CN112041312A - 用作免疫调节剂的化合物 - Google Patents
用作免疫调节剂的化合物 Download PDFInfo
- Publication number
- CN112041312A CN112041312A CN201980028083.6A CN201980028083A CN112041312A CN 112041312 A CN112041312 A CN 112041312A CN 201980028083 A CN201980028083 A CN 201980028083A CN 112041312 A CN112041312 A CN 112041312A
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- Prior art keywords
- chloro
- alkyl
- methoxy
- group
- inden
- Prior art date
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
本申请总体上涉及用作免疫调节剂的化合物。本文提供了化合物、包含此类化合物的组合物及其使用方法。本申请进一步涉及包含至少一种根据本申请的化合物的药物组合物,所述药物组合物可用于治疗各种疾病,包括癌症和传染性疾病。
Description
技术领域
本申请总体上涉及用作PD-1/PD-L1蛋白质/蛋白质和CD80/PD-L1蛋白质/蛋白质相互作用的抑制剂的化合物。本文提供了化合物、包含此类化合物的组合物及其使用方法。本申请进一步涉及包含至少一种根据本申请的化合物的药物组合物,所述药物组合物可用于治疗各种疾病,包括癌症和传染性疾病。
背景技术
程序性死亡-1(CD279)是T细胞上的一种受体,其已显示在与其任一配体(程序性死亡-配体1(PD-L1、CD274、B7-H1)或PD-L2(CD273、B7-DC))结合时抑制来自T细胞受体的活化信号(Sharpe等人,Nat.Imm.2007)。当表达PD-1的T细胞接触表达其配体的细胞时,响应于抗原刺激的功能活性降低,所述功能活性包括增殖、细胞因子分泌和细胞溶解活性。在感染或肿瘤消退期间或在自身耐受性发展期间PD-1/PD-配体的相互作用下调免疫应答(KeirMe,Butte MJ,Freeman GJ,等人Annu.Rev.Immunol.2008;26:Epub)。慢性抗原刺激,诸如在肿瘤疾病或慢性感染期间出现的慢性抗原刺激,致使T细胞表达升高含量的PD-1且在针对慢性抗原的活性方面功能异常(评述于Kim和Ahmed,Curr Opin Imm,2010中)。这被称为“T细胞耗竭”。B细胞也呈现PD-1/PD-配体抑制和“耗竭”。
PD-L1也已经显示与CD80相互作用(Butte MJ等人,Immunity 27:111-122(2007))。已经显示PD-L1/CD80对表达免疫细胞的相互作用为抑制性相互作用。已经显示阻断该相互作用可以消除这种抑制性相互作用(Paterson AM,等人,J Immunol.,187:1097-1105(2011);Yang J,等人J Immunol.8月1日;187(3):1113-9(2011))。
已经显示使用PD-L1的抗体阻断PD-1/PD-L1相互作用在许多系统中恢复和增强T细胞激活。患有晚期癌症的患者受益于使用针对PD-L1的单克隆抗体的疗法(Brahmer等人,New Engl J Med 2012)。肿瘤的临床前动物模型已经显示通过单克隆抗体阻断PD-1/PD-L1路径可以增强免疫应答且实现对多种组织学上不同的肿瘤的免疫应答(Dong H,Chen L.JMol Med.2003;81(5):281-287;Dong H,Strome SE,Salamoa DR,等人Nat Med.2002;8(8):793-800)。
干扰PD-1/PD-L1相互作用也已经显示在慢性感染系统中增强的T细胞活性。小鼠的慢性淋巴细胞性脉络丛脑膜炎(Chronic lymphocytic chorio meningitis)病毒感染也表现出随着阻断PD-L1而改善的病毒清除率和恢复的免疫力(Barber DL,Wherry EJ,Masopust D,等人Nature 2006;439(7077):682-687)。感染HIV-1的人源化小鼠显示对病毒血症增强的防护和CD4+T细胞的减少的病毒消耗(Palmer等人,J.Immunol 2013)。经由针对PD-L1的单克隆抗体阻断PD-1/PD-L1可以恢复HIV患者(Day,Nature2006;Petrovas,J.Exp.Med.2006;Trautman,Nature Med.2006;D’Souza,J.Immunol.2007;Zhang,Blood2007;Kaufmann,Nature Imm.2007;Kasu,J.Immunol.2010;Porichis,Blood 2011)、HCV患者[Golden-Mason,J.Virol.2007;Jeung,J.Leuk.Biol.2007;Urbani,J.Hepatol.2008;Nakamoto,PLoS Path.2009;Nakamoto,Gastroenterology2008]或HBV患者(Boni,,J.Virol.2007;Fisicaro,Gastro.2010;Fisicaro等人,Gastroenterology,2012;Boni等人,Gastro.,2012;Penna等人,J Hep,2012;Raziorrough,Hepatology 2009;Liang,WorldJ Gastro.2010;Zhang,Gastro.2008)的T细胞的体外抗原特异性功能。
也已经显示阻断PD-L1/CD80相互作用可以刺激免疫力(Yang J.,等人,JImmunol.8月1日;187(3):1113-9(2011))。已经显示由阻断PD-L1/CD80相互作用引起的免疫刺激通过与阻断另外的PD-1/PD-L1或PD-1/PD-L2相互作用相结合而得到增强。
免疫细胞表型的改变被假设为是败血性休克的重要因素(Hotchkiss,等人,NatRev Immunol(2013))。这些包括PD-1和PD-L1水平和T细胞凋亡的增加(Guignant等人,Crit.Care(2011))。针对PD-L1的抗体可以降低免疫细胞凋亡的水平(Zhang等人,Crit.Care(2011))。此外,缺乏PD-1表达的小鼠与野生型小鼠相比对败血性休克症状更具抗性(Yang J.,等人.J Immunol.8月1日;187(3):1113-9(2011))。研究表明,使用抗体阻断PD-L1相互作用可以抑制不当免疫应答和改善疾病症状。
除了增强对慢性抗原的免疫应答之外,也已经显示阻断PD-1/PD-L1路径增强对疫苗接种(包括在慢性感染的情形下的治疗性疫苗接种)的应答(S.J.Ha,S.N.Mueller,E.J.Wherry等人,The Journal of Experimental Medicine,第205卷,第3期,第543-555页,2008.;A.C.Finnefrock,A.Tang,F.Li等人,The Journal of Immunology,第182卷,第2期,第980-987页,2009;M.-Y.Song,S.-H.Park,H.J.Nam,D.-H.Choi,和Y.-C.Sung,TheJournal of Immunotherapy,第34卷,第3期,第297-306页,2011)。
PD-1路径是由慢性感染和肿瘤疾病期间的慢性抗原刺激引起的T细胞耗竭中的关键抑制分子。经由靶向PD-L1蛋白来阻断PD-1/PD-L1相互作用已经显示可以在体外和体内恢复抗原特异性T细胞免疫功能,包括在处置肿瘤或慢性感染中增强对疫苗接种的应答。
因此,需要阻断PD-L1与PD-1或CD80的相互作用的药剂。
发明内容
申请人发现有效化合物,所述化合物具有作为PD-L1与PD-1和CD80的相互作用的抑制剂的活性,并因此可以用于治疗性给药以增强在癌症或感染(包括治疗性疫苗)中的免疫力。提供这些化合物用作具有所期望的稳定性、生物利用度、治疗指数和毒性值的药物,所述期望的稳定性、生物利用度、治疗指数和毒性值对于其成药性(drugability)而言是重要的。
在本申请的第一方面中,提供式(I)的化合物
或其药学上可接受的盐,其中:
m为0、1或2;
n’为1、2或3;
Z选自氢、-CH3、-O(CH2)nX和-O(CH2)nAr;其中
n为1、2、3或4;
X选自氢、-CH3、-CF3、CN、-CO2R1、-C(O)NH2、OR1和吡咯烷酮基;
R1为H或C1-C3烷基,其条件为当n为1时,R1为C1-C3烷基;
Ar选自苯并二噁烷基、吲唑基、异喹啉基、异噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基和喹啉基;其中各个环任选地被1、2、3或4个取代基取代,所述取代基独立地选自C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基氨基、C1-C4烷基、(C1-C4烷基)羰基、(C1-C4烷基)磺酰基、酰氨基、氨基羰基、氨基羰基(C1-C3烷基)、-(CH2)qCO2C1-C4烷基、-(CH2)qOH、羧基、氰基、甲酰基、卤素、卤代C1-C4烷基、卤代C1-C4烷氧基、硝基、任选地被一个氰基基团取代的苯基、任选地被一个卤素基团取代的苯基氧基、苯基羰基、吡咯和四氢吡喃;且其中q为0、1、2、3或4;
R2选自氢、C1-C3烷基、氰基、卤素和卤代C1-C3烷基;
v为1或2;
环A为含一个氮原子的5元或6元环,其中所述环通过所述环中的碳原子连接到母体分子部分;和
Rv选自C1-C3烷基、C1-C3烷基羰基氨基和羟基;
R4各自独立地选自C2-C4烯基、C1-C4烷氧基、C1-C4烷基、氰基、卤素和卤代C1-C4烷基;和
R5选自-(CH2)pCHO、-(CH2)pCO2H、-(CH2)wOH、-C(O)NR100R101、-CH(CH3)NRqR8和-(CH2)wNRqR8;其中
R100和R101选自氢、C1-C6烷基和羟基(C1-C6烷基),其任选地被额外的羟基基团取代;或,R100和R101与其所连接的氮原子一起形成6元环,其任选地被羧基基团取代;
p为0、1、2或3;
w为1、2、3或4;
Rq选自氢、C1-C4烷基、苄基、(C3-C6环烷基)C1-C3烷基、卤代C1-C4烷基、任选被第二羟基基团取代的羟基C1-C6烷基和任选被氰基基团取代的吡啶基(C1-C3烷基);和
R8选自氢、C1-C4烷基、-(CH2)nN(CH3)2、羧基C2-C6烯基、羧基C1-C6烷基和羟基C1-C6烷基,其中所述羧基C1-C6烷基和所述羟基C1-C6烷基的烷基部分任选地被一个羟基或苯基基团取代,其中所述苯基基团进一步任选地被羟基基团取代; 和
Rw为-CONH2,
R9选自氢、苄基和甲基;
R9’各自独立地选自氢和C1-C3烷基;
R10选自氢、C1-C3烷基和苄基;
R11选自C2-C4烯基和C1-C4烷基;和
R60选自氢、C1-C6烷基和C1-C6烷氧基羰基,
或
R8和Rq与其所连接的氮原子一起形成环,所述环选自
s为0、1或2;
z为1、2或3;
Q’选自CHR13”、S、O、NH、NC(O)OC1-C6烷基、N(CH2)2OH和NCH3;
R12和R12’独立地选自氢、-CO2H、羟基C1-C4烷基、氧代和-C(O)NHSO2R16;
R13和R13’独立地选自氢、羟基C1-C4烷基、氧代和-CO2H;
R13”选自羟基C1-C3烷基和-CO2H;
R14各自独立地选自C1-C4烷氧基羰基、C1-C6烷基、羧基、卤素、羟基、羟基C1-C4烷基、-NRc’Rd’和苯基氧基羰基,其中所述苯基任选地被硝基基团取代,其中Rc’和Rd’独立地选自氢、C1-C4烷氧基羰基和C1-C4烷基羰基;和
R16选自三氟甲基、环丙基、C1-C4烷基、二甲基氨基和被甲基基团取代的咪唑基。
在第一方面的第二实施方案中,本申请提供式(I)的化合物或其药学上可接受的盐,其中
在第一方面的第三实施方案中,本申请提供式(I)的化合物或其药学上可接受的盐,其中R2为卤素。
在第一方面的第四实施方案中,本申请提供式(I)的化合物或其药学上可接受的盐,其中Z为-O(CH2)nAr,其中n为1,且Ar为被一个氰基基团取代的吡啶基。
在第一方面的第五实施方案中,本申请提供式(I)的化合物或其药学上可接受的盐,其中m为1,且R4为卤素。
在第一方面的第八实施方案中,本申请提供式(I)的化合物或其药学上可接受的盐,其中R5为-CH2OH。
在第一方面的第十实施方案中,本申请提供式(I)的化合物或其药学上可接受的盐,其中:
Z为-O(CH2)nAr,其中n为1,且Ar为被一个氰基基团取代的吡啶基;
R2为卤素;
m为1;
R4为卤素;和
在第二方面中,本申请提供一种药物组合物,其包含式(I)的化合物或其药学上可接受的盐以及药学上可接受的载体。
在第三方面中,本申请提供一种在有需要的受试者中增强、刺激、调节和/或增加免疫应答的方法,所述方法包括向受试者给药治疗有效量的式(I)的化合物或其药学上可接受的盐。在第三方面的第一实施方案中,所述方法还包括在给药式(I)的化合物或其药学上可接受的盐之前、之后或同时给药另外的药剂。在第二实施方案中,所述另外的药剂是抗微生物剂、抗病毒剂、细胞毒性剂、基因表达调节剂和/或免疫应答调节剂。
在第四方面中,本申请提供一种在有需要的受试者中抑制癌细胞生长、增殖或转移的方法,所述方法包括向受试者给药治疗有效量的式(I)的化合物或药学上可接受的盐。在第四方面的第一实施方案中,所述癌症选自黑素瘤、肾细胞癌、鳞状非小细胞肺癌(NSCLC)、非鳞状NSCLC、结直肠癌、去势抵抗性前列腺癌、卵巢癌、胃癌、肝细胞癌、胰腺癌、头颈部鳞状细胞癌、食道癌、胃肠道癌和乳腺癌以及血液恶性肿瘤。
在第五方面,本申请提供了一种在有需要的受试者中治疗传染性疾病的方法,所述方法包括向受试者给药治疗有效量的式(I)的化合物或其药学上可接受的盐。在第五方面的第一实施方案中,所述传染性疾病由病毒引起。在第五方面的第二实施方案中,所述病毒选自HIV、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒、乳头瘤病毒和流感。
在第六方面中,本申请提供了一种在有需要的受试者中治疗败血性休克的方法,所述方法包括向受试者给药治疗有效量的式(I)的化合物或其药学上可接受的盐。
具体实施方式
除非本文中另有具体说明,否则以单数形式提及也可包括复数形式。例如,“一个/种”可指一个/种,或一或多个/种。
如本文所用,短语“化合物或其药学上可接受的盐”指至少一种化合物、所述化合物的至少一种盐或其组合。例如,式(I)的化合物或其药学上可接受的盐包括一种式(I)的化合物;两种式(I)的化合物;式(I)的化合物的一种盐;一种式(I)的化合物和所述式(I)的化合物的一种或多种盐;和一种式(I)的化合物的两种或更多种盐。
除非另有说明,否则假定具有不饱和价态的任何原子具有足以使价态饱和的氢原子。
在整个说明书中,本领域技术人员可以选择基团及其取代基以提供稳定的部分和化合物。
下文列出用于描述本申请的各种术语的定义。当术语单独地或作为较大基团的一部分用于整个本说明书中(除非在特定情况下以其它方式加以限制)时,这些定义适用于所述术语。本文所阐述的定义优先于以引用的方式并入本文中的任何专利、专利申请和/或专利申请公开中所阐述的定义。
如本文所用的术语“C2-C4烯基”是指含有一个或两个双键的2至4个碳原子的烃。
如本文所用的术语“C1-C4烷氧基”是指通过氧原子连接至母体分子部分的C1-C4烷基基团。
如本文所用的术语“C1-C4烷氧基羰基”是指通过羰基基团连接至母体分子部分的C1-C4烷氧基基团。
如本文所用的术语“C1-C6烷氧基羰基”是指通过羰基基团连接至母体分子部分的C1-C6烷氧基基团。
如本文所用的术语“C1-C4烷氧基羰基氨基”是指通过-NH基团连接至母体分子部分的C1-C4烷氧基羰基基团。
如本文所用的术语“C1-C3烷基”是指衍生自含有1至3个碳原子的直链或支链饱和烃的基团。
如本文所用的术语“C1-C4烷基”是指衍生自含有1至4个碳原子的直链或支链饱和烃的基团。
如本文所用的术语“C1-C6烷基”是指衍生自含有1至6个碳原子的直链或支链饱和烃的基团。
如本文所用的术语“C1-C4烷基羰基”是指通过羰基基团连接至母体分子部分的C1-C4烷基基团。
如本文所用的术语“C1-C3烷基羰基氨基”是指RaC(O)NH-,其中Ra为C1-C3烷基基团。
如本文所用的术语“C1-C4烷基磺酰基”是指通过磺酰基基团连接至母体分子部分的C1-C4烷基基团。
如本文所用的术语“酰氨基”是指-C(O)NH2。
如本文所用的术语“氨基羰基”是指-C(O)NH2。
如本文所用的术语“氨基羰基(C1-C3烷基)”是指通过C1-C3烷基基团连接至母体分子部分的氨基羰基基团。
如本文所用的术语“羰基”是指-C(O)-。
如本文所用的术语“羧基”是指-CO2H。
如本文所用的术语“羧基C2-C6烯基”是指通过C2-C6烯基基团连接至母体分子部分的羧基基团。
如本文所用的术语“羧基C1-C6烷基”是指通过C1-C6烷基基团连接至母体分子部分的羧基基团。
如本文所用的术语“氰基”是指-CN。
如本文所用的术语“C3-C6环烷基”是指具有3至6个碳原子和0个杂原子的饱和单环烃环体系。环烷基基团的代表性实例包括但不限于环丙基、环丁基、环戊基和环己基。
如本文所用的术语“(C3-C6环烷基)C1-C3烷基”是指被C3-C6环烷基基团取代的C1-C3烷基基团。
如本文所用的术语“甲酰基”是指-C(O)H。
如本文所用的术语“卤代”和”卤素”是指F、Cl、Br或I。
如本文所用的术语“卤代C1-C4烷氧基”是指通过氧原子连接至母体分子部分的卤代C1-C4烷基基团。
如本文所用的术语“卤代C1-C3烷基”是指被1、2或3个卤素原子取代的C1-C3烷基基团。
如本文所用的术语“卤代C1-C4烷基”是指被1、2或3个卤素原子取代的C1-C4烷基基团。
如本文所用的术语“羟基C1-C3烷基”是指通过C1-C3烷基基团连接至母体分子部分的羟基基团。
如本文所用的术语“羟基C1-C4烷基”是指通过C1-C4烷基基团连接至母体分子部分的羟基基团。
如本文所用的术语“羟基C1-C6烷基”是指通过C1-C6烷基基团连接至母体分子部分的羟基基团。
如本文所用的术语“硝基”是指-NO2。
如本文所用的术语“氧代”是指=O。
如本文所用的术语“苯基羰基”是指通过羰基基团连接至母体分子部分的苯基基团。
如本文所用的术语“苯基氧基”是指通过氧原子连接至母体分子部分的苯基基团。
如本文所用的术语“苯基氧基羰基”是指通过羰基基团连接至母体分子部分的苯基氧基基团。
如本文所用的术语“吡啶基(C1-C3)烷基”是指通过C1-C3烷基基团连接至母体分子部分的吡啶基基团。
短语“药学上可接受的”在本文中用于指在合理医学判断的范畴内适于与人和动物的组织接触使用而无过度毒性、刺激、过敏反应或其它问题或并发症,与合理益处/风险比相匹配的那些化合物、物质、组合物和/或剂型。
式(I)的化合物可形成也在本申请申请范畴内的盐。除非另外说明,否则提及本申请化合物应理解为包括提及一种或多种其盐。术语“盐”表示与无机酸和/或有机酸以及无机碱和/或有机碱形成的酸性盐和/或碱性盐。此外,术语“盐”可包括两性离子(内盐),例如当式(I)的化合物含有碱性部分(诸如胺或吡啶或咪唑环)与酸性部分(诸如羧酸)时。药学上可接受的(即无毒的,生理学上可接受的)盐为优选的,诸如可接受的金属和胺盐,其中阳离子不会明显促成所述盐的毒性或生物活性。然而,其它盐可用于例如在制备期间可采用的分离或纯化步骤,并因此涵盖在本申请的范畴内。所述式(I)的化合物的盐例如可通过使式(I)的化合物与一定量(诸如等量)的酸或碱在介质(诸如使盐沉淀的介质)中或在水性介质中反应,继而冻干来形成。
示例性酸加成盐包括乙酸盐(诸如用乙酸或三卤乙酸(例如三氟乙酸)形成的那些盐)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(用盐酸形成)、氢溴酸盐(用溴化氢形成)、氢碘酸盐、马来酸盐(用马来酸形成)、2-羟基乙磺酸盐、乳酸盐、甲磺酸盐(用甲磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐(pectinates)、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如用硫酸形成的那些盐)、磺酸盐(诸如本文中提及的那些盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(诸如甲苯磺酸盐(tosylate))、十一烷酸盐等。
示例性碱性盐包括铵盐;碱金属盐,诸如钠盐、锂盐和钾盐;碱土金属盐,诸如钙盐和镁盐;钡盐、锌盐和铝盐;与有机碱(例如有机胺)形成的盐,所述有机碱如三烷基胺(诸如三乙胺)、普鲁卡因(procaine)、二苄基胺、N-苄基-β-苯乙胺、1-二苯羟甲胺(1-ephenamine)、N,N'-二苄基乙二胺、脱氢枞胺、N-乙基哌啶、苯甲胺、二环己胺或类似的药学上可接受的胺,以及与氨基酸(诸如精氨酸、赖氨酸等)形成的盐。碱性含氮基团可用如下试剂季铵化,诸如低级烷基卤化物(例如,甲基、乙基、丙基和丁基氯化物,甲基、乙基、丙基和丁基溴化物以及甲基、乙基、丙基和丁基碘化物)、硫酸二烷基酯(例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯)、长链卤化物(例如癸基、月桂基、肉豆蔻基和硬脂基氯化物,癸基、月桂基、肉豆蔻基和硬脂基溴化物以及癸基、月桂基、肉豆蔻基和硬脂基碘化物)、芳烷基卤化物(例如苄基和苯乙基溴化物)等。优选的盐包括单盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
前药的各种形式为本领域中熟知的且描述于以下中:
a)The Practice of Medicinal Chemistry,Camille G.Wermuth等人,第31章,(Academic Press,1996);
b)Design of Prodrugs,由H.Bundgaard编辑,(Elsevier,1985);
c)A Textbook of Drug Design and Development,P.Krogsgaard-Larson和H.Bundgaard编辑,第5章,第113-191页(Harwood Academic Publishers,1991);和
d)Hydrolysis in Drug and Prodrug Metabolism,Bernard Testa和JoachimM.Mayer,(Wiley-VCH,2003)。
本申请的化合物可以包含立体异构体,其中存在不对称或手性中心。取决于手性碳原子周围的取代基的构型,特定的立体化学可以用符号“R”或“S”表示。本发明考虑了各种立体异构体(即,对映异构体和非对映异构体)及其混合物,并且旨在涵盖所有与PD-L1结合的立体异构体。本发明化合物的各个立体异构体可以由包含不对称或手性中心的可商购的起始原料合成制备,或者通过制备外消旋混合物,然后通过本领域普通技术人员熟知的拆分来合成制备。
此外,式(I)的化合物在其制备后可经分离和纯化以获得含有其量以重量计等于或大于99%的式(I)的化合物(“基本上纯”)的组成,其随后如本文所述使用或配制。此类“基本上纯”的式(I)的化合物也作为本申请的部分涵盖在本文中。
“稳定的化合物”和“稳定的结构”旨在指足够稳固从而可以经受由反应混合物至可用纯度程度的分离和配制成有效治疗试剂的化合物。本申请旨在包括稳定的化合物。
“治疗有效量”旨在包括有效抑制PD-1/PD-L1蛋白/蛋白和/或CD80/PD-L1蛋白/蛋白相互作用或有效治疗或预防癌症或传染性疾病(诸如败血性休克、HIV或乙型肝炎、丙型肝炎和丁型肝炎)的单独本申请化合物的量、或本申请化合物的组合的量、或与其它活性成分组合的本申请化合物的量。
如本文所用,“治疗(treating)”或“治疗(treatment)”涵盖治疗哺乳动物,尤其人类的疾病状态,且包括:(a)预防哺乳动物出现所述疾病状态,尤其在此类哺乳动物易于患上所述疾病状态但尚未被诊断为患有所述疾病状态时;(b)抑制所述疾病状态,即遏制其发展;和/或(c)缓解所述疾病状态,即使得所述疾病状态消退。
本申请的化合物旨在包括本申请化合物中出现的原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。作为一般实例但非限制性地,氢的同位素包括氘(D)和氚(T)。碳的同位素包括13C和14C。本申请的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于本文所述的方法,使用适当的同位素标记试剂替代原先使用的未标记试剂来制备。例如,甲基(-CH3)也包括氘化甲基,诸如-CD3。
根据式(I)的化合物和/或其药学上可接受的盐可通过适合于待治疗的病况的任何方式给药,其可根据位点特异性治疗的需要或待递送的式(I)的化合物的量而定。如下类别的药物组合物也涵盖在本申请内,其包含式(I)的化合物和/或其药学上可接受的盐;和一种或多种无毒的药学上可接受的载体和/或稀释剂和/或辅助剂(在本文中统称为"载体"材料)和必要时其它活性成分。式(I)的化合物可通过任何适合的途径给药,优选为适于此类途径的药物组合物形式且为对预期治疗有效的剂量。本申请的所述化合物和组合物可以含有常规药学上可接受的载体、辅助剂和媒介物的剂量单位制剂例如经口服、经粘膜、经直肠或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌肉内和胸骨内)给药。例如,所述药物载体可含有甘露糖醇或乳糖与微晶纤维素的混合物。所述混合物可含有其它组分,诸如润滑剂(例如硬脂酸镁)和崩解剂(诸如交联聚维酮(crospovidone))。载体混合物可填充至明胶胶囊中或压缩为片剂。所述药物组合物可例如以口服剂型或输注形式给药。
对于口服给药,所述药物组合物可呈例如片剂、胶囊、液体胶囊、悬浮液或液体形式。所述药物组合物优选以含有特定量活性成分的剂量单位形式制得。例如,所述药物组合物可以包含约0.1至1000mg,优选约0.25至250mg,且更优选约0.5至100mg范围内的量的活性成分的片剂或胶囊提供。用于人类或其它哺乳动物的适合日剂量可根据患者的病况及其它因素而广泛变化,但可使用常规方法确定。
本文中涵盖的任何药物组合物均可例如经由任何可接受且适合的口服制剂经口服递送。示例性口服制剂包括但不限于,例如片剂、糖锭剂、锭剂、水性和油性悬浮液、可分散粉末或颗粒、乳剂、硬和软胶囊、液体胶囊、糖浆和酏剂。旨在用于口服给药的药物组合物可根据本领域中已知的制备旨在用于口服给药的药物组合物的任何方法制备。为提供药学上适口的制剂,根据本申请的药物组合物可含有至少一种选自甜味剂、调味剂、着色剂、缓和剂、抗氧化剂和防腐剂的试剂。
片剂可例如通过将至少一种式(I)的化合物和/或至少一种其药学上可接受的盐与至少一种适合于制备片剂的无毒的药学上可接受的赋形剂混合来制备。示例性赋形剂包括但不限于,例如惰性稀释剂,例如,碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠;造粒剂和崩解剂,例如,微晶纤维素、交联羧甲基纤维素钠、玉米淀粉和海藻酸;粘合剂,例如,淀粉、明胶、聚乙烯基-吡咯烷酮和阿拉伯胶;和润滑剂,例如,硬脂酸镁、硬脂酸和滑石。此外,片剂可未被包衣或通过常规技术被包衣以掩盖口味使人不快的药物的不佳味道,或延迟活性成分在胃肠道中的崩解和吸收,从而使活性成分的作用维持更长的时间段。示例性水溶性掩味材料包括但不限于羟丙基-甲基纤维素和羟丙基-纤维素。示例性延时材料包括但不限于乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊可例如通过将至少一种式(I)的化合物和/或至少一种其盐与至少一种惰性固体稀释剂(例如,例如碳酸钙;磷酸钙;和高岭土)混合来制备。
软明胶胶囊可例如通过将至少一种式(I)的化合物和/或至少一种其药学上可接受的盐与至少一种水溶性载体(例如,聚乙二醇)和至少一种油性介质(例如,花生油、液体石蜡和橄榄油)混合来制备。
可例如通过将至少一种式(I)的化合物和/或至少一种其药学上可接受的盐与至少一种适合于制备水性悬浮液的赋形剂混合来制备水性悬浮液。适用于制备水性悬浮液的示例性赋形剂包括但不限于,例如助悬剂,例如,羧甲基纤维素钠、甲基纤维素、羟丙基甲基-纤维素、海藻酸钠、海藻酸、聚乙烯-吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或润湿剂,例如,天然存在的磷脂,例如卵磷脂;环氧烷与脂肪酸的缩合产物,例如,聚氧乙烯硬脂酸酯;环氧乙烷与长链脂族醇的缩合产物,例如,十七亚乙基-氧基十六醇;环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如,聚氧乙烯山梨糖醇单油酸酯;以及环氧乙烷与衍生自脂肪酸和己糖醇酸酐的偏酯的缩合产物,例如,聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液也可含有至少一种防腐剂,例如,对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯;至少一种着色剂;至少一种调味剂;和/或至少一种甜味剂,包括但不限于,例如蔗糖、糖精和阿斯巴甜。
油性悬浮液可例如通过使至少一种式(I)的化合物和/或至少一种其药学上可接受的盐悬浮于植物油(例如,花生油;橄榄油;芝麻油;和椰子油)或矿物油(例如,液体石蜡)中来制备。油性悬浮液也可含有至少一种增稠剂,例如,蜂蜡;硬石蜡;和鲸蜡醇。为提供适口的油性悬浮液,可将至少一种上文已描述的甜味剂和/或至少一种调味剂添加至油性悬浮液中。油性悬浮液可进一步含有至少一种防腐剂,包括但不限于,例如抗氧化剂,例如,丁基化羟基茴香醚和α-生育酚。
可分散的粉末和颗粒可例如通过将至少一种式(I)的化合物和/或至少一种其药学上可接受的盐与至少一种分散剂和/或润湿剂、至少一种助悬剂和/或至少一种防腐剂混合来制备。适合的分散剂、润湿剂和助悬剂如上文已描述。示例性防腐剂包括但不限于,例如抗氧化剂,例如抗坏血酸。此外,可分散的粉末和颗粒也可含有至少一种赋形剂,包括但不限于,例如甜味剂、调味剂和着色剂。
至少一种式(I)的化合物和/或至少一种其药学上可接受的盐的乳剂可例如制备为水包油乳剂。包含式(I)的化合物的乳剂的油相可以已知方式由已知成分构成。所述油相可由例如(但不限于)以下提供:植物油,例如,橄榄油和花生油;矿物油,例如,液体石蜡;及其混合物。尽管所述相可仅包含乳化剂,但其也可包含至少一种乳化剂与脂肪或油或脂肪与油两者的混合物。适合的乳化剂包括但不限于,例如天然存在的磷脂,例如大豆卵磷脂;衍生自脂肪酸和己糖醇酸酐的酯或偏酯,例如,脱水山梨糖醇单油酸酯;和偏酯与环氧乙烷的缩合产物,例如,聚氧乙烯脱水山梨糖醇单油酸酯。优选地,亲水性乳化剂与充当稳定剂的亲脂性乳化剂一起包括在内。还优选包括油和脂肪两者。总之,有或没有一种或多种稳定剂的一种或多种乳化剂组成所谓乳化蜡,且所述蜡连同所述油和脂肪组成所谓乳化软膏基质,其形成乳膏制剂的油性分散相。乳剂也可含有甜味剂、调味剂、防腐剂和/或抗氧化剂。适合用于本申请制剂中的乳化剂和乳剂稳定剂包括吐温60、司盘80、鲸蜡硬脂醇、十四烷醇、单硬脂酸甘油酯、月桂基硫酸钠、单独或含蜡的二硬脂酸甘油酯或本领域中所熟知的其它物质。
式(I)的化合物和/或至少一种其药学上可接受的盐也可例如在静脉内、皮下和/或肌肉内经由任何药学上可接受且适合的可注射形式递送。示例性可注射形式包括但不限于例如包含可接受的媒介物和溶剂的无菌水溶液,所述媒介物和溶剂例如,水、林格氏溶液(Ringer's solution)和生理盐溶液;无菌水包油微乳剂;和水性或油性悬浮液。
用于肠胃外给药的制剂可呈水性或非水性等渗无菌注射溶液或悬浮液形式。这些溶液和悬浮液可使用被提及用于口服给药的制剂中的一种或多种载体或稀释剂,或通过使用其它适合的分散剂或润湿剂和悬浮剂,由无菌粉末或颗粒来制备。所述化合物可溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、黄蓍胶和/或各种缓冲液中。其它辅助剂和给药模式在医药领域中深入且广泛地已知。活性成分也可作为具有适当的载体(包括盐水、右旋糖或水)或具有环糊精(即Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即吐温80)的组合物通过注射给药。
无菌可注射制剂也可为在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为1,3-丁二醇中的溶液。可采用的所述可接受的媒介物和溶剂有水、林格氏溶液和生理盐溶液。此外,无菌不挥发性油常规用作溶剂或悬浮介质。为此,可采用任何温和的不挥发性油,包括合成的单-或二甘油酯。此外,诸如油酸的脂肪酸可用于制备可注射剂。
无菌可注射水包油微乳剂可例如通过以下来制备:1)使至少一种式(I)的化合物溶解于油相,例如,大豆油与卵磷脂的混合物中;2)将含有式(I)的油相与水和甘油混合物组合;和3)处理所述组合以形成微乳剂。
无菌水性或油性悬浮液可根据本领域中已知的方法制备。例如,无菌水性溶液或悬浮液可用无毒的肠胃外可接受的稀释剂或溶剂(例如,1,3-丁二醇)制备;和无菌油性悬浮液可用无菌无毒的可接受的溶剂或悬浮介质(例如,无菌不挥发性油(例如合成单-或二甘油酯);和脂肪酸(例如,油酸))制备。
可用于本申请的药物组合物中的药学上可接受的载体、辅助剂和媒介物包括但不限于离子交换剂;氧化铝;硬脂酸铝;卵磷脂;自乳化药物递送系统(SEDDS),诸如d-α-生育酚聚乙二醇1000琥珀酸酯;用于医药剂型的表面活性剂,诸如吐温、聚乙氧基化蓖麻油(诸如CREMOPHOR表面活性剂(BASF))或其它类似聚合物递送基质;血清蛋白,诸如人类血清白蛋白;缓冲物质,诸如磷酸盐;甘氨酸;山梨酸;山梨酸钾;饱和植物脂肪酸的偏甘油酯混合物;水;盐或电解质,诸如鱼精蛋白硫酸盐;磷酸氢二钠;磷酸氢钾;氯化钠;锌盐;胶态二氧化硅;三硅酸镁;聚乙烯基吡咯烷酮;基于纤维素的物质;聚乙二醇;羧甲基纤维素钠;聚丙烯酸酯;蜡;聚乙烯-聚氧丙烯-嵌段聚合物;聚乙二醇和羊毛脂。环糊精(诸如α-环糊精、β-环糊精和γ-环糊精)或经化学改性的衍生物(诸如羟烷基环糊精,包括2-和3-羟丙基-环糊精)或其它溶解的衍生物也可有利地用于增强本文所描述的化学式的化合物的递送。
本申请的药学上活性化合物可根据制药学常规方法进行处理以产生用于向包括人类及其它哺乳动物的患者给药的药剂。所述药物组合物可进行诸如灭菌的常规医药操作和/或可含有常规辅助剂,诸如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等。片剂和丸剂可另外用肠溶包衣来制备。此类组合物也可包含辅助剂,诸如润湿剂、甜味剂、调味剂和芳香剂。
所给药的化合物的量和用本申请的化合物和/或组合物治疗疾病病况的给药方案取决于多种因素,所述因素包括受试者的年龄、体重、性别、医学病况;疾病类型;疾病的严重性;给药途径和频率以及所采用的具体化合物。因此,给药方案可广泛变化,但可常规地使用标准方法确定。每公斤体重约0.001至100mg,优选每公斤体重约0.0025至约50mg且最优选每公斤体重约0.005至10mg的日剂量可以是适当的。日剂量可以每天一至四剂给药。其它给药方案包括每周一剂和每两天的周期一剂。
出于治疗目的,本申请的活性化合物通常与一种或多种适于所示的给药途径的辅助剂组合。如果口服给药,则所述化合物可与乳糖、蔗糖、淀粉粉末、烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、海藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合且随后经压片或胶囊化以方便给药。此类胶囊或片剂可含有如活性化合物于羟丙基甲基纤维素中的分散液中可提供的控制释放制剂。
本申请的药物组合物包含至少一种式(I)的化合物和/或至少一种其药学上可接受的盐和任选的选自任何药学上可接受的载体、辅助剂和媒介物的其它试剂。本申请的替代性组合物包含本文所述的式(I)的化合物或其前药和药学上可接受的载体、辅助剂或媒介物。
本申请的化合物抑制PD-1/PD-L1蛋白/蛋白,从而阻断PD-L1。阻断PD-L1可增强哺乳动物(包括人类)中对癌细胞和传染性疾病的免疫应答。
在一个方面中,本申请涉及在体内使用式(I)的化合物或其盐治疗受试者,从而抑制癌性肿瘤的生长。可单独使用式(I)的化合物或其盐以抑制癌性肿瘤的生长。或者,式(I)的化合物或其盐可与如下所述的其它免疫原性药剂或标准癌症治疗结合使用。
在一个实施方案中,本申请提供一种抑制受试者中的肿瘤细胞生长的方法,其包括向受试者给药治疗有效量的式(I)的化合物或其盐。
在一个实施方案中,提供一种治疗癌症的方法,其包括向有需要的患者给药治疗有效量的式(I)的化合物或其盐。癌症的实例包括其生长可使用本申请化合物抑制的那些,包括通常对免疫疗法有应答的癌症。所治疗的优选癌症的非限制性实例包括黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素难治性前列腺癌)、乳腺癌、结肠癌和肺癌(例如非小细胞肺癌)。此外,本申请包括其生长可使用本申请化合物抑制的难治性或复发性恶性肿瘤。
可使用本申请的方法治疗的其它癌症的实例包括骨癌;胰腺癌;皮肤癌;头颈癌;皮肤或眼内恶性黑素瘤;子宫癌;卵巢癌;直肠癌;肛门区癌;胃癌;睾丸癌;子宫癌;输卵管癌;子宫内膜癌;子宫颈癌;阴道癌;外阴癌;霍奇金病(Hodgkin's Disease);非霍奇金淋巴瘤;食道癌;小肠癌;内分泌系统癌;甲状腺癌;甲状旁腺癌;肾上腺癌;软组织肉瘤;尿道癌;阴茎癌;慢性或急性白血病,包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞白血病(acute lymphoblastic leukemia)、慢性淋巴细胞白血病(chroniclymphocyticleukemia);儿童实体肿瘤;淋巴细胞性淋巴瘤;膀胱癌;肾癌或尿道癌;肾盂癌;中枢神经系统(CNS)赘瘤;原发性CNS淋巴瘤;肿瘤血管生成;脊髓轴肿瘤(spinal axistumor);脑干神经胶质瘤;垂体腺瘤;卡波西肉瘤(Kaposi's sarcoma);表皮样癌;鳞状细胞癌;T细胞淋巴瘤;环境诱发癌,包括由石棉诱发的癌症;和所述癌症的组合。本申请也适用于治疗转移性癌症,尤其是表达PD-L1的转移性癌症(Iwai等人(2005)Int.Immunol.17:133-144)。
任选地,式(I)的化合物或其盐可与另一免疫原性剂组合,所述另一免疫原性剂诸如癌细胞、纯化的肿瘤抗原(包括重组蛋白、肽和碳水化合物分子)、细胞和经编码免疫刺激性细胞因子的基因转染的细胞(He等人(2004)J.Immunol.173:4919-28)。可使用的肿瘤疫苗的非限制性实例包括黑素瘤抗原的肽,诸如gp100、MAGE抗原、Trp-2、MART1和/或酪氨酸酶的肽,或经转染以表达细胞因子GM-CSF的肿瘤细胞。
在人类中,已经显示一些肿瘤具有免疫原性,诸如黑素瘤。预期通过利用PD-L1阻断提高T细胞激活的阈值,预期激活宿主中的肿瘤应答。
所述PD-L1阻断可与疫苗接种方案组合。已设计出针对肿瘤的许多实验性疫苗接种策略(参见Rosenberg,S.,2000,Development of Cancer Vaccines,ASCO EducationalBook Spring:60-62;Logothetis,C.,2000,ASCO Educational Book Spring:300-302;Khayat,D.2000,ASCO Educational Book Spring:414-428;Foon,K.2000,ASCOEducational Book Spring:730-738;还参见Restifo,N.和Sznol,M.,Cancer Vaccines,第61章,第3023-3043页in DeVita,V.等人(编辑),1997,Cancer:Principles and Practiceof Oncology.第5版)。在这些策略之一中,使用自体或同种异体肿瘤细胞制备疫苗。已显示这些细胞疫苗在肿瘤细胞经转导以表达GM-CSF时最有效。已显示GM-CSF为用于肿瘤疫苗接种的抗原呈递的有效激活剂(Dranoff等人(1993)Proc.Natl.Acad.Sci.U.S.A.90:3539-43)。
对各种肿瘤中基因表达和大规模基因表达模式的研究已产生所谓肿瘤特异性抗原的定义(Rosenberg,S A(1999)Immunity 10:281-7)。在许多情况下,这些肿瘤特异性抗原是在肿瘤中和出现肿瘤的细胞中表达的分化抗原,例如黑色素细胞抗原gp100、MAGE抗原和Trp-2。更重要地,许多这些抗原可显示为宿主中发现的肿瘤特异性T细胞的靶标。PD-L1阻断可与许多在肿瘤中表达的重组蛋白和/或肽结合使用以产生针对这些蛋白的免疫应答。这些蛋白通常被免疫系统视为自身抗原且因此对其具耐受性。所述肿瘤抗原也可包括蛋白端粒酶,其是合成染色体端粒所需且在超过85%人类癌症中和仅有限数目的躯体组织中表达(Kim,N等人(1994)Science 266:2011-2013)。(可通过各种方法保护这些体组织免受免疫攻击)。肿瘤抗原也可为由于改变蛋白序列或在两个不相关序列(即费城染色体(Philadelphia chromosome)中的bcr-abl)之间产生融合蛋白的体细胞突变而表达于癌细胞中的“新抗原”,或来自B细胞肿瘤的个体基因型。
其它肿瘤疫苗可包括来自人类癌症中所牵涉的病毒的蛋白,所述病毒诸如人乳头状瘤病毒(HPV)、肝炎病毒(HBV、HDV和HCV)和卡波西疱疹肉瘤病毒(KHSV)。可与PD-L1阻断结合使用的肿瘤特异性抗原的另一形式是从肿瘤组织自身分离的纯化的热休克蛋白(HSP)。这些热休克蛋白含有来自肿瘤细胞的蛋白片段且这些HSP高效地递送至抗原呈递细胞以引起肿瘤免疫力(Suot,R&Srivastava,P(1995)Science 269:1585-1588;Tamura,Y.等人(1997)Science 278:117-120)。
树突状细胞(DC)是可用于引发抗原特异性应答的有效抗原呈递细胞。DC可离体产生且负载有各种蛋白和肽抗原以及肿瘤细胞提取物(Nestle,F.等人(1998)NatureMedicine 4:328-332)。DC也可通过基因方法转导以也表达这些肿瘤抗原。DC也已与肿瘤细胞直接融合用于免疫目的(Kugler,A.等人(2000)Nature Medicine 6:332-336)。作为接种疫苗的方法,DC免疫作用可与PD-L1阻断有效组合以激活更有效的抗肿瘤应答。
PD-L1阻断也可与标准癌症治疗组合。PD-L1阻断可与化学治疗方案有效组合。在这些情形下,可能减少所给药的化学治疗试剂的剂量(Mokyr,M.等人(1998)CancerResearch 58:5301-5304)。此类组合的一个实例是本申请化合物与达卡巴嗪组合用于治疗黑素瘤。此类组合的另一个实例是本申请化合物与白细胞介素-2(IL-2)组合用于治疗黑素瘤。支持所述PD-L1阻断与化学疗法组合使用的科学基本原理在于细胞死亡,所述细胞死亡作为大部分化学治疗化合物的细胞毒性作用的结果,应使得抗原呈递路径中肿瘤抗原的含量增加。可通过细胞死亡而与PD-L1阻断产生协同作用的其它组合疗法为放射、手术和激素去除。这些方案中的每一种在宿主中产生肿瘤抗原源。血管生成抑制剂也可与PD-L1阻断组合。抑制血管生成引起肿瘤细胞死亡,其可将肿瘤抗原送至宿主抗原呈递路径中。
本申请的化合物也可与将表达Fcα或Fcγ受体的效应细胞靶向肿瘤细胞的双特异性化合物组合使用(参见例如美国专利号5,922,845和5,837,243)。可使用双特异性化合物靶向两个单独的抗原。例如,抗-Fc受体/抗肿瘤抗原(例如Her-2/neu)的双特异性抗体已用于使巨噬细胞靶向肿瘤位点。此靶向可更有效地激活肿瘤特异性应答。这些应答的T细胞臂通过使用PD-L1阻断来增强。或者,可通过使用结合于肿瘤抗原和树突状细胞特异性细胞表面标记物的双特异性化合物将抗原直接递送至DC。
肿瘤通过多种机制逃避宿主免疫监视。许多这些机制可通过使肿瘤所表达且具免疫抑制性的蛋白失活来克服。这些尤其包括TGF-β(Kehrl,J.等人(1986)J.Exp.Med.163:1037-1050),IL-10(Howard,M.&O'Garra,A.(1992)Immunology Today 13:198-200)和Fas配体(Hahne,M.等人(1996)Science 274:1363-1365)。结合于且阻断这些实体中的每一种的抑制剂可与本申请化合物组合使用以抵消免疫抑制剂的作用且有利于宿主的肿瘤免疫应答。
激活宿主免疫应答的化合物可与PD-L1阻断组合使用。这些包括树突状细胞表面上的激活DC功能和抗原呈递的分子。抗CD40化合物能够有效地取代辅助性T细胞活性(Ridge,J.等人(1998)Nature 393:474-478)且可与PD-L1阻断结合使用(Ito,N.等人(2000)Immunobiology 201(5)527-40)。诸如CTLA-4(例如美国专利号5,811,097)、OX-40(Weinberg,A.等人(2000)Immunol 164:2160-2169)、4-1BB(Melero,I.等人(1997)NatureMedicine 3:682-685(1997)和ICOS(Hutloff,A.等人(1999)Nature 397:262-266)的T细胞共刺激分子的激活化合物也可提供增加的T细胞激活水平。
骨髓移植目前正用于治疗多种造血来源的肿瘤。虽然移植物抗宿主疾病是该治疗的后果,但可从移植物对肿瘤应答获得治疗益处。PD-L1阻断可用于增加供体移植的肿瘤特异性T细胞的有效性。
本申请的其它方法用于治疗已暴露于特定毒素或病原体的患者。因此,本申请的另一方面提供一种治疗受试者的传染性疾病的方法,其包含向受试者给药治疗有效量的式(I)的化合物或其盐。
类似于如上文所论述其对肿瘤的应用,式(I)的化合物或其盐可单独或作为辅助剂与疫苗组合用于刺激对病原体、毒素和自身抗原的免疫应答。该治疗方法可特别适用的病原体的实例包括当前无有效疫苗的病原体或常规疫苗不完全有效的病原体。其包括(但不限于)HIV、肝炎(甲型、乙型、丙型或丁型)、流感病毒、疱疹、贾第虫(Giardia)、疟疾、利什曼原虫、金黄色葡萄球菌(Staphylococcus aureus)、铜绿假单胞菌(PseudomonasAeruginosa)。PD-L1阻断对于由在感染过程期间呈现改变的抗原的感染物(诸如HIV)建立的感染特别适用。这些新颖表位在给药时被识别为外源的,因此引起强烈T细胞应答,此T细胞应答不会被通过PD-1的负信号抑制。
引起可通过本申请方法治疗的感染的病原性病毒的一些实例包括HIV、肝炎(甲型、乙型、丙型或丁型)、疱疹病毒(例如VZV、HSV-1、HAV-6、HHv-7、HHV-8、HSV-2、CMV和爱泼斯坦-巴尔二氏病毒(Epstein Barr virus))、腺病毒、流感病毒、黄病毒、埃可病毒(echovirus)、鼻病毒、柯萨奇病毒(coxsackie virus)、cornovirus、呼吸道融合细胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒和虫媒病毒脑炎病毒(arboviral encephalitis virus)。
引起可通过本申请方法治疗的感染的病原菌的一些实例包括衣原体(chlamydia)、立克次体细菌(rickettsial bacteria)、分枝杆菌(mycobacteria)、葡萄球菌(staphylococci)、链球菌(streptococci)、肺炎球菌(pneumonococci)、脑膜炎球菌(meningococci)和淋球菌(conococci)、克雷伯氏菌(klebsiella)、变形杆菌(proteus)、沙雷氏菌(serratia)、假单胞菌(pseudomonas)、军团菌(legionella)、白喉(diphtheria)、沙门氏菌(salmonella)、杆菌(bacilli)、霍乱(cholera)、破伤风(tetanus)、肉毒中毒(botulism)、炭疽病(anthrax)、瘟疫(plague)、钩端螺旋体病(leptospirosis)和莱姆病(Lymes disease)细菌。
引起可通过本申请方法治疗的感染的病原性真菌的一些实例包括念珠菌属(Candida)(白色念珠菌(albicans)、克鲁斯氏念珠菌(krusei)、光滑念珠菌(glabrata)、热带念珠菌(tropicalis)等)、新型隐球菌(Cryptococcus neoformans)、曲霉菌属(Aspergillus)(烟曲霉(fumigatus)、黑曲霉(niger)等)、毛霉目属(Genus Mucorales)(毛霉菌属(mucor)、犁头霉属(absidia)、根霉属(rhizophus))、申克氏孢子丝菌(Sporothrixschenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis)和荚膜组织胞浆菌(Histoplasma capsulatum)。
引起可通过本申请方法治疗的感染的病原性寄生虫的一些实例包括溶组织内阿米巴(Entamoeba histolytica)、结肠小袋虫(Balantidium coli)、福氏耐格里阿米巴原虫(Naegleriafowleri)、棘阿米巴虫属(Acanthamoeba sp.)、蓝氏贾第虫(Giardia lambia)、隐胞子虫属(Cryptosporidium sp.)、卡氏肺孢子虫(Pneumocystis carinii)、间日疟原虫(plasmodium vivax)、微小巴贝虫(Babesia microti)、布氏锥虫(Trypanosoma brucei)、克鲁斯氏锥体虫(Trypanosoma cruzi)、杜氏利什曼原虫(Leishmania donovani)、弓形虫(Toxoplasma gondi)和巴西日圆线虫(Nippostrongylus brasiliensis)。
在所有上述方法中,PD-L1阻断可与免疫疗法的其它形式组合,所述免疫疗法的其它形式诸如细胞因子治疗(例如干扰素、GM-CSF、G-CSF、IL-2)或提高肿瘤抗原的呈递的双特异性抗体疗法(参见例如Holliger(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448;Poljak(1994)Structure 2:1121-1123)、疫苗或修饰基因表达的试剂。
本申请的化合物可引起且放大自身免疫应答。实际上,使用肿瘤细胞和肽疫苗诱导抗肿瘤应答表明许多抗肿瘤应答涉及抗自身反应性(在抗-CTLA-4+GM-CSF-修饰的B16黑素瘤中观测到的脱色素(上述van Elsas等人);经Trp-2疫苗接种的小鼠中的脱色素(Overwijk,W.等人(1999)Proc.Natl.Acad.Sci.U.S.A.96:2982-2987);由TRAMP肿瘤细胞疫苗引起的自身免疫前列腺炎(Hurwitz,A.(2000)上述)、在人类的临床试验中观测到的黑素瘤肽抗原疫苗接种和白斑症(vitilago)(Rosenberg,S A和White,D E(1996)J.Immunother Emphasis Tumor Immunol 19(1):81-4)。
因此,可能考虑将抗-PD-L1阻断与各种自身蛋白结合使用从而设计高效产生针对这些自身蛋白的免疫应答用于疾病治疗的疫苗接种方案。例如,阿尔茨海默病涉及在脑中的淀粉样蛋白沉积物中A.β.肽的不当积聚;针对这些淀粉样蛋白的抗体应答能够清除这些淀粉样蛋白沉积物(Schenk等人,(1999)Nature 400:173-177)。
其它自身蛋白也可用作靶标,诸如用于过敏和哮喘治疗的IgE和用于类风湿性关节炎治疗的TNFα。最后,对各种激素的抗体应答可通过使用式(I)的化合物或其盐诱导。针对生殖激素的中和抗体应答可用于避孕。针对特定肿瘤生长所需的激素及其它可溶性因子的中和抗体应答也可视为可能的疫苗接种靶标。
上文关于抗-PD-L1抗体的用途所述的类似方法可用于诱导治疗性自身免疫应答,以治疗具有其它自身抗原(诸如阿尔茨海默病中的淀粉样蛋白沉积物(包括A.β.)、细胞因子(诸如TNFα和IgE)的不当积聚的患者。
本申请的化合物可通过共同给药式(I)的化合物或其盐与感兴趣的抗原(例如疫苗)而用于刺激抗原特异性免疫应答。因此,在另一个方面中,本申请提供了一种提高受试者中对抗原的免疫应答的方法,其包括向受试者给药:(i)抗原;和(ii)式(I)的化合物或其盐,以提高受试者对抗原的免疫应答。所述抗原可为例如肿瘤抗原、病毒抗原、细菌抗原或来自病原体的抗原。此类抗原的非限制性实例包括以上部分中所讨论的那些,诸如上文所讨论的肿瘤抗原(或肿瘤疫苗)或者来自上文所述的病毒、细菌或其它病原体的抗原。
如先前所述,本申请的化合物可与一种或多种其它治疗试剂(例如细胞毒性剂、放射毒性剂或免疫抑制剂)共同给药。本申请的化合物可在另一治疗试剂之前、之后或同时给药,或可与其它已知疗法(例如抗癌疗法,例如放射)共同给药。此类治疗试剂尤其包括本身仅在对患者具毒性或亚毒性的水平下才有效的抗肿瘤剂,诸如阿霉素(doxorubicin)(亚德里亚霉素(adriamycin))、顺铂(cisplatin)、硫酸博来霉素(bleomycin sulfate)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、达卡巴嗪(decarbazine)和环磷酰胺羟基脲(cyclophosphamide hydroxyurea)。顺铂每四周以每剂100mg静脉内给药一次,且亚德里亚霉素每21天以60-75mg/mL剂量静脉内给药一次。共同给药式(I)的化合物或其盐与化学治疗试剂提供两种经由不同机制起作用的抗癌剂,其对人类肿瘤细胞产生细胞毒性作用。此类共同给药可解决因耐药性出现或肿瘤细胞的抗原性变化而使其不与抗体起反应所引起的问题。
包含式(I)的化合物或其盐和使用说明书的试剂盒也属于本申请的范畴。所述试剂盒可进一步含有至少一种其它试剂。试剂盒通常包括指示试剂盒内含物的预期用途的标签。术语标签包括在试剂盒上或与试剂盒一起供应或以其它方式伴随试剂盒的任何书面或记录材料。
以上其它治疗试剂在与本申请化合物组合使用时可以例如Physicians’DeskReference(PDR)中所示或由本领域技术人员以其它方式确定的那些量使用。在本申请的方法中,此类其它治疗试剂可在本申请化合物给药之前、与其同时或在其之后给药。
实施例
本申请在以下实施例中进一步定义。应理解所述实施例仅为了说明而提供。从以上讨论和实施例,本领域技术人员可确定本申请的基本特征,且在不偏离其精神和范畴的情况下,可进行各种改变和修改以使本申请适于各种用途和条件。因此,本申请不受下文所阐述的说明性实施例的限制,而由所附权利要求限定。
如本说明书中所用,下列术语具有所示含义:THF表示四氢呋喃,h或hr表示小时,min表示分钟,rt或RT或Rt表示室温或保留时间(上下文将指示),tR表示停留时间,DMSO表示二甲基亚砜,DMF表示N,N-二甲基甲酰胺,且MeOH表示甲醇。
中间体:4-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-羟基苯甲醛
在0℃,将偶氮二甲酸二异丙基酯(0.76mL,3.87mmol)逐滴添加至4-溴-2,3-二氢-1H-茚-1-醇(750.0mg,3.52mmol)、5-氯-2,4-二羟基苯甲醛(607.0mg,3.52mmol)和三苯基膦(1.02g,3.87mmol)的干燥THF(15mL)溶液中。将所得黄色溶液温热至室温,在室温将其搅拌16小时。真空除去溶剂,并将残余物溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 80g一次性柱上,该柱首先用己烷洗脱200mL,然后用0-50%B洗脱1500mL,其中溶剂B=乙酸乙酯且溶剂A=己烷。合并含所需产物的级分并通过离心蒸发干燥,得到所需产物4-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-羟基苯甲醛(742.6mg,38.9%)为淡黄色固体,将其直接用于下一步。LCMS:tR(停留时间)=1.50min。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U(=μm);柱温箱温度=40℃。1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),7.69(s,1H),7.60(d,J=8.1Hz,1H),7.47(d,J=7.3Hz,1H),7.26(t,J=7.7Hz,1H),6.92(s,1H),6.07(dd,J=6.6,3.7Hz,1H),3.12-3.01(m,1H),2.98-2.87(m,1H),2.75-2.61(m,1H),2.16-2.07(m,1H)。
中间体:5-((5-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-4-氯-2-甲酰基苯氧基)甲基)-烟碱甲腈
将4-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-羟基苯甲醛(500mg,1.36mmol)、5-(氯甲基)烟碱甲腈(270mg,1.77mmol)和碳酸铯(665mg,2.04mmol)在干燥DMF(8mL)中的悬浮液在室温搅拌16小时。真空除去溶剂,并将残余物在乙酸乙酯和水之间分配。分离水相并用乙酸乙酯再萃取一次。合并有机萃取物并用盐水洗涤,经硫酸镁干燥,过滤并浓缩,得到残余物,将其用二氯甲烷和己烷研磨,在抽滤后得到所需产物5-((5-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-4-氯-2-甲酰基苯氧基)甲基)烟碱-甲腈(201.2mg,28.9%),为浅棕褐色固体。将滤液浓缩并溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 40g一次性柱上,该柱首先用己烷洗脱60mL,然后用0-50%B洗脱600mL,其中溶剂B=乙酸乙酯且溶剂A=己烷。合并含所需产物的级分并通过离心蒸发干燥,得到其它产物(101.3mg,10.4%)为褐色固体。随后将这两种级分合并,并直接用于下一步。LCMS:tR=1.43min;LCMS(ESI)m/z=485.05[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters AquityBEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。1H NMR(500MHz,DMSO-d6)δ10.26(s,1H),9.05(s,1H),9.05(s,1H),8.58-8.55(m,1H),7.73(s,1H),7.61(d,J=7.7Hz,1H),7.42(d,J=7.3Hz,1H),7.31-7.13(m,2H),6.31(dd,J=6.6,4.0Hz,1H),5.52(s,2H),3.13-3.04(m,1H),2.98-2.88(m,1H),2.76-2.66(m,1H),2.13-2.05(m,1H)。
中间体:3-((3-溴-2-氯苯氧基)甲基)-1-甲基哌啶
将碳酸钾(0.80g,5.78mmol)一次性添加至3-溴-2-氯苯酚(0.50g,2.41mmol)和3-(溴甲基)-1-甲基哌啶氢溴酸盐(0.66g,2.41mmol)在干燥DMF(10mL)中的搅拌溶液中。将悬浮液在60℃搅拌16小时。冷却至室温后,将混合物随后用乙酸乙酯和水稀释。分离水相,并用乙酸乙酯再萃取一次。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并浓缩,得到油状物,将其溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 24g一次性柱上,该柱首先用二氯甲烷洗脱100mL,然后用0-10%B洗脱650mL,其中溶剂B=甲醇且溶剂A=二氯甲烷。将洗脱液浓缩后,分离出所需产物3-((3-溴-2-氯苯氧基)甲基)-1-甲基哌啶(585.5mg,76%产率)为无色油状物。LCMS:tR=0.97min;LCMS(ESI)m/z=317.85和319.90[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。1H NMR(500MHz,CDCl3)δ7.21(dd,J=8.1,1.0Hz,1H),7.05(t,J=8.1Hz,1H),6.85(d,J=8.2Hz,1H),4.06-3.64(m,2H),2.96(br d,J=10.2Hz,1H),2.74(br d,J=10.4Hz,1H),2.29(s,3H),2.24-2.14(m,1H),1.99(br t,J=10.4Hz,1H),1.91(br t,J=10.2Hz,1H),1.84-1.77(m,1H),1.77-1.69(m,1H),1.69-1.59(m,1H),1.26-1.10(m,1H)。
中间体:3-((2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基)甲基)-1-甲基哌啶
在室温,在装有磁力搅拌器的厚壁螺旋顶部压力管中,将1,1-双(二苯基膦)二茂铁-钯(II)二氯化物(0.12g,0.16mmol)一次性添加至3-((3-溴-2-氯苯氧基)甲基)-1-甲基哌啶(1.0g,3.14mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧杂硼杂环戊烷)(1.20g,4.71mmol)和乙酸钾(0.92g,9.42mmol)在干燥二噁烷(20mL)中的氩气脱气的悬浮液中。将混合物在95℃搅拌4.5小时,然后将其冷却至室温,并通过硅藻土抽滤,以除去无机物。将滤液随后浓缩,得到粗产物为棕色油状物,将其溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 80g一次性柱上,该柱首先用二氯甲烷洗脱300mL,然后用0-20%B洗脱1500mL,其中溶剂A=二氯甲烷且溶剂B=甲醇。合并含所需产物的级分并通过离心蒸发干燥。分离出所需产物(763.1mg,66%)为棕色油状物,将其原样使用,且不使用时将其冷冻。LCMS:tR=1.18min;LCMS(ESI)m/z测量值365.90[M+H]+(硼酸酯);tR=0.86min;LCMS(ESI)m/z测量值283.75[M+H]+(在LCMS中观测到的硼酸)。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。1H NMR(500MHz,氯仿-d)δ7.23-7.20(m,1H),7.19-7.14(m,1H),6.95(dd,J=8.1,1.5Hz,1H),3.93-3.88(m,1H),3.88-3.82(m,1H),2.99(br d,J=10.4Hz,1H),2.74(br d,J=10.7Hz,1H),2.27(s,3H),2.25-2.15(m,1H),2.00-1.92(m,1H),1.91-1.84(m,1H),1.84-1.77(m,1H),1.75-1.69(m,1H),1.68-1.60(m,1H),1.37(s,12H),1.20-1.08(m,1H)。
中间体:5-((4-氯-5-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)甲基)烟碱甲腈
在1打兰小瓶中,将第二代XPhos催化剂(16.3mg,0.021mmol)添加至氩气脱气的3-((2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-苯氧基)甲基)-1-甲基哌啶(126mg,0.21mmol)、5-((5-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-4-氯-2-甲酰基苯氧基)甲基)烟碱甲腈(100mg,0.21mmol)和磷酸钾(110mg,0.52mmol)在THF(1.5mL)和水(0.5mL)中的混合物中。密封小瓶并将混合物在室温搅拌16小时,然后将其在乙酸乙酯和水之间分配。分离水相并用乙酸乙酯再萃取一次,然后合并有机萃取物并用盐水洗涤,经MgSO4干燥,过滤并浓缩,得到粗产物为黄色油状物。将粗产物溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 24g一次性柱上,该柱首先用二氯甲烷洗脱80mL,然后用0-20%B洗脱800mL,其中溶剂B=甲醇且溶剂A=二氯甲烷。合并含所需产物的级分并通过离心蒸发干燥,得到产物5-((4-氯-5-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)甲基)烟碱甲腈(124.1mg,93%)为淡黄色油状物,不使用时将其冷冻。LCMS:tR=1.34min;LCMS(ESI)m/z=642.10和644.05[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
实施例1001:(2S)-1-(5-氯-4-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸
在室温,将硼烷2-皮考啉络合物(4.1mg,0.039mmol)一次性添加至5-((4-氯-5-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)-苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)甲基)烟碱甲腈(25.0mg,0.039mmol)、(S)-哌啶-2-甲酸(10.1mg,0.078mmol)和乙酸(50μL)在干燥DMF(0.5mL)中的搅拌溶液中。将混合物搅拌16小时,然后用氮气流将混合物浓缩至接近干燥。此后,添加甲醇并将所得悬浮液通过注射器过滤并通过制备型LCMS、使用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经25分钟12-52%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为9.7mg,且其LCMS分析估算的纯度为95%.使用两种分析LCMS注射确定最终纯度。进样1条件:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1.0mL/min;检测:UV于220nm。进样1结果:纯度:100.0%;测量质量:755.2;保留时间:1.71min。进样2条件:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1.0mL/min;检测:UV于220nm。进样1结果:纯度:94.7%;测量质量:755.2;保留时间:1.50min。
实施例1002:(2R)-2-((5-氯-4-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
在室温,将1M氰基硼氢化钠的THF(78μL,0.078mmol)溶液在3小时后分批添加至5-((4-氯-5-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基-苯氧基)甲基)烟碱甲腈(25.0mg,0.039mmol)、(R)-2-氨基-3-羟基-2-甲基丙酸(9.3mg,0.078mmol)、乙酸(50μL)、分子筛(25mg)和两滴干燥三乙胺在干燥乙醇(0.5mL)、二氯乙烷(0.2mL)、DMF(0.2mL)和THF(0.2mL)中的搅拌溶液中。将混合物搅拌16小时,然后用氮气流将其浓缩。此后,添加甲醇并将所得悬浮液通过注射器过滤器过滤并通过制备型LCMS、使用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经25分钟10-50%B,然后在100%B保持4分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为5.9mg,且其LCMS分析估算的纯度为99%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:745.15;保留时间:1.46min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:99.2%;测量质量:745.15;保留时间:1.67min。
实施例1003:5-((4-氯-5-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)-甲基)烟碱甲腈
将实施例1003从上述实施例1002的反应混合物和提纯中分离出来。作为三乙酸盐的产物的产率为13.7mg,且其LCMS分析估算的纯度为100%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1mm x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:644.11;保留时间:1.76min。进样2条件:柱:Waters XBridge C18,2.1mmx50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:100.0%;测量质量:644.11;保留时间:2.01min。1HNMR(500MHz,甲醇-d4)δ8.95(br s,1H),8.90(br s,1H),8.35(br s,1H),7.41(br s,1H),7.37-7.31(m,2H),7.30-7.25(m,1H),7.17(br d,J=6.7Hz,1H),7.11(br d,J=7.6Hz,1H),6.99-6.87(m,2H),5.92(br s,1H),5.30(br s,2H),4.64(br s,2H),4.14-4.08(m,1H),4.00(br t,J=7.3Hz,1H),3.43(br d,J=8.2Hz,1H),3.38-3.35(m,1H),3.20(br d,J=9.8Hz,1H),3.05-2.70(series of m,3H),2.63(br s,3H),2.58-2.44(m,3H),2.34(brs,1H),2.16(br s,1H),1.86-1.74(m,1H),1.46-1.35(m,1H)。
中间体:(S)-4-溴-2,3-二氢-1H-茚-1-醇和(R)-4-溴-2,3-二氢-1H-茚-1-醇
两种对映异构体是使用以下条件从手性拆分市售4-溴-2,3-二氢-1H-茚-1-醇(约5.0g)获得的:柱:ChiralCel OD-H,30x250mm,5U;流动相:10%乙腈:乙醇(1:1)/90%CO2;压力:150bar;温度:30℃;流速:120mL/min;UV:220nm;进样:在4.00分钟,0.25mL(在乙腈:乙醇(9:1)中堆积约160mg/mL);级分收集:斜率和水平:峰1窗口:4.50-5.80min,峰2窗口:5.50-7.50min。绝对立体化学通过X射线晶体学测定。
(S)-4-溴-2,3-二氢-1H-茚-1-醇(峰1,2.58g,灰白色固体):LCMS:tR=1.20min。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(400MHz,氯仿-d)δ7.43(d,J=8.0Hz,1H),7.36(d,J=7.5Hz,1H),7.17-7.10(m,1H),5.32(q,J=5.5Hz,1H),3.08(ddd,J=16.7,8.8,4.6Hz,1H),2.89-2.78(m,1H),2.53(dddd,J=13.4,8.5,7.0,4.5Hz,1H),2.03-1.91(m,1H),1.84(br d,J=6.0Hz,1H)。
(R)-4-溴-2,3-二氢-1H-茚-1-醇(峰2,2.53g,灰白色固体):LCMS:tR=1.205min。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(400MHz,氯仿-d)δ7.43(d,J=8.0Hz,1H),7.36(d,J=7.5Hz,1H),7.17-7.10(m,1H),5.31(br t,J=6.0Hz,1H),3.08(ddd,J=16.6,8.7,4.5Hz,1H),2.89-2.77(m,1H),2.53(dddd,J=13.4,8.5,7.0,4.5Hz,1H),2.03-1.91(m,1H),1.85(br s,1H)。
以与实施例1002和实施例1003相同的方式使用手性材料4-溴-2,3-二氢-1H-茚-1-醇和3-((3-溴-2-氯苯氧基)甲基)-1-甲基哌啶制备实施例1004至实施例1011。
实施例1004:((R)-2-((5-氯-4-(((S)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
在室温,将1M氰基三氢硼酸钠(0.17mL,0.17mmol)在3小时后分批添加至5-((4-氯-5-(((S)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基-苯氧基)甲基)烟碱甲腈(55.0mg,0.086mmol)、(R)-2-氨基-3-羟基-2-甲基丙酸(20.4mg,0.17mmol)、乙酸(0.024mL,0.428mmol)、粉末分子筛(25mg)和干燥三乙胺(两滴)在干燥乙醇(0.6mL)、二氯乙烷(0.2mL)、DMF(0.1mL)和THF(0.1mL)中的搅拌溶液中。将混合物搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经22分钟10-50%B,然后在100%B保持6分钟;流速:20mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为39.3mg(60.9%),且其LCMS分析估算的纯度为99%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:99.2%;测量质量:745.15;保留时间:1.48min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:98.9%;测量质量:745.16;保留时间:1.45min。
实施例1005:5-((4-氯-5-(((S)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈
将实施例1005从上述实施例1004的反应混合物的提纯中分离出来。产物的产率为3.6mg(6.1mg),且其LCMS分析估算的纯度为93%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:94.5%;测量质量:644.08;保留时间:1.82min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:93.3%;测量质量:644.08;保留时间:1.79min。
实施例1006:(R)-2-((5-氯-4-(((R)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
将粗物质通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经22分钟10-50%B,然后在100%B保持6分钟;流速:20mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为51.9mg(55.0%),且其LCMS分析估算的纯度为98%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:98.4%;测量质量:745.13;保留时间:1.6min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:99.5%;测量质量:745.16;保留时间:1.54min。
实施例1007:5-((4-氯-5-(((R)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈
将实施例1007从上述实施例1006的反应混合物的提纯中分离出来。产物的产率为14.5mg(17.7%),且其LCMS分析估算的纯度为98%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:98.2%;测量质量:644.11;保留时间:1.76min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:98.7%;测量质量:644.12;保留时间:1.9min。
实施例1008:(R)-2-((5-氯-4-(((S)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
将粗物质通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟12-52%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为29.4mg(56.0%),且其LCMS分析估算的纯度为99%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridgeC18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:745.13;保留时间:1.56min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:99.4%;测量质量:745.14;保留时间:1.46min。
实施例1009:5-((4-氯-5-(((S)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈
将实施例1009从上述实施例1008的反应混合物的提纯中分离出来。产物的产率为6.5mg(13.4%),且其LCMS分析估算的纯度为93%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:98.1%;测量质量:644.11;保留时间:1.92min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:93.3%;测量质量:644.08;保留时间:1.77min。
实施例1010:(R)-2-((5-氯-4-(((R)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
将粗物质通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经25分钟8-48%B,然后在100%B保持6分钟;流速:20mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为46.2mg(80.0%),且其LCMS分析估算的纯度为100%。
使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:745.17;保留时间:1.55min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:100.0%;测量质量:745.13;保留时间:1.42min。
实施例1011:5-((4-氯-5-(((R)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈
将实施例1011从上述实施例1010的反应混合物的提纯中分离出来。产物的产率为5.5mg(10.2%),且其LCMS分析估算的纯度为93%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:93.2%;测量质量:644.12;保留时间:1.89min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:93.2%;测量质量:644.11;保留时间:1.72min。
中间体:1-溴-3-(3-溴丙氧基)-2-氯苯
将碳酸钾(8.3g,60.3mmol)一次性添加至3-溴-2-氯苯酚(10.0g,48.2mmol)和1,3-二溴丙烷(48.9mL,482mmol)在干燥丙酮(400mL)中的搅拌溶液中。将悬浮液在室温搅拌5d(d=天),然后将混合物抽滤以除去盐。滤液随后真空浓缩至浅黄色油状物,将其转移至250mL RBF(圆底烧瓶)中,并使用短程蒸馏头在高真空下进行蒸馏,以除去所有在38-40℃(浴温=70℃)脱离的过量的1,3-二溴丙烷,为无色液体。之后,在蒸馏罐中分离出所需的粗产物,为粘稠的、蜂蜜色的油状物,其是相当纯的,因此“按原样”使用。不需要时将其存储在冰箱中。
LCMS:tR=1.46min。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(500MHz,CDCl3)δ7.26(dd,J=8.0,1.1Hz,1H),7.09(t,J=8.2Hz,1H),6.91(d,J=8.4Hz,1H),4.18(t,J=5.8Hz,2H),3.67(t,J=6.3Hz,2H),2.38(quin,J=6.0Hz,2H)。
中间体:1-溴-3-(3-溴丙氧基)-2-甲基苯
将碳酸钾(9.2g,66.8mmol)一次性添加至3-溴-2-甲基苯酚(10.0g,53.5mmol)和1,3-二溴丙烷(54.3mL,535mmol)在干燥丙酮(400mL)中的搅拌溶液中。将悬浮液在室温搅拌6天,然后将混合物抽滤以除去盐。将滤液随后真空浓缩至浅黄色油状物,将其转移至250mL RBF中,并使用短程蒸馏头在高真空进行蒸馏,以除去所有在28-32℃(浴温=70℃)脱离的过量的1,3-二溴丙烷,为无色液体。之后,在蒸馏罐中分离出所需的粗产物,为淡黄色油状物,按原样使用,不需要时将其存储在冰箱中。
LCMS:tR=1.76min。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(500MHz,CDCl3)δ7.18(d,J=8.0Hz,1H),7.02(t,J=8.1Hz,1H),6.81(d,J=8.0Hz,1H),4.11(t,J=5.8Hz,2H),3.63(t,J=6.4Hz,2H),2.39-2.34(m,2H),2.33(s,3H)。
中间体:N-(1-(3-(3-溴-2-氯苯氧基)丙基)哌啶-4-基)乙酰胺
将碳酸钾(2.43g,17.58mmol)一次性添加至1-溴-3-(3-溴丙氧基)-2-氯苯(2.31g,7.03mmol)和N-(哌啶-4-基)乙酰胺(1.00g,7.03mmol)在干燥乙腈(20mL)和DMF(10mL)中的搅拌溶液中。将混合物加热至60℃持续16小时,然后冷却至室温,并用乙酸乙酯和水稀释。分离水相并用乙酸乙酯再萃取一次。将合并的有机相用盐水洗涤,经硫酸镁干燥,过滤并浓缩至1/4体积,在抽滤后得到产物N-(1-(3-(3-溴-2-氯苯氧基)-丙基)哌啶-4-基)乙酰胺(1.13g,41.2%),为白色固体。将滤液浓缩,溶于最少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 40g一次性柱上,该柱首先用二氯甲烷洗脱150mL,然后用0-20%B洗脱1300mL,其中溶剂A=二氯甲烷且溶剂B=甲醇。合并含所需产物的级分并通过离心蒸发干燥,得到其它产物N-(1-(3-(3-溴-2-氯苯氧基)丙基)-哌啶-4-基)乙酰胺(0.62g,22.4%)为白色固体。
LCMS:tR=0.86min;LCMS(ESI)m/z=388.90和390.90[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(500MHz,CDCl3)δ7.23(dd,J=8.1,1.2Hz,1H),7.07(t,J=8.2Hz,1H),6.88(dd,J=8.2,0.9Hz,1H),5.38-5.10(m,1H),4.08(t,J=6.2Hz,2H),3.94-3.64(m,1H),2.86(br d,J=11.7Hz,2H),2.55(t,J=7.3Hz,2H),2.13(br t,J=11.0Hz,2H),2.05-1.99(m,2H),1.98(s,3H),1.94(br d,J=12.1Hz,2H),1.43(qd,J=11.6,3.7Hz,2H)。
中间体:N-(1-(3-(3-溴-2-甲基苯氧基)丙基)哌啶-4-基)乙酰胺
将碳酸钾(607mg,4.40mmol)一次性添加至1-溴-3-(3-溴丙氧基)-2-甲基苯(542mg,1.76mmol)和N-(哌啶-4-基)乙酰胺(250mg,1.76mmol)在干燥DMF(7mL)中的搅拌溶液中。将混合物加热至60℃持续16小时,然后在氮气流下,在室温过夜将溶剂除去。将残余物溶于二氯甲烷,并将悬浮液超声处理5分钟,并抽滤以除去过量的碳酸钾。将滤液随后浓缩并用最少量的二氯甲烷装载至RediSepRf正相硅胶Teledyne ISCO 24 g一次性柱上,该柱首先用二氯甲烷洗脱150mL,然后用0-20%B洗脱600mL,其中溶剂A=二氯甲烷且溶剂B=甲醇。合并含所需产物的级分并通过离心蒸发干燥。分离出所需产物N-(1-(3-(3-溴-2-甲基苯氧基)丙基)哌啶-4-基)乙酰胺(0.42g,64.4%)为白色固体。
LCMS:tR=1.07min;LCMS(ESI)m/z=368.95和370.90[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(500MHz,氯仿-d)δ7.15(d,J=8.0Hz,1H),6.99(t,J=8.1Hz,1H),6.77(d,J=8.0Hz,1H),5.31(s,1H),4.00(t,J=6.2Hz,2H),3.90-3.68(m,1H),2.87(brd,J=11.5Hz,2H),2.53(t,J=7.4Hz,2H),2.31(s,3H),2.12(brt,J=10.6Hz,2H),2.01-1.88(m,4H),1.98(s,3H),1.44(qd,J=11.7,3.6Hz,2H)。
中间体:(S)-3-((3-(3-溴-2-氯苯氧基)丙基)氨基)丙烷-1,2-二醇
将Hunig碱(1.6mL,9.13mmol)一次性添加至1-溴-3-(3-溴丙氧基)-2-氯苯(1.0g,3.04mmol)和(S)-3-氨基-丙烷-1,2-二醇(1.4g,15.22mmol)在干燥DMF(30mL)中的搅拌溶液中。将混合物随后加热至60℃持续16小时,然后冷却至室温并在氮气流下浓缩。将所得残余物用甲醇(最高达10mL)稀释,通过Whatman 13 mm PVDF注射器过滤器(45μM)过滤,置于5个pHPLC小瓶(2mL)中,并通过制备型HPLC分数份(经12分钟10-100%B梯度,在40ml/min)使用SunFire C18柱(30x100mm,5U)提纯,其中流动相A:5:95乙腈:含10mM乙酸铵的水,以及流动相B:95:5乙腈:含10mM乙酸铵的水。合并含所需产物的级分并通过离心蒸发干燥。分离出提纯的产物(S)-3-((3-(3-溴-2-氯苯氧基)丙基)氨基)-丙烷-1,2-二醇(971.0mg,94%)为淡黄色粘稠油状物,在冰箱中静置过夜时其固化为淡黄色固体。
LCMS:tR=1.04min;LCMS(ESI)m/z=338.00和340.00[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(500MHz,甲醇-d4)δ7.30(dd,J=8.0,0.9Hz,1H),7.19(t,J=8.2Hz,1H),7.12-7.05(m,1H),4.21(t,J=5.7Hz,2H),3.91(br dd,J=8.7,3.6Hz,1H),3.63-3.50(m,2H),3.35(s,1H),3.29-3.24(m,2H),3.18(dd,J=12.5,3.1Hz,1H),3.02(dd,J=12.5,9.3Hz,1H),2.32-2.16(m,2H)。
中间体:(S)-3-((3-(3-溴-2-甲基苯氧基)丙基)氨基)丙烷-1,2-二醇
将Hunig碱(1.70mL,9.74mmol)一次性添加至1-溴-3-(3-溴丙氧基)-2-甲基苯(1.00g,3.25mmol)和(S)-3-氨基丙烷-1,2-二醇(1.48g,16.23mmol)在干燥DMF(30mL)中的搅拌溶液中。将混合物随后加热至60℃持续16小时,然后冷却至室温并在氮气流下浓缩。将所得残余物用甲醇(最高达10mL)稀释,通过Whatman 13mm PVDF注射器过滤器(45μM)过滤,置于5个pHPLC小瓶(2mL)中,并通过制备型HPLC分数份(经12分钟10-100%B梯度,在40ml/min)使用SunFire C18柱(30x100mm,5U)提纯,其中流动相A:5:95乙腈:含10mM乙酸铵的水,以及流动相B:95:5乙腈:含10mM乙酸铵的水。合并含所需产物的级分并通过离心蒸发干燥。分离出提纯的产物(S)-3-((3-(3-溴-2-甲基苯氧基)丙基)氨基)-丙烷-1,2-二醇(944.3mg,91%)为无色油状物,在冰箱中静置时其固化为白色固体。
LCMS:tR=1.07min;LCMS(ESI)m/z=318.07,实测值:318.05和320.05[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=WatersAquity BEHC18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(500MHz,甲醇-d4)δ7.16(d,J=7.9Hz,1H),7.05(t,J=8.1Hz,1H),6.92(d,J=8.2Hz,1H),4.12(t,J=5.8Hz,2H),3.90(br dd,J=8.5,3.6Hz,1H),3.63-3.47(m,2H),3.26-3.19(m,2H),3.16(dd,J=12.5,3.1Hz,1H),3.00(dd,J=12.5,9.2Hz,1H),2.32(s,3H),2.25-2.14(m,2H)。
中间体:(R)-1-(3-(3-溴-2-甲基苯氧基)丙基)吡咯烷-3-醇
将1-溴-3-(3-氯丙氧基)-2-甲基苯(5.15g,19.54mmol)、(R)-吡咯烷-3-醇盐酸盐(3.62g,29.30mmol)、粉末碳酸钾(4.05g,29.3mmol)和碘化钠(2.93g,19.54mmol)在干燥DMF(100mL)中的搅拌悬浮液在80℃加热16小时。将混合物随后冷却至室温,并真空除去溶剂。将残余物在乙酸乙酯和水之间分配,然后分离水相并用乙酸乙酯再萃取一次。合并有机萃取物,用盐水洗涤,经硫酸镁干燥,过滤并浓缩,得到残余物,将其溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 80g一次性柱上,该柱首先用二氯甲烷洗脱200mL,然后用0-100%B洗脱1500mL,其中溶剂A=二氯甲烷且溶剂B=甲醇。合并含所需产物的级分并通过离心蒸发干燥。分离出产物(R)-1-(3-(3-溴-2-甲基苯氧基)丙基)吡咯烷-3-醇(5.10g,83%)为焦糖色的油状物,将其储存在冰箱中并按“原样”使用。通过制备型LCMS用以下条件进一步提纯该产物的一部分(约33mg)以用于表征目的:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟12-52%B,然后在100%B保持5分钟;流速:20mL/min。合并含所需产物的级分并通过离心蒸发干燥。纯产物的产率为25.1mg,且其LCMS分析估算的纯度为98%。使用两种分析LCMS进样确定最终纯度。进样1条件:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1.0mL/min;检测:UV于220nm。进样1结果:纯度:98.2%;测量质量:314.0;保留时间:1.37min。进样2条件:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.75分钟;流速:1.0mL/min;检测:UV于220nm。进样2结果:纯度:98.5%;测量质量:314.0;保留时间:1.38min。
中间体:5-((4-氯-2-甲酰基-5-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)烟碱甲腈
在室温,在厚壁压力管中,将1,1-双(二苯基膦)二茂铁-钯(II)二氯化物(193mg,2.64μmol)一次性添加至5-((5-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-4-氯-2-甲酰基苯氧基)甲基)烟碱甲腈(1.70g,3.51mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧杂硼杂环戊烷)(0.98g,3.87mmol)和乙酸钾(1.04g,10.54mmol)在干燥二噁烷(35mL)中的氩气脱气的悬浮液中。将混合物搅拌,并在80℃加热10小时,然后冷却至室温,并用乙酸乙酯和水稀释。(在此反应之前进行了中试规模的反应(50mg),并在萃取后处理之前将其混合物添加至该反应中。)分离水相并用乙酸乙酯再萃取一次,并将合并的有机萃取物用盐水洗涤,经硫酸镁干燥,过滤并浓缩,得到粗产物为深棕色油状物。将粗产物随后溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶Teledyne ISCO 80g一次性柱上,该柱首先用二氯甲烷洗脱300mL,然后用0-40%B洗脱2700mL,其中溶剂A=己烷且溶剂B=乙酸乙酯。合并含所需产物的级分并通过离心蒸发干燥。分离出5-((4-氯-2-甲酰基-5-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)-烟碱甲腈(1.36g,72.7%)为灰白色固体,将其直接用于下一步并按“原样”使用。
LCMS:tR=1.72min;LCMS(ESI)m/z=531.10[M+H]+。LCMS条件:进样体积=1μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=WatersAquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.05(s,1H),9.05(s,1H),8.57(t,J=2.0Hz,1H),7.71(s,1H),7.68(dd,J=7.3,1.0Hz,1H),7.52(d,J=7.3Hz,1H),7.27(s,1H),7.25(s,1H),6.20(br d,J=3.0Hz,1H),5.53(s,2H),3.27-3.16(m,1H),3.13-3.03(m,1H),2.64-2.53(m,1H),2.06-1.99(m,1H),1.31(s,12H)。
中间体:5-((4-氯-2-甲酰基-5-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)烟碱甲腈
在室温,将第二代XPhos预催化剂(34mg,0.043mmol)一次性添加至(R)-1-(3-(3-溴-2-甲基苯氧基)丙基)吡咯烷-3-醇(134mg,0.43mmol)、5-((4-氯-2-甲酰基-5-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)-烟碱甲腈(250mg,0.47mmol)和磷酸钾(227mg,1.07mmol)在THF(4mL)和水(1mL)中的氩气脱气的混合物中。密封小瓶并将所得悬浮液搅拌16小时,然后将其用乙酸乙酯和水稀释。分离水层,并用乙酸乙酯再萃取一次。将合并的有机萃取物随后用盐水洗涤,经硫酸镁干燥,过滤并浓缩。将粗产物溶于少量的二氯甲烷中,并装载至RediSepRf正相硅胶TeledyneISCO 25g一次性柱上,该柱首先用二氯甲烷洗脱60mL,然后用0-10%B洗脱600mL,其中溶剂A=二氯甲烷且溶剂B=甲醇。合并含所需产物的级分并通过离心蒸发干燥。分离出所需产物5-((4-氯-2-甲酰基-5-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)-烟碱甲腈(171.4mg,62.7%)作为稻草色油状物,以及其它产物5-((4-氯-2-甲酰基-5-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)烟碱甲腈(25.2mg,9.2%)为浅橙色固体,将其作为中心馏分用于表征目的。
LCMS:tR=1.86min;LCMS(ESI)m/z=638.50[M+H]+。LCMS条件:进样体积=1μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=WatersAquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
实施例1012:(2R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苄基)-氨基)-3-羟基-2-甲基丙酸
在室温,在3小时后,将1M氰基三氢硼酸钠(0.10mL,0.094mmol)分批添加至5-((4-氯-2-甲酰基-5-((4-(3-(3-((R)-3-羟基-吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)-甲基)烟碱甲腈(30.0mg,0.047mmol)、(R)-2-氨基-3-羟基-2-甲基丙酸(11.2mg,0.094mmol)、乙酸(13μL,0.235mmol)和粉末分子筛(25mg)在干燥DMF(0.50mL)和MeOH(0.42mL)中的搅拌溶液中。将混合物在室温搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟11-51%B,然后在100%B保持4分钟;流速:20mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为17.7mg(50.3%),且其LCMS分析估算的纯度为99%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:741.19;保留时间:1.51min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:99.1%;测量质量:741.19;保留时间:1.5min。
实施例1013:5-((4-氯-2-(羟基甲基)-5-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)烟碱甲腈
将实施例1013从上述实施例1012的反应混合物的提纯中分离出来。产物的产率为10.7mg(33.3%),且其LCMS分析估算的纯度为94%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:93.6%;测量质量:640.24;保留时间:1.81min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:95.1%;测量质量:640.25;保留时间:1.92min。
实施例1014:(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苄基)-哌啶-2-甲酸
在室温,将1M氰基三氢硼酸钠(0.10mL,0.094mmol)在3小时后分批添加至5-((4-氯-2-甲酰基-5-((4-(3-(3-((R)-3-羟基-吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)-甲基)烟碱甲腈(30.0mg,0.047mmol)、(S)-哌啶-2-甲酸(12.1mg,0.094mmol)、乙酸(13μL,0.235mmol)和粉末分子筛(25mg)在干燥DMF(0.50mL)和MeOH(0.42mL)中的搅拌溶液中。将混合物在室温搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤,并通过制备型LCMS用以下条件提纯:柱:XBridgeC18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经25分钟10-50%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为25.6mg(67.5%),且其LCMS分析估算的纯度为93%。使用分析LCMS来确定最终纯度。
进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:95.7%;测量质量:751.23;保留时间:1.61min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:93.1%;测量质量:751.21;保留时间:1.52min。
实施例1015:(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苄基)-L-高丝氨酸
在室温,将1M氰基三氢硼酸钠(0.10mL,0.094mmol)在3小时后分批添加至5-((4-氯-2-甲酰基-5-((4-(3-(3-((R)-3-羟基-吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)-甲基)烟碱甲腈(30.0mg,0.047mmol)、L-高丝氨酸(11.2mg,0.094mmol)、乙酸(13μL,0.24mmol)和粉末分子筛(25mg)在干燥DMF(0.50mL)和MeOH(0.42mL)中的搅拌溶液中。将混合物在室温搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟9-49%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为25.9mg(71.8%),且其LCMS分析估算的纯度为97%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:98.7%;测量质量:741.19;保留时间:1.55min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95甲醇:含10mM乙酸铵的水;流动相B:95:5甲醇:含10mM乙酸铵的水;温度:50℃;梯度:经3.5分钟0-100%B,然后在100%B保持0.5分钟;流速:0.5mL/min;检测:MS和UV(220nm)。进样2结果:纯度:96.6%;测量质量:741.19;保留时间:2.87min。
中间体:N-(1-(3-(2-氯-3-(1-(2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)-2,3-二氢-1H-茚-4-基)苯氧基)丙基)哌啶-4-基)乙酰胺
在室温,将第二代XPhos预催化剂(34mg,0.043mmol)一次性添加至N-(1-(3-(3-溴-2-氯苯氧基)丙基)-哌啶-4-基)乙酰胺(167mg,0.43mmol)、5-((4-氯-2-甲酰基-5-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)-烟碱甲腈(250mg,0.47mmol)和磷酸钾(227mg,1.07mmol)在THF(4mL)和水(1mL)中的氩气脱气的混合物中。随后密封小瓶,并将所得悬浮液搅拌16小时,然后用乙酸乙酯和水稀释。分离水层,并用乙酸乙酯再萃取一次,然后将合并的有机萃取物用盐水洗涤,经硫酸镁干燥,过滤并浓缩,得到棕色油状物,将其用DMF、THF和甲醇(2:1:1mL)稀释,通过WhatmanPuradisc 13mm PVDF注射器过滤器(45μM)过滤,置入两个pHPLC小瓶(2mL)中,并通过制备型HPLC分4份(经10分钟10-100%B梯度,在40ml/min)使用Waters-XBridge C18 OBD柱(30x100mm,5U)提纯,其中流动相A为10:90乙腈:含0.1%三氟乙酸的水,且流动相B为90:10乙腈:含0.1%三氟乙酸的水。UV波长为220nm。合并含所需产物的级分并通过离心蒸发干燥,得到产物N-(1-(3-(2-氯-3-(1-(2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)-2,3-二氢-1H-茚-4-基)苯氧基)丙基)哌啶-4-基)乙酰胺(186.5mg,61.0%)为无色油状物。
LCMS:tR=1.29min;LCMS(ESI)m/z=713.15和715.10[M+H]+。LCMS条件:进样体积=3μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
实施例1016:(2R)-2-((4-((4-(3-(3-(4-乙酰氨基哌啶-1-基)丙氧基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
在室温,将1M氰基三氢硼酸钠(70μL,0.070mmol)在3小时后分批添加至(R)-2-氨基-3-羟基-2-甲基丙酸(8.4mg,0.070mmol)、N-(1-(3-(2-氯-3-(1-(2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)-2,3-二氢-1H-茚-4-基)苯氧基)丙基)哌啶-4-基)乙酰胺(25.0mg,0.035mmol)、乙酸(10μl,0.175mmol)、分子筛(25mg)和干燥TEA(两滴)在干燥DMF(0.3mL)、甲醇(0.2mL)、乙醇(0.1mL)和THF(0.1mL)中的搅拌溶液中。将混合物在室温搅拌16小时,然后通过注射器过滤器过滤并用DMF和MeOH(1:2)稀释至2mL总体积并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟6-46%B,然后在100%B保持5分钟;流速:25mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为3.7mg(12.3%),且其LCMS分析估算的纯度为95%。
使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:95.4%;测量质量:816.17;保留时间:1.78min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:99.0%;测量质量:816.18;保留时间:1.49min。
实施例1017:(2S)-1-(4-((4-(3-(3-(4-乙酰氨基哌啶-1-基)丙氧基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸
在室温,将1M氰基三氢硼酸钠(70μL,0.070mmol)在3小时后分批添加至N-(1-(3-(2-氯-3-(1-(2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)-2,3-二氢-1H-茚-4-基)苯氧基)丙基)哌啶-4-基)乙酰胺(25.0mg,0.035mmol)、(S)-哌啶-2-甲酸(9.1mg,0.070mmol)、乙酸(10μl,0.175mmol)、粉末分子筛(25mg)和干燥TEA(两滴)在干燥DMF(0.75mL)和THF(0.5mL)中的搅拌溶液中。将混合物搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridgeC18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟8-48%B,然后在100%B保持5分钟;流速:25mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为5.2mg(16.4%),且其LCMS分析估算的纯度为91%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:826.19;保留时间:1.59min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:91.1%;测量质量:826.19;保留时间:1.53min。
实施例1018:(4-((4-(3-(3-(4-乙酰氨基哌啶-1-基)丙氧基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)-L-高丝氨酸
在室温,将1M氰基三氢硼酸钠(80μL,0.080mmol)在3小时后分批添加至L-高丝氨酸(9.7mg,0.081mmol)、N-(1-(3-(2-氯-3-(1-(2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)-2,3-二氢-1H-茚-4-基)苯氧基)丙基)哌啶-4-基)乙酰胺(29.0mg,0.041mmol)、乙酸(12μL,0.20mmol)、粉末分子筛(25mg)和干燥TEA(两滴)在干燥DMF(0.1mL)、乙醇(0.2mL)、二氯乙烷(0.1mL)和THF(0.1mL)中的搅拌溶液中。将混合物在室温搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经25分钟7-47%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为1.8mg(5.3%),且其LCMS分析估算的纯度为97%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:98.4%;测量质量:816.2;保留时间:1.52min。进样2条件:柱:Waters XBridgeC18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:97.2%;测量质量:816.15;保留时间:1.38min。
中间体:5-((4-氯-5-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)甲基)烟碱甲腈
在室温,将第二代XPhos预催化剂(30mg,0.038mmol)一次性添加至(S)-3-((3-(3-溴-2-氯苯氧基)-丙基)氨基)丙烷-1,2-二醇(128mg,0.38mmol)、5-((4-氯-2-甲酰基-5-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)-甲基)烟碱甲腈(220mg,0.41mmol)和磷酸钾(200mg,0.94mmol)在THF(4mL)和水(1mL)中的氩气脱气的混合物中。密封小瓶并将所得悬浮液搅拌16小时,然后用乙酸乙酯和水稀释。分离水层,并用乙酸乙酯再萃取一次,然后将合并的有机萃取物用盐水洗涤,经硫酸镁干燥,过滤并浓缩。将粗产物溶于少量的二氯甲烷,并装载至RediSepRf正相硅胶Teledyne ISCO 12g一次性柱上,该柱首先用二氯甲烷洗脱30mL,然后用0-20%B洗脱240mL且最后用20-100%B洗脱200mL,其中溶剂A=二氯甲烷且溶剂B=甲醇。合并含所需产物的级分并通过离心蒸发干燥,得到产物5-((4-氯-5-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)甲基)烟碱甲腈(117.7mg,47.1%)为橙色固体。该材料直接用于下一步并按“原样”使用。
LCMS:tR=1.26min;LCMS(ESI)m/z=662.10和664.05[M+H]+。LCMS条件:进样体积=1μL;梯度=2-98%B;梯度时间=1.5min;流速=0.8ml/min;波长=220nm;流动相A=0:100乙腈:含0.05%三氟乙酸的水;流动相B=100:0乙腈:含0.05%三氟乙酸的水;柱=Waters Aquity BEH C18,2.1x50mm,1.7U;柱温箱温度=40℃。
实施例1019:(2R)-2-((5-氯-4-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸
在室温将1M氰基三氢硼酸钠(0.90μL,0.090mmol)在3小时后分批添加至5-((4-氯-5-((4-(2-氯-3-(3-(((S)-2,3-二羟基-丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)-甲基)烟碱甲腈(30.0mg,0.045mmol)、(R)-2-氨基-3-羟基-2-甲基丙酸(10.8mg,0.091mmol)、乙酸(13μL,0.23mmol)和粉末分子筛(25mg)在干燥DMF(0.50mL)和MeOH(0.42mL)中的搅拌溶液中。将混合物在室温搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经20分钟7-47%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为10.4mg(30.0%),且其LCMS分析估算的纯度为100%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:100.0%;测量质量:765.16;保留时间:1.64min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:100.0%;测量质量:765.17;保留时间:1.61min。
实施例1020:5-((4-氯-5-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈
将实施例1020从上述实施例1019的反应混合物的提纯中分离出来。产物的产率为4.7mg(14.0%),且其LCMS分析估算的纯度为90%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:92.4%;测量质量:664.09;保留时间:1.9min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:89.8%;测量质量:664.07;保留时间:1.87min。
实施例1021:(5-氯-4-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)-L-高丝氨酸
在室温,将硼烷·2-皮考啉络合物(9.7mg,0.091mmol)在3小时后一次性添加至5-((4-氯-5-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)-氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲酰基苯氧基)甲基)-烟碱甲腈(30.0mg,0.045mmol)、L-高丝氨酸(53.9mg,0.453mmol)、乙酸(26μL,0.45mmol)和粉末分子筛(25mg)在干燥DMF(0.50mL)中的搅拌溶液中。将混合物搅拌16小时,然后用DMF和MeOH(1:2)稀释至2mL总体积,通过注射器过滤器过滤并通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经23分钟3-43%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。将该材料进一步通过制备型LCMS用以下条件提纯:柱:XBridge C18,19x200mm,5U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:经25分钟9-49%B,然后在100%B保持5分钟;流速:20mL/min;柱温:25℃。MS和UV信号触发级分收集。合并含所需产物的级分并通过离心蒸发干燥。产物的产率为2.1mg(5.9%),且其LCMS分析估算的纯度为97%。使用分析LCMS来确定最终纯度。进样1条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样1结果:纯度:98.5%;测量质量:765.18;保留时间:1.5min。进样2条件:柱:Waters XBridge C18,2.1x50mm,1.7U;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B保持0.50分钟;流速:1mL/min;检测:MS和UV(220nm)。进样2结果:纯度:97.1%;测量质量:765.2;保留时间:1.41min。
生物测定
使用PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定研究式(I)的化合物与PD-L1结合的能力。
均相时间分辨荧光(HTRF)结合测定
PD-1与PD-L1的相互作用可使用这两种蛋白的胞外域的可溶的经纯化制剂来评定。PD-1和PD-L1蛋白胞外域被表达为带有检测标签的融合蛋白,对于PD-1,该标签为免疫球蛋白的Fc部分(PD-1-Ig),且对于PD-L1,其为6组氨酸基序(PD-L1-His)。所有结合研究均在由补充有0.1%(w/v)牛血清白蛋白和0.05%(v/v)吐温-20的dPBS组成的HTRF测定缓冲液中进行。对于h/PD-L1-His结合测定,将抑制剂与PD-L1-His(最终10nM)一起在4μl测定缓冲液中预温育15分钟,接着添加在1μl测定缓冲液中的PD-1-Ig(最终20nM)且进一步温育15分钟。使用铕穴状化合物标记的抗Ig(最终1nM)和别藻蓝蛋白(APC)标记的抗His(最终20nM)实现HTRF检测。在HTRF检测缓冲液中稀释抗体且将5μl分配于结合反应顶部。使反应混合物平衡30分钟且使用EnVision荧光计获得所得信号(665nm/620nm的比率)。在人类蛋白PD-1-Ig/PD-L2-His(分别为20和5nM)和CD80-His/PD-L1-Ig(分别为100和10nM)之间进行额外的结合测定。
重组蛋白:使具有免疫球蛋白G(Ig)表位标签的C端人Fc域的人PD-1(25-167)[hPD-1(25-167)-3S-IG]和具有C端His表位标签的人PD-L1(18-239)[hPD-L1(18-239)-TVMV-His]于HEK293T细胞中表达且通过蛋白A亲和色谱法和尺寸排阻色谱法依次纯化。人PD-L2-His和CD80-His经由市售来源获得。
重组人PD-1-Ig的序列
(SEQ ID NO:1)
重组人PD-L1-His的序列
(SEQ ID NO:2)
下表列出PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定中所测量的本申请的代表性实施例的IC50值。
式(I)的化合物具有作为PD-1/PD-L1相互作用的抑制剂的活性,并因此可用于治疗与PD-1/PD-L1相互作用相关的疾病或缺陷。经由抑制PD-1/PD-L1相互作用,本申请的化合物可用于治疗传染性疾病,诸如HIV、败血性休克、甲型肝炎、乙型肝炎、丙型肝炎或丁型肝炎和癌症。
特定实施方案的前述描述将如此充分地揭示本发明的一般性质,以至于其他人可以通过应用本领域技术人员的知识而容易地修改和/或改编诸如这些特定实施方案的各种应用,而无需过度实验,不会脱离本发明的总体概念。因此,基于本文给出的教导和指导,这样的改编和修改旨在在所公开的实施方案的等同形式的含义和范围内。应当理解,本文中的措辞或术语是出于描述而非限制的目的,使得本说明书的术语或措辞应由技术人员根据教导和指导来进行解释。
通过考虑本文公开的发明的说明书和实践,本发明的其它实施方案对本领域技术人员而言将是清楚的。说明书和实施例仅被认为是示例性的,本发明的真实范围和精神由所附权利要求书指示。
本文所公开的所有出版物、专利和专利申请都以引用的方式并入本文,就如同每个单独的出版物、专利或专利申请被明确地和单独地指示通过引用并入本文一样。
序列表
<110> 百时美施贵宝公司
<120> 用作免疫调节剂的化合物
<130> 3338.172PC01/ELE/C-K/PAM
<150> US 62/637,009
<151> 2018-03-01
<160> 2
<170> PatentIn版本3.5
<210> 1
<211> 384
<212> PRT
<213> 人工序列
<220>
<223> hPD1(25-167)-3S-IG
<400> 1
Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe Ser Pro Ala
1 5 10 15
Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr Cys Ser Phe
20 25 30
Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro
35 40 45
Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp Arg Ser Gln
50 55 60
Pro Gly Gln Asp Cys Arg Phe Arg Met Thr Gln Leu Pro Asn Gly Arg
65 70 75 80
Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp Ser Gly Thr
85 90 95
Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln Ile Lys Glu
100 105 110
Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala Glu Val Pro
115 120 125
Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly Gln Phe Gln Gly
130 135 140
Ser Pro Gly Gly Gly Gly Gly Arg Glu Pro Lys Ser Ser Asp Lys Thr
145 150 155 160
His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly Ser Ser
165 170 175
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
180 185 190
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
195 200 205
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
210 215 220
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
225 230 235 240
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Val Gly Lys Glu Tyr
245 250 255
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
260 265 270
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
275 280 285
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
290 295 300
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
305 310 315 320
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
325 330 335
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
340 345 350
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
355 360 365
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375 380
<210> 2
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> hPDL1(18-239)-TVMV-His
<400> 2
Ala Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly
1 5 10 15
Ser Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp
20 25 30
Leu Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile
35 40 45
Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr
50 55 60
Arg Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala
65 70 75 80
Ala Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg
85 90 95
Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys
100 105 110
Val Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp
115 120 125
Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro
130 135 140
Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly
145 150 155 160
Lys Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val
165 170 175
Thr Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys
180 185 190
Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val
195 200 205
Ile Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr Gly Ser
210 215 220
Ser Glu Thr Val Arg Phe Gln Gly His His His His His His
225 230 235
Claims (15)
1.式(I)的化合物:
或其药学上可接受的盐,其中:
m为0、1或2;
n’为1、2或3;
Z选自氢、-CH3、-O(CH2)nX和-O(CH2)nAr;其中
n为1、2、3或4;
X选自氢、-CH3、-CF3、CN、-CO2R1、-C(O)NH2、OR1和吡咯烷酮基;
R1为H或C1-C3烷基,其条件为当n为1时,R1为C1-C3烷基;
Ar选自苯并二噁烷基、吲唑基、异喹啉基、异噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基和喹啉基;其中各个环任选地被1、2、3或4个取代基取代,所述取代基独立地选自C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基氨基、C1-C4烷基、(C1-C4烷基)羰基、(C1-C4烷基)磺酰基、酰氨基、氨基羰基、氨基羰基(C1-C3烷基)、-(CH2)qCO2C1-C4烷基、-(CH2)qOH、羧基、氰基、甲酰基、卤素、卤代C1-C4烷基、卤代C1-C4烷氧基、硝基、任选地被一个氰基基团取代的苯基、任选地被一个卤素基团取代的苯基氧基、苯基羰基、吡咯和四氢吡喃;且其中q为0、1、2、3或4;
R2选自氢、C1-C3烷基、氰基、卤素和卤代C1-C3烷基;
v为1或2;
环A为含一个氮原子的5元或6元环,其中所述环通过所述环中的碳原子连接到母体分子部分;和
Rv选自C1-C3烷基、C1-C3烷基羰基氨基和羟基;
R4各自独立地选自C2-C4烯基、C1-C4烷氧基、C1-C4烷基、氰基、卤素和卤代C1-C4烷基;和
R5选自-(CH2)pCHO、-(CH2)pCO2H、-(CH2)wOH、-C(O)NR100R101、-CH(CH3)NRqR8和-(CH2)wNRqR8;其中
R100和R101选自氢、C1-C6烷基和羟基(C1-C6烷基),其任选地被额外的羟基基团取代;或,R100和R101与其所连接的氮原子一起形成6元环,其任选地被羧基基团取代;
p为0、1、2或3;
w为1、2、3或4;
Rq选自氢、C1-C4烷基、苄基、(C3-C6环烷基)C1-C3烷基、卤代C1-C4烷基、任选被第二羟基基团取代的羟基C1-C6烷基和任选被氰基基团取代的吡啶基(C1-C3烷基);和
R8选自氢、C1-C4烷基、-(CH2)nN(CH3)2、羧基C2-C6烯基、羧基C1-C6烷基和羟基C1-C6烷基,其中所述羧基C1-C6烷基和所述羟基C1-C6烷基的烷基部分任选地被一个羟基或苯基基团取代,其中所述苯基基团进一步任选地被羟基基团取代;
Rw为-CONH2,
R9选自氢、苄基和甲基;
R9’各自独立地选自氢和C1-C3烷基;
R10选自氢、C1-C3烷基和苄基;
R11选自C2-C4烯基和C1-C4烷基;和
R60选自氢、C1-C6烷基和C1-C6烷氧基羰基,
或
R8和Rq与其所连接的氮原子一起形成环,所述环选自
s为0、1或2;
z为1、2或3;
Q’选自CHR13”、S、O、NH、NC(O)OC1-C6烷基、N(CH2)2OH和NCH3;
R12和R12’独立地选自氢、-CO2H、羟基C1-C4烷基、氧代和-C(O)NHSO2R16;
R13和R13’独立地选自氢、羟基C1-C4烷基、氧代和-CO2H;
R13”选自羟基C1-C3烷基和-CO2H;
R14各自独立地选自C1-C4烷氧基羰基、C1-C6烷基、羧基、卤素、羟基、羟基C1-C4烷基、-NRc’Rd’和苯基氧基羰基,其中所述苯基任选地被硝基基团取代,其中Rc’和Rd’独立地选自氢、C1-C4烷氧基羰基和C1-C4烷基羰基;和
R16选自三氟甲基、环丙基、C1-C4烷基、二甲基氨基和被甲基基团取代的咪唑基。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其中R2为卤素。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中Z为-O(CH2)nAr,其中n为1,且Ar为被一个氰基基团取代的吡啶基。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其中m为1,且R4为卤素。
9.根据权利要求1所述的化合物或其药学上可接受的盐,其中R5为-CH2OH。
12.化合物,其选自
(2S)-1-(5-氯-4-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸;
(2R)-2-((5-氯-4-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-5-((4-(2-氯-3-((1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)-甲基)烟碱甲腈;
((R)-2-((5-氯-4-(((S)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-5-(((S)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈;
(R)-2-((5-氯-4-(((R)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-5-(((R)-4-(2-氯-3-(((R)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈;
(R)-2-((5-氯-4-(((S)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-5-(((S)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈;
(R)-2-((5-氯-4-(((R)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-5-(((R)-4-(2-氯-3-(((S)-1-甲基哌啶-3-基)甲氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈;
(2R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苄基)-氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-2-(羟基甲基)-5-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苯氧基)甲基)烟碱甲腈;
(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苄基)-哌啶-2-甲酸;
(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((4-(3-(3-((R)-3-羟基吡咯烷-1-基)丙氧基)-2-甲基苯基)-2,3-二氢-1H-茚-1-基)氧基)苄基)-L-高丝氨酸;
(2R)-2-((4-((4-(3-(3-(4-乙酰氨基哌啶-1-基)丙氧基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
(2S)-1-(4-((4-(3-(3-(4-乙酰氨基哌啶-1-基)丙氧基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸;
(4-((4-(3-(3-(4-乙酰氨基哌啶-1-基)丙氧基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)-L-高丝氨酸;
(2R)-2-((5-氯-4-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)氨基)-3-羟基-2-甲基丙酸;
5-((4-氯-5-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-(羟基甲基)苯氧基)甲基)烟碱甲腈;和
(5-氯-4-((4-(2-氯-3-(3-(((S)-2,3-二羟基丙基)氨基)丙氧基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)-L-高丝氨酸;
或其药学上可接受的盐。
13.药物组合物,其包含根据权利要求1至12中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载体。
14.一种在有需要的受试者中增强、刺激、调节和/或增加免疫应答的方法,所述方法包括向所述受试者给药治疗有效量的根据权利要求1至12中任一项所述的化合物或其药学上可接受的盐。
15.一种在有需要的受试者中抑制癌细胞生长、增殖或转移的方法,所述方法包括向所述受试者给药治疗有效量的根据权利要求1至12中任一项所述的化合物或其药学上可接受的盐。
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