CN117327103A - 取代嘧啶并环类抑制剂及其制备方法和应用 - Google Patents
取代嘧啶并环类抑制剂及其制备方法和应用 Download PDFInfo
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- CN117327103A CN117327103A CN202310795478.7A CN202310795478A CN117327103A CN 117327103 A CN117327103 A CN 117327103A CN 202310795478 A CN202310795478 A CN 202310795478A CN 117327103 A CN117327103 A CN 117327103A
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本发明涉及取代的嘧啶并环类抑制剂及其制备方法和应用。具体地,本发明化合物具有式(I)所示结构,本发明还公开了所述化合物的制备方法及其作为KRAS突变抑制剂的用途,对KRAS突变具有很好的选择性抑制作用且具有更好的药效学、药代动力学性能和更低的毒副作用。
Description
技术领域
本发明属于药物领域,具体涉及一种取代嘧啶并环类抑制剂及其制备方法和应用。
背景技术
在所有人类肿瘤中约四分之一是由RAS突变引起,每年有近一百万人因此而失去生命。在RAS家族中,KRAS突变占到了所有RAS突变的85%。在近90%的胰腺癌、30-40%的结肠癌中、以及15-20%的肺癌中(主要为非小细胞肺癌)中均发现KRAS突变。
KRAS蛋白是由KRAS基因编码的一种小GTP酶,是细胞生长的重要调节蛋白,一旦KRAS被激活后,可以激活多条信号通路,促进细胞的增殖。KRAS蛋白最常发生基因突变的位点是第12、13和61位密码子,其中以12位密码子的突变最为常见。在KRAS G12突变中最主要的突变是G12A、G12C、G12D、G12V、G12S等突变,其中G12C、G12D、G12V等突变主要发生在NSCLC、CRC和胰腺癌中。到目前为止,市场上仍然没有同时针对多种KRAS G12突变的药物被批准上市。
由于KRAS突变靶蛋白在病理学上与多种疾病相关,尤其肺癌、胰腺癌、结直肠癌等,因此目前需要新型的KRAS突变抑制剂用于临床治疗。高选择性高活性的KRAS突变抑制剂可以对KRAS突变导致的癌症等疾病更有效治疗,以及减少脱靶效应的潜力,因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对KRAS突变有选择性抑制作用和/或更好药效学性能的化合物及其用途。
本发明的第一方面,提供一种式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药:
式中,
选自下组基团:/>
R1选自取代或未取代的下组基团:C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、-NRaRb或-ORa;其中,所述取代是指被一个或多个R取代;限定条件是R1不为取代或未取代的Ra、Rb各自独立的选自取代或未取代的下组基团:氢、氘、C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基;其中,所述取代是指被一个或多个R取代;优选的,R1选自取代或未取代的下组基团:
其中,所述取代是指被一个或多个R取代;
R2选自取代或未取代的下组基团:C6-C14芳基、和5-14元杂芳基;其中,所述取代是指被一个或多个R取代;
R3各自独立地选自取代或未取代的下组基团:H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、和4-6元杂环基氧基;
m为0、1、2、3、4、5或6的整数(m优选为0、1或2);
X选自:键、O、NH、N(C1-C3烷基)(X优选为O);
Y选自:键、或取代或未取代的C1-C6亚烷基;其中,所述取代是指被一个或多个R取代(Y优选为C1-C6亚烷基,更优选为亚甲基);
1)Z选自:
其中,环W1选自取代或未取代的下组基团:C3-C20亚环烷基、和4-20元饱和或不饱和的亚杂环基;其中,所述取代是指被一个或多个R取代;
R4选自:H,或者-L1-Q1-L2-L3;限定条件是当W1为时,R4不为H;
其中,
i)Q1选自:O、S、SO2、NH、NR5、CONH、CONR5、SO2NH、SO2NR5;其中,R5选自取代或未取代的下组基团:-C1-C6烷基、-C3-C6环烷基、-4-6元杂环基、-C6-C10芳基、-5-10元杂芳基;其中,所述取代是指被一个或多个R取代;
且L1选自:无、取代或未取代的C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
且L2选自:无、取代或未取代的C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
且L3选自取代或未取代的下组基团:-C1-C6烷基、C1-C6烷氧基、-C3-C6环烷基、-4-10元杂环基、-O-C3-C6环烷基、-O-4-6元杂环基、-C1-C6亚烷基C3-C6环烷基、-C1-C6亚烷基4-6元杂环基、-C1-C6亚烷基-O-C1-C6烷基、-C1-C6亚烷基-O-C3-C6环烷基、-C1-C6亚烷基-O-4-6元杂环基、NHR9’、NR9’R10’;R9’和R10’各自独立地选自取代或未取代的下组基团:C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6烷基、(4-10元杂环基)C1-C6烷基,或R9’和R10’与其连接的N原子共同形成取代或未取代的4-10元杂环基;其中,所述取代是指被一个或多个R取代;
或者
ii)-L1-Q1选自取代或未取代的下组基团:-C4-C8烷基、-C1-C6卤代烷基、-C3-C10环烷基、-4-10元杂环基、-C6-C10芳基、-5-10元杂芳基、-C1-C3亚烷基-(C3-C10环烷基)、-C1-C3亚烷基-(4-10元杂环基)、-C1-C3亚烷基-(C6-C10芳基)、-C1-C3亚烷基-(5-10元杂芳基);其中,所述取代是指被一个或多个R取代;
且L2和L3同时为无;
当X为键时,n选自:0、1、2、3、4、5或6的整数;当X不为键时,n选自:1、2、3、4、5或6的整数;
或者
2)Z选自:限定条件是当/>为/>时,/>不为/>
其中,环W2选自取代或未取代的下组基团:C3-C6亚环烷基、和4-6元饱和或不饱和的亚杂环基;其中,所述取代是指被一个或多个R取代;
L4选自取代或未取代的下组基团:键、C1-C6亚烷基、和氘代C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
Q2选自取代或未取代的下组基团:C1-C6烷氧基、C3-C10环烷基氧基、4-10元杂环基氧基、C3-C10环烷基C1-C6亚烷基氧基、4-10元杂环基C1-C6亚烷基氧基、C3-C10环烷基、4-10元杂环基、NHR9、NR9R10;R9和R10各自独立地选自取代或未取代的下组基团:C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6烷基、(4-10元杂环基)C1-C6烷基,或R9和R10与其连接的N原子共同形成取代或未取代的4-10元杂环基;其中,所述取代是指被一个或多个R取代;
各R相同或不同,各自独立地选自:H、氘、乙烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(=O)、氰基、酯基、胺基、酰胺基、砜基或脲基。
在另一优选例中,R1选自取代或未取代的下组基团:C3-C20环烷基、和4-20元饱和或不饱和的杂环基;其中,所述取代是指被一个或多个R取代;限定条件是R1不为取代或未取代的“”。
在另一优选例中,各R相同或不同,各自独立地选自:H、氘、乙烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(=O)、氰基、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基(如SO2NH2)、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH。
在另一优选例中,选自下组基团:/>
其中,R2的定义如上所述。
在另一优选例中,所述化合物具有式(II-A)或式(II-B)所示的结构:
式中,
R1、R2、R3、X、Y、Z和m的定义如上所述。
在另一优选例中,为/>Z的定义如上所述,优选地,/>选自:
在另一优选例中,所述化合物具有式(III-A1)、式(III-A2)或式(III-B1)、式(III-B2)所示的结构:
式中,
R1、R2、R3、R4、X、Y、W1、W2、L4、Q2、m和n的定义如上所述。
在另一优选例中,所述化合物具有式(IV-A1)、式(IV-A2)或式(IV-B1)、式(IV-B2)所示的结构:
式中,
R1、R2、R3、Y、W1、W2、L4、Q2、m和n的定义如上所述。
在另一优选例中,W1为取代或未取代的的7-10元的双环杂环基或取代或未取代的C7-C10双环环烷基,优选地,W1为取代或未取代的8元含N杂环基,其中,所述取代是指被一个或多个R取代,R的定义如上所述。
在另一优选例中,W1为取代或未取代的的7-10元的双环杂环基、取代或未取代的C7-C10双环环烷基、取代或未取代的的7-12元的三环杂环基、取代或未取代的C7-C12三环环烷基,优选地,W1为取代或未取代的8-12元(例如8、9、10或11)含N杂环基,其中,所述取代是指被一个或多个R取代,R的定义如上所述。
在另一优选例中,选自:
或者选自:
其中,n’为0、1、2、3、4、5、或6的整数;R、R4和n的定义如上所述,R、R4可以取代在多环(如桥环或螺环)的任意一个环上;
更优选地,选自:
其中,n’和R的定义如上所述,R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中,为/>
在另一优选例中,所述化合物具有式V所示的结构
优选地,所述化合物具有式VI所示的结构
其中,R1、R2、R3、R4、X、Y、W1和n的定义如上所述。
在另一优选例中,R3选自:H、卤素、CN、硝基、OH、氨基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基;优选地,R3选自:H、F、甲氧基、甲基、三氟甲基、三氟甲氧基。
在另一优选例中,为/>优选地为/>
在另一优选例中,选自:
在另一优选例中,所述化合物具有式(V-A1)或式(V-B1)所示结构:
式中,
n’为0、1、2、3、4、5、或6的整数;
R1、R2、R3、R、L1、L2、L3、Q1、m、n和n’的定义如上所述。
在另一优选例中,为/>
在另一优选例中,-L1-Q1-L2-L3选自取代或未取代的下组基团:-C1-C6烷氧基、-C3-C10环烷基氧基、-4-10元杂环基氧基、(C3-C10环烷基)C1-C6亚烷基氧基、(4-10元杂环基)C1-C6亚烷基氧基、-O-C1-C6亚烷基-O-(C1-C6烷基)、-C1-C6亚烷基-O-(C1-C6亚烷基(C3-C10环烷基))、-C1-C6亚烷基-O-(C1-C6亚烷基(4-10元杂环基))、-O-C1-C6亚烷基-NHR9”、-O-C1-C6亚烷基-NR9”R10”、-C1-C6亚烷基-O-(C1-C6亚烷基NHR9”)、-C1-C6亚烷基-O-(C1-C6亚烷基NR9”R10”)、-NRn-(C1-C6亚烷基NHR9”)、-NRn-(C1-C6亚烷基NR9”R10”)、-C1-C6亚烷基NHR9”、-C1-C6亚烷基NR9”R10”、NHR9”、NR9”R10”;Rn选自:H或取代或未取代的C-C6烷基;R9”和R10”各自独立地选自取代或未取代的下组基团:C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6烷基、(4-10元杂环基)C1-C6烷基,或R9”和R10”与其连接的N原子共同形成取代或未取代的4-10元杂环基;其中,所述取代是指被一个或多个R取代。
在另一优选例中,-L1-Q1-L2-L3选自取代或未取代的下组基团:-C4-C8烷基、-C1-C6卤代烷基、-C3-C10环烷基、-4-10元杂环基、-C6-C10芳基、-5-10元杂芳基、-C1-C3亚烷基-(C3-C10环烷基)、-C1-C3亚烷基-(4-10元杂环基)、-C1-C3亚烷基-(C6-C10芳基)、-C1-C3亚烷基-(5-10元杂芳基);其中,所述取代是指被一个或多个R取代。
在另一优选例中,-L1-Q1-L2-L3选自:
或者选自:
或者选自:
/>
或者选自:或者选自:
在另一优选例中,选自:
或者选自:
或者选自:
或者选自:
或者选自:
在另一优选例中,R2选自取代或未取代的下组基团:C6-C10芳基、和5-10元杂芳基;其中,所述取代是指被一个或多个R取代;R选自:卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基(如)、C2-C6烯基、C2-C6炔基、酯基(如COC1-C6烷基)、胺基(如NH2、C1-C6烷基NH2)、酰胺基(如CONH2、CONHC1-C6烷基、CONHCH3、CONH-C3-C6环烷基)、砜基(如SO2C1-C6烷基)、脲基、磺酰胺基(如SO2NH2)、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH。
在另一优选例中,选自/>优选地为/>更优选地为/>
在另一优选例中,R2选自取代或未取代的下组基团:苯基、萘基、5-6元单环杂芳基(如吡啶基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃),其中所述取代是被选自下组的一个或多个基团取代:卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基(如)、C2-C6烯基、C2-C6炔基、酯基(如COC1-C6烷基)、胺基(如NH2、C1-C6烷基NH2)、酰胺基(如CONH2、CONHC1-C6烷基、CONHCH3、CONH-C3-C6环烷基)、砜基(如SO2C1-C6烷基)、脲基、磺酰胺基(如SO2NH2)、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH,优选地,R2选自:
/>
在另一优选例中,所述化合物选自下组:
/>
或者选自:
或者选自:
/>
/>
或者选自:
/>
或者选自:
/>
或者选自:
/>
或者选自:
/>
或者选自:
或者选自:
或者选自:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
在另一优选例中,所述化合物优选为实施例中所制备的化合物。
本发明第二方面,提供一种制备式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法,其特征在于,包括步骤:
(i)在惰性溶剂中,碱存在下,有或者没有Pd催化剂,有或者没有缩合剂存在下,式X-I化合物与化合物R1-LG3反应,得到式X-II化合物;
(ii)在惰性溶剂中,碱存在下,有或者没有Pd催化剂存在下,式X-II化合物与式X-III化合物反应,得到式X-IV化合物;
(iii)在惰性溶剂中,碱存在下,有或者没有Pd催化剂存在下,式X-IV化合物与式V-6化合物R2-LG5反应,得到式I化合物;
LG1、LG2、LG3、LG4、以及LG5为离去基团,各自独立地选自:H、OH、卤素、OTf、OTs、OMs、-B(OH)2、-B(KBF3)、-Sn(nBu)3、等;
Pd催化剂选自:Pd(OAc)2、Pd(dba)2、Pd2(dba)3、XPhos PdG2、RuPhos PdG2、XantPhos-Pd-G2、cataCXium A-Pd-G2、XPhos PdG3、RuPhos PdG3、XantPhos-Pd-G3、cataCXium A-Pd-G3、BrettPhos PdG3、SPhos PdG3、tBuXPhos-Pd-G3、XantPhos-Pd-G4、BrettPhos PG4、SPhos Pd G4、cataCXium A-Pd-G4、Rockphos PdG4等;
R1、R2、R3、环A、X、Y、Z、和m的定义如上所述。
本发明第三方面,提供一种药物组合物,其包含一种或多种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药;和药学上可接受的载体。
在另一优选例中,所述药物组合物还包含选自下组的药物:PD-1抑制剂(如纳武利尤单抗(nivolumab)、派姆单抗(pembrolizumab)、pidilizumab、西米普利单抗(cemiplimab)、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10,BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗(durvalumab)、阿特珠单抗(atezolizumab)、阿维单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗(rituximab)、奥妥珠单抗(obinutuzumab)、奥法木单抗(ofatumumab)、维妥组单抗(veltuzumab)、托西莫单抗(tositumomab)、131I-托西莫单抗(131I-tositumomab)、ibritumomab、90Y-ibritumomab、90In-ibritumomab、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如塞瑞替尼(Ceritinib)、阿来替尼(Alectinib)、布加替尼(Brigatinib)、劳拉替尼(Lorlatinib)、奥卡替尼等)、PI3K抑制剂(如艾代拉里斯(Idelalisib)、杜韦利西布(Duvelisib)、Dactolisib、Taselisib、Bimiralisib、Omipalisib、布帕尼西(Buparlisib)等)、BTK抑制剂(如依鲁替尼(Ibrutinib)、替拉鲁替尼(Tirabrutinib)、阿卡替尼(Acalabrutinib)、泽布替尼(Zanubrutinib)、维卡布鲁替尼(Vecabrutinib)等)、EGFR抑制剂(如阿法替尼(Afatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)、达克替尼(Dacomitinib)、埃克替尼(Icotinib)、卡奈替尼(Canertinib)、沙普替尼(Sapitinib)、Naquotinib、吡咯替尼(Pyrotinib)、鲁卡帕尼(Rociletinib)、奥希替尼(Osimertinib)等)、VEGFR抑制剂(如索拉非尼(Sorafenib)、帕唑帕尼片(Pazopanib)、瑞戈非尼(Regorafenib)、司曲替尼(Sitravatinib)、宁格替尼(Ningetinib)、卡博替尼(Cabozantinib)、舒尼替尼(Sunitinib)、多纳非尼等)、HDAC抑制剂(如Givinostat、西达本胺(Tucidinostat)、伏立诺他(Vorinostat)、非美诺司他(Fimepinostat)、Droxinostat、恩替诺特(Entinostat)、达西司特(Dacinostat)、Quisinostat、乙酰地那林(Tacedinaline)等)、CDK抑制剂(如帕博西尼(Palbociclib)、瑞博替尼(Ribociclib)、玻玛西林(Abemaciclib)、嘧西利(Milciclib)、曲拉西利(Trilaciclib)、来罗西利(Lerociclib)等)、MEK抑制剂(如司美替尼(Selumetinib(AZD6244))、曲美替尼(Trametinib(GSK1120212))、PD0325901、U0126、匹马赛替尼(Pimasertib(AS-703026))、PD184352(CI-1040)等)、mTOR抑制剂(如维妥色替(Vistusertib)等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、SOS1抑制剂(如BI 1701963)或其组合。
本发明第四方面,提供一种如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或如第三方面所述的药物组合物的用途,用于制备预防和/或治疗与KRAS突变(如KRAS G12突变)的活性或表达量相关的疾病的药物,优选地,所述的疾病为肿瘤或失调性疾病。
在另一优选例中,所述疾病选自下组:肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
本发明第五方面,提供了一种非诊断性、非治疗性地抑制KRAS突变(如KRAS G12突变)的方法,其包括步骤:向所需对象施用有效量的如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或施用如第三方面所述的药物组合物。
在另一优选例中,所述的对象为哺乳动物,较佳地为人。
本发明第六方面,提供一种体外抑制KRAS突变(如KRAS G12突变)活性的方法,包括步骤:将如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或如第三方面所述的药物组合物与蛋白或者细胞接触,从而抑制KRAS突变(如KRAS G12D)的活性。
在另一优选例中,所述的细胞选自下组:巨噬细胞、肠道细胞(包括肠干细胞、肠上皮细胞)、或其组合。
在另一优选例中,所述的细胞来自啮齿动物(如小鼠、大鼠)、或灵长动物(如人)。
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,意外地制备了一类新型的KRAS突变(如KRASG12突变)有选择性抑制作用和/或更好药效学性能的化合物。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链烷烃基,包含1-20个碳原子,如1-18个碳原子,尤其指1-18个碳原子,优选地包含1-10个碳原子(C1-C10),更优选地包含1-6个碳原子(C1-C6)。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基,十二烷基等等。本发明中,烷基还包括取代烷基。“取代烷基”是指烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环,Rb、Rc和Rd可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、5-14元杂环或C6-C14芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基或取代的烷基”再脱掉一个氢原子所形成的基团,如亚甲基、亚乙基、亚丙基、亚异丙基(如)、亚丁基(如/>)、亚戊基(如/>)、亚己基(如/>)、亚庚基(如/>)、/>等。此外,所述术语还包括亚烷基(如C1-C18亚烷基)的一个亚甲基被一个亚环烷基(如C3-C20亚环烷基)所替换,例如“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”。
术语“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义,是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团,如/>
等。优选地C1-C6亚烷基C3-C6亚环烷基。
本发明中,术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。烯基优选C2-C6烯基,更优选C2-C4烯基。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中,烯基包括取代的烯基。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。炔基优选C2-C6炔基,更优选C2-C4炔基。炔基包括但不限于乙炔基、丙炔基或类似基团。本发明中,炔基还包括取代炔基,取代基可以为卤代、羟基、氰基、硝基等。
本发明中,术语“环烷基”是指完全饱和的环状烃类化合物基团,包括1-4个环,每个环中含有3-8个碳原子。术语“C3-C20”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子环烷基的。环烷基优选地为C3-C14环烷基,更优选地为C3-C10环烷基,更优选地为C3-C6单环环烷基、C7-C10双环或三环环烷基。“取代环烷基”是指环烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。本发明中,“环烷基”包含取代环烷基,典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe、P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、嘧啶并环或稠环取代基,尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、嘧啶并环烷基、嘧啶并环烯基、嘧啶并环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基,上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环烷基的实例包括但不限于:环丙基、环丁基、环戊基、环己基、金刚烷基等。
术语“C3-C20亚环烷基”是指环烷基脱掉两个氢原子所形成的基团,如:等。
本发明中,术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环、4-7元单环、6-11元双环或8-16元三环或多环系统),其中至少有一个杂原子存在于至少有一个碳原子的环中。术语“4-20元杂环基”是指包含4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个环原子的杂环基。“杂环基”与“饱和或不饱和的杂环基”具有相同含义。“杂环基”优选地为4-14元杂环基(包含但不限于如4-6元单环、7-10元双环或8-14元三环或多环系统),更优选地为4-12元杂环基,更优选地为4-10元杂环基,如4-6元单环杂环基、7-11元双环或三环杂环基,更优选地为4-8元杂环基,更优选地为4-6元杂环基。每个含有杂原子的杂环可以带有1,2,3或4个杂原子,这些杂原子选自氮原子、氧原子或硫原子,其中氮原子或硫原子可以被氧化,氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上,优选连接到环或环系分子上的N或C原子。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和嘧啶并环的杂环基;其中涉及到的螺环、稠环和嘧啶并环的杂环基任选与其他基团通过单键相连接,或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接;杂环基团可以是取代的或者未取代的,当被取代时,取代基优选为一个或多个一下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“4-20元亚杂环基”是指杂环基脱掉两个氢原子所形成的基团,如:等。
本发明中,术语“芳基”是指芳香环状烃基团,具有1-5个环,尤其指单环和双环基团。其中,“C6-C14芳基”是指包含6、7、8、9、10、11、12、13或14个环碳原子的芳香环状烃类化合物基团。芳基包括苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等),芳基基团的芳香环可由单键联接(如联苯),或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代,尤其是1-3个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧代基(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基或芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基或芳基。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基,尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基,上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子芳香环状烃基团,其中杂原子选自氧、氮和硫的。其中,“5-14元杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系。杂芳基优选5至10元环,更优选为5元或6元,例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
本发明中,术语“烷氧基”是指具有直链或支链烷氧基,包含烷基-O-、烷基-O-烷基,其中,“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链烷氧基,包含C1-C18烷基-O-、-C1-C6烷基-O-C1-C6烷基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基,更优选C1-C6烷氧基。
本发明中,术语“环烷基氧基”是指环烷基-O-,其中,“C3-C20环烷基氧基”是指C3-C20环烷基-O-,其中,C3-C20环烷基的定义如上所述。
本发明中,术语“杂环基氧基”是指杂环基-O-,其中,“4-20元杂环基氧基”是指4-20元杂环基-O-,其中,4-20元杂环基的定义如上所述。
本发明中,术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。
本发明中,术语“卤素”或“卤”是指氯、溴、氟、碘。
本发明中,术语“卤代”是指被卤素取代。
本发明中,术语“氘代”是指被氘取代。
本发明中,术语“羟基”是指带有结构OH的基团。
本发明中,术语“硝基”是指带有结构NO2的基团。
本发明中,术语“氰基”是指带有结构CN的基团。
本发明中,术语“酯基”是指带有结构-COOR的基团,其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。酯基优选地为-COO C1-C6烷基。
术语“胺基”是指带有结构-NRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R和R'在二烷基胺片段中可以相同或不同。胺基优选地为NH2、NHC1-C6烷基、N(C1-C6烷基)2。
术语“酰胺基”是指带有结构-CONRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R和R'在二烷基胺片段中可以相同或不同。酰胺基优选地为CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)。
术语“砜基”是指带有结构-SO2R的基团,其中R可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。
术语“磺酰胺基”是指带有结构-SO2NRR'的基团,其中R可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。磺酰胺基优选地为-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(C3-C6环烷基)。
术语“脲基”是指带有结构-NRCONR'R"的基团,其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"烷基胺基烷基"是指带有结构-RNHR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R和R'可以相同或不同。
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团,其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"杂环基烷基"是指带有结构-RR'的基团,其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基;R'代表杂环或取代的杂环。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明,假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时,其为相应基团的亚基,例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
本发明中,多个是指2、3、4、5。
活性成分
如本文所用,“本发明化合物”指式I所示的化合物,并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”,指用无机或有机酸和碱形成酸式或碱式的盐。此外,当本发明中的化合物含一个碱性片段时,它包括但不限于吡啶或咪唑,含一个酸性片段时,包括但不限于羧酸,可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒,生理可接受的)盐是首选,虽然其他盐类也有用,例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐,例如,化合物I与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段,包括但不限于胺或吡啶或咪唑环,可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸,如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如,2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如,2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐,水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段,包括但不限于羧酸,可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐,碱土金属盐如钙、镁盐,和有机碱形成的盐(如有机胺),如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺,以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐,如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物),二烷基硫酸盐(如,硫酸二甲酯、二乙酯,二丁酯和二戊酯),长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物),芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物,在治疗相关疾病时,经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物,如水合物。
本发明中的化合物、盐或溶剂合物,可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如,那些由于对各种取代可能存在的不对称碳原子),包括其对映体形式和非对映形式,都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如,作为一个纯的或者实质上是纯的光学异构体具有特殊的活性),或者也可能是混合物,如消旋体,或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型,由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决,例如分步结晶,或通过衍生为非对映异构体分离结晶,或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到,包括但不限于传统的方法,例如与光学活性酸成盐后再结晶。
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内,无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体,以及碳环和杂环的顺式和反式异构体。
在整个说明书中,基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说,化学元素与Periodic Table of the Elements,CAS version,Handbook ofChemistry andPhysics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外,有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University ScienceBooks,Sausalito:1999,也有说明,其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物,包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基,如烷基。所有异构体以及它们的混合物,都包涵在本发明中。
按照本发明,同分异构体的混合物含有异构体的比率可以是多样的。例如,在只有两个异构体的混合物可以有以下组合:50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1,或100:0,异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率,及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢,碳,氮,氧,磷,硫,氟和氯同位素,分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如3H和14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即3H和碳-14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的,例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。在本发明中,术语“前药”指药物经过化学结构修饰引入易离去基团后得到的在体外无活性或活性较小,但是在体内经过酶(如水解酶、氧化酶等)参与或非酶参与(如pH、光照、辐射等)的转化释放出活性药物而发挥药效的化合物。所述前药例如(但并不限于):羧酸酯、磷酸酯、氨基甲酸酯、碳酸酯等。易离去基团结构如(但并不限于):
制备方法
下面更具体地描述本发明式(I-A)和式(I-B)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
典型地,本发明化合物的制备工艺流程如下,其中所用原料和试剂如无特殊说明,均可通过商业途径购买。
优选地,本发明化合物采用如下方法制备
(i)在惰性溶剂中,碱存在下,有或者没有Pd催化剂,有或者没有缩合剂存在下,式X-I化合物与化合物R1-LG3反应,得到式X-II化合物;
(ii)在惰性溶剂中,碱存在下,有或者没有Pd催化剂存在下,式X-II化合物与式X-III化合物反应,得到式X-IV化合物;
(iii)在惰性溶剂中,碱存在下,有或者没有Pd催化剂存在下,式X-IV化合物与式V-6化合物R2-LG5反应,得到式I化合物;
LG1、LG2、LG3、LG4、以及LG5为离去基团,各自独立地选自:H、OH、卤素、OTf、OTs、OMs、-B(OH)2、-B(KBF3)、-Sn(nBu)3、等;
Pd催化剂选自:Pd(OAc)2、Pd(dba)2、Pd2(dba)3、XPhos Pd G2、RuPhos Pd G2、XantPhos-Pd-G2、cataCXium A-Pd-G2、XPhos Pd G3、RuPhos Pd G3、XantPhos-Pd-G3、cataCXium A-Pd-G3、BrettPhos Pd G3、SPhos Pd G3、tBuXPhos-Pd-G3、XantPhos-Pd-G4、BrettPhos Pd G4、SPhos Pd G4、cataCXium A-Pd-G4、Rockphos Pd G4等;
R1、R2、R3、环A、X、Y、Z、和m的定义如上所述。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式I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化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时,式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为:PD-1抑制剂(如利尤单抗(nivolumab)、派姆单抗(pembrolizumab)、pidilizumab、西米普利单抗(cemiplimab)、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10,BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗(durvalumab)、阿特珠单抗(atezolizumab)、阿维单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗(rituximab)、奥妥珠单抗(obinutuzumab)、奥法木单抗(ofatumumab)、维妥组单抗(veltuzumab)、托西莫单抗(tositumomab)、131I-托西莫单抗(131I-tositumomab)、ibritumomab、90Y-ibritumomab、90In-ibritumomab、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如塞瑞替尼(Ceritinib)、阿来替尼(Alectinib)、布加替尼(Brigatinib)、劳拉替尼(Lorlatinib)、奥卡替尼等)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼(Ibrutinib)、替拉鲁替尼(Tirabrutinib)、阿卡替尼(Acalabrutinib)、泽布替尼(Zanubrutinib)、维卡布鲁替尼(Vecabrutinib)等)、EGFR抑制剂(如阿法替尼(Afatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)、达克替尼(Dacomitinib)、埃克替尼(Icotinib)、卡奈替尼(Canertinib)、沙普替尼(Sapitinib)、Naquotinib、吡咯替尼(Pyrotinib)、鲁卡帕尼(Rociletinib)、奥希替尼(Osimertinib)等)、VEGFR抑制剂(如索拉非尼(Sorafenib)、帕唑帕尼片(Pazopanib)、瑞戈非尼(Regorafenib)、司曲替尼(Sitravatinib)、宁格替尼(Ningetinib)、卡博替尼(Cabozantinib)、舒尼替尼(Sunitinib)、多纳非尼等)、HDAC抑制剂(如Givinostat、西达本胺(Tucidinostat)、伏立诺他(Vorinostat)、非美诺司他(Fimepinostat)、Droxinostat、恩替诺特(Entinostat)、达西司特(Dacinostat)、Quisinostat、乙酰地那林(Tacedinaline)等)、CDK抑制剂(如帕博西尼(Palbociclib)、瑞博替尼(Ribociclib)、玻玛西林(Abemaciclib)、嘧西利(Milciclib)、曲拉西利(Trilaciclib)、来罗西利(Lerociclib)等)、MEK抑制剂(如司美替尼(Selumetinib(AZD6244))、曲美替尼(Trametinib(GSK1120212))、PD0325901、U0126、匹马赛替尼(Pimasertib(AS-703026))、PD184352(CI-1040)等)、mTOR抑制剂(如维妥色替(Vistusertib)等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。本发明所述药物组合物的剂型包括(但并不限于):注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
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或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”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的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药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)、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、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
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50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明所述通式(I-A)和式(I-B)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述通式(I)化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物,或施用本发明所述的药物组合物,用于选择性地抑制KRAS突变(如KRAS G12突变)。
与现有技术相比,本发明具有以下主要优点:
(1)所述化合物对KRAS G12突变具有很好的选择性抑制作用;
(2)所述化合物具有更好的药效学、药代动力学性能和更低的毒副作用。
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 LaboratoryPress,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熟练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。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的,测定溶剂包含氘代二甲亚砜(DMSO-d6)、氘代丙酮(CD3COCD3)、氘代氯仿(CDCl3)及氘代甲醇(CD3OD)等,内标采用四甲基硅烷(TMS),化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb 5micron C18100 x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板,TLC采用的是0.15-0.20mm,制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的,或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外,本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行,反应温度均为摄氏度。
实施例
中间体1-1(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇的制备
第一步:1-苄基2-甲基2-(丁-3-烯-1-基)吡咯啉-1,2-二甲酸酯的制备
氮气保护下,在-70℃ 1-苄基2-甲基(S)-吡咯啉-1,2-二甲酸酯(50.0g,190mmol,1.00eq)的THF(100mL)溶液滴加到LiHMDS(1.00M,285mL,1.50eq)中。得到的反应液在-70℃反应2h,随后滴加4-溴丁-1-烯(51.2g,380mmol,38.6mL,2.00eq)。得到的反应液升温至25℃并反应16h随后用饱和NH4Cl(200mL)水溶液淬灭,然后用EtOAc(100mL*3)萃取。合并的有机相用饱和食盐水(200mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(38.0g,120mmol,63.1%产率)。
1H NMR(400MHz,CDCl3)δ7.33(m,5H),5.77(m,1H),5.07(m,4H),3.72(m,3H),3.48(m,2H),2.01(m,8H)。
第二步:1-苄基2-甲基2-(2-(环氧丙烷-2-基)乙基)吡咯啉-1,2-二甲酸酯的制备
在0℃下,1-苄基2-甲基2-(丁-3-烯-1-基)吡咯啉-1,2-二甲酸酯(37.5g,118mmol,1.00eq)的DCM(650mL)溶液中分批加入m-CPBA(60.0g,295mmol,85.0%纯度,2.50eq)。得到的反应液在25℃反应16h,然后用饱和Na2SO3(300mL*3)洗涤。有机相用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到目标产物(29.0g,87.0mmol,73.6%产率)。
1H NMR(400MHz,CDCl3)δ7.33(br d,J=7.88Hz,5H),5.11(m,2H),3.70(m,3H),3.48(m,2H),2.73(m,2H),2.36(m,2H),1.98(m,5H),1.50(m,2H)。
第三步:3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的制备
1-苄基2-甲基2-(2-(环氧丙烷-2-基)乙基)吡咯啉-1,2-二甲酸酯(28.0g,84.0mmol,1.00eq)的MeOH(600mL)溶液中加入Pd/C(6.00g,10.0%wt)。在氢气氛围下,反应物在25℃反应16h然后过滤。滤液减压浓缩得到目标产物(16.8g)。无需纯化直接用于下一步反应。
第四步:3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的制备
氮气保护下,在0℃下3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(1.00g,5.02mmol,1.00eq)的THF(20mL)溶液中加入NaH(602mg,15.1mmol,60.0%wt,3.00eq)。反应液在25℃反应0.5h,随后加入MeI(1.42g,10.0mmol,625μL,2.00eq)。得到的反应液在25℃反应3h,然后在0℃下用H2O(10mL)淬灭后用EtOAc(30mL*2)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到目标产物(1.0g,1.88mmol,37.5%产率)。
1H NMR(400MHz,CDCl3)δ3.66-3.72(m,3H),3.30-3.33(m,3H),2.22-2.43(m,1H),1.83-2.12(m,6H),1.56-1.72(m,1H)。
第五步:(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇的制备
氮气保护下,在0℃下3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(1.00g,4.69mmol,1.00eq)的THF(10mL)溶液中加入LiAlH4(356mg,9.38mmol,2.00eq)。反应液在25℃反应1h,随后在0℃下依次加入H2O(10mL)、15%NaOH(10mL)和H2O(30mL)淬灭,再用EtOAc(50mL*2)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到目标产物(1.1g)。
LC-MS:m/z 186(M+H)+。1H NMR(400MHz,CDCl3)δ4.39(dd,J=10.54,9.03Hz,
1H),4.26(br d,J=6.53Hz,1H),3.97-4.06(m,1H),3.80-3.96(m,2H),3.68-3.76(m,2H),3.50(s,3H),2.04-2.40(m,6H),1.78-1.93(m,2H)。
经SFC分离得到异构体A中间体1-1A和异构体B中间体1-1B:
中间体1-1A:顺式-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 186(M+H)+。
中间体1-1B:反式-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 186(M+H)+。
按中间体1-1同样的合成方法以不同起始原料合成以下化合物:
中间体1-2(3-((乙氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 200(M+H)+。
中间体1-3(3-((异丙氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 214(M+H)+。
中间体1-4(3-((环丙基甲氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 226(M+H)+。
中间体1-5(3-(环丙氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
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LC-MS:m/z 212(M+H)+。
中间体1-6((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 204(M+H)+。
中间体1-7((2R)-2-氟-5-(环丙氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS:m/z 230(M+H)+。
中间体2-1((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷的制备
第一步:7-氟-8-((三异丙基硅基)乙炔基)萘-1,3-二醇的制备
氮气保护下,在室温下7-氟萘-1,3-二醇(5g,28.1mmol,1eq)、(溴乙炔)三异丙基硅烷(7.33g,28.1mmol,1eq)、和醋酸钾(5.51g,56.1mmol,2eq)的dioxane(120mL)溶液中加入二氯化钌1-异丙基-4-甲基-苯(1.20g,1.96mmol,0.07eq)。反应液在110℃反应16h然后过滤。滤饼用EtOAc(200mL*2)洗涤。合并的有机相减压浓缩。残余物用硅胶柱层析分离得到目标产物(8g,22.3mmol,79.5%产率)。
1H NMR(400MHz,CDCl3)δ9.19(m,1H)7.60(dd,J=9.17,5.62Hz,1H),7.18(m,1H),6.73(m,2H),5.29(br s,1H),1.22(m,21H)。
第二步:7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-醇的制备
0℃下7-氟-8-((三异丙基硅基)乙炔基)萘-1,3-二醇(7g,19.5mmol,1eq)和DIEA(5.05g,39.0mmol,6.80mL,2eq)的DCM(100mL)溶液中加入MOMCl(1.66g,20.6mmol,1.57mL,1.06eq)。得到的反应液在25℃反应1.5h然后用H2O(200mL)淬灭,再用1N HCl调节pH 6-7,再用DCM(80.0mLx 2)萃取。合并的有机相用饱和食盐水(200mL)洗涤,再用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到目标产物(4.2g,10.4mmol,53.4%产率)。
1H NMR(400MHz,DMSO-d6)δ8.94-9.20(m,1H),8.93-9.13(m,1H),7.58(dd,J=9.07,5.69Hz,1H),7.10(t,J=8.82Hz,1H),6.89(d,J=2.50Hz,1H),6.73(d,J=1.88Hz,1H),5.12-5.24(m,2H),3.43(s,3H),1.09-1.13(m,21H)。
第三步:7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基三氟甲烷磺酸酯的制备
-40℃下7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-醇(4g,9.94mmol,1eq)的DCM(40mL)溶液中加入DIEA(3.85g,29.8mmol,5.19mL,3eq)和Tf2O(4.21g,14.9mmol,2.46mL,1.5eq)。得到的反应液在-40℃反应0.5h,然后用H2O(20mL)稀释后再用DCM(50mL*2)萃取。合并的有机相用饱和食盐水(100mL)洗涤,再用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到黄色油状目标产物(5g,8.88mmol,89.4%产率,95%纯度).
1H NMR(400MHz,CDCl3)δ7.72(dd,J=9.03,5.27Hz,1H),7.44(d,J=2.26Hz,1H),7.36-7.39(m,1H),7.31-7.35(m,1H),5.20-5.37(m,2H),3.46-3.63(m,3H),1.17-1.33(m,17H)。
第四步:((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷的制备
氮气保护下,7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基三氟甲烷磺酸酯(5g,9.35mmol,1eq)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)-1,3,2-二氧硼环戊烷(4.75g,18.70mmol,2eq)、AcOK(2.75g,28.06mmol,3eq)的甲苯(100mL)溶液中加入Pd(dppf)Cl2(684mg,935umol,0.1eq)。得到的反应液在130℃反应8h然后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到目标产物(3.5g,6.49mmol,69.3%产率)。
LC-MS:m/z 513(M+H)+。1H NMR(400MHz,CDCl3)δ7.68(dd,J=8.93,5.62Hz,1
H),7.52(d,J=2.45Hz,1H),7.39(d,J=2.57Hz,1H),7.24(t,J=8.80Hz,1H),5.18-5.39(m,2H),3.43-3.58(m,3H),1.45(s,12H),1.15-1.21(m,20H)。
按中间体2-2同样的合成方法以不同起始原料合成以下化合物:
LC-MS:m/z 361(M+H)+。
中间体3-12,4,7-三氯-8-氟吡啶[4,3-d]嘧啶的制备
第一步:2-氯-3-氟-5-碘吡啶-4-胺的制备
2-氯-3-氟吡啶-4-胺(10g,68.5mmol)和NIS(18.5g,82.2mmol,1.2eq)的乙腈(50mL)溶液中加入对甲苯磺酸单水合物(0.65g,3.43mmol,0.05eq)。反应液在70℃搅拌16小时,然后用水(30mL)和EtOAc(200mL)稀释。分离的有机相依次用S.aq.Na2CO3、S.aq.Na2SO3和饱和食盐水洗涤,经无水硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(16.6g,61mmol,产率:89%)。无需纯化,直接用于下一步反应。
LC-MS:m/z 273(M+H)+。
第二步:4-氨基-6-氯-5-氟烟酸乙酯的制备
氮气氛围下,2-氯-3-氟-5-碘吡啶-4-胺(8.2g,30mmol,1.0eq)的EtOH(150mL)溶液中加入Pd(PPh3)2Cl2(2.1g,3mmol,0.1eq)和TEA(11.1g,0.11mmol,3.6eq),得到的反应液在CO2氛围下,在80℃反应15小时,然后过滤。滤液减压浓缩至原体积的70-80%然后再次过滤。滤饼收集合并后真空干燥,得到目标产物(定量收率)。无需纯化,直接用于下一步反应。
LC-MS:m/z 219(M+H)+。
第三步:7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇的制备
在0℃下,在上述得到的4-氨基-6-氯-5-氟烟酸乙酯(657mg,3mmol)的THF(7mL)溶液中加入三氯乙酰基异氰酸酯(673mg,3.6mmol,1.2eq)。反应液在rt反应30min然后减压浓缩。残余物中加入MeOH(15mL),并冷却到0℃,随后加入NH3甲醇溶液(7M in MeOH,15mL,105mmol)。得到的反应液在rt反应16小时然后过滤。滤饼用甲醇洗涤然后真空干燥得到目标产物(定量收率)。无需纯化,直接用于下一步反应。
LC-MS:m/z 216(M+H)+。
第四步:2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶的制备
7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇(500mg,2.4mmol)和DIPEA(1.55g,12mmol,5.0eq)的POCl3(5mL)溶液在100℃反应1小时,然后减压浓缩,得到目标化合物(定量收率)。无需纯化,直接用于下一步反应。
LC-MS:m/z 252(M+H)+。
实施例A-1 1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
第一步:1-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
-40℃下,2,4,7-三氯-8-氟-吡啶[4,3-d]嘧啶(1g,4mmol)、DIPEA(2.06g,16mmol)的DCM(10mL)溶液中加入3-甲基哌啶-3-醇(0.46g,4mmol)。反应液在-40℃反应0.5hr,然后用水(10mL)淬灭后用DCM(20mL)萃取。有机相用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用中压过柱机分离得到目标产物(0.53g,40%产率)。
LC-MS:m/z 331(M+H)+。
第二步:1-(7-氯-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
1-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(0.53g,1.6mmol)、((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇(0.33g,1.78mmol)和4A分子筛(0.5g)的二氧六环(4mL)的溶液中加入DIPEA(0.62g,4.8mmol)。反应液在90℃反应10hr,然后过滤。滤液加入乙酸乙酯(10mL)和水(5mL)分层。水相分离后用乙酸乙酯(10mL)萃取。合并的有机相用饱和食盐水(5mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用制备液相分离得到目标产物(0.42g,54%产率)。
LC-MS:m/z 480(M+H)+。
第三步:1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
氮气保护下,1-(7-氯-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(0.4g,0.83mmol)、2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-l-基)-4,4,5,5-四甲基-1,3,2-二氧环戊硼烷(0.4g,1.12mmol)和K3PO4(1.5M水溶液,1.1mL)的THF(2mL)溶液中加入cataCXium A Pd-G3(60mg,0.083mmol)。反应液在65℃反应8hr,然后加入乙酸乙酯(3mL)和水(2mL)分层。水相分离后用乙酸乙酯(3mL)萃取。合并的有机相用饱和食盐水(2mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用制备液相分离得到目标产物(0.31g,55%产率)。
LC-MS:m/z 678(M+H)+。
第四步:1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
0℃下,1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(0.3g,0.44mmol)的乙腈(1.5mL)溶液中加入HCI·dioxane(4M,1.5mL)。反应液在0℃反应0.5hr然后减压浓缩。残余物用制备液相分离得到目标产物(g,31%产率)。
LC-MS:m/z 634(M+H)+。
按照实施例A-1的方法以不同的起始原料合成了以下实施例:
实施例 A-2 1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((反式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
LC-MS:m/z 634(M+H)+。
实施例A-3 1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
LCMS:m/z 652(M+H)+.
实施例A-4 7-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 688(M+H)+.
实施例A-5 7-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((反式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 688(M+H)+.
实施例A-6 7-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 706(M+H)+.
实施例A-7 5-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂卓-2-甲酰胺
LCMS:m/z 727(M+H)+.
实施例A-8 5-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((反式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂卓-2-甲酰胺
LCMS:m/z 727(M+H)+.
实施例A-9 5-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂卓-2-甲酰胺
LCMS:m/z 745(M+H)+.
实施例A-10 1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-((1-(吗菲啉甲基)环丙基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
LCMS:m/z 620(M+H)+.
实施例A-11 7-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-((1-(吗菲啉甲基)环丙基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 674(M+H)+.
实施例A-12 5-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟-2-((1-(吗菲啉甲基)环丙基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂卓-2-甲酰胺
LCMS:m/z 713(M+H)+.
实施例A-13 1-(2-(((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
LCMS:m/z 652(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.93(d,J=2.88Hz,1H),9.23(d,J=2.12Hz,1H),7.62(dd,J=6.04Hz,J=9.12Hz,1H),7.33(m,2H),7.03(d,J=2.60Hz,1H),4.74(d,J=6.88Hz,1H),4.26(m,3H),4.05(m,1H),3.62(d,J=13.16Hz,0.5H),3.52(d,J=13.24Hz,0.5H),3.40(m,1H),3.04(m,1H),2.74(m,1H),2.53(m,1H),2.33(m,1H),1.77(m,13H)。
实施例A-13经手性拆分得异构体A-13A和A-13B:(S)-1-(2-(((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇和(R)-1-(2-(((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
实施例A-13A
LCMS:m/z 652(M+H)+.1H NMR(400MHz,DMSO-d6)δ11.46(br,1H),10.09(d,J=8.0Hz,1H),9.27(s,1H),7.76(m,1H),7.35(m,2H),7.06(m,1H),4.78(m,1H),4.49(m,5H),4.08(m,1H),3.60(m,5H),2.02(m,13H),1.17(d,J=8.0Hz,3H),0.73(m,3H)。
实施例A-13B
LCMS:m/z 652(M+H)+.1H NMR(400MHz,DMSO-d6)δ11.41(br,1H),10.08(d,J=8.0Hz,1H),9.29(s,1H),7.76(m,1H),7.34(m,2H),7.08(m,1H),4.81(m,1H),4.64(m,2H),4.43(m,2H),4.12(m,1H),3.60(m,5H),3.12(m,1H),2.02(m,13H),1.15(d,J=8.0Hz,3H),0.73(m,3H)。
实施例A-14 3-氯-5-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯胺
LCMS:m/z 669(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),6.90(d,J=2.24Hz,1H),6.51(d,J=2.24Hz,1H),6.34(s,2H),4.36(m,3H),4.22(m,3H),3.83(m,1H),3.44(m,1H),3.11(m,1H),3.02(m,1H),2.73(m,1H),2.54(m,1H),2.45(m,1H),2.36(m,1H),1.77(m,14H)。
实施例A-15 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 660(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.18(m,1H),9.19-9.13(d,J=24Hz,1H),8.00-7.97(m,1H),7.47(t,J=8Hz,1H),7.40(s,1H),7.23-7.21(m,1H),4.45-4.37(m,3H),4.29-4.13(m,3H),3.91-3.87(m,1H),3.81-3.78(m,1H),3.51-3.38(m,1H),3.11-3.03(m,2H),2.74-2.68(m,1H),2.45-2.33(m,2H),2.18-1.47(m,13H).
实施例A-15经手性拆分得到异构体A15A及A15B:4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((R)-1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇及4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((S)-1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
异构体A-15A
LCMS:m/z 660(M+H)+.
异构体A-15B
LCMS:m/z 660(M+H)+.
实施例A-16 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 664(M+H)+.
实施例A-16经手性拆分(SFC(仪器:SFC-150(Waters);柱:(R,R)-WHELK-0125*250mm,10um(Daicel);柱温:35℃;流动相:CO2/EtOH[0.5%NH3(7M在MeOH中)]=55/45;流速:100ml/min;背压:100bar;检测波长:214nm;Cycle time:5min。)以及手性HPLC(仪器:Gilson-281;柱:RRW 25*250mm,10um(Daicel);流动相:HEX:ETOH(0.2%DEA)=70:30;流速:30ml/min;检测波长:214nm;循环时间:32min。)得到异构体A16A及A16B:4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((R)-1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇及4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((S)-1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
异构体A-16A
RT:14.092min。LCMS:m/z 664(M+H)+.1HNMR(400MHz,DMSO-d6)δ9.23(d,J=4Hz,1H),7.77-7.74(m,1H),7.36-7.32(m,2H),7.06-7.04(m,1H),4.52-4.48(m,1H),4.42-4.15(m,5H),3.95-3.91(m,1H),3.84-3.80(m,1H),3.55-3.50(m,1H),3.42-3.38(m,1H),3.12-3.07(m,1H),3.04-2.99(m,1H),2.73-2.70(m,1H),2.56-2.54(m,1H),2.44-2.33(m,3H),2.16-2.06(m,3H),2.00-1.97(m,1H),1.92-1.70(m,6H),1.64-1.44(m,3H),0.76-0.71(m,3H).
异构体A-16B
RT:16.978min。LCMS:m/z 664(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.23(d,J=4Hz,1H),7.77-7.74(m,1H),7.36-7.32(m,2H),7.06-7.04(m,1H),4.51-4.19(m,6H),3.95-3.92(m,1H),3.84-3.81(m,1H),3.54-3.50(m,1H),3.43-3.41(m,1H),3.12-3.07(m,1H),3.03-2.99(m,1H),2.73-2.70(m,1H),2.56-2.54(m,1H),2.44-2.33(m,3H),2.16-2.06(m,3H),2.00-1.97(m,1H),1.92-1.70(m,6H),1.64-1.44(m,3H),0.76-0.71(m,3H).
实施例A-17 2-胺基-4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 666(M+H)+.1H NMR(400MHz,DMSO-d6)d 9.26(d,J=6.1Hz,1H),8.13(s,2H),7.44(dd,J=8.5,5.3Hz,1H),7.16(t,J=8.9Hz,1H),4.50–4.34(m,5H),4.24–4.15(m,1H),3.91(d,J=13.4Hz,1H),3.11–2.99(m,1H),2.88–2.75(m,1H),2.41–2.33(m,2H),2.31–2.22(m,2H),2.17–1.96(m,6H),1.93–1.84(m,4H),1.77–1.61(m,3H).
实施例A-18 6-(7-(8-氯-7-氟萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-4-基)-1-氧-6-氮杂螺[3.5]壬烷
LCMS:m/z 654(M+H)+.1H NMR(400MHz,DMSO-d6)d 9.24(s,1H),8.30–8.19(m,2H),7.78–7.69(m,3H),4.50–4.34(m,3H),4.31–4.16(m,3H),3.94–3.81(m,1H),3.20–3.03(m,2H),2.78(d,J=11.9Hz,1H),2.63–2.54(m,1H),2.49–2.34(m,2H),2.16–2.07(m,2H),2.06–1.99(m,1H),1.97–1.80(m,6H),1.80–1.69(m,2H),1.69–1.55(m,2H),1.54–1.45(m,1H).
实施例A-19 3-氯-4-环丙基-5-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)苯酚
LCMS:m/z 642(M+H)+.1H NMR(400MHz,DMSO-d6)d 10.35(s,1H),9.26(d,J=8.7Hz,1H),7.00(d,J=2.5Hz,1H),6.86–6.79(m,1H),4.52–4.34(m,5H),4.26–4.17(m,1H),3.88(d,J=13.4Hz,1H),3.13–3.03(m,1H),2.91–2.77(m,1H),2.50–2.25(m,4H),2.22–1.96(m,6H),1.94–1.86(m,3H),1.84–1.64(m,5H),0.68–0.54(m,2H),0.09–-0.11(m,2H).
实施例A-20 5-氯-4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-6-氟萘-2-醇
LCMS:m/z 670(M+H)+.
实施例A-21 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(2-氧杂-6-氮杂螺[3.4]辛烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 650(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.28(s,1H),7.79-7.75(m,1H),7.38-7.33(m,2H),7.01(m,1H),4.71(d,J=4Hz,2H),4.55(d,J=4Hz,2H),4.27-3.98(m,6H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.73-2.70(m,1H),2.56-2.54(m,1H),2.38-2.33(m,3H),2.18-1.88(m,4H),1.80-1.71(m,2H),1.64-1.44(m,3H),0.73(t,J=8Hz,3H).
实施例A-22 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.4]辛烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 650(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.30(d,J=4Hz,1H),7.79-7.75(m,1H),7.38-7.33(m,2H),7.03-7.01(m,1H),4.47(t,J=8Hz,2H),4.28-4.19(m,6H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.92-2.85(m,1H),2.73-2.67(m,2H),2.56-2.54(m,1H),2.39-2.32(m,2H),2.15-2.05(m,3H),2.01-1.97(m,1H),1.91-1.88(m,1H),1.81-1.71(m,2H),1.64-1.44(m,3H),0.76-0.70(m,3H).
实施例A-23 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.4]庚烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 636(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.94(s,1H),9.01(s,1H),7.78(dd,J=9.1,6.0Hz,1H),7.36(dd,J=11.8,6.1Hz,2H),7.00(d,J=2.3Hz,1H),5.05(s,2H),4.65(t,J=15.7Hz,3H),4.49(t,J=7.4Hz,3H),3.77(s,1H),3.65(s,1H),3.44(dd,J=13.9,7.0Hz,1H),3.18–3.08(m,1H),2.96(t,J=7.5Hz,2H),2.40–1.82(m,10H),0.71(t,J=7.4Hz,3H).
实施例A-24 5-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺
LCMS:m/z 745(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.21(s,1H),7.80-7.76(m,1H),7.39-7.34(m,2H),7.02(m,1H),6.62(s,1H),5.33-5.17(m,2H),4.54-4.52(m,2H),4.39-4.19(m,4H),3.27(s,3H),3.15-3.09(m,1H),3.05-3.00(m,1H),2.95(s,3H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.42-2.34(m,3H),2.15-2.05(m,2H),2.02-1.95(m,1H),1.92-1.89(m,1H),1.81-1.45(m,5H),0.73(t,J=4Hz,3H).
实施例A-25 5-(7-(5-胺基-3-氯-2-(三氟甲基)苯基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺
LCMS:m/z 750(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),6.88(m,1H),6.62(s,1H),6.47(m,1H),6.34(s,2H),5.21(d,J=8Hz,2H),4.51-4.48(m,2H),4.30-4.28(m,2H),4.24-4.18(m,2H),3.25(s,3H),3.12(m,1H),3.02(m,1H),2.94(s,3H),2.74(d,J=12Hz,1H),2.57-2.53(m,1H),2.32(m,2H),2.08-2.05(m,1H),1.99-1.95(m,1H),1.91-1.88(m,1H),1.81-1.45(m,5H).
实施例A-26(S)-7-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 706(M+H)+.1H NMR(400MHz,DMSO-d6)δ11.19(br,1H),10.90(m,1H),10.09(br,1H),9.14(s,1H),8.72(d,J=7.64Hz,1H),7.73(m,1H),7.35(m,2H),7.07(m,1H),4.59(m,3H),3.61(m,2H),3.49(m,3H),3.09(m,1H),2.10(m,14H),0.72(m,3H)
实施例A-27(R)-7-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 706(M+H)+.1H NMR(400MHz,DMSO-d6)δ11.29(br,1H),10.88(m,1H),10.08(br,1H),9.14(s,1H),8.71(d,J=5.20Hz,1H),7.75(m,1H),7.35(m,2H),7.07(m,1H),4.51(m,5H),3.79(m,1H),3.69(m,2H),3.60(m,2H),3.10(m,1H),2.36(m,3H),2.14(m,6H),1.96(m,2H),1.88(m,3H),0.72(m,3H)。
实施例A-28 4-(4-(2-氧-6-氮杂双环[5.1.0]辛烷-6-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 650(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.94(m,1H),9.40(m,1H),7.80-7.76(m,1H),7.38-7.29(m,2H),7.07(s,1H),4.55-4.52(m,1H),4.27-4.18(m,2H),3.92-3.89(m,1H),3.80-3.74(m,2H),3.66-3.59(m,1H),3.50-3.44(m,2H),3.13-3.02(m,2H),2.75-2.72(m,1H),2.58-2.55(m,1H),2.35-2.33(m,1H),2.26-2.07(m,2H),2.02-1.73(m,6H),1.67-1.45(m,3H),1.36-1.30(m,1H),0.78-0.70(m,3H).
实施例A-29 4-(4-((顺式)-2-氧-6-氮杂双环[5.1.0]辛烷-6-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
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LCMS:m/z 646(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.14(m,1H),9.39(m,1H),8.00-7.97(m,1H),7.50-7.46(m,1H),7.40(s,1H),7.20-7.18(m,1H),4.51-4.49(m,1H),4.26-4.16(m,3H),3.93-3.89(m,1H),3.81-3.72(m,2H),3.65-3.59(m,1H),3.48-3.42(m,1H),3.14-3.09(m,1H),3.03-3.00(m,1H),2.75-2.72(m,1H),2.58-2.54(m,1H),2.25-2.17(m,1H),2.12-2.07(m,1H),2.02-1.72(m,6H),1.66-1.45(m,3H),1.34-1.27(m,1H),0.97-0.93(m,1H).
实施例A-29经手性拆分得到两个异构体实施例A-29A和实施例A-29B:4-(4-((1R,7S)-2-氧-6-氮杂双环[5.1.0]辛烷-6-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1S,7R)-2-氧-6-氮杂双环[5.1.0]辛烷-6-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例A-29A
LCMS:m/z 646(M+H)+.
实施例A-29B
LCMS:m/z 646(M+H)+.
实施例A-30 3-(4-(2-氧-6-氮杂双环[5.1.0]辛烷-6-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯胺
LCMS:m/z 655(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),6.88(s,1H),6.52(s,1H),6.31(s,1H),4.51(d,J=16Hz,1H),4.27-4.18(m,2H),3.89-3.85(m,1H),3.77-3.71(m,2H),3.62-3.56(m,1H),3.45-3.41(m,1H),3.13-3.04(m,2H),2.77-2.74(m,1H),2.59-2.50(m,1H),2.19-2.08(m,2H),1.99-1.75(m,6H),1.64-1.48(m,3H),1.35-1.27(m,1H),0.65-0.49(m,1H).
实施例A-31 4-(4-(9-氧-3-氮杂双环[4.2.1]壬烷-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 664(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.95(d,J=8Hz,1H),9.15(s,1H),7.79-7.75(m,1H),7.38-7.33(m,2H),7.07-7.02(m,1H),4.72-4.57(m,3H),4.29-4.11(m,3H),3.89-3.82(m,1H),3.66-3.54(m,1H),3.13-3.04(m,2H),2.77-2.74(m,1H),2.57-2.55(m,1H),2.39-2.24(m,2H),2.12-1.90(m,7H),1.82-1.48(m,7H),0.76-0.71(m,3H).
实施例A-32 3-(4-(6-氧-3-氮杂双环[4.2.1]壬烷-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯胺
LCMS:m/z 655(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),6.88(d,J=2.20Hz,1H),6.47(d,J=2.24Hz,1H),6.33(s,2H),4.67(m,1H),4.39(m,2H),4.20(m,2H),3.77(m,1H),3.65(m,3H),3.09(m,1H),3.01(m,1H),2.70(m,2H),2.54(m,1H),1.77(m,10H)。
实施例A-33 4-(4-(6-氧-3-氮杂双环[4.2.1]壬烷-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 650(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.19(s,1H),7.77(m,1H),7.33(m,2H),7.02(m,1H),4.73(m,1H),4.38(m,1H),4.22(m,2H),3.81(m,1H),3.69(m,3H),3.11(m,1H),3.01(m,1H),2.71(m,2H),2.54(m,1H),2.37(m,1H),2.03(m,11H),0.73(m,3H)。
实施例A-34 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(6-氟-1,4-氧氮杂卓-4-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 655(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.24(d,J=3.00Hz,1H),7.77(m,1H),7.35(m,2H),7.02(d,J=2.60Hz,1H),5.12(m,1H),4.62(m,2H),4.11(m,8H),3.10(m,2H),2.74(m,1H),2.54(m,1H),2.36(m,1H),1.82(m,9H),0.73(m,3H)。
实施例A-35 4-(4-(6,6-二氟-1,4-氧氮杂卓-4-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 674(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.20(s,1H),7.77(dd,J=9.1,6.0Hz,1H),7.35(dd,J=11.2,6.0Hz,2H),7.04(d,J=2.5Hz,1H),4.79(s,1H),4.63(s,1H),4.33–4.15(m,6H),4.15–3.99(m,2H),3.02(m,2H),2.71(d,J=29.5Hz,1H),2.43–2.30(m,1H),2.18–1.71(m,7H),1.57(dd,J=39.7,24.2Hz,3H),0.73(t,J=7.3Hz,3H).
实施例A-36 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(3-氟氮卓-1-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 654(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.22(s,1H),7.79-7.75(m,1H),7.38-7.33(m,2H),7.03-7.01(m,1H),5.16-5.05(m,1H),4.42-4.11(m,6H),4.00-3.90(m,1H),3.12-3.07(m,1H),3.04-2.99(m,1H),2.74-2.71(m,1H),2.56-2.54(m,1H),2.40-2.33(m,1H),2.15-1.73(m,12H),1.65-1.43(m,4H),0.75-0.71(m,3H).
实施例A-37 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(5-甲基-1,4-氧氮杂卓-4-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 652(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.99(d,J=6.4Hz,1H),7.78(dd,J=9.0,6.0Hz,1H),7.36(dd,J=14.0,6.0Hz,2H),7.02(dd,J=19.3,2.3Hz,1H),4.80(s,1H),4.38(d,J=5.1Hz,1H),4.31–4.06(m,3H),3.87(dd,J=12.9,5.9Hz,2H),3.69(d,J=10.5Hz,1H),3.10(dd,J=11.6,6.9Hz,1H),3.02(s,1H),2.73(d,J=11.7Hz,1H),2.33(d,J=6.3Hz,2H),2.13(d,J=42.5Hz,2H),1.96(dd,J=40.9,10.8Hz,3H),1.79(d,J=22.8Hz,2H),1.61(dd,J=22.8,10.5Hz,2H),1.45(s,4H),1.25(s,2H),0.75(q,J=7.1Hz,3H).
实施例A-38 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘基-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂卓-6-醇
LCMS:m/z 668(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.56(s,1H),9.07(s,1H),7.82–7.74(m,1H),7.42–7.34(m,2H),7.04(d,J=12.4Hz,1H),5.18(d,J=8.4Hz,1H),4.66(s,2H),4.38(m,2H),4.10–3.87(m,3H),3.59(m,1H),3.53–3.47(m,2H),3.47–3.42(m,4H),2.34(m,2H),2.14(m,3H),1.88(m,2H),1.32–1.14(m,4H),1.07(t,J=7.0Hz,3H),0.75(t,J=7.3Hz,3H).
实施例A-39 4-(7-(5-胺基-3-氯-2-(三氟甲基)苯基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂卓-6-醇
LCMS:m/z 673(M+H)+.1H NMR(400MHz,DMSO-d6)δ13.13(s,1H),10.96(s,1H),9.02(s,1H),6.90(s,1H),6.48(d,J=2.1Hz,3H),4.80–4.61(m,2H),4.43–3.36(m,15H),3.07(m,1H),2.42–2.24(m,2H),2.21–2.03(m,3H),1.98–1.83(m,3H).
实施例A-40 4-(4-(环丙基(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 608(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.98(s,1H),9.68(s,1H),7.79(dd,J=9.1,6.0Hz,1H),7.43–7.28(m,2H),7.07(d,J=2.4Hz,1H),4.70–4.61(m,2H),3.81(dd,J=13.5,10.4Hz,1H),3.69(dd,J=12.5,5.8Hz,2H),3.52–3.45(m,1H),3.43(d,J=6.0Hz,1H),3.39(d,J=4.0Hz,3H),3.12(s,1H),2.31(ddd,J=22.1,15.5,8.4Hz,3H),2.22–2.13(m,2H),2.06(dd,J=13.1,6.4Hz,1H),2.02–1.94(m,1H),1.94–1.84(m,2H),1.10–1.02(m,2H),0.85(d,J=7.5Hz,1H),0.73(dd,J=17.0,9.5Hz,4H).
实施例A-41 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-环丙基-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 613(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),6.89(d,J=2.0Hz,1H),6.52(d,J=2.1Hz,1H),6.34(s,2H),4.21(d,J=10.6Hz,2H),3.63(s,1H),3.48–3.42(m,1H),3.10(dd,J=11.6,6.8Hz,1H),3.06–2.94(m,1H),2.73(d,J=11.8Hz,1H),2.56(d,J=9.2Hz,1H),2.07(dd,J=13.3,5.7Hz,1H),1.98(dd,J=10.3,5.7Hz,1H),1.90(d,J=13.4Hz,1H),1.87–1.67(m,3H),1.66–1.44(m,4H),1.02(d,J=6.4Hz,2H),0.76(s,2H).
实施例A-42 4-(4-((1-环丙基乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇三氟乙酸盐
LCMS:m/z 636(M+H)+.1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.06(s,1H),9.30(s,1H),7.77(dd,J=9.1,6.0Hz,1H),7.36(dd,J=10.4,6.0Hz,2H),7.03(dd,J=8.6,2.5Hz,1H),4.67–4.56(m,3H),4.31(d,J=6.3Hz,2H),3.85–3.73(m,1H),3.64(s,1H),3.44(ddd,J=18.1,9.7,4.2Hz,2H),3.21–3.07(m,1H),2.46–2.32(m,2H),2.29–2.12(m,4H),2.07–1.95(m,2H),1.87(dd,J=11.5,6.8Hz,2H),1.40(dd,J=17.1,10.6Hz,3H),1.26(dd,J=8.1,4.1Hz,1H),0.79–0.70(m,3H),0.66(dt,J=11.2,8.5Hz,1H),0.49(tdd,J=14.2,9.4,5.0Hz,2H),0.36–0.17(m,1H).
实施例A-43 7-(5--胺基-3-氯-2-(三氟甲基)苯基)-N-(1-环丙基乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺三氟乙酸盐
LCMS:m/z 641(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.26(s,1H),6.89(s,1H),6.47(s,2H),4.69–4.52(m,2H),4.39–4.20(m,1H),3.76(s,1H),3.64(d,J=6.8Hz,1H),3.57–3.36(m,5H),3.15(s,1H),2.48–2.40(m,1H),2.32–2.10(m,3H),2.10–1.79(m,4H),1.36(dd,J=19.6,6.3Hz,3H),1.31–1.16(m,1H),0.63(s,1H),0.56–0.36(m,2H),0.26(s,1H).
实施例A-44 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((反式)-2-氟环丙基)(甲基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 622(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.50(d,J=16Hz,1H),8.0-7.96(m,1H),7.47(t,J=8Hz,1H),7.40(d,J=4Hz,1H),7.20(s,1H),5.09-4.83(m,1H),4.24-4.05(m,3H),4.01(d,J=20Hz,1H),3.34-3.28(m,3H),3.13-3.07(m,1H),3.03-2.99(m,1H),2.73(d,J=12Hz,1H),2.56-2.52(m,1H),2.09-2.03(m,1H),2.00-1.95(m,1H),1.92(d,J=16Hz,1H),1.84-1.43(m,6H),1.33-1.24(m,1H)。
实施例A-44经手性拆分得到两个异构体实施例A-44 A和实施例A-44 B:4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((1S,2S)-2-氟环丙基)(甲基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((1R,2R)-2-氟环丙基)(甲基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例A-44 A LCMS:m/z 622(M+H)+.
实施例A-44 B LCMS:m/z 622(M+H)+.
实施例A-45 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((反式)-2-氟环丙基)(甲基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 626(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.53(s,1H),7.79-7.75(m,1H),7.37-7.33(m,2H),7.05(s,1H),5.06-4.78(m,1H),4.26-4.18(m,2H),4.15-4.08(m,1H),3.32-3.30(m,3H),3.11-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J=12Hz,1H),2.56-2.54(m,1H),2.33(s,1H),2.19-1.97(m,3H),1.91(d,J=12Hz,1H),1.84-1.43(m,6H),1.29-1.15(m,1H)0.75-0.71(m,3H)。
实施例A-46 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-((反式)-2-氟环丙基)-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 631(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),6.90(m,1H),6.51(m,1H),6.33(s,2H),5.01-4.82(m,1H),4.25-4.17(m,2H),4.15-4.06(m,1H),3.29(s,3H),3.14-3.02(m,2H),2.76(d,J=12Hz,1H),2.58-2.51(m,1H),2.10-1.96(m,2H),1.93(d,J=16Hz,1H),1.85-1.46(m,6H),1.21-1.18(m,1H)。
实施例A-47 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((反式)-4-氟四氢呋喃-3-基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 638(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.36(d,J=8Hz,1H),8.92(s,1H),7.99-7.95(m,1H),7.46(t,J=8Hz,1H),7.39(s,1H),7.17-7.14(m,1H),5.49-5.30(m,1H),4.94-4.86(m,1H),4.31-4.20(m,3H),4.07-4.05(m,1H),4.00-3.92(m,2H),3.88-3.84(m,1H),3.13-3.00(m,2H),2.74-2.67(m,1H),2.57-2.53(m,1H),2.12-2.05(m,1H),2.02-1.97(m,1H),1.93-1.90(m,1H),1.85-1.72(m,2H),1.66-1.42(m,3H).
实施例A-48 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((顺式)-4-氟四氢呋喃-3-基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 638(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.46(s,1H),8.88(t,J=8Hz,1H),7.99(t,J=8Hz,1H),7.50-7.45(m,1H),7.41(s,1H),7.19-7.16(m,1H),5.50-5.36(m,1H),5.05-4.97(m,1H),4.29-3.93(m,7H),3.15-3.01(m,2H),2.75-2.72(m,1H),2.59-2.56(m,1H),2.12-1.99(m,2H),1.94-1.91(m,1H),1.83-1.73(m,2H),1.67-1.49(m,3H).
实施例A-49 4-(4-(3,3-二氟氮杂环丁烷-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 626(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.96(s,1H),7.99(dd,J=9.2,5.9Hz,1H),7.53–7.36(m,2H),7.19(d,J=2.5Hz,1H),5.07(m,4H),4.31–4.16(m,2H),3.98(s,1H),3.16–2.97(m,2H),2.73(d,J=11.8Hz,1H),2.56(m,1H),2.01(m,3H),1.78(m,2H),1.68–1.44(m,3H).
实施例A-50 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-4-(3,3-二氟吡咯烷-1-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 640(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.24(s,1H),7.99(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7.41(d,J=2.5Hz,1H),7.20(d,J=2.4Hz,1H),4.42(m,,2H),4.34–4.16(m,4H),3.97(s,1H),3.18–3.08(m,1H),3.03(m,1H),2.78–2.53(m,4H),2.14–2.05(m,1H),2.05–1.97(m,1H),1.96–1.88(m,1H),1.88–1.71(m,2H),1.67–1.43(m,3H).
实施例A-51 4-(4-(1,1-二氟-5-氮杂螺[2.4]庚烷-5-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 666(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.22(d,J=4.6Hz,1H),7.97(dd,J=9.2,5.9Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.18(s,1H),4.26–4.12(m,4H),3.96(d,J=2.5Hz,1H),3.15–3.06(m,1H),3.06–2.97(m,1H),2.72(m,1H),2.55(m,1H),2.34–2.18(m,2H),2.11–2.04(m,1H),1.98(m,1H),1.94–1.68(m,6H),1.67–1.41(m,4H).
实施例B-1 1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
第一步:4-甲氧基-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-7(6H)-碳酸叔丁酯的制备
氮气保护下,2-氯-4-甲氧基-5,6-二氢吡啶[3,4-d]嘧啶-7(8H)-甲酸叔丁酯(3g,10mmol)、((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇(2.22g,12mmol)的甲苯(30mL)溶液中依次加入碳酸铯(9.8g,30mmol)、BINAP(1.25g)和醋酸钯(0.25g)。反应液在110℃反应12hr,然后加入水(60mL)淬灭,再用乙酸乙酯(30mLx 3)萃取。合并的有机相用无水硫酸钠干燥后过滤,滤液减压浓缩。残余物硅胶柱层析分离得到目标产物(3.1g,69%产率)。
LCMS:m/z 449(M+H)+.
第二步:4-甲氧基-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶的制备
0℃下,4-甲氧基-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-7(6H)-碳酸叔丁酯(3g,6.7mmol)的DCM(12mL)溶液中缓慢滴加入TFA(12mL)。反应液在室温反应2hr然后减压浓缩。残余物用冰水(10mL)稀释,然后用饱和碳酸钠水溶液调节pH至7,然后高真空减压浓缩除去水。残余物用饱和碳酸钠水溶液(30mL)稀释,然后用乙酸乙酯(15mLx 6)萃取。合并的有机相用无水硫酸钠干燥后过滤,滤液减压浓缩得到目标产物(2.1g)。无需进一步纯化直接用于下一步反应。
LCMS:m/z 349(M+H)+.
第三步:7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-4-甲氧基-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶的制备
氮气保护下,上一步得到的4-甲氧基-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶(2g,5.73mmol)和8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯(2.85g,7.45mmol)的甲苯(20mL)溶液中依次加入碳酸铯(5.6g)、Xantphos(0.7g)和Pd2(dba)3(0.53g)。反应液在110℃反应6hr,然后通过硅藻土过滤,滤饼用乙酸乙酯(5mLx 3)洗涤。合并的有机相减压浓缩,残余物用制备液相分离得到目标产物(2.53g,65%产率(两步合并))。
LCMS:m/z 581(M+H)+.
第四步:7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4醇的制备
0℃下,EtSH(0.64g,10.3mmol)的DMAc(20mL)溶液中加入NaH(0.41g,60%wt,10.3mmol)。反应液在0℃反应0.5hr,随后加入7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-4-甲氧基-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶(2g,3.44mmol)。反应液在20℃反应1hr,随后加入水(400mL)淬灭。得到的混合物用2N HCl调节pH至6然后用乙酸乙酯(20mLx 3)萃取。合并的有机相用饱和食盐水(20mLx 2)洗涤,再用无水硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(2g)。无需进一步纯化直接用于下一步反应。
LCMS:m/z 567(M+H)+.
第五步:7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基4-甲基苯磺酸酯的制备
0℃下,上一步得到的7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4醇(2g)、DIPEA(1.33g,10.3mmol)and DMAP(50mg,0.41mmol)的DCM(20mL)溶液中加入对甲苯磺酰氯(1g)。反应液在25℃反应0.5hr然后减压浓缩。残余物用制备液相分离得到目标产物(1.74g,70%产率(两步合并))。
LCMS:m/z 721(M+H)+.
第六步:1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基4-甲基苯磺酸酯(100mg,0.14mmol)、3-甲基哌啶-3-醇(33mg,0.28mmol)和4A分子筛(20mg)的DMF(1mL)溶液中加入DIPEA(75mg)。得到的反应液在60℃反应至完全转化。混合物过滤,滤饼用DMF(1mL)洗涤。滤液用制备液相分离得到目标产物(75mg,80.7%产率)。
LCMS:m/z 664(M+H)+.
第七步:1-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇的制备
0℃下,1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇(70mg,0.105mmol)的甲醇(1.5mL)溶液中加入HCl的甲醇溶液(4M,1.5mL)。反应液在0℃反应0.5hr,然后用饱和碳酸氢钠水溶液调节pH至8。得到的混合物用乙酸乙酯(3x 5mL)萃取。合并的有机相用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物用制备液相分离得到目标产物(25mg,38.4%产率)。
LCMS:m/z 620(M+H)+.
按照实施例B-1的方法以不同的起始原料合成了以下实施例:
实施例B-21-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((反式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇
LCMS:m/z 620(M+H)+.
实施例B-31-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇
LCMS:m/z 638(M+H)+.
实施例B-47-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1,3,7-三氮唑螺[4.5]癸烷-2,4-二酮
LCMS:m/z 674(M+H)+.
实施例B-57-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((反式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1,3,7-三氮唑螺[4.5]癸烷-2,4-二酮
LCMS:m/z 674(M+H)+.
实施例B-67-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1,3,7-三氮唑螺[4.5]癸烷-2,4-二酮
LCMS:m/z 692(M+H)+.
实施例B-75-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((顺式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 713(M+H)+.
实施例B-85-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((反式)-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 713(M+H)+.
实施例B-95-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 731(M+H)+.
实施例B-101-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-((1-(吗啡啉甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌啶-3-醇
LCMS:m/z 606(M+H)+.
实施例B-117-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-((1-(吗啡啉甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1,3,7-三氮杂螺[4.5]癸烷-2,4-二酮
LCMS:m/z 660(M+H)+.
实施例B-12 5-(7-(8-乙基-7-氟-3-羟基萘基-1-基)-2-((1-(吗啡啉甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 699(M+H)+.
实施例B-13 5-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 731(M+H)+.1HNMR(400MHz,DMSO-d6)δ7.60(dd,J=5.92Hz,J=8.92Hz,1H),7.26(t,J=9.52Hz,1H),7.01(s,2H),6.52(s,1H),6.07(s,1H),5.05(dd,J=4.44Hz,J=16.16Hz,1H),4.75(dd,J=4.44Hz,J=16.16Hz,1H),4.51(m,2H),4.15(m,1H),3.97(m,4H),3.60(m,1H),3.44(m,3H),3.04(m,9H),2.68(m,2H),2.20(m,1H),1.73(m,11H),1.08(t,J=7.12Hz,3H)。
实施例B-14 5-(2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮卓-2-甲酰胺盐酸盐
LCMS:m/z 731(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.27(s,0.5H),7.61(m,1H),7.26(m,1H),7.01(s,2H),6.53(s,1H),5.84(m,0.5H),5.01(m,1H),4.75(m,1H),4.51(m,2H),4.17(m,1H),3.91(m,4H),3.60(m,1H),3.26(m,3H),2.95(m,6H),2.69(m,3H),1.88(m,12H),1.08(m,3H)。
实施例B-15 5-(7-(2-胺基-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((反式)-2,2-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 733(M+H)+.1H NMR(400MHz,DMSO-d6)δ7.97(s,2H),7.08-7.04(m,1H),6.98(t,J=8Hz,1H),6.54(s,1H),4.81(s,2H),4.48(t,J=4Hz,2H),4.13(s,2H),3.97(s,3H),3.22(s,4H),2.93(s,4H),2.67(s,1H),2.18-1.44(m,11H),1.24(s,4H),0.85(t,J=8Hz,1H)。
实施例B-16 5-(7-(8-氯-7-氟萘-1-基)-2-(((反式)-2,2-2,2-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮卓-2-甲酰胺
LCMS:m/z 721(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.02(dd,J=12Hz,J=8Hz,1H),7.79(d,J=8Hz,1H),7.59(t,J=8Hz,1H),7.54(t,J=8Hz,1H),7.37(d,J=8Hz,1H),6.46(s,1H),4.93(d,J=16Hz,1H),4.79(d,J=16Hz,1H),4.49(t,J=4Hz,2H),4.12-3.91(m,5H),3.76(d,J=16Hz,1H),3.49(d,J=8Hz,1H),3.24-2.94(m,10H),2.71(d,J=12Hz,1H),2.59(d,J=16Hz,1H),2.15(s,1H),2.05-1.65(m,7H),1.60-1.41(m,3H)。
实施例P-1 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-基甲基胺基甲酸酯的合成
氩气保护下,4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-氧杂-6-氮杂螺[3.5]壬烷-6-基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇(30mg,0.045mmol)、DIPEA(12mg,0.090mmol)和二氯甲烷(1mL)的溶液中加入甲基氨基甲酰氯(9mg,0.090mmol)。混合物在室温下反应2hr然后用制备液相分离得到目标产物(15mg,产率:46.3%)。
LCMS:m/z 721(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.25(m,1H),7.99(m,1H),7.87(d,J=2.52Hz,1H),7.75(m,1H),7.50(m,1H),7.31(m,1H),4.23(m,7H),3.54(m,1H),3.11(m,1H),3.01(m,1H),2.69(d,J=4.64Hz,3H),2.55(m,1H),2.42(m,2H),2.01(m,15H),0.76(m,3H)。
按照实施例P-1的方法以不同的起始原料合成了以下实施例:
实施例P-2 4-(4-((顺式)-2-氧-6-氮杂双环[5.1.0]辛烷-6-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-基甲基胺基甲酸酯
LCMS:m/z 703(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.43(s,0.33H),9.38(s,0.67H),8.18(m,1H),7.95(m,1H),7.80(m,1H),7.61(m,1H),7.43(m,1H),4.48(m,1H),4.26(s,0.67H),4.20(m,2H),3.97(s,0.33H),3.89(m,1H),3.73(m,2H),3.62(m,1H),3.44(m,1H),3.11(m,1H),3.02(m,1H),2.70(m,3H),2.55(m,1H),1.81(m,12H),0.93(m,0.67H),0.66(m,0.33H)。
实施例P-3 4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(((反式)-2-氟环丙基)(甲基)胺基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-基甲基胺基甲酸酯
LCMS:m/z 679(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.50(m,1H),8.19(m,1H),7.97(m,1H),7.81(m,1H),7.62(m,1H),7.46(m,1H),5.00(m,1H),4.19(m,4H),3.35(m,1H),3.28(m,1H),3.11(m,1H),3.01(m,1H),2.70(m,3H),2.54(m,1H),1.75(m,12H)。
实施例 生物学测试例
生物学测试评价
以下生物学测试例进一步描述解释本发明,但这些实例并非意味着限制本发明的范围。
ERK磷酸化抑制实验
实验步骤
在384孔板中种入KRAS G12突变细胞(如:AsPC-1(G12D,人转移胰腺腺癌细胞),A549(G12S,人非小细胞肺癌细胞),HCT116(G13D,人结肠癌细胞)、NCI-H358(G12C,人非小细胞肺癌细胞),NCI-H460(Q61H,大细胞肺癌细胞),NCI-H727(G12V,人肺支气管肿瘤细胞),MKNl(WTdep,人胃癌细胞)等),37℃,5%CO2培养箱中培养过夜。
用Echo 500加入200nL稀释好的化合物,DMSO终浓度为0.5%,在37℃,5%CO2培养箱中培养1小时。加入hEGF作用10分钟。
移去培养基,加入细胞固定液,固定细胞
PBS洗1次,冷的100%甲醇孵育,
移去甲醇,加入PBS洗1次。
移去PBS,每孔加入Li-Cor封闭缓冲液,室温封闭1 hr。
移去封闭液,每孔加入一抗混合液,4℃室温孵育过夜。
移去一抗混合液,加入PBST洗3次。
加入二抗混合液,室温避光孵育45 min。
移去二抗混合液,加入PBST洗3次,最后吸出PBST,倒扣离心,1000 rpm离心1 min。
Odyssey CLx读数。
结果表明,本发明实施例化合物对于KRAS突变显示出了很好的抑制活性。
化合物对KRAS突变细胞增殖的抑制实验
阳性参照:MRTX1133
/>
实验步骤
1.细胞培养
(a)复苏细胞于T75细胞培养瓶中:
(b)当细胞融合度达到80-90%,对细胞进行传代。
2.细胞增殖检测
实验步骤
利用纳升移液系统将稀释好的待测化合物加入384孔细胞培养板中,设置复孔。阳性对照组加入等体积的培养基;阴性对照组加入等体积的DMSO,1000 rpm室温离心1 min。
将细胞接种到a)384培养板中,阴性对照组加入等量等体积细胞,阳性对照组仅加入等体积的培养基。1000 rpm室温离心1 min,最终化合物的DMSO终浓度为0.5%,放置于37℃,5%CO2恒温培养箱孵育7天。
加入20μL/well的3D至b)384孔细胞培养板中,避光320rpm震荡20min,避光室温孵育2hrs。
用Envision多功能酶标仪读取发光值。
3.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate,IR):IR(%)=(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100%。在Excel中计算不同浓度化合物的抑制率,然后用GraphPad Prism软件作抑制曲线图和计算相关参数,包括最小抑制率,最大抑制率及IC50。
表1化合物抗细胞增殖活性
表中,“/”表示未测试。
结果表明,本发明实施例化合物对于KRAS突变显示出了很好的抑制活性。
药代动力学测试评价
雄性SD大鼠,体重220g左右,禁食过夜后,腹腔注射给予30mg/kg本发明化合物或对照化合物的溶液[10%皮质醇(captisol)和50mM柠檬酸钠(sodium citrate),pH5为载体]。分别在给于本发明化合物后0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0,12.0和24h采血,用LC/MS/MS测定血浆中本发明化合物或对照化合物的浓度。
由检测结果看出,本发明化合物具有良好的药代动力学特性。
抗肿瘤活性药效学测试评价(NCI-H727 CDX肿瘤模型)
将100uL含5x106 NCI-H727肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况,当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW2,其中L、W分别代表肿瘤长、宽。肿瘤长至~200mm3,对小鼠进行随机分组。小鼠每天灌胃给予相应剂量化合物,同时对其一般状态进行监测。肿瘤每周测量3次,体重每周测量两次。
由检测结果看出,本发明化合物具有良好的抗肿瘤效果。
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 (13)
1.式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药:
式中,
选自下组基团:/>
R1选自取代或未取代的下组基团:C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、-NRaRb或-ORa;其中,所述取代是指被一个或多个R取代;限定条件是R1不为取代或未取代的其中,Ra、Rb各自独立的选自取代或未取代的下组基团:氢、氘、C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基;其中,所述取代是指被一个或多个R取代;
优选的,R1选自取代或未取代的下组基团:
其中,所述取代是指被一个或多个R取代;
R2选自取代或未取代的下组基团:C6-C14芳基、和5-14元杂芳基;其中,所述取代是指被一个或多个R取代;
R3各自独立地选自取代或未取代的下组基团:H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、和4-6元杂环基氧基;
m为0、1、2、3、4、5或6的整数;
X选自:键、O、NH、N(C1-C3烷基);
Y选自:键、或取代或未取代的C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
1)Z选自:
其中,环W1选自取代或未取代的下组基团:C3-C20亚环烷基、和4-20元饱和或不饱和的亚杂环基;其中,所述取代是指被一个或多个R取代;
R4选自:H,或者-L1-Q1-L2-L3;限定条件是当W1为时,R4不为H;
其中,
i)Q1选自:O、S、SO2、NH、NR5、CONH、CONR5、SO2NH、SO2NR5;其中,R5选自取代或未取代的下组基团:-C1-C6烷基、-C3-C6环烷基、-4-6元杂环基、-C6-C10芳基、-5-10元杂芳基;其中,所述取代是指被一个或多个R取代;
且L1选自:无、取代或未取代的C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
且L2选自:无、取代或未取代的C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
且L3选自取代或未取代的下组基团:-C1-C6烷基、C1-C6烷氧基、-C3-C6环烷基、-4-10元杂环基、-O-C3-C6环烷基、-O-4-6元杂环基、-C1-C6亚烷基C3-C6环烷基、-C1-C6亚烷基4-6元杂环基、-C1-C6亚烷基-O-C1-C6烷基、-C1-C6亚烷基-O-C3-C6环烷基、-C1-C6亚烷基-O-4-6元杂环基、NHR9’、NR9’R10’;R9’和R10’各自独立地选自取代或未取代的下组基团:C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6烷基、(4-10元杂环基)C1-C6烷基,或R9’和R10’与其连接的N原子共同形成取代或未取代的4-10元杂环基;其中,所述取代是指被一个或多个R取代;
或者
ii)-L1-Q1选自取代或未取代的下组基团:-C4-C8烷基、-C1-C6卤代烷基、-C3-C10环烷基、-4-10元杂环基、-C6-C10芳基、-5-10元杂芳基、-C1-C3亚烷基-(C3-C10环烷基)、-C1-C3亚烷基-(4-10元杂环基)、-C1-C3亚烷基-(C6-C10芳基)、-C1-C3亚烷基-(5-10元杂芳基);其中,所述取代是指被一个或多个R取代;
且L2和L3同时为无;
当X为键时,n选自:0、1、2、3、4、5或6的整数;当X不为键时,n选自:1、2、3、4、5或6的整数;
或者
2)Z选自:限定条件是当/>为/>时,/>不为/>
其中,环W2选自取代或未取代的下组基团:C3-C6亚环烷基、和4-6元饱和或不饱和的亚杂环基;其中,所述取代是指被一个或多个R取代;
L4选自取代或未取代的下组基团:键、C1-C6亚烷基、和氘代C1-C6亚烷基;其中,所述取代是指被一个或多个R取代;
Q2选自取代或未取代的下组基团:C1-C6烷氧基、C3-C10环烷基氧基、4-10元杂环基氧基、C3-C10环烷基C1-C6亚烷基氧基、4-10元杂环基C1-C6亚烷基氧基、C3-C10环烷基、4-10
元杂环基、NHR9、NR9R10;R9和R10各自独立地选自取代或未取代的下组基团:C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6烷基、(4-10元杂环基)C1-C6烷基,或R9和R10与其连接的N原子共同形成取代或未取代的4-10元杂环基;其中,所述取代是指被一个或多个R取代;
各R相同或不同,各自独立地选自:H、氘、乙烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(=O)、氰基、酯基、胺基、酰胺基、砜基或脲基。
2.如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(II-A)或式(II-B)所示的结构:
式中,
R1、R2、R3、X、Y、Z和m的定义如权利要求1所述。
3.如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(III-A1)、式(III-A2)或式(III-B1)、式(III-B2)所示的结构:
式中,
R1、R2、R3、R4、X、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述。
4.如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(IV-A1)、式(IV-A2)或式(IV-B1)、式(IV-B2)所示的结构:
式中,
R1、R2、R3、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述。
5.如权利要求1-4中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,W1为取代或未取代的的7-10元的双环杂环基、取代或未取代的C7-C10双环环烷基、取代或未取代的的7-12元的三环杂环基、取代或未取代的C7-C12三环环烷基,优选地,W1为取代或未取代的8-12元含N杂环基,其中,所述取代是指被一个或多个R取代,R的定义如上所述;
优选地,选自:
或者选自:
其中,n’为0、1、2、3、4、5、或6的整数;R、R4和n的定义如权利要求1所述,R、R4可以取代在多环(如桥环或螺环)的任意一个环上;
更优选地,选自:
其中,n’为0、1、2、3、4、5、或6的整数;R4、R的定义如权利要求1所述,R可以取代在多环(如桥环或螺环)的任意一个环上。
6.如权利要求1-4中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于选自/>优选地为/>更优选地为/>
7.如权利要求4所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,选自:
8.如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(V-A1)或式(V-B1)所示结构:
式中,
n’为0、1、2、3、4、5、或6的整数;
R1、R2、R3、R、L1、L2、L3、Q1、m、n和n’的定义如权利要求1所述;
优选地,选自/>
更优选地,选自:
或者选自:
或者选自:
或者选自:
或者选自:
9.如权利要求1-8中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,R2选自取代或未取代的下组基团:苯基、萘基、5-6元单环杂芳基(如吡啶基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃),其中所述取代是被选自下组的一个或多个基团取代:卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH;优选地,R2选自:
10.如权利要求1-8中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,所述化合物选自下组:
/>
或者选自:
或者选自:
/>
/>
或者选自:
/>
或者选自:
/>
或者选自:
/>
或者选自:
/>
或者选自:
或者选自:
或者选自:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
11.一种药物组合物,其特征在于,包含一种或多种如权利要求1-10中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药;和药学上可接受的载体。
12.一种如权利要求1-10中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或如权利要求11所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗与KRAS突变的活性或表达量相关的疾病的药物,优选地,所述的疾病为肿瘤或失调性疾病。
13.如权利要求12所述的用途,其特征在于,所述疾病选自下组:肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
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