CN116621860A - Bcl-2抑制剂 - Google Patents
Bcl-2抑制剂 Download PDFInfo
- Publication number
- CN116621860A CN116621860A CN202310439771.XA CN202310439771A CN116621860A CN 116621860 A CN116621860 A CN 116621860A CN 202310439771 A CN202310439771 A CN 202310439771A CN 116621860 A CN116621860 A CN 116621860A
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- Prior art keywords
- methyl
- piperazin
- tetrahydro
- amino
- pyrido
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
本公开内容包括式(A)的化合物,其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11和R12、j、k、m、n、Y、W、W1、W2、W3、V、L、Z1、Q1、Q2、Q3和Q4如本文中限定。还公开了使用这些化合物治疗新生性疾病、自身免疫性疾病或神经变性性疾病的方法。
Description
本申请是申请日为2018年8月22日,申请号为201880067225.5(PCT申请号为PCT/US2018/047444),发明名称为:“Bcl-2抑制剂”的中国发明专利申请的分案申请。
对相关申请的交叉引用
本申请要求于2017年8月23日提交的美国临时申请号62/549,081;和于2018年1月9日提交的美国临时申请号62/615,007的申请日的权益。上述每个申请的全部内容通过引用并入本文。
发明背景
凋亡或程序性细胞死亡是一个保守且受调节的过程,其是清除衰老、受损和不必要的细胞的主要机制。阻断凋亡信号转导的能力是癌症的关键标志,因此对于肿瘤发生、肿瘤维持和化学耐受性是重要的[Hanahan,D.&Weinberg,R.A.The hallmarks ofcancer.Cell 100,57–70(2000)]。BCL-2家族中的促死亡(prodeath)(例如BCL-2相关X蛋白(BAX)、BCL-2拮抗剂/杀手1(BAK)、BCL-2相关细胞死亡激动剂(BAD)、BCL-2样11(BIM)、NOXA和BCL-2结合组分3(PUMA))和促存活(BCL-2、BCL-XL、BCL-2样2(BCL-W)、髓样细胞白血病序列1(MCL-1)和BCL-2相关蛋白A1(BFL-1))蛋白之间的动态结合相互作用控制对程序性细胞死亡的定型。改变这些相对派别之间的平衡提供了一种癌细胞破坏正常细胞凋亡并获得生存优势的手段[Youle,R.J.&Strasser,A.The BCL-2protein family:opposingactivities that mediate cell death.Nat.Rev.Mol.Cell Biol.9,47–59(2008)]。
BCL-2(第一种鉴定的凋亡调节因子)最初是从人B细胞淋巴瘤中存在的t(14;18)易位的断裂点克隆的[Tsujimoto,Y.,et al.Science 228,1440–1443(1985);Cleary,M.L.,et al Cell 47,19–28(1986);Boise,L.H.et al.Cell 74,597–608(1993)]。从那以后,已显示此蛋白质在多种淋巴样恶性的存活中具有主导作用[Vaux,D.L.,et al pre-Bcells.Nature 335,440–442(1988)]。Bcl-2蛋白的过表达与各种癌症和免疫系统病症中对化学疗法的抗性、临床结果、疾病进展、总体预后或其组合关联。Bcl-2蛋白参与膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结肠直肠癌、食道癌、肝细胞癌、淋巴母细胞白血病、滤泡性淋巴瘤、T细胞或B淋巴起源的淋巴样恶性、黑素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌、脾癌等记载于PCT US 2004/36770(以WO 2005/049593公布)和PCT US 2004/37911(以WO 2005/024636公布)。Bcl-2蛋白参与免疫和自身免疫疾病记载于Current Allergy and Asthma Reports 2003,3,378-384;British Journal of Hematology 2000,110(3),584-90;Blood 2000,95(4),1283-92;和New England Journal of Medicine 2004,351(14),1409-1418。在WO 2009/064938中公开了Bcl-2蛋白参与关节炎。在US 2008-0182845 A1中公开Bcl-2蛋白参与骨髓移植物排斥。所有文献通过引用方式并入本文。
在过去的十年中,如下所示的几种Bcl-2抑制剂如ABT-737、ABT-263和ABT-199已经得到鉴定,并进入人临床试验用于癌症治疗。
通过基于核磁共振(NMR)的筛选、平行合成和基于结构的片段药物设计发现了ABT-737[Tillman Oltersdorf,et al,Nature,Vol 435,2005,p 677]。ABT-737是抗凋亡蛋白Bcl-2、Bcl-XL和Bcl-w的小分子抑制剂,具有比以前报道的化合物更有力2至3个数量级的亲和力。机理研究揭示,ABT-737不直接启动凋亡过程,但增强死亡信号的作用,显示与化学治疗剂和放射的协同细胞毒性。ABT-737对来自淋巴瘤和小细胞肺癌细胞系的细胞,以及患者衍生的原代细胞表现出基于单药剂机制的杀伤,并且在动物模型中,ABT-737改善存活,引起建立的肿瘤消退,并且在高百分比的小鼠中产生治愈。不幸的是,ABT-737不能口服生物利用,并且其低水溶性妨碍了其静脉内递送配制剂。
在MedChem的广泛努力后,已开发出口服生物利用性Bcl-2抑制剂ABT-263(Navitoclax)[Cheol-Min Park,et al J.Med.Chem.2008,51,6902–6915]。ABT-263是Bcl-xL、Bcl-2和Bcl-w的有力抑制剂,具有Ki≤0.5nM、≤1nM和≤1nM。ABT-263针对SCLC H146细胞系具有110nM的IC50。在H345异种移植物模型中以100mg/kg/天施用ABT-263时,以80%的TGI和20%的治疗肿瘤观察到显著的抗肿瘤功效,指示肿瘤体积的至少50%缩小。在小细胞肺癌和急性成淋巴细胞白血病的异种移植物模型中,单独口服施用ABT-263引起肿瘤完全消退[Tse C,et al.Cancer Res.2008,68(9),3421-3428]。然而,在临床试验中,ABT-263(navitoclax)对BCL-XL的抑制诱导循环血小板数量的快速浓度依赖性降低。此种基于机制的血小板减少是患者中单药剂navitoclax治疗的剂量限制性毒性,并限制将药物浓度驱动至高效力范围的能力。
因此,BCL-2选择性(不针对BCL-XL)抑制剂将最终导致在淋巴样恶性中维持效力的情况下实质性降低的血小板减少。所致的治疗窗增加应当允许BCL-2依赖性肿瘤类型中更大的BCL-2抑制和临床效力。在广泛的MedChem后,已成功开发ABT-199(GDC-0199)[Andrew J Souers,et al,Nature Medicine,第19,22卷,p202,2013]。ABT-199是一种Bcl-2选择性抑制剂,具有Ki<0.01nM,相对于Bcl-xL和Bcl-w选择性高>4800倍,并且对Mcl-1没有活性。ABT-199以8nM的EC50有力抑制RS4;11细胞。此外,ABT-199诱导RS4;11细胞快速凋亡,其中细胞色素c释放、胱天蛋白酶激活和sub-G0/G1 DNA积累。定量免疫印迹法揭示了对ABT-199的敏感性与Bcl-2的表达密切相关,包括NHL、DLBCL、MCL、AML和ALL细胞系。ABT-199还以3.0nM的平均EC50诱导CLL凋亡。在RS4;11异种移植物中,单剂量100mg/kg的ABT-199引起95%的最大肿瘤生长抑制和152%的肿瘤生长延迟。作为单一药剂或者与苯达莫司汀和其他药剂联用,ABT-199也抑制异种移植物生长(DoHH2,Granta-519)。人I期和II期数据显示了ABT-199对具有17p缺失的CLL高度有力,并且于2016年获得FDA批准。
WO/2017/132474公开了新一类BCL-2抑制剂。然而,仍然强烈需要在本领域继续寻找更有力的BCL-2抑制剂。
发明概述
在第一个实施方案中,本发明提供了式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药:
其中
Q1是6元杂环烷基、6元杂环烯基或6元杂芳基;
Q2是芳基或杂芳基;
Q3是环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基;
Q4是
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、和R12各自独立是H、D、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤素、硝基、氧代、氰基、ORa、SRa、烷基-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRc、烷基-P(O)RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、S(O)(=N(Ra))Rb、-N=S(O)RbRc、SO2N(Rb)Rc、或N(Rb)SO2Rc,其中所述环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选用一个或多个Rd取代;
Ra、Rb、Rc和Rd独立是H、D、烷基、烯基、炔基、卤素、氰基、胺、硝基、羟基、C(O)NHOH、C(O)OH、C(O)NH2、烷氧基、烷氧基烷基、卤代烷基、羟基烷基、氨基烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基氨基、氧代、卤代烷基氨基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选用一个或多个Re取代;
Re是H、D、烷基、烯基、炔基、卤代、氰基、胺、硝基、羟基、C(O)NHOH、烷氧基、烷氧基烷基、卤代烷基、羟基烷基、氨基烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基氨基、氧代、卤代烷基氨基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基;
Z1是键、(CH2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)q、二价烯基基团、或二价炔基基团;
L是键、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基任选用一个或多个Rd取代;
Y、W、和W2各自独立是CH或N;
W1是N;
W3是O或N(Ra);
V是N、C、或CH;
R9基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R9的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R2基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R2的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R10基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R10的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R11和R12基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R11或R12的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R10和R2基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R10或R2的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R4和-Z1-L-R6基团与它们附接的原子一起可以任选形成环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中R4的所述环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基任选用一个或多个Rd取代;
Rb和Rc基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中Rb和Rc的所述环烷基或杂环烷基任选用一个或多个Re取代;
Rd基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中Rd的所述环烷基或杂环烷基任选用一个或多个Re取代;
Re基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基;
j和k各自独立是0、1、2、3、4、5、6、7或8;且
m、n、p、q和r各自独立是0、1、2、3、或4;
任选地,条件是当是/>时,则-Z1-L-R6不是
在第二个实施方案中,本发明提供了以式(B)表示的化合物,其中Z2是-O-、-CH2、-C(O)、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(=N(Ra))-或-P(O)(Ra)-;并且A是-C(R2R2)r-或-O-:
或其N-氧化物,或所述式(B)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中
Z2是-O-、-CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(=N(Ra))-、-P(O)(Ra)-;其中Z2的Ra独立是H、D、C1-C6烷基、C2-C6烯基、C1-C6烷基羰基、C1-C6烷氧基羰基、C3-C6环烷基、5-8元单环杂环烷基、C6-C14芳基、或5-8元单环杂芳基,其中所述C1-C6烷基、C3-C6环烷基、5-8元单环杂环烷基、C6-C14芳基、5-8元单环杂芳基任选用一个或多个Re取代,且
A是-(CR2R2)r-或-O-;其中r是0、1、2、或3;
R2各自独立是H、-(C1-C4)烷氧基、任选用-(C1-C4)烷氧基取代的-(C1-C4)烷基,或
R2基团中的两个与它们附接的同一碳原子一起形成-(C3-C6)环烷基或4-6元杂环状环,其中所述-(C3-C6)环烷基或4-6元杂环状环任选用-(C1-C4)烷基、-(C1-C4)卤代烷基或氧杂环丁基取代;并且剩余变量如第一个实施方案中限定。
在第三个实施方案中,本发明提供了以式(C)表示的化合物:
或其N-氧化物,或所述式(C)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R1是H、D、卤素或-(C1-C4)烷基,并且剩余的变量如第一和/或第二个实施方案中定义。
在第四个实施方案,本发明提供了以式(D)表示的化合物
或其N-氧化物,或所述式(D)的化合物或其N-氧化物的其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中
R5独立是硝基、卤素或-SO2Ra,其中R5的Ra是-(C1-C4)烷基或-(C1-C4)卤代烷基;
Z1是不存在、NH、N(H)(CH2)q、O、S或-(C1-C4)亚烷基,其中q是1、2或3;
L是不存在或任选用-(C3-C6)环烷基取代的-(C1-C4)亚烷基;且
R6是H、D、-N(CH3)-(C1-C4)亚烷基-P(O)((C1-C4)烷氧基)2、-P(O)(N(CH3)2)(OEt)、-P(O)(O-(C1-C4)亚烷基-O-CO-(C1-C4)烷基)2、-(C3-C6)环烷基、苯基、5-7元杂环基、8-10元二环状环,其中-(C3-C6)环烷基、苯基、5-7元杂环基或7-10元二环状环任选用卤素、-OH、-CN、-COOH、-NH2、-N(CH3)2、-(C1-C4)烷基、-(C1-C4)烷氧基、环丙基、4-6元杂环基、-CH2P(O)(OH)2、-CH2P(O)((C1-C4)烷氧基)2、-P(O)((C1-C4)烷基)2或-N=S(O)((C1-C4)烷基)2取代,并且剩余的变量如第一、第二和/或第三个实施方案中限定。
在第五个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或所述根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R9独立是D、卤素、-OH、CN、-NH2、=O、-(C1-C4)烷基、-(C1-C4)烷氧基、-(C1-C4)卤代烷基、-(C1-C4)羟基烷基、-(C3-C6)环烷基或1,3-二硫戊环基;并且k是0、1、2、3或4;并且剩余的变量如第一、第二、第三和/或第四个实施方案中限定。
在第六个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中A是-CH2-或-O-;并且剩余的变量如第一、第二、第三、第四和/或第五个实施方案中限定。
在第七个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中每个R2独立是–CH3;并且n是0或2;并且剩余的变量如第一、第二、第三、第四、第五和/或第六个实施方案中限定。
在第八个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中Z2是-O-;并且剩余的变量如第一、第二、第三、第四、第五、第六和/或第七个实施方案中限定。
在第九个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R1是卤素,如Cl;并且剩余的变量如第一、第二、第三、第四、第五、第六、第七和/或第八个实施方案中限定。
在第十个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R5是硝基;并且剩余的变量如第一、第二、第三、第四、第五、第六、第七、第八和/或第九个实施方案中限定。
在第十一个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中Z1是不存在、NH或O;并且剩余的变量如第一、第二、第三、第四、第五、第六、第七、第八、第九和/或第十个实施方案中限定。
在第十二个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中Z2是-O-、-CH2-、-C(O)-、-NH-、-N-(氧杂环丁基)-、-S-、-S(O)-、-S(O2)-、-S(O)(=NH)-、-S(O)(=NCH3)-或-P(O)(CH3)-;并且剩余的变量如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十和/或第十一个实施方案中限定。
在第十三个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R6是H、D、-(C3-C6)环烷基、苯基、四氢-2H-吡喃基或1,4-二噁烷基,其中-(C3-C6)环烷基、苯基、四氢-2H-吡喃基或1,4-二噁烷基用1或2个选自下组的基团任选取代:卤素、-OH、=O、-(C1-C4)烷基、或-(C1-C4)烷氧基;并且剩余的变量如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一和/或第十二个实施方案中限定。
在第十四个实施方案中,本发明提供了根据结构式A、B、C或D的化合物或其N-氧化物,或根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R6是四氢-2H-吡喃基或1,4-二噁烷基,其中四氢-2H-吡喃基或1,4-二噁烷基用1或2个卤素任选取代;并且剩余的变量如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二和/或第十三个实施方案中限定。
例如,在根据结构式A、B、C或D的化合物或其N-氧化物,根据结构式A、B、C或D的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药中,Z1是-NH-,L是-CH2-,R6是四氢-2H-吡喃基或1,4-二噁烷基,其用1或2个卤素基团任选取代,并且优选地,A是-CH2-或-O-,R1是Cl,R5是硝基,Z2是-O-,每个R2独立是-CH3并且n是0或2,并且R9是甲基(并且k是1)或卤素(并且k是2,诸如二氟)。
还考虑了此类化合物中的任一种的经修饰的化合物,包括与未修饰的化合物相比具有改善的(例如,增强的,更大的)药物溶解性、稳定性、生物利用度和/或治疗指数的修饰。示例性的修饰包括(但不限于)适用的前药衍生物和富含氘的化合物。
用于治疗新生性疾病的药物组合物、其治疗用途、和化合物用于制备用于治疗疾病/病症的药物的用途也在本发明的范围内,所述药物组合物包含本文中所述的一种或多种化合物(例如式(A)-(D)中那些化合物的任一种或其药学上可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药或其N-氧化物)、其修饰物和/或盐和药学上可接受的稀释剂或载体。
本发明还涉及治疗新生性疾病或自身免疫性疾病的方法,其通过对有此需要的受试者施用有效量的本文中所述的一种或多种本发明的化合物(例如式(A)-(D)中那些化合物的任一种或其药学上可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药或其N-氧化物)、其修饰物和/或盐,或包含本发明的化合物的药物组合物。
在某些实施方案中,新生性疾病、自身免疫性疾病或神经变性性疾病以异常(例如,增强或增加)的Bcl-2活性为特征。例如,新生性疾病可以是血液系统恶性或癌症,包括实体瘤;自身免疫性疾病可以是I型糖尿病;并且神经变性性疾病可以是精神分裂症。
在某些实施方案中,新生性疾病是骨髓瘤、多发性骨髓瘤、淋巴瘤、滤泡性淋巴瘤(FL)、非何杰金氏淋巴瘤、白血病、急性白血病、急性成淋巴细胞性白血病(ALL)(例如BCL-2依赖性ALL和儿科ALL)、慢性成淋巴细胞性白血病(CLL)(例如复发/难治性CLL,del(17p)CLL)、慢性髓样白血病(CML)(例如原始细胞危象CML)、套细胞淋巴瘤(MCL)、弥漫性大B细胞淋巴瘤、肺癌如小细胞肺癌(SCLC)、黑素瘤、乳腺癌或前列腺癌,包括其耐药性癌症。
在某些实施方案中,方法进一步包括施用一种或多种有效治疗新生性疾病的其他治疗,例如手术、放射疗法、化学治疗剂(例如苯达莫司汀、NL-101(7-(5-(二(2-氯乙基)氨基)-1-甲基-1H-苯并[d]咪唑-2-基)-N-羟基庚酰胺)、顺铂、卡铂、依托泊苷、拓扑替康)、靶疗法(例如,抗CD20抗体,如利妥昔单抗、Bruton酪氨酸激酶抑制剂如伊布替尼(ibrutinib)和acalabrutinib(ACP-196)、PI3Kδ抑制剂,如idelalisib);抗体-药物缀合物或ADC(例如抗CD30 ADC brentuximab vedotin)、免疫疗法(例如抗PD-1抗体包括派姆单抗(Pembrolizumab)和纳武单抗(nivolumab)或抗PD-L1抗体包括atezolizumab、度伐单抗(Durvalumab)和avelumab)或CAR-T疗法(例如,tisagenlecleucel,axicabtageneciloleucel)。
本文还提供了一种或多种本发明的化合物或其药学上可接受的盐或包含一种或多种本发明的化合物的药物组合物用于制备用于治疗上文提及的疾病或状况的药物的用途。
在本文提供的另一个实施方案中,本发明的化合物或其药学上可接受的盐或包含一种或多种所公开的化合物的药物组合物用于治疗上文提及的疾病或状况。
在下面的描述中阐述了本发明的一个或多个实施例的细节。通过说明书和权利要求书,本发明的其他特征、目的和优点将变得明显。应当理解,本文所述的本发明的所有实施方案/特征(化合物、药物组合物、制备/使用方法等),包括实施例和原始权利要求书中所述的任何特定特征可以彼此组合,除非不适用或明确排除。
发明详述
本文所述的示例性化合物包括但不限于以下化合物:
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基-2,2,3,3-d4)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,2-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2'H-螺[环丙烷-1,3'-吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪]-1'(6'H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2,3,4,6-四氢-1H-吡咯并[2,3-b][1,5]萘啶-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-氧-2,3,4,6-四氢-1H-吡咯并[2,3-b][1,5]萘啶-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-氧-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(4-氧-2,3,4,6-四氢-1H-吡咯并[2,3-b][1,5]萘啶-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2,3,4,6-四氢-1H-吡咯并[3',2':5,6]吡啶并[2,3-b]吡嗪-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(4,4-二氧化-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(4-(甲基亚氨基)-4-氧化-2,3,4,6-四氢-1H-4λ4-吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((2-吗啉代乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-甲基吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((((1r,4r)-4-甲氧基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((((1s,4s)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((((1s,4s)-4-乙基-4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1s,4s)-4-吗啉代环己基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((4-(环丙基氨基)环己基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4,4-二氟环己基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((四氢-2H-吡喃-4-基)甲氧基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((四氢-2H-吡喃-3-基)甲氧基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(2-吗啉代乙氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-甲基吗啉-2-基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((4-(氧杂环丁烷-3-基)吗啉-2-基)甲氧基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-羟基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1r,4r)-4-甲氧基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1s,4s)-4-羟基-4-甲基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1s,4s)-4-乙基-4-羟基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1s,4s)-4-吗啉代环己基)氧)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((4-(环丙基氨基)环己基)氧)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((4,4-二氟环己基)甲氧基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((2-(4-氯苯基)环戊-1-烯-1-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((2-(4-氯苯基)环庚-1-烯-1-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4-(4-氯苯基)-6,6-二甲基-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-4-(甲氧基甲基)-4-甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-5-氟-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((6-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-5-硝基吡啶-3-基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(6,7-二氢咪唑[4',5':5,6]吡啶并[2,3-b][1,4]噁嗪-8(3H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((9-(4-氯苯基)-3-甲基-3-氮杂螺[5.5]十一-8-烯-8-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((9-(4-氯苯基)-3-(1,3-二氟丙烷-2-基)-3-氮杂螺[5.5]十一-8-烯-8-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二氟-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((5-(4-氯苯基)螺[2.5]辛-5-烯-6-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((7-(4-氯苯基)螺[3.5]壬-6-烯-6-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-3'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-3',5,5-三甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-4-(4-((4,4-二甲基-2-(吡啶-3-基)环己-1-烯-1-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((2-(1H-吲哚-5-基)-4,4-二甲基环己-1-烯-1-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-氟-5-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)-2-噁螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-氟-5-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((6-(4-氯苯基)-2-氧杂螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((6-(4-氯苯基)-2-氧杂螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-6-氟苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-5-氟苯甲酰胺,
4-(4-((4'-氯-5,5-二(甲基-d3)-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-2-甲基哌嗪-1-基-2,3,3,5,5,6,6-d7)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
二乙基((2-(((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)吗啉代)甲基)膦酸酯,
二乙基(((3-((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)丙基)(甲基)氨基)甲基)膦酸酯,
2-(((2-((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)乙基)((特戊酰氧基)甲氧基)磷酰基)氧)乙基新戊酸酯,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-甲基-1-氧化磷杂环己-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-羟基-1-氧化磷杂环己-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
((4-(((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)-1-氧化磷杂环己-1-基)氧)甲基新戊酸酯,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-甲基-2-氧化-1,3,2-氧氮磷杂环己(oxazaphosphinan)-5-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((2-(2-甲基-2-氧化-1,3,2-氧氮磷杂环己-3-基)乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-(二甲基磷酰基)哌啶-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-(二甲基磷酰基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
N-((4-(((1,4-二噁螺[4.5]癸-8-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
N-((4-(((2-噁螺[3.5]壬-7-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((2-(己氢呋喃[3,4-c]吡啶-5(3H)-基)乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(3-噁八氢-7H-咪唑[1,5-d][1,4]二氮卓(diazepin)-7-基)乙基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(3-噁八氢-5H-吡咯并[3,4-c]吡啶-5-基)乙基)氨基)苯基)磺酰基)苯甲酰胺,
N-((4-((2-(2-噁-5-氮杂二环[2.2.2]辛-5-基)乙基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((3-羟基-3-甲基二环[3.1.1]庚烷-6-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
N-((4-((2-(2-噁-5-氮杂二环[2.2.1]庚烷-5-基)乙基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
2-((3R)-8-(2-((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)乙基)-6,6-二氟-8-氮杂二环[3.2.1]辛-3-基)乙酸,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((2-(6,6-二氟-8-氮杂二环[3.2.1]辛-8-基)乙基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(四氢-2H-吡喃-4-基)-2-氮杂螺[3.3]庚烷-6-基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-噻喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-亚氨基-1-氧化六氢-1l6-噻喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-(甲基磺酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
N-((4-(((4-氨基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((1-(四氢-2H-吡喃-4-基)环丙基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((2-(5,6-二氢咪唑[1,2-a]吡嗪-7(8H)-基)乙基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((5,6,7,8-四氢咪唑[1,2-a]吡啶-6-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((3-(二氟甲氧基)苯甲基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((3,4,5-三羟基四氢呋喃-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((3,4,5,6-四羟基四氢-2H-吡喃-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4,5-二羟基-6,6-二甲基四氢-2H-吡喃-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((2,3,5-三羟基-6-(羟基甲基)四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((2,3,4,5,6-戊羟基环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(1-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌啶-4-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-5-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-3-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)吡啶酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)烟酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,2-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-(羟基甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(4,4-二氧化-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基-2,2,3,3-d4)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3'H-螺[环丙烷-1,2'-吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪]-1'(6'H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-氧-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-氧-2,3,4,6-四氢-1H-吡咯并[3',2':5,6]吡啶并[2,3-b]吡嗪-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(4-氧-4,6-二氢-1H-吡咯并[2,3-b][1,5]萘啶-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(4-甲基-2,3,4,6-四氢-1H-吡咯并[3',2':5,6]吡啶并[2,3-b]吡嗪-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(4-亚氨基-4-氧化-2,3,4,6-四氢-1H-4λ4-吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(4-甲基-4-氧化-2,3,6-三氢吡咯并[3',2':5,6]吡啶并[3,2-b][1,4]氮杂phosphinin-1-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((3-氟四氢-2H-吡喃-3-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((3-吗啉代丙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-甲基吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((4-(氧杂环丁烷-3-基)吗啉-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((((1s,4s)-4-甲氧基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((((1r,4r)-4-羟基-4-甲基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((((1r,4r)-4-乙基-4-羟基环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((1-(氧杂环丁烷-3-基)哌啶-4-基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1r,4r)-4-吗啉代环己基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-(甲基(氧杂环丁烷-3-基)氨基)环己基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((1,4,4-三氟环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-氟四氢-2H-吡喃-4-基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((3-氟四氢-2H-吡喃-3-基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(3-吗啉代丙氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-甲基吗啉-2-基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((4-(氧杂环丁烷-3-基)吗啉-2-基)甲氧基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-羟基-4-甲基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1s,4s)-4-甲氧基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1r,4r)-4-羟基-4-甲基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1r,4r)-4-乙基-4-羟基环己基)甲氧基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((1-(氧杂环丁烷-3-基)哌啶-4-基)氧)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1r,4r)-4-吗啉代环己基)氧)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((4-(甲基(氧杂环丁烷-3-基)氨基)环己基)氧)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((1,4,4-三氟环己基)甲氧基)苯基)磺酰基)苯甲酰胺,
4-(4-((4-(4-氯苯基)-5,6-二氢-2H-吡喃-3-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(Z)-4-(4-((2-(4-氯苯基)环辛-1-烯-1-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-4-甲氧基-4-甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(5-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)-2,5-二氮杂二环[2.2.2]辛-2-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-(4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基磺亚胺酰基(sulfonimidoyl))苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((5-氯-6-((四氢-2H-吡喃-4-基)甲氧基)吡啶-3-基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-(S-(三氟甲基)磺亚胺酰基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢-[1,4]噁嗪o[3,2-f]吲哚-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((9-(4-氯苯基)-3-异丙基-3-氮杂螺[5.5]十一-8-烯-8-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((9-(4-氯苯基)-3-(氧杂环丁烷-3-基)-3-氮杂螺[5.5]十一-8-烯-8-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二(氟甲基)-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-(1-(4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)环丙基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((6-(4-氯苯基)螺[2.5]辛-5-烯-5-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-2'-氟-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-2',5,5-三甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-4-(4-((4,4-二甲基-2-(吡啶-2-基)环己-1-烯-1-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-4-(4-((4,4-二甲基-2-(1H-吡咯并[2,3-b]吡啶-5-基)环己-1-烯-1-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-氟-5-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)-2-噁螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-氟-5-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-3-氟苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-氟-5-硝基苯基)磺酰基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-6-氟苯甲酰胺,
4-(4-((4'-氯-5,5-二(甲基-d3)-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基-2,2,3,3-d4)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
((2-(((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)甲基)吗啉代)甲基)膦酸,
二乙基(2-((2-((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)乙基)(甲基)氨基)乙基)膦酸酯,
乙基P-(2-((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)乙基)-N,N-二甲基膦酰胺酯(phosphonamidate),
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-(二甲基氨基)-1-氧化磷杂环己-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-乙氧基-1-氧化磷杂环己-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-异丙氧基-1-氧化磷杂环己-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((1,2,3-三甲基-2-氧化-1,3,2-二氮杂磷杂环己(diazaphosphinan)-5-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((2-(2-甲基-2-氧化-1,3,2-二氮杂磷杂环己-1-基)乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-(二甲基磷酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(二甲基磷酰基)-3-硝基苯基)磺酰基)苯甲酰胺,
N-((4-(((1,4-二硫螺[4.5]癸-8-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
N-((4-((2-(6-氮杂螺[2.5]辛-6-基)乙基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((2-(2,2-二氟-7-氮杂螺[3.5]壬-7-基)乙基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(2-(氧杂环丁烷-3-基)八氢-5H-吡咯并[3,4-c]吡啶-5-基)乙基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(1-氧八氢-5H-吡咯并[3,4-c]吡啶-5-基)乙基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((3-羟基二环[3.1.1]庚烷-6-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
N-((4-(((3-氨基-3-甲基二环[3.1.1]庚烷-6-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(5-(氧杂环丁烷-3-基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)乙基)氨基)苯基)磺酰基)苯甲酰胺,
2-((3S)-8-(2-((4-(N-(4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰基)氨磺酰基)-2-硝基苯基)氨基)乙基)-6,6-二氟-8-氮杂二环[3.2.1]辛-3-基)乙酸,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((2-(6,6-二氟-8-氮杂二环[3.2.1]辛-8-基)乙基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
N-((4-((7-噁螺[3.5]壬-2-基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1,1-二氧化四氢-2H-噻喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((1-(异丙基亚氨基)-1-氧化六氢-1l6-噻喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-(S-甲基磺亚胺酰基)吗啉-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氰基四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-((2-(四氢-2H-吡喃-4-基)丙-2-基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((2-(5,6-二氢-[1,2,4]三唑[1,5-a]吡嗪-7(8H)-基)乙基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((1-(噻唑-2-基)哌啶-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((4-(二氟甲氧基)苯甲基)氨基)-3-硝基苯基)磺酰基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((3,5-二羟基四氢呋喃-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((3,4,5-三羟基-6,6-二甲基四氢-2H-吡喃-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((2,3,5-三羟基四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((3,4,5-三羟基-6-(甲基硫代)四氢-2H-吡喃-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((3,4,5-三羟基-6-(((4,5,6-三羟基-2-(羟基甲基)四氢-2H-吡喃-3-基)甲氧基)甲基)四氢-2H-吡喃-2-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(1-((6-(4-氯苯基)-2-噁螺[3.5]壬-6-烯-7-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(1-((6-(4-氯苯基)-2-噁螺[3.5]壬-6-烯-7-基)甲基)-1,2,3,6-四氢吡啶-4-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-4-(1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌啶-4-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-6-(4-((6-(4-氯苯基)-2-噁螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-4-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯基)磺酰基)烟酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-6-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)烟酰胺,
N-((4-((((R)-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((S)-2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
N-((4-((((S)-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((R)-2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-((二甲基(氧)-l6-亚硫烷基)氨基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((2-(4-((二甲基(氧)-l6-亚硫烷基)氨基)哌啶-1-基)乙基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((4-((1-氧化四氢-1l6-噻吩-1-亚基)氨基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺,或
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-((1-(4-((二甲基(氧)-l6-亚硫烷基)氨基)哌啶-1-基)丙-2-基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺。
本发明的化合物可以含有一个或多个不对称碳原子。因此,化合物可以以非对映异构体、对映异构体或其混合物存在。化合物的合成可以采用外消旋体、非对映异构体或对映异构体作为起始材料或中间体。非对映异构化合物可以通过层析或结晶法分离。类似地,对映体混合物可以使用相同的技术或本领域已知的其他技术分离。每个不对称碳原子可以为R或S构型,并且这两种构型在本发明的范围内。
具有一个或多个手性中心的化合物可以以各种立体异构体形式存在。立体异构体是仅在其空间排列上不同的化合物。立体异构体包括所有非对映异构体、对映异构体和差向异构体形式以及外消旋体及其混合物。
术语“几何异构体”是指具有至少两个取代基的环状化合物,其中两个取代基均在环的同一侧(顺式)或其中取代基均在环的相对侧(反式)。当所公开的化合物通过结构命名或描绘而未指示立体化学时,应理解该名称或结构涵盖一种或多种可能的立体异构体或几何异构体,或所涵盖的立体异构体或几何异构体的混合物。
当通过名称或结构描绘几何异构体时,应理解的是,命名或描绘的异构体比另一异构体以更大的程度存在,也就是说,命名或描绘的几何异构体的几何异构体纯度按重量计大于50%,例如至少60%,70%,80%,90%,99%或99.9%纯的。通过将混合物中命名或描绘的几何异构体的重量除以混合物中所有几何异构体的总重量测定几何异构体纯度。
外消旋混合物是指50%的一种对映异构体和50%的其相应的对映异构体。当命名或描述具有一个手性中心的化合物而未指示手性中心的立体化学时,应理解该名称或结构涵盖该化合物的两种可能的对映异构体形式(例如,对映异构体纯的,对映异构体富集的或外消旋的)。当命名或描绘具有两个或更多个手性中心的化合物而未指示手性中心的立体化学时,应理解为该名称或结构涵盖化合物的所有可能的非对映异构体形式(例如,一种或多种非对映异构体的非对映异构体纯的,非对映异构体富集的和等摩尔混合物(例如外消旋混合物))。
对映异构体和非对映异构体混合物可以通过公知的方法,如手性相气相层析,手性相高效液相层析,将化合物结晶为手性盐络合物或在手性溶剂中将化合物结晶为手性盐解析成它们的组分对映异构体或立体异构体。对映异构体和非对映异构体也可以通过公知的非对称合成方法从非对映异构体或对映异构体纯的中间体、试剂和催化剂获得。
当化合物用指示单一对映异构体的名称或结构指定时,除非另有指示,否则该化合物是至少60%,70%,80%,90%,99%或99.9%光学纯的(也称为“对映异构体纯的”)。光学纯度是命名或描绘的对映异构体混合物中的重量除以这两种对映异构体混合物中的总重量。
当所公开的化合物的立体化学由结构命名或描绘,并且该命名或描绘的结构涵盖超过一个立体异构体(例如,如在非对映异构体对中)时,应理解的是,包括所涵盖的立体异构体之一或涵盖的立体异构体的任何混合物。应当进一步理解,所命名或描绘的立体异构体的立体异构体纯度为按重量计至少60%,70%,80%,90%,99%或99.9%。在此种情况下,立体异构体纯度是通过由名称或结构所涵盖的立体异构体混合物中的总重量除以所有立体异构体混合物中的总重量确定的。
也涵盖任何一种此类化合物的经修饰的化合物,包括与未修饰的化合物相比具有改善的(如,增强的、更大的)药学溶解度、稳定性、生物利用性和/或治疗指数的修饰。修饰的实例包括但不限于前药衍生物和氘富集的化合物。例如:
·前药衍生物:当对受试者施用时,前药将在体内转化为本发明的活性化合物[Nature Reviews of Drug Discovery,2008,Volume 7,p255]。注意到,在多个实例中,前药自身也落入根据本发明的化合物的范围范畴内。本发明的化合物的前药可通过标准有机反应制备,例如,通过与氨甲酰化剂(如,1,1酰氧烷基氯化碳(1,1-acyloxyalkylcarbonochloridate)、碳酸对硝基苯酯(para-nitrophenyl carbonate)等)或酰化剂反应制备。制备前药的方法及策略的其它实例记载于Bioorganic and MedicinalChemistry Letters,1994,Vol.4,p.1985。
·氘富集的化合物:氘(D或2H)是氢的稳定的非放射性同位素,并且具有2.0144的原子量。氢天然作为同位素XH(氢或氕)、D(2H或氘)、及T(3H或氚)的混合物存在。氘的天然丰度是0.015%。本领域技术人员认识到在所有具有H原子的化合物中,H原子实际上以H和D的混合物表示,约0.015%是D。因此,具备已经富集至大于其天然丰度0.015%的氘含量的化合物应视为非天然的,因此相对于其非富集的对应体是新的。
应当认识到,本发明的化合物可以以盐及溶剂合物的形式存在并以此形式任选施用。本发明涵盖上述化合物及其修饰的任何药学上可接受的盐和溶剂合物。例如,根据本领域中公知的过程,将本发明的化合物转化为衍生自多种有机酸和无机酸以及有机碱和无机碱的其药学可接受的形式并以此形式使用该化合物,处于本发明的范围内。
当本发明的化合物拥有游离碱形式时,可通过使游离碱形式的化合物与药学可接受的无机酸或有机酸反应而将该化合物制备为药学可接受的酸加成盐,例如,氢卤酸盐,如盐酸盐、氢溴酸盐、氢碘酸盐;其它矿物酸,如硫酸盐、硝酸盐、磷酸盐等;以及烷基和单芳基磺酸盐如乙磺酸盐、甲苯磺酸盐和苯磺酸盐;以及其它有机酸及其相对应的盐,如醋酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸、苯甲酸盐、水杨酸盐和抗坏血酸盐。本发明的其它酸加成盐包括但不限于:己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、盐酸盐、氯苯甲酸盐、环戊基丙酸盐、双葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、延胡索酸盐、半乳糖酸盐(来自粘酸)、半乳糖醛酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、2-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、草酸盐、油酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、膦酸酯及邻苯二甲酸盐。应当理解,游离碱形式的物理性质,如在极性溶剂中的溶解度,典型地在某种程度上不同于其各自的盐形式,但用于本发明的目的时,该盐与其各自的游离碱形式等效。
当本发明的化合物拥有游离酸形式时,可通过使游离酸形式的化合物与药学可接受的无机碱或有机碱反应而制备药学可接受的碱加成盐。此类碱的实例是碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属烷氧化物,如乙醇钾和丙醇钠;以及各种有机碱,如氢氧化铵、哌啶、二乙醇胺和N-甲基谷氨酰胺。还包括本发明的化合物的铝盐。本发明的其它碱加成盐包括但不限于:铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐和锌盐。有机碱加成盐包括但不限于伯胺盐、仲胺盐、叔胺盐、包括天然存在的取代胺在内的取代胺的盐、环状胺的盐和碱性离子交换树脂的盐,如精氨酸、甜菜碱、咖啡因、氯普鲁卡因(chloroprocaine)、胆碱、N,N’-二苄基乙二胺(苄星青霉素(benzathine))、二环己基胺、二乙醇胺、2-二乙基氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺(glucamine)、葡糖胺、组氨酸、海巴明青霉素(hydrabamine)、异丙胺、利多卡因(lidocaine)、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因(procaine)、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟基甲基)甲胺(氨丁三醇)。应当理解,游离酸形式的物理性质,如在极性溶剂中的溶解度,典型地在某种程度上不同于其各自的盐形式,但用于本发明的目的时,该盐与其各自的游离酸形式等效。
在一方面,药学可接受的盐是盐酸盐、氢溴酸盐、甲磺酸盐、甲苯磺酸盐、醋酸盐、延胡索酸盐、硫酸盐、硫酸氢盐、琥珀酸盐、柠檬酸盐、磷酸盐、马来酸盐、硝酸盐、酒石酸盐、苯甲酸盐、碳酸氢盐、碳酸盐、氢氧化钠盐、氢氧化钙盐、氢氧化钾盐、氨丁三醇盐、或其混合物。
本发明的包含含有叔氮的基团的化合物可使用例如下述试剂季胺化:(C1-4)烷基卤化物,如甲基、乙基、异丙基及叔丁基的氯化物、溴化物和碘化物;硫酸二(C1-4)烷基酯,如硫酸二甲酯、硫酸二乙酯和硫酸二戊酯;烷基卤化物,如癸基、十二烷基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;以及芳基(C1-4)烷基卤化物,如苄基氯和苯乙基溴。此类盐允许制备本发明的水溶性和油溶性化合物两者。
具有叔氮原子的抗癌剂的氨氧化物,亦称氨-N-氧化物和N-氧化物,已经作为前药被研发[Mol Cancer Therapy.2004Mar;3(3):233-44]。包含叔氮原子的本发明的化合物可通过试剂,例如过氧化氢(H2O2)、Caro酸或过酸如间氯过氧苯甲酸(mCPBA)氧化以形成氨氧化物。
其中公开的化合物是bcl-2抑制剂。本发明的药物组合物包含一种或多种bcl-2抑制剂或其药学上可接受的盐,以及药学上可接受的载体或稀释剂。
“药学上可接受的载体”和“药学上可接受的稀释剂”是指有助于活性剂配制和/或向受试者施用和/或被受试者吸收的物质,并且可以被包括在本公开的组合物中而不会对受试者引起明显的不良毒理作用。药学上可接受的载体和/或稀释剂的非限制性实例包括水,NaCl,生理盐水溶液,乳酸林格氏液,生理蔗糖,生理葡萄糖,粘合剂,填充剂,崩解剂,润滑剂,包衣,甜味剂,调味剂,盐溶液(例如林格氏液),醇,油,明胶,碳水化合物,例如乳糖,直链淀粉或淀粉,脂肪酸酯,羟甲基纤维素,聚乙烯吡咯烷和色素等。可以对此类制剂进行灭菌,并且如果需要,可以与不会有害地与本文提供的化合物反应或干扰本文提供的化合物的活性的辅助剂如润滑剂,防腐剂,稳定剂,润湿剂,乳化剂,影响渗透压的盐,缓冲剂,着色剂和/或芳香族物质等混合。本领域普通技术人员将认识到其他药物赋形剂适合与公开的化合物一起使用。
本发明的药物组合物任选地包含一种或多种其药学上可接受的载体和/或稀释剂,例如乳糖,淀粉,纤维素和右旋糖。还可以包括其他赋形剂,如调味剂;甜味剂;和防腐剂,例如对羟基苯甲酸甲酯,对羟基苯甲酸乙酯,对羟基苯甲酸丙酯和对羟基苯甲酸丁酯。合适的赋形剂的更完整列表可以在Handbook of Pharmaceutical Excipients(5th Ed.,Pharmaceutical Press(2005))中找到。本领域技术人员将知道如何制备适合各种类型的施用途径的配制剂。用于选择和制备合适配制剂的常规程序和成分在例如Remington’sPharmaceutical Sciences(2003-20版)和1999年出版的The United StatesPharmacopeia:The National Formulary(USP 24NF19)中有所描述。载体、稀释剂和/或赋形剂在与药物组合物的其他成分相容且对其接受者无害的意义上是“可接受的”。
本发明的药物组合物还可以包含其它常规的无药学活性剂。一般用作载体或稀释剂的任何惰性赋形剂均可用于本发明的组合物中,如糖、多元醇、可溶性聚合物、盐和脂质。可采用的糖和多元醇包括但不限于,乳糖、蔗糖、甘露醇、及山梨醇。例示性的可采用的可溶性聚合物为聚氧乙烯、泊洛沙姆(poloxamer)、聚乙烯基吡咯烷酮、及葡聚醣。可用的盐包括但不限于氯化钠、氯化镁和氯化钙。可采用的脂质包括但不限于脂肪酸、甘油脂肪酸酯、糖脂质、及磷脂质。
此外,本发明的药物组合物可进一步包含粘合剂(如,阿拉伯胶、玉米淀粉、明胶、卡波姆、乙基纤维素、瓜尔胶、羟丙基纤维素、羟丙基甲基纤维素、聚维酮)、崩解剂(如,玉米淀粉、马铃薯淀粉、藻酸、二氧化硅、交联羧甲基纤维素钠、交聚维酮、瓜尔胶、羧基乙酸淀粉钠、Primogel)、各种pH和离子强度的缓冲剂(如,tris-HCL、醋酸盐、磷酸盐)、用以防止吸收至表面的添加剂如白蛋白或明胶、洗涤剂(如,Tween 20、Tween 80、Pluronic F68、胆汁酸盐)、蛋白酶抑制剂、表面活性剂(如,月桂基硫酸钠)、渗透促进剂、增溶剂(如,甘油、聚乙烯甘油、环糊精)、助流剂(如,胶体二氧化硅)、抗氧化剂(如,抗坏血酸、偏亚硫酸氢钠、丁酸化羟基苯甲醚)、稳定剂(如,羟丙基纤维素、羟丙基甲基纤维素)、黏度增强剂(如,卡波姆、胶体二氧化硅、乙基纤维素、瓜尔胶)、甜味剂(如,蔗糖、阿斯巴甜、柠檬酸)、芳香剂(如,薄荷油、水杨酸甲酯、或橙味剂)、防腐剂(如,硫柳汞、苯甲醇、对羟基苯甲酸酯类)、润滑剂(如,硬脂酸、硬脂酸镁、聚乙二醇、月桂基硫酸钠)、流动助剂(如,胶体二氧化硅)、增塑剂(如,对苯二甲酸二乙酯、柠檬酸三乙酯)、乳化剂(如,卡波姆、羟丙基纤维素、月桂基硫酸钠、甲基纤维素、羟乙基纤维素、羧甲基纤维素钠)、聚合物涂层(如,泊洛沙姆或泊洛沙胺)、涂层及膜形成剂(如,乙基纤维素、丙烯酸酯、聚甲基丙烯酸酯)及/或佐剂。
在一个实施方案中,药物组合物制备为具有会保护该化合物不被从身体快速清除的载体,如控释配制剂,包括植入物和微胶囊化的递送系统。可使用生物可降解的、生物相容的聚合物,如乙烯-醋酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯、及聚乳酸。制备此类配制剂的方法对于本领域技术人员是明显的。材料亦可从Alza Corporation和NovaPharmaceuticals,Inc商购。脂质体悬浮体(包括用针对病毒抗原的单克隆抗体靶向到感染细胞的脂质体)也可用作药学可接受的载体。这些可根据本领域技术人员已知的方法制备,例如如US专利号4,522,811中描述。
另外,本发明涵盖包含任何固体或液体物理形式的本发明化合物的药物组合物。例如,化合物可以是晶体形式或无定形的形式,且具有任何粒径。该颗粒可以是微粒化的或者可以是成块的微粒、粉末、油、油状悬浮体或任何其它固体或液体物理形式。
当根据本发明的化合物展现不足够的溶解度时,可使用使化合物增溶的方法。此类方法是本领域技术人员已知的,且包括但不限于,pH调节和盐形成;使用共溶剂如乙醇、丙二醇、聚乙二醇(PEG)300、PEG 400、DMA(10-30%)、DMSO(10-20%)、NMP(10-20%);使用表面活性剂如聚山梨醇酯80、聚山梨醇酯20(1-10%)、cremophor EL、Cremophor RH40、Cremophor RH60(5-10%)、Pluronic F68/Poloxamer 188(20-50%)、Solutol HS15(20-50%)、维生素ETPGS、以及d-α-生育酚PEG 1000琥珀酸酯(20-50%);使用络合作用如HPβCD和SBEβCD(10-40%);以及使用先进的途径,如胶束、聚合物的加入、纳米颗粒悬浮体、以及脂质体形成。
极其多种施用方法可与本发明的化合物联用。本发明的化合物可口服、胃肠外、腹膜内、静脉内、动脉内、透皮、舌下、肌肉内、直肠、经口含、鼻内、脂质体、经由吸入、阴道、眼内、经由局部递送(例如,通过导管或支架)、皮下、脂肪内、关节内、或鞘内施用或组合施用。根据本发明的化合物亦可以缓释剂型施用或共施用。化合物可以是气体、液体、半液体或固体形式,以适用于待使用的施用途径的模式配制。对于口服施用,适当的固体口服配制剂包括片剂、胶囊剂、丸剂、颗粒剂、微丸剂、囊剂和泡腾剂、粉末剂等。适当的液体口服配制剂包括溶液、悬浮体、分散体、乳液、油等。对于胃肠外施用,典型使用冻干粉末的重建。
如本文中使用,“酰基”指以式-C(O)-R表示的含有羰基的取代基,其中,R是H、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中,该烷基、烷氧基、碳环和杂环如本文中定义。酰基包括烷酰基(如,乙酰基)、芳酰基(如,苯甲酰基)、及杂芳酰基。
“脂肪族”指以构造碳原子的直链或支链排列为特征的部分,且可以是饱和的,或是具有一个或多个双键或三键的部分不饱和的。
术语“烷基”指含有1至20个碳原子的直链或支链烃(如,C1-C10,C1-C6)。烷基的实例包括但不限于,甲基、亚甲基、乙基、亚乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。优选地,烷基具有1至10个碳原子。更优选地,烷基具有1至4个碳原子。
术语“烯基”指含有2至20个碳原子(如,C2-C10,C2-C6)和一个或多个双键的直链或支链烃。烯基的实例包括但不限于乙烯基、丙烯基和烯丙基。优选地,烯基具有2至10个碳原子。更优选地,烯基具有2至4个碳原子。
术语“炔基”指含有2至20个碳原子(如,C2-C10,C2-C6)和一个或多个三键的直链或支链烃。炔基的实例包括但不限于乙炔基、1-丙炔基、1-丁炔基和2-丁炔基和1-甲基-2-丁炔基。优选地,炔基具有2至10个碳原子。更优选地,炔基具有2至4个碳原子。
术语“烷基氨基”指-N(R)-烷基,其中R可以是H、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基。
“烷氧基”指具有进一步烷基取代基的氧部分。
“烷氧基羰基”指附接至羰基的烷氧基。
“氧代烷基”指进一步经羰基取代的烷基。该羰基可以是醛、酮、酯、酰胺、酸或酰氯。
术语“环烷基”指具有3至30个碳原子(如,C3-C12,C3-C8,C3-C6)的饱和烃环系统。环烷基的实例包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基、及环辛基。术语“环烯基”指具有3至30个碳原子(如,C3-C12)和一个或多个双键的非芳烃环系统。实例包括环戊烯基、环己烯基、及环庚烯基。
术语“杂环烷基”指饱和或不饱和的非芳香族的5至8元的单环状、8至12元的双环状、或11至14元的三环状的环系统,该环系统具有1-4个杂原子(如,O,N,S,B,P,Si或Se),其可以是相同或不同的。杂环烷基的实例包括但不限于哌嗪基、吡咯烷基、二噁烷基、吗啉基和四氢呋喃基。
术语“杂环烯基”指非芳香族的5至8元的单环状、8至12元的双环状、或11至14元的三环状的环系统,该环系统具有一个或多个杂原子(如,O、N、S、P、B、Si或Se)和一个或多个双键。
术语“芳基”指6个碳原子的单环状、10个碳原子的双环状、14个碳原子的三环状的芳环系统。芳基的实例包括但不限于,苯基、萘基和蒽基。
术语“杂芳基”指5至8元的单环状、8至12元的双环状、或11至14元的三环状的芳香族环系统,该环系统具有一个或多个杂原子(如,O、N、S、P、或Se)。杂芳基的实例包括吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基和噻唑基。
上文提及的烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、烷基氨基、芳基和杂芳基包括取代部分和非取代部分两者。位于烷基氨基、环烷基、杂环烷基、环烯基、杂环烯基、芳基和杂芳基上的可能的取代基包括但不限于,C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、C1-C10烷基氨基、芳基氨基、羟基、卤素、氧代(O=)、硫代(S=)、硫基、硅基、C1-C10烷硫基、芳硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨基酰基、氨基硫代酰基、脒基、巯基、酰氨基、硫脲基、硫氰酸酯基、磺酰胺基、胍、脲基、氰基、硝基、酰基、硫代酰基、酰氧基、脲基、氨甲酰基、羧基和羧酸酯。另一方面,位于烷基、烯基或炔基上的可能的取代基包括除C1-C10烷基以外的上文提及的全部取代基。环烷基、环烯基、杂环烷基、杂环烯基、芳基和杂芳基也可彼此稠合。
“氨基”指进一步具有两个取代基的氮部分,其中,每个取代基具有与氮进行α键结的氢或碳原子。除非明确指出,否则本发明的含有氨基部分的化合物可包括其经保护的衍生物。用于氨基部分的适当的保护基包括乙酰基、叔丁氧羰基、苄氧羰基等。
“芳香族”指如下部分,其中构造原子构成不饱和的环系统,该环系统中所有原子均为sp2杂化,且π电子总数等于4n+2。芳香族环可以使得环原子仅为碳原子或可包括碳原子和非碳原子(见杂芳基)。
“氨甲酰基”指基团-OC(O)NRaRb,其中Ra和Rb各自独立为两个进一步的取代基,该取代基中,氢或碳原子位于氮的α位。注意,氨甲酰基部分可包括其经保护的衍生物。适用于氨甲酰基部分的保护基的实例包括乙酰基、叔丁氧羰基、苄氧羰基等。注意,未保护的衍生物和经保护的衍生物均落入本发明的范围内。
“羰基”指基团-C(O)-。注意,羰基可进一步经多种取代基取代以形成不同的羰基,包括酸、酰卤、酰胺、酯和酮。
“羧基”指基团-C(O)O-。注意,本发明的含有羧基部分的化合物可包括其经保护的衍生物,即,其中氧原子经保护基取代。适用于羧基部分的保护基包括苄基、叔丁基等。
“氰基”指基团-CN。
“甲酰基”指基团-CH=O。
“亚胺甲基”指基团–HC=NH。
“卤素”指氟、氯、溴或碘。
作为分离的基团或较大基团的一部分,“卤素取代的烷基”指经一个或多个“卤素”原子取代的“烷基”,此类术语如本申请中所定义。卤素取代的烷基包括卤代烷基、二卤代烷基、三卤代烷基、全卤代烷基等。
“羟基”指基团-OH。
“亚胺衍生物”指包含-C(=NR)-部分的衍生物,其中R包含位于该氮的α位的氢或碳原子。
“异构体”意为任何具有相同分子式,但其原子键结的特性或序列不同或其原子在空间中的排列不同的化合物。其原子在空间中的排列不同的异构体称为“立体异构体”。彼此不是镜像的立体异构体称为“非对映异构体”,而作为无法重叠的镜像的立体异构体称为“对映异构体”或有时“光学异构体”。键结有四个不同取代基的碳原子称为“手性中心”。具有一个手性中心的化合物具有两种相反手性的对映异构形式。两种对映异构形式的混合物称为“外消旋混合物”。
“硝基”指基团-NO2。
“经保护的衍生物”指化合物的衍生物,其中,反应性位点被保护基所阻断。经保护的衍生物可用于制备药物或其本身可能具有抑制剂活性。适用保护基的综合列表可见于T.W.Greene,Protecting Groups in Organic Synthesis,第3版,Wiley&Sons,1999。
术语“取代的”指原子或原子组已经作为附接至另一基团的取代基替换氢。对于芳基和杂芳基,术语“取代的”指其中此类取代被允许的任何水平的取代,即单取代、二取代、三取代、四取代或五取代。独立选择取代基,且该取代可位于任何化学上可及的位置处。术语“未取代的”指给定部分通过可用的价态可仅由氢取代基组成(未取代的)。
如果官能团描述为“任选取代”,则该官能团可以是(1)没有被取代或(2)经取代。如果官能团的碳描述为任选经一系列取代基中的一个或多个取代,则该碳上的一个或多个氢原子(只要存在,可为任何程度)可独立地及/或一起被替换为独立选定的任选的取代基。
“硫化物”意为-S-R,其中,R是H、烷基、碳环、杂环、碳环烷基或杂环烷基。具体的硫化物基团是巯基;烷基硫化物,例如,甲基硫化合物(-S-Me);芳基硫化合物,如苯基硫化合物;芳烷基硫化合物,如,苄基硫化合物。
“亚磺酰基”意为基团-S(O)-。注意,亚磺酰基可进一步经多种取代基取代以形成不同的亚磺酰基团,包括亚磺酸、亚磺酰胺、亚磺酸酯和亚砜。
“磺酰基”意为基团-S(O)(O)-。注意,磺酰基团可进一步经多种取代基取代以形成不同的磺酰基团,包括磺酸、磺酰胺、磺酸酯和砜。
“硫代羰基”意为基团-C(S)-。注意,硫代羰基可进一步经多种取代基取代以形成不同的硫代羰基,包括硫代酸、硫代酰胺、硫代酯、和硫代酮。
“动物”包括人、非人类哺乳动物(如,非人灵长动物、啮齿动物、小鼠、大鼠、仓鼠、狗、猫、兔、牛、马、绵羊、山羊、猪、鹿等)和非哺乳动物(如,鸟类等)。
如本文中使用的“生物利用度”是施用剂量的药物或药物组合物中,完整到达体循环的分数或百分比。通常,当静脉内施用药物时,其生物利用度是100%。但当经由其它途径(如,口服)施用药物时,其生物利用度下降(如,由于不完全吸收和首过代谢而造成生物利用度下降)。改善生物利用度的方法包括前药途径、盐合成、减小粒径、络合、改变物理形态、固体分散体、喷射干燥和热熔融挤出。
“疾病”具体包括动物或其部位的任何不健康状况,且包括可能由施加至该动物的医疗或兽药治疗造成或伴随医疗或兽药治疗的不健康状况,即,此类疗法的“副作用”。
“药学可接受的”指可用于制备药物组合物的通常为安全、非毒性、且既不在生物学上也不在其它方面是不希望的,且包括可为兽医学用途以及人类医药用途所接受的。
“药学可接受的盐”指本发明的化合物的如上文定义的药学可接受的有机盐或无机盐,且该盐具备所希望的药理活性。此类盐包括与无机酸或有机酸形成的酸加成盐。药学可接受的盐也包括碱加成盐,其可在存在能与无机碱或有机碱反应的酸性质子存在时形成。例示性的盐包括但不限于,硫酸盐、柠檬酸盐、醋酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、延胡索酸盐、葡糖酸盐、葡萄糖醛酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐“去铁胺(mesylate)”、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐(即,1,1’-亚甲基-双(2-羟基-3-萘甲酸盐))、碱金属(如,钠和钾)盐、碱土金属(如,镁)盐和铵盐。药学可接受的盐可牵涉纳入另一分子如醋酸根离子、琥珀酸根离子或其它抗衡离子。该抗衡离子可以是任何使母体化合物电荷稳定的有机部分或无机部分。此外,药学可接受的盐在其结构中可具有超过一个的带电原子。对于多个带电原子作为药学可接受的盐的一部分的例子,该盐可具有多个抗衡离子。因此,药学可接受的盐可具有一个或多个带电原子及/或一个或多个抗衡离子。
如国际纯化学和应用化学联合会(The International Union of Pure andApplied Chemistry)所界定,“药效团”是确保与特定生物学靶点的最优超分子相互作用并触发(或阻断)其生物学应答所必需的空间和电子特征的集合。例如,喜树碱(Camptothecin)是公知的药物拓扑替康(topotecan)和伊立替康(irinotecan)的药效团。氮芥是一系列广泛使用的氮芥药物如美法仑(Melphalan)、环磷酰胺(Cyclophosphamide)、苯达莫司汀(Bendamustine)等的药效团。
“前药”意为一种化合物,其在体内可代谢性地转化为根据本发明的活性药物。例如,包含羟基的抑制剂可以以酯的形式施用,该酯在体内可通过水解转化为羟基化合物。
“稳定性”通常指药物保留其特性而不丧失潜能的时间长度。有时这指货架期。影响药物稳定性的因素还特别包括药物的化学结构、配方中的杂质、pH、含水量、以及环境因素如温度、氧化、光和相对湿度。可通过提供适当的化学及/或晶体修饰(如,可改变水合作用动力学的表面修饰;可具有不同性质的不同晶体)、赋形剂(如,除该剂型中该活性物质外的任何物质)、封装条件、存储条件等来改善稳定性。
本文中描述的组合物的“治疗有效量”指以适用于任何医疗处置的合理的效益/风险比,对所治疗的受试者提供治疗效果的该组合物的量。该治疗效果可以是客观的(即,可通过一些测试或标志物测量)或主观的(即,受试者呈现效果的迹象或感觉)。上述组合物的有效量可以是从约0.1mg/kg至约500mg/kg的范围,优选从约0.2至约50mg/kg。有效剂量还将依据施用途径以及与其它药剂合用的可能性而改变。但应理解,本发明的组合物的每日总剂量将由主治医生在可靠医疗判断的范畴内决定。对于特定患者的具体治疗有效剂量水平将取决于多种因素,包括被治疗的病症和该病症的严重性;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康情况、性别和饮食;施用时间、施用途径、以及所采用的具体化合物的排泄速率;治疗的持续时间;与所采用的具体化合物组合使用或同时使用的药物;以及医疗领域公知的类似因素。
如本文中所用,术语“治疗”指将化合物施用于具有新生性或免疫病症、或具有其症状或素因的受试者,目的为治愈、痊愈、缓解、解除、改变、补救、减轻、改善或影响该病症、该病症的症状或该病症的素因。
术语“有效量”指在该受试者中赋予所希望的疗效所需的活性剂的量。如本领域技术人员所知,有效量可依据施用途径、赋形剂的使用、以及与其它试剂共用的可能性而改变。
“受试者”指人类和非人类动物。非人类动物的实例包括所有脊椎动物,如哺乳动物,如非人灵长动物(尤其是高级灵长动物)、非人哺乳动物、狗、啮齿动物(如,小鼠或大鼠)、豚鼠、猫、和非哺乳动物如鸟类、两栖动物、爬行动物等。在优选的实施方案中,受试者是人类。另一具体实施例中,受试者是实验动物或适合作为疾病模型的动物。
“组合疗法”包括对受试者施用本发明的受试化合物以及与该化合物进一步组合的另一生物活性成分(例如但不限于,第二种且不同的抗新生物剂)和非药物疗法(例如但不限于手术或放射治疗)。例如,本发明的化合物可以与其它药学活性化合物或非药物疗法,优选能够增强本发明化合物的效果的化合物组合使用。本发明的化合物可与其它疗法同时施用(作为单一制剂或分离的制剂)或序贯施用。通常,组合疗法设想在单个治疗周期或单个疗程中施用两种或多种药物/治疗。
在一个实施方案中,本发明的化合物与一种或多种传统化学治疗剂组合施用。传统的化学治疗剂包括肿瘤学领域中的多种治疗方法。为了缩小肿瘤,破坏手术后剩余的剩余癌细胞,诱导缓解,维持缓解和/或减轻与癌症或其治疗有关的症状,在疾病的各个阶段施用这些药剂。此类药剂的实例包括但不限于烷基化试剂,例如氮芥(例如,苯达莫司汀,环磷酰胺,美法仑,氯丁酸苄酯,异环磷酰胺),亚硝基脲(例如卡莫司汀,洛莫司汀和链佐星),亚乙基亚胺(例如塞替派,六甲基黑色素),烷基磺酸盐(例如,白消安),肼和三嗪(例如,六甲蜜胺,丙卡巴肼,达卡巴嗪和替莫唑胺)和铂基试剂(例如,卡铂,顺铂和奥沙利铂);植物生物碱,例如鬼臼毒素(例如依托泊苷和替尼泊苷(Tenisopide)),紫杉烷类(例如紫杉醇和多西他赛),长春花生物碱(例如长春新碱,长春花碱和长春瑞滨);抗肿瘤抗生素,例如色霉素(例如放线菌素D和普卡霉素),蒽环类药物(例如多柔比星,柔红霉素,表柔比星,米托蒽醌和伊达比星),以及杂类抗生素例如丝裂霉素和博来霉素;抗代谢物,例如叶酸拮抗剂(例如甲氨蝶呤),嘧啶拮抗剂(例如5-氟尿嘧啶,氟尿苷(Foxuridine),阿糖胞苷,卡培他滨和吉西他滨),嘌呤拮抗剂(例如6-巯基嘌呤和6-硫代鸟嘌呤)和腺苷脱氨酶抑制剂(例如克拉屈滨,氟达拉滨,奈拉滨(Nelarabine)和喷司他丁);拓扑异构酶抑制剂,例如拓扑异构酶I抑制剂(托泊替康,伊立替康),拓扑异构酶II抑制剂(例如安吖啶,依托泊苷,磷酸依托泊苷,替尼泊苷),以及杂类抗新生物药物,例如核糖核苷酸还原酶抑制剂(羟基脲),肾上腺皮质类固醇抑制剂(米托坦)、抗微管剂(雌莫司汀)和类维生素A(贝沙罗汀,异维A酸,维甲酸(ATRA)。
在本发明的一方面,可以将化合物与一种或多种调节与多种疾病状态有关的蛋白激酶的靶向抗癌剂组合施用。此类激酶的实例可包括但不限于ABL1、ABL2/ARG、ACK1、AKT1、AKT2、AKT3、ALK、ALK1/ACVRL1、ALK2/ACVR1、ALK4/ACVR1B、ALK5/TGFBR1、ALK6/BMPR1B、AMPK(A1/B1/G1)、AMPK(A1/B1/G2)、AMPK(A1/B1/G3)、AMPK(A1/B2/G1)、AMPK(A2/B1/G1)、AMPK(A2/B2/G1)、AMPK(A2/B2/G2)、ARAF、ARK5/NUAK1、ASK1/MAP3K5、ATM、Aurora A、Aurora B、Aurora C、AXL、BLK、BMPR2、BMX/ETK、BRAF、BRK、BRSK1、BRSK2、BTK、CAMK1a、CAMK1b、CAMK1d、CAMK1g、CAMKIIa、CAMKIIb、CAMKIId、CAMKIIg、CAMK4、CAMKK1、CAMKK2、CDC7-DBF4、CDK1-细胞周期蛋白A、CDK1-细胞周期蛋白B、CDK1-细胞周期蛋白E、CDK2-细胞周期蛋白A、CDK2-细胞周期蛋白A1、CDK2-细胞周期蛋白E、CDK3-细胞周期蛋白E、CDK4-细胞周期蛋白D1、CDK4-细胞周期蛋白D3、CDK5-p25、CDK5-p35、CDK6-细胞周期蛋白D1、CDK6-细胞周期蛋白D3、CDK7-细胞周期蛋白H、CDK9-细胞周期蛋白K、CDK9-细胞周期蛋白T1、CHK1、CHK2、CK1a1、CK1d、CK1epsilon、CK1g1、CK1g2、CK1g3、CK2a、CK2a2、c-KIT、CLK1、CLK2、CLK3、CLK4、c-MER、c-MET、COT1/MAP3K8、CSK、c-SRC、CSF1R、CTK/MATK、DAPK1、DAPK2、DCAMKL1、DCAMKL2、DDR1、DDR2、DLK/MAP3K12、DMPK、DMPK2/CDC42BPG、DNA-PK、DRAK1/STK17A、DYRK1/DYRK1A、DYRK1B、DYRK2、DYRK3、DYRK4、EEF2K、EGFR、EIF2AK1、EIF2AK2、EIF2AK3、EIF2AK4/GCN2、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHB1、EPHB2、EPHB3、EPHB4、ERBB2/HER2、ERBB4/HER4、ERK1/MAPK3、ERK2/MAPK1、ERK5/MAPK7、FAK/PTK2、FER、FES/FPS、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1/VEGFR1、FLT3、FLT4/VEGFR3、FMS、FRK/PTK5、FYN、GCK/MAP4K2、GRK1、GRK2、GRK3、GRK4、GRK5、GRK6、GRK7、GSK3a、GSK3b、Haspin、HCK、HGK/MAP4K4、HIPK1、HIPK2、HIPK3、HIPK4、HPK1/MAP4K1、IGF1R、IKKa/CHUK、IKKb/IKBKB、IKKe/IKBKE、IR、IRAK1、IRAK4、IRR/INSRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR/VEGFR2、KHS/MAP4K5、LATS1、LATS2、LCK、LCK2/ICK、LKB1、LIMK1、LOK/STK10、LRRK2、LYN、LYNB、MAPKAPK2、MAPKAPK3、MAPKAPK5/PRAK、MARK1、MARK2/PAR-1Ba、MARK3、MARK4、MEK1、MEK2、MEKK1、MEKK2、MEKK3、MELK、MINK/MINK1、MKK4、MKK6、MLCK/MYLK、MLCK2/MYLK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、MNK1、MNK2、MRCKa/、CDC42BPA、MRCKb/、CDC42BPB、MSK1/RPS6KA5、MSK2/RPS6KA4、MSSK1/STK23、MST1/STK4、MST2/STK3、MST3/STK24、MST4、mTOR/FRAP1、MUSK、MYLK3、MYO3b、NEK1、NEK2、NEK3、NEK4、NEK6、NEK7、NEK9、NEK11、NIK/MAP3K14、NLK、OSR1/OXSR1、P38a/MAPK14、P38b/MAPK11、P38d/MAPK13、P38g/MAPK12、P70S6K/RPS6KB1、p70S6Kb/、RPS6KB2、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PASK、PBK/TOPK、PDGFRa、PDGFRb、PDK1/PDPK1、PDK1/PDHK1、PDK2/PDHK2、PDK3/PDHK3、PDK4/PDHK4、PHKg1、PHKg2、PI3Ka、(p110a/p85a)、PI3Kb、(p110b/p85a)、PI3Kd、(p110d/p85a)、PI3Kg(p120g)、PIM1、PIM2、PIM3、PKA、PKAcb、PKAcg、PKCa、PKCb1、PKCb2、PKCd、PKCepsilon、PKCeta、PKCg、PKCiota、PKCmu/PRKD1、PKCnu/PRKD3、PKCtheta、PKCzeta、PKD2/PRKD2、PKG1a、PKG1b、PKG2/PRKG2、PKN1/PRK1、PKN2/PRK2、PKN3/PRK3、PLK1、PLK2、PLK3、PLK4/SAK、PRKX、PYK2、RAF1、RET、RIPK2、RIPK3、RIPK5、ROCK1、ROCK2、RON/MST1R、ROS/ROS1、RSK1、RSK2、RSK3、RSK4、SGK1、SGK2、SGK3/SGKL、SIK1、SIK2、SLK/STK2、SNARK/NUAK2、SRMS、SSTK/TSSK6、STK16、STK22D/TSSK1、STK25/YSK1、STK32b/YANK2、STK32c/YANK3、STK33、STK38/NDR1、STK38L/NDR2、STK39/STLK3、SRPK1、SRPK2、SYK、TAK1、TAOK1、TAOK2/TAO1、TAOK3/JIK、TBK1、TEC、TESK1、TGFBR2、TIE2/TEK、TLK1、TLK2、TNIK、TNK1、TRKA、TRKB、TRKC、TRPM7/CHAK1、TSSK2、TSSK3/STK22C、TTBK1、TTBK2、TTK、TXK、TYK1/LTK、TYK2、TYRO3/SKY、ULK1、ULK2、ULK3、VRK1、VRK2、WEE1、WNK1、WNK2、WNK3、YES/YES1、ZAK/MLTK、ZAP70、ZIPK/DAPK3、KINASE、MUTANTS、ABL1(E255K)、ABL1(F317I)、ABL1(G250E)、ABL1(H396P)、ABL1(M351T)、ABL1(Q252H)、ABL1(T315I)、ABL1(Y253F)、ALK(C1156Y)、ALK(L1196M)、ALK(F1174L)、ALK(R1275Q)、BRAF(V599E)、BTK(E41K)、CHK2(I157T)、c-Kit(A829P)、c-KIT(D816H)、c-KIT(D816V)、c-Kit(D820E)、c-Kit(N822K)、C-Kit(T670I)、c-Kit(V559D)、c-Kit(V559D/V654A)、c-Kit(V559D/T670I)、C-Kit(V560G)、c-KIT(V654A)、C-MET(D1228H)、C-MET(D1228N)、C-MET(F1200I)、c-MET(M1250T)、C-MET(Y1230A)、C-MET(Y1230C)、C-MET(Y1230D)、C-MET(Y1230H)、c-Src(T341M)、EGFR(G719C)、EGFR(G719S)、EGFR(L858R)、EGFR(L861Q)、EGFR(T790M)、EGFR、(L858R,T790M)、EGFR(d746-750/T790M)、EGFR(d746-750)、EGFR(d747-749/A750P)、EGFR(d747-752/P753S)、EGFR(d752-759)、FGFR1(V561M)、FGFR2(N549H)、FGFR3(G697C)、FGFR3(K650E)、FGFR3(K650M)、FGFR4(N535K)、FGFR4(V550E)、FGFR4(V550L)、FLT3(D835Y)、FLT3(ITD)、JAK2(V617F)、LRRK2(G2019S)、LRRK2(I2020T)、LRRK2(R1441C)、p38a(T106M)、PDGFRa(D842V)、PDGFRa(T674I)、PDGFRa(V561D)、RET(E762Q)、RET(G691S)、RET(M918T)、RET(R749T)、RET(R813Q)、RET(V804L)、RET(V804M)、RET(Y791F)、TIF2(R849W)、TIF2(Y897S)和TIF2(Y1108F)。
在本发明的另一方面,本发明化合物可以与一种或多种调节非激酶生物学靶标,途径或过程的靶向抗癌剂联合给药。此类靶途径或过程包括但不限于热激蛋白(例如HSP90),聚ADP(二磷酸腺苷)-核糖聚合酶(PARP),缺氧诱导因子(HIF),蛋白酶体,Wnt/Hedgehog/Notch信号传导蛋白,TNF-α,基质金属蛋白酶,法呢基转移酶,凋亡途径(例如Bcl-xL,Bcl-2,Bcl-w),组蛋白脱乙酰基酶(HDAC),组蛋白乙酰基转移酶(HAT)和甲基转移酶(例如组蛋白赖氨酸甲基转移酶,组蛋白精氨酸甲基转移酶,DNA甲基转移酶等)和其他免疫疗法(例如抗PD1,抗PDL1,抗CTLA4,CAR-T,IDO,A2A拮抗剂等)。
在本发明的另一方面,将本发明的化合物与一种或多种其他抗癌剂组合施用,所述其他抗癌剂包括但不限于基因疗法,RNAi癌症疗法,化学保护剂(例如,氨磺汀(amfostine),美司钠,右雷佐生),抗体缀合物(例如brentuximab vedotin,ibritumomabtioxetan),癌症免疫疗法(例如白介素-2),癌症疫苗(例如sipuleucel-T)或单克隆抗体(例如贝伐单抗(Bevacizumab),阿仑珠单抗(Alemtuzumab),利妥昔单抗,曲妥珠单抗等)。
在本发明的另一方面,主题化合物与放射疗法或手术组合施用。放射通常在内部(在癌症部位附近植入放射性物质)或从使用光子(X射线或γ射线)或粒子放射的机器外部传递。在组合疗法进一步包括放射治疗的情况下,可以在任何合适的时间进行放射治疗,只要获得了由治疗剂和放射治疗的组合的共同作用产生的有益效果即可。例如,在适当的情况下,当从治疗剂的施用暂时去除放射治疗时,可能直到几天甚至几周,仍可获得有益效果。
在某些实施方案中,本发明的化合物与放射疗法,手术或抗癌剂中的一种或多种组合施用,所述放射治疗剂,手术或抗癌剂包括但不限于DNA破坏剂,抗代谢物,拓扑异构酶抑制剂,抗微管剂,激酶抑制剂,表观遗传剂,HSP90抑制剂,PARP抑制剂和靶向VEGF,HER2,EGFR,CD50,CD20,CD30,CD33等的抗体。
在某些实施方案中,本发明的化合物与下列一种或多种组合施用:阿巴瑞克、醋酸阿比特龙、阿地白介素、阿仑珠单抗、六甲蜜胺、阿那曲唑、天冬酰胺酶、苯达莫司汀、贝伐单抗、贝沙罗汀、比卡鲁胺、博来霉素、硼替佐比(bortezombi)、brentuximab vedotin、白消安、卡培他滨、卡铂、卡莫司汀、西妥昔单抗、苯丁酸氮芥、顺铂、克拉屈滨、氯法拉滨、氯米芬、克唑替尼、环磷酰胺、达沙替尼、柔红霉素脂质体、地西他滨、地加瑞克(degarelix)、地尼白介素2(denileukin diftitox)、地尼白介素2、地诺单抗(denosumab)、多西他赛、多柔比星、多柔比星脂质体、表柔比星、甲磺酸艾日布林(eribulin mesylate)、厄洛替尼、雌莫司汀、磷酸依托泊苷、依维莫司、依西美坦、氟达拉滨、氟尿嘧啶、福莫司汀、氟维司群、吉非替尼、吉西他滨、gemtuzumab ozogamicin、醋酸戈舍瑞林、醋酸组氨瑞林、羟基脲、ibritumomab tiuxetan、伊达比星、异环磷酰胺、甲磺酸伊马替尼、干扰素alfa 2a、ipilimumab、ixabepilone、二苯磺酸拉帕替尼(lapatinib ditosylate)、来那度胺、来曲唑、亚叶酸钙、乙酸亮丙瑞林、左旋咪唑、洛莫司汀、氮芥、美法仑、甲氨蝶呤、丝裂霉素C、米托蒽醌、奈拉滨(nelarabine)、尼洛替尼(nilotinib)、奥沙利铂、紫杉醇、紫杉醇蛋白结合颗粒、帕米膦酸(pamidronate)、帕尼单抗(Panitumumab)、培门冬酶、PEG干扰素alfa-2b、培美曲塞二钠、喷司他丁、雷洛昔芬、利妥昔单抗、索拉非尼、链佐星、马来酸舒尼替尼、他莫昔芬、西罗莫司(temsirolimus)、替尼泊苷、沙利度胺、托瑞米芬、托西莫单抗、曲妥珠单抗、维甲酸、乌拉莫司汀、凡德他尼(Vandetanib)、威罗菲尼(vemurafenib)、长春瑞滨、唑来磷酸、派姆单抗(Pembrolizumab)、纳武单抗(nivolumab)、阿特珠单抗(atezolizumab)、度伐单抗(durvalumab)、阿维单抗(avelumab)、tisagenlecleucel、放射疗法或手术。
本发明进一步提供了用于预防或治疗新生性疾病或自身免疫性疾病的方法。在一个实施方案中,本发明涉及在需要治疗的受试者中治疗新生性疾病或自身免疫疾病的方法,该方法包括对所述受试者施用治疗有效量的本发明化合物。在一个实施方案中,本发明进一步提供了本发明的化合物在制备用于中止或减少新生性疾病或自身免疫性疾病的药物中的用途。
在某些实施方案中,新生性疾病是肺癌、头颈癌、中枢神经系统癌、前列腺癌、睾丸癌、结肠直肠癌、胰腺癌、肝癌、胃癌、胆道癌、食道癌、胃肠道间质瘤、乳腺癌、宫颈癌、卵巢癌、子宫癌、白血病、淋巴瘤、多发性骨髓瘤、黑素瘤、基底细胞癌、鳞状细胞癌、膀胱癌、肾癌、肉瘤、间皮瘤、胸腺瘤、骨髓增生异常综合症或骨髓增生性疾病。
可以使用根据本发明的化合物和组合物影响的自身免疫疾病包括但不限于变态反应、阿尔茨海默氏病、急性播散性脑脊髓炎、艾迪生(Addison)氏病、强直性脊柱炎、抗磷脂抗体综合征、哮喘、动脉粥样硬化、自身免疫性溶血性贫血、自身免疫性溶血和血小板减少状态、自身免疫性肝炎、自身免疫性内耳疾病、大疱性类天疱疮、乳糜泻、chagas病、慢性阻塞性肺疾病、慢性特发性血小板减少性紫癜(ITP)、churg-strauss综合征、克罗恩氏病、皮肌炎、1型糖尿病、子宫内膜异位症、肺出血肾炎综合征(Goodpasture’ssyndrome)(及相关的肾小球肾炎和肺出血)、格雷夫斯病(graves’disease)、格-巴二氏综合征(guillain-barrésyndrome)、桥本病、化脓性汗腺炎、特发性血小板减少性紫癜、间质性膀胱炎、肠易激综合征、红斑狼疮、硬斑病、多发性硬化、重症肌无力、发作性睡病、神经性肌强直、帕金森氏病、寻常型天疱疮、恶性贫血、多肌炎、原发性胆汁性肝硬化、银屑病、银屑病关节炎、类风湿性关节炎、精神分裂症、感染性休克、硬皮病、斯耶格伦病(Sjogren'sdisease)、系统性红斑狼疮(及相关肾小球肾炎)、颞动脉炎、移植器官的器官移植物排斥和超急性排斥、血管炎(与ANCA相关的血管炎病(vasculitides)和其他血管炎病)、白癜风和韦格纳肉芽肿病。
应理解,本发明并不限于本文中显示和描述的具体实施方案,可做出多种改变和修饰而不悖离由权利要求书所界定的本发明的精神和范畴。
根据本发明的化合物可根据多种方案合成。必要的起始材料可通过标准有机化学过程获得。联系下述代表性的合成方案和实施例,可更好地理解本发明的化合物和过程,这些方案和实施例仅用作例示而非限制本发明的范围。对于所公开的实施方案的各种改变和修饰对于该领域技术人员是显而易见的,且可做出改变和修饰,包括但不限于与化学结构、取代基、衍生物、及/或本发明的方法相关的改变和修饰,而不悖离本发明的精神和所附权利要求书的范围。
合成中间体的典型方法记载于下文方案1:通用方案1中的R1、R2、m和n与上文发明概述部分中描述的那些相同。/>
在方案1中,合适的酮起始材料1-1可以与三溴化磷(tribromophosphine)反应以形成醛中间体1-2,其可以与Boc保护的哌嗪偶联以形成中间体1-3。此后,1-3会经由Suzuki反应与合适的苯基硼酸偶联以形成中间体1-4,接着进行脱boc(de-boc)过程以产生关键的中间体1-5。
合成中间体(其中R5是NO2)的典型方法记载于下文方案2中。通用方案2中的R4、R5、L和R6与上文发明概述部分中描述的那些相同。
方案2
在方案2中,起始材料2-1与合适的醇或胺反应,将产生2-2。
合成的典型方法记载于下文方案3中。在方案3中,中间体3-6是商品化的。3-6的游离NH的保护产生3-7,其经由Buckwald偶联和亲核芳香取代转化成3-8。双重脱保护给出3-9,其被O-烷基化以提供酯3-10,随后进行环闭合以形成3-11。3-11的还原产生中间体3-12。
方案3
合成(其中R9和k与上文发明概述部分中描述的那些相同)的典型方法记载于下文方案3-2(方法A)、3-3(方法B)、3-4(方法C)中。
方法A
方案3-2
在方案3-2中,商品化起始材料3-2-1的游离NH的保护产生3-2-2,其经由亲核芳香族取代(PG=Boc,Ts)转化成3-2-3。3-2-3经由Buchwald偶联进行环闭合以给出3-2-4,其被脱保护以提供中间体3-2-5。
方法B
方案3-3
在方案3-3中,商品化起始材料3-3-1的游离NH的保护产生3-3-2,其经由亲核芳香族取代转化成3-3-3。脱保护提供3-3-4,随后进行Buchwald环闭合以产生中间体3-3-5。
方法C
方案3-4
在方案3-4中,商品化起始材料3-4-1的游离NH的保护产生3-4-2,其经由亲核芳香族取代转化成3-4-4,并且随后进行Buchwald或Ullmann偶联。3-4-4的Mitsunobu反应给出3-4-5,其被脱保护以产生中间体3-4-6。
合成(其中R9和k与上文发明概述部分中描述的那些相同)的典型方法记载于下文方案3-5(方法A)中。
方法A
方案3-5
在方案3-5中,商品化起始材料3-5-1的游离NH的保护产生3-5-2,其经由亲核芳香族取代(PG=Boc,Ts)转化成3-5-3。3-5-3经由Buchwald偶联进行环闭合以给出3-5-4,其被脱保护以提供中间体3-5-5。
合成(其中R9和k与上文发明概述部分中描述的那些相同)的典型方法记载于下文方案3-8中。/>
方案3-8
在方案3-8中,3-8-1(其从方案3-5,3-6,3-7合成)的硫醚N-氧化与m-CPBA反应以形成3-8-2。
(其中k与上文发明概述部分中描述的那些相同)中间体可以通过与方案3、方案3-2(方法A)、3-3(方法B)、3-4(方法C)、方案3-5和方案3-8相似的路径制备。
(其中Q是6元环,R7、R8、R9、Y、W、W1和k与上文发明概述部分中描述的那些相同)的其它中间体可以通过与方案3、方案3-2(方法A)、3-3(方法B)、3-4(方法C)、方案3-5、和方案3-8相似的路径制备。
合成式(D)化合物(其中Z2是O)的典型方法记载于方案I:
在方案I中,中间体1-5经历用选择的对氟-2-溴-苯甲酸盐的亲核芳香族取代以给出I-2。I-2与合适的胺中间体的Buckwald偶联产生I-3。序贯地将I-3用TFA脱保护以除去SEM基团并且用NaOH脱保护以除去酯基团,产生游离羧酸中间体I-5。I-5与2-2的偶联提供具有式(D)的最终产物。
具有不同Z的式(D)的化合物可以通过使用合适的起始材料和中间体通过与通用方案I相似的方法制备。
式(C)、(B)和(A)的化合物可以通过使用合适的起始材料和中间体通过与通用方案I相似的方法制备。
联系下述实施例,可更好地理解本发明的化合物和过程,所述实施例意图仅用作例示而非限制本发明的范围。对于所公开的实施方案的各种改变和修饰对于本领域技术人员是显而易见的,且可做出改变和修饰,包括但不限于与化学结构、取代基、衍生物、及/或本发明的方法相关的改变和修饰,而不悖离本发明的精神和所附权利要求书的范围。
若呈现NMR数据,则1H谱在XL400(400MHz)上获得并且以来自Me4Si的ppm低磁场报告,在括号中指示质子数、多重态和以赫兹计的偶联常数。若呈现HPLC数据,则使用Agilent1100系统进行分析。若呈现LC/MS数据,则使用Applied Biosystems API-100质谱仪和Shimadzu SCL-10A LC柱进行分析。
实施例1-1:制备1-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪
合成2-溴-4,4-二甲基环己-1-烯甲醛(2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde)2:将无水氯仿(57ml)和无水N,N-二甲基甲酰胺(9mL)的溶液在氮气下冷却到约3℃(内部温度),之后以一定的速率逐滴引入三溴化磷(10mL,0.1mol),使得将反应维持于约3℃。在完成添加后,允许反应缓慢温热到约10℃,然后将温度提高到70℃,在此将其维持30min。将反应冷却到室温并且在20分钟内缓慢添加3,3-二甲基环己酮1(5g,0.04mol)。在完成反应后,将反应温热到70℃,并且将其搅拌1.5h。然后,将混合物冷却到0℃,并且缓慢添加4M乙酸钠溶液(53ml)。使用5M NaOH溶液将所得溶液的pH调节到约7,然后用庚烷(100mLx3)提取混合物。将组合的有机级份干燥(Na2SO4),过滤,并且在减压下浓缩以给出2-溴-4,4-二甲基环己-1-烯甲醛2(4g,49%),为黄色油。
合成2-(4-氯苯基)-4,4-二甲基环己-1-烯甲醛3:对室温的1,4-二噁烷中的2-溴-4,4-二甲基环己-1-烯甲醛2(5g,0.023mol)和4-氯苯基硼酸(3.6g,0.023mol)脱气溶液(50mL)添加2M Na2CO3溶液(20.4ml)。将氮气起泡到混合物2min,然后添加PdCl2(dppf)(0.5g)。将反应烧瓶加热到120℃,在此将其维持3h。此时间后,将悬浮液冷却到室温,并且过滤通过Celite。将收集的固体用另外的二氯甲烷清洗,并且在减压下浓缩组合的滤液和清洗液。通过用PE:EA=20:1在硅土上的柱层析的纯化给出2-(4-氯苯基)-4,4-二甲基环己-1-烯甲醛3(3g,53%),为白色固体。MS:249[M+H]+
合成(2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲醇4:将MeOH中的2-(4-氯苯基)-4,4-二甲基环己-1-烯甲醛3(20g,80.6mmol)溶液(100mL)冷却到0℃,以一定的比例对反应逐份添加NaBH4(3.1g,80.6mmol),使得将反应维持于0~5℃。添加后,于0℃将混合物搅拌1h。将水缓慢添加到混合物,并且用EA(200mL x3)提取,用卤水清洗有机层,用Na2SO4干燥,过滤,并且在减压下浓缩以给出(2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲醇4(15g,75%),为白色固体。MS:233[M+H-H2O]+
合成1-(2-(溴甲基)-5,5-二甲基环己-1-烯基)-4-氯苯5:将Et2O中的(2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲醇4(15g,0.060mol)溶液(300ml)冷却到0℃,之后对混合物逐滴添加三溴化磷(7.5mL),添加后,将混合物搅拌1h,于0℃达90分钟。对反应混合物添加H2O,之后用EA提取。将有机层用饱和的NaHCO3溶液和卤水清洗,并且用Na2SO4干燥,过滤并且在减压下浓缩以给出1-(2-(溴甲基)-5,5-二甲基环己-1-烯基)-4-氯苯5(18g,96%),为无色油。
合成叔丁基4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-羧化物:对室温的二氯甲烷中的1-溴-2-(溴甲基)-5,5-二甲基环己-1-烯5(21g,0.067mol)和叔丁基哌嗪-1-羧化物(12.4g,0.067mol)溶液(200ml)添加TEA(12.2g,0.12mol)。将反应搅拌2h。在减压下浓缩反应混合物以给出粗产物。通过用PE:EA=20:1在硅土上的柱层析纯化提供叔丁基4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯yl)甲基)哌嗪-1-羧化物6(21g,75%)。
合成盐酸1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪:对MeOH中的叔丁基4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪-1-羧化物6(30g,0.072mol)溶液(20ml)添加浓HCl(50mL)。将反应搅拌24小时,然后在减压下浓缩。添加饱和Na2CO3溶液以调节pH至约8-9,并且用二氯甲烷提取混合物(x2)。将组合的提取物用卤水清洗,干燥(Na2SO4),过滤并且在加压下浓缩。将油产物用MeOH/HCl(g)(3M,500mL)处理,搅拌1小时,然后在减压下浓缩以得到产物盐酸1-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)甲基)哌嗪IM-14-1(23g,83%).MS:319[M+H]+ 1H NMR(400MHz,DMSO)δ11.51(s,1H),9.60(s,1H),9.18(s,1H),7.45(d,J=8.2Hz,2H),7.15(d,J=8.0Hz,2H),3.43(s,8H),2.84(s,2H),2.39(s,2H),2.03(s,2H),1.45(t,J=6.0Hz,2H),0.96(s,6H)。
实施例1-2:制备3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺
对500mL装备有机械搅拌器的三颈RB烧瓶加载4-氯-3-硝基苯磺酰胺(23.7g,100mmol)、DIPEA(12.9g,100mmol)、(四氢-2H-吡喃-4-基)甲胺(11.5g,100mmol)和乙腈(200mL)。将反应混合物调节到内部温度80℃,并且搅动不小于12小时。将产物溶液冷却到40℃,并且搅拌不小于1小时,直至观察到沉淀物。将产物浆体进一步冷却到20℃。在不小于1小时内将水(80mL)缓慢加载,并且将混合物冷却到10℃,并且搅拌不小于2小时,之后通过过滤收集。用乙腈:水的1:1混合物(40mL)清洗湿饼。用水(80mL)于40℃将湿饼漂洗不小于1小时,之后通过过滤收集。用水(20mL)漂洗湿饼,于75℃在真空下干燥以给出3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(24.5g,78%),为橙色固体。1H NMR(400MHz,DMSO)δ8.60(t,J=5.9Hz,1H),8.48(d,J=2.2Hz,1H),7.84(dd,J=9.2,2.0Hz,1H),7.54–7.18(m,3H),3.86(dd,J=11.3,3.2Hz,2H),3.35(s,2H),3.27(t,J=10.9Hz,2H),1.92(ddd,J=11.2,7.4,3.9Hz,1H),1.62(d,J=11.4Hz,2H),1.27(qd,J=12.3,4.4Hz,2H)。
实施例1-3:制备3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺
将盐酸(4-氟噁烷-4-基)甲胺(500mg,2.95mmol,1.00当量)、4-氟-3-硝基苯-1-氨苯磺胺(650mg,2.95mmol,1.00当量)、四氢呋喃(15mL)、Cs2CO3(2.8g,8.59mmol,3.00当量)置于50-mL圆底烧瓶中。在油浴中于50℃将所得的溶液搅拌14h。将反应混合物冷却到室温。将所得的混合物过滤,并且在真空下浓缩。用乙酸乙酯/石油醚(4:1)将残留物应用到硅胶柱上。这产生650mg(66%)4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯-1-苯磺酰胺,为黄色固体。LCMS(ES,m/z):M+1:334.H-NMR:(300MHz,DMSO,ppm):δ8.58(t,J=6.3Hz,1H),8.49(d,J=2.1Hz,1H),7.90–7.80(m,1H),7.44(d,J=9.3Hz,1H),7.34(s,2H),3.87–3.70(m,4H),3.61–3.50(m,2H),1.95–1.70(m,4H)。
实施例1-4:用于合成6-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,2,3,6-四氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪的改善方法
将6-氟吡啶-2-胺(11.2g,99.91mmol,1.00当量)、CH3CN(100mL)、NBS(21.4g,120.24mmol,1.20当量)置于250-mL 3颈圆底烧瓶中。将所得的溶液于室温搅拌过夜。然后,通过添加200mL水淬灭反应。将所得的溶液用3x100mL乙酸乙酯提取,并且组合有机层。将所得的混合物用3x100mL卤水清洗。通过无水硫酸钠干燥混合物,然后过滤,并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:5)将此残留物应用到硅胶柱上。这产生12g(63%)5-溴-6-氟吡啶-2-胺,为白色固体。LCMS(ES,m/z):M+1:191,193。
将AcOH(1000mL)中的5-溴-6-氟吡啶-2-胺(110g,575.91mmol,1.00当量),碘(硫烷基)胺(142.5g,633.33mmol,1.10当量)置于2000-mL 4颈圆底烧瓶中。将所得的溶液于室温搅拌过夜。然后通过添加3000mL水淬灭反应。通过过滤收集固体。这产生170g(93%)5-溴-6-氟-3-碘吡啶-2-胺,为白色固体。H-NMR:(CDCl3,300MHz)δ:7.98(d,J=14.4Hz,1H),4.94-5.00(bs,2H)。
将四氢呋喃中的5-溴-6-氟-3-碘吡啶-2-胺(170g,536.45mmol,1.00当量)溶液(1500mL)、CuI(10.2g,53.56mmol,0.10当量)、TEA(500mL)、二氯钯;二(三苯基磷烷)(11.2g,15.96mmol,0.03当量)、乙基(乙炔基)二甲基硅烷(63g,561.27mmol,1.20当量)置于3000-mL 3颈圆底烧瓶中。将所得的溶液于室温搅拌1过夜。然后淬灭反应通过添加2000mL水。将所得的溶液用3x1000mL乙酸乙酯提取并且组合有机层。用3x1000mL卤水清洗所得的混合物。用无水硫酸钠干燥混合物,然后过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:1)将残留物应用到硅胶柱上。这产生120g(78%)5-溴-6-氟-3-[2-(三甲基甲硅烷基)乙炔基]吡啶-2-胺,为黄色油。LCMS(ES,m/z):M+1:289,287
将二氯甲烷中的5-溴-6-氟-3-[2-(三甲基甲硅烷基)乙炔基]吡啶-2-胺(84g,292.48mmol,1.00当量)溶液(1000mL),吡啶(57.8g,730.72mmol,2.50当量)置于2000-mL4-颈圆底烧瓶中。这继之以在0度搅拌的情况下逐滴添加氯化乙酰(50.2g,639.51mmol,2.20当量)。将所得的溶液于室温搅拌过夜。然后通过添加1000L水淬灭反应。将所得的混合物用2x1000mL水清洗。用无水硫酸钠干燥混合物并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:10)将残留物应用到硅胶柱上。这产生80g(83%)N-[5-溴-6-氟-3-[2-(三甲基甲硅烷基)乙炔基]吡啶-2-基]乙酰胺,为白色固体。LC-MS:(ES,m/z):M+1=331,R,T=1.669min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度
将四氢呋喃中N-[5-溴-6-氟-3-[2-(三甲基甲硅烷基)乙炔基]吡啶-2-基]乙酰胺(80g,242.98mmol,1.00当量)溶液(300mL),TBAF(四氢呋喃中1M)(729mL,3.00当量)置于2000-mL圆底烧瓶中。于70度将所得的溶液搅拌12h。将反应混合物冷却到室温。在真空下浓缩所得的混合物。然后通过添加500mL水淬灭反应。将所得的溶液用3x300mL乙酸乙酯提取并且组合有机层。将所得的溶液用3x300mL卤水清洗。用无水硫酸钠干燥混合物并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-4:1)将残留物应用到硅胶柱上。这产生15g(29%)5-溴-6-氟-1H-吡咯并[2,3-b]吡啶,为白色固体。LC-MS:(ES,m/z):M+1=213,R,T=1.451min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度
将N,N-二甲基甲酰胺中的5-溴-6-氟-1H-吡咯并[2,3-b]吡啶(15g,69.76mmol,1.00当量)溶液(150mL)置于用惰性氮气气氛扫气并维持的250-mL 3-颈圆底烧瓶中。这继之以于0度按份添加氢化钠(4.2g,175.00mmol,1.50当量)。在0.5h搅拌后,在0度搅拌的情况下对此逐滴添加SEMCl(14g,84.34mmol,1.20当量)。允许所得的溶液在搅拌的情况下在室温再反应3h。然后通过添加300mL水淬灭反应。将所得的溶液用3x200mL乙酸乙酯提取并且组合有机层。将所得的混合物用3x200mL卤水清洗。用无水硫酸钠干燥混合物并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:10)将残留物应用到硅胶柱上。这产生15g(62%)5-溴-6-氟-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶,为黄色油。H-NMR-:(CDCl3,300MHz)δ:8.19(d,J=8.7Hz,1H),7.37(d,J=3.6Hz,1H),6.54(d,J=3.6Hz,1H),5.64(s,2H),3.58(t,J=8.1Hz,2H),0.98-0.93(t,J=8.1Hz,2H),0.00(s,9H)。用具有BBOF探头的BrukerAvanceIII HD 300MHz完成NMR谱的测量。
将二噁烷中的5-溴-6-氟-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶(6.9g,19.98mmol,1.00当量)溶液(70mL)、t-BuOK(6.84g,60.96mmol,3.00当量)、x-antphos(2.3g,3.98mmol,0.20当量)、Pd2(dba)3.CHCl3(1.9g,0.10当量)、二苯甲酮亚胺(4.32g,23.84mmol,1.20当量)置于250-mL圆底烧瓶中。于100℃将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:20)将残留物应用到硅胶柱上。这产生3.6g(粗)6-(叔-丁氧基)-N-(二苯基亚甲基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-5-胺,为白色油。LC-MS-:(ES,m/z):M+1=500。
将二噁烷中的6-(叔-丁氧基)-N-(二苯基亚甲基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-5-胺(3.6g,7.20mmol,1.00当量)溶液(15mL),二噁烷中的4M HCl(20mL)置于50-mL圆底烧瓶中。于室温将所得的溶液搅拌2h。然后通过添加50mL饱和碳酸氢钠淬灭反应。通过过滤收集固体。这产生1g(50%)5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-醇,为白色固体。LC-MS:(ES,m/z):M+1=280,R,T=0.811min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度
将CH3CN中的5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-醇(1g,3.58mmol,1.00当量)溶液(50mL),Cs2CO3(1.75g,5.37mmol,1.50当量),2-氯乙酸乙酯(438mg,3.57mmol,1.00当量)置于100-mL圆底烧瓶中。于70度将所得的溶液搅拌2h。将反应混合物冷却到室温。然后通过添加50mL水淬灭反应。将所得的溶液用3x50mL乙酸乙酯提取并且组合有机层。将所得的混合物用3x50mL卤水清洗。用无水硫酸钠干燥混合物,然后过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:1)将残留物应用到硅胶柱上。这产生1g(76%)乙基2-[(5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-基)氧]乙酸酯,为白色固体。LC-MS:(ES,m/z):M+1=366。
将乙醇中的乙基2-[(5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-基)氧]乙酸酯(1g,2.74mmol,1.00当量)溶液(20mL),Cs2CO3(1.78g,5.46mmol,2.00当量)置于100-mL圆底烧瓶中。在回流下将所得的溶液搅拌过夜。将反应混合物冷却到室温。将所得的混合物过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:2)将残留物应用到硅胶柱上。这产生400mg(46%)4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮,为白色固体。LC-MS:(ES,m/z):M+1=320。
将四氢呋喃中的4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮(400mg,1.25mmol,1.00当量)溶液(mL)置于用惰性氮气气氛扫气并维持的25-mL圆底烧瓶中。这继之以于-78度按份添加LiAlH4(95mg,2.50mmol,2.00当量)。将所得的溶液于室温搅拌4h。然后通过添加20mL水淬灭反应。将固体过滤出来。将所得的溶液用3x20mL乙酸乙酯提取并且组合有机层。将所得的混合物用3x20mL卤水清洗。用无水硫酸钠干燥混合物并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:1)将残留物应用到硅胶柱上。这产生180mg(47%)4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为褐色油。H-NMR:(CDCl3,300MHz)δ:7.36(s,1H),7.28(s,1H),7.25(d,J=3.3Hz,1H),6.31(d,J=3.3Hz,1H),5.58(s,2H),4.48-4.52(m,2H),3.72-3.60(m,2H),3.60-3.52(m,2H),0.92-0.87(m,2H),0.00(s,9H)。
实施例2:通过使用上述实施例1-4的中间体制备NW-4-8,其公开于我们先前的申请WO/2017/132474。
将DMA中的1-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪(15.09g,47.32mmol,1.00当量)溶液(150mL)、DIEA(12.9g,99.81mmol,2.00当量)、2-溴-4-氟苯甲酸甲酯(11.6g,49.78mmol,1.00当量)置于250-mL圆底烧瓶中。于100度将所得的溶液搅拌12h。将反应混合物冷却到室温。然后通过添加50mL水淬灭反应。将所得的溶液用3x100mL乙酸乙酯提取并且组合有机层。将所得的混合物用3x100mL卤水清洗。用无水硫酸钠干燥混合物,然后过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:5)将残留物应用到硅胶柱上。这产生7g(粗)2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯,为黄色油。LC-MS(ES,m/z):M+1=533,531。
将二噁烷中的4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯(175mg,0.57mmol,1.00当量)溶液(10mL)、Cs2CO3(560mg,1.72mmol,3.00当量)、XantPhos Pd G2(CAS:1375325-77-1)(53mg,0.06mmol,0.10当量)、2-溴-4-(4-[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基哌嗪-1-基)苯甲酸甲酯(334.7mg,0.63mmol,1.10当量)置于40-mL圆底烧瓶。于110度将所得的溶液搅拌2h。将反应混合物冷却到室温。将固体过滤出来。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生200mg(46%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基)苯甲酸甲酯,为黄色油。LC-MS:(ES,m/z):M+1=756,R,T=1.252min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度。
将四氢呋喃中的4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基)苯甲酸甲酯(200mg,0.26mmol,1.00当量)溶液(20mL)、TBAF(3mg,0.01mmol)、乙烷-1,2-二胺(3mL)置于50-mL圆底烧瓶。于60度将所得的溶液搅拌24h。将反应混合物冷却到室温。然后通过添加30mL水淬灭反应。用2x30mL乙酸乙酯将所得的溶液提取并且组合有机层。用2x30mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:2)将残留物应用到硅胶柱上。这产生90mg(54%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸甲酯,为黄色固体。LC-MS(ES,m/z):M+1=626,R,T=1.052min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度。
将四氢呋喃/MeOH/H2O(2/2/2mL)中的4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸甲酯(90mg,0.14mmol,1.00当量)溶液,氢氧化钠(23mg,0.57mmol,4.00当量)置于8-mL圆底烧瓶。于60度将所得的溶液搅拌过夜。将反应混合物冷却到室温。然后通过添加5mL水淬灭反应。用氯化氢(1mol/L)将溶液的pH值调节至6。用2x10mL乙酸乙酯将所得的溶液提取并且组合有机层。用3x10mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:1)将残留物应用到硅胶柱上。这产生70mg(80%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸,为黄色固体。
LC-MS(ES,m/z):M+1=612,R,T=1.005min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度。
将二氯甲烷中的4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸(35mg,0.06mmol,1.00当量)溶液(5mL),4-二甲基氨基吡啶(27.8mg,0.23mmol,4.00当量),3-硝基-4-[(噁烷-4-yl甲基)氨基]苯-1-磺酰胺(21.7mg,0.07mmol,1.20当量),EDCI(22mg,0.11mmol,2.00当量)置于8-mL圆底烧瓶中。将所得的溶液于室温搅拌过夜。在真空下浓缩所得的混合物。通过Prep-HPLC用以下条件纯化粗产物(Waters-2767):柱,X-bridgeRP18,5um,19*100mm;流动相,0.03%氨水(0.03% NH4HCO3和NH4OH)和CH3CN(32%CH3CN在6分钟内直至52%);检测器,UV 254nm。这产生28.3mg(54%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-([3-硝基-4-[(噁烷-4-yl甲基)氨基]苯]磺酰基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酰胺,为黄色固体.LC-MS-:(ES,m/z):(ES,m/z):M+1=909,R.T=1.52min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度。H-NMR:(CDCl3,300MHz)δ:8.70(s,1H),8.46(m,2H),8.10-8.06(m,1H),7.89-7.60(m,1H),7.10(s,1H),6.94-6.71(m,5H),6.49(s,1H),6.16(s,1H),4.70-4.65(m,2H),4.00-4.10(m,2H),3.67-3.19(m,7H),3.20-3.00(m,4H),2.78(s,1H),2.58-2.52(m,2H),2.27-2.17(m,3H),2.05-1.98(m,4H),1.74-1.70(m,3H),1.55-1.40(m,3H),0.98(s,6H)。用具有BBOF探头的BrukerAvanceIII HD 300MHz完成NMR谱的测量。
实施例3:制备4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺
将二氯甲烷中的4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸(35mg,0.06mmol,1.00当量)溶液(5mL)、4-二甲基氨基吡啶(27.8mg,0.23mmol,4.00当量)、EDCI(22mg,0.11mmol,2.00当量)、4-[(4-氟噁烷-4-基)甲基]氨基-3-硝基苯-1-磺酰胺(22.7mg,0.07mmol,1.20当量)置于8-mL圆底烧瓶。将所得的溶液于室温搅拌过夜。在真空下浓缩所得的混合物。通过Prep-HPLC用以下条件(Waters-2767)纯化粗产物:柱,X-bridge RP18,5um,19*100mm;流动相,0.03%氨水(0.03% NH4HCO3和NH4OH)和CH3CN(32%CH3CN在6分钟内直至52%);检测器,UV 254nm。这产生26.2mg(50%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-[(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯)磺酰基]-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酰胺,为黄色固体。LC-MS:(ES,m/z):(ES,m/z):M+1=927,R,T=1.27min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;在3.5分钟中线性梯度从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR:(CDCl3,300MHz)δ:12.38(bs,1H),8.69(d,J=2.1Hz,1H),8.58(t,J=6.3Hz,1H),8.44(s,1H),8.07(d,J=9.0Hz,1H),7.90-7.87(m,1H),7.24-7.22(m,2H),7.08(s,1H),6.94(m,2H),6.85(s,1H),6.80-6.77(m,2H),6.49(s,1H),6.14(s,1H),4.74-4.67(m,2H),3.91-3.80(m,2H),3.80-3.44(m,6H),3.17(m,4H),2.77(s,1H),2.22-2.10(m,6H),2.00(s,2H),1.98-1.75(m,3H),1.80-1.60(m,2H),1.55-1.40(m,2H),0.94(s,6H)。用具有BBOF探头的BrukerAvanceIII HD 300MHz完成NMR谱的测量。
实施例4:制备4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基-2,2,3,3-d4)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺
合成4-[[2-(三甲基甲硅烷基)乙氧基]甲基](12,12-2H2)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮:将4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮(90mg,0.28mmol,1当量)、D2O(1mL)、MeOD(1mL)、Na2CO3(89.6mg,0.85mmol,3.00当量)置于8-mL小瓶。于60℃在油浴中将所得的溶液搅拌48h。用3x3mL二氯甲烷将所得的溶液提取。用无水硫酸钠干燥有机层并且在真空下浓缩。这产生60mg(66%)4-[[2-(三甲基甲硅烷基)乙氧基]甲基](12,12-2H2)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮,为黄色固体。LC-MS-PH-PHNW-4-34-1:(ES,m/z):M+1=322,用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-34-2:(d-DMSO,300ppm):7.44-7.41(m,2H),6.43-6.42(d,J=6Hz,1H),5.46-5.41(m,2H),3.51-3.46(m,2H),1.24(s,1H),0.86-0.79(m,4H),-0.04--0.05(m,9H)。
合成4-[[2-(三甲基甲硅烷基)乙氧基]甲基](11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯:将4-[[2-(三甲基甲硅烷基)乙氧基]甲基](12,12-2H2)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮(60mg,0.19mmol,1当量),THF(3mL)置于8-mL小瓶。这继之以于0℃按份添加LiAlD4(31.3mg,0.75mmol,3.99当量)。将所得的溶液于室温搅拌过夜。然后通过添加1mL D2O淬灭反应。用3x5mL乙酸乙酯将所得的溶液提取。用无水硫酸钠干燥有机层并且在真空下浓缩。这产生25mg(43.28%)4-[[2-(三甲基甲硅烷基)乙氧基]甲基](11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体。LC-MS-PH-PHNW-4-34-2:(ES,m/z):M+1=931.H-NMR-PH-PHNW-4-34-2:(CDCl3,300ppm):7.35(s,1H),7.17-7.15(d,J=6Hz,1H),6.35-6.34(d,J=3Hz,1H),5.56-5.53(m,2H),3.58-3.52(m,2H),2.08(s,1H),1.28(s,1H),0.93-0.88(m,3H),-0.04--0.05(m,9H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(4-[[2-(三甲基甲硅烷基)乙氧基]甲基](11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基)苯甲酸甲酯:将4-[[2-(三甲基甲硅烷基)乙氧基]甲基](11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(25mg,0.08mmol,1当量)、2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯(55.9mg,0.11mmol,1.3当量)、二噁烷(5mL)、Cs2CO3(52.6mg,0.16mmol,2当量)、氯[9,9-二甲基-4,5-二(二苯基膦基)呫吨(xanthene)][2-氨基-1,1-联苯基-2-基]钯(II)(5mg)置于8-mL小瓶。于100℃在油浴中将所得的溶液搅拌2h。在完成反应后,将粗溶液浓缩并且用乙酸乙酯/石油醚(0:1-1:1)将残留物应用到硅胶柱上。这产生20mg(32.56%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(4-[[2-(三甲基甲硅烷基)乙氧基]甲基](11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基)苯甲酸甲酯,为黄色固体。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯。将甲基4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(4-[[2-(三甲基甲硅烷基)乙氧基]甲基](11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),(20mg,0.03mmol,1当量)、THF(2mL)、TBAF(100mg,0.38mmol,14.54当量)、乙-1,2-二胺(1mL,0.02mmol,0.63当量)置于8-mL小瓶。于70℃将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:1)将残留物应用到硅胶柱上。这产生12mg(72.40%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体。LC-MS-PH-PHNW-4-34-4:(ES,m/z):M+1=630。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸:将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(12mg,0.02mmol,1当量)、MeOH(1mL)、H2O(1mL)、THF(1mL)、NaOH(3.0mg,0.08mmol,3.94当量)置于8-mL小瓶。于60℃在油浴中将所得的溶液搅拌过夜。用HCl(1mol/L)将溶液的pH值调节至5。在真空下浓缩反应混合物。在硅胶柱上应用残留物,并且用PE/EA(1:0-2:3)洗脱。这产生9mg(76.71%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸,为灰白色固体。LC-MS-PH-PHNW-4-34-5:(ES,m/z):M+1=616.用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酰胺:将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸(9mg,0.01mmol,1当量)、4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯-1-磺酰胺(6.3mg,0.02mmol,1.3当量)、DCM(2mL)、DMAP(7.1mg,0.06mmol,3.98当量)、EDCI(5.6mg,0.03mmol,2当量)置于8-mL小瓶。于室温将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。用二氯甲烷/甲醇(10:1)将残留物应用到硅胶柱上。这产生6mg(44.10%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)-2-[(11,11,12,12-2H4)-13-氧-2,4,10-三氮杂三环[7.4.0.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酰胺,为黄色固体。LC-MS-PH-PHNW-4-34-0:(ES,m/z):M+1=931。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。H-NMR-PH-PHNW-4-34-0:(d-DMSO,300ppm):8.57(s,1H),8.37(s,1H),7.58-7.55(m,1H),7.37-7.35(m,3H),7.08-7.05(m,3H),6.87-6.76(m,3H),3.76-3.73(m,6H),3.57-3.53(m,6H),3.33(m,3H),2.76-2.73(m,2H),2.26-2.20(m,6H),1.98(m,2H),1.81-1.76(m,5H),1.41-1.39(m,5H),1.39(m,4H),0.91-0.88(m,6H)。
实施例5:制备4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺
合成叔丁基1-(5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-6-基氧基)丙-2-基氨基甲酸酯。于0℃将叔丁基1-羟基丙-2-基氨基甲酸酯(2.28g,13.05mmol,1.50当量)、DMF(30mL)、NaH(0.87g,21.75mmol,2.50当量)置于250mL圆底烧瓶10min。添加5-溴-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(3.0g,8.70mmol,1.00当量)。于室温将所得的溶液搅拌过夜。用200mL H2O洗脱所得的溶液。将所得的溶液用3x300mL乙酸乙酯提取并且组合有机层。用1x200mL H2O和1x200mL氯化钠(水性)将所得的混合物清洗。在真空下浓缩所得的混合物。用PE/EA(5:1)将残留物应用到硅胶柱上。这产生2.2g(50%)叔丁基1-(5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-6-基氧基)丙-2-基氨基甲酸酯,为黄色油。LC-MS-PH-PHNW-4-35-1(ES,m/z):LC-MS(M+1):502;RT=1.50min.用反相柱(C18)完成保留的测量。Shimadzu LCMS2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05% TFA);洗脱液B:乙腈;线性梯度在2.0分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成叔丁基2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪e-1(6H)-羧化物。将叔丁基1-(5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-6-基氧基)丙-2-基氨基甲酸酯(2.2g,4.39mmol,1.00当量)、二噁烷e(25mL)、Cs2CO3(4.30g,13.17mmol,3.00当量)、X-phosPd 3G(1.04g,1.317mmol,0.30当量)置于100mL圆底烧瓶。于100℃在N2下将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。用PE/EA(3:1)将残留物应用到硅胶柱上。这产生1.26g(68%)叔丁基2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪e-1(6H)-羧化物,为黄色油。LC-MS-PH-PHNW-4-35-2(ES,m/z):LC-MS(M+1):420;RT=1.84min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-ODS,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在2.6分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.0mL/min。
合成2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,2,3,6-四氢吡咯[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪:将叔丁基2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-羧化物(1.26g,3.00mmol,1.00当量)、DCM(15mL)、ZnBr2(10.0g,30mmol,10.0当量)置于250mL圆底烧瓶。将所得的溶液于室温搅拌3h。将所得的溶液用50mL NaHCO3洗脱。用3x50mL DCM将所得的溶液提取并且组合有机层。用1x50mL H2O和1x50mL氯化钠(水性)将所得的混合物清洗。在真空下浓缩所得的混合物。用PE/EA(1:1)将残留物应用到硅胶柱上。这产生800mg(83%)2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,2,3,6-四氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪,为黄色油.LC-MS-PH-PHNW-4-35-3(ES,m/z):LC-MS(M+1):320;RT=1.54min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-ODS,2.6microm;洗脱液A:水(0.05% TFA);洗脱液B:乙腈;线性梯度在2.6分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.0mL/min。
合成4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸甲酯:将叔丁基1-(5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-6-基氧基)丙-2-基氨基甲酸酯(300mg,0.94mmol,1.00当量)、二噁烷(15mL)、Cs2CO3(920mg,2.82mmol,3.00当量)、XantphosPd 2G(83mg,0.094mmol,0.10当量)、2-溴-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸甲酯(1.0g,1.88mmol,2.00当量)置于100mL圆底烧瓶。于110℃在N2下将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。用PE/EA(5:1)将残留物应用到硅胶柱上。这产生360mg(50%)4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸甲酯,为黄色油。LC-MS-PH-PHNW-4-35-4(ES,m/z):LC-MS(M+1):770;RT=1.56min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-ODS,2.6microm;洗脱液A:水(0.05% TFA);洗脱液B:乙腈;线性梯度在2.6分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.0mL/min
合成4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸甲酯:叔丁基甲基4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-6-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸酯(300mg,0.39mmol,1.00当量)、THF(10mL)、TBAF(3.0g)、乙-1,2-二胺(5mL)置于100mL圆底烧瓶。于60℃将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。通过2N HCl将混合物调节PH<7。用3x200mL EA将所得的溶液提取并且组合有机层。用1x10mL H2O和1x10mL氯化钠(水性)将所得的混合物清洗。在真空下浓缩所得的混合物。这产生120mg(48%)4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸甲酯,为黄色油。LC-MS-PH-PHNW-4-35-5(ES,m/z):LC-MS(M+1):640;RT=2.82min.用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uHPH-C18,2.6microm;洗脱液A:水(0.05% NH4HCO3);洗脱液B:甲醇;线性梯度在3.5分钟中从10%乙腈至98%乙腈;炉温40℃;流动:0.8mL/min
合成4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸。将4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸甲酯(70mg,0.11mmol,1.00当量)、MeOH/H2O(5/5mL)、NaOH(44mg,1.10mmol,10当量)置于50mL圆底烧瓶。于60℃将所得的溶液搅拌3h。在真空下浓缩所得的混合物。用二氯甲烷/甲醇(10:1)将残留物应用到硅胶柱上。这产生50mg(73%)4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸,为白色固体。LC-MS-PH-PHNW-4-35-6(ES,m/z):LC-MS(M+1):626;RT=2.45min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u HPH-C18,2.6microm;洗脱液A:水(0.05%NH4HCO3);洗脱液B:甲醇;线性梯度在3.5分钟中从10%乙腈至98%乙腈;炉温40℃;流动:0.8mL/min。
合成4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺:将4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酸(40mg,0.064mol,1.00当量)、DCM(4mL)、EDCI(49mg,0.256mmol,4.00当量)、DMAP(16mg,0.128mmol,2.00当量)、4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯磺酰胺(28mg,0.0832mol,1.30当量)置于50-mL 1-颈圆底烧瓶。于40℃将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。这产生2.9mg(70%)4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,为黄色固体。LC-MS-PH-PHNW-4-35-0A(ES,m/z):LC-MS(M+1):941;RT=5.02min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uAscentis Express C18,2.6microm;洗脱液A:水(0.05% TFA);洗脱液B:甲醇;线性梯度在7.0分钟中从5%乙腈至95%乙腈;炉温40℃;流动:1.0mL/min。
实施例6:制备(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺和(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺
合成12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮:将5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-ol(1.5g,5.37mmol,1当量)、DMF(50mL)、K2CO3(2.2g,16.11mmol,3当量)置于100-mL圆底烧瓶。这继之以于0℃搅拌的情况下逐滴添加2-氯丙酰氯(1.4g,10.74mmol,2当量)。将所得的溶液于室温搅拌过夜。然后通过添加50mL水淬灭反应。用2x50mL乙酸乙酯将所得的溶液提取。用2x50mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生500mg(27.93%)12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮,为黄色固体。LC-MS-PH-PHNW-4-37-1:(ES,m/z):M+1=334,R,T=1.123min.用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-37-1:(CDCl3,300ppm):8.34(s,1H),7.63(d,J=3Hz,1H),7.42-7.28(m,1H),6.46(d,J=3Hz,1H),5.68(s,2H),4.92-4.85(m,1H),3.63-3.53(m,2H),1.85-1.81(d,J=12Hz,3H),0.94-0.89(m,2H),-0.154(s,9H)。用具有BBOF探头的BrukerAvanceIII HD 300MHz完成NMR谱的测量。
合成12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯和(12R或S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(假设)和(12S或R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(假设):将12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮(500mg,1.50mmol,1当量),THF(20mL)置于100-mL 3-颈圆底烧瓶。这继之以于0℃按份添加LiAlH4(113.8mg,3.00mmol,2当量)。于室温将所得的溶液搅拌1过夜。然后通过添加20mL水淬灭反应。将固体过滤出来。用2x20mL乙酸乙酯将所得的溶液提取。用2x20mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生450mg(93%)12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体。
通过手性-Prep-HPLC用以下条件纯化粗12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(450mg):(SHIMADZU LC-20AT):柱,CHIRALPAK IC;流动相A:正己烷,相B:乙醇;检测器,220nm。这产生200mg(44%)(12R或S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体(假设)。
这产生200mg(44%)(12S或R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体(假设)。
LC-MS-PH-PHNW-4-37-2:(ES,m/z):M+1=320,R,T=1.107min。
用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.
H-NMR-PH-PHNW-4-37-2:(CDCl3,300ppm):7.63(s,1H),7.17(s,1H),6.36-6.35(d,J=3Hz,1H),5.57-5.52(m,2H),4.59-4.55(m,1H),3.62-3.46(m,3H),3.18-3.14(m,1H),1.62-1.44(m,3H),0.93-0.88(m,2H),-0.17(s,9H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,4,10-三氮杂三环[7.4.0.0^3,7]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(假设):将(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(200mg,0.63mmol,1当量)、2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯(399.6mg,0.75mmol,1.2当量)、Cs2CO3(611.9mg,1.88mmol,3当量)、二噁烷(5mL)、氯[9,9-二甲基-4,5-二(二苯基膦基)呫吨][2-氨基-1,1-联苯基-2-基]钯(II)(120mg)置于8-mL小瓶。于110℃在油浴中将所得的溶液搅拌2hr。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:10)将残留物应用到硅胶柱上。这产生250mg(51.83%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,4,10-三氮杂三环[7.4.0.0^3,7]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体(假设)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(假设),将甲基4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2(250mg,0.32mmol,1当量)、TBAF(3g,11.47mmol,35.36当量),、THF(30mL)、乙-1,2-二胺(2g,33.28mmol,102.56当量)置于100-mL圆底烧瓶。于70℃在油浴中将所得的溶液搅拌12h。然后通过添加50mL水淬灭反应。用2x50mL乙酸乙酯将所得的溶液提取。用3x50mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生90mg(43%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体(假设)。H-NMR-PH-PHNW-4-37-50:(CDCl3,300ppm):8.24(s,1H),7.89-7.86(d,J=9Hz,1H),7.32-7.24(m,6H),7.14-7.01(m,1H),6.97-6.94(m,2H),6.73-6.65(m,2H),6.18(s,1H),3.67-3.53(m,3H),3.32-3.18(m,3H),2.98-2.80(m,1H),2.30-2.04(m,6H),1.99(s,2H),1.56-1.50(m,5H),0.91-0.88(m,6H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸(假设)。将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(90mg,0.14mmol,1当量)、MeOH(1mL)、H2O(1mL)、THF(1mL)、NaOH(22.5mg,0.56mmol,4当量)置于8-mL小瓶。于60℃在油浴中将所得的溶液搅拌过夜。用HCl(1mol/L)将溶液的pH值调节至5。在真空下浓缩所得的混合物。用二氯甲烷/甲醇(1:0-10:1)将残留物应用到硅胶柱上。这产生80mg(90%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸,为黄色固体(假设)。LC-MS-PH-PHNW-4-37-60:(ES,m/z):M+1=626,R,T=1.035min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酰胺(假设):4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸(90mg,0.14mmol,1当量)、4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯-1-磺酰胺(57.5mg,0.17mmol,1.2当量)、DCM(5mL)、DMAP(70.2mg,0.57mmol,4当量)、EDCI(55.1mg,0.29mmol,2.00当量)置于8-mL小瓶。于室温将所得的溶液搅拌过夜。将所得的混合物浓缩。通过快速-Prep-HPLC用以下条件(IntelFlash-1)纯化粗产物:柱,C18硅胶;流动相,在5min内水(0.1%FA)和ACN(48.0% CAN在7min中直至53.0%,在1min中保持95.0%,在1min中降低至48.0%,在1min中保持48.0%);检测器,UV 254nm.这产生28mg(20%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酰胺,为黄色固体(假设)。提交19.8mg产物(假设)。LC-MS-PH-PHNW-4-37-0:(ES,m/z):M+1=941,R,T=3.04min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-37-0:(d-DMSO,300ppm):8.59(s,1H),8.54(s,1H),7.55-7.53(m,1H),7.36-7.29(d,J=6Hz,3H),7.12-7.06(m,3H),6.80-6.72(m,3H),5.95(m,1H),4.53-4.51(m,1H),3.78-3.43(m,7H),3.21-3.00(m,5H),2.22-2.17(m,5H),1.96-1.75(m,6H),1.58-1.56(m,5H),0.93-0.88(m,6H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,2,5,7-四烯-10-基]苯甲酸甲酯(假设):将(12S或R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯e(200mg,0.63mmol,1当量)、2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯(399.6mg,0.75mmol,1.2当量)、Cs2CO3(611.9mg,1.88mmol,3当量)、二噁烷(5mL)、氯[9,9-二甲基-4,5-二(二苯基膦基)呫吨][2-氨基-1,1-联苯基-2-基]钯(II)(120mg)置于8-mL小瓶。于110℃在油浴中将所得的溶液搅拌2h。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:10)将残留物应用到硅胶柱上。这产生250mg(51%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体(假设)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(假设):将甲基4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2(250mg,0.32mmol,1当量)、TBAF(3g,11.47mmol,35.36当量)、THF(30mL)、乙-1,2-二胺(2g,33.28mmol,102.56当量)置于100-mL圆底烧瓶。于70℃在油浴中将所得的溶液搅拌12h。然后通过添加50mL水淬灭反应。用2x50mL乙酸乙酯将所得的溶液提取。用3x50mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生90mg(43%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体(假设)。
LC-MS-PH-PHNW-4-38-50:(ES,m/z):M+1=640,R,T=1.424min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-38-50:(CDCl3,300ppm):8.24(s,1H),7.89-7.86(d,J=9Hz,1H),7.32-7.24(m,6H),7.14-7.01(m,1H),6.97-6.94(m,2H),6.73-6.65(m,2H),6.18(s,1H),3.67-3.53(m,3H),3.32-3.18(m,3H),2.98-2.80(m,1H),2.30-2.04(m,6H),1.99(s,2H),1.56-1.50(m,5H),0.91-0.88(m,6H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸(假设):将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(90mg,0.14mmol,1当量)、MeOH(1mL)、H2O(1mL)、THF(1mL)、NaOH(22.5mg,0.56mmol,4.00当量)置于8-mL小瓶。于60℃在油浴中将所得的溶液搅拌过夜。用HCl(1mol/L)将溶液的pH值调节至5。在真空下浓缩所得的混合物。用氯仿/甲醇(1:0-10:1)将残留物应用到硅胶柱上。这产生80mg(90%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸,为固体(假设):LC-MS-PH-PHNW-4-38-60:(ES,m/z):M+1=626,R,T=1.039min.用反相柱(C18)完成保留的测量。ShimadzuLCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酰胺(假设):将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸(90mg,0.14mmol,1当量)、4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯-1-磺酰胺(57.5mg,0.17mmol,1.2当量)、DCM(5mL)、DMAP(70.2mg,0.57mmol,4当量)、EDCI(55.1mg,0.29mmol,2当量)置于8-mL小瓶。于室温将所得的溶液搅拌过夜。将所得的混合物浓缩。通过快速-Prep-HPLC用以下条件(IntelFlash-1)纯化粗产物:柱,C18硅胶;流动相,在5min内水(0.1%FA)和ACN(48.0% ACN在7min中直至53.0%,在1min中保持95.0%,在1min中降低至48.0%,在1min中保持48.0%);检测器,UV 254nm.这产生26mg(19%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)-2-[(12S或R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酰胺,为黄色固体。提交19.6mg产物(假设)。LC-MS-PH-PHNW-4-38-0:(ES,m/z):M+1=941,R,T=3.036min.用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-38-0:(d-DMSO,300ppm):8.56(s,1H),8.36(s,1H),7.62-7.54(m,1H),7.37-7.30(m,3H),7.14-7.04(m,3H),6.98-6.92(m,3H),5.94(m,1H),4.53(m,1H),3.79-3.71(m,4H),3.65-3.54(m,3H),3.44(m,4H),2.78-2.73(m,2H),2.23-2.18(m,6H),1.97-1.91(m,2H),1.87-1.81(m,4H),1.50-1.20(m,5H),0.91-0.88(m,6H)。
实施例7:制备4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺
合成12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-11-酮:将5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-醇(1g,3.58mmol,1当量)、CH3CN(20mL)、2-溴-2-甲基丙酸甲酯(647.9mg,3.58mmol,1.0当量)、Cs2CO3(1.7g,5.37mmol,1.5当量)置于100-mL圆底烧瓶。于80℃在油浴中将所得的溶液搅拌2h。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(1:3)将残留物应用到硅胶柱上。这产生270mg(21%)12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-11-酮,为浅黄色固体。LC-MS-PH-PHNW-4-40-2:(ES,m/z):M+1=348,R,T=1.164min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯:将12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-11-酮(250mg,0.72mmol,1当量),THF(3mL)置于8-mL小瓶。这继之以于0℃按份添加LiAlH4(54.6mg,1.44mmol,2当量)。将所得的溶液于室温搅拌过夜。然后通过添加5mL水淬灭反应。将固体过滤出来。用2x10mL乙酸乙酯将所得的溶液提取。用无水硫酸钠干燥有机层并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:5)将残留物应用到硅胶柱上。这产生140mg(58%)12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯,为黄色固体。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基)苯甲酸酯:将12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯(140mg,0.42mmol,1当量)、2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯(267.9mg,0.50mmol,1.2当量)、Cs2CO3(410.3mg,1.26mmol,3当量)、二噁烷(2mL)、氯[9,9-二甲基-4,5-二(二苯基膦基)呫吨][2-氨基-1,1-联苯基-2-基]钯(II)(80mg)置于8-mL小瓶。于110℃在油浴中将所得的溶液搅拌2h。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生130mg(39%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基)苯甲酸甲酯,为黄色固体。LC-MS-PH-PHNW-4-40-4:(ES,m/z):M+1=784,R,T=1.331min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸甲酯:将甲基4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-(12,12-二甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),(130mg,0.17mmol,1当量),TBAF(3g),THF(10mL),乙-1,2-二胺(2g)置于40-mL小瓶。于60℃在油浴中将所得的溶液搅拌过夜。然后通过添加10mL水淬灭反应。用2x10mL乙酸乙酯将所得的溶液提取。用3x10mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生110mg(粗)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸甲酯,为黄色固体。LC-MS-PH-PHNW-4-40-5:(ES,m/z):M+1=654,R,T=1.107min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸:将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸甲酯(80mg,0.12mmol,1当量),MeOH(1mL),THF(1mL),H2O(1mL),NaOH(19.6mg,0.49mmol,4当量)置于8-mL小瓶。于60℃在油浴中将所得的溶液搅拌过夜。用HCl(1mol/L)将溶液的pH值调节至5。在真空下浓缩所得的混合物。用二氯甲烷/甲醇(1:0-10:1)将残留物应用到硅胶柱上。这产生60mg(76.64%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸,为黄色固体。LC-MS-PH-PHNW-4-40-6:(ES,m/z):M+1=640,R,T=1.359min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)苯甲酰胺:将4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯-1-磺酰胺(37.5mg,0.11mmol,1.2当量),DCM(5mL),4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸(60mg,0.09mmol,1当量),EDCI(35.9mg,0.19mmol,2当量),DMAP(45.8mg,0.37mmol,4当量)置于8-mL小瓶。将所得的溶液于室温搅拌过夜。在真空下浓缩所得的混合物。通过快速-Prep-HPLC用以下条件(IntelFlash-1)纯化粗产物:柱,C18硅胶;流动相,水(0.1%FA)和ACN(48.0%ACN在7min中直至53.0%,在1min内保持95.0%,在1min内降低至48.0%,在5内;检测器,UV254nm。这产生25mg(27%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[12,12-二甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]-N-(4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯磺酰基)苯甲酰胺,为黄色固体。提交20.6mg产物。LC-MS-PH-PHNW-4-40-0:(ES,m/z):M+1=955,R,T=2.655min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-40-0:(d-DMSO,300ppm):8.56(s,1H),8.36(s,1H),7.56-7.49(m,2H),7.36-7.33(m,2H),7.06-7.00(m,3H),6.93-6.90(m,1H),6.88-6.74(M,2H),5.99(m,1H),3.78-3.74(m,4H),3.67-3.50(m,2H),3.23(m,4H),2.76-2.72(m,2H),2.22-2.16(m,6H),1.96-1.75(m,6H),1.41-1.39(m,8H),0.91-0.88(m,6H)。
实施例8:制备4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺
合成3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯磺酰胺:将(四氢-2H-吡喃-3-基)甲胺(200mg,1.74mmol,1.00当量),THF(5mL),4-氟-3-硝基苯-1-磺酰胺(383mg,1.74mmol,1.00当量),Cs2CO3(1.134g,3.48mmol,2.00当量)置于50-mL圆底烧瓶。于50度在油浴中将所得的溶液搅拌3h。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(1/1)将残留物应用到硅胶柱上。这产生270mg(49.3%)3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯磺酰胺,为黄色固体。LC-MS-PH-PHNW-4-41-1:(ES,m/z):M+1=316,R,T=1.25min。用反相柱(C18)完成保留的测量.Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-ODS,2.6microm;洗脱液A:水(0.5%FA);洗脱液B:乙腈(0.05%TFA);线性梯度在2.6分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.0mL/min。
合成4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-3-基)甲基)氨基)苯基)磺酰基)苯甲酰胺:将二氯甲烷中的4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1,3(7),5,8-四烯-10-基]苯甲酸(50mg,0.082mmol,1.00当量)(5mL),EDCI(63mg,0.328mmol,4.00当量),4-二甲基氨基吡啶(20mg,0.164mmol,2.00当量),3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(26mg,0.082mmol,1.00当量)置于100-mL圆底烧瓶。于40℃将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。通过Prep-HPLC用以下条件(Waters-2767)纯化粗产物:柱,X-bridge RP18,5um,19*100mm;流动相,0.03%氨水(0.03% NH4HCO3和NH4OH)和CH3CN(32% CH3CN在6min中直至52%);检测器,UV 254nm。这产生12.8mg(17%)4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,为黄色固体。LC-MS-PH-PHNW-4-41-0:(ES,m/z):M+1=909,R,T=1.60min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.0分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。1H NMR(300MHz,氯仿-d)δ12.40(s,1H),8.72(s,1H),8.63(s,1H),8.44(t,J=5.5Hz,1H),8.10(d,J=9.0Hz,1H),7.93–7.82(m,1H),7.25(s,4H),7.13(t,J=2.9Hz,1H),7.00–6.68(m,6H),6.52(s,1H),6.17(d,J=3.3Hz,1H),4.71(dd,J=23.6,10.7Hz,2H),3.99–3.79(m,3H),3.70(s,1H),3.57(dd,J=18.5,10.9Hz,3H),3.46–3.17(m,7H),2.80(s,2H),2.29(s,3H),2.21(s,2H),2.03(d,J=12.3Hz,5H),1.75–1.60(m,4H),1.44(d,J=8.7Hz,3H),1.28(s,1H),0.97(s,6H),0.87(s,1H)。用具有BBOF探头的BrukerAvanceIII HD 300MHz完成NMR谱的测量。
实施例9:制备(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺
合成6-(叔-丁氧基)-N-(二苯基亚甲基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-5-胺:将二噁烷中5-溴-6-氟-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶(20.7g,60mmol,1.00当量)溶液(300mL),t-BuOK(20.5g,180mmol,3.00当量),xantphos(6.9g,12mmol,0.20当量),Pd2(dba)3.CHCl3(5.7g,0.10当量),二苯甲酮亚胺(14.04g,78mmol,1.20当量)置于250-mL圆底烧瓶。于100℃将所得的溶液搅拌过夜。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:20)将残留物应用到硅胶柱上。这产生15g(粗)6-(叔-丁氧基)-N-(二苯基亚甲基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-5-胺,为白色油。LC-MS-PH-PHNW-4-7-9:(ES,m/z):M+1=500。
合成5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-醇盐酸盐:将二噁烷中的6-(叔-丁氧基)-N-(二苯基亚甲基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-5-胺(15g,30.02mmol,1.00当量)(120mL),HCl/二噁烷(4M,30mL)置于500-mL圆底烧瓶。于室温将所得的溶液搅拌5h。用500mL醚洗脱所得的溶液。通过过滤收集固体。这产生5g(粗)5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-醇盐酸盐,为红色固体,Q-NMR显示了它可以转化成3盐酸盐。LC-MS-PH-PHNW-4-10-1:(ES,m/z):M+1=280,R,T=0.811min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度。
合成12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮:将5-氨基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-醇(1.5g,5.37mmol,1当量),DMF(50mL),K2CO3(2.2g,16.11mmol,3当量)置于100-mL圆底烧瓶。这继之以在0℃搅拌的情况下逐滴添加2-氯丙酰氯(1.4g,10.74mmol,2当量)。将所得的溶液于室温搅拌过夜。然后通过添加50mL水淬灭反应。用2x50mL乙酸乙酯将所得的溶液提取。用2x50mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生500mg(27.93%)12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮,为黄色固体。LC-MS-PH-PHNW-4-37-1:(ES,m/z):M+1=334,R,T=1.123min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-37-1:(CDCl3,300ppm):8.34(s,1H),7.63(d,J=3Hz,1H),7.42-7.28(m,1H),6.46(d,J=3Hz,1H),5.68(s,2H),4.92-4.85(m,1H),3.63-3.53(m,2H),1.85-1.81(d,J=12Hz,3H),0.94-0.89(m,2H),-0.154(s,9H)。
合成12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯和(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯和(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯:将12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-11-酮(500mg,1.50mmol,1当量),THF(20mL)置于100-mL 3-颈圆底烧瓶。这继之以于0℃按份添加LiAlH4(113.8mg,3.00mmol,2当量)。于室温将所得的溶液搅拌1过夜。然后通过添加20mL水淬灭反应。将固体过滤出来。用2x20mL乙酸乙酯将所得的溶液提取。用2x20mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生450mg(93%)12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体。
通过手性-Prep-HPLC用以下条件纯化粗12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(450mg):(SHIMADZU LC-20AT):柱,CHIRALPAK IC;流动相A:正己烷,相B:乙醇;检测器,220nm.这产生200mg(44%)of(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体。
这产生200mg(44%)(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为黄色固体。LC-MS-PH-PHNW-4-37-2:(ES,m/z):M+1=320,R,T=1.107min。
用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex2.6u XB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR-PH-PHNW-4-37-2:(CDCl3,300ppm):7.63(s,1H),7.17(s,1H),6.36-6.35(d,J=3Hz,1H),5.57-5.52(m,2H),4.59-4.55(m,1H),3.62-3.46(m,3H),3.18-3.14(m,1H),1.62-1.44(m,3H),0.93-0.88(m,2H),-0.17(s,9H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,4,10-三氮杂三环[7.4.0.0^3,7]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯:将(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(200mg,0.63mmol,1当量),2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯(399.6mg,0.75mmol,1.2当量),Cs2CO3(611.9mg,1.88mmol,3当量),二噁烷(5mL),氯[9,9-二甲基-4,5-二(二苯基膦基)呫吨][2-氨基-1,1-联苯基-2-基]钯(II)(120mg)置于8-mL小瓶。于110℃在油浴中将所得的溶液搅拌2hr。在真空下浓缩所得的混合物。用乙酸乙酯/石油醚(0:1-1:10)将残留物应用到硅胶柱上。这产生250mg(51.83%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,4,10-三氮杂三环[7.4.0.0^3,7]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯。甲基4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2(250mg,0.32mmol,1当量),TBAF(3g,11.47mmol,35.36当量),THF(30mL),乙-1,2-二胺(2g,33.28mmol,102.56当量)置于100-mL圆底烧瓶。于70℃在油浴中将所得的溶液搅拌12h。然后通过添加50mL水淬灭反应。用2x50mL乙酸乙酯将所得的溶液提取。用3x50mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:3)将残留物应用到硅胶柱上。这产生90mg(43%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体。H-NMR-PH-PHNW-4-37-50:(CDCl3,300ppm):8.24(s,1H),7.89-7.86(d,J=9Hz,1H),7.32-7.24(m,6H),7.14-7.01(m,1H),6.97-6.94(m,2H),6.73-6.65(m,2H),6.18(s,1H),3.67-3.53(m,3H),3.32-3.18(m,3H),2.98-2.80(m,1H),2.30-2.04(m,6H),1.99(s,2H),1.56-1.50(m,5H),0.91-0.88(m,6H)。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸。将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(90mg,0.14mmol,1当量),MeOH(1mL),H2O(1mL),THF(1mL),NaOH(22.5mg,0.56mmol,4当量)置于8-mL小瓶。于60℃在油浴中将所得的溶液搅拌过夜。用HCl(1mol/L)将溶液的pH值调节至5。在真空下浓缩所得的混合物。用二氯甲烷/甲醇(1:0-10:1)将残留物应用到硅胶柱上。这产生80mg(90%)4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸,为黄色固体。LC-MS:(ES,m/z):M+1=626,R,T=1.035min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min。
合成(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺。将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R或S)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸(90mg,0.14mmol,1当量),4-[[(4-氟噁烷-4-基)甲基]氨基]-3-硝基苯-1-磺酰胺(57.5mg,0.17mmol,1.2当量),DCM(5mL),DMAP(70.2mg,0.57mmol,4当量),EDCI(55.1mg,0.29mmol,2.00当量)置于8-mL小瓶。于室温将所得的溶液搅拌过夜。将所得的混合物浓缩。通过Flash-Prep-HPLC用以下条件(IntelFlash-1)纯化粗产物:柱,C18硅胶;流动相,在5min内水(0.1%FA)和ACN(48.0% ACN在7min中直至53.0%,在1min中保持95.0%,在1min中降低至48.0%,在1min中保持48.0%);检测器,UV 254nm。这产生22mg(20%)(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺。LC-MS:(ES,m/z):M+1=923,R,T=2.653min。用反相柱(C18)完成保留的测量。Shimadzu LCMS 2020;50*3.0Kinetex 2.6uXB-C18,2.6microm;洗脱液A:水(0.05%TFA);洗脱液B:乙腈;线性梯度在3.5分钟中从5%乙腈至100%乙腈;炉温40℃;流动:1.5mL/min.H-NMR:(d-CDCl3,300ppm):8.62(s,1H),8.44-8.42(m,2H),8.09-8.06(m,1H),7.85-7.70(m,1H),7.28-7.22(m,2H),6.94-6.80(m,3H),6.72-6.62(m,2H),6.10(s,1H),4.05-4.00(m,2H),3.50-3.17(m,10H),2.95-2.35(m,2H),2.27-2.19(m,4H),1.98-1.70(m,5H),1.60-1.26(m,11H),0.95(s,6H)。
实施例10:制备(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺
合成N-[(2R)-2-羟基丙基]-4-甲基苯-1-磺酰胺:将(2R)-1-氨基丙-2-醇(5g,1当量),DCM(70mL),TsCl(12.67g,1当量)置于250-mL圆底烧瓶。这继之以于0℃添加TEA(7.41g,1.1当量)。于0℃将所得的溶液搅拌3hr。将所得的混合物浓缩。用乙酸乙酯/石油醚(1/1)将残留物应用到硅胶柱上。这产生8gN-(2R)-2-羟基丙基]-4-甲基苯-1-磺酰胺,为白色固体。1H NMR((300MHz,DMSO-d6,ppm):δ7.74-7.63(m,2H),7.52-7.34(m,3H),4.66(d,J=4.7Hz,1H),3.58(qd,J=6.3,4.8Hz,1H),2.73-2.50(m,2H),2.39(s,3H),0.99(d,J=6.2Hz,3H)。
合成2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯:DMA中的1-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪(15.09g,47.32mmol,1.00当量)溶液(150mL),DIEA(12.9g,99.81mmol,2.00当量),2-溴-4-氟苯甲酸甲酯(11.6g,49.78mmol,1.00当量)置于250-mL圆底烧瓶。于100度将所得的溶液搅拌12h。将反应混合物冷却到室温。然后通过添加50mL水淬灭反应。用3x100mL乙酸乙酯将所得的溶液提取并且组合有机层。用3x100mL卤水将所得的混合物清洗。用无水硫酸钠干燥混合物,然后过滤并且在真空下浓缩。用乙酸乙酯/石油醚(0:1-1:5)将残留物应用到硅胶柱上。这产生7g(粗)2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯,为黄色油。LC-MS:(ES,m/z):M+1=533,531。
合成N-[(2R)-2-[(5-溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-基)氧]丙基]-4-甲基苯-1-磺酰胺:将N-[(2R)-2-羟基丙基]-4-甲基苯-1-磺酰胺(1g,1.5当量),DMF(3mL)置于100-mL圆底烧瓶。这继之以于0℃在10min中添加NaH(0.35g,3当量)。于0℃对此添加5-溴-6-氟-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶(1g,1当量)。于室温将所得的溶液搅拌4hr。然后通过添加20mL水淬灭反应。用3x50mL乙酸乙酯将所得的溶液提取并且将有机层组合并且浓缩。用乙酸乙酯/石油醚(1/3)将残留物应用到硅胶柱上。这产生400mg N-[(2R)-2-[(5-溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-基)氧]丙基]-4-甲基苯-1-磺酰胺,为黄色固体。1H-NMR(300MHz,DMSO-d6,ppm):δ8.18(s,1H),7.72-7.62(m,2H),7.41(d,J=3.5Hz,1H),7.28(d,J=8.0Hz,2H),6.42(d,J=3.6Hz,1H),5.50(q,J=10.8Hz,2H),5.16(q,J=6.1Hz,1H),3.53-3.38(m,2H),3.13(dd,J=13.4,6.0Hz,1H),2.98(dd,J=13.4,5.8Hz,1H),2.29(s,3H),1.28(d,J=6.2Hz,3H),0.80(ddt,J=16.1,14.1,7.1Hz,2H),0.13(s,9H)。
合成(12R)-12-甲基-10-(4-甲基苯磺酰基)-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯:将N-[(2R)-2-[(5-溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-6-基)氧]丙基]-4-甲基苯-1-磺酰胺(3.9g,1当量),二噁烷(50mL),t-BuXPhos3G(560mg,0.1当量),Cs2O3(6.9g,3当量)置于用惰性氮气气氛扫气并维持的100-mL圆底烧瓶。于90℃将所得的溶液搅拌4hr。将所得的混合物浓缩。用乙酸乙酯/石油醚(1/3)将残留物应用到硅胶柱上。这产生3.3g(12R)-12-甲基-10-(4-甲基苯磺酰基)-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为无色油。1H-NMR(300MHz,DMSO-d6,ppm):δ8.28(s,1H),7.56-7.39(m,3H),7.39-7.30(m,2H),6.52(d,J=3.6Hz,1H),5.43(s,2H),4.28(dd,J=14.6,2.6Hz,1H),3.61-3.41(m,3H),3.26-3.11(m,1H),2.35(s,3H),1.32-1.11(m,3H),0.89-0.74(m,2H),0.11(s,9H)。
合成(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯:于室温将Na(1.3 1g,9.4当量),萘(0.76g,6当量)置于100-mL 3-颈圆底烧瓶。这继之以添加DME(15mL)达30min。于-78℃对此添加THF中的(12R)-12-甲基-10-(4-甲基苯磺酰基)-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯e(2.8g,1当量)溶液(15mL)。于室温将所得的溶液搅拌3hr。然后通过添加30mL NH4Cl淬灭反应。用3x100mL乙酸乙酯将所得的溶液提取并且将有机层组合并且浓缩。用乙酸乙酯/石油醚(1/3)将残留物应用到硅胶柱上。这产生1.4g(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯,为无色油。LC-MS(ES,m/z):320[M+1]+;RT=1.61min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯:将(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯(1.178g,1当量),2-溴-4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)苯甲酸甲酯(2.35g,1.2当量),二噁烷(15mg,15当量),Cs2CO3(3.62g,3当量),XantPhos(328mg,0.1当量)置于用惰性氮气气氛扫气并维持的250-mL圆底烧瓶。于110℃将所得的溶液搅拌2hr。将所得的混合物浓缩。用乙酸乙酯/石油醚(1/3)将残留物应用到硅胶柱上。这产生3.2g 4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12S)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体。LC-MS(ES,m/z):770[M+1]+;RT=1.33min。
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯:将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-4-[[2-(三甲基甲硅烷基)乙氧基]甲基]-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(3.2g,1当量),THF(50mL),TBAF(20g),乙-1,2-二胺(33g)置于250-mL圆底烧瓶。于70℃将所得的溶液搅拌5hr。然后通过添加50mL水淬灭反应。用3x100mL乙酸乙酯将所得的溶液提取并且将有机层组合并且浓缩。用二氯甲烷/甲醇(10/1)将残留物应用到硅胶柱上。这产生2.2g 4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯,为黄色固体。LC-MS-(ES,m/z):640[M+1]+;RT=2.51min
合成4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸:将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸甲酯(2.2g,1当量),MEOH/H2O/THF(10mL/10ml/10mL)置于250-mL圆底烧瓶。于60℃将所得的溶液搅拌5hr。将所得的混合物浓缩。用3x100mL二氯甲烷将所得的溶液提取并且将有机层组合并且浓缩。用二氯甲烷/甲醇(10/1)将残留物应用到硅胶柱上。这产生1.6g4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸,为黄色油。LC-MS(ES,m/z):626[M+1]+;RT=2.47min
合成(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺:将4-(4-[[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基]哌嗪-1-基)-2-[(12R)-12-甲基-13-氧-2,4,10-三氮杂三环[7.4.0.0^[3,7]]十三-1(9),2,5,7-四烯-10-基]苯甲酸(1.6g,1当量),DCM(20mL),3-硝基-4-[[(噁烷-4-基)甲基]氨基]苯-1-磺酰胺(890mg,1.2当量),DMAP(1.25g,4当量),EDCI(980mg,2当量)置于250-mL圆底烧瓶。于室温将所得的溶液搅拌14hr。将所得的混合物浓缩。用EA/DCM(1/10)将残留物应用到硅胶柱上。这产生0.82g(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,为黄色固体。LC-MS(ES,m/z):923[M+1]+;RT=3.50min.[a]=+17.8(C=0.105g/100mL in CH2Cl2,T=27.0℃)1H NMR(300MHz,CDCl3,ppm):δ12.48(s,1H),8.62(d,J=2.4Hz,2H),8.54-8.38(m,1H),8.16-7.95(m,1H),7.81-7.71(m,1H),7.32-7.12(m,6H),7.07(t,J=2.9Hz,1H),6.97-6.77(m,3H),6.76-6.60(m,2H),6.52(s,1H),6.09(d,J=3.0Hz,1H),4.88(d,J=7.7Hz,1H),4.02(dd,J=11.8,4.2Hz,2H),3.55-3.34(m,4H),3.32-3.14(m,5H),3.08(s,1H),2.77(d,J=9.6Hz,2H),2.28(s,3H),2.19(s,2H),1.99(d,J=7.6Hz,4H),1.72(d,J=12.7Hz,2H),1.45(ddd,J=24.5,12.3,5.8Hz,6H),0.94(d,J=2.1Hz,6H)。
通过与上述方案和实施例中公开的那些方法基本上相同,相似或类似的方法制备下述化合物。
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生物实施例1:Bcl-2竞争结合(荧光偏振)测定法
经荧光标记的23个氨基酸的肽BH3购自CalBiochem(NLWAAQRYGRELRRMSDKFVD)。未结合的荧光素标记的BH3肽相对于激发光的偏振面的平面发射随机光,从而导致较低的偏振度(mP)值。当肽与Bcl-2结合时,复合物较慢翻滚,并且发射光可以具有更高水平的偏振,从而导致更高的mP值。此结合测定法在96孔板中进行,并且每个测定法包含15和30nM的标记的肽和纯化的Bcl-2蛋白(购自R&D Systems,Inc)。测定缓冲液含有20mM Hepes(pH7.0),50mM KCl,5mM MgCl2,20mM Na2MoO4,0.lmg/ml牛Gamma球蛋白和0.01% NP40。将化合物在DMSO中稀释,并以20μM至2nM的浓度范围添加到最终测定法。在室温下温育3小时后在扣除背景的情况下通过BioTek Synergy II确定极化度(mP)值。使用具有S形剂量-应答曲线拟合的Prism软件计算IC50。使用ABT-737作为参考化合物。用一定剂量范围的测试化合物进行的此类测定法允许测定近似的IC50值。尽管本发明化合物的抑制特性随预期的结构变化而变化,但这些试剂通常表现出的活性在IC50=0.1–1000nM的范围内。
生物学实施例2:依赖于BCL-2的急性成淋巴细胞性白血病(ALL)细胞系RS4;11的体外抗增殖测定法
通过PerkinElmer ATPliteTM发光测定系统测定细胞抗增殖。简言之,将各种测试癌细胞系以每孔约1×104个细胞的密度接种在Costar 96孔板中,并在补充有5% FBS或10%正常人血清(NHS)的培养基中与不同浓度的化合物温育约72小时。然后通过添加5mL底物缓冲液来重建一个冻干的底物溶液小瓶,并轻轻搅拌直至溶液均匀。将约50μL哺乳动物细胞裂解溶液添加到微板的每孔的100μL细胞悬浮液,并将该板在定轨振荡器中以约700rpm摇动约五分钟。该程序用于裂解细胞并稳定ATP。接下来,将50μL底物溶液添加至孔中,并将微孔板在定轨振荡器中以约700rpm振荡5分钟。最后,通过PerkinElmer微板闪烁计数器测量发光。用一定剂量范围的测试化合物进行的此类测定法允许测定本发明化合物的细胞抗增殖IC50。下表列出了本发明某些化合物的IC50值。如下所示,实施例3比NW-4-8(实施例2)以及ABT-199都更有效。
化合物 | IC50, RS4;11 5%FBS |
ABT-199 | 5.5nM |
WO/2017/132474中的实施例12 | 15.8nM |
实施例2(NW-4-8) | 4.8nM |
实施例3 | 2.6nM |
下表列出了本发明的某些化合物的另一项研究的IC50值。
化合物 | IC50, RS4;11 5%FBS |
ABT-199 | 9.2nM |
实施例3 | 1.4nM |
实施例6(S,假设) | 3.2nM |
实施例6(R,假设) | 1.3nM |
实施例7 | 5.6nM |
下表列出了本发明的某些化合物的另一项研究的IC50值。
化合物 | IC50, RS4;11 5%FBS |
ABT-199 | 4.7nM |
实施例10 | 3.1nM |
生物学实施例3:依赖于BCL-XL的系小细胞肺癌(SCLC)细胞系H146的体外抗增殖测定法
通过PerkinElmer ATPliteTM发光测定系统测定细胞抗增殖法。简言之,将各种测试癌细胞系以每孔约1×104个细胞的密度接种在Costar 96孔板中,并在补充有5% FBS的培养基中与不同浓度的化合物温育约72小时。然后通过添加5mL底物缓冲溶液来重建一个冻干的底物溶液小瓶,并轻轻搅拌直至溶液均匀。将约50μL哺乳动物细胞裂解溶液添加到微板的每孔的100μL细胞悬浮液,并将该板在定轨振荡器中以约700rpm摇动约五分钟。该程序用于裂解细胞并稳定ATP。接下来,将50μL底物溶液添加至孔中,并将微板在定轨振荡器中以约700rpm振荡5分钟。最后,通过PerkinElmer闪烁计数器测量发光。用一定剂量范围的测试化合物进行的此类测定允许测定本发明化合物的细胞抗增殖IC50。
生物学实施例4:小鼠PK研究
通过静脉内和口服施用,在CD-1小鼠中评估化合物的药动学。IV剂量在颈静脉中以缓慢推注施用,并且通过管饲法施用口服剂量。IV给药的配制剂为在水中20% HPBCD中的5% DMSO,并且PO配制剂为2.5% DMSO,10%EtOH,20% Cremphor EL,67.5% D5W。IV臂的PK时间点是剂量后5、15、30分钟、1、2、4、6、8、12、24小时,并且对于PO臂的PK时间点是剂量后15、30分钟、1、2、4、6、8、12、24小时。在每个时间点收集约0.03mL血液。将每个样品的血液转移到含有EDTA-K2的塑料微型离心管中,并通过在4℃离心机中以4000g离心5分钟,在15分钟内收集血浆。血浆样品储存在聚丙烯管中。在分析之前,将样品存储在-75±15℃的冰箱中。使用LC-MS/MS方法分析血浆样品中化合物的浓度。WinNonlin(PhoenixTM,版本6.1)或其他类似软件用于药动学计算。在任何可能的情况下从血浆浓度与时间的数据计算以下药动学参数:IV施用:C0,CL,Vd,T1/2,AUCinf,AUClast,MRT,回归点数;PO施用:Cmax,Tmax,T1/2,AUCinf,AUClast,F%,回归点数。使用描述性统计数据(例如平均值,标准差)描述了药动学数据。另外的药动学或统计学分析由贡献科学家酌情进行,并记录在数据汇总中。口服给药po,10mg/kg的PK结果示于下表。如下所示,许多化合物的PK显著好于NW-4-8(实施例2),参见AUC和/或生物利用度值。
化合物 | AUC(h*ng/mL) | t1/2(小时) | 生物利用度 |
实施例2(NW-4-8) | 10,365 | 2.7 | 68% |
实施例6(S) | 12,068 | 74% | |
实施例6(R) | 16,114 | 3.2 | |
实施例7 | 10,972 | 3.2 | 90% |
实施例9 | 19,922 | 4.1 | |
实施例10 | 34,982 | 4.1 | 78% |
为了比较目的,口服给药po,10mg/kg WO/2017/132474中的某些化合物的PK结果使用相同的方法获得,并且显示于下表中。
化合物 | AUC(h*ng/mL) |
WO/2017/132474中的实施例12 | 1,088 |
WO/2017/132474中的实施例16 | 849 |
WO/2017/132474中的实施例18 | 1,890 |
生物学实施例5:体内异种移植研究
选择实施例3的化合物在依赖于BCL-2的急性成淋巴细胞性白血病RS4;11异种移植模型中进行体内研究。CB.17SCID小鼠在6-8周龄时从供应商处获得,并适应至少7天的时段。然后将癌细胞植入裸鼠中。根据具体的肿瘤类型,通常在植入后约两周可检测到肿瘤。当肿瘤大小达到约100-200mm3时,将具有可察觉的肿瘤大小和形状的动物随机分成各8只小鼠的组,包括一个媒介物对照组和处理组。给药随每个研究的目的和时间而有所变化,其通常进行约3-4周。每周通常测量三次肿瘤大小和体重。在测定肿瘤大小变化外,使用最后一次肿瘤测量来生成肿瘤大小变化率(T/C值),由国家癌症研究所开发的用于异种移植肿瘤评估的标准指标。在大多数情况下,使用以下公式计算%T/C值:如果ΔT>0,则%T/C=100xΔT/ΔC。然而,当发生肿瘤消退(ΔT<0)时,使用以下公式:%T/T0=100×ΔT/T0。认为<42%的值是显著的。
如下所示,7剂实施例3化合物产生剂量依赖性的肿瘤生长减少。以100mg/kg,实施例3的化合物在第18天导致肿瘤完全消退。
组 | 小鼠 | 药剂 | mg/kg | 路径 | 日程表 | BW最低值 | 肿瘤体积 |
1 | 8 | 媒介物 | 媒介物 | po | qd x 7 | -2.10% | 1124mm3 |
2 | 8 | 实施例3 | 25 | po | qd x 7 | -3.60% | 368mm3 |
3 | 8 | 实施例3 | 50 | po | qd x 7 | -2.90% | 26mm3 |
4 | 8 | 实施例3 | 100 | po | qd x 7 | -2.10% | 0mm3 |
5 | 8 | ABT-199 | 50 | po | qd x 7 | -3.60% | 0mm3 |
如下所示,实施例10化合物也产生剂量依赖性肿瘤生长降低。以50mg/kg,实施例10化合物导致第19天的肿瘤消退。
综上,本发明涉及以下方面:
1.式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药:
其中
Q1是6元杂环烷基、6元杂环烯基或6元杂芳基;
Q2是芳基或杂芳基;
Q3是环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基;
Q4是
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、和R12各自独立是H、D、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤素、硝基、氧代、氰基、ORa、SRa、烷基-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRc、烷基-P(O)RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、S(O)(=N(Ra))Rb、-N=S(O)RbRc、SO2N(Rb)Rc、或N(Rb)SO2Rc,其中所述环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选用一个或多个Rd取代;
Ra、Rb、Rc和Rd独立是H、D、烷基、烯基、炔基、卤素、氰基、胺、硝基、羟基、C(O)NHOH、C(O)OH、C(O)NH2、烷氧基、烷氧基烷基、卤代烷基、羟基烷基、氨基烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基氨基、氧代、卤代烷基氨基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选用一个或多个Re取代;
Re是H、D、烷基、烯基、炔基、卤代、氰基、胺、硝基、羟基、C(O)NHOH、烷氧基、烷氧基烷基、卤代烷基、羟基烷基、氨基烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基氨基、氧代、卤代烷基氨基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基;
Z1是键、(CH2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)q、二价烯基基团、或二价炔基基团;
L是键、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基任选用一个或多个Rd取代;
Y、W、和W2各自独立是CH或N;
W1是N;
W3是O或N(Ra);
V是N、C、或CH;
R9基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R9的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R2基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R2的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R10基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R10的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R11和R12基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R11或R12的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R10和R2基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R10或R2的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R4和-Z1-L-R6基团与它们附接的原子一起可以任选形成环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中R4的所述环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基任选用一个或多个Rd取代;
Rb和Rc基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中Rb和Rc的所述环烷基或杂环烷基任选用一个或多个Re取代;
Rd基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中Rd的所述环烷基或杂环烷基任选用一个或多个Re取代;
Re基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基;
j和k各自独立是0、1、2、3、4、5、6、7或8;且
m、n、p、q和r各自独立是0、1、2、3、或4;
任选地,条件是当是/>时,则-Z1-L-R6不是
2.根据项1的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中所述化合物以式(B)表示:
其中
Z2是-O-、-CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(=N(Ra))-、-P(O)(Ra)-;其中Z2的Ra独立是H、D、C1-C6烷基、C2-C6烯基、C1-C6烷基羰基、C1-C6烷氧基羰基、C3-C6环烷基、5-8元单环杂环烷基、C6-C14芳基、或5-8元单环杂芳基,其中所述C1-C6烷基、C3-C6环烷基、5-8元单环杂环烷基、C6-C14芳基、5-8元单环杂芳基任选用一个或多个Re取代,且
A是-(CR2R2)r-或-O-;其中r是0、1、2、或3;
R2各自独立是H、-(C1-C4)烷氧基、任选用-(C1-C4)烷氧基取代的-(C1-C4)烷基,或
R2基团中的两个与它们附接的同一碳原子一起形成-(C3-C6)环烷基或4-6元杂环状环,其中所述-(C3-C6)环烷基或4-6元杂环状环任选用-(C1-C4)烷基、-(C1-C4)卤代烷基或氧杂环丁基取代。
3.根据项2的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中所述化合物以式(C)表示:
其中R1是H、D、卤素或-(C1-C4)烷基。
4.根据项3的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中所述化合物以式(D)表示:
其中
R5独立是硝基、卤素、或-SO2Ra,其中R5的Ra是-(C1-C4)烷基或-(C1-C4)卤代烷基;
Z1是不存在、NH、N(H)(CH2)q、O、S、或-(C1-C4)亚烷基,其中q是1、2、或3;
L是不存在或任选用-(C3-C6)环烷基取代的-(C1-C4)亚烷基;且
R6是H、D、-N(CH3)-(C1-C4)亚烷基-P(O)((C1-C4)烷氧基)2、-P(O)(N(CH3)2)(OEt)、-P(O)(O-(C1-C4)亚烷基-O-CO-(C1-C4)烷基)2、-(C3-C6)环烷基、苯基、5-7元杂环基、8-10元二环状环,其中所述-(C3-C6)环烷基、苯基、5-7元杂环基、或7-10元二环状环任选用卤素、-OH、-CN、-COOH、-NH2、-N(CH3)2、-(C1-C4)烷基、-(C1-C4)烷氧基、环丙基、4-6元杂环基、-CH2P(O)(OH)2、-CH2P(O)((C1-C4)烷氧基)2、-P(O)((C1-C4)烷基)2或-N=S(O)((C1-C4)烷基)2取代。
5.根据项4的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R9独立是D、卤素、-OH、CN、-NH2、=O、-(C1-C4)烷基、-(C1-C4)烷氧基、-(C1-C4)卤代烷基、-(C1-C4)羟基烷基、-(C3-C6)环烷基、或1,3-二硫戊环基;且k是0、1、2、3、或4。
6.根据项4或5的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中A是-CH2-或-O-。
7.根据项4-6中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中每个R2独立是–CH3;且n是0或2。
8.根据项4-7中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中Z2是-O-。
9.根据项4-8中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R1是Cl。
10.根据项4-9中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R5是硝基。
11.根据项4-10中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中Z1是不存在、NH或O。
12.根据项4-11中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中Z2是-O-、-CH2-、-C(O)-、-NH-、-N-(氧杂环丁基)-、-S-、-S(O)-、-S(O2)-、-S(O)(=NH)-、-S(O)(=NCH3)-、或-P(O)(CH3)-。
13.根据项4-12中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R6是H、D、-(C3-C6)环烷基、苯基、四氢-2H-吡喃基、或1,4-二噁烷基,其中所述-(C3-C6)环烷基、苯基、四氢-2H-吡喃基或1,4-二噁烷基任选用1或2个选自下组的基团取代:卤素、-OH、=O、-(C1-C4)烷基、或-(C1-C4)烷氧基。
14.根据项4-13中任一项的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中R6是四氢-2H-吡喃基或1,4-二噁烷基,其中所述四氢-2H-吡喃基或1,4-二噁烷基任选用1或2个选自卤素的基团取代。
15.根据项1的化合物或其N-氧化物,或其药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药,其中所述化合物是:
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,2-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(4,4-二氧化-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)-2-(3-(三氟甲基)-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噻嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基-2,2,3,3-d4)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-(2-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
N-((4-((((R)-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((S)-2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(R)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺,
N-((4-((((S)-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((R)-2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-2-((S)-3-甲基-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,
(S)-N-((4-(((1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)苯甲酰胺,
(R)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((2-氟-1,4-二噁烷-2-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺,或
4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-2-(3,3-二氟-2,3-二氢吡咯并[3',2':5,6]吡啶并[2,3-b][1,4]噁嗪-1(6H)-基)-N-((4-(((4-氟四氢-2H-吡喃-4-基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺。
16.药物组合物,其包含如项1中限定的式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药和药学可接受稀释剂或载体。
17.治疗新生性疾病、自身免疫性疾病或神经变性性疾病的方法,其包括对有此需要的受试者施用有效量的如项1中限定的式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药。
18.项16的方法,其中所述新生性疾病、所述自身免疫性疾病或所述神经变性性疾病以异常的(例如增强或增加的)Bcl-2活性为特征,诸如血液恶性疾病/癌症、I类糖尿病、或精神分裂症。
19.项16的方法,其中所述新生性疾病是骨髓瘤、多发性骨髓瘤、淋巴瘤、滤泡性淋巴瘤(FL)、非何杰金氏淋巴瘤、白血病、急性白血病、急性成淋巴细胞性白血病(ALL)(例如依赖于BCL-2的ALL和儿科ALL)、慢性成淋巴细胞白血病(CLL)(如复发/难治性CLL、del(17p)CLL)、慢性髓样白血病(CML)(如原始细胞危象CML)、套细胞淋巴瘤(MCL)、弥漫性大B-细胞淋巴瘤、肺癌诸如小细胞肺癌(SCLC)、黑素瘤、乳腺癌或前列腺癌、包括其药物抗性癌症。
20.项16-19中任一项的方法,其进一步包括施用一种或多种有效治疗所述新生性疾病的进一步治疗,诸如手术、放射疗法、化学治疗剂(诸如苯达莫司汀、NL-101、顺铂、卡铂、依托泊苷、拓扑替康)、靶向治疗剂(如利妥昔单抗、依鲁替尼、ACP-196、艾代拉利司(Idelalisib));抗体-药物缀合物或ADC(如brentuximab vedotin)、免疫疗法(诸如派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、阿特珠单抗(atezolizumab)、德瓦鲁单抗(durvalumab)、阿维鲁单抗(avelumab))或CAR-T疗法(例如tisagenlecleucel,axicabtagene ciloleucel)。
Claims (5)
1.式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药:
其中
Q1是6元杂环烷基、6元杂环烯基或6元杂芳基;
Q2是芳基或杂芳基;
Q3是环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基;
Q4是
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、和R12各自独立是H、D、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基、卤素、硝基、氧代、氰基、ORa、SRa、烷基-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRc、烷基-P(O)RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、S(O)(=N(Ra))Rb、-N=S(O)RbRc、SO2N(Rb)Rc、或N(Rb)SO2Rc,其中所述环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选用一个或多个Rd取代;
Ra、Rb、Rc和Rd独立是H、D、烷基、烯基、炔基、卤素、氰基、胺、硝基、羟基、C(O)NHOH、C(O)OH、C(O)NH2、烷氧基、烷氧基烷基、卤代烷基、羟基烷基、氨基烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基氨基、氧代、卤代烷基氨基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选用一个或多个Re取代;
Re是H、D、烷基、烯基、炔基、卤代、氰基、胺、硝基、羟基、C(O)NHOH、烷氧基、烷氧基烷基、卤代烷基、羟基烷基、氨基烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基氨基、氧代、卤代烷基氨基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基;
Z1是键、(CH2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)q、二价烯基基团、或二价炔基基团;
L是键、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基任选用一个或多个Rd取代;
Y、W、和W2各自独立是CH或N;
W1是N;
W3是O或N(Ra);
V是N、C、或CH;
R9基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R9的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R2基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R2的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R10基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R10的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R11和R12基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R11或R12的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R10和R2基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中R10或R2的所述环烷基或杂环烷基任选用一个或多个Rd取代;
R4和-Z1-L-R6基团与它们附接的原子一起可以任选形成环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基,其中R4的所述环烷基、环烯基、杂环烷基、杂环烯基、芳基、或杂芳基任选用一个或多个Rd取代;
Rb和Rc基团与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中Rb和Rc的所述环烷基或杂环烷基任选用一个或多个Re取代;
Rd基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基,其中Rd的所述环烷基或杂环烷基任选用一个或多个Re取代;
Re基团中的两个与它们附接的原子一起可以任选形成环烷基或杂环烷基;
j和k各自独立是0、1、2、3、4、5、6、7或8;且
m、n、p、q和r各自独立是0、1、2、3、或4;
任选地,条件是当是/>时,则-Z1-L-R6不是
2.药物组合物,其包含如权利要求1中限定的式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药和药学可接受稀释剂或载体。
3.治疗新生性疾病、自身免疫性疾病或神经变性性疾病的方法,其包括对有此需要的受试者施用有效量的如权利要求1中限定的式(A)的化合物或其N-氧化物或所述式(A)的化合物或其N-氧化物的药学可接受的盐、溶剂合物、多形体、互变异构体、立体异构体、同位素形式或前药。
4.选自以下的化合物:
其中各变量如权利要求1中所定义。
5.通过PerkinElmer ATPliteTM发光测定系统测定细胞抗增殖的方法,包括以下步骤:
将各种测试癌细胞系以每孔约1×104个细胞的密度接种在Costar 96孔板中,并在补充有5%FBS或10%正常人血清(NHS)的培养基中与不同浓度的化合物温育约72小时;
然后通过添加5mL底物缓冲液来重建一个冻干的底物溶液小瓶,并轻轻搅拌直至溶液均匀;
将约50μL哺乳动物细胞裂解溶液添加到微板的每孔的100μL细胞悬浮液,并将该板在定轨振荡器中以约700rpm摇动约五分钟;
该程序用于裂解细胞并稳定ATP;
接下来,将50μL底物溶液添加至孔中,并将微孔板在定轨振荡器中以约700rpm振荡5分钟;
最后,通过PerkinElmer 微板闪烁计数器测量发光。
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