herein can be used to initially assess the efficacy of inhibiting PARP activity in an in vitro assay. The invention discloses At least one compound, at least one stereoisomer of the compound, and/or at least one pharmaceutically acceptable salt can be further used to test the efficacy of the cancer in an in vivo experiment. For example, at least one compound, at least one stereoisomer of the compound, and/or at least one pharmaceutically acceptable salt disclosed herein can be administered to an animal (eg, a mouse model) having cancer, thereby evaluating the A therapeutic effect of at least one compound, an isomer thereof, and/or at least one pharmaceutically acceptable 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 experimental results, the dosage and route of administration to animals and humans can be determined.
對於吸入式給藥方式,本發明揭示的至少一個化合物、其立體異構體及/或至少一種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。本發明揭示的至少一個化合物、其立體異構體及/或至少一種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,可以將本發明揭示的至少一個化合物、其立體異構體及/或至少一種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 mode of administration, at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt disclosed herein can be conveniently delivered as an aerosol spray from a compressor or nebulizer. The at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt disclosed herein may also be delivered in the form of a powder of a dosage form or inhalation of a powder composition with the aid of a spray dry powder inhaler device. A metered dose inhalation nebulizer (MDI) is a typical inhalation delivery system that can make at least one compound, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt disclosed herein at least one propellant, such as A suspension or solution from a fluorocarbon and a hydrocarbon compound.
對於眼部給藥,眼用製劑可以通過將適量重量百分比的本發明揭示的至少一個化合物、其立體異構體及/或至少一種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,使得比如本發明揭示的至少一個化合物、其立 體異構體及/或至少一種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 ophthalmic administration, ophthalmic preparations may be prepared by formulating a suitable amount by weight of a solution or suspension of at least one compound, a stereoisomer thereof and/or at least one pharmaceutically acceptable salt disclosed herein. An ophthalmic carrier, such as at least one compound disclosed in the present invention, The isomer and/or at least one pharmaceutically acceptable salt remains 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.
本發明揭示的至少一個化合物、其立體異構體及/或至少一種藥學上可以接受的鹽有用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。 Pharmaceutically acceptable dosage forms of at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt disclosed herein 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,可以從每天0.1到2000毫克。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毫克粉末形式的本發明揭示的至少一個化合物、其立體異構體及/或至少一種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, at least one compound, stereoisomers, and/or at least one pharmaceutically acceptable amount disclosed herein in the form of 100 mg of powder. Acceptable salt, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.
在一些實施例中,混合物選自于本發明中的至少一個化合物、其立體異構體及/或至少一種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。然後將膠囊洗滌和乾燥。 In some embodiments, the mixture is selected from at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt and digestible oil, such as soybean oil, cottonseed oil or olive oil, in the present invention. It 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 capsules are then 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毫克選來自于本發明中的化合物至少一個化合物、其立體異構體及/或至少一種藥學上 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 may be prepared by conventional procedures, each dosage unit comprising, for example, 100 mg of a compound selected from the invention, at least one compound, a stereoisomer thereof, and/or at least one pharmaceutically acceptable 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%重量比的本發明揭示的至少一個化合物、其立體異構體及/或至少一種藥學上可接受的鹽,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 herein, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt, 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毫克細碎的本發明揭示的至少一個化合物、其立體異構體,及/或至少一種藥學上可接受的鹽,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 finely divided at least one compound disclosed herein, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt, 100 mg of sodium carboxymethylcellulose. , 5 mg sodium benzoate, 1 gram sorbitol solution, USP and 0.025 ml vanillin.
當本發明揭示的至少一個化合物、其立體異構體,及/或至少一種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至少兩種試劑同時或者依次給藥,或者以固定劑量的至少兩種活性成分的組合物給藥。 The same dosage form may be used when at least one compound, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt disclosed herein is administered stepwise or together with at least one other therapeutic agent. 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. Thus, the simultaneous administration of the term is understood to mean the administration of at least two agents simultaneously or sequentially, or in a fixed dose of a combination of at least two active ingredients.
本發明揭示的至少一個化合物、其立體異構體,及/或至少一種藥學上可以接受的鹽可以以單一活性成分給藥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合給藥。 The at least one compound, stereoisomer thereof, and/or at least one pharmaceutically acceptable salt disclosed herein may be administered as a single active ingredient or in combination with at least one second active ingredient, for example, selected from the well-known Other active ingredients for treating cancer are administered in combination.
通用反應方案 General reaction scheme
本發明揭示的化合物,及/或其藥學上可以接受的鹽,可由市售的原料和本發明製備的原料合成。下面的方案描述了一些揭示的化合物的製備方法。 The compounds disclosed herein, and/or pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials and starting materials prepared in accordance with the present invention. The following schemes describe the preparation of some of the disclosed compounds.
在這個方案中,分子式1中的3-氨基-2-離去基-苯甲酸酯(離去基,例如Br、I、OTf)與分子2中的環狀1,3-二羰基化合物反應,得到分子3中的烯胺酮,然後用一個催化劑,如鈀,環合,得到分子式4中的氧代哢唑甲酸酯,然後該酯與水合肼環合得到式(I)、(II)或者(III)中的二氮雜卓並哢唑酮衍生物。 In this embodiment, the 3-amino-2-ionol-benzoate (the leaving group such as Br, I, OTf) in the formula 1 is reacted with the cyclic 1,3-dicarbonyl compound in the molecule 2. The enaminone in molecule 3 is obtained, and then cyclized with a catalyst such as palladium to obtain an oxocarbazole formate in the formula 4, and then the ester is cyclized with hydrazine hydrate to obtain the formula (I) , (II ) . ) or (III) in diazepino Long trazodone derivative.
本方案中第一步,使用Dean-Stark裝置,溶劑可以是甲苯等,回流下反應。用色譜矽膠柱純化分離,得到的分 子式3中的烯胺酮。 In the first step of the scheme, a Dean-Stark apparatus is used, and the solvent may be toluene or the like, and the reaction is carried out under reflux. Purification by chromatography on a silica gel column, the obtained fraction The enaminone in subformula 3.
本方案中的第二步,使用鈀/磷催化劑,以乙腈或者DMF作溶劑,加熱下反應。這個分子內的Heck反應(Bozell,J.J.,Hegedus,L.S.J.Org.Chem.1981,46,2561;Maruyama,J.,Yamashida,H.,Watanabe,T.,Arai,S.,Nishida,A.Tetrahedron 2009,65,1327,引入本文作為參考),一般需要大約5-24小時。分子式4中的氧代哢唑甲酸酯採用標準的後處理條件分離得到,可以用色譜純化也可以用重結晶純化。 In the second step of the scheme, a palladium/phosphorus catalyst is used, and the reaction is carried out by heating with acetonitrile or DMF as a solvent. Heck reaction in this molecule (Bozell, JJ, Hegedus, LSJ Org. Chem. 1981, 46, 2561; Maruyama, J., Yamashida, H., Watanabe, T., Arai, S., Nishida, A. Tetrahedron 2009 , 65, 1327, incorporated herein by reference), generally takes about 5-24 hours. The oxocarbazole formate in Formula 4 is isolated using standard post-treatment conditions and can be purified either by chromatography or by recrystallization.
式(I)中新化合物合成的第三步,分子式4中化合物發生分子內的環合反應,得到方案1所示的式(I)、(II)或(III)中的二氮雜卓並哢唑酮衍生物。環合反應可以代表性的使用1-2當量的水合肼,和適當的醇做溶劑。環合反應可以代表性的從50℃到醇回流條件下,例如,0.25至4小時反應完成。 In the third step of synthesizing the novel compound in the formula (I) , the compound in the formula 4 undergoes an intramolecular cyclization reaction, and the diazapine in the formula (I) , (II) or (III) shown in the scheme 1 is obtained. Oxazolone derivatives. The cyclization reaction can be typically carried out using 1-2 equivalents of hydrazine hydrate, and a suitable alcohol as a solvent. The cyclization reaction can be typically carried out from 50 ° C to an alcohol reflux condition, for example, 0.25 to 4 hours.
方案2描述了一些式(III)中的化合物的合成。分子式a中的化合物也是式(III)中的一個化合物,也可以用方案1中的方法製備。 Scheme 2 describes the synthesis of some of the compounds of formula (III) . The compound of the formula a is also a compound of the formula (III) , which can also be produced by the method of the scheme 1.
分子式a中的化合物脫保護得到分子式b中的化合物(也是式(III)中的化合物)。分子式b中的化合物與親電試劑 繼續發生相應的烷基化,耦合,或者還原烷基化反應,得到式(III)中的一些化合物。親電試劑例如鹵烷基、鹵代芳烴、羧酸、醯氯、磺醯氯、醛、酮等。 Deprotection of the compound of formula a yields a compound of formula b (also a compound of formula (III) ). The compound of formula b and the electrophile continue to undergo corresponding alkylation, coupling, or reductive alkylation to provide some of the compounds of formula (III) . Electrophiles such as haloalkyl, halogenated arene, carboxylic acid, hydrazine chloride, sulfonium chloride, aldehyde, ketone, and the like.
反應實例Reaction example
下面的實施例的目的是純粹的示例性的,不應該以任何方式進行限制。雖已盡力確保資料(例如,量、溫度等)的準確性,但一些實驗誤差和偏差在所難免。除非另有說明,溫度是攝氏溫度。試劑購自Sigma-Aldrich公司,阿法埃莎(Alfa Aesar),或TCI等商業供應商,除非另有說明,無需進一步純化,可直接使用。 The following examples are intended to be purely exemplary and should not be construed in any way. While every effort has been made to ensure the accuracy of the data (eg, volume, temperature, etc.), some experimental errors and deviations are inevitable. Unless otherwise stated, the temperature is Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise stated.
除非另有說明,下列反應在無水溶劑中,氮氣或氬氣的正壓下或使用乾燥管進行;反應瓶上裝有橡膠隔膜,通過注射器加入底物和試劑;玻璃器皿烘乾及/或加熱乾燥。 Unless otherwise stated, the following reactions are carried out in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; the reaction flask is filled with a rubber septum, the substrate and reagents are added via a syringe; the glassware is dried and/or heated. dry.
除非另有說明,柱色譜純化在有一個矽膠柱的Biotage系統上進行(製造商:Dyax公司),或使用二氧化矽seppak筒(Waters),或是採用事先裝填好的矽膠柱,在一個Teledyne Isco combiflash純化系統進行。 Unless otherwise indicated, column chromatography purification was performed on a Biotage system with a silica gel column (manufacturer: Dyax), or with a ceria seppak cartridge (Waters), or with a pre-filled silica gel column in a Teledyne Isco combiflash purification system is carried out.
核磁資料使用Varian設備於400MHz運行。核磁資料使用的溶劑有CDCl3、CD2Cl2、CD3OD、D2O、d6-DMSO、d6-acetone或(CD3)2CO,以四甲基矽烷(0.00ppm)為基準或者以殘留溶劑為基準(CDCl3:7.25ppm;CD3OD:3.31ppm;D2O:4.79ppm;d6-DMSO:2.50ppm;d6-acetone:2.05;(CD3)2CO:2.05)。當標明峰形多樣性時,以下簡寫表示不同峰形:s(單峰)、d(雙重峰)、t(三重峰)、q(四重峰)、qn(五重峰)、sx(六 重峰)、m(多重峰)、br(寬峰),dd(兩個雙重峰)、dt(兩個三重峰)。如果給出了耦合常數,則以Hertz(Hz)為單位。溶劑外其他試劑以Chemdraw 12.0版本命名。 The nuclear magnetic data was run at 400 MHz using a Varian device. The solvent used in the nuclear magnetic data is CDCl 3 , CD 2 Cl 2 , CD 3 OD, D 2 O, d 6 -DMSO, d 6 -acetone or (CD 3 ) 2 CO, based on tetramethyl decane (0.00 ppm). Or based on residual solvent (CDCl 3 : 7.25 ppm; CD 3 OD: 3.31 ppm; D 2 O: 4.79 ppm; d 6 -DMSO: 2.50 ppm; d 6 -acetone: 2.05; (CD 3 ) 2 CO: 2.05 ). When the peak shape diversity is indicated, the following abbreviations indicate different peak shapes: s (single peak), d (double peak), t (triplet), q (quadruple), qn (five peak), sx (six Heavy peak), m (multiple peak), br (wide peak), dd (two double peaks), dt (two triplets). If a coupling constant is given, it is in Hertz (Hz). Other reagents other than solvent are named after Chemdraw 12.0.
以下示例中,使用了以下簡寫:
例1:化合物1-19的合成 Example 1: Synthesis of Compound 1-19
化合物1:2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
步驟1:2-溴-3-((3-氧基環己基-1-烯-1-基)氨基)苯甲
酸甲酯
3-氨基-2-溴苯甲酸甲酯(2.39g,10.0mmol)和1,3-二羰基環己烷(1.12g,10.0mmol)在25℃,氮氣保護下溶於乙酸(10mL)。反應混合物在80℃下反應8小時。(反應混合旋幹)所得的固體用色譜柱純化(洗脫劑:正己烷和乙酸乙酯)得到2-溴-3-((3-氧基環己基-1-烯-1-基)氨基)苯甲酸甲酯(2.46g,76%),為一棕褐色泡沫狀物質。1H NMR(CDCl3-d1)δ 7.53-7.55(m,2H),7.37(dd,1H,J=7.2,8.4Hz),6.34(br s,1H),5.57(s,1H),3.95(s,3H),2.56-2.59(m,2H),2.40-2.42(m,2H),2.08-2.11(m,2H)。MS(ESI)m/e[M+1]+ 324.0。 Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and 1,3-dicarbonylcyclohexane (1.12 g, 10.0 mmol) were dissolved in acetic acid (10 mL). The reaction mixture was reacted at 80 ° C for 8 hours. (Reaction mixture spin-drying) The obtained solid was purified by chromatography (eluent: n-hexane and ethyl acetate) to give 2-bromo-3-((3-oxycyclohexyl-1-en-1-yl)amino Methyl benzoate (2.46 g, 76%) as a tan foam. 1 H NMR (CDCl 3 -d 1 ) δ 7.53-7.55 (m, 2H), 7.37 (dd, 1H, J = 7.2, 8.4 Hz), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.42 (m, 2H), 2.08-2.11 (m, 2H). MS (ESI) m / e [M+1] + 324.0.
步驟2:4-氧-2,3,4,9-四氫-1H-哢唑-5-甲酸甲酯
2-溴-3-(3-氧基環己基-1-烯基胺)苯甲酸甲酯(0.97g,3.0mmol),醋酸鈀(0.14g,0.6mmol)、三(鄰甲基苯基)磷(0.73g,2.4mmol)、三乙胺(0.38g,3.6mmol)、乙腈(10mL)的混合物,氮氣保護下在封管中加熱至100℃,反應20小時。反應混合物冷卻,加入DCM(3×50mL)和水(10mL)。有機相分離,水洗,無水硫酸鈉乾燥,濃縮,剩餘物用矽膠色譜柱純化(洗脫劑:0-100%乙酸乙酯的正己烷溶液)得到目標化合物(0.61g,84%).1H NMR(CDCl3-d1)δ 9.47(s,1H),7.36-7.40(m,2H),7.22(t,1H,J=7.8Hz),2.90-2.92(m,2H), 2.51-2.54(m,2H),2.14-2.16(m,2H)。MS(ESI)m/e[M+1]+244.0。 Methyl 2-bromo-3-(3-oxocyclohexyl-1-enylamine)benzoate (0.97 g, 3.0 mmol), palladium acetate (0.14 g, 0.6 mmol), tris (o-methylphenyl) A mixture of phosphorus (0.73 g, 2.4 mmol), triethylamine (0.38 g, 3.6 mmol) and acetonitrile (10 mL) was heated to 100 ° C in a sealed tube under nitrogen atmosphere for 20 hours. The reaction mixture was cooled and DCM (3×50 mL) and water (10 mL). The organic phase was separated, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue purified by column chromatography using silica gel: to give the title compound (eluant 0-100% ethyl acetate in n-hexane) (0.61g, 84%) 1 H. NMR (CDCl 3 -d 1 ) δ 9.47 (s, 1H), 7.36-7.40 (m, 2H), 7.22 (t, 1H, J = 7.8 Hz), 2.90 - 2.92 (m, 2H), 2.51-2.54 ( m, 2H), 2.14 - 2.16 (m, 2H). MS (ESI) m / e [M+1] + 244.0.
步驟3:2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
4-氧-2,3,4,9-四氫-1H-哢唑-5-甲酸甲酯(73mg,0.3mmol),溶於甲醇(4mL),加入乙酸(0.15mL,2.6mmol)和水合肼(0.86mL,1.5mmol),加熱回流8小時。反應生成的固體熱過濾,依次用水,乙酸乙酯,二氯甲烷洗滌,得到目標化合物(42mg,62%)。1H NMR(DMSO-d6)δ 11.70(s,1H),9.79(s,1H),7.36-7.38(m,2H),7.05(t,1H,J=7.8Hz),2.77-2.79(m,2H),2.35-2.37(m,2H),1.92-1.93(m,2H)。MS(ESI)m/e[M+1]+ 226.0。 Methyl 4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate (73 mg, 0.3 mmol), dissolved in methanol (4 mL), ethyl acetate (0.15mL, 2.6mmol) and hydrated肼 (0.86 mL, 1.5 mmol) was heated to reflux for 8 h. The solid which was formed by the reaction was filtered, washed with water, ethyl acetate 1 H NMR (DMSO-d 6 ) δ 11.70 (s, 1H), 9.79 (s, 1H), 7.36-7.38 (m, 2H), 7.05 (t, 1H, J = 7.8 Hz), 2.77-2.79 (m) , 2H), 2.35-2.37 (m, 2H), 1.92-1.93 (m, 2H). MS (ESI) m / e [ M + 1] + 226.0.
以下反應實例,化合物2至19,採用與合成化合物1類似的方法,以相應的取代的或非取代的3-氨基-2-溴苯甲酸甲酯和1,3-二羰基環狀化合物為原料,由本領域的熟練操作人員合成。 In the following reaction examples, compounds 2 to 19 are prepared in a similar manner to the synthesis of compound 1, using the corresponding substituted or unsubstituted methyl 3-amino-2-bromobenzoate and a 1,3-dicarbonyl cyclic compound. , synthesized by skilled operators in the field.
例2:化合物20-21的合成 Example 2: Synthesis of Compound 20-21
化合物20:8-氧-3,4,8,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-2(1H)-甲酸苄酯
步驟1:3-((2-溴-3-(甲氧基羰基)苯基)氨基)-5-氧-5,6-二氫吡啶-1(2H)-甲酸苄酯
3-氨基-2-溴苯甲酸甲酯(0.25g,1.1mmol)和3,5-二氧基哌啶-1-甲酸苄酯(0.13g,0.55mmol)在25℃,氮氣保護下溶於乙酸(10mL)。混合物70℃攪拌8小時。所得固體用色譜柱純化(洗脫劑:正己烷和乙酸乙酯)得到3-((2-溴-3-(甲 氧基羰基)苯基)氨基)-5-氧-5,6-二氫吡啶-1(2H)-甲酸苄酯0.13g(51%),為一棕褐色泡沫狀物質。1H NMR(CDCl3-d1)δ 7.53-7.58(m,3H),7.42-7.48(m,5H),5.56(s,1H),5.16(s,2H),4.46(s,2H),4.13(s,2H),3.93(s,3H)。MS(ESI)m/e[M+1]+ 459.0。 Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxypiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved at 25 ° C under nitrogen. Acetic acid (10 mL). The mixture was stirred at 70 ° C for 8 hours. The obtained solid was purified by chromatography (eluent: n-hexane and ethyl acetate) to give 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6- Hydrogen pyridine-1(2H)-benzyl formate 0.13 g (51%) was a tan foamy material. 1 H NMR (CDCl 3 -d 1 ) δ 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H), 5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS (ESI) m / e [M+1] + 459.0.
步驟2:4-氧-3,4-二氫-1H-吡啶並[3,4-b]吲哚-2,5(9H)-2-甲酸苄酯-5-甲酸甲酯
3-((2-溴-3-(甲氧基羰基)苯基)氨基)-5-氧-5,6-二氫吡啶-1(2H)-甲酸苄酯(0.13g,0.28mmol)、醋酸鈀(0.013g,0.06mmol),三(鄰甲基苯基)磷(0.72g,0.19mmol)、三乙胺(0.36g,0.36mmol)、乙腈(2mL)的混合物,氮氣保護下在封管中加熱至100℃,反應9小時。反應混合物冷卻,加入DCM(3×50mL)和水(10mL)萃取。有機相分離,水洗,無水硫酸鈉乾燥,濃縮,剩餘物用色譜柱純化(洗脫劑:0-100%乙酸乙酯的正己烷溶液)得到目標化合物(0.076g,72%)。1H NMR(CDCl3-d1)δ 9.62(s,1H),7.24-7.50(m,8H),5.18(s,2H),4.88(s,2H),4.27(s,2H),3.98(s,3H)。MS(ESI)m/e[M+1]+ 379.0。 3-((2-Bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (0.13 g, 0.28 mmol), a mixture of palladium acetate (0.013 g, 0.06 mmol), tris(o-methylphenyl)phosphine (0.72 g, 0.19 mmol), triethylamine (0.36 g, 0.36 mmol), acetonitrile (2 mL) The tube was heated to 100 ° C and reacted for 9 hours. The reaction mixture was cooled and extracted with EtOAc EtOAc m. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate sulfatessssssssssssssssssss 1 H NMR (CDCl 3 -d 1 ) δ 9.62 (s, 1H), 7.24 - 7.50 (m, 8H), 5.18 (s, 2H), 4.88 (s, 2H), 4.27 (s, 2H), 3.98 ( s, 3H). MS (ESI) m / e [ M + 1] + 379.0.
步驟3:8-氧-3,4,8,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-2(1H)-甲酸苄酯
4-氧-3,4-二氫-1H-吡啶並[3,4-b]吲哚-2,5(9H)-2-甲酸苄酯-5-甲酸甲酯(70mg,0.18mmol),溶於甲醇(4mL),加入乙酸(0.15mL,2.6mmol)、水合肼(0.86mL,1.5mmol)加熱回流8小時。反應生成的固體熱過濾,依次用水,乙酸乙酯,二氯甲烷洗滌,得到目標化合物(61mg,94%)。1H NMR(DMSO-d6)δ 11.8(s,1H),10.1(s,1H),7.54(d,1H,J=8.4Hz),7.48(d,1H,J=7.2Hz),7.38(m,4H),7.32(m,1H),7.18(dd,1H,J=8.4,7.2Hz),5.15(s,2H),4.82(m,2H),4.28(m,2H)。MS(ESI)m/e[M+1]+ 361。 Methyl 4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-2-carboxylate-5-carboxylate (70 mg, 0.18 mmol), Dissolved in methanol (4 mL), added acetic acid (0.15 mL, 2.6 mmol), EtOAc (EtOAc: The solid formed by the reaction was filtered, washed with EtOAcjjjjjjjj 1 H NMR (DMSO-d 6 ) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.54 (d, 1H, J = 8.4 Hz), 7.48 (d, 1H, J = 7.2 Hz), 7.38 ( m, 4H), 7.32 (m, 1H), 7.18 (dd, 1H, J = 8.4, 7.2 Hz), 5.15 (s, 2H), 4.82 (m, 2H), 4.28 (m, 2H). MS (ESI) m / e [M+1] + 361.
6-氟-8-氧-3,4,8,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-2(1H)-甲酸苄酯 6 -Fluoro-8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-2(1H)-benzyl formate
化合物21以2-溴-5-氟-3-氨基-苯甲酸甲酯和3,5-二氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物20類似的方法,由本領域的熟練操作人員合成。1H NMR(DMSO-d6)δ 11.9(s,1H),10.3(s,1H),7.33-7.45(m,6H),7.23(dd,1H,J=10.2,1.8Hz),5.15(s,2H),4.79-4.83(m,2H),4.28-4.30(m,2H)。MS(ESI)m/e[M+1]+ 379。 Compound 21 is prepared from 2-bromo-5-fluoro-3-amino-benzoic acid methyl ester and 3,5-dioxypiperidine-1-carboxylic acid benzyl ester in a similar manner to the synthesis of compound 20 , from the art. Skilled operator synthesis. 1 H NMR (DMSO-d 6 ) δ 11.9 (s, 1H), 10.3 (s, 1H), 7.33-7.45 (m, 6H), 7.23 (dd, 1H, J = 10.2, 1.8 Hz), 5.15 (s , 2H), 4.79-4.83 (m, 2H), 4.28-4.30 (m, 2H). MS (ESI) m/e [M+1] + 379.
例3:化合物22-25的合成 Example 3: Synthesis of Compound 22-25
化合物22:10-甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
步驟1:9-甲基-4-氧-2,3,4,9-四氫-1H-哢唑-5-甲酸甲酯
4-氧-2,3,4,9-四氫-1H-哢唑-5-甲酸甲酯(0.27g,1mmol)在0℃,氮氣保護下溶於THF(5ml),加入叔丁醇鉀(0.12g,1.05mmol)。反應混合物攪拌30分鐘後,加入碘甲烷(0.76g,5.0mmol)。3小時後,反應混合物濃縮,所得剩餘物加入EtOAc(40ml)和1N HCl(5ml),有機相分出,依次用1N HCl(2×80ml)和食鹽水(2×10ml)洗滌,無水硫酸鈉乾燥,過濾,濃縮,得到一個固體(0.46g)。固體無需進一步純化,直接用於下一步反應。1H NMR(DMSO-d6)δ 7.35-7.39(m,2H),7.29(t,1H,J=7.2Hz),4.01(s,3H),3.72(s,3H),2.93-2.95(m,2H),2.54-2.56(m,2H),2.23-2.26(m,2H)。MS(ESI)m/e[M+1]+ 258.0。 Methyl 4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate (0.27 g, 1 mmol) was dissolved in THF (5 mL). (0.12 g, 1.05 mmol). After the reaction mixture was stirred for 30 minutes, iodomethane (0.76 g, 5.0 mmol) was added. After 3 hours, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjj Filtered and concentrated to give a solid (0.46 g). The solid was used in the next step without further purification. 1 H NMR (DMSO-d 6 ) δ 7.35-7.39 (m, 2H), 7.29 (t, 1H, J = 7.2 Hz), 4.01 (s, 3H), 3.72 (s, 3H), 2.93 - 2.95 (m) , 2H), 2.54-2.56 (m, 2H), 2.23 - 2.26 (m, 2H). MS (ESI) m/e [M+1] + 258.0.
步驟2:10-甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
目標化合物採用與合成化合物1的第三步類似的方法合成。1H NMR(DMSO-d6)δ 9.88(s,1H),7.55(d,1H,J=7.8Hz,),7.45(d,1H,J=7.8Hz,),7.15(t,1H,J=7.8Hz),3.70(s,3H),2.77-2.79(m,2H),2.35-2.37(m,2H),1.92-1.93(m,2H)。MS(ESI)m/e[M+1]+240.0。 The target compound was synthesized in a similar manner to the third step of the synthesis of Compound 1 . 1 H NMR (DMSO-d 6 ) δ 9.88 (s, 1H), 7.55 (d, 1H, J = 7.8 Hz,), 7.45 (d, 1H, J = 7.8 Hz,), 7.15 (t, 1H, J) = 7.8 Hz), 3.70 (s, 3H), 2.77-2.79 (m, 2H), 2.35-2.37 (m, 2H), 1.92-1.93 (m, 2H). MS (ESI) m/e [M+1] + 240.0.
化合物23:2,2,10-三甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
化合物23以2,2-二甲基-4-氧-2,3,4,9-四氫-1H-哢唑-5-甲酸甲酯和碘甲烷為原料,採用與化合物22類似的方法,由本領域的熟練操作人員合成。1H NMR(DMSO-d6)δ 9.86(s,1H),7.42-7.53(m,2H),7.12(t,1H,J=7.8Hz),3.66(s,3H),2.67(s,2H),2.20(s,2H),1.04(s,6H)。MS(ESI)m/e[M+1]+ 268。 Compound 23 is prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate and methyl iodide in a similar manner to compound 22 . Synthesized by skilled operators in the art. 1 H NMR (DMSO-d 6 ) δ 9.86 (s, 1H), 7.42-7.53 (m, 2H), 7.12 (t, 1H, J = 7.8 Hz), 3.66 (s, 3H), 2.67 (s, 2H) ), 2.20 (s, 2H), 1.04 (s, 6H). MS (ESI) m/e [M+1] + 268.
化合物24:10-苄基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
化合物24以2,2-二甲基-4-氧-2,3,4,9-四氫-1H-哢唑 -5-甲酸甲酯和氯化苄為原料,採用與化合物22類似的方法,由本領域的熟練操作人員合成。1H NMR(DMSO-d6)δ 9.96(s,1H),7.56(d,1H,J=8.4Hz),7.47(d,1H,J=7.8Hz),7.11-7.33(m,6 H),5.45(s,2H),2.82-2.84(m,2H),2.41-2.43(m,2H),1.97-2.00(m,2H)。MS(ESI)m/e[M+1]+ 316。 Compound 24 is prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate and benzyl chloride in a similar manner to compound 22 . , synthesized by skilled operators in the field. 1 H NMR (DMSO-d 6 ) δ 9.96 (s, 1H), 7.56 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.11 - 7.33 (m, 6 H) , 5.45 (s, 2H), 2.82-2.84 (m, 2H), 2.41-2.43 (m, 2H), 1.97-2.00 (m, 2H). MS (ESI) m/e [M+1] + 316.
化合物25:2,2,5,10-四甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
目標化合物採用與化合物22的第一步類似的方法合成。2,2二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮(0.02g,0.08mmol)與NaH(2.4mg,0.1mmol)和碘甲烷(0.06g,0.4mmol)在DMF(2ml)中反應,得到目標化合物(20mg,95%),為一黃色固體。1H NMR(DMSO-d6)δ7.51-7.55(m,2H),7.16(t,1H,J=7.8Hz),3.69(s,3H),3.42(s,3H),2.72(s,2H),2.27(s,2H),1.09(s,6H)。MS(ESI)m/e[M+1]+282。 The target compound was synthesized in a similar manner to the first step of Compound 22 . 2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (0.02 g </RTI></RTI><RTIID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; 1 H NMR (DMSO-d 6 ) δ 7.51 - 7.55 (m, 2H), 7.16 (t, 1H, J = 7.8 Hz), 3.69 (s, 3H), 3.42 (s, 3H), 2.72 (s, 2H), 2.27 (s, 2H), 1.09 (s, 6H). MS (ESI) m/e [M+1] + 282.
例4:化合物26的合成 Example 4: Synthesis of Compound 26
化合物26:8-氟-2,2-二甲基-2,3-二氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-1,6(5H,10H)-二酮
8-氟-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮(0.5g,1.8mmol)溶于無水二氧六環(25mL),加入SeO2(0.32g,2.7mmol)。混合物回流40小時,通過矽藻土過濾,乙醚洗滌,濾液濃縮。剩餘物用色譜柱純化得到目標產物(200mg,38%),為一固體。1H NMR(DMSO-d6)δ 12.70(s,1H),10.90(s,1H),7.41(dd,1H,J=10.2,1.8Hz),7.09(dd,1H,J=9.6,1.8Hz),2.87(s,2H),1.23(s,6H)。MS(ESI)m/e[M+1]+ 286。 8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H) - one (0.5g, 1.8mmol) was dissolved in anhydrous dioxane (25mL), was added SeO 2 (0.32g, 2.7mmol). The mixture was refluxed for 40 h, filtered over EtOAc EtOAcEtOAcEtOAc The residue was purified with EtOAcqqq elut elut elut 1 H NMR (DMSO-d 6 ) δ 12.70 (s, 1H), 10.90 (s, 1H), 7.41 (dd, 1H, J = 10.2, 1.8 Hz), 7.09 (dd, 1H, J = 9.6, 1.8 Hz) ), 2.87 (s, 2H), 1.23 (s, 6H). MS (ESI) m/e [M+1] + 286.
例5:化合物27的合成 Example 5: Synthesis of Compound 27
化合物27:8-氟-1-羥基-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
8-氟-2,2-二甲基-2,3-二氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-1,6(5H,10H)-二酮(50mg,0.18mmol)溶於MeOH(10mL),0℃下加入NaBH4(0.18mmol),攪拌半小時。反應液倒入冰水中,用EtOAc(5mL×3)萃取,有機相合併,依次用水(5mL×3)和食鹽水(5mL×3)洗滌,無水硫酸鈉乾燥,過濾。濾液濃縮,剩餘物用色譜柱純化得到粗品,粗品用製備HPLC純化得到目標產物(5mg),為一黃色固體。1H NMR(DMSO-d6)δ 11.9(s,1H),10.1(s,1H),7.23(dd,1H,J=9.2,2.0Hz),7.17(dd,1H,J=10.8,2.4Hz),5.68(d,1H,J=6.0Hz),5.49(d,1H,J=6.0Hz),2.31(s,2H),1.00(s,3H),0.88(s, 3H)。MS(ESI)m/e[M+1]+ 288。 8-fluoro-2,2-dimethyl-2,3-dihydro-[1,2]diazepine [3,4,5,6-def]carbazole-1,6(5H,10H) - dione (50mg, 0.18mmol) was dissolved in MeOH (10mL), at 0 ℃ was added NaBH 4 (0.18mmol), stirred for half an hour. The reaction mixture was poured into EtOAc (EtOAc) (EtOAc m. The filtrate was concentrated and the residue was purifiedjjjjjjlilili 1 H NMR (DMSO-d 6 ) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.23 (dd, 1H, J = 9.2, 2.0 Hz), 7.17 (dd, 1H, J = 10.8, 2.4 Hz ), 5.68 (d, 1H, J = 6.0 Hz), 5.49 (d, 1H, J = 6.0 Hz), 2.31 (s, 2H), 1.00 (s, 3H), 0.88 (s, 3H). MS (ESI) m / e [M+1] + 288.
例6:化合物28-39的合成 Example 6: Synthesis of Compound 28-39
化合物28:10-(2-(二甲氨基)乙基)-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮(94mg,0.37mmol)的DMF(10mL)溶液冷卻至0℃,緩慢加入K2CO3(205mg,1.48mmol)和N,N-二甲氨基-2-氯乙烷(53mg,0.37mmol)。混合物70℃下攪拌4小時,冷卻後加入水(10mL)。乙酸乙酯(2×20mL)萃取,有機相合併,無水硫酸鈉乾燥,過濾,濾液濃縮,剩餘物用色譜柱純化得到目標產物(90mg,75%),為一黃色固體。1H NMR(DMSO-d6)δ 9.91(s,1H),7.58(d,1H,J=7.8Hz),7.47(d,1H,J=7.8Hz),7.16(t,1H,J=7.8Hz),4.23(m,2H),2.74(s,2H),2.51(m,2H),2.25(s,2H),2.18(s,6H),1.07(s,6H)。MS(ESI)m/e[M+1]+ 325。 2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (94 mg , 0.37mmol) in DMF (10mL) was cooled to 0 ℃, was slowly added K 2 CO 3 (205mg, 1.48mmol ) and N, N- dimethylamino-2-chloroethane (53mg, 0.37mmol). The mixture was stirred at 70 ° C for 4 hours, and after cooling, water (10 mL) was added. The title compound (90 mg, 75%) was obtained as a yellow solid. 1 H NMR (DMSO-d 6 ) δ 9.91 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.23 (m, 2H), 2.74 (s, 2H), 2.51 (m, 2H), 2.25 (s, 2H), 2.18 (s, 6H), 1.07 (s, 6H). MS (ESI) m / e [M + 1] + 325.
化合物29-39採用和化合物28類似的方法,使用相應的原料,由本領域熟練操作人員合成。 Compounds 29-39 were synthesized in a similar manner to Compound 28 using the corresponding starting materials and synthesized by those skilled in the art.
例7:化合物40的合成 Example 7: Synthesis of Compound 40
化合物40:10-(2-(二甲胺基)乙基)-8-氟-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
化合物40以8-氟-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮和N,N-二甲胺基-2-氯乙烷為原料,採用與化合物28類似的方法製備。1H NMR(DMSO-d6)δ 10.1(s,1H),7.56(dd,1H,J=9.6,1.8Hz),7.21(dd,1H,J=10.2,1.8Hz),4.22(m,2H),2.74(s,2H),2.51(m,2H),2.26(s,2H),2.17(s,6H),1.06(s,6H)。MS(ESI)m/e[M+1]+343。 Compound 40 is 8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]carbazole-6 (1H)-ketone and N,N-dimethylamino-2-chloroethane were used as starting materials, which were prepared in a similar manner to compound 28 . 1 H NMR (DMSO-d 6 ) δ 10.1 (s, 1H), 7.56 (dd, 1H, J = 9.6, 1.8 Hz), 7.21. (dd, 1H, J = 10.2, 1.8 Hz), 4.22 (m, 2H) ), 2.74 (s, 2H), 2.51 (m, 2H), 2.26 (s, 2H), 2.17 (s, 6H), 1.06 (s, 6H). MS (ESI) m/e [M+1] + 343.
例8:化合物41的合成 Example 8: Synthesis of Compound 41
化合物41:2,2-二甲基-10-(環氧乙基-2-基-甲基)-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
化合物41以2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮和2-(氯甲基)環氧乙烷為原料,採用與化合物28類似的方法製備。1H NMR(DMSO-d6)δ 9.96(s,1H),7.65(d,1H,J=8.4Hz),7.49(d,1H,J=7.8Hz),7.18(dd,1H,J=8.4,7.8Hz),4.60-4.63(m,1H),4.21-4.24(m,1H),3.27-3.29(m,1H),2.76-2.77(m,1H),2.75(s,2H),2.46-2.48(m,1H),2.26(s,2H),0.92(s,6H)。MS(ESI)m/e[M+1]+ 310。 Compound 41 is 2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)- The ketone and 2-(chloromethyl)oxirane were used as starting materials and were prepared in a similar manner to compound 28 . 1 H NMR (DMSO-d 6 ) δ 9.96 (s, 1H), 7.65 (d, 1H, J = 8.4 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.18 (dd, 1H, J = 8.4 , 7.8 Hz), 4.60-4.63 (m, 1H), 4.21-4.24 (m, 1H), 3.27-3.29 (m, 1H), 2.76-2.77 (m, 1H), 2.75 (s, 2H), 2.46- 2.48 (m, 1H), 2.26 (s, 2H), 0.92 (s, 6H). MS (ESI) m/e [M+1] + 310.
例9:化合物42的合成 Example 9: Synthesis of Compound 42
化合物42:2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物20(34mg,0.1mmol)溶於甲醇(10mL),加入10%鈀碳(10mg),在氫氣下室溫下攪拌5小時。混合物通過矽藻土過濾,甲醇洗滌。濾液濃縮,剩餘物製備HPLC純化得到目標產物的甲酸鹽,為一白色固體(13mg,50%)。1H NMR(DMSO-d6)δ 11.7(s,1H),9.86(s,1H),7.40-7.45(m,2H),7.09(t,1H,J=8.0Hz),3.94(s,2H),3.41(s,2H)。MS(ESI)m/e[M+1]+227。 Compound 20 (34 mg, 0.1 mmol) was dissolved in methanol (10 mL), and then 10% palladium carbon (10 mg). The mixture was filtered through celite and washed with methanol. The filtrate was concentrated, and the residue was purified by ethylamine. 1 H NMR (DMSO-d 6 ) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.40-7.45 (m, 2H), 7.09 (t, 1H, J = 8.0 Hz), 3.94 (s, 2H) ), 3.41 (s, 2H). MS (ESI) m / e [M + 1] + 227.
例10:化合物43的合成 Example 10: Synthesis of Compound 43
化合物43:6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物43以化合物21和10%鈀碳為原料,採用與化合物42類似的方法製備。1H NMR(DMSO-d6)δ 11.8(s,1H),10.04(s,1H),7.29(dd,1H,J=10.0,1.6Hz),7.11(dd,1H,J=10.4,1.6Hz),3.93(s,2H),3.45(s,2H)。MS(ESI)m/e[M+1]+ 245。 Compound 43 was prepared from Compound 21 and 10% palladium on carbon in a similar manner to Compound 42 . 1 H NMR (DMSO-d 6 ) δ 11.8 (s, 1H), 10.04 (s, 1H), 7.29 (dd, 1H, J = 10.0, 1.6 Hz), 7.11 (dd, 1H, J = 10.4, 1.6 Hz ), 3.93 (s, 2H), 3.45 (s, 2H). MS (ESI) m / e [M+1] + 245.
例11:化合物44的合成 Example 11: Synthesis of Compound 44
化合物44:2-甲基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
步驟1:2-甲基-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯
4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯(0.04g,0.016mmol)和NaCNBH3(2.4mg,0.04mmol),加入MeOH(2mL),再加入27%的甲醛水溶液(0.5mL)。反應混 合物攪拌2小時,加入2N HCl(2mL),攪拌15分鐘。反應混合物加入濃的NaOH水溶液,調節至pH=11。二氯甲烷(3×10mL)萃取,有機相合併,食鹽水洗滌,無水硫酸鈉乾燥,過濾,濃縮。粗品無需進一步純化可直接用於下一步反應。 4-oxo-2,3,4,9-tetrahydro -1H- pyrido [3,4-b] indol-5-carboxylate (0.04g, 0.016mmol), and NaCNBH 3 (2.4mg, 0.04mmol MeOH (2 mL) was added followed by a 27% aqueous solution of formaldehyde (0.5 mL). The reaction mixture was stirred for 2 h, then added 2N EtOAc (2 mL) The reaction mixture was added to a concentrated aqueous NaOH solution and adjusted to pH = 11. The mixture was extracted with dichloromethane (3×10 mL). The crude product was used directly in the next reaction without further purification.
步驟2:2-甲基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物44以2-甲基-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和水合肼為原料,採用與合成化合物1類似的步驟合成。1H NMR(DMSO-d6)δ 11.7(s,1H),9.87(s,1H),7.43(d,1H,J=8.0Hz),7.39(d,1H,J=7.6Hz),7.14(dd,1H,J=8.0,7.6Hz),3.70(s,2H),3.13(s,2H),2.39(s,3H)。MS(ESI)m/e[M+1]+ 241。 Compound 44 is prepared from methyl 2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate. Synthetic Compound 1 was synthesized in a similar manner. 1 H NMR (DMSO-d 6 ) δ 11.7 (s, 1H), 9.87 (s, 1H), 7.43 (d, 1H, J = 8.0 Hz), 7.39 (d, 1H, J = 7.6 Hz), 7.14 ( Dd, 1H, J = 8.0, 7.6 Hz), 3.70 (s, 2H), 3.13 (s, 2H), 2.39 (s, 3H). MS (ESI) m / e [M+1] + 241.
例12:化合物45的合成 Example 12: Synthesis of Compound 45
化合物45:2-異丙基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物45以4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和丙酮為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)δ 11.7(s,1H),9.83(s,1H),7.43(d,1H,J=8.4Hz),7.38(d,1H,J=7.6Hz),7.08(dd,1H, J=8.4,7.6Hz),3.78(s,2H),3.26(s,2H),2.93-2.96(m,1H),1.04(d,6H,J=6.4Hz)。MS(ESI)m/e[M+1]+ 269。 Compound 45 is prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and acetone using a similar procedure to that of compound 44 . synthesis. 1 H NMR (DMSO-d 6 ) δ 11.7 (s, 1H), 9.83 (s, 1H), 7.43 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.08 ( Dd, 1H, J = 8.4, 7.6 Hz), 3.78 (s, 2H), 3.26 (s, 2H), 2.93 - 2.96 (m, 1H), 1.04 (d, 6H, J = 6.4 Hz). MS (ESI) m/e [M+1] + 269.
例13:化合物46的合成 Example 13: Synthesis of Compound 46
化合物46:6-氟-2-異丙基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物46以7-氟-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和丙酮為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)δ 11.8(s,1H),10.1(s,1H),7.35(dd,1H,J=2.4,9.6Hz),7.18(dd,1H,J=2.4,10.2Hz),3.82(s,2H),3.32(s,2H),2.98-3.00(m,1H),1.09(d,6H,J=7.2Hz)。MS(ESI)m/e[M+1]+ 287。 Compound 46 is synthesized from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and acetone. 44 similar steps to synthesize. 1 H NMR (DMSO-d 6 ) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.35 (dd, 1H, J = 2.4, 9.6 Hz), 7.18 (dd, 1H, J = 2.4, 10.2 Hz ), 3.82 (s, 2H), 3.32 (s, 2H), 2.98-3.00 (m, 1H), 1.09 (d, 6H, J = 7.2 Hz). MS (ESI) m/e [M+1] + 287.
例14:化合物47的合成 Example 14: Synthesis of Compound 47
化合物47:2-(環丙羰基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
步驟1:2-(環丙羰基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯
4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯(0.21g,0.82mmol)溶於二氯甲烷(10mL),0℃下加入環丙基甲醯氯(0.074mL,0.82mmol)和N,N-二異丙基乙胺(0.143mL),-5℃攪拌1小時,蒸幹溶劑,製備薄層色譜分離得到目標產物(170mg)。MS(ESI)m/e[M+1]+ 313。 Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.21 g, 0.82 mmol) was dissolved in dichloromethane (10 mL). Add cyclopropylmethyl hydrazine chloride (0.074 mL, 0.82 mmol) and N,N-diisopropylethylamine (0.143 mL) at 0 ° C, stir at -5 ° C for 1 hour, and evaporate the solvent to obtain a thin layer chromatography. Target product (170 mg). MS (ESI) m/e [M+1] + 313.
步驟2:2-(環丙羰基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮 Step 2: 2-(cyclopropylcarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one
化合物47以2-(環丙羰基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和水合肼為原料,採用與合成化合物1類似的步驟合成。1H NMR(DMSO-d6)δ 11.9(s,1H),10.0(s,1H),7.47-7.53(m,2H),7.17(dd,1H,J=7.2,7.8Hz),4.89(s,2H),4.35(s,2H),2.08-2.11(m,1H),0.78-0.79(m,4H)。MS(ESI)m/e[M+1]+ 295。 Compound 47 is prepared from methyl 2-(cyclopropylcarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate. , synthesized in a similar manner to the synthesis of Compound 1 . 1 H NMR (DMSO-d 6 ) δ 11.9 (s, 1H), 10.0 (s, 1H), 7.47-7.53 (m, 2H), 7.17 (dd, 1H, J = 7.2, 7.8 Hz), 4.89 (s) , 2H), 4.35 (s, 2H), 2.08-2.11 (m, 1H), 0.78-0.79 (m, 4H). MS (ESI) m/e [M+1] + 295.
例15:化合物48的合成 Example 15: Synthesis of Compound 48
化合物48:2-(環丙羰基)-4-(2-(二甲氨基)乙基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物48以2-(環丙羰基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮和N,N-二甲氨基-2-氯乙烷為原料,採用與合成化合物28類似的步驟合成。1H NMR(DMSO-d6)δ 10.0(s,1H),7.67(d,1H,J=8.4Hz),7.51(d,1H, J=7.8Hz),7.23(dd,1H,J=8.4,7.8Hz),5.22(s,1H),4.98(s,1H),4.55(s,1H),4.28-4.35(m,3H),2.58-2.62(m,2H),2.19(s,6H),2.09-2.13(m,1H),0.79(s,4H)。MS(ESI)m/e[M+1]+ 366。 Compound 48 is 2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one and N, N-dimethylamino-2-chloroethane was used as a starting material, which was synthesized in a similar manner to the compound of Compound 28 . 1 H NMR (DMSO-d 6 ) δ 10.0 (s, 1H), 7.67 (d, 1H, J = 8.4 Hz), 7.51 (d, 1H, J = 7.8 Hz), 7.23 (dd, 1H, J = 8.4 , 7.8 Hz), 5.22 (s, 1H), 4.98 (s, 1H), 4.55 (s, 1H), 4.28-4.35 (m, 3H), 2.58-2.62 (m, 2H), 2.19 (s, 6H) , 2.09-2.13 (m, 1H), 0.79 (s, 4H). MS (ESI) m / e [M+1] + 366.
例16:化合物49的合成 Example 16: Synthesis of Compound 49
化合物49:2-(環丙羰基)-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物49以7-氟-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和環丙基甲醯氯為原料,採用與合成化合物47類似的步驟合成。1H NMR(DMSO-d6)δ 9.64(s,1H),6.80-7.08(m,2H),4.95(s,1H),4.74(s,1H),4.40(s,1H),4.20(s,1H),2.03-2.07(m,1H),0.75(s,4H)。MS(ESI)m/e [M+1]+313。 Compound 49 is prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and cyclopropylformamidine chloride. Synthesized using a similar procedure to the synthesis of Compound 47 . 1 H NMR (DMSO-d 6 ) δ 9.64 (s, 1H), 6.80-7.08 (m, 2H), 4.95 (s, 1H), 4.74 (s, 1H), 4.40 (s, 1H), 4.20 (s) , 1H), 2.03-2.07 (m, 1H), 0.75 (s, 4H). MS (ESI) m / e [M+1] + 313.
例17:化合物50的合成 Example 17: Synthesis of Compound 50
化合物50:2-(環丙羰基)-4-(2-(二甲氨基)乙基)-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物50以2-(環丙羰基)-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮和N,N-二甲氨基-2- 氯乙烷為原料,採用與合成化合物28類似的步驟合成。1H NMR(DMSO-d6)δ 10.0(s,1H),7.66(dd,1H,J=2.4,9.6Hz),7.26(dd,1H,J=2.4,10.2Hz),5.21(s,1H),4.96(s,1H),4.55(s,1H),4.27-4.36(m,3H),2.56-2.59(m,2H),2.18(s,6H),2.11-2.13(m,1H),0.79(s,4H)。MS(ESI)m/e[M+1]+ 384。 Compound 50 is 2-(cyclopropylcarbonyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)- ketones and N, N- dimethylamino-2-chloroethane as starting material, and the synthetic procedure similar to the synthesis of compound 28. 1 H NMR (DMSO-d 6 ) δ 10.0 (s, 1H), 7.66 (dd, 1H, J = 2.4, 9.6 Hz), 7.26 (dd, 1H, J = 2.4, 10.2 Hz), 5.21 (s, 1H) ), 4.96 (s, 1H), 4.55 (s, 1H), 4.27-4.36 (m, 3H), 2.56-2.59 (m, 2H), 2.18 (s, 6H), 2.11-2.13 (m, 1H), 0.79 (s, 4H). MS (ESI) m/e [M+1] + 384.
例18:化合物51的合成 Example 18: Synthesis of Compound 51
化合物51:2-三甲基乙醯基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物51以4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和三甲基乙醯氯為原料,採用與合成化合物47類似的步驟合成。1H NMR(DMSO-d6)9.63(s,1H),7.27-7.47(m,2H),6.96(s,1H),4.89(s,2H),4.33(s,2H),1.24(s,9H)。MS(ESI)m/e[M+1]+ 311。 Compound 51 is prepared by using 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid methyl ester and trimethylacetamidine chloride as raw materials. Compound 47 was synthesized in a similar manner. 1 H NMR (DMSO-d 6 ) 9.63 (s, 1H), 7.27-7.47 (m, 2H), 6.96 (s, 1H), 4.89 (s, 2H), 4.33 (s, 2H), 1.24 (s, 9H). MS (ESI) m / e [M + 1] + 311.
例19:化合物52的合成 Example 19: Synthesis of Compound 52
化合物52:6-氟-2-三甲基乙醯基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物52以7-氟-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和三甲基乙醯氯為原料,採用與合成化合物47類似的步驟合成。1H NMR(DMSO-d6)δ 11.9(s,1H), 10.2(s,1H),7.45(dd,1H,J=2.4,9.6Hz),7.22(dd,1H,J=2.4,10.2Hz),4.92(s,2H),4.42(s,2H),1.24(s,9H)。MS(ESI)m/e[M+1]+329。 Compound 52 is prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and trimethylacetamidine chloride. Synthesized using a similar procedure to the synthesis of Compound 47 . 1 H NMR (DMSO-d 6 ) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.45 (dd, 1H, J = 2.4, 9.6 Hz), 7.22 (dd, 1H, J = 2.4, 10.2 Hz ), 4.92 (s, 2H), 4.42 (s, 2H), 1.24 (s, 9H). MS (ESI) m/e [M+1] + 329.
例20:化合物53的合成 Example 20: Synthesis of Compound 53
化合物53:2-環己基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物53以4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和環己酮為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)δ 11.7(s,1H),9.86(s,1H),7.47(d,1H,J=7.8Hz),7.42(d,1H,J=7.8Hz),7.12(t,1H,J=7.8Hz),3.91(s,2H),3.38(s,2H),2.50-2.56(m,1H),1.58-1.84(m,4H),1.11-1.31(m,6H)。MS(ESI)m/e[M+1]+309。 Compound 53 is based on 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid methyl ester and cyclohexanone, and is similar to synthetic compound 44. The steps are synthesized. 1 H NMR (DMSO-d 6 ) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.47 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 7.8 Hz), 7.12 ( t,1H,J=7.8Hz), 3.91(s,2H), 3.38(s,2H), 2.50-2.56(m,1H), 1.58-1.84(m,4H),1.11-1.31(m,6H) . MS (ESI) m / e [M + 1] + 309.
例21:化合物54的合成 Example 21: Synthesis of Compound 54
化合物54:2-(3,3-二甲基丁基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物54以2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮和3,3-二甲基正丁醛為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)11.9(s,1H),9.89(s,1H),7.48(d,1H,J=7.8Hz),7.43(d,1H,J=7.2Hz), 7.13(dd,1H,J=7.2,7.8Hz),3.81(br s,2H),3.29(br s,2H),2.57-2.58(m,2H),1.43-1.46(m,2H),0.91(s,9H)。MS(ESI)m/e[M+1]+ 311。 Compound 54 is 2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]indole-8(1H)-one and 3,3-dimethyl-n-butyraldehyde As a raw material, it was synthesized in a similar manner to the synthesis of Compound 44 . 1 H NMR (DMSO-d 6 ) 11.9 (s, 1H), 9.89 (s, 1H), 7.48 (d, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.13 (dd , 1H, J=7.2, 7.8 Hz), 3.81 (br s, 2H), 3.29 (br s, 2H), 2.57-2.58 (m, 2H), 1.43-1.46 (m, 2H), 0.91 (s, 9H) ). MS (ESI) m / e [M + 1] + 311.
例22:化合物55的合成 Example 22: Synthesis of Compound 55
化合物55:6-氟-2-甲基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物55以2-溴-5-氟-3-氨基苯基酸甲酯和3,5-二氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)11.9(s,1H),10.1(s,1H),7.36(dd,1H,J=1.8,9.6Hz),7.20(dd,1H,J=1.8,10.2Hz),3.75(s,2H),3.24(s,2H),2.44(s,3H)。MS(ESI)m/e[M+1]+ 259。 Compound 55 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . 1 H NMR (DMSO-d 6 ) 11.9 (s, 1H), 10.1 (s, 1H), 7.36 (dd, 1H, J = 1.8, 9.6 Hz), 7.20 (dd, 1H, J = 1.8, 10.2 Hz) , 3.75 (s, 2H), 3.24 (s, 2H), 2.44 (s, 3H). MS (ESI) m/e [M+1] + 259.
例23:化合物56的合成 Example 23: Synthesis of Compound 56
化合物56:2-丙基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物56以4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和正丙醛為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)δ 11.7(s,1H),9.92(s,1H),7.47(d,1H,J=7.8Hz),7.43(d,1H,J=7.8Hz),7.13(t,1H,J=7.8Hz),3.81(s,2H),3.28(s,2H),2.50-2.55(m,2H),1.51-1.54(m, 2H),0.89(t,3H,J=7.8Hz)。MS(ESI)m/e[M+1]+ 269。 Compound 56 is prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and n-propanal, using a similar compound as compound 44 . Step synthesis. 1 H NMR (DMSO-d 6 ) δ 11.7 (s, 1H), 9.92 (s, 1H), 7.47 (d, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.13 ( t,1H,J=7.8Hz),3.81(s,2H), 3.28(s,2H), 2.50-2.55(m,2H),1.51-1.54(m, 2H),0.89(t,3H,J= 7.8 Hz). MS (ESI) m/e [M+1] + 269.
例24:化合物57的合成 Example 24: Synthesis of Compound 57
化合物57:6-氟-2-丙基-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物57以2-溴-5-氟-3-氨基苯基酸甲酯和3,5-二氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)11.8(s,1H),10.1(s,1H),7.36(dd,1H,J=1.8,9.0Hz),7.19(dd,1H,J=1.8,10.2Hz),3.80(s,2H),3.30(s,2H),2.50-2.54(m,2H),1.50-1.54(m,2H),0.89(t,3H,J=7.8Hz)。MS(ESI)m/e[M+1]+ 287。 Compound 57 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . 1 H NMR (DMSO-d 6 ) 11.8 (s, 1 H), 10.1 (s, 1 H), 7.36 (dd, 1H, J = 1.8, 9.0 Hz), 7.19 (dd, 1H, J = 1.8, 10.2 Hz) , 3.80 (s, 2H), 3.30 (s, 2H), 2.50-2.54 (m, 2H), 1.50-1.54 (m, 2H), 0.89 (t, 3H, J = 7.8 Hz). MS (ESI) m/e [M+1] + 287.
例25:化合物58的合成 Example 25: Synthesis of Compound 58
化合物58:2-乙基-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物58以2-溴-5-氟-3-氨基苯基酸甲酯和3,5-二氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)11.8(s,1H),10.1(s,1H),7.35(dd,1H,J=2.4,9.6Hz),7.19(dd,1H,J=2.4,10.2Hz),3.80(s,2H),3.30(s,2H),2.60-2.64(m,2H),1.09(t,3H,J=7.2Hz)。MS(ESI)m/e[M+1]+ 273。 Compound 58 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . 1 H NMR (DMSO-d 6 ) 11.8 (s, 1 H), 10.1 (s, 1H), 7.35 (dd, 1H, J = 2.4, 9.6 Hz), 7.19 (dd, 1H, J = 2.4, 10.2 Hz) , 3.80 (s, 2H), 3.30 (s, 2H), 2.60-2.64 (m, 2H), 1.09 (t, 3H, J = 7.2 Hz). MS (ESI) m / e [M+1] + 273.
例26:化合物59的合成 Example 26: Synthesis of Compound 59
化合物59:2-正丁基-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物59以2-溴-5-氟-3-氨基苯基酸甲酯和3,5-二氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物44類似的步驟合成。1H NMR(DMSO-d6)11.8(s,1H),10.1(s,1H),7.36(dd,1H,J=2.4,9.6Hz),7.19(dd,1H,J=2.4,10.2Hz),3.80(s,2H),3.30(s,2H),2.54-2.57(m,2H),1.47-1.50(m,2H),1.30-1.34(m,2H),0.91(t,3H,J=7.2Hz)。MS(ESI)m/e[M+1]+ 301。 Compound 59 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . 1 H NMR (DMSO-d 6 ) 11.8 (s, 1 H), 10.1 (s, 1H), 7.36 (dd, 1H, J = 2.4, 9.6 Hz), 7.19 (dd, 1H, J = 2.4, 10.2 Hz) , 3.80 (s, 2H), 3.30 (s, 2H), 2.54-2.57 (m, 2H), 1.47-1.50 (m, 2H), 1.30-1.34 (m, 2H), 0.91 (t, 3H, J = 7.2 Hz). MS (ESI) m / e [M + 1] + 301.
例27:化合物60的合成 Example 27: Synthesis of Compound 60
化合物60:2-(2-(二甲氨基)乙基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
步驟1:2-(2-(二甲氨基)乙基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯
4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲 酯(183mg,0.75mol)溶於DMF(20ml),加入2-氯-N,N-二甲基乙胺鹽酸鹽(107mg,0.75mmol)和K2CO3(207mg,1.5mmol)。反應液50℃攪拌至原料消失。反應液加入二氯甲烷(15ml)稀釋,水洗三次。有機相無水硫酸鎂乾燥,蒸幹大部分溶劑,粗品用矽膠柱純化(洗脫劑CH2Cl2/MeOH/NH3.H2O),得到2-(2-(二甲氨基)乙基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯(0.09g)。MS(ESI)m/e[M+1]+ 316。 Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (183 mg, 0.75 mol) was dissolved in DMF (20 mL). chloro -N, N- dimethyl-ethanamine hydrochloride (107mg, 0.75mmol) and K 2 CO 3 (207mg, 1.5mmol ). The reaction solution was stirred at 50 ° C until the starting material disappeared. The reaction solution was diluted with dichloromethane (15 ml) and washed with water three times. The organic phase was dried over anhydrous magnesium sulfate, and most of the solvent was evaporated to dryness, the crude product is purified by silica gel column chromatography (eluent CH 2 Cl 2 / MeOH / NH 3 .H 2 O), to give 2- (2- (dimethylamino) ethyl Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.09 g). MS (ESI) m/e [M+1] + 316.
步驟2:2-(2-(二甲氨基)乙基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物60以2-(2-(二甲氨基)乙基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和水合肼為原料,採用與合成化合物1類似的步驟合成。1H NMR(DMSO-d6)δ 9.92(s,1H),7.60(d,1H,J=8.4Hz),7.46(d,1H,J=7.8Hz),7.13(dd,1H,J=8.4,7.8Hz),4.20-4.22(m,2H),4.03(s,2H),3.41(s,2H),2.51-2.54(m,2H),2.18(s,6H)。MS(ESI)m/e[M+1]+ 298。 Compound 60 is 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid The ester and hydrazine hydrate were used as starting materials and synthesized in a similar manner to the synthesis of Compound 1 . 1 H NMR (DMSO-d 6 ) δ 9.92 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.13 (dd, 1H, J = 8.4 , 7.8 Hz), 4.20-4.22 (m, 2H), 4.03 (s, 2H), 3.41 (s, 2H), 2.51-2.54 (m, 2H), 2.18 (s, 6H). MS (ESI) m/e [M+1] + 298.
例28:化合物61的合成 Example 28: Synthesis of Compound 61
化合物61:2-(2-(二甲氨基)乙基)-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物61以2-溴-5-氟-3-氨基苯基酸甲酯和3,5-二 氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物60類似的步驟合成。1H NMR(DMSO-d6)δ 10.1(s,1H),7.58(dd,1H,J=1.8,10.2Hz),7.21(dd,1H,J=1.8,10.2Hz),4.20-4.22(m,2H),4.03(s,2H),3.42(s,2H),2.51-2.54(m,2H),2.19(s,6H)。MS(ESI)m/e[M+1]+316。 Compound 61 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound compound 60 . 1 H NMR (DMSO-d 6 ) δ 10.1 (s, 1H), 7.58 (dd, 1H, J = 1.8, 10.2 Hz), 7.21. (dd, 1H, J = 1.8, 10.2 Hz), 4.20-4.22 (m) , 2H), 4.03 (s, 2H), 3.42 (s, 2H), 2.51-2.54 (m, 2H), 2.19 (s, 6H). MS (ESI) m/e [M+1] + 316.
例29:化合物62的合成 Example 29: Synthesis of Compound 62
化合物62:2-(2-氨基-2-甲基丙醯基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
步驟1:2-(2-(((苄氧基)羰基)氨基)-2-甲基丙醯基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯
4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯(36mg),2-(((苄氧基)羰基)氨基)-2-甲基丙酸(21mg),溶於DMF(8ml),加入二異丙基乙胺(58mg),再加入HATU(86mg)溶於DMF(2ml)的溶液。反應混合物室溫攪拌16小時。DMF蒸幹得到2-(2-(((苄氧基)羰基)氨基)-2-甲基丙醯基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯,無需進一步純化,可直接用於下一步反應。 Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (36 mg), 2-(((benzyloxy)carbonyl)amino 2-methylpropionic acid (21 mg), dissolved in DMF (8 ml), diisopropylethylamine (58 mg) was added, and then a solution of HATU (86 mg) dissolved in DMF (2 ml). The reaction mixture was stirred at room temperature for 16 hours. DMF was evaporated to dryness to give 2-(2-(((benzyl))carbonyl)amino)-2-methylpropenyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyridine and [ Methyl 3,4-b]indole-5-carboxylate was used in the next step without further purification.
步驟2:(2-甲基-1-氧-1-(8-氧-8,9-二氫-2,4,9,10-四氮雜環庚基[def]芴-2(1H,3H,4H)-基)丙基-2-基)氨基甲酸苄酯
目標產物以2-(2-(((苄氧基)羰基)氨基)-2-甲基丙醯基)-4-氧-2,3,4,9-四氫-1H-吡啶並[3,4-b]吲哚-5-甲酸甲酯和水合肼為原料,採用與合成化合物1類似的方法合成。1H NMR(DMSO-d6)δ 11.8(s,1H),10.2(s,1H),7.18-7.55(m,8H),4.82-4.91(m,4H),4.43-4.55(m,2H),1.25(s,6H)。MS(ESI)m/e[M+1]+ 446。 The target product is 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropenyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyridin[3 , 4-b]indole-5-formic acid methyl ester and hydrazine hydrate were used as starting materials, and synthesized in a similar manner to the synthesis of compound 1. 1 H NMR (DMSO-d 6 ) δ 11.8 (s, 1H), 10.2 (s, 1H), 7.18-7.55 (m, 8H), 4.82-4.91 (m, 4H), 4.43-4.55 (m, 2H) , 1.25 (s, 6H). MS (ESI) m / e [M+1] + 446.
步驟3:2-(2-氨基-2-甲基丙醯基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物62以(2-甲基-1-氧-1-(8-氧-8,9-二氫-2,4,9,10-四氮雜環庚基[def]芴-2(1H,3H,4H)-基)丙基-2-基)氨基甲酸苄酯和鈀碳(10%)為原料,採用與合成化合物42類似的步驟合成。1H NMR(DMSO-d6)δ 11.8(s,1H),9.99(s,1H),7.48(d,1H,J=8.0Hz),7.43(d,1H,J=7.2Hz),7.13(dd,1H,J=8.0,7.2Hz),5.29-5.31(m,2H),4.69-4.75(m,2H),1.26(s,6H)。MS(ESI)m/e[M+1]+ 312。 Compound 62 is (2-methyl-1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacycloheptyl [def] 芴-2 (1H, 3H, 4H) - yl) propyl-2-yl) carbamate and palladium on carbon (10%) as a starting material, was synthesized in a procedure similar to the synthesis of compound 42. 1 H NMR (DMSO-d 6 ) δ 11.8 (s, 1H), 9.99 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.13 ( Dd, 1H, J = 8.0, 7.2 Hz), 5.29 - 5.31 (m, 2H), 4.69 - 4.75 (m, 2H), 1.26 (s, 6H). MS (ESI) m / e [M+1] + 312.
例30:化合物63的合成 Example 30: Synthesis of Compound 63
化合物63:(S)-叔丁基(1-氧-1-(8-氧-8,9-二氫-2,4,9,10-四氮雜環庚基[def]芴-2(1H,3H,4H)-基)-3-苯丙基-2-基)氨基甲酸酯
化合物63以2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮和(S)-2-((叔丁基羰基)氨基)-3-苯丙酸為原料,採用與合成化合物62類似的步驟合成。1H NMR(DMSO-d6)δ11.8(s,1H),10.0(s,1H),7.51(d,1H,J=8.0Hz),7.05-7.47(m,7H),4.96-5.02(m,1H),4.25-4.81(m,4H),2.62-2.88(m,2H),1.27(s,6H),1.16(s,3H)。MS(ESI)m/e[M+1]+ 474。 Compound 63 is 2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one and (S)-2-((tert-butyl) The carbonyl)amino)-3-phenylpropionic acid was used as a starting material and synthesized in a similar manner to the compound 62 . 1 H NMR (DMSO-d 6 ) δ 11.8 (s, 1H), 10.0 (s, 1H), 7.51 (d, 1H, J = 8.0 Hz), 7.05-7.47 (m, 7H), 4.96-5.02 ( m, 1H), 4.25-4.81 (m, 4H), 2.62-2.88 (m, 2H), 1.27 (s, 6H), 1.16 (s, 3H). MS (ESI) m / e [M+1] + 474.
例31:化合物64的合成 Example 31: Synthesis of Compound 64
化合物64:(S)-2-(2-氨基-3-苯丙醯基)-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物64以化合物63和氯化氫為原料,採用與合成化合物62類似的步驟合成。1H NMR(DMSO-d6)δ11.9(s,1H),10.1(s,1H),7.48(d,1H,J=8.0Hz),7.48-7.52(m,2H),7.10-7.20(m,6H),4.93-4.96(m,3H),4.18-4.25(m,2H),4.00-4.03(m,2H),2.78-2.85(m,1H),2.61-2.65(m,1H)。MS(ESI)m/e[M+1]+ 374。 Compound 64 was synthesized from compound 63 and hydrogen chloride using a procedure similar to that of compound 62 . 1 H NMR (DMSO-d 6 ) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.48-7.52 (m, 2H), 7.10-7.20 ( m, 6H), 4.93-4.96 (m, 3H), 4.18-4.25 (m, 2H), 4.00-4.03 (m, 2H), 2.78-2.85 (m, 1H), 2.61-2.65 (m, 1H). MS (ESI) m/e [M+1] + 374.
例32:化合物65的合成 Example 32: Synthesis of Compound 65
化合物65:2-(2-氨基-2-甲基丙醯基)-6-氟-2,3,4,9-四氫-2,4,9,10-四氮雜環庚基[def]芴-8(1H)-酮
化合物65以2-溴-5-氟-3-硝基苯基酸甲酯和3,5-二氧基哌啶-1-甲酸苄酯為原料,採用與合成化合物62類似的步驟合成。1H NMR(DMSO-d6)δ 12.1(s,1H),10.2(s,1H),7.40(dd,1H,J=1.8,10.2Hz),7.20(dd,1H,J=1.8,10.2Hz),5.25(s,2H),4.75(s,1H),1.32(s,6H)。MS(ESI)m/e[M+1]+330。 Compound 65 was synthesized from methyl 2-bromo-5-fluoro-3-nitrophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to that of compound 62 . 1 H NMR (DMSO-d 6 ) δ 12.1 (s, 1H), 10.2 (s, 1H), 7.40 (dd, 1H, J = 1.8, 10.2 Hz), 7.20 (dd, 1H, J = 1.8, 10.2 Hz) ), 5.25 (s, 2H), 4.75 (s, 1H), 1.32 (s, 6H). MS (ESI) m/e [M+1] + 330.
例33:化合物66的合成 Example 33: Synthesis of Compound 66
化合物66:5,10-雙(2-羥乙基)-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮(100mg,0.39mmol)溶於乾燥的DMF(8mL),冰浴下加入NaH(47mg,1.95mmol)。反應混合物在0℃下攪拌40分鐘。在0℃下加入2-(2-溴代乙氧基)四氫-2H-吡喃(194mg,1.17mmol)後,室溫攪拌6小時。加入水(100mL),用二氯甲烷(50mL×3)和乙酸乙酯(50mL×3)萃取,有機相合併,飽和食鹽水洗滌,無水硫酸鈉乾燥。有機相濃縮得到粗品。粗品溶於甲醇(15mL),加入對甲苯磺酸一水合物(100mg,0.52mmol),反應混合物室溫攪拌16小時。加入水(150mL),用乙酸乙酯(50mL×3)萃取,有機相合併,依次用碳 酸氫鈉水溶液和飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮,剩餘物用製備薄層色譜純化(DCM/MeOH=10/1)得到5,10-雙(2-羥乙基)-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮(40mg,30%),為一黃色固體。1H NMR(DMSO-d6)δ 7.57(m,2H),7.15(dd,1H,J=7.2,8.4Hz),4.88(t,1H,J=5.4Hz),4.61(t,1H,J=6.0Hz),4.21(t,2H,J=5.4Hz),3.94(t,2H,J=6.6Hz),3.94(t,2H,J=6.6Hz),3.63-3.68(m,2H),2.77(s,2H),2.28(s,2H),1.08(s,6H)。MS(ESI)m/e[M+1]+ 342.2。 2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (100 mg , 0.39 mmol) was dissolved in dry DMF (8 mL). The reaction mixture was stirred at 0 ° C for 40 minutes. After adding 2-(2-bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol) at 0 ° C, it was stirred at room temperature for 6 hr. Water (100 mL) was added, and the mixture was combined with methylene chloride (50 mL × 3) and ethyl acetate (50 mL × 3). The organic phase was concentrated to give a crude material. The crude product was dissolved in MeOH (15 mL). Water (150 mL) was added, and the mixture was combined with EtOAc EtOAc. /MeOH = 10/1) to give 5,10-bis(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [ 3,4,5,6-def]carbazole-6(1H)-one (40 mg, 30%) as a yellow solid. 1 H NMR (DMSO-d 6 ) δ 7.57 (m, 2H), 7.15 (dd, 1H, J = 7.2, 8.4 Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.61 (t, 1H, J) =6.0 Hz), 4.21 (t, 2H, J = 5.4 Hz), 3.94 (t, 2H, J = 6.6 Hz), 3.94 (t, 2H, J = 6.6 Hz), 3.63 - 3.68 (m, 2H), 2.77 (s, 2H), 2.28 (s, 2H), 1.08 (s, 6H). MS (ESI) m / e [ M + 1] + 342.2.
例34:化合物67的合成 Example 34: Synthesis of Compound 67
化合物67:10-(2-羥乙基)-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮
2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮(100mg,0.39mmol)溶於乾燥的DMF(8mL),加入2-(2-溴乙氧基)四氫-2H-吡喃(194mg,1.17mmol)和碳酸鉀(215mg,1.6mmol),反應混合物加熱至70℃,攪拌11.5小時。加入水(100mL),用乙酸乙酯(50mL×3)萃取,有機相合併,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮得到黃色油狀粗品。粗品加入甲醇(15mL),對甲苯磺酸一水合物(100mg,0.52mmol),反應混合物室溫攪拌1小時。加入水(100mL),用乙酸乙酯(50mL×3)萃取,有機相合併,依次用碳 酸氫鈉水溶液和飽和食鹽水洗滌,無水硫酸鈉乾燥。濃縮,剩餘物用矽膠色譜柱純化(流動相:正己烷/乙酸乙酯)得到80mg(69%收率)的10-(2-羥乙基)-2,2-二甲基-2,3,5,10-四氫-[1,2]二氮雜卓[3,4,5,6-def]哢唑-6(1H)-酮,為一黃色固體。1H NMR(DMSO-d6)δ 9.89(s,1H),7.58(d,1H,J=8.4Hz),7.47(d,1H,J=7.2Hz),7.15(dd,1H,J=7.2,8.4Hz),4.88(t,1H,J=5.4Hz),4.21(t,2H,J=5.4Hz),3.65-3.68(m,1H),2.76(s,2H),2.25(s,2H),1.07(s,6H)。MS(ESI)m/e[M+1]+ 298.1。 2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (100 mg , 0.39 mmol) dissolved in dry DMF (8 mL), EtOAc (EtOAc (EtOAc) Stir at 1100 hours to 70 °C. Water (100 mL) was added, and the mixture was evaporated. Methanol (15 mL), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol). Water (100 mL) was added, and the mixture was evaporated. Concentration, the residue was purified with a silica gel column (mobile phase: n-hexane/ethyl acetate) to afford 80 mg (69% yield) of 10-(2-hydroxyethyl)-2,2-dimethyl-2,3 , 5,10-Tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one as a yellow solid. 1 H NMR (DMSO-d 6 ) δ 9.89 (s, 1H), 7.58 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.2 Hz), 7.15 (dd, 1H, J = 7.2 , 8.4 Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.21 (t, 2H, J = 5.4 Hz), 3.65-3.68 (m, 1H), 2.76 (s, 2H), 2.25 (s, 2H) ), 1.07 (s, 6H). MS (ESI) m / e [ M + 1] + 298.1.
例35:化合物68的合成 Example 35: Synthesis of Compound 68
化合物68:(R)-10a-甲基-7,8,9,10,10a,11-六氫-5,6,7a,11-四氮雜環庚基[def]環戊基[a]芴-4(5H)-酮
步驟1:(R)-甲基2-(1-(苄氧羰基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯
四(三苯基膦)鈀(0)(1.72g,1.5mmol)和CuI(0.29g,1.5mmol),加入甲苯(54mL)和3-氨基-2-溴-苯甲酸甲酯(2.3g,10mmol),(R)-苄基2-乙炔基-2-甲基吡咯烷-1-甲酸酯(3.0g,12mmol),三乙胺(7mL,50mmol)。混合物氮氣保護下加熱至100℃攪拌18小時。冷卻,加入水(20mL)。用乙酸乙酯(20mL×3)萃取,有機相合併,飽和食鹽水(20mL) 洗滌,無水硫酸鎂乾燥,過濾。濾液濃縮至幹,剩餘物用矽膠色譜柱純化(流動相:二氯甲烷)得到(R)-苄基2-((2-氨基-6-(甲氧羰基)苯基)乙炔基)-2-甲基吡咯烷-1-甲酸酯(2.31g)。 Tetrakis(triphenylphosphine)palladium(0) (1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol), toluene (54 mL) and methyl 3-amino-2-bromo-benzoate (2.3 g, 10 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), triethylamine (7 mL, 50 mmol). The mixture was heated to 100 ° C under nitrogen for a period of 18 hours. Cooled and added water (20 mL). Extracted with ethyl acetate (20 mL×3), combined organic layers, brine (20 mL) Washed, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness, and the residue was purified using silica gel column (mobile phase: dichloromethane) to afford (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2 Methylpyrrolidine-1-carboxylate (2.31 g).
(R)-苄基2-((2-氨基-6-(甲氧羰基)苯基)乙炔基)-2-甲基吡咯烷-1-甲酸酯(1.1g,2.8mmol)和二溴乙烷(5.21g,2.8mmol),溶於乙醇(20mL),加入鋅粉(1.43g,22mmol),回流8小時。反應液過濾,濾液濃縮至3mL,倒入水(15mL)中,用乙酸乙酯(20mL×3)萃取,有機相合併,無水硫酸鈉乾燥,過濾。濾液濃縮得到淡棕色油狀物,用矽膠色譜柱純化(流動相:正己烷:乙酸乙酯=5:1)得到(R)-甲基2-(1-(苄氧羰基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯(307mg,0.78mmol)。1H NMR(CDCl3-d)δ 10.3(s,1H),7.83(d,1H,J=7.8Hz),7.53(d,1H,J=7.8Hz),7.29-7.35(m,5H),7.16(t,1H,J=7.8Hz),6.96(s,1H),5.15(s,2H),3.95(s,3H),3.56-3.59(m,2H),2.83-2.85(m,1H),2.03-2.07(m,2H),1.84-1.93(m,4H)。MS(ESI)m/e[M+1]+393.0。 (R)-Benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (1.1 g, 2.8 mmol) and dibromo Ethane (5.21 g, 2.8 mmol) was dissolved in ethanol (20 mL). The reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated The filtrate was concentrated to give a pale brown oil (yield: hexane: ethyl acetate = 5:1) to afford (R)-methyl 2-(1-(benzyloxycarbonyl)-2- Tetrahydropyrrol-2-yl)-1H-indole-4-carboxylate (307 mg, 0.78 mmol). 1 H NMR (CDCl 3 -d) δ 10.3 (s, 1H), 7.83 (d, 1H, J = 7.8 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.29-7.35 (m, 5H), 7.16(t,1H,J=7.8Hz), 6.96(s,1H), 5.15(s,2H),3.95(s,3H),3.56-3.59(m,2H),2.83-2.85(m,1H) , 2.03-2.07 (m, 2H), 1.84-1.93 (m, 4H). MS (ESI) m / e [M+1] + 393.0.
步驟2:(R)-甲基2-(2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯
(R)-甲基2-(1-(苄氧羰基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯(307mg,0.78mol)、甲醇(10mL)和10%鈀碳(50mg),室溫氫氣下攪拌2小時。反應混合物經矽藻土過濾,濾液濃縮得到(R)-甲基2-(2-甲基四氫吡咯-2-基)-1H- 吲哚-4-甲酸酯(190mg,94%)。1H NMR(CDCl3-d1)δ 10.9(s,1H),7.86(d,1H,J=7.8Hz),7.63(d,1H,J=7.8Hz),7.24(t,1H,J=7.8Hz),7.14(s,1H),3.96(s,3H),3.40-3.43(m,1H),3.12-3.15(m,1H),2.78-2.81(m,1H),2.23-2.26(m,3H),1.94(s,3H)。MS(ESI)m/e[M+1]+ 259.0。 (R)-Methyl 2-(1-(benzyloxycarbonyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-carboxylate (307 mg, 0.78 mol), methanol (10 mL And 10% palladium on carbon (50 mg), stirred at room temperature under hydrogen for 2 hours. The reaction mixture was filtered over EtOAc EtOAc (EtOAc)EtOAc. 1 H NMR (CDCl 3 -d 1 ) δ 10.9 (s, 1H), 7.86 (d, 1H, J = 7.8 Hz), 7.63 (d, 1H, J = 7.8 Hz), 7.24 (t, 1H, J = 7.8 Hz), 7.14 (s, 1H), 3.96 (s, 3H), 3.40-3.43 (m, 1H), 3.12-3.15 (m, 1H), 2.78-2.81 (m, 1H), 2.23 - 2.26 (m , 3H), 1.94 (s, 3H). MS (ESI) m/e [M+1] + 259.0.
步驟3:(R)-甲基2-(1-(2-甲氧基-2-氧代乙基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯
(R)-甲基2-(2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯(190mg,0.74mmol)溶於乙腈(25ml),加入甲基溴乙酸乙酯(250mg,1.6mmol)和N,N-二異丙基乙胺(350mg,2.7mmol)。反應混合室溫攪拌20小時,加入二氯甲烷(15ml),水洗三次。有機相無水硫酸鎂乾燥,過濾,濃縮得到(R)-甲基2-(1-(2-甲氧基-2-氧代乙基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯(146mg)。1H NMR(CDCl3-d)δ 7.85(d,1H,J=7.8Hz),7.13-7.29(m,3H),4.92(s,2H),3.95(s,3H),3.70(s,3H),3.56-3.62(m,2H),1.95-2.06(m,4H),1.94(s,3H)。MS(ESI)m/e[M+1]+ 331.0。 (R)-Methyl 2-(2-methyltetrahydropyrrol-2-yl)-1H-indole-4-carboxylate (190 mg, 0.74 mmol) dissolved in acetonitrile (25 mL) Ethyl ester (250 mg, 1.6 mmol) and N,N-diisopropylethylamine (350 mg, 2.7 mmol). The reaction mixture was stirred at room temperature for 20 hours, then dichloromethane (15 ml) was added and washed three times with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to afford (D)-methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrol-2-yl)- 1H-indole-4-carboxylate (146 mg). 1 H NMR (CDCl 3 -d) δ 7.85 (d, 1H, J = 7.8 Hz), 7.13 - 7.29 (m, 3H), 4.92 (s, 2H), 3.95 (s, 3H), 3.70 (s, 3H) ), 3.56-3.62 (m, 2H), 1.95-2.06 (m, 4H), 1.94 (s, 3H). MS (ESI) m / e [ M + 1] + 331.0.
步驟4:(R)-甲基11b-甲基-6-氧-2,3,5,6,11,11b-六氫-1H-吲哚嗪[8,7-b]吲哚-7-甲酸酯
(R)-甲基2-(1-(2-甲氧基-2-氧代乙基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯(146mg,0.44mmol)置於25mL反應瓶中,加入無水甲基磺酸(10mL)。加熱至60℃反應1小時。反應混合物用冰水浴冷卻,加水(2.0mL)稀釋。加入碳酸氫鈉水溶液調節至PH值在8左右。用乙酸乙酯(20mL×3)萃取,有機相合併,飽和食鹽水(1×20mL)洗滌,無水硫酸鈉乾燥,過濾。濾液濃縮,剩餘物用矽膠色譜柱純化(流動相:20-60%的乙酸乙酯的正己烷溶液)得到(R)-甲基11b-甲基-6-氧-2,3,5,6,11,11b-六氫-1H-吲哚嗪[8,7-b]吲哚-7-甲酸酯(58mg,44%)。MS(ESI)m/e[M+1]+ 299.0。 (R)-Methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-carboxylate ( 146 mg, 0.44 mmol) was placed in a 25 mL reaction flask and anhydrous methanesulfonic acid (10 mL) was added. The reaction was heated to 60 ° C for 1 hour. The reaction mixture was cooled with an ice water bath and diluted with water. Add sodium bicarbonate aqueous solution to adjust to a pH of about 8. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The filtrate was concentrated, and the residue was purified on a silica gel column (mobile phase: 20-60% ethyl acetate in n-hexane) to afford (R)-methyl 11b-methyl-6-oxo-2,3,5,6 , 11,11b-Hexahydro-1H-pyridazine [8,7-b]indole-7-carboxylate (58 mg, 44%). MS (ESI) m / e [ M + 1] + 299.0.
步驟5:(R)-10a-甲基-7,8,9,10,10a,11-六氫-5,6,7a,11-四氮雜環庚基[def]環戊基[a]芴-4(5H)-酮
(R)-甲基11b-甲基-6-氧-2,3,5,6,11,11b-六氫-1H-吲哚嗪[8,7-b]吲哚-7-甲酸酯(58mg,0.19mmol),溶於甲醇(10mL),加入乙酸(0.4mL)和水合肼(0.2mL),加熱回流7小時,冷卻,加入水(5mL),用乙酸乙酯(5mL×3)萃取,有機相合併,飽和食鹽水洗滌(10mL),無水硫酸鎂乾燥,過濾。濾液濃縮,剩餘物用製備薄層色譜純化(流動相:二氯甲烷)得到(R)-10a-甲基-7,8,9,10,10a,11-六氫-5,6,7a,11-四氮雜環庚 基[def]環戊基[a]芴-4(5H)-酮(40mg)。1H NMR(DMSO-d6)δ 12.9(s,1H),10.6(s,1H),7.50-7.52(m,2H),7.12(t,1H,J=7.8Hz),3.24-3.26(m,1H),2.91(d,1H,J=18.4Hz),2.37-2.38(m,1H),2.30-2.32(m,1H),2.20-2.21(m,1H),1.95-1.96(m,1H),1.41-1.43(m,1H),1.34(s,3H),1.18-1.19(m 1H)。MS(ESI)m/e[M+1]+ 281.0。 (R)-Methyl 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]indole-7-formate (58 mg, 0.19 mmol), dissolved in MeOH (10 mL), EtOAc (EtOAc) (EtOAc) The organic layer was combined and washed with brine (10 mL). The filtrate was concentrated and the residue was purified by preparative thin layer chromatography (mobile phase: methylene chloride) to afford (R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a, 11-tetraazacycloheptyl [def]cyclopentyl[a]indole-4(5H)-one (40 mg). 1 H NMR (DMSO-d 6 ) δ 12.9 (s, 1H), 10.6 (s, 1H), 7.50-7.52 (m, 2H), 7.12 (t, 1H, J = 7.8 Hz), 3.24-3.26 (m) , 1H), 2.91 (d, 1H, J = 18.4 Hz), 2.37-2.38 (m, 1H), 2.30-2.32 (m, 1H), 2.20-2.21 (m, 1H), 1.95-1.96 (m, 1H) ), 1.41-1.43 (m, 1H), 1.34 (s, 3H), 1.18-1.19 (m 1H). MS (ESI) m / e [ M + 1] + 281.0.
例36:化合物69的合成 Example 36: Synthesis of Compound 69
化合物69:(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氫-5,6,7a,11-四氮雜環庚基[def]環戊基[a]芴-4(5H)-酮
步驟1:2-溴-5-氟-3-(2,2,2-三氟乙醯氨基)苯甲酸甲酯
3-氨基-2-溴-苯甲酸甲酯(25.0g,100mmol)溶於二氯甲烷(250mL),加入碳酸鉀(42.0g,302mmol),5-10℃,氮氣保護下,加入2,2,2-三氟乙酸酐(249.0g,1.197mol)。反應混合物25℃攪拌過夜。加入二氯甲烷稀釋,依次用水(200mL×2)和碳酸氫鈉水溶液(200mL×2)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到2-溴-5-氟-3-(2,2,2-三氟乙醯氨基)苯甲酸甲酯(34.0g,98%),為一白色固體。1H NMR(CDCl3-d1)δ 8.87(s,1H),8.36(d,1H,J=6.4Hz),7.43(d,1H,J=5.2Hz),3.98 (s,3H)。 3-amino-2-bromo-benzoic acid methyl ester (25.0 g, 100 mmol) was dissolved in dichloromethane (250 mL), potassium carbonate (42.0 g, 302 mmol) was added, 5-10 ° C, under nitrogen, 2,2 2-Fluoroacetic anhydride (249.0 g, 1.197 mol). The reaction mixture was stirred at 25 ° C overnight. Diluted with dichloromethane, washed with water (200 mL × 2) and aqueous sodium hydrogen carbonate (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-bromo-5-fluoro-3-(2,2,2 Methyl trifluoroacetamidoamino)benzoate (34.0 g, 98%) as a white solid. 1 H NMR (CDCl 3 -d 1 ) δ 8.87 (s, 1H), 8.36 (d, 1H, J = 6.4 Hz), 7.43 (d, 1H, J = 5.2 Hz), 3.98 (s, 3H).
步驟2:(R)-苄基2-((4-氟-2-(甲氧羰基)-6-(2,2,2三氟乙醯氨基)苯基)乙炔基)-2-甲基吡咯烷-1-甲酸酯
2-溴-5-氟-3-(2,2,2-三氟乙醯氨基)苯甲酸甲酯(27.52g,80mmol)溶於DMF(200mL),加入(PPh3)2PdCl2(2.8g,4mmol),(R)-苄基2-乙炔基-2-甲基吡咯烷-1-甲酸酯(19.44g,80mmol),碘化亞銅(764mg,4mmol),四甲基胍(27.6g,240mmol),氮氣保護下加熱至80℃,攪拌16小時。反應混合冷卻,加入乙酸乙酯(3×200mL)和水(800mL),有機相分離,水(2×200mL)洗滌,無水硫酸鈉乾燥,濃縮。剩餘物用矽膠色譜柱純化(流動相:0-30%乙酸乙酯的正己烷溶液)得到(R)-苄基2-((4-氟-2-(甲氧羰基)-6-(2,2,2三氟乙醯氨基)苯基)乙炔基)-2-甲基吡咯烷-1-甲酸酯(21g,53%),為一白色固體。1H NMR(DMSO-d1)δ 11.01(s,1H),7.64-7.77(m,1H),7.36(m,5H),7.19-7.31(m,1H),5.04-5.12(m,2H),3.85(s,3H),3.44-3.47(m,2H),2.0-2.29(m,2H),1.90-1.97(m,2H),1.69(s,3H)。MS(ESI)m/e[M+1]+ 507.0。 Methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate (27.52 g, 80 mmol) was dissolved in DMF (200 mL) and (PPH 3 ) 2 PdCl 2 (2.8 g, 4 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (19.44 g, 80 mmol), cuprous iodide (764 mg, 4 mmol), tetramethylhydrazine ( 27.6 g, 240 mmol), heated to 80 ° C under nitrogen atmosphere and stirred for 16 hours. The reaction mixture was cooled, EtOAc (EtOAc m. The residue was purified with a silica gel column (mobile phase: 0-30% ethyl acetate in n-hexane) to afford (R)-benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2) , 2,2,3-trifluoroethylamino)phenyl)ethynyl)-2-methylpyrrolidin-1-carboxylate (21 g, 53%) as a white solid. 1 H NMR (DMSO-d 1 ) δ 11.01 (s, 1H), 7.64-7.77 (m, 1H), 7.36 (m, 5H), 7.19-7.31 (m, 1H), 5.04-5.12 (m, 2H) , 3.85 (s, 3H), 3.44 - 3.47 (m, 2H), 2.0-2.29 (m, 2H), 1.90-1.97 (m, 2H), 1.69 (s, 3H). MS (ESI) m / e [ M + 1] + 507.0.
步驟3:(R)-甲基6-氟-2-(2-甲基-1-(2,2,2-三氟乙醯基)吡咯烷-2-基)-1H-吲哚-4-甲酸酯
(R)-苄基2-((4-氟-2-(甲氧羰基)-6-(2,2,2三氟乙醯氨基)苯基)乙炔基)-2-甲基吡咯烷-1-甲酸酯(5.0g,10mmol)溶於甲苯,室溫下加入溴化鋅(11.25g,50mmol),氮氣保護下,加熱至80℃,攪拌15小時。減壓蒸幹溶劑,剩餘物中加入二氯甲烷(500mL)和水(800mL),有機相分離,水(2×200mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮,剩餘物用色譜矽膠柱純化(流動相:0-50%的乙酸乙酯的正己烷溶液)得到(R)-甲基6-氟-2-(2-甲基-1-(2,2,2-三氟乙醯基)吡咯烷-2-基)-1H-吲哚-4-甲酸酯(1.9g,51%),為一黃色固體。1H NMR(CDCl3-d1)δ 9.97(s,1H),7.62(d,1H,J=10.2Hz),7.27(d,1H,J=9.6Hz),7.05(d,1H,J=1.2Hz),3.98(s,3H),3.86-3.88(m,2H),2.91-2.96(m,1H),2.25-2.28(m,1H),2.12-2.16(m,2H),1.99(s,3H)。MS(ESI)m/e[M+1]+ 507.0。 (R)-Benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine- 1-formate (5.0 g, 10 mmol) was dissolved in toluene, and zinc bromide (11.25 g, 50 mmol) was added at room temperature, and the mixture was heated to 80 ° C under a nitrogen atmosphere and stirred for 15 hours. The solvent was evaporated to dryness <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Mobile phase: 0-50% ethyl acetate in n-hexane) afforded (R)-methyl 6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroethyl) Pyrrolidin-2-yl)-1H-indole-4-carboxylate (1.9 g, 51%) as a yellow solid. 1 H NMR (CDCl 3 -d 1 ) δ 9.97 (s, 1H), 7.62 (d, 1H, J = 10.2 Hz), 7.27 (d, 1H, J = 9.6 Hz), 7.05 (d, 1H, J = 1.2 Hz), 3.98 (s, 3H), 3.86-3.88 (m, 2H), 2.91-2.96 (m, 1H), 2.25-2.28 (m, 1H), 2.12-2.16 (m, 2H), 1.99 (s) , 3H). MS (ESI) m / e [ M + 1] + 507.0.
步驟4:(R)-甲基6-氟-2-(2-甲基吡咯烷-2-基)-1H-吲哚-4-甲酸酯
(R)-甲基6-氟-2-(2-甲基-1-(2,2,2-三氟乙醯基)吡咯烷-2-基)-1H-吲哚-4-甲酸酯(1.0g,1.9mmol)溶於甲醇,室溫下加入NaBH4(706mg,11.4mmol)。反應混合物氮氣保護下加熱回流4小時,減壓蒸幹溶劑,剩餘物加入二氯甲烷(200mL),依次用水(200mL)和飽和食鹽水(200mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到目標化合物(R)-甲基6-氟-2-(2-甲基吡咯烷-2-基)-1H-吲哚-4-甲酸酯(727mg,98%),為一黃色 油狀物。1H NMR(CD3OD-d1)δ 7.50(dd,1H,J=10.2,2.4Hz),7.32(d,1H,J=9.0,2.4Hz),6.93(s,1H),3.97(s,3H),3.03-3.12(m,2H),2.27-2.32(m,1H),1.88-1.98(m,3H),1.60(s,3H)。MS(ESI)m/e[M+1]+ 276.0。 (R)-methyl 6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-indole-4-carboxylic acid ester (1.0g, 1.9mmol) was dissolved in methanol, at room temperature was added NaBH 4 (706mg, 11.4mmol). The reaction mixture was heated under reflux for 4 hr. EtOAc (EtOAc m. Compound (R)-Methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (727 mg, 98%). 1 H NMR (CD 3 OD-d 1 ) δ 7.50 (dd, 1H, J = 10.2, 2.4 Hz), 7.32 (d, 1H, J = 9.0, 2.4 Hz), 6.93 (s, 1H), 3.97 (s) , 3H), 3.03-3.12 (m, 2H), 2.27-2.32 (m, 1H), 1.88-1.98 (m, 3H), 1.60 (s, 3H). MS (ESI) m / e [ M + 1] + 276.0.
步驟5:(R)-甲基6-氟-2-(1-(2-甲氧基-2-氧代乙基)-2-甲基吡咯烷-2-基)-1H-吲哚-4-甲酸酯
(R)-甲基6-氟-2-(2-甲基吡咯烷-2-基)-1H-吲哚-4-甲酸酯(1.0g,1.27mol),溶於乙腈(50ml),加入甲基溴乙酸乙酯(0.58g,3.82mmol),和N,N-二異丙基乙胺(0.82g,6.35mmol),反應混合物室溫攪拌20小時。加入二氯甲烷(15mL),水洗三次,無水硫酸鎂乾燥,過濾,濃縮得到(R)-甲基6-氟-2-(1-(2-甲氧基-2-氧代乙基)-2-甲基吡咯烷-2-基)-1H-吲哚-4-甲酸酯(0.85g)。1H NMR(CD3OD-d4)δ 7.47(dd,1H,J=2.4,12.0Hz),7.27(dd,1H,J=2.4,9.0Hz),6.89(s,1H),3.95(s,3H),3.66-3.68(m,1H),3.64(s,3H),3.16-3.17(m,2H),2.72-2.75(m,1H),1.88-2.02(m,4H),1.44(s,3H)。MS(ESI)m/e[M+1]+ 349.0。 (R)-Methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (1.0 g, 1.27 mol), dissolved in acetonitrile (50 ml). Methyl bromoacetate (0.58 g, 3.82 mmol), and N,N-diisopropylethylamine (0.82 g, 6.35 mmol). Dichloromethane (15 mL) was added, washed with water three times, dried over anhydrous magnesium sulfate, filtered and evaporated to afford (R)-methyl 6-fluoro-2-(1-(2-methoxy-2-oxoethyl)- 2-Methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (0.85 g). 1 H NMR (CD 3 OD-d 4 ) δ 7.47 (dd, 1H, J = 2.4, 12.0 Hz), 7.27 (dd, 1H, J = 2.4, 9.0 Hz), 6.89 (s, 1H), 3.95 (s) , 3H), 3.66-3.68 (m, 1H), 3.64 (s, 3H), 3.16-3.17 (m, 2H), 2.72-2.75 (m, 1H), 1.88-2.02 (m, 4H), 1.44 (s , 3H). MS (ESI) m / e [ M + 1] + 349.0.
步驟6:(R)-甲基9-氟-11b-甲基-6-氧-2,3,5,6,11,11b-六氫-1H-吲哚嗪[8,7-b]吲哚-7-甲酸酯
(R)-甲基6-氟2-(1-(2-甲氧基-2-氧代乙基)-2-甲基四氫吡咯-2-基)-1H-吲哚-4-甲酸酯(100mg)置於25mL反應瓶中,加入無水甲基磺酸(6mL)。加熱至60℃反應1小時。反應混合物冰水浴冷卻,加入蒸餾水(6.0mL)稀釋。加入碳酸氫鈉水溶液調節至PH值在8左右。用乙酸乙酯(5mL×3)萃取,有機相合併,飽和食鹽水(1×5mL)洗滌,無水硫酸鈉乾燥,過濾。濾液濃縮,剩餘物用薄層製備板純化得到(R)-甲基9-氟11b-甲基-6-氧-2,3,5,6,11,11b-六氫-1H-吲哚嗪[8,7-b]吲哚-7-甲酸酯(30mg)。1H NMR(CDCl3-d)δ 7.14-7.224(m,2H),4.03(s,3H),3.81-3.84(m,1H),3.57-3.59(m,1H),3.22-3.24(m,1H),2.92-2.94(m,1H),2.39-2.40(m,1H),2.16-30 2.17(m,1H),1.93-1.94(m,1H),1.63(s,3H),1.56-1.57(m,1H)。MS(ESI)m/e[M+1]+ 317.0。 (R)-Methyl 6-fluoro 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-A The acid ester (100 mg) was placed in a 25 mL reaction flask and anhydrous methanesulfonic acid (6 mL) was added. The reaction was heated to 60 ° C for 1 hour. The reaction mixture was cooled in an ice water bath and diluted with distilled water (6.0 mL). Add sodium bicarbonate aqueous solution to adjust to a pH of about 8. The mixture was extracted with ethyl acetate (5 mL, EtOAc). The filtrate was concentrated, and the residue was purified using a thin-layer preparation plate to obtain (R)-methyl 9-fluoro 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]indole-7-formate (30 mg). 1 H NMR (CDCl 3 -d) δ 7.14-7.224 (m, 2H), 4.03 (s, 3H), 3.81-3.84 (m, 1H), 3.57-3.59 (m, 1H), 3.22-3.24 (m, 1H), 2.92-2.94 (m, 1H), 2.39-2.40 (m, 1H), 2.16-30 2.17 (m, 1H), 1.93-1.94 (m, 1H), 1.63 (s, 3H), 1.56-1.57 (m, 1H). MS (ESI) m / e [ M + 1] + 317.0.
步驟7:(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氫-5,6,7a,11-四氮雜環庚基[def]環戊基[a]芴-4(5H)-酮
(R)-甲基9-氟-11b-甲基-6-氧-2,3,5,6,11,11b-六氫-1H-吲哚嗪[8,7-b]吲哚-7-甲酸酯(90mg),溶於甲醇(30mL),加入乙酸(0.54g)和水合肼(0.28g),加熱回流5小時,冷卻,加入水(5mL),用乙酸乙酯(5mL×3)萃取,有機相合併,飽和食鹽水洗滌(10mL),無水硫酸鎂乾燥,過濾。濾液濃縮,剩餘物用薄層製備色譜純化(流動相:二氯甲烷)得到(R)-2- 氟-10a-甲基-7,8,9,10,10a,11-六氫-5,6,7a,11-四氮雜環庚基[def]環戊基[a]芴-4(5H)-酮(80mg)。1H NMR(DMSO-d6)δ 11.9(s,1H),10.2(s,1H),7.30(d,1H,J=9.6Hz),7.20(d,1H,J=10.2Hz),3.76(d,1H,J=16.4Hz),3.34(d,1H,J=16.4Hz),2.99-3.02(m,1H),2.54-2.58(m,1H),2.35-2.40(m,1H),1.90-1.94(m,1H),1.73-1.75(m,1H),1.48(s,3H),1.43-1.45(m,1H)。MS(ESI)m/e[M+1]+ 299。 (R)-methyl 9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]吲哚-7 - Formate (90 mg), dissolved in MeOH (30 mL), EtOAc (EtOAc) (EtOAc) (EtOAc) The extract was combined, and the organic layer was combined, washed with brine (10 mL) The filtrate was concentrated, and the residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 6,7a,11-tetraazacycloheptyl[def]cyclopentyl[a]indole-4(5H)-one (80 mg). 1 H NMR (DMSO-d 6 ) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.30 (d, 1H, J = 9.6 Hz), 7.20 (d, 1H, J = 10.2 Hz), 3.76 ( d, 1H, J = 16.4 Hz), 3.34 (d, 1H, J = 16.4 Hz), 2.99-3.02 (m, 1H), 2.54-2.58 (m, 1H), 2.35-2.40 (m, 1H), 1.90 -1.94 (m, 1H), 1.73-1.75 (m, 1H), 1.48 (s, 3H), 1.43-1.45 (m, 1H). MS (ESI) m/e [M+1] + 299.
生物活性 Biological activity
PARP-1酶活測定 PARP-1 enzyme activity assay
PARP-1酶活測定的方法源自改進的高通量同源PARP螢光法抑制分析試劑盒(Trevigen)。在含有終濃度為100mMTris-HCl pH 8.0、100mMNaCl、20mM MgCl2和1% DMSO的緩衝液中,8.8nM的PARP1預先和不同濃度的化合物室溫孵育30分鐘。加入500nM NAD和20ng/uL活化的DNA(Sigma)以啟動PARP1的自我聚腺苷二磷酸核醣聚合(auto-PARylation)反應,該反應條件為室溫40分鐘。加入迴圈酶法測定試劑室溫反應50分鐘以檢測反應後剩餘的NAD含量。迴圈酶法測定試劑含有終濃度分別為1%的乙醇、0.3U/ml的乙醇脫氫酶、25μM的刃天青和0.25U/ml的心肌黃酶。NAD的濃度與螢光信號(Ex=540nm,Em=590nm)成正比。基於不同濃度化合物下的剩餘酶活(即NAD減少的速率)計算出化合物的半抑制濃度(IC50)。 The method of PARP-1 enzyme activity assay is derived from an improved high-throughput homologous PARP fluorostainment assay kit (Trevigen). In a buffer containing a final concentration of 100 mM Tris-HCl pH 8.0, 100 mM NaCl, 20 mM MgCl2, and 1% DMSO, 8.8 nM of PARP1 was pre-incubated with different concentrations of compound for 30 minutes at room temperature. 500 nM NAD and 20 ng/uL activated DNA (Sigma) were added to initiate a self-poly-ADP ribose polymerization reaction of PARP1 at room temperature for 40 minutes. The loop enzymatic assay reagent was added to the room temperature reaction for 50 minutes to detect the remaining NAD content after the reaction. The loop enzymatic assay reagent contained ethanol at a final concentration of 1%, 0.3 U/ml alcohol dehydrogenase, 25 μM resazurin, and 0.25 U/ml diaphorase. The concentration of NAD is proportional to the fluorescence signal (Ex = 540 nm, Em = 590 nm). Calculated based on the residual activity of the compound (i.e., the rate of decrease NAD) at various concentrations of compound inhibition concentration (IC 50).
PARP-2和PARP-3酶活測定 PARP-2 and PARP-3 enzyme activity assay
PARP-2和PARP-3酶活測定採用商品化的 PARP-2/PARP-3化學發光分析試劑盒(BPS Biosciences)以及與其配套的檢測方法。簡而言之,先將組蛋白包被在高結合力酶標板上,再加入PARP-2或PARP-3以及不同濃度的化合物共同孵育0.5小時。然後加入生物素化的NAD和活化的DNA。通過加入鏈黴親和素標記的辣根過氧化物酶和可以產生化學發光的辣根過氧化物酶底物來檢測已生物素化的聚腺苷二磷酸核醣聚合(PARylation)產物。最後基於不同濃度化合物下的剩餘酶活計算出化合物的半抑制濃度(IC50)。 The PARP-2 and PARP-3 enzyme assays were performed using the commercial PARP-2/PARP-3 chemiluminescence assay kit (BPS Biosciences) and its associated assays. Briefly, histones were first coated on high-binding plate, and then PARP-2 or PARP-3 was added and various concentrations of compounds were incubated for 0.5 hours. Biotinylated NAD and activated DNA are then added. The biotinylated poly(ADP-ribose) ribylation product was detected by the addition of streptavidin-labeled horseradish peroxidase and a horseradish peroxidase substrate that can produce chemiluminescence. Finally, the compound is calculated based on the residual enzyme activity at different concentrations of compound inhibition concentration (IC 50).
Tankyrase-2酶活測定 Tankyrase-2 enzyme activity assay
Tankyrase-2酶活測定採用商品化的Tankyrase-2化學發光分析試劑盒(BPS Biosciences)以及與其配套的檢測方法。首先將GST融合的Tankyrase-2(利用杆狀病毒昆蟲表達系統表達與純化的重組蛋白)包被在谷胱甘肽預包被的微孔板上。再和不同濃度的化合物孵育0.5小時。然後加入生物素化的NAD。通過加入鏈黴親和素標記的辣根過氧化物酶和可以產生化學發光的辣根過氧化物酶底物來檢測已生物素化的自我聚腺苷二磷酸核醣聚合(auto-PARylation)產物。最後基於不同濃度化合物下的剩餘酶活計算出化合物的半抑制濃度(IC50)。 The Tankyrase-2 enzyme assay uses the commercially available Tankyrase-2 chemiluminescence assay kit (BPS Biosciences) and its associated assay. GST-fused Tankyrase-2 (expressed with a baculovirus insect expression system and purified recombinant protein) was first coated onto a glutathione pre-coated microplate. Incubate with different concentrations of compound for 0.5 hours. Biotinylated NAD is then added. The biotinylated self poly polyadenyl ribose auto-PARylation product was detected by the addition of streptavidin-labeled horseradish peroxidase and a horseradish peroxidase substrate that can produce chemiluminescence. Finally, the compound is calculated based on the residual enzyme activity at different concentrations of compound inhibition concentration (IC 50).
聚腺苷二磷酸核醣聚合(PARylation)測定 Determination of poly(ADP-ribose) ribylation (PARylation)
將Hela細胞在培養基(100μLDMEM,內含10%胎牛血清、0.1mg/mL青鏈黴素、2mM L-穀氨醯胺)裡以每孔5000個細胞的初始濃度接種于黑壁底透的96孔板中。在5%二氧化碳的37℃培養箱內培養4小時。然後加入經連續稀釋 後在0.1% DMSO培養基中終濃度為0.01μM至10μM的共8個濃度點的化合物。繼續在5%二氧化碳的37℃培養箱內培養18小時後,滴加60μL雙氧水溶液(在PBS中終濃度200μM)以激發DNA損傷。其中無雙氧水處理細胞作為陰性對照。將培養板於37℃放置5分鐘後,倒置培養板輕輕除去培養基。往板內滴加冰鎮處理的甲醇(每孔100μL)以固定細胞,並於-20℃冰箱中放置20分鐘。倒置培養板棄去液體並用PBS(每孔120μL)洗十次以去除固定劑後加入檢測液(每孔50μL)。檢測液含PBS、0.1%吐溫、1mg/mL牛血清白蛋白、PAR單克隆一抗(Alexis ALX-804-220,1:2000)、AlexaFluor 488標記的抗小鼠二抗(MolecularProbes A11029,1:2000)、核酸染料DAPI(Molecular Probes D3571,150nM)。4℃避光過夜孵育後,去除檢測液,用PBS(每孔120μL)洗6次,在ArrayScan VTI儀器(ThermoFisher)上讀板。通過檢測AlexaFluor 488信號(XF100_485_20,曝光時間0.05秒)以監測PAR聚合物含量;通過檢測DAPI信號(XF100_386_23,曝光時間0.01秒)用以鑒定細胞核數目。通過計算每孔細胞核Alexa Fluor 488的螢光總強度與DAPI標記的總細胞數的比值平均數可以得到單個細胞核螢光強度的平均值(代表細胞中PAR聚合物的含量)。基於不同濃度化合物下的剩餘酶活計算出化合物的半效應濃度(EC50)。 Hela cells were inoculated into the black wall at an initial concentration of 5000 cells per well in medium (100 μL MEM containing 10% fetal bovine serum, 0.1 mg/mL chelostine, 2 mM L-glutamine). In a 96-well plate. Incubate for 4 hours in a 37 ° C incubator with 5% carbon dioxide. Then add serial dilution A total of 8 concentration points of the compound were then dosed from 0.01 μM to 10 μM in 0.1% DMSO medium. After continuing to incubate for 18 hours in a 37 ° C incubator with 5% carbon dioxide, 60 μL of an aqueous solution of hydrogen peroxide (final concentration of 200 μM in PBS) was added dropwise to excite DNA damage. Among them, the cells were treated with no hydrogen peroxide as a negative control. After the plate was allowed to stand at 37 ° C for 5 minutes, the medium was gently inverted to remove the medium. Ice-treated methanol (100 μL per well) was added dropwise to the plate to fix the cells, and placed in a refrigerator at -20 ° C for 20 minutes. The liquid was discarded by inverting the plate and washed ten times with PBS (120 μL per well) to remove the fixing agent, and then the test solution (50 μL per well) was added. The test solution contains PBS, 0.1% Tween, 1 mg/mL bovine serum albumin, PAR monoclonal primary antibody (Alexis ALX-804-220, 1:2000), AlexaFluor 488-labeled anti-mouse secondary antibody (Molecular Probes A11029, 1 : 2000), nucleic acid dye DAPI (Molecular Probes D3571, 150 nM). After incubating overnight at 4 ° C in the dark, the test solution was removed, washed 6 times with PBS (120 μL per well), and the plate was read on an ArrayScan VTI instrument (ThermoFisher). The PAR polymer content was monitored by detecting the AlexaFluor 488 signal (XF100_485_20, exposure time 0.05 sec); the number of nuclei was identified by detecting the DAPI signal (XF100_386_23, exposure time 0.01 sec). The average of the individual cell nuclear fluorescence intensities (representing the amount of PAR polymer in the cells) can be obtained by calculating the ratio of the total fluorescence intensity of Alexa Fluor 488 per well to the total number of cells labeled with DAPI. The half effect concentration (EC50) of the compound was calculated based on the remaining enzyme activity at different concentrations of the compound.
本發明中報導的例1-69的化合物通過實驗發現對PARP有抑制作用,例如PARP-1、PARP-2、PARP-3和端錨聚合酶-2(Tankyrase-2),IC50值的範圍從納摩爾以下至10 微摩爾。 The compounds of Examples 1-69 reported in the present invention have been found to have an inhibitory effect on PARP, such as PARP-1, PARP-2, PARP-3, and Tankyrase-2, and the range of IC 50 values. From below nanomolar to 10 micromolar.
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