CN117642408A - 含硒杂环类化合物及其药用组合物和应用 - Google Patents
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
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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
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Abstract
本发明提供了一种具有式(I)所示结构的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物。该类化合物可作为KRAS G12D抑制剂,用于治疗高增殖性疾病,例如癌症。
Description
本发明涉及化学医药技术领域,具体涉及一种含硒杂环类化合物及其药用组合物和应用。
KRAS基因的全名叫kirsten rat sarcoma viral oncogene,翻译成中文是“Kirsten大鼠肉瘤病毒癌基因同源物”。KARS基因编码的蛋白是一种小GTP酶(smallGTPASe),它属于RAS超蛋白家族,它们首先是在由强致癌性病毒引起的大鼠肉瘤的研究中被鉴定出来的。RAS基因家族与人类肿瘤相关的基因有三种—H-RAS、K-RAS和N-RAS,分别定位在11、12和1号染色体上。由于RAS在许多重要细胞信号网络的轴上处于中心位置,因此它们与许多癌症标志有关,研究表明RAS是人类癌症中最常出现突变的致癌基因,目前已经在所有人类肿瘤的大约1/5中发现了突变引起的RAS蛋白激活。在RAS基因中,K-RAS对人类癌症影响最大,它好像分子开关:当正常时能控制调控细胞生长的路径;发生异常时,则导致细胞持续生长,并阻止细胞自我毁灭。它参与细胞内的信号传递,当K-RAS基因突变时,该基因永久活化,不能产生正常的RAS蛋白,使细胞内信号传导紊乱,细胞增殖失控而癌变。
研究表明,KRAS基因突变占RAS基因突变总数的85%(NRAS(12%)次之,HRAS(3%)最少)。在人类癌症中,KRAS基因突变出现在接近90%的胰腺癌中,30-40%的结肠癌中,17%的子宫内膜癌中,15-20%的肺癌中(大多为NSCLC)。它也会在胆管癌、宫颈癌、膀胱癌、肝癌和乳腺癌等癌症类型中出现。也就是说,在上述多种癌症中,有高比例的KRAS基因突变。
最常见的KRAS突变常见于P-环中的残基G12和G13以及残基Q61处。其中,KRAS G12D突变存在于25.0%的胰腺导管腺癌患者、13.3%的结肠直肠癌患者和10.1%的直肠癌患者中。所有非小细胞肺癌患者的4.1%和所有小细胞肺癌患者的1.7%存在KRAS G12D突变,因此开发KRAS G12D抑制剂将对多种癌症的治疗提供新的方案。
KRAS在恶性肿瘤中的作用众所周知,KRAS在各种肿瘤类型中频繁突变的发现使KRAS成为制药行业治疗癌症的一个非常有吸引力的靶点。尽管三十年来化学家们进行了大规模发现探索,但是目前尚无KRAS抑制剂上市。开发KRAS抑制剂的兴趣和努力仍在继续。特别是激活KRAS突变体的抑制剂,尤其是KRAS G12D。
因此,有必要开发新的KRAS G12D抑制剂,以治疗由KRAS G12D介导的癌症。
发明内容
针对上述问题,本发明提供了一类含硒杂环类化合物或其药学上可接受的盐或其立体异构体,该类化合物可作为KRAS G12D抑制剂,用于治疗高增殖性疾病,例如癌症。
具体技术方案包括如下。
具有式(I)所示结构的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物:
其中:
T1选自:N、-CR4;R4选自:氢、卤素、氰基、氨基、羟基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C2-C8炔基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的3-8元杂环基、R5取代或者未取代的5-10元杂芳基、-C(=O)R、-S(=O)R、-S(=O)2R;各R5分别独立地选自:氢、氘、卤素、羟基、羧基、酰胺基、氰基、氨基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C2-C3炔基;各R分别独立地选自:H、OH、氨基、C1-C6烷基胺基、二(C1-C6烷基)胺基、C1-C6烷基、C1-C6烷氧基;
T2、T3、T4分别独立地选自:N、-CR6;各R6分别独立地选自:氢、氘、卤素、氰基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基、R5取代或者未取代的C3-C8环烷基;
T5、T6、T7分别独立地选自:N、NR7、羰基、-CR8,并且含有T5、T6和T7的环A和与其相并的含氮杂环共同形成杂芳基或者杂芳酮基;各R7分别独立地选自:R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C3-C8环烷基;各R8分别独立地选自:氢、卤素、氰基、醛基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基、R5取代或者未取代的C2-C8烯基、R5取代或者未取代的C2-C8炔基;
T8选自:N、-CR9;R9选自:氢、卤素、氰基、硝基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C2-C8炔基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基;
R1选自:-OR10、-SR10、-NHR10、-CHO、-S(=O)R11、-S(=O)2R11、-COOR11、-CONHR11、R5取代或者未取代的C1-C8烷基、各R10分别独立地选自:H、C1-C8烷基、各R11分别独立地选自:氢、C1-C8烷基;各R12分别独立地选自:R5取代或者未取代的C1-C20烷基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的5-10元杂芳基;
R2选自:取代或者未取代的3-10元含氮杂环基;
R3选自:H、R5取代或者未取代的C1-C10烷基、R5取代或者未取代的5-10元杂芳基、C1-C6烷基胺基、二(C1-C6烷基)胺基、R5取代或者未取代的3-10元含氮杂环基、-L-R13;L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-CF2-、-C=C-、-C≡C-、-Se-;R13选自:氢、卤素、氨基、R5取代或者未取代的C1-C10烷基、R5取代或者未取代的C3-C10环烷基、取代或者未取代的3-10元含氮杂环基、-Q-R13’;Q选自:R5取代或者未取代的C1-C6亚烷基、R13’选自:取代或者未取代的3-10元含氮杂环基、R5取代或者未取代的5-10元杂芳基、C1-C6烷基胺基、二(C1-C6烷基)胺基、氨基;各m分别独立地为:0、1、2;p为:1、2、3、4。
在其中一些实施例中,T1选自:N、-CR4;R4选自:氢、卤素、氰基、氨基、羟基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C1-C3烷氧基、R5取代或者未取代的C1-C3烷基胺基、R5取代或者未取代的C1-C3烷硫基、R5取代或者未取代的C1-C3烷硒基、R5取代或者未取代的C3-C6环烷基、R5取代或者未取代的C2-C3炔基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的3-6元杂环基、R5取代或者未取代的5-6元杂芳基、-C(=O)R、-S(=O)R、-S(=O)2R;各R5分别独立地选自:氢、氘、卤素、羟基、羧基、酰胺基、氰基、氨基、C1-C3烷基、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C2-C3炔基;各R分别独立地选自:H、OH、氨基、C1-C3烷基胺基、二(C1-C3烷基)胺基、二(C1-C3烷基)胺基、C1-C3烷基、C1-C3烷氧基。
在其中一些实施例中,R4选自:氢、卤素、氰基、氨基、羟基、甲氧基、三氟甲氧基、三氟甲基、二氟甲基、甲基、乙基、丙基、异丙基、乙炔基、丙炔基、羟基取代的丙炔基、二氟甲基取代的丙炔基、氰基取代的丙炔基、氨基取代的丙炔基、三氟甲基取代的乙炔基、环丙基、羟基取代的环丙基、卤素取代的环丙基、1-甲基咪唑基、-C(=O)R;各R分别独立地选自:H、OH、氨基、甲胺基、二甲胺基、乙胺基、二乙胺基、甲氧基、乙氧基。
在其中一些实施例中,T2、T3、T4分别独立地选自:N、-CR6;各R6分别独立地选自:氢、氘、卤素、氰基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C1-C3烷基胺基、R5取代或者未取代的C1-C3烷氧基、R5取代或者未取代的C1-C3烷硫基、R5取代或者未取代的C1-C3烷硒基、R5取代或者未取代的C3-C6环烷基。
在其中一些实施例中,各R6分别独立地选自:氢、氘、卤素、氰基、甲基、异丙基、三氟甲基、二氟甲基、环丙基、甲氧基、甲硫基、甲硒基、三氟甲氧基、乙氧基、异丙氧基。
在其中一些实施例中,所述含硒杂环类化合物具有如下式(II)或者式(III)所示结构:
其中,T7选自:N、-CR8。
在其中一些实施例中,各R7分别独立地选自:R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C6环烷基;各R8分别独立地选自:氢、卤素、氰基、醛基、R5取代或者未取代的C1-C3烷基胺基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C6环烷基、R5取代或者未取代的C1-C3烷氧基、R5取代或者未取代的C1-C3烷硫基、R5取代或者未取代的C1-C3烷硒基、R5取代或者未取代的C2-C3烯基、R5取代或者未取代的炔基。
在其中一些实施例中,各R7分别独立地选自:甲基、乙基、丙基、异丙基、三氟乙基、三氟甲基、环丙基、环丁基、环戊基、环己基;各R8分别独立地选自:氢、卤素、氰基、醛基、甲基、三氟甲基、二氟甲基、甲氧基、乙氧基、甲硫基、异丙氧基、三氟甲氧基、三氟乙氧基、环丙基、氨基、乙烯基、氟代环丙基、乙炔基。
在其中一些实施例中,T8选自:N、-CR9;R9选自:氢、卤素、氰基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C6环烷基。
在其中一些实施例中,R9选自:氢、氰基。
在其中一些实施例中,所述含硒杂环类化合物具有如下式(IV)所示结构:
在其中一些实施例中,R1选自:-OR10、-SR10、-NHR10、-CHO、-S(=O)R11、-S(=O)2R11、-COOR11、-CONHR11、R5取代或者未取代的C1-C3烷基、各R10分别独立地选自:H、C1-C3烷基、各R11分别独立地选自:氢、C1-C3烷基;各R12分别独立地选自:R5取代或者未取代的C1-C10烷基、R5取代或者未取代的苯基、R5取代或者未取代的5-6元杂芳基。
在其中一些实施例中,R1选自:-OR10、-CHO、-COOH、-COOCH3、-CONH2、-CONHCH3、-CH3、-CF2H、-CF3、-OCH3、-SCH3、-NHR10、各R10分别独立地选自:H、甲基、各R11分别独立地选自:氢、甲基;各R12分别独立地选自:甲基、乙基、正丙基、异丙基、正丁基、叔丁基、戊基、苯基。
在其中一些实施例中,其特征在于,R2选自:
其中,各X分别独立地选自:N、CR16;R16选自:H、卤素、-CN、-OH、-COOH、C1-C8烷基;
n选自:0、1、2、3;
各R14分别独立地选自:氢、R5取代或者未取代的C1-C8烷基、氰基;
各R15分别独立地选自:氢、C1-C8烷基、R11选自:氢、C1-C8烷基;各R12分别独立地选自:R5取代或者未取代的C1-C20烷基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的5-10元杂芳基。
在其中一些实施例中,各X分别独立地选自:N、CR16;R16选自:H、卤素、-CN、-OH、-COOH、C1-C3烷基;
n选自:0、1、2、3;
各R14分别独立地选自:氢、R5取代或者未取代的C1-C3烷基、氰基;
各R15分别独立地选自:氢、C1-C3烷基、R11选自:氢、C1-C3烷基;各R12分别独立地选自:R5取代或者未取代的C1-C20烷基、R5取代或者未取代的苯基、R5取代或者未取代的5-6元杂芳基。
在其中一些实施例中,R2选自:
X选自:CH、N、CF、-CCH3、-CCN、-C(OH);
R14选自:氢、C1-C6烷基、氰基、-CH2CN、-CH2OH、-CH2NH2、-CH2COOH、-CH2CONH2、-CH2CH2NH2;
R15选自:氢、C1-C3烷基、R11选自:氢、C1-C3烷基;R12选自:R5取代或者未取代的C1-C12烷基、R5取代或者未取代的苯基、R5取代或者未取代的5-6元杂芳基。
在其中一些实施例中,R2选自:X选自:CH、N;R14选自:H、甲基、乙基、丙基、氰基、-CH2CN;R15选自:H、甲基、乙基、丙基、 R11选自:H、甲基;各R12分别独立地选自:H、正丁基、叔丁基、异丙基、甲基、
乙基、辛烷基、壬烷基、十一烷基、戊烷基、庚烷基、已烷基、苯基、4-氟苯基。
在其中一些实施例中,所述含硒杂环类化合物具有如下式(IV)所示结构:
其中,R2选自:X选自:CH、N;R14选自:H、甲基、乙基、丙基;R15选自:H、甲基、乙基、丙基;
R8选自:氢、氟、氯、甲基、三氟甲基、二氟甲基。
在其中一些实施例中,R3选自:H、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的5-6元杂芳基、C1-C3烷基胺基、二(C1-C3烷基)胺基、R5取代或者未取代的6-8元含氮杂环基、-L-R13;L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-CF2-、-C=C-、-C≡C-、-Se-;R13选自:氢、卤素、氨基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C8环烷基、R17和R18取代或者未取代的3-8元含氮杂环基、-Q-R13’;Q选自:R5取代或者未取代的C1-C3亚烷基、R13’选自:R17和R18取代或者未取代的3-8元含氮杂环基、R5取代或者未取代的5-6元杂芳基、C1-C3烷基胺基、二(C1-C3烷基)胺基、氨基;
各R17分别独立地选自:氢、氘、R5取代或者未取代的C1-C6烷基、R5取代或者未取代的C3-C8环烷基;
各R18分别独立地选自:氢、氘、氨基、氰基、羟基、卤素、R19取代或者未取代的C1-C6烷基、R5取代或者未取代的C1-C6烷氧基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的5-10元杂芳基;
R19选自:氢、氘、卤素、羟基、羧基、酰胺基、氰基、氨基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C2-C3炔基、
R20选自:R5取代或者未取代的5-6元杂环基,C1-C6烷基胺基、二(C1-C3烷基)胺基。
在其中一些实施例中,R13选自:氢、卤素、氨基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C8环烷基,或者R13选自如下基团:
在其中一些实施例中,R3选自:H、C1-C3烷基、卤素取代的C1-C3烷基、R5取代或者未取代的咪唑基、R5取代或者未取代的四氮唑基、R5取代或者未取代的吡唑基、C1-C3烷基胺基、二(C1-C3烷基)胺基、-L-R13;
L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-C=C-、-Se-;
R13选自:H、C1-C3烷基、卤素取代的C1-C3烷基、氨基取代的C1-C3烷基、甲胺基取代的C1-C3烷基、二甲胺基取代的C1-C3烷基、
各R17分别独立地选自:氢、C1-C3烷基、氘代C1-C3烷基、乙炔基取代的C1-C3烷基、甲氧基取代的C1-C3烷基;
各R18分别独立地选自:氢、卤素、C1-C3烷基、C1-C3烷氧基、R19取代的C1-C3烷基;
R19选自:R20选自:R5取代或者未取代的吗啉基,C1-C3烷基胺基、二(C1-C3烷基)胺基。
在其中一些实施例中,R3选自:H、甲基、二氟甲基、三氟甲基、1-甲基-咪唑-4-基、四氮唑基、1-甲基-5-氰基-吡唑-4-基、二甲胺基、-L-R13;
L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-C=C-、-C≡C-、-Se-;
R13选自:H、甲基、三氟乙基、氨基取代的乙基、甲胺基取代的乙基、氨基取代的异丙基、
各R17分别独立地选自:氢、甲基、氘代甲基、乙炔基取代的甲基、甲氧基取代的乙基;
各R18分别独立地选自:氢、卤素、甲基、甲氧基、R19取代的甲基;
R19选自:R20选自:吗啉基,二甲胺基。
在其中一些实施例中,R3选自:-L-R13;
L选自:-O-、-S-、-Se-;
R13选自:三氟乙基、氨基取代的乙基、甲胺基取代的乙基、氨基取代的异丙基、
各R17分别独立地选自:氢、甲基、氘代甲基、甲氧基取代的乙基;
各R18分别独立地选自:氢、氟、氯。
在其中一些实施例中,所述的含硒杂环类化合物选自如下化合物:
本发明还提供了上述含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物的应用,包括如下技术方案。
上述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物在制备KRAS G12D抑制剂中的应用。
上述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物在制备预防和/或治疗由KRAS G12D结合其受体介导的疾病的药物中的应用。
在其中一些实施例中,所述由KRAS G12D结合其受体介导的疾病为过渡增殖性疾病。
在其中一些实施例中,所述过渡增殖性疾病为肿瘤。
在其中一些实施例中,所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、胃腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、子宫内膜癌、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤、恶性黑色素瘤、肾癌、膀胱癌、卵巢癌、宫颈癌、喉癌、多发性骨髓瘤、B淋巴瘤。
本发明还提供了一种预防和/或治疗由KRAS G12D介导的疾病的方法,包括如下技术方案。
一种预防和/或治疗由KRAS G12D介导的疾病的方法,包括:施用安全有效量的所述含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物。
在其中一些实施例中,所述由KRAS G12D介导的疾病为过渡增殖性疾病。
在其中一些实施例中,所述过渡增殖性疾病为肿瘤。
在其中一些实施例中,所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、胃腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、子宫内膜癌、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤、恶性黑色素瘤、肾癌、膀胱癌、卵巢癌、宫颈癌、喉癌、多发性骨髓瘤、B淋巴瘤。
本发明还提供了一种预防和/或治疗肿瘤的药用组合物,包括如下技术方案。
一种预防和/或治疗肿瘤的药用组合物,由活性成分和药学上可接受的辅料制备得到,所述活性成分包括上述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物。
本发明的发明人经过广泛而深入地研究,意外研发出一种结构新颖的含硒杂环类化合物,该类化合物能够有效抑制KRAS G12D的活性并且能抑制多种肿瘤细胞的增殖、迁移和侵袭,能够用于预防或者治疗KRAS G12D介导的疾病,例如肿瘤。
本发明试验结果表明,本发明的化合物在体外作为KRAS G12D的抑制剂表现出比以前
已知的化合物更高的效力,并且,相比现有已知的KRAS G12D抑制剂具有更低的毒性,安全性更高。
本发明所述化合物中,当任何变量(例如R5等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用短语“Rf取代”,“R取代”被认为与短语“被至少一个取代基取代”相当,且在此情况下优选的实施方案将具有1-4个取代基。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或者6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基或环己基等。
术语“烷氧基”指具有-O-烷基结构的基团,如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
术语“杂环基”为饱和或部分不饱和的单环或多环环状取代基(包括单环、螺环、并环、桥环等),其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,其中含氮杂环基是指至少一个环原子为N。例如:等。
术语“杂芳基”指含有1、2或3个选自O、N或S的杂原子的芳香环,本发明范围内的杂芳基包括但不限于:喹唑啉、喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基等。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
本发明包括式(I)、式(II)、式(III)化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本发明所述立体异构体,即(取决于其结构)作为对映体、非对映体、顺型/反型异构体(syn-/anti-isomer)、顺式/反式(cis-/trans-isomer)异构体、差向异构体以及(E)-/(Z)-异构体。式(I)、式(II)、式(III)化合物可以以纯立体异构体的形式或者以立体异构体的任何混合物的形式用于本发明的上下文中,在后一种情况中优选外消旋体。
术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受的盐不仅包括本文所述特定化合物的示例性盐,也包括所有式(I)、式(II)、式(III)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
在一个实施方案中,本发明提供了一种利用具有式(I)、式(II)、式(III)、式(IV)或者式(V)所示结构的化合物及其药学可接受的盐或其立体异构体或者其前药分子或者其氘代物治疗或预防人或其它哺乳动物由KRAS G12D介导的疾病(优选肿瘤等过渡增殖性疾病或症状)的方法。该方法包括:施用安全有效量的本发明所述含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物。
在一个实施方案中,本发明所设计的化合物及其药学可接受的盐可以用于治疗或控制非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、胃腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、子宫内膜癌、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤、恶性黑色素瘤、肾癌、膀胱癌、卵巢癌、宫颈癌、喉癌、多发性骨髓瘤、B淋巴瘤等。
药物组合物
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体。
本发明所述的“活性成分”包括本发明所述的式I、式(II)、式(III)、式(IV)或者式(V)化合物。
本发明所述的“活性成分”和药物组合物可用作KRASG12D抑制剂以用于治疗或预防由KRAS G12D介导的疾病,优选用于预防和/或治疗肿瘤。
“安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。
“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分能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
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(如吐温 )、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。
在另一优选例中,本发明(I)、式(II)、式(III)、式(IV)或者式(V)化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中,本发明(I)、式(II)、式(III)、式(IV)或者式(V)化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分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、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
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,活性成分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。
所述的固体剂型还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,这种组合物中活性成分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。
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。除了活性成分外,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。
除了活性成分外,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,或者与其他治疗药物(如降糖药)联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量。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。
联合用药
式(I)、式(II)、式(III)、式(IV)或者式(V)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式和剂量保持不变,而同时或随后服用式(I)、式(II)、式(III)、式(IV)或者式(V)化合物。当式(I)、式(II)、式(III)、式(IV)或者式(V)化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)、式(II)、式(III)、式(IV)或者式(V)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)、式(II)、式(III)、式(IV)或者式(V)化合物与其它一种或几种已知药物。当式(I)、式(II)、式(III)、式(IV)或者式(V)化合物与其它一种或几种药物进行药物联用时,式(I)、式(II)、式(III)、式(IV)或者式(V)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式(I)、式(II)、式(III)、式(IV)或者式(V)化合物进行药物联用的药物或活性成分包括但不局限为:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、
PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
在一个实施方案中,可以与式(I)、式(II)、式(III)化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺
素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本发明说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
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,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件,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。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下为具体的实施例:
中间体IN-1的合成:(3-氰基-4-(5,5-二甲基-1,3,2-二氧硼烷-2-基)苯并[b]硒酚-2-基)氨基甲酸叔丁酯(IN-1)
步骤一:2-氟-6-(甲氧基甲氧基)苯甲氰的合成
将化合物2-氟-6-羟基苯甲腈(5g,36.5mmol)和三乙胺(10mL,73mmol)依次加入100mL干燥的二氯甲烷中,然后缓慢滴加氯甲基甲醚(3.3mL,44mmol)。室温搅拌5h后,加水分离有机相。减压蒸干有机相,经柱层析得无色油状化合物(5.4g),收率81%。
LC-MS(ESI)m/z:182(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.77–7.64(m,1H),7.22–7.15(m,1H),7.15–7.06(m,1H),5.40(s,2H),3.43(s,3H).
步骤二:2-(甲氧基甲氧基)-6-(甲基硒基)苯甲氰的合成
在氩气保护的条件下,向二硫苏糖醇(18.8g,122mmol)的超干DMF溶液中缓慢加入二甲基二硒醚(13.75g,73mmol)。室温搅拌30min后,移至冰浴,并逐滴加入2-氟-6-(甲氧基甲氧基)苯甲氰(22g,122mmol)的DMF溶液。继续室温搅拌30min后,缓慢加入DBU(45mL,305mmol)。待反应完全后,向体系中加入200mL冰水,并用乙酸乙酯萃取,蒸干有机相后,经柱层析,得白色固体化合物26.28g,收率84%。
LC-MS(ESI)m/z:257(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.59–7.49(m,1H),7.20–7.10(m,2H),5.36(s,2H),3.42(s,3H),2.46(s,3H).
步骤三:2-((2-氰基-3-(甲氧基甲氧基)苯基)硒基)乙酸乙酯的合成
将2-(甲氧基甲氧基)-6-(甲基硒基)苯甲氰(7.68g,30mmol)加入80mL溴乙酸乙酯中,并在130℃的温度下,搅拌过夜。待反应完全后,减压蒸干溶剂,经柱层析得9.16g无色油状液体,收率93%。
LC-MS(ESI)m/z:329(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.57(tt,J=8.3,2.4Hz,1H),7.35(dt,J=7.9,2.2Hz,1H),7.23(dt,J=8.3,2.1Hz,1H),5.37(s,2H),4.08–4.00(m,2H),3.89(s,2H),3.42(d,J=2.3Hz,3H),1.14–1.06(m,3H).
步骤四:3-氨基-4-(甲氧基甲氧基)苯并[b]硒吩-2-羧酸乙酯的合成
将2-((2-氰基-3-(甲氧基甲氧基)苯基)硒基)乙酸乙酯(31g,94mmol)和氢化钠(7.28g,182mmol)依次加入300mL无水四氢呋喃中,并在氩气保护的条件下,40℃搅拌30min。待反应完全后,加入冰水并用乙酸乙酯萃取,减压蒸干有机相后,柱层析得28g淡黄色固体,收率90%。
LC-MS(ESI)m/z:329(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.54(d,J=7.9Hz,1H),7.36(t,J=8.0Hz,1H),7.28(s,2H),7.06(d,J=8.1Hz,1H),5.42(s,2H),4.22(q,J=7.1Hz,2H),3.45(s,3H),1.27(t,J=7.1Hz,3H).
步骤五:3-碘-4-(甲氧基甲氧基)苯并[b]硒吩-2-甲酸乙酯的合成
将3-氨基-4-(甲氧基甲氧基)苯并[b]硒吩-2-羧酸乙酯(10g,30mmol)溶于150mL无水四氢呋喃,然后在冰浴条件下,依次加入亚硝酸叔丁酯(7.3mL,61mmol)和氟硼酸(3.9mL,61mL)。待反应完全后,减压抽滤得10g红色粉末固体。然后将该固体溶于100mL无水乙腈,并分批加入碘化钠(9g,60mL),室温搅拌过夜。待反应完全后,加入冰水,并用乙酸乙酯萃取。经柱层析得淡黄色固体7.11g,收率54%。
LC-MS(ESI)m/z:440(M+H)+;
步骤六:3-氰基-4-(甲氧基甲氧基)苯并[b]硒吩-2-羧酸乙酯的合成
在氩气保护条件下,将3-碘-4-(甲氧基甲氧基)苯并[b]硒吩-2-甲酸乙酯(2.2g,5mmol)、氰化亚铜(0.67g,7.5mmol)和四(三苯基膦)钯(0.29g,0.25mmol)依次加入50mL无水DMF中,维持120℃,反应3h。待反应完全后,蒸干溶剂,经柱层析得白色固体1.53g,收率90%。
LC-MS(ESI)m/z:339(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.1Hz,1H),7.53(t,J=8.1Hz,1H),7.21(d,J=8.0Hz,1H),5.41(s,2H),4.40(q,J=7.1Hz,2H),3.49(s,3H),1.35(t,J=7.1Hz,3H).
步骤七:3-氰基-4-(甲氧基甲氧基)苯并[b]硒吩-2-羧酸的合成
向3-氰基-4-(甲氧基甲氧基)苯并[b]硒吩-2-羧酸乙酯(3.8g,11.2mmol)的甲醇溶液(50mL)中,加入10mL氢氧化钠水溶液(10M),60℃搅拌2h,待反应完全后,蒸干溶剂,并用稀盐酸调至中性。有大量白色固体生成,减压抽滤,收集滤饼并干燥,得白色固体3.3g,收率95%。
LC-MS(ESI)m/z:311(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.70(d,J=8.0Hz,1H),
7.36(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),5.34(s,2H),3.48(s,3H).
步骤八:(3-氰基-4-(甲氧基甲氧基)苯并[b]硒酚-2-基)氨基甲酸叔丁酯的合成
将3-氰基-4-(甲氧基甲氧基)苯并[b]硒吩-2-羧酸(3.3g,10.6mmol)、叠氮磷酸二苯酯(3.2g,12mmol)和三乙胺(1.6mL,12mmol)加入50mL叔丁醇中,85℃搅拌8h,待反应完全后,减压蒸干溶剂,经柱层析得3.2g白色固体,收率80%。
LC-MS(ESI)m/z:382(M+H)+;1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),7.62(dd,J=7.8,0.9Hz,1H),7.20(t,J=8.0Hz,1H),7.06(dd,J=8.1,0.9Hz,1H),5.30(s,2H),3.47(s,3H),1.52(s,9H).
步骤九:(3-氰基-4-羟基苯并[b]硒酚-2-基)氨基甲酸叔丁酯的合成
将(3-氰基-4-(甲氧基甲氧基)苯并[b]硒酚-2-基)氨基甲酸叔丁酯(3g,7.87mmol)溶于50mL甲醇,氩气保护条件下,滴加1mL浓盐酸,45℃搅拌30min。待反应完全后,蒸干溶剂,经柱层析得2.5g白色固体,收率94%。
LC-MS(ESI)m/z:338(M+H)+;1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.09(s,1H),7.39(dd,J=7.9,0.9Hz,1H),7.07(t,J=7.9Hz,1H),6.77(dd,J=7.9,1.0Hz,1H),1.52(s,9H).
步骤十:2-((叔丁氧基羰基)氨基)-3-氰基苯并[b]硒酚-4-基三氟甲磺酸酯的合成
将(3-氰基-4-羟基苯并[b]硒酚-2-基)氨基甲酸叔丁酯(2g,6mmol)溶于50mL无水二氯甲烷中,氩气保护条件下,依次加入三氟甲磺酸酐(2g,7.2mL)和吡啶(0.95mL,11.8mmol)。然后在冰浴条件搅拌2h。待反应完全后,蒸干溶剂,经柱层析得2.4g白色固体,收率87%。
LC-MS(ESI)m/z:470(M+H)+;1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.17(dd,J=7.8,1.0Hz,1H),7.50(d,J=8.1Hz,1H),7.41(t,J=8.0Hz,1H),1.54(s,9H).
步骤十一:(3-氰基-4-(5,5-二甲基-1,3,2-二氧硼烷-2-基)苯并[b]硒酚-2-基)氨基甲酸叔丁酯的合成
将2-((叔丁氧基羰基)氨基)-3-氰基苯并[b]硒酚-4-基三氟甲磺酸酯(0.47g,1mmol)、联硼酸新戊二醇酯(0.86g,3.8mmol)、双(二苯基膦苯基醚)二氯化钯(II)(72mg,0.1mmol)和醋酸钾(0.3g,3mmol)依次加入20mL无水二氧六环中,氩气保护条件下,95℃搅拌4h,待反应完全后,蒸干溶剂,经柱层析得0.35g白色固体,收率80%。
LC-MS(ESI)m/z:434(M+H)+;1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.00(dd,J=7.9,1.2Hz,1H),7.45(dd,J=7.2,1.2Hz,1H),7.21(t,J=7.5Hz,1H),3.75(s,4H),1.53(s,9H),1.04(s,6H).
中间体2的合成:叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(IN-2)
步骤一:2-氨基-4-溴-5-氯-3-氟苯甲酸的合成
将2-氨基-4-溴-3-氟苯甲酸(90g,384.2mmol)溶于900mL的DMF中,室温搅拌10min,随后分批加入NCS(59g,441.8mmol),加毕,室温搅拌过夜。待原料完全消失后,加入1L水,抽滤并收集滤饼。烘干后得到101g化合物,收率99%。
LC-MS(ESI)m/z:269.47[M-H]+
步骤二:7-溴-6-氯-8-氟喹唑啉-2,4(1H,3H)-二酮的合成
将2-氨基-4-溴-5-氯-3-氟苯甲酸(10g,37.2mmol),尿素(69g,1148mmol)加入500mL的三口瓶中,升温至180℃反应3h。待反应完全后,降温至室温,加入125mL水,搅拌10min,固体缓慢析出,抽滤,再用200mL热水洗涤滤饼,收集滤饼并干燥,得到11.3g化合物,收率99%
1H NMR(400MHz,DMSO-d6)δ7.20(s,1H),5.43(s,2H).
LC-MS(ESI)m/z:290.9[M-H]+
步骤三,四:叔丁基(1R,5S)-3-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯)的合成
将7-溴-6-氯-8-氟喹唑啉-2,4(1H,3H)-二酮(11g,37mmol)和168mL三氯氧磷加入到500mL反应瓶中,升温至110℃,再加入0.5mL的DMF,反应过夜,原料完全消失后,将三氯氧磷旋干,得粗产物。向反应瓶中再加入(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(14g,65mmol),DIEA(48g,372mmol),169mL1,4-二氧六环。室温搅拌1h。待反应完毕,旋干反应溶液,柱层析(石油醚:乙酸乙酯=10:1到4:1),得到11.3g化合物,收率60.2%。
1H NMR(400MHz,DMSO-d6)δ7.20(s,1H),4.34(d,J=11.65Hz,1H),4.20(s,1H),3.78(s,1H),3.64(t,J=13.24,13.0,2H),3.16-3.07(m,1H),2.87.2.70(m,1H),2.05-1.68(m,12H).
LC-MS(ESI)m/z:507.23[M+H]+
步骤五:叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)
甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
将(1R,5S)-3-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(10g,19.7mmol),((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(4.7g,29.6mmol),200mL1,4-二氧六环,DIEA(7.6g,58.9mmol)加入到350mL的封管里,110℃反应过夜。待TLC检测反应完全后,加入200mL的水和200mL乙酸乙酯萃洗三次,干燥有机相,浓缩,柱层析(石油醚:乙酸乙酯=10:1到4:1)得到6.23g产物,产率51.2%。
1H NMR(500MHz,Chloroform-d)δ7.83(s,1H),5.07–4.82(m,1H),4.19(dd,J=3.1,0.7Hz,2H),4.11–4.00(m,2H),3.84(dd,J=12.3,7.0Hz,2H),3.73(dd,J=12.4,7.1Hz,2H),3.62–3.30(m,2H),3.04–2.74(m,2H),2.15–1.74(m,10H),1.47(s,9H).LC-MS(ESI)m/z:629.13[M+H]+
中间体IN-3和IN-4的合成:叔丁基(1R,5S)-3-(7-溴-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-甲氧基吡啶[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(IN-3)和叔丁基(1R,5S)-3-(7-溴-2-(((2S,7aR)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-5-甲基-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(IN-4)
步骤一:(1R,5S)-3-(6-氯-2-(甲硫基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
将三乙胺(28mL,208mmol)和(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(35.4g,167mmol)依次加入4,6-二氯-2-(甲硫基)-5-硝基嘧啶(40g,167mmol)的无水四氢呋喃溶液(500mL)中,0℃下搅拌3h,反应体系有大量固体生成。TLC检测反应完全后,抽
滤并收集滤饼。烘干后得到68g化合物,无需纯化直接下一步,收率98%。
LC-MS(ESI)m/z:416[M+H]+;1H NMR(400MHz,Chloroform-d)δ4.42–4.22(m,2H),4.03–3.57(m,2H),3.39–3.26(m,2H),2.53(s,3H),2.02–1.91(m,2H),1.74–1.66(m,2H),1.50(s,9H).
步骤二:叔丁基(1R,5S)-3-(6-((E)-3-乙氧基-3-氧代丙酸-1-烯-1-基)-2-(甲硫基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
将(1R,5S)-3-(6-氯-2-(甲硫基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(2.1g,5mmol)、丙烯酰乙酯(1g,10mmol)、N-甲基二环己胺(1.95g,10mmol)、三二亚苄基丙酮二钯(0.46g,0.5mmol)和四氟硼酸三叔丁基膦(0.29g,1mmol)依次加入100mL超干DMF中,氩气保护条件下,100℃反应10h,待反应完全后,放至室温。向反应体系中加入200mL冰水,用乙酸乙酯萃取,蒸干有机层,经柱层析得1.92g化合物,收率80%。
LC-MS(ESI)m/z:480[M+H]+;1H NMR(400MHz,Chloroform-d)δ7.65(d,J=15.1Hz,1H),7.21(d,J=15.1Hz,1H),4.42–4.23(m,4H),4.05–3.59(m,2H),3.37–3.25(m,2H),2.56(s,3H),1.99–1.90(m,2H),1.74–1.67(m,2H),1.51(s,9H),1.35(t,J=7.1Hz,3H).
步骤三:叔丁基(1R,5S)-3-(5-氨基-6-((E)-3-乙氧基-3-氧代丙酸-1-烯-1-基)-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
将叔丁基(1R,5S)-3-(6-((E)-3-乙氧基-3-氧代丙酸-1-烯-1-基)-2-(甲硫基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(10g,21mmol)和钯碳0.7g加入200mL甲醇中,氢气氛围下,室温反应5h,待反应完全后,过滤,蒸干溶剂。剩余固体经柱层析分离得9.2g黄色固体,收率99%。
LC-MS(ESI)m/z:450[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.96(d,J=14.9Hz,1H),6.83(d,J=14.9Hz,1H),5.05(s,2H),4.24–4.13(m,4H),3.79–3.67(m,2H),3.03(d,J=12.4Hz,2H),2.43(s,3H),1.91–1.72(m,4H),1.43(s,9H),1.26(q,J=6.2,5.3Hz,3H).
步骤四:叔丁基(1R,5S)-3-(2-(甲硫基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
向叔丁基(1R,5S)-3-(5-氨基-6-((E)-3-乙氧基-3-氧代丙酸-1-烯-1-基)-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(2.0g,4.4mmol)的无水乙醇溶液中,加入乙醇钠(0.61g,8.8mmol)。氩气保护条件下,70℃反应1h,待反应完全后,蒸干溶剂,经柱层析得1.5g淡黄色固体,收率85%。
LC-MS(ESI)m/z:404[M-H]-;1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),7.85(d,J=9.0Hz,1H),7.09(d,J=9.0Hz,1H),5.76–4.88(m,2H),4.22(s,2H),3.20(d,J=13.0Hz,2H),
2.48(s,3H),1.89–1.82(m,2H),1.78–1.72(m,2H),1.45(s,9H).
步骤五:叔丁基(1R,5S)-3-(2-(甲基磺酰基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
将叔丁基(1R,5S)-3-(2-(甲硫基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(0.4g,1mmol)溶于10mL无水二氯甲烷中,0℃下分批加入间氯过氧苯甲酸(0.52g,3mmol),继续搅拌30min,待反应完全后,抽滤,蒸干溶液,经柱层析分离得0.3g黄色固体,收率79%。
LC-MS(ESI)m/z:436[M-H]-。1H NMR(500MHz,Chloroform-d)δ7.84(d,J=11.0Hz,1H),6.61(d,J=10.8Hz,1H),4.09–3.87(m,5H),3.72–3.56(m,3H),3.42(s,3H),2.03–1.78(m,3H),1.45(s,9H).
步骤六:叔丁基(1R,5S)-3-(2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
将叔丁基(1R,5S)-3-(2-(甲基磺酰基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(0.86g,2mmol)和((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(0.64g,4mmol)溶于20mL无水四氢呋喃中,冰浴下加入氢化钠(0.2g,5mmol)。然后移至室温反应10h后,加入100mL水,并用乙酸乙酯萃取,减压蒸干有机层,剩余固体经柱层析得0.87g固体,收率86%。
LC-MS(ESI)m/z:515[M+H]+。1H NMR(500MHz,Chloroform-d)δ7.74(d,J=11.0Hz,1H),6.55(d,J=11.0Hz,1H),4.97(dt,J=46.3,7.0Hz,1H),4.25–4.14(m,2H),4.11–4.00(m,2H),3.91–3.78(m,2H),3.76–3.70(m,2H),3.63–3.29(m,2H),2.96–2.76(m,2H),2.17–1.98(m,2H),1.99–1.89(m,4H),1.88–1.79(m,4H),1.47(s,9H).
步骤七:叔丁基(1R,5S)-3-(7-溴-2-(((2S,7aR)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
将叔丁基(1R,5S)-3-(2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(0.87g,1.7mmol)、乙酸钠(0.25g,2.5mmol)加入20mL冰乙酸中,0℃下滴加0.1ml液溴,室温搅拌过夜,待反应完全后,蒸干溶剂,剩下固体经柱层析得0.4g黄色化合物,收率36%。
LC-MS(ESI)m/z:593[M+H]+。1H NMR(500MHz,Chloroform-d)δ7.24(s,1H),4.94(dt,J=46.5,7.1Hz,1H),4.19(dd,J=2.6,0.8Hz,2H),4.11–4.02(m,2H),3.89–3.80(m,2H),3.79–3.71(m,2H),3.57–3.30(m,2H),3.02–2.88(m,1H),2.85–2.78(m,1H),2.15–2.00(m,2H),1.97–1.91(m,4H),1.87–1.77(m,4H),1.47(s,9H).
步骤八:叔丁基(1R,5S)-3-(7-溴-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-甲
氧基吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(IN-3)和叔丁基(1R,5S)-3-(7-溴-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-甲基-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(IN-4)的合成
将叔丁基(1R,5S)-3-(7-溴-2-(((2S,7aR)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(0.61g,1mmol)和碳酸钾(0.28g,2mmol)加入10mL无水乙腈中,室温搅拌5min,然后逐滴加入碘甲烷(0.29g,2mmol),继续搅拌过夜,待反应完全后,蒸干溶剂,经柱层析分离,得中间体IN-3(0.36g,收率:59%)和IN-4(0.15g,收率:25%)。
IN-3:LC-MS(ESI)m/z:606[M+H]+;1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),5.02–4.85(m,1H),4.19(dd,J=3.1,0.8Hz,2H),4.10–4.01(m,2H),3.97–3.93(m,2H),3.92(s,3H),3.82–3.75(m,2H),3.62–3.33(m,2H),3.02–2.78(m,2H),2.14–2.01(m,1H),1.99–1.89(m,5H),1.88–1.77(m,4H),1.47(s,9H).
IN-4:LC-MS(ESI)m/z:606[M+H]+,1H NMR(500MHz,Chloroform-d)δ7.43(s,1H),5.02–4.86(m,1H),4.19(dd,J=3.1,0.8Hz,2H),4.10–4.01(m,2H),3.77–3.65(m,4H),3.63–3.32(m,2H),3.30(s,3H),3.01–2.77(m,2H),2.13–2.01(m,2H),1.99–1.85(m,4H),1.86–1.73(m,4H),1.51(s,9H).
实施例1:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6020)
将中间体IN-1(155mg,0.36mmol)、中间体IN-2(150mg,0.24mmol)、DPEPhosPdCl2(26mg,0.04mmol)和碳酸铯(195mg,0.6mmol)加入10mL超干甲苯中,氩气保护条件下,100℃反应3h,TLC检测,待反应完全后,蒸干溶剂,经柱层析得白色固体102mg,收率50%。
将上一步所得固体溶于6M的氯化氢乙醇溶液(10mL)中,室温搅拌1h,蒸干溶剂,所得粗产物经手性柱(CHIRALPAK AD-H,ADH0CE-XG136,0.46cm I.D.×25cm L;Hexane/EtOH/DEA=60/40/0.1(V/V/V);1.0mL/min)分离得目标产物30mg,收率38%。
LC-MS(ESI)m/z:669(M+H)+,1H NMR(400MHz,DMSO-d6)δ7.93–7.75(m,4H),7.20–7.09(m,2H),5.37–5.16(m,1H),4.27(d,J=12.1Hz,2H),4.08(dd,J=10.3,1.6Hz,1H),3.99(dd,J=10.4,3.1Hz,1H),3.57–3.47(m,4H),3.12–3.05(m,2H),3.02–2.98(m,1H),2.86–
2.78(m,1H),2.16–2.11(m,1H),2.06–2.00(m,2H),1.86–1.73(m,4H),1.67–1.57(m,3H).。
实施例2:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-甲氧基吡啶并[3,2-d]嘧啶-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6021)
以中间体IN-3代替实施例1中的中间体IN-2,化合物ZX6021的合成步骤同实施例1,LC-MS(ESI)m/z:648(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.80(s,1H),7.65–7.60(m,2H),7.50–7.40(m,1H),5.03–4.85(m,1H),4.19(dd,J=3.1,0.8Hz,2H),3.99(s,3H),3.62–3.47(m,5H),3.43–3.33(m,1H),3.19–3.11(m,2H),2.97–2.78(m,2H),2.13–2.04(m,1H),1.89–1.82(m,5H),1.79–1.64(m,4H).
实施例3:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪7a(5H)-基)甲氧基)-5-甲基-6-氧代-5,6-二氢吡啶并[3,2-d]嘧啶-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6022)
以中间体IN-4代替实施例1中的中间体IN-2,化合物ZX6022的合成步骤同实施例1,LC-MS(ESI)m/z:648(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.88(dd,J=7.4,1.5Hz,1H),7.64(dd,J=7.4,1.5Hz,1H),7.39(t,J=7.5Hz,1H),4.94(dt,J=46.5,7.0Hz,1H),4.19(dd,J=3.1,0.8Hz,2H),3.62–3.46(m,6H),3.43–3.33(m,1H),3.23(s,3H),3.20–3.11(m,2H),2.98(t,J=7.4Hz,1H),2.96–2.78(m,2H),2.14–2.03(m,1H),1.89–1.77(m,5H),1.77–1.69(m,4H).
实施例4:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-((1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6023)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6023,LC-MS(ESI)m/z:666(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.65–7.56(m,2H),7.40(t,J=7.5Hz,1H),4.02(s,2H),3.56–3.40(m,4H),3.19–3.09(m,2H),2.79–2.70(m,4H),2.50–2.37(m,2H),1.93–1.81(m,4H),1.79–1.67(m,8H).
实施例5:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-((1-(吗啉代甲基)环丙基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6024)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6024,LC-MS(ESI)m/z:682(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.63(dd,J=7.5,1.5Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.40(t,J=7.4Hz,1H),4.01(s,2H),3.69(t,J=7.1Hz,4H),3.56–3.40(m,4H),3.19–3.09(m,2H),2.66(t,J=7.1Hz,4H),2.51(s,2H),1.96–1.82(m,4H),1.79–1.66(m,4H).
实施例6:4-((S)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6025)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6025,LC-MS(ESI)m/z:704(M+H)+。1H NMR(500MHz,Chloroform-d)δ8.16(s,1H),7.71(dd,J=7.5,1.6Hz,1H),7.51(dd,J=7.5,1.6Hz,1H),7.41(t,J=7.5Hz,1H),4.94(dp,J=46.3,7.0Hz,1H),4.19(dd,J=3.2,0.8Hz,2H),3.63–3.49(m,5H),3.45–3.33(m,1H),3.22–3.10(m,2H),3.04–2.94(m,2H),2.87–2.74(m,1H),2.15–1.97(m,1H),1.92–1.77(m,5H),1.77–1.67(m,3H).
实施例7:4-((R)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((R)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6026)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6026,LC-MS(ESI)m/z:626(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.62(dd,J=7.4,1.6Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),4.10(dd,J=7.0,3.5Hz,2H),3.56–3.40(m,4H),3.38–3.26(m,1H),3.20–3.10(m,2H),3.05–2.98(m,1H),2.67–2.58(m,1H),2.32(s,3H),1.79–1.60(m,8H).
实施例8:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6027)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6027,LC-MS(ESI)m/z:644(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.62(dd,J=7.4,1.6Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),5.09–4.86(m,1H),4.16(d,J=6.9Hz,2H),3.56–3.41(m,5H),3.19–3.11(m,3H),3.10–3.02(m,1H),2.53–2.39(m,1H),2.37(s,3H),2.06–1.90(m,1H),1.81–1.66(m,4H).
实施例9:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6028)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6028,LC-MS(ESI)m/z:610(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.64(dd,J=7.5,1.5Hz,1H),7.58(dd,J=7.5,1.5Hz,1H),7.41(t,J=7.5Hz,1H),4.94–4.74(m,2H),3.59–3.40(m,4H),3.25–3.09(m,2H),1.73(qdd,J=6.7,4.3,1.6Hz,4H).
实施例10:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6029)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6029,LC-MS(ESI)m/z:640(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.62(dd,J=7.4,1.5Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),4.01(s,2H),3.56–3.40(m,4H),3.20–3.09(m,2H),2.47–2.36(m,2H),2.26(s,6H),1.91–1.81(m,4H),1.78–1.69(m,4H).
实施例11:4-((R)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((R)-1-(2-甲氧基乙基)吡咯烷-2-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6030)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6030,LC-MS(ESI)m/z:670(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.62(dd,J=7.4,1.5Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.40(t,J=7.5Hz,1H),4.08(d,J=7.0Hz,2H),3.57–3.40(m,6H),3.27(s,4H),3.20–3.08(m,2H),2.91–2.76(m,4H),1.81–1.59(m,8H).
实施例12:4-((7R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6031)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6031,LC-MS(ESI)m/z:623(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.62(dd,J=7.4,1.6Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),3.56–3.39(m,8H),3.25–3.08(m,4H),1.79–1.67(m,8H).
实施例13:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-((1-甲基-1H-吡咯-2-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6032)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6032,LC-MS(ESI)m/z:622
(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.62(dd,J=7.4,1.6Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),6.96–6.93(m,1H),5.94(dd,J=7.5,1.5Hz,1H),5.75(t,J=7.4Hz,1H),5.26–5.17(m,2H),3.64(s,3H),3.56–3.40(m,4H),3.20–3.09(m,2H),1.80–1.65(m,4H).
实施例14:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-2-((1-(二甲基氨基)环丁基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6033)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6033,LC-MS(ESI)m/z:640(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.62(dd,J=7.4,1.5Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),4.29–4.13(m,2H),3.56–3.40(m,4H),3.19–3.08(m,2H),2.35(s,6H),2.05–1.92(m,4H),1.79–1.69(m,4H),1.69–1.60(m,2H).
实施例15:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2S,5S)-5-甲氧基-1-甲基吡咯烷-2-基)氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6034)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6034,LC-MS(ESI)m/z:642(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.62(dd,J=7.4,1.6Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.39(t,J=7.5Hz,1H),4.62–4.53(m,1H),4.44–4.24(m,1H),3.61–3.39(m,4H),3.24(s,3H),3.18–3.09(m,2H),2.36(t,J=1.5Hz,3H),2.25–2.06(m,2H),1.91–1.82(m,2H),1.79–1.67(m,4H).
实施例16:2-氨基-4-((R)-2-(2-氨基乙氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟喹唑啉-7-基)苯并[b]硒吩-3-腈(ZX6035)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6035,LC-MS(ESI)m/z:572(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.64(dd,J=7.4,1.5Hz,1H),7.58(dd,J=7.5,1.6Hz,1H),7.42(t,J=7.5Hz,1H),4.40–4.25(m,2H),3.56–3.39(m,4H),3.37–3.19(m,2H),3.18–3.09(m,2H),1.80–1.63(m,4H).
实施例17:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(2-(甲基氨基)乙氧基)喹唑啉-7-基)-2-氨基苯并[b]硒吩-3-腈(ZX6036)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6036,LC-MS(ESI)m/z:586(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.64(dd,J=7.4,1.5Hz,1H),7.59(dd,J=7.5,1.6Hz,1H),7.41(t,J=7.5Hz,1H),4.38–4.18(m,2H),3.65–3.37(m,4H),3.32–3.22(m,2H),3.18–3.09(m,2H),2.53(s,3H),1.82–1.62(m,4H).
实施例18:2-氨基-4-((R)-2-(((R)-1-氨基丙-2-基)氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-氯-8-氟喹唑啉-7-基)苯并[b]硒吩-3-腈(ZX6037)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6037,LC-MS(ESI)m/z:586
(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.64(dd,J=7.4,1.5Hz,1H),7.59(dd,J=7.5,1.6Hz,1H),7.41(t,J=7.5Hz,1H),4.82–4.61(m,1H),3.61–3.39(m,4H),3.23–3.08(m,4H),1.83–1.63(m,4H),1.47(d,J=6.8Hz,2H).
实施例19:2-氨基-4-((R)-2-((R)-2-氨基丙氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟喹唑啉-7-基)苯并[b]硒吩-3-腈(ZX6038)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6038,LC-MS(ESI)m/z:586(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.64(dd,J=7.4,1.5Hz,1H),7.59(dd,J=7.5,1.6Hz,1H),7.41(t,J=7.5Hz,1H),4.13–3.98(m,2H),3.58–3.35(m,5H),3.23–3.07(m,2H),1.81–1.64(m,4H),1.15(d,J=6.8Hz,3H).
实施例20:2-氨基-4-((R)-2-((1-氨基环丙基)甲氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟喹唑啉-7-基)苯并[b]硒吩-3-腈(ZX6039)
参照中间体IN-2和化合物ZX6020的合成方法合成化合物ZX6039,LC-MS(ESI)m/z:598(M+H)+。1H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.64(dd,J=7.5,1.5Hz,1H),7.58(dd,J=7.5,1.5Hz,1H),7.41(t,J=7.5Hz,1H),4.10–3.89(m,2H),3.56–3.49(m,2H),3.46–3.40(m,2H),3.20–3.08(m,2H),2.04–1.86(m,4H),1.80–1.66(m,4H).
实施例21:4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氨基苯并[b]噻吩-3-腈(ZX6040)
化合物ZX6040的合成方法参考专利WO2021118877和US20200115375。LC-MS(ESI)m/z:623(M+H)+。1H NMR(500MHz,Chloroform-d)δ7.94(s,1H),7.73(dd,J=6.7,2.3Hz,1H),7.52–7.45(m,2H),5.12–4.71(m,1H),4.27–4.14(m,2H),3.69–3.31(m,6H),3.22–3.07(m,2H),3.00–2.76(m,2H),2.20–1.93(m,1H),1.90–1.65(m,9H).
实施例22:化合物对肿瘤细胞的增殖抑制作用
本实施例以CCK-8细胞计数试剂盒(Dojindo)检测化合物对细胞的增殖抑制作用,具体步骤如下:
1)细胞接种:处于细胞对数生长期的Kras G12D突变的AGS(胃癌细胞),Kras G12D突变的AsPC-1(人转移胰腺腺癌细胞),BaF3-KRAS-G12D(poly)(Kras G12D突变)等肿瘤细胞分别按不同密度(细胞生长速度不一样)接种在不同96孔板中(3000-10000细胞/100μl/孔)。
2)工作液配制:以细胞培养所需相应培养基作为稀释液(含或不含溶媒DMSO),稀释受试化合物和对照化合物储备液,获得所需浓度为终浓度3倍的系列浓度的工作液,各浓度组中的溶媒DMSO含量与溶媒对照组相一致。
3)共孵育:接种24hr后,向96孔板加入化合物系列浓度的母液100μl/孔,混匀后共培养72hr。所有组别至少3个复孔,每个化合物6个浓度。空白对照组:只加培养基,不加细胞和药物,排除培养基对比色的干扰。
4)吸光度测定:从96孔板吸走培养基后,每孔加入10μl CCK-8溶液,共培养4hr后,充分振荡使其均匀,在酶标仪上测定A450及A650处的吸光值。
5)数据处理:得到的A450-A650原始数据,得到各处理孔的细胞存活率(计算方法如下);然后将细胞存活率数据及其对应的化合物浓度输入GraphPad Prism 8.0 Demo软件,使用非线性回归模型计算化合物对不同细胞的IC50值。
6)细胞存活率的计算:细胞存活率(%)=[(As-Ac)/(Ab-Ac)]×100%](As:实验孔;
Ab:溶媒对照孔;Ac:空白对照孔)。
7)测试结果如表1所示:本发明制备的大部分化合物对Kras G12D突变的AGS等肿瘤细胞具有良好的增殖抑制作用。其中,本发明的含硒杂环化合物(ZX-6020)相较对应的硫代化合物(ZX-6040)活性有大于10倍的提升。
表1
实施例23:化合物的急性毒性
选择合格的健康ICR小鼠(年龄6-8周,体重18-20g),每组3只。用配置好的化合物溶液(溶媒:5%DMSO+25%蓖麻油乙醇混合物(5/2)+70%PBS;澄明溶液,pH均在7~9),以设定剂量单次静脉给药,观察死亡情况。
测试结果如表2所示:本发明的含硒杂环化合物相较对应的硫代化合物具有更低的毒性,
安全性更高。
表2
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (34)
- 具有式(I)所示结构的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物:其中:T1选自:N、-CR4;R4选自:氢、卤素、氰基、氨基、羟基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C2-C8炔基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的3-8元杂环基、R5取代或者未取代的5-10元杂芳基、-C(=O)R、-S(=O)R、-S(=O)2R;各R5分别独立地选自:氢、氘、卤素、羟基、羧基、酰胺基、氰基、氨基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C2-C3炔基;各R分别独立地选自:H、OH、氨基、C1-C6烷基胺基、二(C1-C6烷基)胺基、C1-C6烷基、C1-C6烷氧基;T2、T3、T4分别独立地选自:N、-CR6;各R6分别独立地选自:氢、氘、卤素、氰基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基、R5取代或者未取代的C3-C8环烷基;T5、T6、T7分别独立地选自:N、NR7、羰基、-CR8,并且含有T5、T6和T7的环A和与其相并的含氮杂环共同形成杂芳基或者杂芳酮基;各R7分别独立地选自:R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C3-C8环烷基;各R8分别独立地选自:氢、卤素、氰基、醛基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5取代或者未取代的C1-C8烷硒基、R5取代或者未取代的C2-C8烯基、R5取代或者未取代的C2-C8炔基;T8选自:N、-CR9;R9选自:氢、卤素、氰基、硝基、R5取代或者未取代的C1-C8烷基、R5取代或者未取代的C1-C8烷基胺基、R5取代或者未取代的C2-C8炔基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C1-C8烷氧基、R5取代或者未取代的C1-C8烷硫基、R5 取代或者未取代的C1-C8烷硒基;R1选自:-OR10、-SR10、-NHR10、-CHO、-S(=O)R11、-S(=O)2R11、-COOR11、-CONHR11、R5取代或者未取代的C1-C8烷基、各R10分别独立地选自:H、C1-C8烷基、各R11分别独立地选自:氢、C1-C8烷基;各R12分别独立地选自:R5取代或者未取代的C1-C20烷基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的5-10元杂芳基;R2选自:取代或者未取代的3-10元含氮杂环基;R3选自:H、R5取代或者未取代的C1-C10烷基、R5取代或者未取代的5-10元杂芳基、C1-C6烷基胺基、二(C1-C6烷基)胺基、R5取代或者未取代的3-10元含氮杂环基、-L-R13;L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-CF2-、-C=C-、-C≡C-、-Se-;R13选自:氢、卤素、氨基、R5取代或者未取代的C1-C10烷基、R5取代或者未取代的C3-C10环烷基、取代或者未取代的3-10元含氮杂环基、-Q-R13’;Q选自:R5取代或者未取代的C1-C6亚烷基、R13’选自:取代或者未取代的3-10元含氮杂环基、R5取代或者未取代的5-10元杂芳基、C1-C6烷基胺基、二(C1-C6烷基)胺基、氨基;各m分别独立地为:0、1、2;p为:1、2、3、4。
- 根据权利要求1所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,T1选自:N、-CR4;R4选自:氢、卤素、氰基、氨基、羟基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C1-C3烷氧基、R5取代或者未取代的C1-C3烷基胺基、R5取代或者未取代的C1-C3烷硫基、R5取代或者未取代的C1-C3烷硒基、R5取代或者未取代的C3-C6环烷基、R5取代或者未取代的C2-C3炔基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的3-6元杂环基、R5取代或者未取代的5-6元杂芳基、-C(=O)R、-S(=O)R、-S(=O)2R;各R5分别独立地选自:氢、氘、卤素、羟基、羧基、酰胺基、氰基、氨基、C1-C3烷基、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C2-C3炔基;各R分别独立地选自:H、OH、氨基、C1-C3烷基胺基、二(C1-C3烷基)胺基、二(C1-C3烷基)胺基、C1-C3烷基、C1-C3烷氧基。
- 根据权利要求2所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R4选自:氢、卤素、氰基、氨基、羟基、甲氧基、 三氟甲氧基、三氟甲基、二氟甲基、甲基、乙基、丙基、异丙基、乙炔基、丙炔基、羟基取代的丙炔基、二氟甲基取代的丙炔基、氰基取代的丙炔基、氨基取代的丙炔基、三氟甲基取代的乙炔基、环丙基、羟基取代的环丙基、卤素取代的环丙基、1-甲基咪唑基、-C(=O)R;各R分别独立地选自:H、OH、氨基、甲胺基、二甲胺基、乙胺基、二乙胺基、甲氧基、乙氧基。
- 根据权利要求1所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,T2、T3、T4分别独立地选自:N、-CR6;各R6分别独立地选自:氢、氘、卤素、氰基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C1-C3烷基胺基、R5取代或者未取代的C1-C3烷氧基、R5取代或者未取代的C1-C3烷硫基、R5取代或者未取代的C1-C3烷硒基、R5取代或者未取代的C3-C6环烷基。
- 根据权利要求4所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,各R6分别独立地选自:氢、氘、卤素、氰基、甲基、异丙基、三氟甲基、二氟甲基、环丙基、甲氧基、甲硫基、甲硒基、三氟甲氧基、乙氧基、异丙氧基。
- 根据权利要求1所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,所述含硒杂环类化合物具有如下式(II)或者式(III)所示结构:其中,T7选自:N、-CR8。
- 根据权利要求1所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,各R7分别独立地选自:R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C6环烷基;各R8分别独立地选自:氢、卤素、氰基、醛基、R5取代或者未取代的C1-C3烷基胺基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C6环烷基、R5取代或者未取代的C1-C3烷氧基、R5取代或者未取代的C1-C3烷硫基、R5取代或者未取代的C1-C3烷硒基、R5取代或者未取代的C2-C3烯基、R5取代或者未取代的炔基。
- 根据权利要求7所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者 其前药分子或者其氘代物,其特征在于,各R7分别独立地选自:甲基、乙基、丙基、异丙基、三氟乙基、三氟甲基、环丙基、环丁基、环戊基、环己基;各R8分别独立地选自:氢、卤素、氰基、醛基、甲基、三氟甲基、二氟甲基、甲氧基、乙氧基、甲硫基、异丙氧基、三氟甲氧基、三氟乙氧基、环丙基、氨基、乙烯基、氟代环丙基、乙炔基。
- 根据权利要求1所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,T8选自:N、-CR9;R9选自:氢、卤素、氰基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C6环烷基。
- 根据权利要求9所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R9选自:氢、氰基。
- 根据权利要求1-10任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,所述含硒杂环类化合物具有如下式(IV)所示结构:
- 根据权利要求1-10任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R1选自:-OR10、-SR10、-NHR10、-CHO、-S(=O)R11、-S(=O)2R11、-COOR11、-CONHR11、R5取代或者未取代的C1-C3烷基、各R10分别独立地选自:H、C1-C3烷基、各R11分别独立地选自:氢、C1-C3烷基;各R12分别独立地选自:R5取代或者未取代的C1-C10烷基、R5取代或者未取代的苯基、R5取代或者未取代的5-6元杂芳基。
- 根据权利要求12所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R1选自:-OR10、-CHO、-COOH、-COOCH3、-CONH2、-CONHCH3、-CH3、-CF2H、-CF3、-OCH3、-SCH3、-NHR10、各R10分别独立地选自:H、甲基、各R11分别独立地选自:氢、甲基;各R12分别独立地选自:甲基、乙基、正丙基、异丙基、正丁基、叔丁基、戊基、苯基。
- 根据权利要求1-10任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R2选自:其中,各X分别独立地选自:N、CR16;R16选自:H、卤素、-CN、-OH、-COOH、C1-C8烷基;n选自:0、1、2、3;各R14分别独立地选自:氢、R5取代或者未取代的C1-C8烷基、氰基;各R15分别独立地选自:氢、C1-C8烷基、R11选自:氢、C1-C8烷基;各R12分别独立地选自:R5取代或者未取代的C1-C20烷基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的5-10元杂芳基。
- 根据权利要求14所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,各X分别独立地选自:N、CR16;R16选自:H、卤素、-CN、-OH、-COOH、C1-C3烷基;n选自:0、1、2、3;各R14分别独立地选自:氢、R5取代或者未取代的C1-C3烷基、氰基;各R15分别独立地选自:氢、C1-C3烷基、R11选自:氢、C1-C3烷基;各R12分别独立地选自:R5取代或者未取代的C1-C20烷基、R5取代或者 未取代的苯基、R5取代或者未取代的5-6元杂芳基。
- 根据权利要求15所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R2选自:X选自:CH、N、CF、-CCH3、-CCN、-C(OH);R14选自:氢、C1-C6烷基、氰基、-CH2CN、-CH2OH、-CH2NH2、-CH2COOH、-CH2CONH2、-CH2CH2NH2;R15选自:氢、C1-C3烷基、R11选自:氢、C1-C3烷基;R12选自:R5取代或者未取代的C1-C12烷基、R5取代或者未取代的苯基、R5取代或者未取代的5-6元杂芳基。
- 根据权利要求16所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R2选自:X选自:CH、N;R14选自:H、甲基、乙基、丙基、氰基、-CH2CN;R15选自:H、甲基、乙基、丙基、 R11选自:H、甲基;各R12分别独立地选自:H、正丁基、叔丁基、异丙基、甲基、乙基、辛烷基、壬烷基、十一烷基、戊烷基、庚烷基、已烷基、苯基、4-氟苯基。
- 根据权利要求1-10任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,所述含硒杂环类化合物具有如下式(V)所示结构:其中,R2选自:X选自:CH、N;R14选自:H、甲基、乙基、丙基;R15选自:H、甲基、乙基、丙基;R8选自:氢、氟、氯、甲基、三氟甲基、二氟甲基。
- 根据权利要求1-10任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R3选自:H、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的5-6元杂芳基、C1-C3烷基胺基、二(C1-C3烷基)胺基、R5取代或者未取代的6-8元含氮杂环基、-L-R13;L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-CF2-、-C=C-、-C≡C-、-Se-;R13选自:氢、卤素、氨基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C8环烷基、R17和R18取代或者未取代的3-8元含氮杂环基、-Q-R13’;Q选自:R5取代或者未取代的C1-C3亚烷基、 R13’选自:R17和R18取代或者未取代的3-8元含氮杂环基、R5取代或者未取代的5-6元杂芳基、C1-C3烷基胺基、二(C1-C3烷基)胺基、氨基;各R17分别独立地选自:氢、氘、R5取代或者未取代的C1-C6烷基、R5取代或者未取代的C3-C8环烷基;各R18分别独立地选自:氢、氘、氨基、氰基、羟基、卤素、R19取代或者未取代的C1-C6烷基、R5取代或者未取代的C1-C6烷氧基、R5取代或者未取代的C3-C8环烷基、R5取代或者未取代的C6-C10芳基、R5取代或者未取代的5-10元杂芳基;R19选自:氢、氘、卤素、羟基、羧基、酰胺基、氰基、氨基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C2-C3炔基、R20选自:R5取代或者未取代的5-6元杂环基,C1-C6烷基胺基、二(C1-C3烷基)胺基。
- 根据权利要求19所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R13选自:氢、卤素、氨基、R5取代或者未取代的C1-C3烷基、R5取代或者未取代的C3-C8环烷基,或者R13选自如下基团:
- 根据权利要求20所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R3选自:H、C1-C3烷基、卤素取代的C1-C3烷基、R5取代或者未取代的咪唑基、R5取代或者未取代的四氮唑基、R5取代或者未取代的吡唑基、C1-C3烷基胺基、二(C1-C3烷基)胺基、-L-R13;L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-C=C-、-Se-;R13选自:H、C1-C3烷基、卤素取代的C1-C3烷基、氨基取代的C1-C3烷基、甲胺基取代的C1-C3烷基、二甲胺基取代的C1-C3烷基、各R17分别独立地选自:氢、C1-C3烷基、氘代C1-C3烷基、乙炔基取代的C1-C3烷基、甲氧基取代的C1-C3烷基;各R18分别独立地选自:氢、卤素、C1-C3烷基、C1-C3烷氧基、R19取代的C1-C3烷基;R19选自:R20选自:R5取代或者未取代的吗啉基,C1-C3烷基胺基、二(C1-C3烷基)胺基。
- 根据权利要求21所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R3选自:H、甲基、二氟甲基、三氟甲基、1-甲基-咪唑-4-基、四氮唑基、1-甲基-5-氰基-吡唑-4-基、二甲胺基、-L-R13;L选自:-O-、-NH-、-S-、-S(=O)-、-S(=O)2-、-C(=O)-、-C(=O)(NH)-、-C(=NH)(NH)-、-CH2-、-C=C-、-C≡C-、-Se-;R13选自:H、甲基、三氟乙基、氨基取代的乙基、甲胺基取代的乙基、氨基取代的异丙基、各R17分别独立地选自:氢、甲基、氘代甲基、乙炔基取代的甲基、甲氧基取代的乙基;各R18分别独立地选自:氢、卤素、甲基、甲氧基、R19取代的甲基;R19选自:R20选自:吗啉基,二甲胺基。
- 根据权利要求22所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,R3选自:-L-R13;L选自:-O-、-S-、-Se-;R13选自:三氟乙基、氨基取代的乙基、甲胺基取代的乙基、氨基取代的异丙基、各R17分别独立地选自:氢、甲基、氘代甲基、甲氧基取代的乙基;各R18分别独立地选自:氢、氟、氯。
- 根据权利要求1所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物,其特征在于,选自如下化合物:
- 权利要求1-24任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物在制备KRAS G12D抑制剂中的应用。
- 权利要求1-24任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物在制备预防和/或治疗由KRAS G12D介导的疾病的药物中的应用。
- 根据权利要求26所述的应用,其特征在于,所述由KRAS G12D介导的疾病为过渡增殖性疾病。
- 根据权利要求27所述的应用,其特征在于,所述过渡增殖性疾病为肿瘤。
- 根据权利要求28所述的应用,其特征在于,所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、胃腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、子宫内膜癌、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤、恶性黑色素瘤、肾癌、膀胱癌、卵巢癌、宫颈癌、喉癌、多发性骨髓瘤、B淋巴瘤。
- 一种预防和/或治疗由KRAS G12D介导的疾病的方法,其特征在于,所述方法包括:施用安全有效量的权利要求1-24任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物。
- 根据权利要求30所述的方法,其特征在于,所述由KRAS G12D介导的疾病为过渡增殖性疾病。
- 根据权利要求31所述的方法,其特征在于,所述过渡增殖性疾病为肿瘤。
- 根据权利要求32所述的方法,其特征在于,所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、胃腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、子宫内膜癌、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤、恶性黑色素瘤、肾癌、膀胱癌、卵巢癌、宫颈癌、喉癌、多发性骨髓瘤、B淋巴瘤。
- 一种预防和/或治疗肿瘤的药用组合物,其特征在于,由活性成分和药学上可接受的辅料制备得到,所述活性成分包括权利要求1-24任一项所述的含硒杂环类化合物或其药学上可接受的盐或其立体异构体或者其前药分子或者其氘代物。
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