CN117769554A - Kras突变蛋白的小分子抑制剂 - Google Patents
Kras突变蛋白的小分子抑制剂 Download PDFInfo
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- CN117769554A CN117769554A CN202280052819.5A CN202280052819A CN117769554A CN 117769554 A CN117769554 A CN 117769554A CN 202280052819 A CN202280052819 A CN 202280052819A CN 117769554 A CN117769554 A CN 117769554A
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- 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
式(I)的化合物或其药学上可接受的盐可以抑制Kirsten大鼠肉瘤(KRAS)蛋白的G12C、G12D和/或G12V突变体并且预期具有作为治疗剂的效用,例如用于治疗癌症。本公开还提供了包含式(I)的化合物或其药学上可接受的盐的药物组合物。本公开还涉及使用所述化合物或其药学上可接受的盐治疗和预防癌症的方法以及制备用于此目的的药物的方法。
Description
相关申请的交叉引用
本申请要求2021年5月28日提交的美国临时申请号63/194,852的权益,其全部内容通过引用并入本文。
技术领域
本发明涉及抑制例如Kirsten大鼠肉瘤(KRAS)蛋白的G12C突变体、G12D突变体和G12V突变体的KRAS小分子抑制剂,并且涉及包含式(I)的化合物的药物组合物以及使用此类化合物治疗包括癌症在内的疾病的方法。
背景技术
RAS是分子量约为21kDa的小单体GTP结合蛋白,充当分子开/关转换。RAS可以通过与鸟嘌呤核苷酸交换因子(GEF)(例如,SOS1)的蛋白质结合来与GTP结合,从而迫使释放结合的核苷酸,并释放GDP。当RAS与GTP结合时,它会被激活(打开)并招募和激活其他受体信号传播所需的蛋白质,例如c-Raf和PI 3-激酶。RAS还具有酶活性,可切割GTP核苷酸的末端磷酸并将核苷酸转化为GDP。转化速度通常很慢,但可以通过GTP酶激活蛋白(GAP)类蛋白质(例如RasGAP)显著加快。当GTP转换为GDP时,RAS被失活(关闭)。
RAS亚家族的公知成员包括HRAS、KRAS和NRAS。其中,KRAS突变在许多恶性肿瘤中观察到:86%的胰腺导管腺癌(PDAC)、41%的结直肠癌(CRC)和32%的肺腺癌(LUAD;非小细胞肺癌(NSCLC)的一种亚型)。突变通常发生在KRAS12位甘氨酸残基(“G12”);G12突变分别占KRAS突变总数的91%(PDAC)、68%(CRC)和85%(LUAD)。G12氨基酸取代的分布因组织类型而异。LUAD中最常见的突变是半胱氨酸(“G12C”)(46%)的突变,而PDAC(45%)和CRC(45%)中的主要突变是天冬氨酸(“G12D”)的突变。在所有PDAC(35%)、CRC(30%)和LUAD(23%)的G12突变中,很大一部分都观察到G12突变为缬氨酸(“G12V”)。(Nature ReviewsDrug Discovery,19,533-552,2020)。
正在大力开发KRAS-G12C抑制剂。目前已经报道了几种针对半胱氨酸残基的共价抑制剂,其中一些已经进行了临床研究,例如AMG510(NCT03600883)、MRTX849(NCT03785249)和JNJ-74699157(NCT04006301)。然而,KRAS-G12C突变仅占所有KRAS突变的一小部分,并且主要发现于LUAD中。为了有效抑制其他常见的KRAS突变蛋白,例如KRAS-G12D和KRAS-G12V,需要采取不同的方法,因为这些突变体在活性位点缺乏反应性半胱氨酸(Nature Reviews Drug Discovery,19,533-552,2020)。
发明内容
本公开提供了调节突变型KRAS、HRAS和/或NRAS蛋白的小分子抑制剂,并且可以是用于治疗癌症的有价值的药物活性化合物。在一些实施方案中,所公开的化合物选择性抑制KRAS-G12C、KRAS-G12D和/或KRAS-G12V蛋白。式(I)的化合物:
及其药学上可接受的盐可以调节KRAS、HRAS和/或NRAS活性的活性,从而影响调节与肿瘤病症相关的细胞生长、分化和增殖的信号传导途径。在某些实施方案中,式(I)的化合物可以抑制KRAS-G12C、KRAS-G12D和/或KRAS-G12V蛋白。本公开还提供了制备式(I)的化合物的方法、使用此类化合物治疗肿瘤病症的方法、以及包含式(I)的化合物的药物组合物。
具体实施方案
本公开的化合物
在一个实施方案中,本发明提供了一种具有结构式(I)的化合物或其药学上可接受的盐,如上所示,其中:
X选自由以下组成的组:
(i)6至9元单环的或稠合双环的或桥联双环的杂环烷基,其中所述杂环烷基是饱和的并含有1至2个选自由N、S和O组成的组的杂原子;
(ii)8至10元螺杂环烷基,其中所述螺杂环烷基是饱和的并含有1至2个选自由N和O组成的组的杂原子;
(iii)以及
其中,当X是(i)或(ii)时,X未被取代或独立地被1至4个选自由以下组成的组的Rx取代基取代:卤素、羟基、C1-C6烷基、C1-C3羟基烷基、C1-C6氟烷基、羧基、氨基甲酰基、C1-C3羧烷基、氧代、氰基、氰基甲基、氨基、吡唑基、噁二唑基、-NHC(0)C1-C3烷氧基C1-C3烷基、-NHC(O)C1-C3烷氧基C6-C10芳基、C1-C3烷氧基、甲氧基(C1-C3)烷基、氨基(C1-C3)烷基、C1-C3烷基氨基(C1-C3)烷基、C1-C3二烷基氨基、C1-C3二烷基氨基(C1-C3)烷基、和NHC(O)C5-C10杂芳基,其中杂芳基可被C1-C3烷基取代;
环Y是9至10元双环环系,其中该环系是部分不饱和的或芳香族的,并且其中环Y含有0至2个氮杂原子;
其中环Y未被取代或独立地被1至4个Ry取代基取代,所述取代基选自由以下组成的组:卤素、羟基、氨基、C1-C3烷基、C2-C3炔基和C1-C3氟烷基;
Z选自由以下组成的组:
(i)5至8元单环的或双环的杂环烷基,其中所述杂环烷基是饱和的并含有1个氮杂原子,并且其中所述杂环烷基未被取代或被1个选自由以下组成的组的取代基RZHC取代:卤素、C1-C3烷基和亚甲基(C1-C3烷基)(C1-C3烷基)氨基甲酸酯;
(ii)其中M选自由以下组成的组:羟基、C1-C3二烷基氨基和C1-C4烷基氨基,并且其中所述环丙基基团未被取代或被至多2个卤素基团取代;
(iii)其中P是5至8元单环的或稠合双环的或桥联双环的杂环烷基,其中所述杂环烷基是饱和的并含有1至2个选自由N和O组成的组的杂原子,其中所述杂环烷基未被取代或被1个选自由以下组成的组的Rp取代基取代:卤素、羟基、C1-C3羟烷基、C1-C3氰基烷基、氨基甲酰基、C1-C3烷氧基、氰基、-NHC(O)C1-C3烷基和噁二唑基,并且其中所述环丙基基团未被取代或被至多2个卤素基团取代;
下标m是0或1;以及
下标n是1或2。
在另一个实施方案中,本公开提供了式(I)的化合物,其中环Y是
在另一个实施方案中,本公开提供了式(I)的化合物,其中环Y是
在另一个实施方案中,本公开提供了式(I)的化合物,其中X是
并且其中X未被取代或独立地被1至4个Rx取代基取代。
在另一个实施方案中,本公开提供了式(I)的化合物,其中X被1至4个选自由以下组成的组的Rx取代基取代:卤素、羟基、C1-C6烷基、C1-C3羟烷基、C1-C6氟烷基、羧基、氨基甲酰基、C1-C3羧烷基、氧代、氰基、氰基甲基、氨基、吡唑基、噁二唑基、-NHC(O)C1-C3烷氧基C1-C3烷基、-NHC(O)C1-C3烷氧基C6-C10芳基和NHC(O)C5-C10杂芳基,其中杂芳基可被C1-C3烷基取代。
在另一个实施方案中,本公开提供了式(I)的化合物,其中X是
在另一个实施方案中,本公开提供了式(I)的化合物,其中X是其中下标p是0、1或2。
在另一个实施方案中,本公开提供了式(I)的化合物,其中X是
在另一个实施方案中,本公开提供了式(I)的化合物,其中Z是
在另一个实施方案中,本发明提供式(I)的化合物,其中下标m是1。
在另一个实施方案中,本发明提供式(I)的化合物,其中下标n是1。
在另一个实施方案中,本发明提供式(I)的化合物,其中下标n是2。
在具体的实施方案中,本公开提供了如下文所阐述的实例1-151中任一项所述的化合物或其药学上可接受的盐。
本公开包括本文定义的化合物的药学上可接受的盐,包括本文定义的所有结构式、实施方案和类别的药学上可接受的盐。
定义
除非另外定义,本文所使用的所有技术和科学术语具有与本发明所属领域的技术人员通常所理解的相同的意义。
如本公开全文所使用的,“式(I)的化合物”应理解为包括“式(I)的化合物或其药学上可接受的盐”。同样地,“式(I)的化合物”、“本文公开的化合物”、“本文描述的化合物”、“本公开的化合物”等可互换使用并且包括化合物及其药学上可接受的盐。
“烷基”以及具有前缀“烷”的其他基团,例如烷氧基等,是指可以是直链或支链或其组合的碳链,含有指定数量的碳原子。例如,C1-C6烷基是指具有一个(即甲基)至多6个碳原子(即己基)的烷基。在特定的实施方案中,直链烷基具有1-6个碳原子并且支链烷基具有3-7个碳原子。烷基的实例包括甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基、戊基、己基、庚基、辛基、壬基等。
“烷氧基”和“烷基-O-”可互换使用并且是指与氧连接的烷基。
“烷氧基烷基”是指烷氧基-烷基,其中烷氧基和烷基基团如先前所定义。与母体部分的键合是通过烷基组分的碳原子进行的。合适的烷氧基烷基基团的非限制性实例包括甲氧基烷基,例如甲氧基甲基和甲氧基乙基。
“炔基”是指含有至少一个碳-碳三键并且可以是直链或支链的脂族烃基。非限制性实例包括乙炔基、丙炔基和丁炔基。
“芳基”是指含有5-14个碳原子的单环、双环或三环碳环芳族环或环系统,其中至少一个环是芳族的。非限制性实例包括苯基和萘基。
“烷氧基芳基”是指烷氧基-芳基,其中烷氧基和芳基如先前所定义。与母体部分的键合是通过芳基组分的碳原子进行的。合适的烷氧基芳基的非限制性实例包括甲氧基苯基。
“氨基烷基”是指-烷基-NH2基团,其中烷基如先前所定义。与母体部分的键合是通过烷基组分的碳原子进行的。合适的氨基烷基的非限制性实例包括氨基甲基和氨基乙基。“烷基氨基”是指-NH-烷基,其中烷基如先前所定义。与母体部分的键合是通过氨基组分的氮进行的。
“双环系统”是指两个连接的环。这些环可以是稠合的,即共享两个相邻原子,或“螺环”,即仅共享单个原子,或“桥连”,即共享三个或更多个原子,其中两个桥头原子通过含有至少一个原子的桥连接。同样,双环可以是芳环、杂环、环烷基环等。
“氨基甲酰基”是指H2N-C(O)-基团,其是通过失去氨基甲酸的-OH基团而形成的单价基团。与母体基团的键合是通过羰基组分的碳原子进行的。
“羧基烷基”是指羧基(COOH)-烷基,其中烷基如先前所定义。与母体基团的键合是通过烷基组分的碳原子进行的。
“氰基烷基”是指-烷基-CN基团,其中烷基如先前所定义。与母体部分的键合是通过烷基组分的碳原子进行的。合适的氰基烷基的非限制性实例包括氰基甲基和3-氰基丙基。
“环烷基”是指饱和环状烃基。在具体实施方案中,环烷基具有3-12个碳原子,形成1-3个稠合的碳环。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基等。
“二烷基氨基”是指如前所定义的烷基氨基,其中氨基原子被两个烷基取代基取代,所述取代基可以相同或不同,例如,-N(CH3)2或-N(CH3)(CH2CH3)。
“二烷基氨基烷基”是指如先前所定义的氨基烷基,其中氨基原子也被两个烷基取代基取代。氨基原子上取代的烷基可以相同或不同。合适的二烷基氨基烷基的非限制性实例包括二甲基氨基甲基[(CH3)2NCH2-]和N-乙基-N-甲基氨基乙基[(CH3CH2)(CH3)N-CH2CH2-]。
“氟烷基”包括单取代的以及多氟取代的烷基,直至全氟取代的烷基。例如,包括氟甲基、1,1-二氟乙基、三氟甲基或1,1,1,2,2-五氟丁基。
除非另有说明,“卤素”或“卤代”包括氟(氟代)、氯(氯代)、溴(溴代)和碘(碘代)。在一个实施方案中,卤素是氟(-F)或氯(-C1)。
“杂芳基”是指芳香族单环、双环和三环结构,其中环中的一个或多个原子,即杂原子,是碳以外的元素。杂原子通常是O、S或N原子。杂芳基的实例包括吡唑基、噁二唑基、吡啶基、嘧啶基、吡咯基、哒嗪基、异噁唑基、噻唑基、噁唑基、吲哚基、苯并噁唑基、苯并噻唑基和咪唑基。
“杂环烷基”或“杂环的环”或“杂环”是指包含约3至约10个环原子、优选约5至约10个环原子的非芳族单环、双环、三环或桥环系统,其中一个或多个环系中的原子中的一个或多个为碳以外的元素,例如氮、氧、磷或硫,单独或组合。环系中不存在相邻的氧和/或硫原子。在一些实施方案中,杂环烷基含有约5至约6个环原子。杂环基根名称之前的前缀氮杂、氧杂、磷杂或硫杂分别表示至少一个氮、氧、磷或硫原子作为环原子存在。在一些实施方案中,杂环烷基的氮或硫原子可以任选地被氧化成相应的N-氧化物、S-氧化物或S,S-二氧化物。合适的单环杂环基环的非限制性实例包括哌啶基、吡咯烷基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,4-二噁烷基、四氢呋喃基、四氢噻吩基、磷烷、膦烷、1-氧代膦-1-鎓等。“螺杂环烷基”是指其中环仅共享单个原子且至少一个环是杂环烷基的稠环系统。
“羟基烷基”是指HO-烷基-基团,其中烷基如先前所定义。与母体部分的键合是通过烷基基团的碳原子进行的。优选的羟烷基含有低级烷基。合适的羟烷基的非限制性实例包括羟甲基和2-羟乙基。
“亚甲基(C1-C3烷基)(C1-C3烷基)氨基甲酸酯”是指具有的结构。换句话说,氨基甲酸酯基团具有连接至氮原子的如前所定义的烷基。
当任何变量(例如,Ry)在任何成分中或者在本文的式(I)或其他通式中出现超过一次时,其每次出现时的定义独立于其在其他每次出现时的定义。取代基和/或变量的组合只有在这种组合产生稳定的化合物时才是允许的。在选择本公开的化合物时,本领域普通技术人员将认识到,各种取代基,例如Ry的选择应符合化学结构连通性和稳定性的公知原理。除非有相反的明确说明,否则环(例如,芳基、杂芳基环或饱和杂芳基环)中的任何原子上被指定的取代基取代是允许的,前提是这种环取代在化学上是允许的,并且产生稳定的化合物。“稳定的”化合物是可以制备和分离的化合物,并且其结构和性质在足以允许该化合物用于本文所述目的(例如,对受试者进行治疗或预防给药)的一段时间内保持或可以导致保持基本不变。
术语“取代的”应被视为包括指定取代基的多重取代度。当公开或要求保护多个取代基部分时,取代的化合物可独立地被一个或多个所公开或要求保护的取代基部分单个或多个取代。独立取代是指(两个或更多个)取代基可以相同或不同。
除非另有明确描绘或描述,结构式中描绘的具有“浮动”键的变量,例如Rx,允许存在于与该变量相连的环上的任何可用碳原子上。当在式(I)或其任何实施方案中提到一个部分是“任选取代的”时,这是指式(I)或其实施方案涵盖在该部分上含有所述一个取代基(或多个取代基)的化合物,以及在该部分上不含有所述一个取代基(或多个取代基)的化合物。
如本文所使用的波浪线表示与化合物的其余部分的连接点。
式(I)的化合物可以含有一个或多个不对称中心并且因此可以作为外消旋体和外消旋混合物、单一对映异构体、非对映异构混合物和单独的非对映异构体存在。式(I)的化合物中存在的不对称中心可全部彼此独立地具有S构型或R构型。式(I)的化合物包括所有可能的对映异构体和非对映异构体以及两种或更多种立体异构体的混合物,例如所有比例的对映异构体和/或非对映异构体的混合物。因此,对映体是本公开的主题,其为对映体纯形式,既有左旋的也有右旋的对映体,为外消旋体形式,也有两种对映体以所有比例混合的形式。在顺式/反式异构的情况下,本公开包括顺式形式和反式形式两者以及这些形式的所有比例的混合物。本公开意指涵盖式(I)的化合物的所有此类立体异构形式。当结构式或化学名称指定立体中心处的特定构型时,意指由该指定立体中心产生的化合物的对映异构体或立体异构体。当式(I)的化合物的结构式表示手性中心处为直线时,该结构式包括与手性中心相关的S和R立体异构体及其混合物。
式(I)的化合物可以通过例如从合适的溶剂(例如甲醇或乙酸乙酯或其混合物)中分级结晶,或通过使用光学活性固定相的手性色谱法而分离成其单独的非对映异构体。绝对立体化学可以通过结晶产物或结晶中间体的X射线晶体学来确定,如果需要,用含有已知绝对构型的不对称中心的试剂进行衍生。振动圆二色性(VCD)也可用于测定绝对立体化学。可替代地,式(I)的化合物的任何立体异构体或异构体可以通过使用光学纯的起始材料或已知绝对构型的试剂的立体定向合成来获得。
如果需要,可以分离化合物的外消旋混合物,从而分离出各个对映体。分离可以通过本领域公知的方法进行,例如将化合物的外消旋混合物偶联到对映体纯的化合物上形成非对映体混合物,然后通过标准方法如分级结晶或色谱法分离各个非对映体。偶联反应通常是使用对映体纯的酸或碱形成盐。然后可通过裂解所添加的手性残基将非对映体衍生物转化为纯对映体。化合物的外消旋混合物也可以通过使用手性固定相的色谱方法直接分离,该方法是本领域众所周知的。
含有烯属双键的式(I)的化合物,除非另有说明,它们意在包括E和Z几何异构体两者。
本文所述的一些化合物可以互变异构体的形式存在,其具有不同的氢连接点并伴有一个或多个双键位移。例如,酮及其烯醇形式是酮-烯醇互变异构体。式(I)的化合物涵盖单独的互变异构体及其混合物。
当单键周围的旋转能垒足够高以阻止给定温度下的自由旋转时,本文所述的一些式(I)的化合物可以作为阻转异构体存在,从而允许分离具有不同性质的各个构象异构体。单独的阻转异构体及其混合物涵盖在本公开的式(I)的化合物内。拆分后,各个阻转异构体可以按照既定惯例进行指定,例如国际纯粹应用化学联合会(IUPAC)2013年推荐规定的惯例。
在式(I)的化合物中,原子可以表现出它们的天然同位素丰度,或者一个或多个原子可以人工富集具有相同原子序数、但原子质量或质量数不同于自然界中主要发现的原子质量或质量数的特定同位素。本文描述和要求保护的本公开旨在包括式(I)的化合物及其实施方案的所有合适的同位素变体。例如,氢(H)的不同同位素形式包括氕(1H)和氘(2H,在本文中也表示为D)。氕是自然界中发现的主要氢同位素。富集氘可以提供某些治疗优势,例如增加体内半衰期或减少剂量需求,或者可以提供可用作生物样品表征标准的化合物。通过本领域技术人员公知的常规技术或通过类似于本文方案和实例中所述的方法,使用合适的富集同位素的试剂和/或中间体,无需过多实验即可制备富集同位素的化合物。
术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸制备的盐。当式(I)的化合物呈酸性时,其相应的盐可以方便地由药学上可接受的无毒碱(包括无机碱和有机碱)制备。衍生自此类无机碱的盐包括铝、铵、钙、铜、三价铁、亚铁、锂、镁、锰、钾、钠、锌等盐。优选的是铵盐、钙盐、镁盐、钾盐和钠盐。由药学上可接受的有机无毒碱制备的盐包括衍生自天然存在和合成来源的伯胺、仲胺和叔胺的盐。可以形成盐的药学上可接受的有机无毒碱包括例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴胺、异丙胺、二环己胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当式(I)的化合物呈碱性时,其相应的盐可以方便地由药学上可接受的无毒无机酸和有机酸制备。此类酸包括例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙基磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。优选柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。如果式(I)的化合物在分子中同时含有酸性基团和碱性基团,则本公开除了所提到的盐形式之外还包括内盐或甜菜碱(两性离子)。盐可以通过本领域技术人员已知的常规方法由式(I)的化合物获得,例如通过与有机或无机酸或碱在溶剂或分散剂中组合,或者通过阴离子交换或与其他盐的阳离子交换。本公开还包括式(I)的化合物的所有盐,由于生理相容性低,它们不直接适合用于药物,但可以用作例如化学反应的中间体或用于制备药学上可接受的盐。
此外,式(I)的化合物可以以无定形形式和/或一种或多种结晶形式存在,因此式(I)的化合物的所有无定形和结晶形式及其混合物,包括实例,旨在包括在本公开的范围内。另外,一些式(I)的化合物可以与水(即水合物)或常见有机溶剂例如但不限于乙酸乙酯形成溶剂化物。本发明化合物的此类溶剂化物和水合物,特别是药学上可接受的溶剂化物和水合物,以及非溶剂化和无水形式同样涵盖在本公开的范围内。
导致体内转化为本公开范围内的化合物的式(I)的化合物的任何药学上可接受的前药修饰也在本公开的范围内。
术语“治疗有效(或有效)量”和类似的描述如“治疗有效量”或“有效剂量”旨在意指将引起组织、系统、动物或人的研究者、兽医、医生或其他临床医生所寻求的生物学或医学反应的式(I)化合物的量。在一个优选的实施方案中,术语“治疗有效量”是指缓解人患者的至少一种临床症状的式(I)的化合物的量。术语“预防有效(effective)(或有效(efficacious))量”和类似的描述如“预防有效的量”旨在意指表示将预防或降低组织、系统、动物或人中生物或医学事件发生风险的式(I)化合物的量,所述生物或医学事件是研究者、兽医、医生或其他临床医生所寻求预防的。
式(I)的化合物的剂量
使用式(I)的化合物的剂量方案根据多种因素进行选择,包括患者的类型、物种、年龄、体重、性别和医疗状况;待治疗病况的严重程度;选择施用的化合物的效力;施用途径;以及患者的肾功能和肝功能。为了确定预防、对抗或阻止病况进展所需的治疗有效或预防有效剂量的目的,对这些因素的考虑完全在普通技术临床医生的能力范围内。应当理解,特定的每日剂量可以同时是治疗有效量(例如用于治疗肿瘤病况)和预防有效量(例如用于预防肿瘤病况)。
虽然个体需求不同,但式(I)的化合物的有效量的最佳范围的确定在本领域技术范围内。对于在例如本文确定的病况和病症的治愈性或预防性治疗中向人施用而言,式(I)的化合物的典型剂量可以是约0.05mg/kg/天至约50mg/kg/天、或至少0.05mg/kg、或至少0.08mg/kg、或至少0.1mg/kg、或至少0.2mg/kg、或至少0.3mg/kg、或至少0.4mg/kg、或至少0.5mg/kg以及其间的任何量至约50mg/kg或更少、或约40mg/kg或更少、或约30mg/kg或更少、或约20mg/kg或更少、或约10mg/kg或更少以及其间的任何量,例如其可以是约2.5mg/天(0.5mg/kg x5kg)至约5000mg/天(50mg/kg x100kg)。例如,化合物的剂量可以是约0.1mg/kg/天至约50mg/kg/天、或约0.05mg/kg/天至约10mg/kg/天、或约0.05mg/kg/天至约5mg/kg/天、或约0.05mg/kg/天至约3mg/kg/天、或约0.07mg/kg/天至约3mg/kg/天、或约0.09mg/kg/天至约3mg/kg/天、或约0.05mg/kg/天至约0.1mg/kg/天、或约0.1mg/kg/天至约1mg/kg/天、或约1mg/kg/天至约10mg/kg/天、或约1mg/kg/天至约5mg/kg/天、或约1mg/kg/天至约3mg/kg/天、或约3mg/天至约500mg/天、或约5mg/天至约250mg/天、或约10mg/天至约100mg/天、或约3mg/天至约10mg/天、或约100mg/天至约250mg/天。此类剂量可以以单剂量施用或可以分为多剂量。
药物组合物
式(I)的化合物及其药学上可接受的盐可以单独作为药物、彼此混合或以药物组合物的形式施用于动物,优选哺乳动物,特别是人。术语“受试者”或“患者”包括使用本发明活性剂来预防或治疗医学病况的动物,优选哺乳动物,尤其是人。向受试者施用药物包括自我施用和由他人向患者施用。受试者可能需要或期望治疗现有疾病或医学病况,或者可能需要或期望预防性治疗以预防或降低所述疾病或医学病况发生的风险。如本文所用,“需要”治疗现有病况或预防性治疗的受试者涵盖医疗专业人员对需要的确定以及患者对此类治疗的期望。
因此,本公开还提供了用作药物的式(I)的化合物及其药学上可接受的盐、它们用于调节突变型KRAS、HRAS和/或NRAS蛋白的活性的用途,并且特别是它们在治疗和预防下述疾病或病症中的用途,以及它们在制备用于这些目的的药物中的用途。在某些实施方案中,式(I)的化合物及其药学上可接受的盐抑制KRAS-G12C、KRAS-G12D和/或KRAS-G12V蛋白。
此外,本公开提供了药物组合物,其包含作为活性成分的有效剂量的至少一种式(I)的化合物和/或其药学上可接受的盐和常规药学上可接受的载剂,即一种或多种药学上可接受的载剂物质和/或添加剂。
因此,本公开提供了例如所述化合物及其药学上可接受的盐,用作药物组合物,所述药物组合物包含有效剂量的至少一种式(I)的化合物和/或药学上可接受的盐作为活性成分其和常规药学上可接受的载剂,以及所述化合物和/或其药学上可接受的盐在治疗或预防下述疾病或病症例如癌症中的用途,以及它们在制备用于这些目的的药物中的用途。
根据本公开的药物组合物可以口服施用,例如以丸剂、片剂、漆片、糖衣片、颗粒剂、硬和软明胶胶囊、水、醇或油溶液、糖浆、乳液或悬浮液的形式,或直肠给药,例如以栓剂的形式。还可以肠胃外施用,例如以注射或输注溶液的形式皮下、肌内或静脉内施用。
其他合适的施用形式是例如经皮或局部施用,例如以软膏剂、酊剂、喷雾剂或透皮治疗系统,或者例如微胶囊、植入物或棒的形式。优选的施用形式取决于例如待治疗的疾病及其严重程度。
药物组合物中本文所述的化合物和/或其药学上可接受的盐的活性化合物的量通常为每剂量0.01至200mg,或0.1至200mg,或1至200mg,但是取决于药物组合物的类型,它也可以更高。在一些实施方案中,药物组合物中式(I)的化合物和/或其药学上可接受的盐的活性化合物的量为每剂量0.01至10mg。药物组合物通常包含0.5至90重量%的至少一种式(I)的化合物和/或其药学上可接受的盐。药物组合物的制备可以以本身已知的方式进行。为此目的,一种或多种式(I)的化合物和/或其药学上可接受的盐,与一种或多种固体或液体药物载体物质和/或添加剂(或辅助物质)一起,并且如果需要,与其他具有治疗或预防作用的药学活性化合物组合制成合适的施用形式或剂型,然后可以将其用作人或兽药中的药物。
为了生产丸剂、片剂、糖衣片和硬明胶胶囊,可以使用例如乳糖、淀粉(例如玉米淀粉)或淀粉衍生物、滑石、硬脂酸或其盐等。软明胶胶囊和栓剂的载体是例如脂肪、蜡、半固体和液体多元醇、天然或硬化油等。用于制备溶液(例如注射溶液)或乳液或糖浆的合适载体是例如水、生理上可接受的氯化钠溶液、醇类如乙醇、甘油、多元醇、蔗糖、转化糖、葡萄糖、甘露醇、植物油等。还可以冻干式(I)化合物及其药学上可接受的盐,并使用所得冻干物,例如,用于制备注射或输注制剂。用于微胶囊、植入物或棒的合适载体是例如乙醇酸和乳酸的共聚物。
除了活性化合物和载体之外,药物组合物还可以含有常规添加剂,例如填充剂、崩解剂、粘合剂、润滑剂、润湿剂、稳定剂、乳化剂、分散剂、防腐剂、甜味剂、着色剂、调味剂、芳香剂、增稠剂、稀释剂、缓冲物质、溶剂、增溶剂、用于实现储库效应的试剂、用于改变渗透压的盐、包衣剂和/或抗氧化剂。
式(I)的化合物的使用方法
本申请提供了抑制RAS介导的细胞信号传导的方法,所述方法包括使细胞与式(I)的化合物或其药学上可接受的盐接触。RAS介导的信号转导的抑制可以通过本领域已知的多种方法来评估和证明。非限制性实例包括(a)RAS的GTP酶活性降低;(b)GTP结合亲和力的降低或GDP结合亲和力的增加;(c)GTP的Koff增加,或GDP的Koff减少;(d)RAS途径下游信号传导分子水平降低,例如pMEK、pERK或pAKT水平降低;和/或(e)RAS复合物与下游信号传导分子(包括但不限于Raf)的结合减少。试剂盒和市售测定可用于确定上述的一种或多种。
本申请还提供了使用式(I)的化合物(或其药学上可接受的盐)或含有此类化合物的药物组合物来治疗疾病病况的方法,所述疾病病况包括但不限于由突变型KRAS、HRAS和/或NRAS蛋白(例如,癌症),并且在一些实施方案中,KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变体所涉及的病况。
在一些实施方案中,提供了治疗癌症的方法,所述方法包括向需要此类治疗的受试者施用治疗有效量的式(I)的化合物(或其药学上可接受的盐)或包含此类化合物的任何前述药物组合物。在一些实施方案中,癌症由KRAS、HRAS或NRAS突变介导,例如KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变。在各种实施方案中,癌症是胰腺癌、结肠直肠癌或肺癌。在一些实施方案中,癌症是胆囊癌、甲状腺癌或胆管癌。
在一些实施方案中,本公开提供了治疗有需要的受试者中的病症的方法,其中所述方法包括确定受试者是否具有KRAS、HRAS或NRAS突变(例如,KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变),并且如果确定受试者具有KRAS、HRAS或NRAS突变,则向受试者施用治疗有效量的式(I)的化合物或其药学上可接受的盐。
所公开的化合物抑制不依赖贴壁的细胞生长,因此具有抑制肿瘤转移的潜力。因此,本公开的另一个实施方案提供了一种抑制肿瘤转移的方法,所述方法包括施用有效量的式(I)的化合物。
KRAS、HRAS或NRAS突变也在血液恶性肿瘤(例如,影响血液、骨髓和/或淋巴结的癌症)中被鉴定。因此,某些实施方案涉及将式(I)的化合物(例如,以药物组合物的形式)施用给需要治疗血液恶性肿瘤的受试者。此类恶性肿瘤包括但不限于白血病和淋巴瘤。例如,本公开的化合物可用于治疗急性淋巴细胞白血病(ALL)、急性粒细胞白血病(AML)、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、慢性粒细胞白血病(CML)、急性单核细胞白血病(AMoL)和/或其他白血病等疾病。在其他实施方案中,所述化合物可用于治疗淋巴瘤例如霍奇金淋巴瘤或非霍奇金淋巴瘤。在各种实施方案中,所述化合物可用于治疗浆细胞恶性肿瘤,例如多发性骨髓瘤、套细胞淋巴瘤和华氏巨球蛋白血症。
确定肿瘤或癌症是否包含KRAS、HRAS或NRAS突变(例如,KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变)可通过评估编码KRAS、HRAS或NRAS蛋白的核苷酸序列、通过评估KRAS、HRAS或NRAS蛋白的氨基酸序列,或通过评估推定的KRAS、HRAS或NRAS突变蛋白的特征来进行。野生型人KRAS、HRAS或NRAS的序列是本领域已知的。
用于检测KRAS、HRAS或NRAS核苷酸序列中的突变的方法也是本领域技术人员已知的。这些方法包括但不限于聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)测定、聚合酶链式反应-单链构象多态性(PCR-SSCP)测定、实时PCR测定、PCR测序、突变体等位基因特异性PCR扩增(MASA)测定、直接测序、引物延伸反应、电泳、寡核苷酸连接测定、杂交测定、TaqMan测定、SNP基因分型测定、高分辨率熔解测定和微阵列分析。在一些实施方案中,通过实时PCR评估样品的KRAS、HRAS或NRAS突变(例如,KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变)。在实时PCR中,使用特异针对KRAS、HRAS或NRAS突变的荧光探针。当存在突变时,探针结合并检测到荧光。在一些实施方案中,使用KRAS、HRAS或NRAS基因中的特定区域(例如,外显子2和/或外显子3)的直接测序方法来鉴定KRAS、HRAS或NRAS突变。
用于检测KRAS、HRAS或NRAS蛋白中的突变(例如,KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变)的方法是本领域技术人员已知的。这些方法包括但不限于使用突变蛋白特异性结合剂(例如抗体)、蛋白电泳和蛋白质印迹、以及直接肽测序检测KRAS、HRAS或NRAS突变。
可以评估许多组织样品以确定肿瘤或癌症是否包含KRAS、HRAS或NRAS突变(例如,KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变)。在一些实施方案中,样品取自患有肿瘤或癌症的受试者。在一些实施方案中,样品是新鲜的肿瘤/癌症样品。在一些实施方案中,样品是冷冻肿瘤/癌症样品。在一些实施方案中,样品是福尔马林固定石蜡包埋的样品。在一些实施方案中,样品是循环肿瘤细胞(CTC)样品。在一些实施方案中,将样品处理成细胞裂解物。在一些实施方案中,样品被加工成DNA或RNA。
本申请还提供了治疗过度增殖性病症的方法,所述方法包括向有需要的受试者施用治疗有效量的式(I)的化合物或其药学上可接受的盐。在一些实施方案中,所述方法涉及治疗患有癌症的受试者,所述癌症例如急性髓性白血病、青少年癌症、儿童肾上腺皮质癌、AIDS相关癌症(如淋巴瘤和卡波济氏肉瘤)、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎瘤、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑肿瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、非典型畸胎瘤、胚胎性肿瘤、生殖细胞瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓增生异常、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、肝外导管原位癌(DCIS)、胚胎肿瘤、CNS癌、子宫内膜癌、室管膜瘤、食道癌、嗅神经母细胞瘤、尤因肉瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、眼癌、骨纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌瘤、胃肠道间质瘤(GIST)、生殖细胞瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、贲门癌、肝癌、霍奇金淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、胰腺神经内分泌肿瘤、肾癌、喉癌、唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、具有隐匿原发性的转移性鳞状颈癌、中线道癌、口腔癌;多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样肉芽肿、骨髓发育不良综合征、骨髓增生异常/骨髓增生性肿瘤、多发性骨髓瘤、默克尔细胞癌、恶性间皮瘤、骨的恶性纤维组织细胞瘤和骨肉瘤、鼻腔和副鼻窦癌、鼻咽癌、成神经细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌(非小细胞肺癌)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳头状瘤病、副神经节瘤、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽喉癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、胃(stomach)(胃(gastric))癌、小细胞肺癌;小肠癌、软组织肉瘤、T细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、滋养细胞肿瘤、罕见的儿童期癌症、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱发的癌症。在一些实施方案中,所述方法涉及治疗非癌性过度增殖性病症,例如皮肤良性增生(例如,牛皮癣)、再狭窄或前列腺增生(例如,良性前列腺肥大(BPH))。
在一些实施方案中,治疗方法涉及治疗肺癌,并且该方法包括向有需要的受试者施用治疗有效量的式(I)的化合物(或包含此类化合物的药物组合物)。在某些实施方案中,肺癌是非小细胞肺癌(NSCLC),例如腺癌、鳞状细胞肺癌或大细胞肺癌。在一些实施方案中,肺癌是小细胞肺癌。式(I)的化合物可提供治疗益处的其他肺癌包括但不限于腺体肿瘤、类癌肿瘤和未分化癌。
本公开还提供了通过将蛋白质与有效量的式(I)的化合物接触来调节突变的KRAS、HRAS或NRAS蛋白质活性(例如,由KRAS-G12C、KRAS-G12D和/或KRAS-G12V突变产生的活性)的方法。调节可以是抑制或激活蛋白质活性。在一些实施方案中,本公开提供了通过将突变的KRAS、HRAS或NRAS蛋白质(例如,KRAS-G12C、KRAS-G12D和/或KRAS-G12Y突变体)与溶液中有效量的式(I)的化合物接触来抑制蛋白质活性的方法。在一些实施方案中,本公开提供了通过接触表达感兴趣的蛋白质的细胞、组织或器官来抑制突变的KRAS、HRAS或NRAS蛋白质活性的方法。在一些实施方案中,本公开提供了通过向受试者施用有效量的式(I)的化合物来抑制受试者(包括但不限于啮齿动物和哺乳动物(例如,人))中的蛋白质活性的方法。
组合疗法
一种或多种另外的药理学活性剂可以与式(I)的化合物(或其药学上可接受的盐)组合施用。另外的活性剂(或多种活性剂)旨在意指在体内有活性的药物活性剂(或多种活性剂),包括在施用后转化为药物活性形式的不同于式(I)的化合物的前药。另外的活性剂还包括所述另外的活性剂的游离酸、游离碱和药学上可接受的盐。一般而言,任何合适的一种或多种另外的活性剂,包括化疗剂或治疗性抗体,可以与式(I)化合物在单一剂量制剂(例如,固定剂量药物组合)中的任何组合中使用,或者在一种或多种分开的剂量制剂中使用,所述分开的剂量制剂允许向受试者同时或依序施用活性剂(分开的活性剂的共同施用)。另外,式(I)的化合物(或药学上可接受的盐)可以与放射疗法、激素疗法、手术或免疫疗法组合施用。
本申请还提供了用于组合治疗的方法,其中已知另外的活性剂调节其他途径,或同一途径的其他组分,或甚至与式(I)化合物或其药学上可接受的盐联合使用的重叠的靶酶组。在一个实施方案中,此类疗法包括但不限于一种或多种式(I)的化合物与化疗剂、免疫治疗剂、激素和抗激素剂、靶向治疗剂和抗血管生成剂的组合,以提供协同或相加的治疗效果。在另一个实施方案中,此类治疗包括放射治疗以提供协同或相加治疗效果。
另外的活性剂(即,另外的抗癌剂)的实例包括化疗剂(例如,细胞毒性剂)、免疫治疗剂、激素和抗激素剂、靶向治疗剂和抗血管生成剂。许多抗癌剂可分为一组或多组。虽然某些抗癌剂已被分类在本文的特定组或亚组中,但是这些药剂中的许多也可以列在一个或多个其他组或亚组中,如本领域目前所理解的。应当理解,本文中将特定试剂分类到特定组中并不旨在进行限制。许多抗癌剂目前是本领域已知的并且可以与本公开的化合物组合使用。
此外,药剂可以是激动剂、拮抗剂、变构调节剂、毒素,或者更一般地,可以起到抑制或刺激其靶标(例如,受体或酶激活或抑制)的作用。例如,适合使用特异性结合并抑制生长因子活性的一种或多种药剂(例如,抗体、抗原结合区或可溶性受体),例如肝细胞生长因子(HGF,也称为分散因子)的拮抗剂,以及特异性结合其受体“c-met”的抗体或抗原结合区。
在一个实施方案中,另外的抗癌剂是化疗剂、免疫治疗剂、激素剂、抗激素剂、靶向治疗剂或抗血管生成剂(或血管生成抑制剂)。在一个实施方案中,另外的抗癌剂选自由以下组成的组:化疗剂、有丝分裂抑制剂、植物生物碱、烷化剂、抗代谢物、铂类似物、酶、拓扑异构酶抑制剂、类维生素A、氮丙啶、抗生素、激素剂、抗激素剂、抗雌激素、抗雄激素、抗肾上腺、雄激素、靶向治疗剂、免疫治疗剂、生物反应调节剂、细胞因子抑制剂、肿瘤疫苗、单克隆抗体、免疫检查点抑制剂、抗PD-1剂、抗PD-Ll剂、集落刺激因子、免疫调节剂、免疫调节酰亚胺(IMiD)、抗CTLA4剂、抗LAG1剂、抗OX40剂、GITR激动剂、CAR-T细胞、BiTE、信号转导抑制剂、生长因子抑制剂、酪氨酸激酶抑制剂、EGFR抑制剂、组蛋白脱乙酰酶(HAC)抑制剂、蛋白酶体抑制剂、细胞周期抑制剂、抗血管生成剂、基质金属蛋白酶(MMP)抑制剂、肝细胞生长因子抑制剂、TOR抑制剂、KDR抑制剂、VEGF抑制剂、HIF-1α抑制剂、HIF-2α抑制剂、成纤维细胞生长因子(FGF)抑制剂、RAF抑制剂、MEK抑制剂、ERK抑制剂、PI3K抑制剂、AKT抑制剂、MCL-1抑制剂、BCL-2抑制剂、SHP2抑制剂、HER-2抑制剂、BRAF抑制剂、基因表达调节剂、自噬抑制剂、细胞凋亡诱导剂、抗增殖剂和糖酵解抑制剂。
在一个实施方案中,另外的抗癌剂是化疗剂。化疗剂的非限制性实例包括有丝分裂抑制剂和植物生物碱、烷化剂、抗代谢物、铂类似物、酶、拓扑异构酶抑制剂、类维生素A、氮丙啶和抗生素。
有丝分裂抑制剂和植物生物碱的非限制性实例包括紫杉烷类,例如卡巴他赛、多西他赛、拉罗他赛、奥他赛、紫杉醇和替西他赛;地美可辛;埃博霉素;艾瑞布林;依托泊苷(VP-16);磷酸依托泊苷;诺维本;诺斯卡品(noscapine);替尼泊苷;沙利吉斯汀(thaliblastine);长春碱;长春新碱;长春地辛;长春氟宁;和长春瑞滨。
烷化剂的非限制性实例包括氮芥类,例如苯丁酸氮芥、氯萘嗪、氯磷酰胺、细胞磷烷、雌莫司汀、异环磷酰胺、甘露莫司汀、氮芥、盐酸氮芥、美法仑、诺万比钦、苯乙酯、泼尼莫司汀、三(2-氯乙基)胺、曲磷酰胺和尿嘧啶芥;烷基磺酸盐,如白消安、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);亚硝基脲类(nitrosureas),如卡莫司汀、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、环己亚硝脲、尼莫司汀(nimustine)、雷莫司汀(ranimnustine)、链脲佐菌素(streptozotocin)和TA-07;乙烯亚胺和甲基三胺,例如六甲蜜胺、塞替派、三乙基三聚氰胺、三乙基硫磷酰胺、三亚乙基磷酰胺和三羟甲基三聚氰胺;安莫司汀;苯达莫司汀;达卡巴嗪;依托格鲁(etoglucid);伊罗乌尔文(iroiulven);马磷酰胺(mafosfamide);二溴甘露醇;二溴卫矛醇;哌泊溴烷;丙卡巴肼;替莫唑胺(temozolomide);曲奥舒凡;和三嗪醌。
抗代谢物的非限制性实例包括叶酸类似物,例如氨基蝶呤、去蝶呤、依达曲沙、甲氨蝶呤、蝶呤、雷替曲塞和曲甲曲沙;嘌呤类似物,例如6-巯基嘌呤、6-硫鸟嘌呤、氟达拉滨、呋咯地辛、硫代米林和硫鸟嘌呤;嘧啶类似物,例如5-氟尿嘧啶(5-FU)、6-氮杂尿苷、安西他滨、阿扎胞苷、卡培他滨、卡莫氟、阿糖胞苷、地西他滨、双脱氧尿苷、多西氟尿苷(doxifiuridine)、多西氟尿苷(doxifluridine)、依西他滨、氟尿苷、加西他滨、吉西他滨和沙帕西他滨;3-氨基吡啶-2-甲醛硫代缩氨基脲;溴尿苷;克拉屈滨;环磷酰胺;阿糖胞苷;emitefur;羟基脲;巯基嘌呤;奈拉滨;培美曲塞;喷司他丁;替加氟;和曲沙西他滨。
铂类似物的非限制性实例包括卡铂、顺铂、双环铂、七铂、洛铂、奈达铂、奥沙利铂、沙铂和四硝酸三铂。
酶的非限制性实例包括天冬酰胺酶和培门冬酶。
拓扑异构酶抑制剂的非限制性实例包括吖啶甲酰胺、阿莫那非、安吖啶、贝洛替康、醋酸艾司替铵、依替康、吲哚咔唑、伊立替康、鲁托替康、米托蒽醌、拉唑烷、鲁比替康、SN-38、索布唑烷和拓扑替康。
类维生素A的非限制性实例包括阿利维A酸、贝沙罗汀、芬维A胺、异维A酸、利阿唑、RII视黄酰胺和维A酸。
氮丙啶的非限制性实例包括苯多巴、卡波醌、美杜巴和乌多巴。
抗生素的非限制性实例包括嵌入抗生素;蒽二酮;蒽环类抗生素,例如阿克拉比星、氨柔比星、道诺霉素、柔红霉素、多柔比星、表柔比星、伊达比星、美诺加利、诺加霉素、吡柔比星和戊柔比星;6-重氮-5-氧代-L-正亮氨酸;阿克拉霉素;放线菌素;安曲霉素;偶氮丝氨酸;博来霉素;放线菌素;加利车霉素;卡柔比星;洋红霉素;嗜癌霉素;色霉素;更生霉素;地托比星(detorubicin);依索比星(esorubicin);埃斯培拉霉素(esperamicin);格尔德霉素(geldanamycin);麻西罗霉素;丝裂霉素;丝裂霉素C;霉酚酸;橄榄霉素;能灭瘤(novantrone);培洛霉素;甲基丝裂霉素(porfiromycin);泊非霉素(potfiromycin);嘌呤霉素;三铁阿霉素(quelamycin);瑞贝卡霉素(rebeccamycin);罗多比星;链黑菌素;链脲佐菌素;坦螺旋霉素(tanespimycin);杀结核菌素;乌苯美司;净司他丁;净司他丁斯酯(zinostatin stimalamer);和佐柔比星。
在一个实施方案中,另外的抗癌剂是激素和/或抗激素剂(即,激素治疗)。激素和抗激素剂的非限制性实例包括抗雄激素,例如阿比特龙、阿帕鲁胺、比卡鲁胺、达洛鲁胺、恩杂鲁胺、氟他胺、戈舍瑞林、亮丙瑞林和尼鲁胺;抗雌激素,例如4-羟基他莫昔芬、芳香酶抑制4(5)-咪唑、EM-800、磷雌醇、福维司群、酮昔芬、LY 117018、奥纳司酮、雷洛昔芬、他莫昔芬、托瑞米芬和三氧芬;抗肾上腺药,例如氨基鲁米特、右氨基鲁米特、米托坦和曲洛斯坦;雄激素,例如卡普睾酮(calusterone)、屈他雄酮丙酸酯、环硫雄醇、美雄烷和睾内酯;阿巴瑞克(abarelix);阿那曲唑(anastrozole);西曲瑞克;德舍瑞林;依西美坦(exemestane)、法倔唑;非那雄胺(finasteride);福美司坦(formestane);组氨瑞林(RL 0903);人绒毛膜促性腺激素;兰瑞肽;LDI 200(Milkhaus);来曲唑(letrozole)、亮丙瑞林;米非司酮;那法瑞林;萘福定(nafoxidine);奥萨酮(osaterone);强的松;促甲状腺素α;和曲普瑞林(triptorelin)。
在一个实施方案中,另外的抗癌剂是免疫治疗剂(即,免疫疗法)。免疫治疗剂的非限制性实例包括生物反应调节剂、细胞因子抑制剂、肿瘤疫苗、单克隆抗体、免疫检查点抑制剂、集落刺激因子和免疫调节剂。
生物反应调节剂的非限制性实例,包括细胞因子抑制剂(细胞因子),例如干扰素和白细胞介素,包括干扰素α/干扰素α,例如干扰素α-2、干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素α-n3、干扰素α-1、聚乙二醇干扰素α-2a、聚乙二醇干扰素α-2b和白细胞α干扰素;干扰素β,例如干扰素β-la和干扰素β-lb;干扰素γ,例如天然干扰素γ-1a和干扰素γ-1b;阿地白介素;白细胞介素-1β;白细胞介素-2;奥普瑞白介素;索纳敏(sonermin);他索纳明;和病毒利嗪。
肿瘤疫苗的非限制性实例包括APC 8015、AVICINE、膀胱癌疫苗、癌症疫苗(Biomira)、胃泌素17免疫原、Maruyama疫苗、黑色素瘤裂解物疫苗、黑色素瘤肿瘤裂解物疫苗(New York Medical College)、黑色素瘤疫苗(New York University)、黑色素瘤疫苗(Sloan Kettering Institute)、BCG(Bacillus Calmette-Guerin)和病毒黑色素瘤细胞裂解物疫苗(Royal Newcastle Hospital)。
单克隆抗体的非限制性实例包括阿巴戈沃单抗、阿德木单抗、aflibercept、阿伦单抗、博纳吐单抗、布仑妥昔单抗-维多汀、CA 125单抗(Biomira)、癌症单抗(JapanPharmaceutical Development)、达克利珠单抗、达拉图穆单抗、地诺单抗、依决洛单抗、奥加米星吉妥珠单抗、HER-2和Fc单抗(Medarex)、替坦-艾瑞妥莫单抗、独特型105AD7单抗(CRC Technology)、独特型CEA单抗(Trilex)、伊匹单抗、林妥珠单抗、LYM-1-碘131单抗(Techni clone)、米妥莫单抗、莫西妥单抗、奥法木单抗、多态性上皮粘蛋白-钇90单抗(Antisoma)、雷珠单抗、利妥昔单抗和曲妥珠单抗。
免疫检查点抑制剂的非限制性实例包括抗PD-1剂或抗体,例如西米普利单抗、纳武单抗和帕博利珠单抗;抗PD-L1剂或抗体,例如阿替利珠单抗、阿维鲁单抗和德瓦鲁单抗;抗CTLA-4剂或抗体,例如易匹单抗;抗-LAG1剂;和抗0X40剂。
集落刺激因子的非限制性实例包括α达贝泊汀、α依泊汀、β依泊汀、非格司亭、粒细胞巨噬细胞集落刺激因子、来格司亭、雷迪司亭、米莫司亭、莫格司亭、那托格司亭、聚乙二醇化非格司亭和沙格司亭。
另外的免疫治疗剂的非限制性实例包括BiTE、CAR-T细胞、GITR激动剂、咪喹莫特、免疫调节酰亚胺(IMiD)、错配双链RNA(Ampligen)、瑞西莫德、SRL 172和胸腺法新。
在一个实施方案中,另外的抗癌剂是靶向治疗剂(即,靶向治疗)。靶向治疗剂包括例如单克隆抗体和小分子药物。靶向治疗剂的非限制性实例包括信号转导抑制剂、生长因子抑制剂、酪氨酸激酶抑制剂、EGFR抑制剂、组蛋白脱乙酰酶(HDAC)抑制剂、蛋白酶体抑制剂、细胞周期抑制剂、血管生成抑制剂、基质金属蛋白酶(MMP)抑制剂、肝细胞生长因子抑制剂、TOR抑制剂、KDR抑制剂、VEGF抑制剂、成纤维细胞生长因子(FGF)抑制剂、MEK抑制剂、ERK抑制剂、PI3K抑制剂、AKT抑制剂、MCL-1抑制剂、BCL-2抑制剂、SHP2抑制剂、HER-2抑制剂、BRAF抑制剂、基因表达调节剂、自噬抑制剂、细胞凋亡诱导剂、抗增殖剂和糖酵解抑制剂。
信号转导抑制剂的非限制性实例包括酪氨酸激酶抑制剂、多激酶抑制剂、安罗替尼、阿伐替尼、阿西替尼、达沙替尼、多韦替尼、伊马替尼、仑伐替尼、洛尼达明、尼罗替尼、尼达尼布、帕唑帕尼、培维索曼、波纳替尼、凡德他尼和EGFR抑制剂。
EGFR抑制剂的非限制性实例包括EGFR的小分子拮抗剂,例如阿法替尼、布加替尼、厄洛替尼、吉非替尼、拉帕替尼和奥西替尼;基于抗体的EGFR抑制剂,包括任何可以通过其天然配体部分或完全阻断EGFR激活的抗EGFR抗体或抗体片段。基于抗体的EGFR抑制剂可以包括例如以下中描述的那些:Modjtahedi,H.,等人,1993,Br.J.Cancer 67:247-253;Teramoto,T.,等人,1996,Cancer 77:639-645;Goldstein等人,1995,Clin.Cancer Res.1:1311-1318;Huang,S.M.,等人,1999,Cancer Res.15:59(8):1935-40;和Yang,X.,等人,1999,Cancer Res.59:1236-1243;单克隆抗体单抗E7.6.3(Yang,1999,同上);Mab C225(ATCC登录号HB-8508),或具有其结合特异性的抗体或抗体片段;特异性反义核苷酸或siRNA;阿法替尼、西妥昔单抗;马妥珠单抗;奈西妥木单抗;尼妥珠单抗;帕尼妥木单抗;和扎鲁木单抗。
组蛋白脱乙酰酶(HDAC)抑制剂的非限制性实例包括贝利司他、帕比司他、罗米地辛和伏立诺他。
蛋白酶体抑制剂的非限制性实例包括硼替佐米、卡非佐米、伊沙佐米、马佐米(salinosporamide a)和奥普佐米。
细胞周期抑制剂(包括CDK抑制剂)的非限制性实例包括阿贝西利、夫拉平度、帕博西尼和瑞博西尼。
在一个实施方案中,另外的抗癌剂是抗血管生成剂(或血管生成抑制剂),包括但不限于基质金属蛋白酶(MMP)抑制剂;VEGF抑制剂;EGFR抑制剂;TOR抑制剂,例如依维莫司和替西罗莫司;PDGFR激酶抑制剂,例如克莱拉尼;HIF-Iα抑制剂,例如PX 478;HIF-2α抑制剂,例如WO 2015/035223中描述的贝组替凡和HIF-2α抑制剂;成纤维细胞生长因子(FGF)或FGFR抑制剂例如B-FGF和RG 13577;肝细胞生长因子抑制剂;KDR抑制剂;抗Ang1和抗Ang2剂;抗Tie2激酶抑制剂;Tek拮抗剂(US2003/0162712;US 6,413,932);抗TWEAK剂(US 6,727,225);ADAM整合素结构域拮抗整合素与其配体的结合(US2002/0042368);抗eph受体和/或抗肝配蛋白抗体或抗原结合区(US 5,981,245;5,728,813;5,969,110;6,596,852;6,232,447;和6,057,124);和抗PDGF-BB拮抗剂以及特异性结合PDGF-BB配体的抗体或抗原结合区。
基质金属蛋白酶(MMP)抑制剂的非限制性实例包括MMP-2(基质金属蛋白酶2)抑制剂、MMP-9(基质金属蛋白酶9)抑制剂、普力司他、RO 32-3555和RS13-0830。有用的基质金属蛋白酶抑制剂的实例描述于例如WO 96/33172、WO 96/27583、EP 1004578、WO 98/07697、WO98/03516、WO 98/34918、WO 98/34915、WO 98/33768、WO 98/30566、EP 0606046、EP0931788、WO 90/05719、WO 99/52910、WO 99/52889、WO 99/29667、WO 1999/007675、EP1786785、EP 1181017、US2009/0012085、US 5,863,949、US 5,861,510和EP 0780386。优选的MMP-2和MMP-9抑制剂是那些具有很少或没有抑制MMP-1活性的抑制剂。更优选的是相对于其它基质金属蛋白酶选择性抑制MMP-2和/或MMP-9的那些(即,MAP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12和MMP-13)。
VEGF和VEGFR抑制剂的非限制性实例包括贝伐单抗、西地尼布、CEP 7055、CP547632、KRN 633、奥兰替尼、帕唑帕尼、培加他尼、培加他尼八钠、塞马尼布、索拉非尼、舒尼替尼、VEGF拮抗剂(Borean,Denmark)和VEGF-TRAPTM。
另外的抗癌剂还可以是另一种抗血管生成剂、包括但不限于2-甲氧基雌二醇、AE941、阿仑单抗、α-D148单抗(Amgen,US)、阿尔法他汀、醋酸阿奈可他、血管抑制素、血管生成抑制剂、(SUGEN,US)、血管抑素、抗-Vn单抗(Crucell,Netherlands)、阿替莫德、阿昔替尼、AZD 9935、BAY RES2690(Bayer,Germany,BC 1(Genoa Institute of Cancer Research,Italy)、贝洛拉尼、benefin(Lane Labs,US)、卡赞替尼、CDP 791(Celltech Group,UK)、软骨素酶AC、西仑吉肽(cilengitide)、考布他汀A4前药、CP 564959(OSI,US)、CV247、CYC 381(Harvard University,US)、E 7820、EHT 0101、内皮抑素、恩扎妥林盐酸盐、ER-68203-00(IVAX,US)、纤维蛋白原-E片段、Flk-1(ImClone Systems,US)、FLT 1(VEGFR 1)的形式、FR-111142、GCS-100、GW 2286(GlaxoSmithKline,UK)、IL-8、伊洛司他、IM-862、伊索拉定、KM-2550(Kyowa Hakko,Japan)、来那度胺(lenalidomide)、乐伐替尼、MAbα5β3整合素、第二代(Applied Molecular Evolution,USA和Medlmmune,US)、MAb VEGF(Xenova,UK)、马立马司他(marimastat)、maspin(Sosei,Japan)、转移抑制素、莫托拉明C、M-PGA、奥布布林、OX14503、PI 88、血小板因子4、PPI 2458、雷姆赛卢单抗、rBPI 21和BPI衍生的抗血管生成药物(XOMA,US)、瑞拉非尼、SC-236、SD-7784(Pfizer,US)、SDX 103(University ofCalifornia at San Diego,US)、SG 292(Telios,US)、SU-0879(Pfizer,US)、TAN-1120、TBC-1635、替塞瓦替尼、四硫代钼酸盐、沙利度胺(thalidomide)、血小板反应蛋白1抑制剂、Tie-2配体(Regeneron,US)、组织因子途径抑制剂(EntreMed,US)、肿瘤坏死因子-α抑制剂、塔姆他丁、TZ 93、尿激酶纤溶酶原激活剂抑制剂、瓦迪梅赞、万迪他尼、血管抑素、瓦他拉尼、VE-钙粘蛋白-2拮抗剂、黄根醇、XL 784(Exelixis,US)、齐夫-阿柏西普和ZD 6126。
在实施方案中,另外的抗癌剂是破坏或抑制RAS-RAF-ERK或PI3K-AKT-TOR信号传导途径的另外的活性剂或者是PD-1和/或PD-L1拮抗剂。在实施方案中,另外的抗癌剂是RAF抑制剂、EGFR抑制剂、MEK抑制剂、ERK抑制剂、PI3K抑制剂、AKT抑制剂、TOR抑制剂、MCL-1抑制剂、BCL-2抑制剂、SHP2抑制剂、蛋白酶体抑制剂或免疫治疗,包括单克隆抗体、免疫调节酰亚胺(IMiD)、抗PD-1、抗PDL-1、抗CTLA4、抗LAG1和抗OX40剂、GITR激动剂、CAR-T细胞、和BiTE。
RAF抑制剂的非限制性实例包括达拉非尼、恩科拉非尼、瑞戈非尼、索拉非尼和维罗非尼。
MEK抑制剂的非限制性实例包括二甲替尼、CI-1040、考比替尼、PD318088、PD325901、PD334581、PD98059、瑞美替尼、司美替尼和曲美替尼。
ERK抑制剂的非限制性实例包括WO 2017/068412中描述的LY3214996、LTT462、MK-8353、SCH772984、拉沃昔替尼、尤利塞替尼和ERKi。
PI3K抑制剂的非限制性实例包括17-羟基渥曼青霉素类似物(例如WO 06/044453);AEZS-136;阿培利司;AS-252424;布帕利西布(buparlisib);CAL263;考泮利司;CUDC-907;达克利司(WO 06/122806);去甲氧基绿胶霉素;杜韦利西布(duvelisib);GNE-477;GSK1059615;IC87114;伊代拉利西布(idelalisib);INK1117;LY294002;Palomid 529;帕沙利西布(paxalisib);哌立福新;PI-103;PI-103盐酸盐;匹替利司(例如WO 09/036,082;WO 09/055,730);PIK 90;PWT33597;SF1126;索诺利西布(sonolisib);TGI 00-115;TGX-221;XL147;XL-765;渥曼青霉素;和ZSTK474。
AKT抑制剂的非限制性实例包括Akt-1-1(抑制Akt1)(Barnett等人(2005)Biochem.J.,385(Pt.2),399-408);Akt-1-1,2(Barnett等人(2005)Biochem.J.385(Pt.2),399-408);API-59CJ-Ome(例如,Jin等人(2004)Br.J.Cancer 91,1808-12);1-H-咪唑并[4,5-c]吡啶基化合物(例如,WO05011700);吲哚-3-甲醇及其衍生物(例如,美国专利号6,656,963;Sarkar和Li(2004)J Nutr.134(12Suppl),3493S-3498S);哌立福辛、Dasmahapatra等人(2004)Clin.Cancer Res.10(15),5242-52,2004);磷脂酰肌醇醚脂质类似物(例如,Gills和Dennis(2004)Expert.Opin.Investig.Drugs 13,787-97);三西立滨(Yang等人(2004)Cancer Res.64,4394-9);咪唑并噁腙化合物,包括反式-3-氨基-1-甲基-3-[4-(3-苯基-5H-咪唑并[1,2-c]吡啶并[3,4-e][1,3]噁嗪-2-基)苯基]-环丁醇盐酸盐(WO 2012/137870);afuresertib;;康力美芬;MK2206;帕他色替,以及WO 2011/082270和WO 2012/177844中公开的那些。
TOR抑制剂的非限制性实例包括地福莫司;ATP竞争性TORC1/TORC2抑制剂,包括PI-103、PP242、PP30和Torin 1;FKBP12增强剂中的TOR抑制剂、雷帕霉素及其衍生物,包括替西罗莫司、依维莫司,WO 9409010;雷帕霉素及其类似物(rapalogs),例如如WO 98/02441和WO 01/14387中所公开的,例如AP23573、AP23464或AP23841;40-(2-羟乙基)雷帕霉素、40-[3-羟基(羟甲基)甲基丙酸酯]-雷帕霉素;40-表-(四唑基)-雷帕霉素(也称为ABT578);32-脱氧雷帕霉素;16-戊炔氧基-32(S)-二氢雷帕霉素,以及WO 05/005434中公开的其他衍生物;US 5,258,389、WO 94/090101、WO 92/05179、US 5,118,677、US 5,118,678、US 5,100,883、US 5,151,413、US 5,120,842、WO 93/111130、WO 94/02136、WO 94/02485、WO 95/14023、WO 94/02136、WO 95/16691、WO 96/41807、WO 96/41807和US 5,256,790中公开的衍生物;和含磷雷帕霉素衍生物(例如WO05/016252)。
MCL-1抑制剂的非限制性实例包括AMG-176、MIK665和S63845。
SHP2抑制剂的非限制性实例包括WO 2019/167000和WO 2020/022323中描述的SHP2抑制剂。
适合使用的抗癌剂的另外的非限制性实例包括2-乙基酰肼、2,2’,”-三氯三乙胺、ABVD、醋葡醛内酯、乙酰甘露聚糖、醒磷酰胺糖苷(aldophosphamide glycoside)、阿拉丁、氨磷汀、氨基乙酰丙酸、阿那格雷、安瑟(ANCER)、安塞斯蒂姆(ancestim)、抗CD22免疫毒素、抗肿瘤草药、阿帕齐醌、阿格拉宾(arglabin)、三氧化二砷、硫唑嘌呤(azathioprine)、BAM002(Novelos)、bcl-2(Genta)、阿莫司汀(bestrabucil)、比利考达、比生群(bisantrene)、溴隐亭、溴菌素、苔藓虫素、丁硫氨酸亚砜亚胺、花萼苷、细胞周期非特异性抗肿瘤药、西莫白介素、氯膦酸盐、克霉唑、阿糖胞苷阿磷酯、DA 3030(Dong-A)、地佛法明(defofamine)、地托-迪尼白介素、右丙亚胺、地吖醌(diaziquone)、二氯乙酸、地拉西普、迪码器莫内酯、二十二醇、多克骨化醇、依地福新、依氟鸟氨酸、EL532(Elan)、elfomithine、依沙芦星、恩尿嘧啶、依他硝唑、埃克苏林德、铁甘油醇、叶酸补充剂,例如叶酸、加西托新(gacytosine)、硝酸镓、吉莫拉西/奥替拉西/替加氟组合(S-l)、glycopine、组胺二盐酸盐、HIT双氯芬酸、HLA-B7基因治疗(Vical)、人胎儿甲胎蛋白、伊班膦酸盐、伊班膦酸、ICE化疗方案、伊美克松、碘苯胍、IT-101(CRLX101)、拉尼奎达、LC 9018(Yakult)、来氟米特(leflunomide)、香菇多糖、左旋咪唑+氟尿嘧啶、洛伐他汀、硫蒽酮、马索罗酚、美拉胂醇、甲氧氯普胺、米替福新、米普罗昔芬、米托胍腙、米托唑胺、莫哌达醇(mopidamol)、莫泰克斯钆、MX6(高德美)、纳洛酮+喷他佐辛、硝基胺(nitracrine)、诺拉曲塞(nolatrexed)、NSC 631570奥曲肽(Ukrain)、奥拉帕尼、P-30蛋白、PAC-1、帕利弗明、帕米膦酸盐、帕米膦酸、戊聚糖多硫酸钠、苯来美特(phenamet)、沙培林、匹克生琼、铂、鬼臼酸(podophyllinic acid)、卟吩姆钠、PSK(多糖-K)、兔抗胸腺细胞多克隆抗体、rasburiembodiment、视黄酸、铼Re 186依替膦酸盐、罗莫肽、钐(153Sm)lexidronam、西佐喃、苯乙酸钠、斯帕磷酸、锗螺胺(spirogermanium)、89氯化锶、苏拉明、苦马豆素、他拉泊芬、塔里奎达、他扎罗汀(tazarotene)、替加氟尿嘧啶、替莫泊芬、细交链孢菌酮酸、四氯十氧化物、血小板生成素、乙基硫紫嘌呤锡、替拉扎明、TLC ELL-12、托西莫单抗-碘131、三氟尿苷和替匹拉西组合、肌钙蛋白I(Harvard University,US)、乌拉坦(urethan)、瓦尔斯波达尔(valspodar)、维替泊芬(verteporfin)、唑来膦酸和佐苏奎达尔(zosuquidar)。
本公开还提供了使用本文提供的式(I)的化合物或药物组合物与放射疗法组合来治疗癌症的方法。用于施用放射疗法的技术是本领域已知的,并且这些技术可以用于本文描述的组合疗法中。式(I)的化合物在该组合疗法中的施用可以如本文所述来确定。
放射疗法可以通过多种方法中的一种或多种方法的组合来实施,包括但不限于外束疗法、内放射疗法、植入放射、立体定向放射外科、全身放射疗法、放射疗法和永久或暂时的间质近距离放射疗法。本文所用的术语“近距离放射疗法”是指通过插入体内肿瘤或其他增殖性组织疾病部位或其附近的空间受限的放射性材料来递送的放射疗法。该术语旨在包括但不限于暴露于放射性同位素(例如,At-211、I-131、I-125、Y-90、Re-186、Re-188、Sm-153、Bi-212、P-32和Lu的放射性同位素)。用作本公开的细胞调节剂的合适的辐射源包括固体和液体。作为非限制性示例,辐射源可以是放射性核素,例如作为固体源的I-125、I-131、Yb-169、Ir-192、作为固体源的I-125或发射光子、β粒子、伽马辐射或其他治疗射线的其他放射性核素。放射性材料也可以是由放射性核素的任何溶液制成的流体,例如I-125或I-131的溶液,或者放射性流体可以使用包含固体放射性核素的小颗粒的合适流体的浆料产生,例如Au-198、Y-90。此外,放射性核素可以包含在凝胶或放射性微球中。
本公开还提供了用于组合疗法的方法,其中已知另外的活性剂调节其他途径,或同一途径的其他组分,或甚至与式(I)化合物或其药学上可接受的盐组合使用的重叠的靶酶组。在一个实施方案中,此类疗法包括但不限于一种或多种式(I)的化合物与化疗剂、免疫治疗剂、激素治疗剂、治疗性抗体、靶向治疗剂和放射治疗的组合,以提供协同或相加的治疗效果。
本公开的化合物可以与本文所公开的药剂或其他适合的药剂组合使用,这取决于所治疗的病况。因此,在一些实施方案中,本公开的一种或多种化合物将与如上所述的其他药剂共同施用。当用于组合疗法时,本文描述的化合物与第二药剂同时或单独施用。这种组合施用可以包括以相同剂型同时施用两种药剂、以单独剂型同时施用和单独施用。即,式(I)的化合物和任何上述药剂可以一起配制在同一剂型中并同时施用。可替代地,式(I)的化合物和和上述任何药剂可以同时施用,其中两种药剂存在于单独制剂中。在另一个替代方案中,可以在施用式(I)的化合物后立即施用上述任何药剂,或反之亦然。在单独施用方案的一些实施方案中,式(I)的化合物和上述任何药剂的施用相隔几分钟,或相隔几小时,或相隔几天。
由于本公开的一个方面考虑了用可以分开施用的药学活性化合物的组合治疗疾病/病况,本公开进一步涉及以试剂盒形式组合单独的药物组合物。该试剂盒包含两种独立的药物组合物:式(I)的化合物和第二药物化合物。该试剂盒包括用于容纳单独的组合物的容器,例如分开的瓶子或分开的箔包。容器的其他实例包括注射器、盒子和袋子。在一些实施方案中,试剂盒包含单独组分的使用说明。当单独的组分优选以不同的剂型(例如口服和肠胃外)施用、以不同的剂量间隔施用时,或者当处方医疗保健专业人员需要滴定组合的各个组分时,试剂盒形式是特别有利的。
本公开还提供了式(I)的化合物或其药学上可接受的盐,用于在疗法中使用,或者式(I)的化合物或其药学上可接受的盐在疗法中的用途。本公开还提供了式(I)的化合物或其药学上可接受的盐,用于治疗癌症,或者式(I)的化合物或其药学上可接受的盐用于治疗癌症的用途。本发明还提供式(I)的化合物或其药学上可接受的盐,其用于制备用于治疗癌症的药物,或式(I)的化合物或其药学上可接受的盐用于制备用于治疗癌症的药物的用途。本公开还提供了式(I)的化合物或其药学上可接受的盐和另外的抗癌剂,用于治疗癌症,或者式(I)的化合物或其药学上可接受的盐和另外的抗癌剂用于治疗癌症的用途。本发明还提供了式(I)的化合物或其药学上可接受的盐和另外的抗癌剂,其用于制备用于治疗癌症的药物,或式(I)的化合物或其药学上可接受的盐和另外的抗癌剂用于制备用于治疗癌症的药物的用途。本公开还提供了包含式(I)的化合物或其药学上可接受的盐的药物组合物,该药物组合物用于治疗癌症,或者包含式(I)化合物或其药学上可接受的盐的药物组合物用于治疗癌症的用途。本公开还提供了包含式(I)的化合物或其药学上可接受的盐和另外的抗癌剂的药物组合物,该药物组合物用于治疗癌症,或者包含式(I)的化合物或其药学上可接受的盐和另外的抗癌剂的药物组合物用于治疗癌症的用途。
制备本公开化合物的方法
本文描述的化合物可以根据以下方案和实施例的程序,使用合适的材料来制备,并通过以下具体实施例进一步举例说明。实施例进一步说明本公开化合物的制备细节。本领域技术人员将容易理解,可以使用以下制备程序的条件和方法的已知变化来制备这些化合物。例如,在一些情况下,可以改变进行反应方案的步骤的顺序以促进反应或避免不需要的反应产物。提供这些实施例仅是为了进一步说明的目的,并不旨在限制本公开。
在整个合成方案和实施例中,除非另有说明,缩写词和首字母缩写词可以具有以下含义:s:单峰、d:双峰,t:三峰、q:四峰、sep:七峰、dd:双双峰、dt:双三峰、td:三双峰、tt:三三峰、ddd:双双双峰、ddt:双双三峰、dtd:双三双峰、tdd:三双双峰、m:多峰、br:宽峰、brs:宽单峰、tert:三、DMSO-d6:氘代二甲亚砜、CDCl3:氘代氯仿、CD3OD:氘代甲醇、THF:四氢呋喃,DMF:N,N-二甲基甲酰胺、DMSO:二甲亚砜、DCM:二氯甲烷、IPE:二异丙醚、MTBE:甲基叔丁基醚、EtOAc:乙酸乙酯、AcOH:乙酸、TFA:三氟乙酸、MeOH:甲醇、EtOH:乙醇、DIAD:偶氮二甲酸二异丙酯、TMAD:N,N,N’,N’-四甲基偶氮二酰胺、Et3N:三乙胺、DIEA:N,N-二异丙基乙胺、RT:室温、NIS:N-碘代琥珀酰亚胺、Pd(dppf)Cl2:[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)和HATU:1-[双(二甲基氨基)亚甲基]-lH-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐、KOAc:醋酸钾。
除非另有说明,实施例中使用的试剂均为市售产品。硅胶柱色谱法和碱性硅胶柱色谱法使用Shoko Scientific Co.,Ltd.或Biotage制造的预装柱。AVANCE NEO 400光谱仪(400MHz;BRUKER)和AVANCE III HD 500光谱仪(500MHz;BRUKER)用于NMR光谱。对于含有四甲基硅烷的氘代溶剂,使用四甲基硅烷作为内参比。对于其他情况,使用NMR溶剂作为内参比进行测量。所有δ值均以ppm表示。使用Biotage制造的Initiator(商标)进行微波反应。Waters制造的XSelect CSH C18 OBD制备柱用于制备型反相HPLC。
2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯('Int-J003-Pl)
步骤A:1,4-二氧杂螺[4.5]癸-8-酮O-乙基磺酰肟(Int-J00l)
在-15℃下向1,4-二氧杂螺[4.5]癸-8-酮肟(3.00g,17.5mmol)和三甲胺(2.96mL,21.0mmol)在二氯甲烷(30mL)中的溶液中添加乙磺酰氯(1.84mL,19.3mmol),将混合物在相同温度下搅拌0.5小时。将水(15mL)加入到反应混合物中,并分离有机层。将有机层用盐酸(1M,15mL)、饱和碳酸氢钠溶液(15mL)和盐水(15mL)洗涤,并将有机层用硫酸钠干燥。过滤产物溶液,滤液不经任何纯化即用于下一步。
ESI-MS m/z[M+H]+264。
步骤B:9-甲基-1.4-二氧杂-8-氮杂螺[4.6]十一烷-8-甲酸苄酯(Int-J002)
在-78℃下向三甲基铝(1.40M己烷溶液,25.0mL,35.0mmol)的搅拌溶液中滴加上述1,4-二氧杂螺[4.5]癸-8-酮O-乙基磺酰肟(Int-J00l)的二氯甲烷溶液。将反应混合物温热至0℃并搅拌1小时。向混合物中滴加氢化二异丁基铝(1.00M己烷溶液,26.3mL,26.3mmol),将混合物在0℃下搅拌1h。将反应混合物用二氯甲烷(15mL)稀释,并将氟化钠(10.5g,0.25mol)和水(4.4mL)加入到反应混合物中。将混合物在室温下剧烈搅拌1小时,并过滤。将滤液减压浓缩,并将乙酸乙酯(50mL)和水(50mL)加入到残余物中。向混合物中在室温下加入碳酸氢钠(30g,0.36mol)和氯甲酸苄酯(11.9g,70.0mmol),并将反应混合物搅拌1小时。分离有机层,用水洗涤,并减压浓缩。通过快速硅胶色谱法(0-40%,己烷中的乙酸乙酯梯度)纯化残余物,得到9-甲基-1,4-二氧杂-8-氮杂螺[4.6]十一烷-8-甲酸苄酯(Int-J002)(3.60g)。ESI-MS m/z[M+H]+306。
步骤C:2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003)
向9-甲基-1,4-二氧杂-8-氮杂螺[4.6]十一烷-8-甲酸苄酯(Int-J002)(21.0g,68.8mmol)在丙酮(300mL)和水(100mL)中的溶液中加入甲苯-4-磺酸水合物(19.6g,103mmol)。将混合物在40℃下搅拌7小时后,将反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化残余物,得到2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003)(14.7g)。ESI-MS m/z[M+H]+262。
步骤D:2-甲基-5-氧代氮杂环庚烷-l-甲酸苄酯(Int-J003-P1和Int-J003-P2))
分离外消旋2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003),并得到手性2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003-Pl,在以下分析条件下)用于合成。
分析条件:色谱柱(CHIRALCEL OD-H,4.6mmID x250mmL,5μL),洗脱液(己烷/2-丙醇,700/300(v/v)),流速(1.0mL/min),温度(30℃)、浓度(0.5mg/mL)、进样体积(10μL)
2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003-P1)的保留时间:6.053min
2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003-P2)的保留时间:7.945min
5,5-二氟-2-甲基氮杂环庚烷(Int-K002)
在0℃下向2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003-Pl)(200mg,0.765mmol)在二氯甲烷(1.5mL)中的溶液中添加二甲基氨基三氟化硫(0.700mL,6.41mmol)。在室温下搅拌混合物2小时后,通过添加饱和Na2CO3水溶液猝灭反应。反应混合物用CHCl3萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化残余物,得到二氟化化合物。
向二氟化化合物的乙醇(10mL)溶液中添加Pd(OH)2/C(269mg,0.383mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌1小时。将反应混合物过滤并真空浓缩,得到5,5-二氟-2-甲基氮杂环庚烷(Int-K002)(20.0mg)。ESI-MS m/z[M+H]+150。
7-甲基氮杂环庚烷-4-醇盐酸盐(Int-K003-A)
步骤A:5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-P1和P2)
在0℃下向2-甲基-5-氧代氮杂环庚烷-1-甲酸苄酯(Int-J003Pl)(400mg,1.53mmol)在MeOH(16mL)中的溶液中添加1.0M三仲丁基硼氢化锂的THF溶液(1.53mL,1.53mmol)。将混合物在室温下搅拌1小时后,通过添加H2O猝灭反应。反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化残余物,得到5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-P1,第一洗脱)。ESI-MS m/z[M+H]+264。以及5-羟基-2-甲基氮杂环庚烷-1-羧基苄酯(Int-K011-P2,第二洗脱)。ESI-MS m/z[M+H]+264。
步骤B:7-甲基氮杂环庚烷-4-醇盐酸盐(Int-K003-A)
向5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-P1,第一洗脱)(79.0mg,0.300mmol)在乙醇(3.0mL)中的溶液中添加Pd(OH)2/C(105mg,0.150mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌30分钟。将反应混合物过滤,将4.0M HCl的二噁烷溶液(1.0mL)添加到滤液中。将滤液真空浓缩,得到7-甲基氮杂环庚烷-4-醇盐酸盐(Int-K003-A)。ESI-MS m/z[M+H]+130。
7-甲基氮杂环庚烷-4-醇盐酸盐Int-K003-B)
7-甲基氮杂环庚烷-4-醇盐酸盐(Int-K003-B)通过与7-甲基氮杂环庚烷-4-醇盐酸盐(Int-K003-A)相似的路线使用5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-P2,第二洗脱)代替5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-P1,第一洗脱)合成。ESI-MS m/z[M+H]+130。
5-氟-2-甲基氮杂环庚烷盐酸盐(Int-K004-A)
在0℃下向5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-Pl,第一洗脱)(175mg,0.665mmol)在二氯甲烷(1.3mL)中的溶液中添加二甲基氨基三氟化硫(0.143mL,1.31mmol)。在室温下搅拌混合物1小时后,通过添加饱和Na2CO3水溶液猝灭反应。反应混合物用CHCl3萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化残余物,得到氟化化合物。
向氟化化合物的乙醇(5.0mL)溶液中添加Pd(OH)2/C(69.3mg,0.0987mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌1小时。将反应混合物过滤,将4.0MHCl的二噁烷溶液(1.0mL)添加到滤液中。将滤液真空浓缩,得到5-氟-2-甲基氮杂环庚烷盐酸盐(Int-K004-A)。ESI-MS m/z[M+H]+132。
5-氟-2-甲基氮杂环庚烷盐酸盐(Int-K004-B)
5-氟-2-甲基氮杂环庚烷盐酸盐(Int-K004-B)通过与5-氟-2-甲基氮杂环庚烷盐酸盐(Int-K004-A)相似的路线使用5-羟基-2-甲基氮杂环庚烷-l-甲酸苄酯(Int-K011-P2,第二洗脱)代替5-羟基-2-甲基氮杂环庚烷-1-甲酸苄酯(Int-K011-Pl,第一洗脱)合成。ESI-MS m/z[M+H]+132。
2-(3-羟基哌啶-3-基)乙腈盐酸盐(Int-XX023)
向1-氧杂-5-氮杂螺[2.5]辛烷-5-甲酸苄酯(950mg,3.84mmol)在EtOH(20mL)和水(20mL)中的溶液中添加氰化钠(282mg,5,76mmol)。在室温下搅拌混合物4小时后,用EtAOc萃取反应物,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。将残余物通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化,得到氰化化合物。
向氰化化合物(110mg,0.401mmol)的乙醇(2.0mL)溶液中添加Pd(OH)2/C(141mg,0.200mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌1小时。将反应混合物过滤,将4.0M HCl的二噁烷溶液(1.0mL)添加到滤液中。将滤液真空浓缩,得到2-(3-羟基哌啶-3-基)乙腈盐酸盐(Int-XX023)。ESI-MS m/z[M+H]+141。
3-羟基-8-碘-1-萘甲酸(Int-T002)
步骤A:3-氨基-8-碘-l-萘甲酸(Int-T001)
向8-碘-3-硝基-1-萘甲酸(1g,2.9mmol)在乙酸乙酯(40mL)乙醇(15mL)中的混合物中添加5%Rh/C(0.5g)并向烧瓶中装入H2。将混合物在室温下搅拌。24小时后,将反应混合物通过硅藻土垫过滤,并将滤液浓缩至干,得到粗制3-氨基-8-碘-1-萘甲酸(Int-T001)(0.94g),为棕色固体,将其无需纯化即可用于下一步。1H NMR(400MHz,DMSO-d6)δ=5,71(brs,2H),6.87(d,J=2.4Hz,1H),7.00(dd,J=8.1,7.3Hz,1H),7.12(d,J=2.4Hz,1H),7.60(d,J=8.2Hz,1H),7.8(d,J=7.3Hz,1H),13.14(brs,1H)。LCMS(ESI):m/z[M+H]+314。
步骤B:3-羟基-8-碘-1-萘甲酸(Int-T002)
向粗制3-氨基-8-碘-1-萘甲酸(Int-T00l)(0.94g)在1M硫酸水溶液(38mL)中的冰冷混合物中缓慢滴加亚硝酸钠(0.228g,3.3mmol)于水(1mL)中的溶液。将混合物搅拌1小时并温热至室温。将反应混合物滴加至回流的40%硫酸水溶液(108mL)中。将反应混合物加热回流1小时,然后通过玻璃棉塞快速热过滤以除去不溶的烧焦物质。将滤液冷却至室温,形成沉淀。通过过滤收集沉淀物并用水洗涤,得到3-羟基-8-碘-1-萘甲酸(Int-T002)(0.54g)。1H NMR(400MHz,DMSO-d6)δ=7.13(dd,J=8.1,7.3Hz,1H),7.22(d,J=2.8Hz,1H),7.24(d,J=2.8Hz,1H),7.82(dd,J=8.3,0.8Hz,1H),8.01(dd,J=7.3,1.2Hz,1H),10.22(brs,1H)。LCMS(ESI):m/z[M+H]+315。
(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-羟基-5,7-二氢-6H-吡咯并[3,
4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L004)
步骤A:2-氯-4-((2-硝基苄基)氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸
叔丁酯(Int-L001)
向2,4-二氯-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(55.0g,0.190mol)和(2-硝基苯基)甲醇(29.0g,0.190mol)在甲苯(550mL)中的搅拌溶液中添加碳酸铯(92.6g,0.284mol),并将混合物温热至85℃并搅拌14小时。将混合物冷却至室温并过滤,并将滤液减压浓缩。向残余物中加入乙腈(400mL)和水(200mL)并将混合物悬浮2天。过滤固体,并将固体在85℃下悬浮于乙酸乙酯(400mL)中1小时,然后冷却至室温。过滤固体并减压干燥,得到2-氯-4-((2-硝基苄基)氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-L001)(21g)。ESI-MS m/z[M+H]+407,409。
步骤B:N,N-二甲基-1-(1-(((4-((2-硝基苄基)氧基)-6,7-二氢-5H-吡咯并[3,4-
d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-L002)
向2-氯-4-((2-硝基苄基)氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯的混合物(Int-L00l)(10.0g,24.6mmol)、(1-((二甲基氨基)甲基)环丙基)甲醇(4.13g,32.0mmol)、rac-BINAP(2.30g,3.69mmol)和乙酸钯(II)(414mg,1.84mmol)的甲苯(100mL)溶液中添加碳酸铯(20.0g,61.5mmol),并将混合物温热至130℃并搅拌3小时。将混合物冷却至室温并过滤,并将滤液减压浓缩。通过快速NH-硅胶色谱法(0-100%,己烷中的乙酸乙酯梯度)纯化残余物,得到偶联产物。向偶联产物的二氯甲烷(50mL)溶液中添加三氟乙酸(30mL)并将混合物搅拌1小时。减压除去三氟乙酸,残余物通过快速NH-硅胶色谱法纯化(0-50%,甲醇梯度在乙酸乙酯中),得到N,N-二甲基-1-(1-(((4-((2-硝基苄基)氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-L002)(7.94g)。ESI-MS m/z[M+H]+400。
步骤C:(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-((2-硝基苄基)氧基)-5,
7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(Int-L003)
向3-(羟基-8-碘-1-萘甲酸(Int-T002)(5.19g,16.5mmol)、1-羟基苯并三唑一水合物(2.53g,16.5mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(3.26g,16.5mmol)和N,N-二异丙基乙胺(7.02mL,41.3mmol)在N,N-二甲基甲酰胺(55mL)中的混合物中添加N,N-二甲基-1-(1-(((4-((2-硝基苄基)氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-L002)(5.50g,13.8mmol),并将混合物在室温下搅拌7小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将残余物通过快速NH-硅胶色谱法(0-60%,甲醇梯度在乙酸乙酯中)纯化,得到(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-((2-硝基苄基)氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(Int-L003)(8.77g)。ESI-MS m/z[M+H]+696。
步骤D:(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-羟基-5,7-二氢-6H-吡咯
并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L004)
向(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-((2-硝基苄基)氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(Int-L003)(7.00g,10.1mmol)和铁(粉末,2.81g,50.3mmol)在四氢呋喃(56mL)中的搅拌悬浮液中加入盐酸(1M,56.0mL,5.56mmol),并将混合物在室温搅拌2小时。将混合物用甲醇(100mL)和乙酸乙酯(100mL)稀释,并将混合物过滤并浓缩至干。向残余物中加入乙酸乙酯(30mL)和甲醇(3mL),并将混合物悬浮1小时。过滤沉淀并减压干燥,得到(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-羟基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L004)(6.80g)。ESI-MS m/z[M+H]+561。
(4-羟基-2-((1-(吗啉代甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧
啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L005)
(4-羟基-2-((1-(吗啉甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L005)通过使用(1-(吗啉甲基)环丙基)甲醇代替(1-((二甲基氨基)甲基)环丙基)甲醇与2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-羟基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L004)类似的途径合成。ESI-MS m/z[M+H]+603。
(R)-(1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲醇(Int-UU8-1)
步骤A:2-[(乙酰氧基)甲基]丙-2-烯-1-基乙酸酯(Int-UUl)
向5L 4颈圆底烧瓶中装入3-氯-2-(氯甲基)丙-1-烯(600g,4.80mol)、三乙胺(1.46kg,14.40mol)和乙酸(721g,12.0mol)。将所得溶液在70℃下搅拌过夜。将反应混合物冷却至室温并通过添加3L水猝灭。用乙酸乙酯(3×1L)萃取所得溶液并用盐水溶液(2×1L)洗涤合并的有机层。将有机层用无水硫酸钠干燥。过滤干燥溶液并浓缩滤液。将残余物通过硅胶柱用乙酸乙酯/石油醚(1:6)纯化,得到2-[(乙酰氧基)甲基]丙-2-烯-1-基乙酸酯(Int-UU1)。
步骤B:[1-[(乙酰氧基)甲基]-2,2-二氟环丙基]甲基乙酸酯(Int-UU2)
向维持氮气惰性气氛的20-L 4颈圆底烧瓶中放入2-[(乙酰氧基)甲基]丙-2-烯-1-基乙酸酯(Int-UU1)(600g,3,48mol)的二甘醇二甲醚(5L)溶液。随后在搅拌下于180℃下在5小时内滴加ClCF2CO2Na(2.65kg,17.4mol)在二甘醇二甲醚(5L)中的溶液。将所得溶液在180℃搅拌1小时。将反应混合物冷却至室温并通过添加H2O(5L)猝灭。用石油醚(4×2L)萃取所得溶液并合并有机层。合并的有机层用水(3×2L)洗涤并经无水硫酸钠干燥。过滤干燥的溶液,并将滤液浓缩至干,得到[1-[(乙酰氧基)甲基]-2,2-二氟环丙基]甲基乙酸酯(Int-UU2),其无需纯化即可直接用于下一步。
步骤C:[2,2-二氟-1-(羟甲基)环丙基]甲醇(Int-UU3)
向20-L 4颈圆底烧瓶中放入[1-[(乙酰氧基)甲基]-2,2-二氟环丙基]甲基乙酸酯(Int-UU2)(800g,3.60mol)、MeOH(10L)和K2CO3(995g,7.20mol)。将所得溶液在室温下搅拌过夜。滤出固体。浓缩滤液。然后通过添加水(2L)稀释所得混合物。用乙酸乙酯(5×1L)萃取所得溶液。合并有机层并用无水硫酸钠干燥。过滤干燥溶液并真空浓缩滤液。将残余物通过硅胶柱色谱法用乙酸乙酯/石油醚(1:1)纯化,得到[2,2-二氟-1-(羟甲基)环丙基]甲醇(Int-UU3)。1H NMR(300MHz,DMSO-d6)δ1.30(t,J=8.8Hz,2H),3.52(m,4H),4.79(t,J=5.6Hz,2H)。
步骤D:(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU4)
用氮气吹扫配备有倾倒式氮气适配器的500mL单颈圆底烧瓶,然后加入氢化钠(4.52g,113mmol)和N,N-二甲基甲酰胺(100mL)。将悬浮液冷却至0℃。分批添加固体[2,2-二氟-1-(羟甲基)环丙基]甲醇(Int-UU3)(12.0g,87mmol)。将混合物搅拌1小时,同时升温至室温。将所得反应混合物冷却至0℃并用苄基溴(10.3mL,87mmol)在N,N-二甲基甲酰胺(10mL)中的溶液处理。将混合物在室温搅拌1小时,然后用饱和氯化铵水溶液(10mL)和水(10mL)处理。将混合物在乙酸乙酯(75mL)和水(75mL)之间分配。将有机层用1重量%LiCl水溶液(30mL×3)洗涤,用无水硫酸钠干燥,过滤并浓缩滤液。通过硅胶柱色谱法纯化(220g,0至40%EtOAc/己烷),得到(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU4)。1H NMR(499MHz,甲醇-d4)δ7.39-7.32(m,4H),7.32-7.26(m,1H),4.62-4.49(m,2H),3.79-3.64(m,3H),3.60(dd,J=10.4,2.1Hz,1H),1.35(dddd,J=29.1,12.5,8.0,4.5Hz,2H)。
步骤E:(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU5-1)
外消旋(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU4)使用SFC手性色谱法(AD-H(21mm x250mm,5μm;条件:5%MeOH w/0.1%NH4OH和5%H2O)拆分,得到(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU5-1,峰1)。1H NMR(499MHz,甲醇-d4)δ7.39-7.26(m,5H),4.58-4.51(m,2H),3.78 -3.67(m,3H),3.60(dd,J=10.4,2.0Hz,1H),1.35(dddd,J=28.4,12.5,8.0,4.5Hz,2H)。还分离出(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU5-2,峰2)。
步骤F:(S)-(l-((苄氧基)甲基)-2,2-二氟环丙基)甲基甲磺酸酯(Int-UU6-1)
将(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU5-1)(3.25g,14.24mmol)在DCM(30mL)中的溶液冷却至0℃并用三乙胺(7.94mL,57.0mmol)处理,然后甲磺酰氯(2.22mL,28.5mmol)在DCM(2.2mL)中的溶液处理。将反应混合物搅拌,同时历时3小时温热至室温。将反应混合物通过硅胶柱色谱法纯化(0至100%EtOAc/己烷),得到(S)-(1-((苄氧基)甲基)-2,2-二氟环丙基)甲基甲磺酸酯(Int-UU6-1)。MS(ESI):m/z[M+Na]+329。
步骤G:(R)-1-(1-((苄氧基)甲基)-2,2-二氟环丙酰)-N,N-二甲基甲胺(Int-UU7-
l)
将(S)-(1-((苄氧基)甲基)-2,2-二氟环丙基)甲基甲磺酸酯(Int-UU6-1)(4.10g,13,4mmol)和二甲胺(2M,在THF中)(33.5mL,(66.9mmol)用碳酸钾(3.70g,26.8mmol)处理。将烧瓶盖上并在50℃下加热24小时。将反应混合物冷却至室温,用水(20mL)稀释,并用乙酸乙酯萃取。将合并的有机层用无水硫酸钠干燥,过滤并浓缩滤液。将粗残余物通过硅胶柱色谱法纯化(120g,0至100%[1:3EtOH/EtOAc]/己烷),得到(R)-1-(1-((苄氧基)甲基)-2,2-二氟环丙基)-N,N-二甲基甲胺(Int-UU7-1)。MS(ESI):m/z[M+H]+256。
步骤H:(R)-(1-((二甲基氨基)甲基)-2,2-二氟环丙炔)甲醇(Int-UU8-1)
(R)-1-(1-((苄氧基)甲基)-2,2-二氟环丙基)-N,N-二甲基甲胺(Int-UU7-1)(2.96g,11.6mmol)和Pd/C(10wt%,湿载体)(0.618g,0.580mmol)的2,2,2-三氟乙醇(20.0mL)溶液装入100mL回收烧瓶中,并在氢气(1atm,气球)下于室温下搅拌20小时。将混合物通过CELITE垫过滤并用甲醇(3×10mL)冲洗垫。将合并的滤液和洗液用3M HCl的甲醇溶液(12mL,36.0mmol)处理,然后真空浓缩,得到澄清、无色的粘性糖浆。添加乙醚(10mL)并搅拌混合物以引发沉淀。将混合物真空浓缩,然后用乙醚(10mL)处理并超声处理1分钟。倾析出二乙醚。将固体真空干燥,得到(R)-(1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲醇(Int-UU8-1)。MS(ESI):m/z[M+H]+166。使用Int-UU5-2作为中间体,通过与上述类似的反应顺序合成(S)-(1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲醇(Int-UU8-2)。MS(ESI):m/z[M+H]+166。
(2R,7aS)-2-氟代四氢-1H-吡咯嗪-7a(5H)-基)甲醇(lnt-VV6)
步骤A:2-(2-(氯甲基)烯丙基)-5-氧代吡咯烷-2-甲酸乙酯(Int-VV1)
在-40℃下于N2下将LiHMDS(1.00M,2.55L)逐滴添加至5-氧代吡咯烷-2-甲酸乙酯(200.g,1.27mol)和3-氯-2-(氯甲基)丙-1-烯(255g,2.04mol,236mL)在THF(2.00L)中的溶液中。将混合物在20℃下搅拌20小时。
将反应混合物倒入饱和NH4Cl溶液(1.00L)中并用1N HCl将混合物的pH调节至6~7。用EtOAc(500mL×3)萃取双相溶液。合并有机层,用盐水(600mL)洗涤,并减压浓缩,得到粗残余物。粗物质通过硅胶柱色谱法纯化(洗脱液:石油醚:乙酸乙酯=50:1至1:1梯度),得到2-(2-(氯甲基)烯丙基)-5-氧代吡咯烷-2-甲酸乙酯(Int-VV1)。1H NMR(400MHz,CDCI3)δ5.06(br d,J=17Hz,2H),4.14-4.38(m,3H),3.73(br d,J=16Hz,1H),3.06(br d,J=16Hz,1H),2.70-2.85(m,1H),2.53-2.66(m,1H),2.36-2.50(m,2H),2.09-2.21(m,1H),1.23-1.31(m,3H)。
步骤B:2-亚甲基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV2)
在0℃下于氮气下将2-(2-(氯甲基)烯丙基)-5-氧代吡咯烷-2-甲酸乙酯(Int-VV1)(500.g,2.03mol)在THF(500mL)中的溶液滴加至氢化钠(97.7g,2.44mol,60.0%纯度)在THF(3.00L)中的混合物中。将反应混合物在氮气下于70℃下搅拌12小时。将反应混合物冷却并倒入饱和氯化铵溶液(2.00L)中,并在5℃下搅拌1小时。用EtOAc(600mL×3)萃取双相混合物。合并的有机层用盐水(500mL×2)洗涤,经无水Na2SO4干燥,过滤,减压浓缩。将粗残余物通过硅胶柱色谱法纯化(洗脱剂:石油醚:乙酸乙酯=50:1至1:1),得到2-亚甲基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV2)。1H NMR(400MHz,CDCl3)δ4.96-5.13(m,2H),4.27(br d,J=16Hz,1H),4.19(q,J=7Hz,2H),3.71(br d,J=16Hz,1H),3.04(d,J=16Hz,1H),2.69-2.83(m,1H),2.59(ddd,J=2,9,13Hz,1H),2.40-2.52(m,2H),1.96-2.22(m,1H),1.26(t,J=7Hz,3H)。
步骤C:2,5-二氧四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV3)
臭氧(239mmol)(0.5~1m3/h)鼓泡入2-亚甲基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV2)(160.g,765mmol)在DCM(1.60L)和MeOH(160mL)中的溶液中,在-70℃下持续9小时。向反应混合物中鼓入氮气以清除过量的臭氧。然后,在-70℃下将二甲基硫醚(76.0g,1.22mol)添加至混合物中。将反应混合物在20℃下搅拌14小时。将反应混合物减压浓缩,得到残余物。将粗残余物通过硅胶柱色谱法纯化(洗脱剂:石油醚:乙酸乙酯=50:1至1:1),得到2,5-二氧四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV3)。1H NMR(400MHz,CDCI3)δ4.22(q,J=7Hz,2H),4.07-4.12(m,1H),3.54(dd,J=1,18Hz,1H),2.92-3.03(m,2H),2.74-2.88(m,1H),2.42-2.51(m,2H),2.12-2.23(m,1H),1.27(t,J=7Hz,3H)
步骤D:2-羟基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV4)
在0℃下于N2下向2,5-二氧四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV3)(200g,947mmol)在EtOH(2.00L)中的溶液中添加NaBH4(10.8g,284mmol)。将反应混合物在0℃下搅拌10分钟。在5℃下通过添加饱和NH4Cl(50.0mL)猝灭反应混合物,并将混合物在5℃下搅拌0.5小时。将反应混合物减压浓缩。然后合并来自四个相同反应的粗产物。将粗残余物通过硅胶柱色谱法纯化(洗脱剂:石油醚:乙酸乙酯=50:1至1:1),得到2-羟基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV4)。1H NMR(400MHz,CDCl3)δ4.54-4.70(m,1H),4.16-4.31(m,2H),3.93(dd,J=6.0,13Hz,1H),3.09(d,J=13Hz,1H),2.75-2.90(m,1H),2.39-2.63(m,4H),2.01-2.13(m,1H),1.83(dd,J=6,14Hz,1H),1.29(t,J=7Hz,3H)。
步骤E:(2R,7aS)-2-氟-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV5)
在-70℃下于N2下向2-羟基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV4)在DCM(600mL)中的溶液中逐滴添加DAST(90.7g,563mmol,74.4mL)。将反应混合物温热至20℃并搅拌16小时。通过在10℃下添加EtOH(50.0mL)来淬灭反应,然后用水(300mL)稀释并用DCM(200mL×2)萃取。合并的有机层用盐水(200mL)洗涤,经无水Na2SO4干燥,过滤,并减压浓缩。合并来自六个相同反应的粗产物并通过硅胶柱色谱法纯化(石油醚:乙酸乙酯=50:1至1:1)。该材料通过使用HCl改性剂(MeCN/水,含0.05%HCl改性剂)的制备型HPLC进一步纯化。使用手性SFC(Daicel Chiralpak AS(50mm x250mm,10um;条件:0.1%NH4OH的EtOH溶液)拆分外消旋混合物,得到(2R,7aS)-2-氟-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV5,峰2)。1H NMR(400MHz,CDCI3):δ5.16-5.43(m,1H),4.14-4.27(m,3H),3.06-3.26(m,1H),2.57-2.85(m,3H),2.38-2.50(m,1H),2.07--2.30(m,2H),1.28(t,J=7Hz,3H)。
步骤F:((2R,7aS)-2-氟代四氢-1H-吡咯嗪-7a(5H)-基)甲醇(Int-VV6)
在0℃下于氮气下将(2R,7aS)-2-氟-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(Int-VV5)(82.0g,381mmol)在THF(300mL)中的溶液添加至LAH(21.7g,571mmol)在THF(520mL)中的混合物中。将反应混合物温热至70℃并搅拌3小时。将反应混合物冷却至0℃并通过在0℃下于氮气下添加Na2SO4.10 H2O来猝灭。将反应混合物在20℃下搅拌0.5小时,然后过滤。将滤饼用EtOAc(600mL×5)洗涤并将滤液经无水Mg2SO4干燥。过滤混合物,减压浓缩滤液,得到残余物。将粗残余物通过硅胶柱色谱法(SiO2,DCM:甲醇=100:1至10:l)纯化,得到((2R,7aS)-2-氟代四氢-1H-吡咯嗪-7a(5H)-基)甲醇(Int-VV6)。1H NMR(400MHz,CDCl3):δ5.06-5.34(m,1H),3.25(s,2H),3.08-3.23(m,3H),2.85-3.08(m,2H),2.00-2.12(m,2H),1.74-1.93(m,4H)。
4-溴-6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑(Int-HHH5)
步骤A:1-溴-5-氟-2-碘-3-甲基苯(Int-HHH1)
将2-溴-4-氟-6-甲基苯胺(200g,0.983mol)溶解在MeCN(800mL)中。将所得混合物冷却至0℃。将浓缩HCl(12M,245mL)添加到反应混合物中,同时保持反应温度在0℃。将NaNO2(81.1g,1.18mol eq)在水(400mL)中的溶液滴加到反应混合物中,保持反应温度在0℃。将所得混合物在0℃搅拌0.5小时。然后在0℃下将KI(195g,1.18mol)在水(400mL)中的溶液滴加到反应混合物中。将所得混合物升温至室温并在20℃下搅拌12小时。使用上述条件在另外一批中重复该反应。将两批反应合并。通过NaOH水溶液将产物混合物调节至pH 8-9并且水相用EtOAc(2.00L x2)萃取。将有机相经Na2SO4干燥,过滤并浓缩。获得的残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯=1:0至0:1),得到1-溴-5-氟-2-碘-3-甲基苯(Int-HHH1)。1H NMR(400MHz,CDCl3)δ7.27-7.22(m,1H),6.95(dd,J=2.4,8.8Hz,1H),2.56(s,3H)。
步骤B:1-溴-5-氟-3-甲基-2-(三氟甲基)苯(Int-HHH2)
将1-溴-5-氟-2-碘-3-甲基苯(Int-HHH1)(100g,0.317mol)溶解在DMF(1.50L)中。在25℃下向该混合物中添加CuI(514g,2.70mol)和2,2-二氟-2-(氟磺酰基)乙酸甲酯(518g,2.70mol)。将反应混合物在60℃下加热并搅拌12小时。使用上述条件在另外3批中重复该反应。将四批反应合并并用水(24L)淬灭。该混合物用石油醚(8.00L x2)萃取。将合并的有机层用盐水(4L×2)洗涤并经Na2SO4干燥。过滤干燥溶液,真空浓缩滤液,得到含有1-溴-5-氟-3-甲基-2-(三氟甲基)苯(Int-HHH2)的粗物质,将其直接用于下一步无需纯化。
步骤C:2-溴-6-氟-4-甲基-3-三氟甲基)苯甲醛(Int-HHH3)
将1-溴-5-氟-3-甲基-2-(三氟甲基)苯(Int-HHH2)(100g,0.382mol)溶解在2-MeTHF(500mL)中。将反应混合物冷却至-65℃。在-65℃下将2M LDA溶液(213mL,426mmol)添加到混合物中。将反应混合物在-65℃下搅拌0.5小时。在-65℃下向该混合物中滴加DMF(31.2g,0.420mol)。将反应混合物在-65℃搅拌2小时。使用上述条件在另外2批中重复该反应。将三批反应合并。使用1M HCl将反应混合物pH调节至3-4并用2-MeTHF(500mL×2)萃取水相。有机相经Na2SO4干燥,过滤,浓缩,得到2-溴-6-氟-4-甲基-3-(三氟甲基)苯甲醛(Int-HHH3),其无需进一步纯化即可用于下一步。
步骤D:4-溴-6-甲基-5-(三氟甲基')-1H-吲唑(Int-HHH4)
将2-溴-6-氟-4-甲基-3-(三氟甲基)苯甲醛(Int-HHH 3)(100g,0.351mol)溶解在THF(800mL)中。在25℃下向该混合物中添加N2H4·H2O(53.7g,1.05mol)。将混合物在60℃下加热并搅拌2小时。将产物混合物用水(400mL)猝灭并用EtOAc(200mL×2)萃取。将合并的有机层用盐水(200mL)洗涤并经Na2SO4干燥。过滤干燥溶液,真空浓缩滤液,得到残余物。使用上述条件在另外2批中重复该反应。将三批反应合并。将获得的残余物与DCM(100mL)在15℃下研磨2小时。通过过滤收集固体,得到4-溴-6-甲基-5-(三氟甲基)-1H-吲唑(Int-HHH4)。1H NMR(400MHz,CDCI3)δ10.61 -10.20(m,1H),8.20(d,J=0.8Hz,lH),7.34(d,J=0.6Hz,1H),2.67-2.63(m,3H)。
步骤E:4-溴-6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑(Int-
HHH5)
将4-溴-6-甲基-5-(三氟甲基)-1H-吲唑(Int-HHH4)(60.0g,0.215mol)溶解在DCM(240mL)和MeCN(240mL)中。在20℃下将DHP(21.7g,0.258mol)和TsOH·H2O(8.18g,0.043mol)添加至混合物中。将反应混合物在20℃下搅拌12小时。将水(200mL)添加至产物混合物中。用DCM(200mL×2)萃取所得混合物。将合并的有机层用盐水(200mL)洗涤并经Na2SO4干燥。过滤干燥溶液并减压浓缩滤液。所得残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯=1:0至0:1)纯化,得到4-溴-6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑(Int-HHH5)。1H NMR(400MHz,CDCI3-d)δ8.12(s,1H),7.44(s,1H),5.69(dd,J=3,9Hz,1H),4.09-3.94(m,1H),3.81-3.69(m,1H),2.69-2.63(m,3H),2.56-2.43(m,1H),2.19-2.14(m,1H),2.12-2.04(m,1H),1.87-1.73(m,2H),1.71-1.63(m,1H)。
1,8-二溴-3-(甲氧基甲氧基)萘(Int-W002)
步骤A:2,4,5-三溴萘-1-胺(Int-W001)
在0℃下向5-溴萘-1-胺(63g,280mmol)在DMA(1260mL)中的溶液添加NBS(106g)。将混合物温热至室温并搅拌3小时。将反应混合物用Na2SO3(75g)的H2O(380mL)溶液和NaHCO3(24g)的H2O(1100mL)溶液稀释并搅拌1小时。通过过滤收集沉淀物并用水洗涤,得到2,4,5-三溴萘-1-胺(Int-W001)(97g),为紫色固体。1H NMR(400MHz,CDCI3)δ7.99(s,1H),7.97-7.95(1H,m),7.86-7.84(1H,m),7.31-7.29(1H,m),4.65(2H,brs)。LCMS(ESI):m/z[M+H]+379.9。
步骤B:1,8-二溴-3-(甲氧基甲氧基)萘(Int-W002)
在0℃下向2,4,5-三溴萘-1-胺(Int-W001)(60g,160mmol)在AcOH(780mL)和丙酸(300mL)中的悬浮液中分份添加NaNO2(11g)并将反应混合物搅拌20分钟。将反应混合物在0℃下用H2O(1800mL)稀释并搅拌1小时。过滤浆液并用H2O洗涤固体,得到4,5-二溴-2-羟基萘-1-重氮,其无需进一步纯化即可使用。
在0℃下向4,5-二溴-2-羟基萘-1-重氮在EtOH(1600mL)中的悬浮液中分批添加NaBH4(15g)并且搅拌反应混合物30分钟。将混合物温热至室温并搅拌过夜。将反应混合物冷却至0C并用水(1500mL)和5M HCl水溶液(79mL)稀释。将混合物蒸发以除去EtOH并用CHCl3萃取。合并的有机层用盐水洗涤并经Na2SO4干燥并真空蒸发,得到4,5-二溴萘-2-醇,其无需进一步纯化即可使用。
在0C下,向4,5-二溴萘-2-醇在CH2Cl2(900mL)中的溶液中添加i-Pr2NEt(170mL)和MOMCl(36m)。在室温下搅拌1小时后,将反应混合物用EtOAc和饱和NaHCO3水溶液稀释。分离有机层,并用EtOAc萃取水层。合并的有机层用盐水洗涤,经Na2SO4干燥,并蒸发。通过硅胶柱色谱法纯化所得残余物,得到1,8-二溴-3-(甲氧基甲氧基)萘(Int-W002)(17.4g)。1H NMR(400MHz,氯仿-d)δ=7.82(dd,J=1.3,7.4Hz,1H),7.75-7.71(m,2H),7.41(d,J=2.6Hz,1H),7.26-7.20(m,J=8.0,8.0Hz,1H),5.29(s,2H),3.53(s,3H)。
实施例1:(4-(氮杂环-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,7-
二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例1)
向(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-羟基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L004)(15.0mg,0.0237mmol)和对甲苯磺酰氯(9.9mg,0.0521mmol)在DMF(0.3mL)中的混合物中添加N,N-二异丙基乙胺(0.032mL,0.189mmol)并将混合物在室温下搅拌0.5小时。向混合物中添加六亚甲基亚胺(0.0107mL,0.0947mmol)并将混合物在70℃下搅拌1小时。然后将NaOH水溶液(2M,0.4mL)添加至混合物中并将混合物在70℃下再搅拌1小时。将混合物冷却至室温并用DMSO(0.5mL)稀释,产物混合物通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(4-(氮杂环庚烷-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例1)。ESI-MS m/z[M+H]+642。1H NMR(400MHz,DMSO-d6)δ10.2(s,1H),8.03-7.98(m,1H),7.87-7.82(m,1H),7.29-7.26(m,1H),7.16-7.10(m,2H),4.98(br s,1H),4.70-4.45(m,2H),4.19-4.00(m,4H),3.70-3.62(m,1H),2.35-2.18(m,2H),2.16(s,3H),2.12(s,3H),1.83-1.70(m,2H),1.60-1.34(m,8H),0.59-0.56(m,2H),0.54-0.51(m,2H)。
下表中的化合物通过使用(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-羟基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮二盐酸盐(Int-L004)或(1-((二甲基氨基)甲基)环丙基)甲醇和相应的胺与实施例1相似的途径合成。
表1
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实施例82:(4-(3-氨基-5-羟基哌啶-1-基)-2-((1-((二甲基氨基)甲基)环丙基)
甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例82)
向(1-(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-6-(3-羟基-8-碘-1-萘甲酰基)-6,7二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-5-羟基哌啶-3-基)氨基甲酸叔丁酯(实施例67)(30mg,0.0395mmol)的二氯甲烷(5mL)溶液中添加三氟乙酸(5mL)并将混合物搅拌1小时。减压除去三氟乙酸并通过快速NH-硅胶色谱法纯化残余物(0-50%,甲醇梯度于乙酸乙酯中),得到(4-(3-氨基-5-羟基哌啶-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例82)。ESI-MSm/z[M+H]+659。
实施例83:N-(1-(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-6-(3-羟基-8-碘-
1-萘甲酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-5-羟基哌啶-3-基)-1-甲基-1H-吡
唑-5-甲酰胺(实施例83)
向1-甲基-1H-吡唑-5-甲酸(3.0mg,0.0237mmol)、1-羟基苯并三唑一水合物(2.9mg,0.0189mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(3.6mg,0.0189mmol)和N,N-二异丙基乙胺(0.006mL,0.0316mmol)的N,N-二甲基甲酰胺(0.3mL)的混合物中添加(4-(3-氨基-5-羟基哌啶-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例82)(10mg,0.015mmol),并将混合物在室温下搅拌5小时。用DMSO(0.6mL)稀释混合物,并通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化产物混合物,得到N-(1-(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-6-(3-羟基-8-碘-1-萘甲酰基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-5-羟基哌啶-3-基)-1-甲基-1H-吡唑-5-甲酰胺(实施例83)。ESI-MS m/z[M+H]+767。1HNMR(400MHz,DMSO-d6)δ10.3(s,1H),8.49-8.13(m,1H),8.04-7.96(m,1H),7.89-7.78(m,1H),7.47-7.39(m,1H),7.30-7.20(m,1H),7.18-7.05(m,2H),6.84-6.66(m,1H),5.15-4.52(m,2H),4.28-3.65(m,7H),3.64-3.12(m,10H)2.25-2.18(m,1H),2.16(s,3H),2.11(s,3H),1.93-1.43(m,1H),0.61-0.48(m,2H),0.40-0.30(m,2H)
实施例84-1:(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚
烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(Ex.84-1)
步骤A:2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6- 甲酸叔丁酯('Int-84a')
向2,4-二氯-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(3.88g,13,4mol)和2-甲基氮杂环庚烷盐酸盐(2.00g,13,4mol)的DME(30mL)搅拌溶液中添加N,N-二异丙基乙胺(6.82mL,40.1mmol),并将混合物温热至50℃并搅拌5小时。将混合物冷却至室温,用乙酸乙酯稀释。用水洗涤稀释的混合物,并将混合物减压浓缩。通过快速硅胶色谱法(0-40%,己烷中的乙酸乙酯梯度)纯化残余物,得到2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a)(3.52g)。ESI-MS m/z[M+H]+367,369。
步骤B:2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-
甲酸叔丁酯(Int-84a-1峰1和Int-84a-2峰2),手性HPLC
外消旋2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a)通过手性HPLC分离(色谱柱:Chiral Art SB 4.6(YMC),己烷/EtOH 0.1%二乙胺),得到2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a-1,第一洗脱)。ESI-MS m/z[M+H]+367,369)。以及2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a-2,第二洗脱)。ESI-MS m/z[M+H]+367,369。
步骤C:N,N-二甲基-1-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并 [3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-84b)
向2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a-2峰2,第二洗脱)(360mg,0.981mmol)、(1-((二甲基氨基)甲基)环丙基)甲醇(254mg,1.96mmol)、二氯[9,9-二甲基-4,5-双(二苯基膦)呫吨]钯(II)(74mg,0.098mmol)在甲苯(10mL)中的混合物中添加碳酸铯(959mg,2.94mmol),并将混合物温热至130℃并搅拌3小时。将混合物冷却至室温并过滤,滤液减压浓缩。通过快速硅胶色谱法(0-25%,氯仿中的甲醇梯度)纯化残余物,得到偶联产物。向偶联产物的二氯甲烷(2mL)溶液中添加三氟乙酸(2mL)并将混合物搅拌1小时。减压除去三氟乙酸,残余物通过快速NH-硅胶色谱法纯化(0-50%,在乙酸乙酯中的甲醇梯度),得到N,N-二甲基-1-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-84b)(180mg)。ESI-MS m/z[M+H]+360。
步骤D:实施例84-1:(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮
杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实
施例84)
向3-羟基-8-碘-1-萘甲酸(Int-T002)(105mg,0.334mmol)、1-羟基苯并三唑一水合物(51mg,0.334mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(64g,0.334mmol)和N,N-二异丙基乙胺(0.14mL,0.834mmol)在N,N-二甲基甲酰胺(1mL)中的混合物中添加N,N-二甲基-1-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-84b)(100mg,0.278mmol),并将混合物在40℃下搅拌2h。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将残余物通过快速NH-硅胶色谱法(0-60%,于乙酸乙酯中的甲醇梯度)纯化,得到(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例84-1)。ESI-MS m/z[M+H]+656。1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),8.02-7.98(m,1H),7.88-7.80(m,1H),7.29-7.24(m,1H),7.19-7.09(m,2H),5.15-5.04(m,1H),4.96-4.88(m,1H),4.70-4.38(m,1H),4.22-4.00(m,5H),3.21-2.80(m,3H),2.26-2.10(m,1H),2.15(s,3H),2.11(s,3H),1.85-0.90(m,8H),0.59-0.50(m,2H),0.39-0.31(m,2H)。
实施例84-2:(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲
基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2)
步骤A:(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-
2-基)氧基)甲基)环丙基)甲醇(Int-84c-1)
向2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a)(1.50g,4.09mmol)、1,1-双(羟甲基)环丙烷(1.25g,12.3mmol)、RuPhosPd G3(171mg,0.204mmol)的1,4-二噁烷(15mL)混合物中添加铯碳酸盐(4.00g,12.3mmol),并将混合物温热至110℃并搅拌15分钟。将混合物冷却至室温并过滤,并将滤液减压浓缩。将残余物通过快速硅胶色谱法纯化(40-80%,己烷中的乙酸乙酯梯度),得到偶联产物。向偶联产物的二氯甲烷(5mL)溶液中添加三氟乙酸(5mL)并将混合物搅拌1小时。减压除去三氟乙酸,残余物通过快速NH-硅胶色谱法纯化(0-50%,甲醇梯度于乙酸乙酯中),得到(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-84c-1)(1.36g)。ESI-MS m/z[M+H]+333。
步骤B:(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基氮杂
环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2)
向3-羟基-8-碘-1-萘甲酸(Int-T002)(1.54g,4.91mmol)、1-羟基苯并三唑一水合物(751mg,4.91mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(941g,4.91mmol)和N,N-二异丙基乙胺(2.09mL,12.3mmol)的N,N-二甲基甲酰胺(15mL)的混合物中添加(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-84c-1)(1.36g,4.09mmol),并将混合物在室温下搅拌2小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将残余物悬浮于乙酸乙酯(10mL)中,过滤固体并减压干燥,得到(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2)(1.45g)。ESI-MS m/z[M+H]+629。
实施例85:(3-羟基-8-碘萘-1-基)(2-((1-(((R)-3-甲氧基哌啶-1-基)甲基)环丙
基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮
(实施例85)
在0℃下向(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2)(20.0mg,0.0318mmol)和N,N-二异丙基乙胺(27mL,0.159mmol)的DMF(0.3mL)混合物加入乙磺酰氯(12.3mg,0.0955mmol),并将混合物在0℃下搅拌0.5小时。向混合物中添加(R)-3-甲氧基哌啶(18.3mg,0.159mmol)并将混合物在70℃下搅拌1小时。然后将甲醇(0.1mL)和NaOH水溶液(2M,0.2mL)添加至混合物中并将混合物在70℃下再搅拌0.5小时。将混合物冷却至室温,用DMSO(0.6mL)稀释,通过反相HPLC(MeCN/含0.1%甲酸的水)纯化产物混合物,得到(3-羟基-8-碘萘-1-基)(2-((1-(((R)-3-甲氧基哌啶-1-基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例85)。ESI-MS m/z[M+H]+726。1H NMR(400MHz,DMSO-d6)δ10.2(s,1H),8.04-7.98(m,1H)7.88-7.82(m,1H),7.30-7.26(m,1H),7.19-7.09(m,2H),5.15-5.03(m,1H),4.98-4.87(m,1H),4.70-4.35(m,2H)
4.21-3.99(m,5H),3.23(s,1.5H),3.28(s,1.5H),3.15-2.78(m,2H),2.31-2.11(m,2H),2.00-0.95(m,24H),0.61-0.51(m,2H),0.40-0.31(m,2H)。
下表中的化合物通过使用实施例84-2和相应的胺与实施例85相似的途径合成。
表2
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实施例84-2a:(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-
(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2a)
步骤A:(R)-2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧
啶-6-甲酸叔丁酯(Int-84a-3)
向2,4-二氯-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(2.13g,7.35mol)和(R)-2-甲基氮杂环庚烷盐酸盐(1.00g,6.68mol)在DME(20mL)中的搅拌溶液中添加N,N-二异丙基乙胺(3.41mL,20.0mmol),并将混合物温热至60℃并搅拌4小时。将混合物冷却至室温,用乙酸乙酯稀释。用水洗涤稀释的混合物,并将混合物减压浓缩。通过快速硅胶色谱法(0-40%,己烷中的乙酸乙酯梯度)纯化残余物,得到(R)-2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a-3)(1.92g)。ESI-MS m/z[M+H]+367,369。
步骤B:(R)-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧
啶-2-基)氧基)甲基)环丙基)甲醇(Int-84c-21)
向(R)-2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a-3)(920mg,2.51mmol)、l,l-双(羟甲基)环丙烷(768mg,7.52mmol)、RuPhos Pd G3(52.4mg,0.0627mmol)的1,4-二噁烷(15mL)混合物中加入碳酸铯(2.45g,7.52mmol),并将混合物温热至110℃并搅拌30分钟。将混合物冷却至室温并过滤,并将滤液减压浓缩。将残余物通过快速硅胶色谱法纯化(40-80%,己烷中的乙酸乙酯梯度),得到偶联产物。向偶联产物的二氯甲烷(5mL)溶液中添加三氟乙酸(5mL)并将混合物搅拌1小时。减压除去三氟乙酸,残余物通过快速NH-硅胶色谱法纯化(0-50%,于乙酸乙酯中的甲醇梯度),得到(R)-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-84c-2)(500mg)。ESI-MS m/z[M+H]+333。
步骤C:(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基
氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2a)
向3-羟基-8-碘-1-萘甲酸(Int-T002)(471mg,1.50mmol)、1-羟基苯并三唑一水合物(230mg,1.50mmol)、1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(288mg,1.50mmol)和N,N-二异丙基乙胺(0.64mL,3.75mmol)在N,N-二甲基甲酰胺(5mL)中的混合物中添加(R)-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-84c-2)(416mg,1.25mmol),并将混合物在室温下搅拌5小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。混合物用乙酸乙酯稀释,稀释的混合物用水洗涤,混合物减压浓缩。将残余物通过快速NH-硅胶色谱法(0-100%,己烷中的乙酸乙酯梯度)纯化,得到(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2a)(580mg)。ESI-MS m/z[M+H]+629。
实施例93:(R)-(3-羟基-8-碘萘-1-基)(2-((l-((4-甲氧基哌啶-1-基)甲基)环丙
基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮
(实施例93)
实施例93通过使用(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2a)和4-甲氧基哌啶与实施例85相似的程序合成。ESI-MS m/z[M+H]+726。1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),8.03-7.98(m,1H),7.87-7.82(m,1H),7.29-7.25(m,1H),7.19-7.09(m,2H),5.18-5.04(m,1H),4.96-4.88(m,1H),4.69-4.35(m,2H),4.22-4.00(m,4H),3.21(s,1.5H),3.19(s,1.5H),2.80-2.65(m,2H),2.38-2.15(m,2H),2.10-0.95(m,19H),0.59-0.50(m,2H),0.39-0.30(m,2H)。
实施例94:(R)-(2-((1-((1,4-氧杂氮杂环庚烷-4-基)甲基)环丙基)甲氧基)-4-
(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)
甲酮(实施例94)
实施例94通过使用(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例84-2a)和1,4-氧杂氮杂环庚烷与实施例85相似的程序合成。ESI-MS m/z[M+H]+712。
实施例95:(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((l-(羟甲基)环丙基)甲氧
基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例95)
步骤A:(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧
啶-6-甲酸叔丁酯(Int-95a)
在室温下,向2,4-二氯-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(900mg,3.10mmol)和(R)-3-甲基哌啶-3-醇盐酸盐(470mg,3.10mmol)在N,N-二甲基乙酰胺(5.0mL)中的溶液中添加N,N-二异丙基乙胺(1.62mL,9.31mmol)。将混合物在室温下搅拌40分钟后,通过添加H2O猝灭反应。反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-100%,己烷中的EtOAc梯度)纯化残余物,得到(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-95a)(1.12g)。ESI-MS m/z[M+H]+369,371。
步骤B:(R)-1-(2-((1-羟甲基)环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧
啶-4-基)-3-甲基哌啶-3-醇(Int-95b)
在室温下向(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-95a)(50.0mg,0.136mmol)、环丙烷-1,1-二基二甲醇(41.5mg,0.407mmol)和RuPhos Pd G3(3,40mg,0.00407mmol)的1,4-二噁烷(0.7mL)溶液中添加碳酸铯(132mg,0.407mmol)。将混合物在100℃下搅拌1小时后,将反应混合物冷却至室温,过滤并真空浓缩。将残余物溶解在EtOAc中,用H2O和盐水洗涤,经Na2SO4干燥,过滤并真空浓缩,得到偶联产物。向偶联产物的二氯甲烷(2.6mL)溶液中添加三氟乙酸(1.0mL)。将混合物在室温下搅拌3小时后,将反应混合物真空浓缩。将残余物通过快速NH-硅胶色谱法纯化(0-50%,EtOAc中的MeOH梯度),得到(R)-1-(2-((1-(羟甲基)环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-95b)(37.5mg)。ESI-MS m/z[M+H]+335。
步骤C:实施例95(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-(羟甲基)环丙基)甲
氧基)-5,7-二羟基-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例95)
在室温下向(R)-1-(2-((1-(羟甲基)环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-95b)(37.5mg,0.112mmol)、3-羟基-8-碘-1-萘甲酸(Int-T002)(38.7mg,0.123mmol)、l-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(23.6mg,0.123mmol)和1-羟基苯并三唑水合物(18.9mg,0.123mmol)的DMF(1.2mL)溶液中添加N,N-二异丙基乙胺(0.0977mL,0.561mmol)。将混合物在室温下搅拌15小时后,通过添加H2O猝灭反应。反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。将残余物通过快速NH-硅胶色谱法(0-50%,EtOAc中的MeOH梯度)和反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-(羟甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例95)。ESI-MS m/z[M+H]+631。1H NMR(400MHz,DMSO-d6)δ10.3-10.2(m,1H),8.02-7.96(m,1H),7.87-7.80(m,1H),7.29-7.24(m,1H),7.16-7.08(m,2H),5.06-4.83(m,1H),4.68-4.34(m,4H),4.26-3.96(m,4H),3.90-3.64(m,1H),3.57-3,44(m,1H),3.25-2.96(m,2H),1.85-1.38(m,4H),1.13(s,3H),0.80(d,J=10.6Hz,1H),0.52-0.39(m,4H)。
实施例96:(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-(哌啶-1-基甲基)环丙基)
甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例96)
在-5℃下向(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-(羟甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例95)(10.0mg,0.0159mmol)的N,N-二甲基乙酰胺(0.3mL)的溶液中加入乙磺酰氯(0.00333mL,0.0352mmol)和三乙胺(0.0111mL,0.0793mmol)。将混合物在5℃搅拌1小时后,向反应混合物中添加哌啶(0.00783mL,0.0793mmol)。将混合物在75℃下搅拌2小时后,将2.0M NaOH水溶液(0.2mL)添加至混合物中并将混合物在75℃下搅拌30分钟。将反应混合物冷却至室温,用DMSO(0.5mL)稀释并通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-(哌啶-1-基甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例96)。ESI-MS m/z[M+H]+698。1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),8.02-7.96(m,1H),7.87-7.80(m,1H),7.29-7.24(m,1H),7.16-7.08(m,2H),5.06-4.82(m,1H),4.70-4.33(m,3H),4.19-3.96(m,4H),3.87-3.65(m,1H),2.39-2.13(m,6H),1.84-1.25(m,11H),1.13(s,3H),0.80(d,J=10.4Hz,1H),0.60-0.46(m,2H),0.38-0.27(m,2H)。
下表中的化合物通过使用实施例95和相应的胺与实施例96相似的途径合成。
表3
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(R)-(3-羟基-8-碘萘-1-基)(2-((1-羟甲基)环丙基)甲氧基)-4-(3-甲基-3-((三
甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基甲酮(Int-108e)
步骤A:(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-dl嘧
啶-6-甲酸苄酯(Int-108a)
在室温下向2,4-二氯-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸苄酯(300mg,0.925mmol)和(R)-3-甲基哌啶-3-醇盐酸盐(140mg,0.925mmol)的N,N-二甲基乙酰胺(5.0mL)溶液中加入N,N-二异丙基乙胺(0.450mL,2.58mmol)。在室温下搅拌混合物30分钟后,通过添加H2O淬灭反应。将反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化残余物,得到(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸苄酯(Int-108a)(357mg)。ESI-MS m/z[M+H]+403,405。
步骤B:(R)-2-氯-4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-
6H-吡咯并[3,4-d]嘧啶-6-甲酸苄酯(Int-108b)
在室温下向(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸苄酯(Int-108a)(357mg,0.885mmol)的DMF(3.0mL)溶液中添加咪唑(121mg,1.77mmol)和三甲基氯硅烷(0.340mL,2.68mmol)。将混合物在室温下搅拌15小时后,通过添加H2O猝灭反应。反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速硅胶色谱法(0-40%,己烷中的EtOAc梯度)纯化残余物,得到(R)-2-氯-4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸苄酯(Int-108b)(375mg)。ESI-MS m/z[M+H]+475,477。
步骤C:(R)-(1-(((4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-6,7-二
氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-108c)和(R)-(1-(((4-(3-
甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-6,7-二氢-5H-吡咯并3,4-d]嘧啶-2-基)氧
基)甲基)环丙基)乙酸甲酯(Int-108d)
在室温下向(R)-2-氯-4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸苄酯(Int-108b)(375mg,0.788mmol)、环丙烷-1,1-二基二甲醇(242mg,2.36mmol)和RuPhos Pd G3(19.8mg,0.0236mmol)于1,4-二噁烷(5.0mL)中的溶液中加入碳酸铯(771mg,2.36mmol)。将混合物在100℃下搅拌1小时后,将反应混合物冷却至室温,用EtOAc稀释,过滤并真空浓缩。通过快速NH-硅胶色谱法(50-100%,己烷中的EtOAc梯度)纯化残余物,得到偶联产物。
向偶联产物的乙醇(20mL)溶液中添加Pd(OH)2/C(277mg,0.394mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌1小时。将反应混合物过滤并真空浓缩。将残余物通过快速NH-硅胶色谱法(0-30%,EtOAc中的MeOH梯度)纯化,得到(R)-(1-(((4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-108c)(40.5mg)。ESI-MS m/z[M+H]+407和(R)-(l-(((4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)乙酸甲酯(Int-108d)(105mg)。ESI-MS m/z[M+H]+449。
步骤D:(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(3-甲
基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮
(Int-108e)
在室温下向(R)-(1-(((4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲醇(Int-108c)(40.5mg,0.0996mmol)、(R)-(1-(((4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)乙酸甲酯(Int-108d)(105mg,0.234mmol)、3-羟基-8-碘-1-萘甲酸(Int-T002)(115mg,0.366mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(69.3mg,0.361mmol)和1-羟基苯并三唑水合物(57.0mg,0.372mmol)的DMF(3,4mL)溶液中添加N,N-二异丙基乙胺(0.174mL,0.999mmol)中。将混合物在室温下搅拌3小时后,向反应混合物中添加MeOH(1.0mL)和2.0M NaOH水溶液(1.0mL)。将混合物在室温下搅拌20分钟后,通过添加2.0M HCl水溶液(1.0mL)猝灭反应。将反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。将残余物通过快速NH-硅胶色谱法纯化(0-40%,EtOAc中的MeOH梯度),得到(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(Int-108e)。ESI-MS m/z[M+H]+703。
实施例108:(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-((4-甲氧基哌啶-1-基)
甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲
酮(实施例108)
在5℃下,向(R)-(3-羟基-8-碘萘-1-基)(2-((1-(羟甲基)环丙基)甲氧基)-4-(3-甲基-3-((三甲基甲硅烷基)氧基)哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(Int-108e)(22.0mg,0.0313mmol)的N,N二甲基乙酰胺(0.4mL)溶液中加入乙磺酰氯(0.00890mL,0.0939mmol)和三乙胺(0.0220mL,0.157mmol)。将混合物在5℃下搅拌15分钟后,向反应混合物中添加4-甲氧基哌啶(0.0194mL,0.157mmol)。将混合物在60℃下搅拌3小时后,将2.0M NaOH水溶液(0.1mL)添加到混合物中并将混合物在60℃下搅拌30分钟。向反应混合物中添加6.0M HCl水溶液(0.1mL)并将反应混合物在60℃下搅拌10分钟。反应混合物冷却至室温,用DMSO(0.5mL)稀释并通过反相HPLC(MeCN/含0.1%甲酸的水)纯化,得到(R)-(4-(3-羟基-3-甲基哌啶-1-基)-2-((1-((4-甲氧基哌啶-1-基)甲基)环丙基)甲氧基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例108)。ESI-MS m/z[M+H]+728。
下表中的化合物通过使用Int-108e和相应的胺与实施例108相似的途径合成。
表4
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实施例112:(2-((1-(((R)-3-氟吡咯烷-1-基)甲基)环丙基)甲氧基)-4-((R)-3-
羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)
甲酮(实施例112)
步骤A:2-((1-(((R)-3-氟吡咯烷-1-基)甲基)环丙基)甲氧基)-4-((R)-3-羟基-
3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-dl嘧啶-6-甲酸叔丁酯(Int-112a)
向(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶6-甲酸叔丁酯(Int-95a)(100mg,0.271mmol)、(R)-(1-((3-氟吡咯烷-1-基)甲基)环丙基)甲醇(93.9mg,0.542mmol)和RuPhos Pd G3(6.80mg,0.00813mmol)的1,4-二噁烷(1.5mL)溶液中添加碳酸铯(265mg,0.813mmol)。将混合物在100℃下搅拌3小时后,将反应混合物冷却至室温,过滤并真空浓缩。将残余物通过快速NH-硅胶色谱法纯化(50-100%,己烷中的EtOAc梯度),得到2-((1-(((R)-3-氟吡咯烷-1-基)甲基)环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-112a)(156mg)。ESI-MS m/z[M+H]+506。
步骤B:实施例112 (2-((1-(((R)-3-氟吡咯烷-1-基)甲基)环丙基)甲氧基)-4-
((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘
萘-1-基)甲酮(实施例112)
向2-((1-(((R)-3-氟吡咯烷-1-基)甲基)环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-112a)(137mg,0.271mmol)的氯仿(3.0mL)溶液中添加4.0M HCl的二噁烷溶液(0.68mL)。将混合物在室温下搅拌4天后,将反应混合物真空浓缩,得到胺产物。
在室温下向胺产物、3-羟基-8-碘-1-萘甲酸(Int-T002)(93.7mg,0.298mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(57.2mg,0.298mmol)和1-羟基苯并三唑水合物(45.7mg,0.298mmol)的DMF(3.0mL)溶液中添加N,N-二异丙基乙胺(0.472mL,2.71mmol)。将混合物在室温下搅拌24小时后,通过添加H2O猝灭反应。反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化残余物,得到(2-((1-(((R)-3-氟吡咯烷-1-基)甲基)环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例112)。ESI-MS m/z[M+H]+702。1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),8.02-7.96(m,1H),7.87-7.80(m,1H),7.29-7.23(m,1H),7.16-7.07(m,2H),5.26-4.83(m,2H),4.68-4.33(m,2H),4.20-3.93(m,4H),3.87-3.65(m,1H),2.87-2.68(m,2H),2.34-2.22(m,2H),2.16-1.95(m,1H),1.91-1.70(m,2H),1.68-1.40(m,3H),1.34-1.20(m,2H),1.13(s,3H),0.89-0.75(m,3H),0.60-0.47(m,2H),0.45-0.31(m,2H)。
下表中的化合物通过使用Int-95a和相应的氨基醇与实施例112相似的途径合成。
表5
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实施例117:(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-3-羟基-3-
甲基哌啶-1-基)-5,7-二氢-6H-吡咯[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施
例117)
步骤A:2-(((R)-1-((苄氧基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-
3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-117a)
在室温下,向(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶6-甲酸叔丁酯(Int-95a)(400mg,1.08mmol)、(S)-(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU5-2)(371mg,1.63mmol)和RuPhos Pd G3(27.2mg,0.0325mmol)的1,4-二噁烷(5.0mL)溶液中添加碳酸铯(1.06g,3.25mmol)。将混合物在100℃下搅拌6小时后,将反应混合物冷却至室温,过滤并真空浓缩。通过快速硅胶色谱法(10-100%,己烷中的EtOAc梯度)纯化残余物,得到2-(((R)-1-((苄氧基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-117a)(466mg))。ESI-MS m/z[M+H]+561。
步骤B:(R)-1-(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-6,7-二氢-5H-吡
咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-117b)
向2-(((R)-1-((苄氧基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-117a)(466mg,0.830mmol)的乙醇(5.0mL)溶液中添加Pd(OH)2/C(400mg,0.570mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌2小时。将反应混合物过滤并真空浓缩。向所得产物的二氯甲烷(8.0mL)溶液中添加三氟乙酸(1.6mL)。将混合物在室温下搅拌2小时后,将反应混合物真空浓缩。将残余物通过快速NH-硅胶色谱法纯化(0-50%,EtOAc中的MeOH梯度),得到(R)-1-(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-117b)(259mg)。ESI-MS m/z
[M+H]+371。
步骤C:实施例117(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-3-羟
基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲
酮(实施例117)
在室温下向(R)-1-(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-117b)(259mg,0.699mmol)、3-羟基-8-碘-1-萘甲酸(Int-T002)(241mg,0.769mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(147mg,0.769mmol)和1-羟基苯并三唑水合物(118mg,0.769mmol)的DMF(7.0mL)溶液中加入二异丙基乙胺(0.609mL,3,49mmol)。将混合物在室温下搅拌9小时后,通过添加H2O猝灭反应。将反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。将残余物通过快速NH-硅胶色谱法(0-50%,MeOH梯度在EtOAc中)和反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例117)。ESI-MS m/z[M+H]+667。1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),8.02-7.96(m,1H),7.87-7.80(m,1H),7.29-7.24(m,1H),7.17-7.07(m,2H),5.10-4.84(m,2H),4.71-4.48(m,2H),4.48-4.30(m,2H),4.27-4.11(m,2H),4.08-3.67(m,1H),3.62-3,49(m,2H),3.10-2.98(m,1H),1.86-1.24(m,7H),1.14(s,3H),0.86-0.76(m,1H)。
实施例118:(2-(((R)-l-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-
((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘
萘-1-基)甲酮(实施例118)
在5℃下向(2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例117)(29.1mg,0.0437mmol)的N,N-二甲基乙酰胺(0.45mL)溶液中添加乙磺酰氯(0.00869mL,0.0917mmol)和三乙胺(0.0614mL,0.437mmol)。将混合物在5℃下搅拌15分钟后,向反应混合物中添加二甲胺的2.0M THF溶液(0.220mL,0.440mmol)。将混合物在75℃下搅拌3小时后,将2.0MNaOH水溶液(0.4mL)添加至混合物中并将混合物在75℃下搅拌30分钟。将反应混合物冷却至室温,用DMSO(0.4mL)稀释并通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例118)。ESI-MS m/z[M+H]+694。1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),8.02-7.95(m,1H),7.87-7.80(m,1H),7.29-7.23(m,1H),7.16-7.07(m,2H),5.07-4.86(m,1H),4.72-3.99(m,6H),3.91-3.67(m,1H),3.60-3,47(m,1H),3.13-2.98(m,1H),2.25(d,J=12.7Hz,1H),2.19-2.07(m,6H),1.85-1.35(m,6H),1.14(s,3H),0.94-0.75(m,2H)。
下表中的化合物通过使用实施例117和相应的胺与实施例118相似的途径合成。
表6
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实施例124:(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例124)
步骤A:2-(((R)-1-((苄氧基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮
杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124a)
在室温下向(R)-2-氯-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-84a-3)(200mg,0.545mmol)、(S)-(1-((苄氧基)甲基)-2,2-二氟环丙基)甲醇(Int-UU5-2)(187mg,0.818mmol))和RuPhos Pd G3(13.7mg,0.0164mmol)的1,4-二噁烷(1.5mL)溶液中添加碳酸铯(533mg,1.64mmol)。将混合物在100℃下搅拌5小时后,将反应混合物冷却至室温,过滤并真空浓缩。通过快速硅胶色谱法(0-50%,己烷中的EtOAc梯度)纯化残余物,得到2-(((R)-1-((苄氧基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124a)(305mg)。ESI-MS m/z[M+H]+559。
步骤B:2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚
烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124b)
向2-(((R)-1-((苄氧基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124a)(305mg,0.545mmol)的乙醇(5.5mL)溶液中添加Pd(OH)2/C(191mg,0.273mmol)。将反应混合物用H2气体和真空吹扫三次,并在室温下搅拌2小时。将反应混合物过滤并真空浓缩。通过快速NH-硅胶色谱法(30-100%,己烷中的EtOAc梯度)纯化残余物,得到2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124b)(253mg)。ESI-MS m/z[M+H]+469。
步骤C:2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲
基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124c)
在5℃下向2-(((R)-2,2-二氟-1-(羟甲基)环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124b)(253mg,0.539mmol)的N,N-二甲基乙酰胺(5.0mL)溶液中加入乙磺酰氯(0.0562mL),0.593mmol)和三乙胺(0.379mL,2.70mmol)。将混合物在5℃下搅拌10分钟后,向反应混合物中添加二甲胺的2.0M THF溶液(1.35mL,2.70mmol)。将混合物在60℃下搅拌14小时后,通过添加H2O猝灭反应。将反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速NH-硅胶色谱法(30-100%,己烷中的EtOAc梯度)纯化残余物,得到2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124c)(216mg)。ESI-MS m/z[M+H]+496。
步骤D:实施例124(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-
4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘
萘-1-基)甲酮(实施例124)
向2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-124c)(216mg,0.435mmol)的氯仿(4.0mL)溶液中添加4.0M HCl的二噁烷溶液(2.2mL)。将混合物在室温下搅拌30分钟后,将反应混合物真空浓缩,得到胺产物。
在室温下,向胺产物、3-羟基-8-碘-1-萘甲酸(Int-T002)(97.0mg,0.309mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(59.2mg,0.309mmol)和1-羟基苯并三唑水合物(47.3mg,0.309mmol)的DMF(3.0mL)溶液中添加N,N-二异丙基乙胺(0.244mL,1.40mmol)。将混合物在室温下搅拌13小时后,通过添加H2O猝灭反应。反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。将残余物通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例124)。ESI-MS m/z[M+H]+692。1H NMR(400MHz,DMSO-d6)δ10.2(s,1H),8.03-7.96(m,1H),7.87-7.80(m,1H),7.29-7.23(m,1H),7.19-7.07(m,2H),5.16-4.85(m,1H),4.79-4.00(m,5H),3.80-3.55(m,1H),3.05-2.85(m,1H),2.37-2.20(m,2H),2.17-2.06(m,6H),1.96-1.56(m,4H),1.55-1.25(m,4H),1.25-0.52(m,6H)。
实施例125-1:(3-氨基-8-碘萘-l-基)(2-(((R)-l-((二甲基氨基)甲基)-2,2-二 氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧 啶-6-基)甲酮(实施例125)
步骤A:2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟
基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-125a)
在室温下向(R)-2-氯-4-(3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶6-甲酸叔丁酯(Int-95a)(100mg,0.271mmol)、(R)-(1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲醇(Int-UU8-1)盐酸盐(82.0mg,0.407mmol)和RuPhos Pd G3(6.80mg,0.00813mmol)的1,4-二噁烷(1.5mL)溶液中添加碳酸铯(265mg,0.813mmol)和N,N-二异丙基乙胺(0.0944mL,0.542mmol)。将混合物在100℃下搅拌14小时后,将反应混合物冷却至室温,过滤并真空浓缩。将残余物通过快速NH-硅胶色谱法纯化(20-100%,己烷中的EtOAc梯度),得到2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-125a)(104mg)。ESI-MS m/z[M+H]+498。
步骤B:(R)-1-(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-6,7-
二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-125b)
向2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酸叔丁酯(Int-125a)(104mg,0.210mmol)的二氯甲烷(2.0mL)溶液中添加三氟乙酸(0.4mL)。将混合物在室温下搅拌2小时后,将反应混合物真空浓缩。将残余物通过快速NH-硅胶色谱法纯化(0-50%,EtOAc中的MeOH梯度),得到(R)-1-(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-125b)(72.8mg)。ESI-MS m/z[M+H]+398。
步骤C:实施例125-1 (3-氨基-8-碘萘-1-基)(2-(((R)-1-((二甲基氨基)甲基)-
2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-
d]嘧啶-6-基)甲酮(实施例125-1)
在室温下向(R)-1-(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(Int-125b)(6.00mg,0.0151mmol)、3-氨基-8-碘-萘-1-甲酸(Int-T00l)(5.20mg,0.0166mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(3.18mg,0.0166mmol)和1-羟基苯并三唑水合物(2.54mg,0.0166mmol)的DMF(0.15mL)溶液中添加N,N-二异丙基乙胺(0.0131mL,0.0755mmol)。将混合物在室温下搅拌14小时后,通过添加H2O猝灭反应。将反应混合物用EtOAc萃取,用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。将残余物通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(3-氨基-8-碘萘-1-基)(2-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例125-1)。ESI-MS m/z[M+H]+693。1H NMR(400MHz,DMSO-d6)δ7.82-7.77(m,1H),7.67-7.60(m,1H),7.03-6.96(m,2H),6.94-6.89(m,1H),5.69(s,2H),5.06-4.80(m,1H),4.65-4.00(m,6H),3.57-3,47(m,2H),2.18-2.06(m,6H),1.84-1.35(m,6H),1.25-1.19(m,2H),1.14(s,3H),0.89-0.76(m,2H)。
实施例125-2:(3-氨基-8-碘萘-1-基)(2-((1-((二甲基氨基)甲基)环丙基)甲氧
基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例
125-2)
向3-氨基-8-碘-1-萘甲酸(Int-T00l)(52mg,0.167mmol)、1-羟基苯并三唑一水合物(26mg,0.167mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(32mg,0.167mmol)和N,N-二异丙基乙胺(0.071mL,0.417mmol)的N,N-二甲基甲酰胺(2mL)混合物中添加N,N-二甲基-1-(1-(((4-(2-甲基氮杂环庚烷-1-基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-84b)(50mg,0.139mmol),并将混合物在室温下搅拌3小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化残余物,得到(3-氨基-8-碘萘-1-基)(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)甲酮(实施例125-2)(30mg)。ESI-MS m/z[M+H]+655。
实施例126:(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚
烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(8-乙炔基-3-羟基萘-1-基)甲酮(实施
例126)
向碘化铜(I)(2.9mg,0.0153mmol)、二(三苯基膦)二氯化钯(II)(11mg,0.0153mmol)、(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(3-羟基-8-碘萘-1-基)甲酮(实施例84)(100mg,0.0153mmol)、三乙胺(0.107mL,0.763mmol)的N,N-二甲基甲酰胺(3mL)溶液中添加三异丙基甲硅烷基乙炔(0.102mL,0.458mmol)。将容器抽真空并回填氮气,并将混合物在95℃下搅拌0.5小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将残余物通过快速NH-硅胶色谱法(0-40%,甲醇梯度在乙酸乙酯中)纯化,得到偶联产物。
向偶联产物的四氢呋喃(2mL)溶液中添加四丁基氟化铵(0.229mL,0.229mmol,1M,在四氢呋喃中)并将混合物在室温下搅拌0.5小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将残余物通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化,得到(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-(2-甲基氮杂环庚烷-1-基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)(8-乙炔基-3-羟基萘-1-基)甲酮(实施例126)。ESI-MS m/z[M+H]+554。1H NMR(400MHz,DMSO-d6)δ10.2(s,1H),7.89-7.84(m,1H),7.58-7.52(m,1H),7.48-7.39(m,1H),7.31-7.26(m,1H),7.12-7.06(m,1H),5.20-4.80(m,2H),4.61-4.30(m,2H),4.17-3.95(m,4H),3.13-2.75(m,1H),2.25-2.08(m,2H),2.16(s,3H),2.11(s,3H),2.00-0.95(m,12H),0.59-0.48(m,2H),0.39-0.31(m,2H).
下表中的化合物通过使用相应的碘化物样品与实施例126相似的途径合成。
表7
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7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧
基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144e-l)和Int-144e-2异构体(混合物)
步骤A:2-氯-4-((2-硝基苄基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸
叔丁酯(Int-144a)
向2,4-二氯-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(20.0g,65,7mmol)和(2-硝基苯基)甲醇(13.1g,85.5mmol)的甲苯(200mL)搅拌溶液中添加碳酸铯(42.9g,0.131mmol),并将混合物温热至80℃并搅拌3小时。将混合物冷却至室温并用乙酸乙酯(200mL)稀释。将混合物用水(200mL)洗涤两次,并将有机层减压浓缩。将MeCN(300mL)和水(60mL)添加至残余物中并将混合物在80℃下悬浮1小时。将悬浮液冷却至室温,过滤固体并减压干燥,得到2-氯-4-((2-硝基苄基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-144a)(15.7g)。ESI-MS m/z[M+H]+421,423。
步骤B:2-((l-((二甲基氨基)甲基)环丙基)甲氧基)-4-((2-硝基苄基)氧基)-5,
8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-144b)
向2-氯-4-((2-硝基苄基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-144a)(1.96g,4.66mmol)、(1-((二甲基氨基)甲基)环丙基)甲醇(1.20g,9.29mmol)和二氯[9,9-二甲基-4,5-双(二苯基膦)呫吨]钯(II)(352mg,0.466mmol)的甲苯(20mL)混合物中添加碳酸铯(4.55g,14.0mmol),并将混合物温热至110℃并搅拌3小时。将混合物冷却至室温并过滤,并将滤液减压浓缩。残余物通过快速硅胶色谱法纯化(0-25%,MeOH梯度在氯仿中)。将获得的残余物通过快速NH-硅胶色谱法(0-80%,己烷中的乙酸乙酯梯度)纯化,得到2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-((2-硝基苄基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-144b)(1.90g)。ESI-MS m/z[M+H]+514。
步骤C:N,N-二甲基-1-(1-(((4-((2-硝基苄基)氧基)-5,6,7,8-四氢吡啶并[3,4-
d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-144c)
向2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-4-((2-硝基苄基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-144b)(2.20g,4.28mmol)的二氯甲烷(20mL)溶液中添加三氟乙酸(10mL)并将混合物在室温下搅拌1小时。减压除去三氟乙酸,并通过快速NH-硅胶色谱法(0-20%,MeOH梯度于乙酸乙酯中)纯化残余物,得到N,N-二甲基-1-(1-(((4-((2-硝基苄基)氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲胺(Int-144c)(1.64g)。ESI-MS m/z[M+H]+414。
步骤D:1-(1-(((7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-4-((2-硝基苄基)氧基)-
5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)-N,N-二甲基甲胺(Int-144d-
1)和Int-144d-2异构体(混合物)
将甲苯(16mL)中的N,N-二甲基-1-(1-(((4-((2-硝基苄基)氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2-基)氧)甲基)环丙基)甲胺(Int-144c)(1.65g,3.99mmol)、1,8-二溴-3-(甲氧基甲氧基)萘(Int-W002)(2.76g,7.98mmol)、二氯[9,9-二甲基-4,5-双(二苯基膦)呫吨]钯(II)(905mg,1.20mmol)和碳酸铯(3.90g,12.0mmol)添加到密封管中。将反应容器抽真空并用氮气回填3次。将混合物在125℃下搅拌14小时,并将混合物冷却至室温。过滤混合物,减压浓缩滤液。残余物通过快速硅胶色谱法纯化(0-25%,MeOH梯度在氯仿中)。获得的残余物通过快速NH-硅胶色谱法纯化(0-8%,己烷中的乙酸乙酯梯度),得到1-(1-(((7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-4-((2-硝基苄基)氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)-N,N-二甲基甲胺(Int-144d-1)作为Int-144d-2异构体的混合物(400mg)。ESI-MS m/z[M+H]+678,680。
步骤E:7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-((二甲基氨基)甲基)环丙
基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144e-1)和异构体(混合物)
(Int-144e-2)
向1-(1-(((7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-4-((2-硝基苄基)氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)-N,N-二甲基甲胺(Int-144d-1)和Int-144d-2异构体(255mg,0.376mmol)和铁(粉末,210mg,3.76mmol)的四氢呋喃(6.0mL)混合物中添加盐酸(0.5M,6.0mL),并将混合物在室温下搅拌2小时。过滤混合物,并将滤液减压浓缩至干。通过快速NH-硅胶色谱法(0-100%,MeOH梯度于乙酸乙酯中)纯化残余物,得到7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144e-1)作为Int-144e-2异构体的混合物(180mg)。ESI-MS m/z[M+H]+543,545。
7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-(吗啉代甲基)环丙基)甲氧基)-5,
6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144f-1)和Int-144f-2异构体(混合物)
Int-144f-1和Int-144f-2异构体的混合物通过使用(1-(吗啉代甲基)环丙基)甲醇与7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144e-1)相似的路径合成。
ESI-MS m/z[M+H]+585,587。
实施例144:(R)-1-(7-(8-溴-3-羟基萘-1-基)-2-((1-((二甲基氨基)甲基)环丙
基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(实施例144)
向7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144e-1)(33mg,0.0607mmol)和N,N-二异丙基乙胺(0.031mL,0.182mmol)的二氯甲烷(1mL)溶液中添加p-甲苯磺酰氯(18mg,0.0911mmol),并将混合物在室温下搅拌3小时。将(R)-哌啶-3-醇(20mg,0.198mmol)添加至混合物中,并将混合物在60℃下搅拌3小时。减压除去溶剂,并将盐酸盐(4M,在1,4-二噁烷中,2mL)加入到残余物中,并将混合物蒸发至干燥。通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化残余物,得到(R)-1-(7-(8-溴-3-羟基萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(实施例144)。ESI-MS m/z[M+H]+582,584。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),7.73-7.68(m,1H),7.56-7.25(m,1H),7.23-7.18(m,1H),6.98-6.95(m,1H),6.91-6.87(m,1H),4.65(s,0.5H),4.42(s,0.5H),4.15-4.00(m,4H),3.62-3.05(m,4H),2.63-2.52(m,2H),2.25-2.19(m,2H),2.16(s,6H),1.95-1.40(m,5H),1.28-1.22(m,1H),1.15(s,1.5H),1.07(s,1.5H),0.58-0.55(m,2H),0.38-0.35(m,2H)。
下表中的化合物通过使用7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144e-1)或7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((1-(吗啉代甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(Int-144f-1)和相应的胺于实施例144相似的途径合成。
表8
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(3R)-3-甲基-1-(7-(6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑-
4-基)-2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(Int-149e)
步骤A:4-羟基-2-(甲硫基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯
(Int-149a)
向1-(叔丁基)4-乙基3-氧代哌啶-1,4-二甲酸酯(10.0g,36.9mmol)和S-甲基异硫脲硫酸盐(20.5g,73.7mmol)在甲醇(200mL)的溶液中加入甲醇钠(9.96g,184mmol)并将混合物在60℃下搅拌4小时。将反应混合物冷却至室温,然后将盐酸(6M,20.0mL,120mmol)添加至混合物中。减压除去甲醇,并将水(150mL)和乙酸乙酯(150mL)加入到残余物中。过滤沉淀物,用乙酸乙酯(30mL)冲洗,干燥,得到4-羟基-2-(甲硫基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-149a)(4.70g)。ESI-MS m/z[M+H]+298。
步骤B:2-(甲硫基)-4-(((三氟甲基)磺酰基)氧基)-5,8-二氢吡啶并[3,4-d]嘧
啶-7(6H)-甲酸叔丁基酯(Int-149b)
在0℃下,向4-羟基-2-(甲硫基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-149a)(2.00g,6.73)和N,N-二异丙基乙胺(3,43mL,20.2mmol)的二氯甲烷(20mL)溶液中加入三氟甲磺酸酐(1.10mL,6.73mmol),并将混合物在室温下搅拌1小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。通过快速硅胶色谱法(0-30%,己烷中的乙酸乙酯梯度)纯化残余物,得到2-(甲硫基)-4-(((三氟甲基)磺酰基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-149b)(1.50g)。ESI-MS m/z[M+H]+430。
步骤C:(R)-4-(3-羟基-3-甲基哌啶-1-基)-2-(甲硫基)-5,8-二氢吡啶并[3,4-d]
嘧啶-7(6H)-甲酸叔丁酯(Int-149c)
向2-(甲硫基)-4-(((三氟甲基)磺酰基)氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-149b)(600mg,1.40mmol)和(R)-3-甲基哌啶-3-醇盐酸盐(233mg,1.54mmol)的DMA(10mL)溶液中加入N,N-二异丙基乙胺(3,43mL,20.2mmol),并将混合物在室温下搅拌3小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将残余物通过快速硅胶色谱法(0-80%,己烷中的乙酸乙酯梯度)纯化为(R)-4-(3-羟基-3-甲基哌啶-1-基)-2-(甲硫基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-149c)(570mg)。ESI-MS m/z[M+H]+395。
步骤D:(R)-3-甲基-1-(2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌
啶-3-醇(lnt-149d)
向(R)-4-(3-羟基-3-甲基哌啶-1-基)-2-(甲硫基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(Int-149c)(570mg,1.44mmol)的二氯甲烷(5mL)溶液中添加三氟乙酸(5mL)并将混合物在室温下搅拌1小时。减压除去三氟乙酸,并通过快速NH-硅胶色谱法(0-20%,乙酸乙酯中的MeOH梯度)纯化残余物,得到(R)-3-甲基-1-(2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(Int-149d)(430mg)。ESI-MS m/z[M+H]+295。
步骤E:(3R)-3-甲基-1-(7-(6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-
吲唑-4-基)-2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(Int-149e)
向(R)-3-甲基-1-(2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(Int-149d)(150mg,0.509mmol)、4-溴-6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑(Int-HHH5)(278mg,0.764mmol)、RuPhos Pd G3(42.6mg,0.0509mmol)的1,4-二噁烷(2.0mL)混合物中添加碳酸铯(498mg,1.53mmol),并将混合物温热至100℃并搅拌2小时。将混合物冷却至室温并过滤,并将滤液减压浓缩。将残余物通过快速硅胶色谱法纯化(10-70%,己烷中的乙酸乙酯梯度),得到(3R)-3-甲基-1-(7-(6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑-4-基)-2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(Int-149e)(175mg)。ESI-MS m/z[M+H]+577。
实施例149:(R)-l-(2-((l-((二甲基氨基)甲基)环丙基)甲氧基)-7-(6-甲基-5-
(三氟甲基)-1H-吲唑-4-基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇
甲酸酯(实施例149)
在0℃下向(3R)-3-甲基-1-(7-(6-甲基-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑-4-基)-2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌啶-3-醇(Int-149e)(15mg,0.0260mmol)的乙酸乙酯(3mL)溶液中加入3-氯过苯甲酸(6.4mg,0.0260mmol),将混合物在0℃下搅拌0.5小时。将水(3mL)加入到混合物中,并将混合物用饱和碳酸氢钠溶液(3mL)洗涤。减压除去溶剂。在0℃下,向粗产物和(1-((二甲基氨基)甲基)环丙基)甲醇(10mg,0.078mmol)在四氢呋喃(1mL)中的溶液中添加叔丁醇钾(1.0M,在THF中,0.039mL)。将混合物在0℃下搅拌0.5小时。将混合物用乙酸乙酯稀释,并将稀释的混合物用水洗涤,并将混合物减压浓缩。将三氟乙酸(0.5mL)加入到残余物中并将混合物在室温下搅拌1小时。减压除去三氟乙酸并通过反相HPLC(MeCN/含有0.1%甲酸的水)纯化残余物,得到(R)-1-(2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-7-(6-甲基-5-(三氟甲基)-1H-吲唑-4-基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇甲酸酯(实施例149)。ESI-MS m/z[M+H]+574。1H NMR(400MHz,DMSO-d6)δ13,4(s,1H),8.32(s,1H),7.36(s,1H),4.60-4.44(m,1H),4.24-4.04(m,4H),3.62-3.20(m,9H),2.90-2.60(m,2H),2.58-2.54(m,3H),2.38-2.10(m,4H),1.90-1.75(m,1H),1.62-1.53(m,4H),1.12(s,3H),0.79-0.37(m,4H)。
下表中的化合物通过使用相应的氨基醇与实施例149相似的途径合成。
表9
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测定
SOS催化核苷酸交换测定的程序
重组KRAS G12C(氨基酸1-169,SEQ ID NO:1)、KRAS G12D(氨基酸1-169,SEQ IDNO:2)、KRAS G12V(氨基酸1-169,SEQ ID NO:3)和SOS1(氨基酸564-1049,SEQ ID NO:4)蛋白在大肠杆菌中表达并通过亲和层析纯化。为了制备每种BODIPY FL GDP结合的KRAS突变蛋白,将50μM KRAS突变蛋白与0.5mM BODIPY FL GDP(Invitrogen,G22360)在上样缓冲液(20mM Tris-HCl(pH 7.5)、50mM NaCl、1mM DTT和2.5mM EDTA)中在冰上孵育1小时。孵育后,添加MgCl2至终浓度10mM,然后在室温下孵育30分钟。让混合物通过NAP-5柱以去除游离核苷酸,并使用纯化的BODIPY FL GDP结合KRAS G12C、G12D和G12V蛋白进行化合物评估。
为了测量化合物对重组KRAS突变体的GDP-GTP交换率的抑制活性,将每种BODIPYFL GDP结合的KRAS突变蛋白(版本1:25nM,版本2:2.5nM)与不同浓度的化合物在反应缓冲液(20mM Tris-HCl(pH 7.5)、100mM NaCl、1mM MgCl2、2mM DTT、0.1%Tween 20)中于25℃下一起孵育1小时。孵育后,加入重组SOS1和GMPPNP(Jena Bioscience GmbH,NU-401)并在室温下孵育30分钟,以在KRAS突变体上进行SOS1依赖性GDP-GTP交换反应。通过计算交换反应前后BODIPY FL的荧光强度比来测量用鸟苷-5’-[(β,γ)-亚氨基]三磷酸四锂盐(GMPPNP)替换BODIPY FL GDP。通过将没有测试化合物(DMSO对照)的反应的荧光比率和没有SOS1和GMPPNP的反应的荧光比率分别设定为0%和100%抑制来计算抑制%。使用4-参数逻辑模型分析剂量反应曲线以计算IC50值。表A显示了结果。
表A:
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细胞抗增殖测定程序
将含有纯合KRAS-G12V激活突变的SW620细胞(CCL-227TM)和含有纯合KRAS-G12C激活突变的MIA PaCa-2细胞(由Sumitomo Dainippon Pharma Co.,Ltd.提供)在T175烧瓶中的生长培养基(含有10%胎牛血清(HyClone,SH30910.03)的RPMI培养基1640(Fujifilm Wako Pure Chemical Corporation,187-02705)中培养。胰蛋白酶/EDTA(Nacalai Tesque,32777-44)消化后在生长培养基中收获细胞,并接种到/>384-孔U底微孔板(Sumitomo Bakelite Co.,Ltd.,MS-9384W)中,每个密度为250个细胞/孔,并在37℃、5%CO2下孵育过夜。
用DMSO稀释测试化合物,得到最终浓度的500倍的浓度。将所得测试化合物的DMSO溶液用用于悬浮细胞的生长培养基稀释并添加到细胞培养板的每个孔中,得到0.2%的DMSO终浓度,然后在37℃、5%CO2下孵育持续3天。
向所有细胞添加CellTiter-3D试剂(Promega,G9683)并混合10分钟。混合后三十分钟,在EnVision板读数器(PerkinElmer)上测量发光。使用4-参数逻辑模型分析剂量反应曲线,以计算IC50值。表B显示了结果。
表B:
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序列
SEQ ID NO:1-重组KRAS G12C
SEQ ID NO:2-重组KRAS G12D
SEQ ID NO:3-重组KRAS G12V
SEQ ID NO:4-SOS1
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Claims (27)
1.一种式(I)的化合物或其药学上可接受的盐
其中
X选自由以下组成的组:
(i)6至9元单环的或稠合双环的或桥联双环的杂环烷基,其中所述杂环烷基是饱和的并含有1至2个选自由N、S和O组成的组的杂原子;
(ii)8至10元螺杂环烷基,其中所述螺杂环烷基是饱和的并含有1至2个选自由N和O组成的组的杂原子;
(iii)和
其中,当X是(i)或(ii)时,X未被取代或独立地被1至4个Rx取代基取代,所述Rx取代基选自由以下组成的组:卤素、羟基、C1-C6烷基、C1-C3羟烷基、C1-C6氟烷基、羧基、氨基甲酰基、C1-C3羧烷基、氧代、氰基、氰基甲基、氨基、吡唑基、噁二唑基、-NHC(O)C1-C3烷氧基C1-C3烷基、-NHC(O)C1-C3烷氧基C6-C10芳基、C1-C3烷氧基、甲氧基(C1-C3)烷基、氨基(C1-C3)烷基、C1-C3烷基氨基(C1-C3)烷基、C1-C3二烷基氨基、C1-C3二烷基氨基(C1-C3)烷基、和NHC(O)C5-C10杂芳基,其中杂芳基可被C1-C3烷基取代;
环Y是9至10元双环环系,其中该环系是部分不饱和的或芳香族的,并且其中环Y含有0至2个氮杂原子;
其中环Y未被取代或独立地被1至4个Ry取代基取代,所述Ry取代基选自由以下组成的组:卤素、羟基、氨基、C1-C3烷基、C2-C3炔基和C1-C3氟烷基;
Z选自由以下组成的组:
(i)5至8元单环的或双环的杂环烷基,其中所述杂环烷基是饱和的并含有1个氮杂原子,并且其中所述杂环烷基未被取代或被1个选自由以下组成的组的取代基RZHC取代:卤素、C1-C3烷基和亚甲基(C1-C3烷基)(C1-C3烷基)氨基甲酸酯;
(ii)其中M选自由以下组成的组:羟基、C1-C3二烷基氨基和C1-C4烷基氨基,并且其中环丙基基团未被取代或被至多2个卤素基团取代;
(iii)其中P是5至8元单环的或稠合双环的或桥联双环的杂环烷基,其中所述杂环烷基是饱和的并含有1至2个选自由N和O组成的组的杂原子,其中所述杂环烷基未被取代或被1个选自由以下组成的组的Rp取代基取代:卤素、羟基、C1-C3羟烷基、C1-C3氰基烷基、氨基甲酰基、C1-C3烷氧基、氰基、-NHC(O)C1-C3烷基和噁二唑基,并且其中环丙基基团未被取代或被至多2个卤素基团取代;
下标m是0或1;以及
下标n是1或2。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中环Y是
3.如权利要求2所述的化合物或其药学上可接受的盐,其中环Y是
4.如权利要求1所述的化合物或其药学上可接受的盐,其中X是
并且其中X未被取代或独立地被1至4个Rx取代基取代。
5.如权利要求4所述的化合物或其药学上可接受的盐,其中X被1至4个选自由以下组成的组的Rx取代基取代:卤素、羟基、C1-C6烷基、C1-C3羟烷基、C1-C6氟烷基、羧基、氨基甲酰基、C1-C3羧烷基、氧代、氰基、氰基甲基、氨基、吡唑基、噁二唑基、-NHC(O)C1-C3烷氧基C1-C3烷基、-NHC(O)C1-C3烷氧基C6-C10芳基和NHC(O)C5-C10杂芳基,其中杂芳基可被C1-C3烷基取代。
6.如权利要求5所述的化合物或其药学上可接受的盐,其中X是
7.如权利要求1所述的化合物或其药学上可接受的盐,其中X是其中下标p是0、1或2。
8.如权利要求1所述的化合物或其药学上可接受的盐,
其中X是
9.如权利要求1所述的化合物或其药学上可接受的盐,其中Z是
10.如权利要求1所述的化合物或其药学上可接受的盐,其中下标m是1。
11.如权利要求1所述的化合物或其药学上可接受的盐,其中下标n是1。
12.如权利要求1所述的化合物或其药学上可接受的盐,其中下标n是2。
13.如权利要求1所述的化合物,选自实施例1-151,或其药学上可接受的盐。
14.一种药物组合物,其包含如权利要求1-13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剂。
15.一种药物组合物,其包含如权利要求1-13中任一项所述的化合物或其药学上可接受的盐、另外的抗癌剂和药学上可接受的载剂。
16.一种抑制KRAS-G12D蛋白的方法,所述方法包括使KRAS-G12D蛋白与如权利要求1-13中任一项所述的化合物或其药学上可接受的盐接触以抑制所述KRAS-G12D蛋白的活性。
17.一种抑制KRAS-G12C蛋白的方法,所述方法包括使KRAS-G12C蛋白与如权利要求1-13中任一项所述的化合物或其药学上可接受的盐接触以抑制所述KRAS-G12C蛋白的活性。
18.一种抑制KRAS-G12V蛋白的方法,所述方法包括使KRAS-G12V蛋白与如权利要求1-13中任一项所述的化合物或其药学上可接受的盐接触以抑制所述KRAS-G12V蛋白的活性。
19.一种治疗癌症的方法,所述方法包括向需要此类治疗的受试者施用治疗有效量的如权利要求1-13中任一项所述的化合物或其药学上可接受的盐。
20.如权利要求19所述的方法,其进一步包括向所述受试者施用另外的活性剂。
21.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其用于在疗法中使用,或者如权利要求1-13中任一项所述的化合物或其药学上可接受的盐在疗法中的用途。
22.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其用于在治疗癌症中使用,或者如权利要求1-13中任一项所述的化合物或其药学上可接受的盐用于治疗癌症的用途。
23.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其用于制备用于治疗癌症的药物,或者如权利要求1-13中任一项所述的化合物或其药学上可接受的盐用于制备用于治疗癌症的药物的用途。
24.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐和另外的抗癌剂,其用于在治疗癌症中使用,或如权利要求1-13中任一项所述的化合物或其药学上可接受的盐和另外的抗癌剂用于治疗癌症的用途。
25.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐和另外的抗癌剂,其用于制备用于治疗癌症的药物,或如权利要求1-13中任一项所述的化合物或其药学上可接受的盐和另外的抗癌剂用于制备用于治疗癌症的药物的用途。
26.包含如权利要求1-13中任一项所述的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于治疗癌症,或者包含如权利要求1-13中任一项所述的化合物或其药学上可接受的盐的药物组合物用于治疗癌症的用途。
27.包含如权利要求1-13中任一项所述的化合物或其药学上可接受的盐和另外的抗癌剂的药物组合物,所述药物组合物用于治疗癌症,或者包含如权利要求1-13中任一项所述的化合物或其药学上可接受的盐和另外的抗癌剂的药物组合物用于治疗癌症的用途。
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