CN113767103B - 新型螺环类K-Ras G12C抑制剂 - Google Patents
新型螺环类K-Ras G12C抑制剂 Download PDFInfo
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- CN113767103B CN113767103B CN202080029934.1A CN202080029934A CN113767103B CN 113767103 B CN113767103 B CN 113767103B CN 202080029934 A CN202080029934 A CN 202080029934A CN 113767103 B CN113767103 B CN 113767103B
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- 229910052736 halogen Inorganic materials 0.000 claims description 32
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- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 18
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
一类螺环类化合物及其制备方法和用途。具体地,本发明涉及式(1)所示的化合物及其制备方法,以及式(1)化合物及其各光学异构体、各晶型、药学上可接受的盐作为G12C突变体K‑Ras蛋白不可逆抑制剂在抗肿瘤等Ras相关疾病的药物制备中的用途。
Description
本申请要求申请日为2019年8月15日的中国专利申请CN2019107569656的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域,更具体而言,涉及一类新型K-Ras G12C抑制剂,及其制备方法和该类化合物的使用方法。
背景技术
Ras蛋白家族是细胞内重要的信号转导传递分子,在生长发育中发挥了重要的作用。大量的体外肿瘤细胞,动物模型以及人类肿瘤样本的分析和研究表明Ras家族蛋白的过度激活是人类肿瘤发展的早期事件,是多种癌症发生和发展的重要诱因。因此靶向和抑制Ras蛋白的活性是治疗相关肿瘤的重要手段。
Ras蛋白存在两种形式,其与GDP结合,处于未激活静息状态;而当细胞接收诸如生长因子刺激等信号时,Ras蛋白与GTP结合,被激活。活化的Ras蛋白招募多种信号转接蛋白,促进下游信号分子诸如ERK,S6的磷酸化,从而激活Ras信号转导通路,调节细胞生长、存活、迁移和分化。Ras蛋白自身的GTPase酶活性可将GTP水解回GDP。并且细胞内存在GTP酶激活蛋白(GAPs)与Ras相互作用大大促进Ras GTPase的活性,从而防止Ras蛋白的过度激活。
Ras蛋白家族中K-Ras,H-Ras以及N-Ras蛋白上的突变是多种肿瘤的常见的基因突变之一,是导致肿瘤中Ras蛋白过度激活的主要因素。与野生型的Ras蛋白相比,这些突变导致Ras蛋白活性不为调控,稳定结合GTP,持续激活,从而促进肿瘤细胞的生长,迁移以及分化。这其中K-Ras蛋白的突变最为常见,占所有Ras突变的85%,而N-Ras(12%)和H-Ras(3%)则相对少见。K-Ras突变在多种癌症中极为普遍:包括胰腺癌(95%)、结肠直肠癌(45%)和肺癌(25%)等,而在乳腺癌、卵巢癌和脑癌中相对罕见(<2%)。K-Ras突变位点主要集中于G12位,其中G12C的突变最为常见。例如在非小细胞肺癌(NSCLC)中,K-Ras G12C占所有K-Ras突变的50%,其次是G12V和G12D。基因组学研究表明,非小细胞肺癌中的K-Ras突变不与EGFR、ALK、ROS1、RET和BRAF突变共存,而与STK11、KEAP1和TP53等突变共存,提示K-Ras突变可能与STK11、KEAP1和TP53突变等协同作用参与细胞的恶性转变,增生和侵袭。除了肿瘤以外,Ras蛋白的异常激活也参与了包括糖尿病,神经退行性疾病等非肿瘤性疾病,由此可见,靶向Ras蛋白的小分子化合物可使大批携带特定基因变异的的癌症病人和Ras通路过度激活的非癌症性病人受益。
然而,自从肿瘤中Ras突变被发现四十年来,虽然我们对Ras通路致病机制有了更为深入的了解,但是对于大量携带Ras蛋白突变以及Ras通路过度激活的病人,尚未有有效的靶向Ras蛋白的治疗手段。因此开发高活性的针对Ras蛋白特别是突变频率较高的K-RasG12C蛋白的小分子抑制剂,具有重要的临床意义。
发明内容
本发明旨在提供一类结构通式如式(1)所示的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:
式(1)中:
L为化学键或NH;
A为一个二价含有1-2个N原子的4-12元饱和或部分饱和的单环、双环、桥环或螺环,所述单环、双环、桥环或螺环可任选被一个或多个R2所取代,当被多个R2取代时,R2可以相同或不同,R2为H、CN、C1-C3烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基;
R1为芳基或杂芳基,所述芳基或杂芳基可被1-3个下述基团所取代:卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,当被多个取代基取代时,所述取代基可以相同或不同;
表示V和Z之间为单键或双键,当Z为CO,且V为/>时,V和Z之间为单键连接;或,当V为N,且Z为/>时,V和Z之间为双键连接;
Ra、Rb、Rc和Rd均为H,Re和Rf和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Rc、Rd、Re和Rf均为H,Ra和Rb和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Ra、Rb、Re和Rf均为H时,Rc和Rd和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;和
E是能够与K-Ras突变体蛋白的12位的半胱氨酸残基形成共价键的亲电部分,
其中,
Y为化学键或C1-C6亚烷基;
R3为胺基取代烷基、环烷基、烷基取代酰胺基、杂环基、芳基或杂芳基,所述杂环基、芳基或杂芳基均可被1-3个下述基团所取代:卤素、O、CN、OH、羟基取代烷基、二烷基取代胺基、C1-C6烷基、C3-C6环烷基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,当被多个取代基取代时,所述取代基可以相同或不同。
在另一优选例中,其中所述通式(1)化合物结构如通式(1A)或通式(1B)所示:
其中:
L为化学键或NH;
A为一个二价含有1-2个N原子的4-12元饱和或部分饱和的单环、双环、桥环或螺环,所述单环、双环、桥环或螺环可任选被一个或多个R2所取代,当被多个R2取代时,R2可以相同或不同,R2为H、CN、C1-C3烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基;
R1为芳基或杂芳基,所述芳基或杂芳基可被1-3个下述基团所取代:卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,当被多个取代基取代时,所述取代基可以相同或不同;
Y为化学键或C1-C6亚烷基;
R3为胺基取代烷基、环烷基、烷基取代酰胺基、杂环基、芳基或杂芳基,所述杂环基、芳基或杂芳基均可被1-3个下述基团所取代:卤素、O、CN、OH、羟基取代烷基、二烷基取代胺基、C1-C6烷基、C3-C6环烷基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,当被多个取代基取代时,所述取代基可以相同或不同;
Ra、Rb、Rc和Rd均为H,Re和Rf和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Rc、Rd、Re和Rf均为H,Ra和Rb和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Ra、Rb、Re和Rf均为H时,Rc和Rd和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;和
E是能够与K-Ras突变体蛋白的12位的半胱氨酸残基形成共价键的亲电部分。
在另一优选例中,其中所述通式(1),通式(1A)和通式(1B)中,E为一个含亲电碳碳双键或碳碳叁键的基团。
在另一优选例中,其中所述通式(1),通式(1A)和通式(1B)中,E为: 其中,R4为H、F、CF3、OMe或-CH2OMe,R5为H、Me、Et、CN、-CONH2、-CH2F、-CHF2、CF3、-CH2OH、CH2OMe、/>
在另一优选例中,其中所述通式(1),通式(1A)和通式(1B)中,-A-L-E为: 其中,n为1或2,L为化学键或NH,R2为H、CN、C1-C3烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基。
在另一优选例中,其中所述通式(1),通式(1A)和通式(1B)中,Y为化学键、-CH2-、-CH(Me)-或-CH2CH2-。
在另一优选例中,其中所述通式(1),通式(1A)和通式(1B)中,R1为: 其中R6和R7独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基。
在另一优选例中,其中所述通式(1),通式(1A)和通式(1B)中,R3为: 其中n为1、2或3,R8和R9独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,R10为C1-C3烷基、C3-C6环烷基、C3-C6环烷基烷基、C1-C3烷氧基烷基、卤素取代C1-C3烷基、卤素取代C3-C6环烷基或/>
在各种不同实施方式中,化合物具有下表1中所列结构中的一个:
表1:本发明代表性化合物列表:
/>
/>
/>
/>
/>
/>
/>
/>
/>
本发明的另一个目的是提供了一种药物组合物,它含有药理上可接受的赋形剂或载体,以及本发明通式(1)化合物、或其各光学异构体、药学上可接受的无机或有机盐做为活性成分。
本发明的再一个目的提供了本发明的上述化合物、或其各光学异构体、药学上可接受的无机或有机盐用于制备治疗RAS相关疾病中的应用。
应理解,本发明的前述一般性描述和以下详细描述都是示例性和说明性的,旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式通式(1)化合物的制备方法,但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外,在此提到的溶剂,温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得,如,但不限于Aldrich Chemical Co.(Milwaukee,Wis.)或Sigma Chemical Co.(St.Louis,Mo.)。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成,包括发现于March,ADVANCED ORGANICCHEMISTRY 4th Ed.,(Wiley 1992);Carey和Sundberg,ADVANCED ORGANIC CHEMISTRY 4thEd.,Vols.A和B(Plenum 2000,2001),Green和Wuts,PROTECTIVE GROUPS IN ORGANICSYNTHESIS 3rd Ed.,(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面,本文所述的化合物根据工艺中公知的方法。然而方法的条件,例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。一方面,本发明还提供了一种所述的通式通式(1)所示化合物的制备方法,其采用下列一般反应流程1或2制备:
一般反应流程1
通式(1)化合物的实施方式可根据一般反应流程1(方法A)制备,其中Ra、Rb、Rc、Rd、Re、Rf、R1、R2、R3、A、E及Y如上文中所定义。如一般反应流程1所示,原料S(参照本专利制备例1-9中描述的方法合成)和片段A在碱性条件下生产A1,A1脱除保护基(例如Boc)得到A2,A2和R1-X偶联得到A3,A3化合物在氧化剂存在下生成A4,A4在适当条件下和R3-Y-OH的片段反应生成A5,A5脱除保护基(例如Cbz)得到A6,A6和酰氯或酸酐化合物反应生成A7。
一般反应流程2
通式(1)化合物的实施方式可根据一般反应流程2(方法B)制备,其中Ra、Rb、Rc、Rd、Re、Rf、R1、R2、R3、A、E及Y如上文中所定义,X表示氯、溴、碘或OTf。如一般反应流程2所示,中间体A1在氧化剂存在下生成B1,B1在碱性条件下水解成B2,B2在适当条件下和R3-Y-X的片段反应生成B3,B3脱除保护基(例如Boc)得到B4,B4和R1-X偶联得到B5,B5脱除保护基(例如Cbz)得到B6,B6和酰氯或酸酐化合物反应生成B7。
化合物的进一步形式
“药学上可接受”这里指一种物质,如载体或稀释液,不会使化合物的生物活性或性质消失,且相对无毒,如,给予个体某物质,不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式,该形式不会引起对给药有机体的重要的刺激,且不会使化合物的生物活性和性质消失。在某些具体方面,药学上可接受的盐是通过式(1)化合物与酸反应获得,如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式,尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂,且是在与药学上可接受溶剂如水,乙醇等,结晶化过程中选择性形成的。当溶剂是水时形成水合物,或当溶剂是乙醇时形成醇化物。式(1)化合物的溶剂化物按照本文所述的方法,很方便的制得或形成。举例说明,式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得,使用的有机溶剂包括但不限于,二氧杂环乙烷,四氢呋喃,乙醇或甲醇。此外,在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之,对于在此提供的化合物和方法为目的,溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中,式(1)化合物被制备成不同的形式,包括但不限于,无定形,粉碎形和毫微-粒度形式。此外,式(1)化合物包括结晶型,也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图,红外光谱,熔点,密度,硬度,晶型,光和电的性质,稳定性和溶解性。不同的因素如重结晶溶剂,结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面,式(1)化合物有一个或多个立体中心,并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心,取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体,并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
术语
如果无另外说明,用于本发明申请,包括说明书和权利要求书中的术语,定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
“烷基”指饱和的脂肪烃基团,包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用,“烷基”包括未取代和取代的烷基,尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH3,CH3CH2,CF3,CHF2,CF3CH2,iPr,nPr,iBu,cPr,nBu或tBu。
“环烷基”指3至6元全碳单环脂肪烃基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。例如,环丙基、环丁基、环戊基、环己烷、环己二烯等。
“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基,如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用,“烷氧基”包括未取代和取代的烷氧基,尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH3,OCF3,CHF2O,CF3CH2O,iPrO,nPrO,iBuO,cPrO,nBuO或tBuO。
“芳基”指具有至少一个芳环结构的基团,即具有共轭的π电子系统的碳环芳基,如苯环和萘环。
“杂芳基”指含有一个或多个杂原子(O,S或N)的芳香基团,杂芳基是单环或多环的,例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环基基团稠和。杂芳基的例子包括但不限于,吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基和吡咯并嘧啶基。
“卤素”指氟、氯、溴或碘。
术语“键”或“单键”指两个原子间或两个片断间(当通过键来连接的原子被认为是大结构的一部分时)的化学键。一方面,当本文所述的基团是一个键时,缺少参考基团,允许在剩余的确定基团间形成一个键。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。这样,如,环己基、吡啶基、吡喃基、噻喃基是六元环,环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
特定药学及医学术语
术语“可接受的”,如本文所用,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用,包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善或预防潜在代谢综合症;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或预防或治疗由疾病或症状引起的征兆。
如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药,可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物,以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心,并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心,取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体,并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用,且都是指当施用于个体(人类或动物)时,能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物,或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等,而可在施用个体体内形成该活性化合物的一相当用量者。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值,此处已尽可能精确地呈现具体实施例中的相关数值。然而,任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处,“约”通常是指实际数值在一特定数值或范围的正负10%、5%、1%或0.5%之内。或者是,“约”一词代表实际数值落在平均值的可接受标准误差之内,视本领域技术人员的考虑而定。除了实验例之外,或除非另有明确的说明,当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此,除非另有相反的说明,本说明书与附随权利要求书所揭示的数值参数皆为约略的数值,且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义,此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外,在不和上下文冲突的情形下,本说明书所用的单数名词涵盖该名词的复数型;而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明化合物或药物组合物治疗疾病的方法,包括但不限于涉及G12C K-Ras、G12C H-Ras和/或G12C N-Ras突变的病况(例如癌症)。
在一些事实方案中,提供了用于癌症治疗的方法,该方法包括给予有需要的个体有效量的任何前述的保护结构(1)化合物的药物组合物。在一些实施方案中,癌症由K-Ras、H-Ras和/或G12C N-Ras突变介导。在其它实施方案中,该癌症是肺癌、胰腺癌、结肠癌、MYH相关息肉病或结肠直肠癌。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂,其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时,可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~1000mg,优选10~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势,使本发明的内容变得十分明了。在此应理解,下述的详细说明及实例描述了具体的实施例,仅用于参考。在阅读了本发明的说明内容后,本领域的技术人员可对本发明作各种改动或修改,这些等价形势同样落于本申请所限定的范围。
所有实施例中,1H-NMR用Vian Mercury 400核磁共振仪记录,化学位移以δ(ppm)表示;分离用硅胶未说明均为200-300目,洗脱液的配比均为体积比。
本发明采用下述缩略词:Ar代表氩气;aq代表水溶液;(Boc)2O代表二碳酸二叔丁酯;CDCl3代表氘代氯仿;CD3OD代表氘代甲醇;CH3CN代表乙腈;CH3NO2代表硝基甲烷;(COCl)2代表草酰氯;Cs2CO3代表碳酸铯;CuI代表碘化亚铜;DBU代表1,8-二氮杂环[5,4,0]十一烯-7;DCM代表二氯甲烷;DIPEA代表二异丙基乙基胺;Dioxane代表1,4-二氧六环;DMF代表二甲基甲酰胺;DMSO代表二甲基亚砜;EA代表乙酸乙酯;EtOH代表乙醇;EtONa代表乙醇钠;h代表小时;NaOH代表氢氧化钠;NaOMe代表甲醇钠;LC-MS代表液相-质谱;m-CPBA代表间氯过氧苯甲酸;MeOH代表甲醇;min代表分钟;MS代表质谱;Na2CO3代表碳酸钠;NaH代表氢化钠;NMR代表核磁共振;Pd2(dba)3代表三(二亚苄基丙酮)二钯;PE代表石油醚;SOCl2代表氯化亚砜;t-BuOK代表叔丁醇钾;t-BuONa代表叔丁醇钠;TFA(CF3COOH)代表三氟乙酸;Tf2O代表三氟甲磺酸酐;THF代表四氢呋喃;Xantphos代表4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。
具体实施方式
制备例1:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,8′-二氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(S-1)的合成
(E)-3-(1-((叔丁氧基羰基)氨基)环丙基)丙烯酸甲酯
500mL三口瓶中加入2-(二乙氧基磷酰基)乙酸甲酯(21.0g,0.1mol),干燥THF(200mL),Ar气保护下降温至-20℃,后在-20℃~-10℃滴加LiHMDS(130mL,1M in THF,0.13mol),滴毕,混合液-10℃搅拌30min,后在-10℃下滴加(1-醛基环丙基)氨基甲酸叔丁酯(16.7g,90mmol)的THF(30mL)溶液,滴毕,混合液-10℃~rt.搅拌5h。LC-MS监测反应完成后,加饱和氯化铵溶液(100mL)淬灭,EA(100mL)萃取,有机相用饱和氯化钠溶液(100mL)洗涤,浓缩至干,残留物柱层析(EA/PE=0/5to 1/5)纯化得淡棕色油状物(13.46g,收率:62%),ESI-MS m/z:242.0[M+H]+。
(E)-3-(1-((叔丁氧基羰基)(2-甲氧基-2-氧代乙基)氨基)环丙基)丙烯酸甲酯
500mL单口瓶中加入(E)-3-(1-((叔丁氧基羰基)氨基)环丙基)丙烯酸甲酯(13.4g,55.5mmol),DMF(135mL),Ar气保护下降温至0℃后分批加入NaH(2.89g,60%inmineral,72.2mmol),加毕,体系0~5℃搅拌30min,后加入溴乙酸乙酯(10.2g,66.6mmol),混合液室温搅拌反应20h。LC-MS监测反应完成后,体系加饱和氯化铵溶液(100mL)淬灭,EA(100mL*2)萃取,合并有机相用饱和氯化钠溶液(100mL)洗涤,浓缩至干,残留物柱层析(EA/PE=0/5 to 1/5)纯化得淡棕色油状物(8.87g,收率51%),ESI-MS m/z:336.0[M+Na]+。
3-(1-((叔丁氧基羰基)(2-甲氧基-2-氧代乙基)氨基)环丙基)丙酸甲酯
500mL单口瓶中加入(E)-3-(1-((叔丁氧基羰基)(2-甲氧基-2-氧代乙基)氨基)环丙基)丙烯酸甲酯(8.87g,28.34mmol),MeOH(170mL),10%Pd/C(800mg,wet%=50%),H2置换三次后室温下常压氢化20h。LC-MS监测反应完成后,体系硅藻土过滤,滤液浓缩至干得无色油状物(9.1g,收率100%),ESI-MS m/z:338.0[M+Na]+。
4-(叔丁基)7-乙基6-氧代-4-氮杂螺[2.5]辛烷-4,7-二羧酸酯
将3-(1-((叔丁氧基羰基)(2-甲氧基-2-氧代乙基)氨基)环丙基)丙酸甲酯(9.1g,28.34mmol)溶于无水甲醇(180mL)中,Ar保护下加入新制的甲醇钠(2.30g,42.51mmol),后升温至回流反应5h,LC-MS监测反应完毕,混合液调pH至5~6,浓缩,残留物加入乙酸乙酯(100mL),H2O(100mL),水相再用EA(50mL)萃取,合并有机相用饱和氯化钠溶液(50mL)洗涤,浓缩,柱层析(PE/EA=10/1 to 2/1)纯化得到近无色油状物(3.3g,收率41%),ESI-MS m/z:284.0[M+H]+。
2′-(甲硫基)-4′-氧代-3′,4′,5′,8′-四氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]]嘧啶]-7′-甲酸叔丁酯
往250mL单口瓶中加入4-(叔丁基)7-乙基6-氧代-4-氮杂螺[2.5]辛烷-4,7-二羧酸酯(3.3g,11.65mmol)和MeOH(66mL),Ar保护下分别加入甲醇钠(3.14g,58.2mmol)和S-甲基异硫脲硫酸盐(3.5g,17.5mmol),室温反应20h。LC-MS和TLC监测(PE/EA=2/1),反应完成后,混合液冰浴下用2NHCl调pH至5~6,减压浓缩。残留物中加入H2O(60mL)和EA(15mL),打浆搅拌半小时,过滤,烘干得类白色固体(3.43g,收率91%),ESI-MS m/z:324.1[M+H]+。
2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,8′-二氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯
往250mL三口瓶中加入2′-(甲硫基)-4′-氧代-3′,4′,5′,8′-四氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]]嘧啶]-7′-甲酸叔丁酯(3.43g,10.6mmol),DIPEA(4.1g,31.8mmol)和DCM(70mL),Ar保护下,冰浴冷却至0-5℃,滴加Tf20(3.89g,13.78mmol)的DCM(20mL)溶液,滴加完毕后,混合液室温搅拌反应20h。TLC监测(PE/EA=2/1)反应完全后,加H2O(100mL)淬灭,后滴加1N HCl调pH至5~6,分液,有机相用饱和氯化钠溶液(50mL)洗涤,浓缩,残留物柱层析纯化(PE/EA=10/0 to 5/1)得类白色固体(3.5g,收率72.6%),ESI-MSm/z:456.1[M+H]+。
制备例2:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,8′-二氢-7′H-螺[环丁烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(S-2)的合成
以(1-醛基环丁基)氨基甲酸叔丁酯为原料,采用中间体S-1的合成方法得到目标中间体S-2,ESI-MS m/z:470.1[M+H]+。
制备例3:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,8′-二氢-7′H-螺[氧杂环丁烷-3,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(S-3)的合成
以(3-甲酰基氧杂环丁烷-3-基)氨基甲酸叔丁酯为原料,采用中间体S-1的合成方法得到目标中间体S-3,ESI-MS m/z:472.1[M+H]+。
制备例4:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,6′-二氢-7′H-螺[环丙烷-1,8′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(S-4)的合成
1-氨基环丙烷-1-甲酸乙酯
将1-氨基环丁烷-1-甲酸(10.1g,0.1mol)溶于乙醇(100mL)中,冰浴下缓慢滴加二氯亚砜(23.8g,0.2mol),滴毕后室温反应20h,LC-MS监测反应完毕,混合液浓缩,残留物加入DCM(100mL)和碳酸氢钠水溶液(100mL),搅拌,分液,水相再用(100mL*2)萃取,合并有机相用饱和氯化钠溶液(100mL*2)洗涤,无水硫酸钠干燥,过滤,浓缩得到浅黄色油状物(9.08g,收率70%),ESI-MS m/z:130.1[M+H]+。
1-((4-乙氧基-4-氧代丁基)氨基)环丙烷-1-甲酸乙酯
将1-氨基环丙烷-1-羧酸乙酯(9.08g,70.4mmol)溶于乙腈(200mL)中,加入DIPEA(18.2g,141mmol),4-溴丁酸乙酯(27.5g,141mmol),Ar保护下升温至80℃反应20h,LC-MS监测反应完毕,浓缩,残留物加入乙酸乙酯(200mL),H2O(100mL),搅拌,分液,水相再用乙酸乙酯(100mL)萃取,合并有机相用饱和氯化钠(100mL)洗涤,浓缩,残留物柱层析(DCM/MeOH=20/0 to 20/1)纯化得到浅黄色油状物(8.70g,收率51%),ESI-MS m/z:244.2[M+H]+。
1-((叔丁氧基羰基)(4-乙氧基-4-氧代丁基)氨基)环丙烷-1-甲酸乙酯
将1-((4-乙氧基-4-氧代丁基)氨基)环丙烷-1-羧酸乙酯(8.70g,35.8mmol)用THF(100mL)和H2O(50mL)溶解,加入Boc2O(15.7g,72mmol)和Na2CO3(11.4g,0.107mol),混合液升至60℃搅拌反应20h,LC-MS监测反应完成后,反应液加入EA(100mL)和H2O(100mL),搅拌,分液,有机相浓缩,残留物经柱层析(PE/EA=5/0 to 5/1)纯化得到无色油状物(7.61g,收率62%),ESI-MS m/z:344.2[M+H]+。
4-(叔丁基)7-乙基-8-氧代-4-氮杂螺[2.5]辛烷-4,7-二羧酸酯
将1-((叔丁氧基羰基)(4-乙氧基-4-氧代丁基)氨基)环丙烷-1-甲酸乙酯(7.61g,22.2mmol)溶于无水乙醇(140mL)中,Ar保护下加入新制的乙醇钠(2.26g,33.3mmol),后升温至回流反应5h,LC-MS监测反应完毕,混合液调pH至5~6,浓缩,残留物加入乙酸乙酯(100mL)和H2O(100mL),水相再用EA(50mL)萃取,合并有机相用饱和氯化钠溶液(50mL)洗涤,浓缩,柱层析(PE/EA=10/1 to 2/1)纯化得到近无色油状物(2.31g,收率35%),ESI-MSm/z:298.0[M+H]+。
2′-(甲硫基)-4′-羰基-3′,4′,5′,6′-四氢-7′H-螺[环丙烷-1,8′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯
往250mL单口瓶中加入4-(叔丁基)7-乙基-8-氧代-4-氮杂螺[2.5]辛烷-4,7-二羧酸酯(4.76g,16.0mmol)和EtOH(100mL),Ar保护下分别加入乙醇钠(5.44g,80mmol)和S-甲基异硫脲硫酸盐(4.8g,24mmol),室温反应20h。LC-MS和TLC监测(PE/EA=2/1),反应完成后,混合液冰浴下用2N HCl调pH至5~6,减压浓缩。残留物中加入H2O(60mL)和EA(30mL),打浆搅拌半小时,过滤,烘干得类白色固体(4.24g,收率82%),ESI-MS m/z:324.1[M+H]+。
2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,6′-二氢-7′H-螺[环丙烷-1,8′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯
往250mL三口瓶中加入2′-(甲硫基)-4′-羰基-3′,4′,5′,6′-四氢-7′H-螺[环丁烷-1,8′-吡啶并[3,4-d]嘧啶]-7′-羧酸叔丁酯(4.24g,13.11mmol),DIPEA(5.08g,39.40mmol)和DCM(100mL),Ar保护下,冰浴冷却至0-5℃,滴加Tf2O(4.45g,15.75mmol)的DCM(20mL)溶液,滴加完毕,混合液室温搅拌反应20h。TLC监测(PE/EA=2/1)反应完全后,加H2O(100mL)淬灭,后滴加1N HCl调pH至5~6,分液,有机相用饱和氯化钠溶液(50mL)洗涤,浓缩,残留物柱层析纯化(PE/EA=10/0 to 10/1)得类白色固体(4.35g,收率73%),ESI-MSm/z:456.1[M+H]+。
制备例5:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,6′-二氢-7′H-螺[环丁烷-1,8′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(S-5)的合成
以1-氨基环丁基-1-甲酸为原料,采用中间体S-4的合成方法得到目标中间体S-5,ESI-MS m/z:470.1[M+H]+。
制备例6:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-5′,6′-二氢-7′H-螺[氧杂环丁烷-1,8′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(S-6)的合成
以3-氨基氧杂环丁烷-3-甲酸为原料,采用片段S-4的合成方法得到目标中间体S-6,ESI-MS m/z:472.1[M+H]+。
制备例7:2′-(甲硫基)-4′-(((三氟甲基)磺酰)氧基)-6′H-螺[氧杂环丁烷-3,5′-吡啶并[3,4-d]嘧啶]-7′(8′H)-甲酸叔丁酯(S-7)的合成
2-(氧杂环丁环-3-亚基)乙酸乙酯
将氧杂环丁烷-3-酮(10.8g,150mm0l)溶于二氯甲烷(150mL)中,冰浴下加入乙氧基甲酰基亚甲基三苯基磷(52.2g,150mmol),加毕,室温反应过夜,LC-MS监测反应完毕,浓缩得到白色固体,固体用PE/EA(10/1,100mL)打浆,滤液浓缩,柱层析(PE/EA=20/1to 5/1),得到近无色胶状物(15g,收率70%),ESI-MS m/z:143.0[M+H]+。
2-(3-(硝基甲基)氧杂环丁烷-3-基)乙酸乙酯
将2-(氧杂环丁环-3-亚基)乙酸乙酯(14.2g,100mL)溶于硝基甲烷(100mL)中,加入DBU(1.52g,10mmol),室温反应过夜,LC-MS监测反应完毕,浓缩,残留物用乙酸乙酯溶解,用稀酸洗,浓缩后柱层析(PE/EA=20/1 to 5/1)得到近无色胶状物(10g,收率50%),ESI-MS m/z:204.0[M+H]+。
2-(3-(氨基甲基)氧杂环丁烷-3-基)乙酸乙酯
将2-(3-(硝基甲基)氧杂环丁烷-3-基)乙酸乙酯(6.1g,30mmol)溶于乙醇(100mL)中,加入三氟乙酸(6.8g,60mmol),加入10%Pd/C(1.36g,wet%=20%),通入H2,50℃反应过夜,LC-Ms监测,反应完毕,过滤,浓缩后所得初产物直接投入下一步反应,ESI-MS m/z:174.1[M+H]+。
N-(叔丁氧基羰基)-N-((3-(2-乙氧基-2-羰基乙基)氧杂环丁烷-3-基)甲基)甘氨酸乙酯
将2-(3-(氨基甲基)氧杂环丁烷-3-基)乙酸乙酯(理论量,30mmol)溶于乙腈(150mL)中,加入溴乙酸乙酯(5.0g,30mmol),碳酸钾(20g,150mmol),升温50℃反应过夜,LC-MS监测,反应完毕,过滤,浓缩后用二氯甲烷(150mL)溶解,加入DIPEA(7.74g,60mmol),Boc2O(7.8g,36mmol),室温反应过夜,LC-MS监测,反应完毕,反应液用水洗,浓缩后柱层析(PE/EA=20/1 to 5/1)得到近无色胶状物(5.4g,收率50%),ESI-MS m/z:360.1[M+H]+。
6-(叔丁基)9-乙基8-羰基-2-氧杂-6-氮杂螺[3.5]壬烷-6,9-二羧酸酯
将N-(叔-丁氧基羰基)-N-((3-(2-乙氧基-2-羰基乙基)氧杂环丁烷-3-基)甲基)甘氨酸乙酯(7.2g,20mmol)溶于无水乙醇(60mL)中,加入新制的乙醇钠(2.7g,40mmol),升温回流反应5h,LC-MS监测,反应完毕,调PH至中性,浓缩,加入乙酸乙酯(100mL)溶解,用水洗,饱和氯化钠溶液洗,浓缩后柱层析(PE/EA=10/1 to 2/1)得到近无色胶状物(2.5g,收率40%),ESI-MS m/z:314.1[M+H]+。
2′-(甲硫基)-4′-羰基-4′,8′-二氢-3′H-螺[氧杂环丁烷-3,5′-吡啶并[3,4-d]嘧啶]-7′(6′H)-甲酸叔丁酯
往250mL单口瓶中加入6-(叔丁基)9-乙基8-羰基-2-氧杂-6-氮杂螺[3.5]壬烷-6,9-二羧酸酯(5g,15.96mmol)和EtOH(100mL),Ar保护下分别加入乙醇钠(5.43g,79.8mmol)和S-甲基异硫脲硫酸盐(4.8g,23.9mmol),室温反应过夜。LC-MS监测和TLC点板(PE/EA=2/1),冰浴冷却,用2NHCl调PH至5,浓缩,往粗品中加入H2O(30mL)和EA(30mL),打浆搅拌半小时,过滤,烘干得类白色固体(4.3g,收率79%),ESI-MS m/z:340.1[M+H]+。
2′-(甲硫基)-4′-(((三氟甲基)磺酰)氧基)-6′H-螺[氧杂环丁烷-3,5′-吡啶并[3,4-d]嘧啶]-7′(8′H)-甲酸叔丁酯
往250mL单口瓶中加入2′-(甲硫基)-4′-羰基-4′,8′-二氢-3′H-螺[氧杂环丁烷-3,5′-吡啶并[3,4-d]嘧啶]-7′(6′H)-羧酸叔丁酯(4.0g,11.80mmol),DIPEA(4.57g,35.40mmol)和DCM(50mL),Ar保护下,冰浴冷却至0-5℃,滴加Tf2O(5.0g,17.7mmol)的DCM(10mL)溶液,滴加完毕,室温反应,TLC点板(PE/EA=2/1),原料基本反应完全后,将反应液浓缩后柱层析纯化(PE/EA=1/0 to 10/1)得黄色固体(3.3g,收率60%),ESI-MS m/z:472.0[M+H]+。
制备例8:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-6′H-螺[环丁烷-1,5′-吡啶并[3,4-d]嘧啶]-7′(8′H)-甲酸叔丁酯(S-8)的合成
以环丁酮为原料,采用片段S-7的合成方法得到目标中间体S-8,ESI-MS m/z:470.1[M+H]+。
制备例9:2′-(甲硫基)-4′-(((三氟甲基)磺酰基)氧基)-6′H-螺[环丙烷-1,5′-吡啶并[3,4-d]嘧啶]-7′(8′H)-甲酸叔丁酯(S-9)的合成
以2-环丙基亚甲基乙酸乙酯为原料,采用片段S-7的合成方法得到目标中间体S-9,ESI-MS m/z:456.1[M+H]+。
实施例1:2-((S)-1-丙烯酰基-4-(2′-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7′-(萘-1-基)-7′,8′-二氢-5′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-2-基)乙腈(化合物1)的合成
化合物1根据如下文所述的方法A制备:
(S)-4′-(4-((苄氧基)羰基)-3-(氰基甲基)哌嗪-1-基)-2′-(甲硫基)-5′,8′-二氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(1-1)
往500mL单口瓶中加入S-1(9.1g,20.0mmol),DIPEA(5.16g,40mmol),苄基(S)-2-(氰基甲基)哌嗪-1-羧酸苄酯(5.22g,20.0mmol)和DMF(91mL),Ar保护下,升温至100℃反应1小时,TLC监测(PE/EA=10/1),原料反应完全,将反应液冷却至室温后,加入水(100mL),用EA(100mL*2)萃取,合并有机相,饱和氯化钠溶液洗,有机相浓缩,柱层析纯化(PE/EA=1/0to 2/1)得白色固体1-1(10.6g,收率94%),ESI-MS m/z:565.3[M+H]+。
(S)-4′-(4-((苄氧基)羰基)-3-(氰基甲基)哌嗪-1-基)-2′-(甲基磺酰基)-5′,8′-二氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁基酯(1-2)
往500mL单口瓶中加入1-1(10.6g,18.8mmol)和DCM(210mL),Ar保护下,冰浴冷却至0-5℃,加入m-CPBA(11.4g,65.8mmol),冰浴下反应2小时。TLC监测(PE/EA=1/5),原料反应完全,往反应液中加入饱和碳酸氢钠溶液(60mL),搅拌,分液,水相再用DCM(100mL*2)萃取,合并有机相,饱和氯化钠溶液洗,有机相浓缩后柱层析纯化(PE∶EA=1∶0to 1∶1)得白色固体1-2(9.1g,收率81%),ESI-MS m/z:597.2[M+H]+。
4′-((S)-4-((苄氧基)羰基)-3-(氰基甲基)哌嗪-1-基)-2′-(((S)-1-甲基吡咯烷-2-基)甲氧基叔丁基)-5′,8′-二氢7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(1-3)
往500mL单口瓶中加入(S)-(1-甲基吡咯烷-2-基)甲醇(2.108g,18.30mmol)和甲苯(180mL),Ar气保护下冰浴降温至0~5℃,然后加入叔丁醇钾(2.57g,22.88mmol),0~5℃搅拌反应15min后,加入1-2(9.1g,15.25mmol),混合液0~10℃搅拌反应2h。LC-MS和TLC监测(PE/EA=1/1),原料反应完全后,体系加入饱和氯化铵(100mL)淬灭,搅拌,分液,水相再用EA(90mL*2)萃取,合并有机相用饱和氯化钠溶液(90mL*2)洗涤,浓缩,残留物经柱层析纯化(EA/PE=0/1to 1/2)得类白色固体1-3(7.23g,收率75%),ESI-MS m/z:632.3[M+H]+。
(S)-2-(氰基甲基)-4-(2′-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7′,8′-二氢-5′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-1-甲酸苄酯(1-4)
250mL单口瓶中加入1-3(7.23g,11.44mmol),DCM(140mL)和TFA(25.2g,221mmol),混合液室温搅拌反应2h。LC-MS监测反应完全后,体系浓缩,残留物加入DCM(200mL),碳酸氢钠溶液(100mL),室温搅拌30min后分液,水相再用DCM(100mL)萃取,合并有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤后浓缩至干得黄棕色油状1-4(5.66g,收率93%),ESI-MS m/z:532.3[M+H]+。
(S)-2-(氰基甲基)-4-(2′-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7′-(萘-1-基)-7′,8′二氢-5′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-1-甲酸苄酯(1-5)
100mL单口瓶中加入1-4(266mg,0.5mmol),1-溴萘(166mg,0.75mmol),t-BuONa(144mg,1.5mmol)和Dioxane(20mL),Ar置换保护后再加入Sphos-G3-Pd(87mg,0.1mmol),混合液Ar保护下升温至回流搅拌反应20h。LC-MS监测反应完成后,体系加水淬灭,EA(20mL*2)萃取,有机相用饱和氯化钠洗涤,浓缩后柱层析纯化(DCM/MeOH/NH4OH=40/1/0.02)得淡棕色油状物1-5(72mg,收率22%),ESI-MS m/z:658.4[M+H]+。
2-((S)-4-(2′-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7′-(萘-1-基)-7′,8′-二氢-5′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-2-基)乙腈(1-6)
50mL单口瓶中加入1-5(72mg,0.11mmol),MeOH(10mL)和10%Pd/C(20mg,wet%=50%),H2置换三次后室温常压下搅拌20h。LC-MS监测反应完成后,体系过滤,滤液浓缩得黄色泡沫状固体1-6(58mg,收率100%),ESI-MS m/z:524.3[M+H]+。
2-((S)-1-丙烯酰基-4-(2′-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7′-(萘-1-基)-7′,8′-二氢-5′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-2-基)乙腈(化合物1)
50mL单口瓶中加入1-6(58mg,0.11mmol),DCM(5mL),DIPEA(42mg,0.33mmol),Ar保护下冰浴降温至0℃,后滴加丙烯酰氯(9mg,0.10mmol)的DCM溶液,滴毕,体系0-5℃搅拌1h。LC-MS监测反应完全后,加水淬灭,分液,水相用DCM(10mL)萃取,合并有机相用饱和氯化钠溶液(10mL)洗涤,浓缩后残留物经pre-TLC纯化得到类白色固体化合物1(13mg,收率20%)。
1H NMR(400MHz,CDCl3)δ:7.97(m,1H),7.72-7.21(m,6H),6.63-6.52(m,1H),6.24(dd,J=16.9,1.9Hz,1H),5.72(ddd,J=10.5,3.2,1.9Hz,1H),4.66(d,J=11.9Hz,1H),4.32(m,3H),3.64-3.51(m,3H),3.48-3.22(m,4H),2.74(s,3H),2.53-2.32(m,7H),1.86-1.65(m,4H),0.65-0.46(m,4H);ESI-MS m/z:578.3[M+H]+。
实施例2-实施例93:化合物2-化合物93的合成
以中间体S-1至S-9为起始原料,采用合成方法A,类似于化合物1的合成方法,可以得到化合物2-化合物93。
实施例94:2-((S)-1-(2-氟丙烯酰基)-4-(7′-(8-甲基萘-1-基)-1′-(((S)-1-甲基吡咯烷-2-基)甲基)-2′-氧-1′,5′,7′,8′-四氢-2′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-2-基)乙腈(化合物94)的合成
化合物94根据如下文所述的方法B制备:
(S)-4′-(4-((苄氧基)羰基)-3-(氰基甲基)哌嗪-1-基)-2′-氧代-1′,2′,5′,8′-四氢-7′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(94-1)
往250mL单口瓶中加入1-2(5.27g,8.83mmol)和1,4-二氧六环(100mL),然后加入氢氧化钠溶液(44.1mL,2N),室温反应过夜,TLC监测(PE/EA=1/1)原料反应完全后,用2N盐酸调pH至7,析出固体,过滤得白色固体94-1,滤液再用EA(50mL)萃取,饱和氯化钠溶液洗,无水硫酸钠干燥,过滤,浓缩后粗品加入EA(5mL)打浆搅拌,过滤得白色固体94-1,合并得到产物94-1(3.82g,收率81%),ESI-MS m/z:535.2[M+H]+。
4′-((S)-4-((苄氧基)羰基)-3-(氰基甲基)哌嗪-1-基)-1′-(((S)-1-甲基吡咯烷-2-基)甲基)-2′-氧代-1′,2′,5′,8′-四氢-7′-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-7′-甲酸叔丁酯(94-2)
100mL封管反应器中加入94-1(1.26g,2.36mmol),Cs2CO3(1.53g,4.70mmol),(S)-2-(溴甲基)-1-甲基吡咯烷(632mg,3.55mmol),CuI(89mg,0.47mmol)和DMSO(24mL),密封后升至100℃搅拌反应20h。体系降至室温,加入饱和氯化铵溶液(20mL)淬灭,室温搅拌30min后加EA(20mL*2)萃取,合并有机相用饱和氯化钠溶液(20mL*2)洗涤,浓缩,残留物柱层析(DCM/MeOH=30/0 to 20/1)纯化得黄棕色固体94-2(610mg,收率41%),ESI-MS m/z:632.3[M+H]+。
(S)-2-(氰基甲基)-4-(1′-(((S)-1-甲基吡咯烷-2-基)甲基)-2′-氧代-1′,5′,7′,8′-四氢-2′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-1-甲酸苄酯(94-3)
250mL单口瓶中加入94-2(610mg,0.966mmol),DCM(10mL)和TFA(2.20g,19.31mmol),混合液室温搅拌反应4h。LC-MS监测反应完全后,体系浓缩,残留物加入DCM(20mL),碳酸氢钠溶液(20mL),室温搅拌30min后分液,水相再用DCM(20mL)萃取,合并有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩得黄棕色油状94-3(493mg,收率96%),ESI-MS m/z:532.3[M+H]+。
(S)-2-(氰基甲基)-4-(7′-(8-甲基萘-1-基)-1′-(((S)-1-甲基吡咯烷-2-基)甲基)-2′-氧代-1′,5′,7′,8′-四氢-2′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-1-甲酸苄酯(94-4)
250mL单口瓶中加入94-3(272mg,0.512mmol),1-溴-8-甲基萘(170mg,0.768mmol),叔丁醇钠(98mg,1.024mmol),Xantphos(58mg,0.1mmol)和Dioxane(10mL),Ar置换保护后再加入Pd2(dba)3(46mg,0.05mmol),混合液Ar保护下升温至回流搅拌反应20h。LC-MS监测反应完成后。体系加水淬灭。EA(20mL*2)萃取。有机相用饱和氯化钠洗涤。浓缩后柱层析纯化(MeOH/DCM=0/1 to 1/40 to 1/20)得淡棕色油状物94-4(62mg,收率18%),ESI-MS m/z:672.4[M+H]+。
2-((S)-4-(7′-(8-甲基萘-1-基)-1′-(((S)-1-甲基吡咯烷-2-基)甲基)-2′-氧代-1′,5′,7′,8′-四氢-2′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-2-基)乙腈(94-5)
100mL单口瓶中加入94-4(62mg,0.092mmol),MeOH(10mL)和10%Pd/C(20mg,wet%=50%),H2置换三次后室温常压下搅拌20h。LC-MS监测反应完成后,体系过滤,滤液浓缩得黄色泡沫状固体94-5(55mg,收率100%),ESI-MS m/z:538.3[M+H]+。
2-((S)-1-(2-氟丙烯酰基)-4-(7′-(8-甲基萘-1-基)-1′-(((S)-1-甲基吡咯烷-2-基)甲基)-2′-氧-1′,5′,7′,8′-四氢-2′H-螺[环丙烷-1,6′-吡啶并[3,4-d]嘧啶]-4′-基)哌嗪-2-基)乙腈(化合物94)
50mL单口瓶中加入2-氟-丙烯酸(25mg,0.277mmol),DCM(5mL)和DMF(2mg),Ar置换保护后降温至0℃,后滴加草酰氯(30mg,0.236mmol)的DCM(2mL)溶液,滴毕,混合液室温搅拌2h。后将该混合液再次冰浴降温至0℃,后依次滴加94-5(47mg,0.088mmol)的DCM(2mL)溶液,DIPEA(57mg,0.44mmol)的DCM(2mL)溶液。混合液冰浴下搅拌1h。LC-MS监测反应完成后,加水(10mL)淬灭反应,分液,水相用DCM(10mL)萃取,合并有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,粗品pre-TLC纯化得类白色固体94(22mg,收率41%)。
1H NMR(400MHz,CDCl3)δ:7.64(d,J=19.2Hz,2H),7.31(m,4H),5.40(d,J=47.5Hz,1H),5.23(d,J=16.7Hz,1H),4.49(m,1H),4.33-3.97(m,1H),3.74-3.51(m,4H),3.52-3.21(m,5H)3.18-2.75(m,6H),2.65(s,3H),2.56-2.35(m,4H),1.94-1.82(m,4H),0.62-0.35(m,4H);ESI-MS m/z:610.3[M+H]+.
实施例95-实施例165:化合物95-化合物165的合成
以中间体S-1至S-9为起始原料,采用合成方法B,类似于化合物94的合成方法,可以得到化合物95-化合物165。
实施例166:化合物对H358细胞内pERK和ERK蛋白含量的检测
H358细胞种植于24孔板中,生长一天后,加入待测化合物(浓度为1μM),化合物作用24小时后,裂解细胞后,将细胞裂解液,转移至96孔ELISA板子中,运用ELISA试剂盒(abcam 176660)测定裂解液中pERK和ERK水平,计算pERK和ERK的比值,并与DMSO组对比,计算化合物抑制pERK活性的百分比,结果见下列表2。
表2.本发明化合物对H358细胞内pERK水平的抑制活性
/>
/>
+表示抑制率小于或等于50%
++表示抑制率为50%至90%
+++表示抑制率大于90%。
实施例167化合物对H358细胞的抗增殖活性
2500个H358细胞种植于超低吸附的96孔板(corning,7007)中,生长一天后,加入梯度稀释化合物(最高30μM,5倍稀释,一共五个剂量),加入化合物三天后,加入Cell TiterGlow(Promega,G9681)评价小球的生长情况,计算IC50值,结果见下列表3。
表3.本发明化合物对H358细胞的抗增殖活性
/>
/>
+表示化合物的IC50大于30μM
++表示化合物的IC50为1至30μM
+++表示化合物的IC50小于1μM。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (8)
1.一种结构如通式(1)所示的化合物或其各光学异构体、药学上可接受的盐:
式(1)中:
L为化学键或NH;
-A-L-E为:其中,n为1或2,R2为H、CN、C1-C3烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基;
R1为: 其中R6和R7独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基;
表示V和Z之间为单键或双键,当Z为CO,且V为/>时,V和Z之间为单键连接;或,当V为N,且Z为/>时,V和Z之间为双键连接;
Ra、Rb、Rc和Rd均为H,Re和Rf和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Rc、Rd、Re和Rf均为H,Ra和Rb和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Ra、Rb、Re和Rf均为H时,Rc和Rd和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;和
E为:其中,R4为H、F、CF3、OMe或-CH2OMe,R5为H、Me、Et、CN、-CONH2、-CH2F、-CHF2、CF3、-CH2OH、CH2OMe、/>
其中,
Y为化学键或C1-C6亚烷基;
R3为: 其中n为1、2或3,R8和R9独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,R10为C1-C3烷基、C3-C6环烷基、C3-C6环烷基烷基、C1-C3烷氧基烷基、卤素取代C1-C3烷基、卤素取代C3-C6环烷基或/>
所述式(1)所示的化合物不为
2.如权利要求1所述的化合物,结构如通式(1A)或通式(1B)所示:
其中:
L为化学键或NH;
-A-L-E为:其中,n为1或2,R2为H、CN、C1-C3烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基;
R1为: 其中R6和R7独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基;
Y为化学键或C1-C6亚烷基;
R3为: 其中n为1、2或3,R8和R9独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基,R10为C1-C3烷基、C3-C6环烷基、C3-C6环烷基烷基、C1-C3烷氧基烷基、卤素取代C1-C3烷基、卤素取代C3-C6环烷基或/>
Ra、Rb、Rc和Rd均为H,Re和Rf和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Rc、Rd、Re和Rf均为H,Ra和Rb和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;或,Ra、Rb、Re和Rf均为H时,Rc和Rd和它们相连的碳原子形成C3-C6环烷基或C4-C6杂环;和
E为:其中,R4为H、F、CF3、OMe或-CH2OMe,R5为H、Me、Et、CN、-CONH2、-CH2F、-CHF2、CF3、-CH2OH、CH2OMe、/>
3.如权利要求1或2所述的化合物,其中所述通式(1),通式(1A)和通式(1B)中,Y为化学键、-CH2-、-CH(Me)-或-CH2CH2-。
4.一种化合物,或其一种药学上可接受的盐,其中所述化合物具有以下结构之一:
/>
/>
5.一种用于治疗、调节和/或预防与K-Ras G12C突变体蛋白相关的疾病的药物组合物,其特征在于,它含有药学上可接受的赋形剂或载体,以及作为活性成分的权利要求1-4任一项所述的化合物、或其各光学异构体、药学上可接受的盐。
6.如权利要求5所述的药物组合物,其特征在于,所述的组合物为口服剂型。
7.如权利要求5所述的药物组合物,其特征在于,所述的组合物为注射剂型。
8.一种权利要求1-4任一项所述的化合物、或其各光学异构体、药学上可接受的盐的用途,其特征是用于制备治疗由K-Ras G12C突变介导的疾患的药物;
所述的疾患是癌症,所述癌症是肺癌、胰腺癌、结肠癌、MYH相关息肉病或结肠直肠癌。
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