CN113754653A - 一种kras g12c抑制剂化合物及其用途 - Google Patents
一种kras g12c抑制剂化合物及其用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明提供了一种KRAS G12C抑制剂化合物及其合成和用途,具体地,本发明提供了一种如式(I)所示的化合物,及其光学异构体、氘代物、水合物、溶剂合物或其药学上可接受的盐。所述的化合物可以作为KRAS G12C抑制剂,用于治疗与KRAS G12C活性或表达量相关的疾病。
Description
技术领域
本发明涉及一类作为KRas G12C抑制剂化合物,及其异构体、溶剂合物及该化合物的盐类和以该化合物或其盐类为活性成分的药物,及其在治疗和/或预防KRas G12C活性或表达量相关疾病,如治疗肿瘤的药物中的用途。
背景技术
Kirsten Rat肉瘤2病毒癌基因同源物(KRas)是一种小的GTP酶,是Ras癌基因家族的成员。KRas在非活性状态(GDP结合)和活性状态(GTP结合)之间转变提供分子开关循环,以将从多个酪氨酸激酶接收的上游细胞信号转导至下游效应子,从而调节多种生理/病理过程,包括细胞增殖。
KRas在恶性肿瘤中的众所周知的作用以及在各种肿瘤类型中KRas的这些频繁突变的发现使KRas成为制药行业用于癌症治疗的具有高度吸引力的靶标。尽管开发用于治疗癌症的KRas抑制剂的研究已有三十年的历史,但没有任何KRas抑制剂表现出足够的安全性和/或功效以获得监管部门的批准
抑制KRas活性的化合物在研究领域中仍然是非常活跃,例如包括破坏诸如鸟嘌呤核苷酸交换因子等效应子的化合物以及靶标KRas G12C的化合物。显然,仍然继续有兴趣和努力来开发KRas的抑制剂,特别是活化KRas突变体的抑制剂,包括KRas G12C。
因此,开发直接靶向KRas G12C突变的新型小分子抑制剂在临床上仍然具有未满足的临床需求。通过广泛的研究,本发明的化合物和/或药物组合物对KRas G12C具有在体外具有强烈的抑制作用,有希望在临床上使因为KRas G12C突变的病人获益,因此具有巨大的临床价值。
发明内容
本发明的目的是提供一种直接靶向KRas G12C突变的新型小分子抑制剂。
本发明的第一方面,提供了一种如下式(I)所示的化合物,及其光学异构体、水合物、溶剂合物、氘代化物或其药学上可接受的盐:
其中,
A为4-12元饱和或部分饱和的碳环或杂环(包括单环、桥连环或螺环型环);其中,所述的杂环为包括1、2、3或4个杂原子,且所述的杂原子各自独立地选自O、N或S(O)p;
R2选自下组:-C(O)R7;其中,所述的R7选自下组:取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基;
各个X各自独立地选自取代或未取代的选自下组的基团:CH2、NR1、O、S或S(O)2,前提是各个X形成化学上稳定的结构;
R1选自下组:卤素、取代或未取代的C1-C6烷基;
所述的B环为取代或未取代的4-8元杂环基(包括饱和或不饱和的单环、桥连环或螺环型环);
R4具有如下式所示的结构:
所述的R5和R6各自独立地为选自下组的基团:氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基;
且R3和R6不同时为氢;
n、m各自独立地选自下组:1、2、3或4;
p、q、u各自独立地选自下组:0、1、2或3;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素,C1-C6烷基,卤代的C1-C6烷基,C1-C6烷氧基,卤代的C1-C6烷氧基,C3-C8环烷基,卤代的C3-C8环烷基,氧代,-CN,羟基,氨基,羧基,C2-C6酰胺,磺酰胺,砜基;未取代或被一个或多个取代基取代的选自下组的基团:C6-C10芳基,卤代的C6-C10芳基,具有1-3个选自N、S和O的杂原子的5-10元杂芳基,卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基,且所述的取代基选自下组:卤素,C1-C6烷基、C1-C6烷氧基、=O。
在另一优选例中,所述的式(I)化合物具有如下式(II)所示的结构:
其中,
R4a和R4b各自独立地选自下组:卤素、氨基、C2-C6酰胺。
在另一优选例中,所述的R3选自下组:H,或如下式所示的基团:
在另一优选例中,所述的R3选自下组:H,或如下式所示的基团:
在另一优选例中,所述的R2为取代或未取代的-C(O)-CH=CH2或-C(O)-CF=CH2。
在另一优选例中,所述的A环为取代或未取代的5-7元含氮饱和环。
在另一优选例中,所述的式(III)化合物具有如下式所示的结构:
在另一优选例中,所述的化合物选自下组:
本发明的第二方面,提供了一种药物组合物,其含有药学上可接受的载体和本发明第一方面所述的化合物,异构体、溶剂合物或其药学上可接受的盐或水合物。
在另一优选例中,所述的药物组合物用于治疗、缓解或预防与KRas活性或表达量相关的疾病或病症。
在另一优选例中,所述的疾病或病症为癌症。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物,或其药学上可接受的盐或水合物的用途,其用于制备治疗、缓解或预防与KRas活性或表达量相关的疾病或病症的药物组合物;较佳地,所述的疾病或病症为癌症。
在另一优选例中,所述的癌症选自下组:心脏癌、肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤、支气管癌、肺癌、支气管腺瘤、肉瘤、淋巴瘤、软骨性错构瘤、间皮瘤、食道癌、胃癌、胰腺癌、小肠癌、大肠癌、结直肠癌、肾癌、膀胱和尿道癌、前列腺癌、睾丸癌、绒毛癌、肉瘤、肝癌、胆管癌、血管肉瘤、血管瘤胆囊癌、壶腹癌、胆管癌、成骨肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤、多发性骨髓瘤、恶性巨细胞瘤软骨瘤、骨软骨瘤和巨细胞瘤、脑瘤、生殖细胞瘤、子宫癌、阴道癌。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,意外地发现了一种如式(I)所示的化合物。所述的化合物表现出优异的KRas抑制活性,可用于治疗由KRas活性或表达量介导的疾病。所述的化合物对KRas G12C具有出乎意料的活性,可用于与KRas G12C的活性或表达量相关的疾病的治疗、缓解或预防。基于上述发现,发明人完成了本发明。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C4烷基表示具有1-4个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环、并环或螺环形式。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“水合物”是指本发明化合物与水进行配位形成的配合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、具体实施方式与其他化学合成方法的结合所形成的实施方式、以及本领域技术人员所熟知的等同替换方式,优选的实施方式包括但不限于本申请的实施例。
本申请所使用的溶剂可以经市售获得。本申请采用的缩略词如:aq代表水溶液;HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐;EDC代表N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐;m-CPBA代表3-氯过氧苯甲酸;eq代表当量、等量;CDI代表羰基二咪唑;DCM代表二氯甲烷;PE代表石油醚;DIAD代表偶氮二羧酸二异丙酯;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;Cbz代表苄氧羰基,一种氨基保护基;Boc代表叔丁基氧羰基,一种氨基保护基;HOAc代表乙酸;NaCNBH3代表氰基硼氢化钠;r.t.代表室温;THF代表四氢呋喃;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺;Boc2O代表二-叔丁基二碳酸酯;LDA代表二异丙基氨基锂。
药物组合物和施用方法
由于本发明化合物具有优异的作为KRas G12C抑制剂的活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)KRas G12C活性或表达量相关疾病或病症,例如癌症等。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学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。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有1-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”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和本发明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。药学上可以接受的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。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内、皮下或外用)。
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。
本发明化合物可以单独给药,或者与其他药学上可接受的治疗剂联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗细胞因子和/或干扰素介导的疾病。
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1~2000mg,优选1~500mg。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。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例
实施例1
第一步
将苯甲酰基异硫氰酸酯(22.00g,134.96mmol)溶解在四氢呋喃(300mL)中,氮气置换后,在冰浴下缓慢加入化合物1a(20.00g,141.69mmol),反应体系在室温下搅拌0.5小时。向反应体系中加入5N的氢氧化钠溶液(33mL,161.95mmol)和水(45mL),反应体系升温至80℃下搅拌3.5小时。加入水(300mL)和乙酸乙酯(300mL),分液,水相用乙酸乙酯(200mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到化合物1b(26.40g),收率:93%。
MS-ESI计算值[M+1]+201,实测值:201。
第二步
将化合物1b(2.00g,9.99mmol)溶解在氯仿(25mL)中,氮气置换后,冰浴下缓慢加入液溴(0.53mL,10.20mmol),冰浴下搅拌0.5小时,然后反应体系在70℃搅拌2小时。将反应液冷却到-20℃,有固体析出,过滤,固体用正己烷(20mL)洗涤得到粗品1c(2.70g)。
MS-ESI计算值[M+1]+199,实测值:199。
第三步
将粗品1c(2.70g,9.99mmol)溶解在二氯甲烷(50mL)中,氮气置换三次后,冰浴下缓慢加入三溴化硼(6.10mL,12.10mmol),室温搅拌过夜后,将反应液冷却到0℃,缓慢加入甲醇(10mL)淬灭反应后,加入5N的氢氧化钠溶液(5mL,25.00mmol)中和反应,搅拌10分钟,过滤,固体用冷的二氯甲烷(20mL)洗涤得到粗品1d(1.70g)。
MS-ESI计算值[M+1]+185,实测值:185。
第四步
将粗品1d(1.70g,9.99mmol)溶解在1,4-二氧六环(40mL)中,然后冰水浴下加入三乙胺(1.96g,19.40mmol),4-二甲氨基吡啶(56mg,0.46mmol),缓慢加入二碳酸二叔丁酯(4.64g,21.30mmol),氮气置换后,室温搅拌过夜后,加入水(30mL)和乙酸乙酯(30mL),分液,水相用乙酸乙酯(20mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到残余物,将残余物溶解在甲醇(20mL)中,然后加入甲醇钠(2.8mL,13.86mmol),氮气置换后,室温搅拌过夜后,加入水(30mL)和乙酸乙酯(30mL),分液,水相用乙酸乙酯(20mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到残余物,残余物经柱层析(乙酸乙酯:石油醚=0-100%)得到化合物1e(1.50g),三步收率:53%。
MS-ESI计算值[M+1]+285,实测值:285。
第五步
将1e(1.50g,5.28mmol)溶解在二氯甲烷(20mL)中,然后冰浴下加入吡啶(0.86mL,10.56mmol),氮气置换三次后,缓慢加入三氟甲磺酸酐(1.10mL,6.34mmol),在0℃下搅拌1.5小时后,减压浓缩得到残余物,残余物经柱层析(乙酸乙酯:石油醚=0-100%)得到化合物1f(1.30g)。收率:59%。MS-ESI计算值[M+1]+417,实测值:417。
第六步
将1f(2.00g,4.81mmol)溶解在1,4-二氧六环(15mL)中,然后加入双联硼频那醇脂(244mg,9.62mmol),乙酸钾(142mg,14.42mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(352mg,0.48mmol),通氮气三分钟后,在110℃下微波反应1小时后,加入水(30mL)和乙酸乙酯(30mL),分液,水相用乙酸乙酯(20mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到残余物,残余物经柱层析(甲醇:二氯甲烷=0-100%)得到化合物1g(481mg),收率:32%。
MS-ESI计算值[M+1]+313,实测值:313。
第七步
将1h(1.00g,3.38mmol),1i(628mg,3.38mmol)和三乙胺(1.71g,16.9mmol)溶解在二氯甲烷中,氮气置换三次后,在35℃下搅拌4h后,加入水(30mL)和乙酸乙酯(30mL),分液,水相用乙酸乙酯(20mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到残余物,残余物经柱层析(乙酸乙酯:石油醚=0-100%)纯化得到化合物1j(1.30g),收率:86%。MS-ESI计算值[M+1]+518,实测值:518。
第八步
将1j(650mg,1.33mmol),1g(500mg,1.59mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(109mg,0.13mmol)和磷酸钾(432mg,2.00mmol)溶解在水(3mL)和二氧六环(9mL)混合溶剂中,氮气置换,在90℃下搅拌16小时后,加入水(30mL)和乙酸乙酯(30mL),分液,水相用乙酸乙酯(20mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到残余物,残余物经柱层析(乙酸乙酯:石油醚=0-100%)得到化合物1k(300mg),收率:32%。
MS-ESI计算值[M+1]+706,实测值:706。
第九步
将1k(300mg,0.43mmol)溶解四氢呋喃(6mL)中,加入氢氧化钯(50mg),氢气置换,在室温下搅拌2h后,直接过滤减压浓缩得到化合物1l(200mg),收率:82%。
MS-ESI计算值[M+1]+572,实测值:572。
第十步
将1l(200mg,0.35mmol)溶解在三氟乙酸(2mL)和二氯甲烷(6mL)的混合溶液中,氮气置换,在室温下搅拌16小时后,直接减压浓缩得到化合物1m(160mg),收率:96%。
MS-ESI计算值[M+1]+472,实测值:472。
第十一步
将1m(100mg,0.21mmol)和2-氟丙烯酸(21mg,0.23mmol)溶解在N,N-二甲基甲酰胺(3mL)中,再加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(121mg,0.32mmol),N,N-二异丙基乙胺(83mg,0.64mmol),氮气置换,在室温下搅拌0.5小时后,加入水(30mL)和乙酸乙酯(30mL),分液,水相用乙酸乙酯(20mL x 3)萃取,有机相合并后,无水硫酸钠干燥,过滤,减压浓缩得到残余物,残余物经柱层析(甲醇:二氯甲烷=0-100%)得到化合物1(30mg),收率:26%。
MS-ESI计算值[M+1]+544,实测值:544。
1H NMR(400MHz,CD3OD)δ8.67(s,1H),8.03(s,1H),7.26-7.24(m,1H),7.02-6.97(m,1H),5.39-5.25(m,2H),4.89(d,J=38.5Hz,2H),4.58-4.32(m,2H),4.17(brs,1H),3.78-3.58(m,3H),3.33(s,1H),3.22-2.95(m,2H).
生物活性测试
收取处于对数生长期的Ba/F3 KRAS-G12C稳转细胞株,调整细胞浓度并添加90μL细胞悬液至96孔板中,置于细胞培养箱内培养过夜;配制10倍浓度的药物溶液,最高浓度为100μM,9个浓度,3倍稀释,在接种有细胞的96孔板中每孔加入10μL药物溶液或培养液对照,每个药物浓度设置三个复孔;将已加药的96孔板中的细胞置于细胞培养箱内继续培养72小时,将细胞板平衡至室温后,向各孔内加入100μL CellTiter-GloTM检测试剂,在定轨摇床上振荡5分钟裂解细胞、室温放置20分钟以稳定冷光信号后,采用SpectraMax多标记微孔板检测仪读取冷光值。使用GraphPad Prism 7.0软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC50值。测试结果如下表。
实施例 | IC<sub>50</sub>(nM) |
实施例1 | A |
注:A代表A<=100nM;B代表100nM<B<=1000nM;C代表C>=1000nM。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如下式(I)所示的化合物,及其光学异构体、水合物、溶剂合物、氘代化物或其药学上可接受的盐:
其中,
A为4-12元饱和或部分饱和的碳环或杂环(包括单环、桥连环或螺环型环);其中,所述的杂环为包括1、2、3或4个杂原子,且所述的杂原子各自独立地选自O、N或S(O)p;
R2选自下组:-C(O)R7;其中,所述的R7选自下组:取代或未取代的C2-C6烯基,取代或未取代的C2-C6炔基;
各个X各自独立地选自取代或未取代的选自下组的基团:CH2、NR1、O、S或S(O)2,前提是各个X形成化学上稳定的结构;
R1选自下组:卤素、取代或未取代的C1-C6烷基;
所述的B环为取代或未取代的4-8元杂环基(包括饱和或不饱和的单环、桥连环或螺环型环);
R4具有如下式所示的结构:
所述的R5和R6各自独立地为选自下组的基团:氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基;
且R3和R6不同时为氢;
n、m各自独立地选自下组:1、2、3或4;
p、q、u各自独立地选自下组:0、1、2或3;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素,C1-C6烷基,卤代的C1-C6烷基,C1-C6烷氧基,卤代的C1-C6烷氧基,C3-C8环烷基,卤代的C3-C8环烷基,氧代,-CN,羟基,氨基,羧基,C2-C6酰胺,磺酰胺,砜基;未取代或被一个或多个取代基取代的选自下组的基团:C6-C10芳基,卤代的C6-C10芳基,具有1-3个选自N、S和O的杂原子的5-10元杂芳基,卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基,且所述的取代基选自下组:卤素,C1-C6烷基、C1-C6烷氧基、=O。
4.如权利要求1所述的化合物,其特征在于,所述的R2为取代或未取代的-C(O)-CH=CH2或-C(O)-CF=CH2。
5.如权利要求1所述的化合物,其特征在于,所述的A环为取代或未取代的5-7元含氮饱和环。
8.一种药物组合物,其含有药学上可接受的载体和本发明第一方面所述的化合物,异构体、溶剂合物或其药学上可接受的盐或水合物。
在另一优选例中,所述的药物组合物用于治疗、缓解或预防与KRas活性或表达量相关的疾病或病症。
在另一优选例中,所述的疾病或病症为癌症。
9.如权利要求1-7任一所述的化合物,或其药学上可接受的盐或水合物的用途,其用于制备治疗、缓解或预防与KRas活性或表达量相关的疾病或病症的药物组合物;较佳地,所述的疾病或病症为癌症。
10.如权利要求9所述的用途,其特征在于,所述的癌症选自下组:心脏癌、肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤、支气管癌、肺癌、支气管腺瘤、肉瘤、淋巴瘤、软骨性错构瘤、间皮瘤、食道癌、胃癌、胰腺癌、小肠癌、大肠癌、结直肠癌、肾癌、膀胱和尿道癌、前列腺癌、睾丸癌、绒毛癌、肉瘤、肝癌、胆管癌、血管肉瘤、血管瘤胆囊癌、壶腹癌、胆管癌、成骨肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤、多发性骨髓瘤、恶性巨细胞瘤软骨瘤、骨软骨瘤和巨细胞瘤、脑瘤、生殖细胞瘤、子宫癌、阴道癌。
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