CN115515958A - 一种新型磺酰胺类menin-MLL相互作用抑制剂、其制备方法及医药用途 - Google Patents
一种新型磺酰胺类menin-MLL相互作用抑制剂、其制备方法及医药用途 Download PDFInfo
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- CN115515958A CN115515958A CN202280003521.5A CN202280003521A CN115515958A CN 115515958 A CN115515958 A CN 115515958A CN 202280003521 A CN202280003521 A CN 202280003521A CN 115515958 A CN115515958 A CN 115515958A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
提供式(Ⅰ)化合物、其药用盐及其制备方法和用途。该化合物在治疗疾病和病症中可用作药剂,所述疾病和病症包括癌症,由menin‑MLL相互作用介导的其它疾病。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种新型磺酰胺类menin-MLL相互作用抑制剂、其制备方法及医药用途。
背景技术
混合谱系白血病重排(mixed lineage leukemia-rearranged,MLL-r)是一种预后不良的急性白血病,由MLL1基因自发易位引起。易位产生的MLL-r融合蛋白以高亲和力与核蛋白Menin结合,Menin-MLL相互作用通过驱动特定的转录程序导致白血病发生。
当前尚无针对MLL-r或NPM1突变的急性髓细胞白血病(AML)药物或疗法获批,MLL融合蛋白的存在是白血病预后不良的标志,MLL-r白血病患者对目前可用的治疗反应不佳,5年总生存率约为35%;MLL基因的易位与儿童的5年无病生存期降低13-34%有关,MLL-r的AML成年患者的平均五年生存率仅为5-10%。NPM1突变型AML 5年总生存率约为50%。此外,AML复发率高,约50%病人会在1-2年内复发,且多数复发的AML最终会转为复发/难治AML,目前尚无针对复发/难治性AML的有效治疗方案。AML存在巨大分子异质性,携带不同突变的患者可能具有截然不同的预后。AML药物研发的方向为更精准地靶向不同突变,开发针对不同突变的靶向药物。
Menin-MLL相互作用抑制剂属于表观遗传抑制剂,能够阻断Menin和白血病细胞中MLL融合蛋白(MLL-r)的相互作用。当前已有2个化合物临床在研,SNDX-5613正在开展用于携带MLL重排或NPM1突变的复发/难治急性白血病患者的临床1/2期研究,KO-539正在进行用于携带MLL重排或NPM1突变的复发/难治急性白血病的临床1期研究。
综上所述,Menin-MLL相互作用抑制剂作为药物研发具有很好的应用前景,开发新型高效低毒的Menin-MLL相互作用抑制剂具有良好的临床需求。
发明内容
本发明提供式(Ⅰ)化合物、其光学异构体或其药学上可接受的盐:
其中:
A选自C6-C10芳基或C4-C10杂芳基,所述芳基、杂芳基可独立的被R1、R2或R3取代;
B选自C4-C8环烷基、C6-C10芳基、C5-C10杂芳基,所述环烷基、芳基、杂芳基可独立的被Rb1或Rb2取代;
L选自C3-C10的杂单环胺、并环胺、桥环胺或螺环胺;
Q选自-C(Rq1Rq2)-、-C(=O)-、-S(=O)-或-S(=O)2-;
X选自-O-、-CRx1 Rx2或-NRx1 Rx2;
Rx1、Rx2各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rq1、Rq2各自独立地选自H或C1-C6烷基;
Rb1、Rb2各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C3卤代烷基;
R1、R2、R3各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、-C(O)NR1aR2a、-S(O)NR1aR2a、-S(O)2NR1aR2a、-C(O)R1a、-S(O)2R1a、-NR1aS(O)R2a、-NR1aS(O)2R2a、-NR1aC(O)R2a、C6-C10芳基、5-7元杂芳基、C3-C8环烷基或3-8元杂环基,其中C6-C10芳基、5-7元杂芳基、C3-C8环烷基、3-8元杂环基可任选地被一个或多个-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C6卤代烷基取代;R1a、R2a在每次出现时各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;R1b、R2b在每次出现时各自独立地选自H或C1-C6烷基;
n为1、2、3或4。
本申请的另一个目的在于提供式(I)所示结构的化合物、其光学异构体或其药学上可接受的盐,
其中,A选自C6-C10芳基或5-10元杂芳基,所述芳基、杂芳基可独立的被R1、R2或R3取代;
B选自C4-C8环烷基、C6-C10芳基或5-10元杂芳基,所述环烷基、芳基或杂芳基可独立的被Rb1或Rb2取代;
L选自4-10元的杂单环胺、并环胺、桥环胺或螺环胺;
Q选自-C(Rq1Rq2)-、-C(=O)-、-S(=O)-或-S(=O)2-;
X选自-O-、-CRx1 Rx2或-NRx1 Rx2;
Rx1、Rx2各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rq1、Rq2各自独立地选自H或C1-C6烷基;
Rb1、Rb2各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C3卤代烷基;
R1、R2、R3各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、-C(O)NR1aR2a、-S(O)NR1aR2a、-S(O)2NR1aR2a、-C(O)R1a、-S(O)2R1a、-NR1aS(O)R2a、-NR1aS(O)2R2a、-NR1aC(O)R2a、C6-C10芳基、5-10元杂芳基、C3-C8环烷基或4-8元杂环烷基,其中C6-C10芳基、510元杂芳基、C3-C8环烷基、4-8元杂环烷基可任选地被一个或多个-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C6卤代烷基取代;R1a、R2a在每次出现时各自独立地选自H、C1-C6烷基、C3-C6环烷基或4-6元杂环烷基;
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;R1b、R2b在每次出现时各自独立地选自H或C1-C6烷基;
n为1、2、3或4。
在某些优选的实施方案中,A选自取代或未取代的的苯基、萘基、噻吩或吡啶。
在某些更优选的实施方案中,A选自取代或未取代的苯基或噻吩。
在某些更为优选的实施方案中,式(Ⅰ)化合物或其光学异构体具有Ia、Ib、Ic、Id所示的结构:
其中,L选自4-10元的杂单环胺、并环胺、桥环胺或螺环胺;
Q选自-C(Rq1Rq2)-、-C(=O)-、-S(=O)-或-S(=O)2-;
X选自-O-、-CRx1 Rx2或-NRx1 Rx2;
Rx1、Rx2各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rq1、Rq2各自独立地选自H或C1-C6烷基;
Rb1、Rb2各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C3卤代烷基;
R1、R2、R3各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、-C(O)NR1aR2a、-S(O)NR1aR2a、-S(O)2NR1aR2a、-C(O)R1a、-S(O)2R1a、-NR1aS(O)R2a、-NR1aS(O)2R2a、-NR1aC(O)R2a、C6-C10芳基、5-7元杂芳基、C3-8环烷基或4-8元杂环烷基,其中C6-C10芳基、5-10元杂芳基、C3-C8环烷基、4-8元杂环烷基可任选地被一个或多个-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C6卤代烷基取代;R1a、R2a在每次出现时各自独立地选自H、C1-C6烷基、C3-C6环烷基或4-6元杂环烷基;
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;R1b、R2b在每次出现时各自独立地选自H或C1-C6烷基;
n为1、2、3或4。
作为一种优选的方案,B选自C4-C8环烷基。
在某些优选的实施方案中,L选自:
在某些更优选的实施方案中,L选自:
其中,p端连接嘧啶基,q端连接Q。
在某些优选的实施方案中,Q为-CH2。
在某些优选的实施方案中,R1、R2、R3各自独立地选自H、卤素、-C(O)NR1aR2a或5-6元杂芳基,其中5-6元杂芳基、可任选地被一个或多个C1-C6烷基取代;R1a、R2a在每次出现时各自独立地选自H或C1-C3烷基;
在某些优选的实施方案中,Rm、Rn在每次出现时各自独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;
在某些更优选的实施方案中,Rm、Rn独立地选自H、-OH、F、Cl、氰基、氨基、甲基、乙基、甲氧基、三氟甲基、三氟甲氧基、C1-C3氰基烷基、C1-C3羟基烷基或-C(O)NH2;
在某些更优选的实施方案中,n为1、2或3。
在某些优选的实施方案中,所述化合物选自:
本发明的化合物可按照常规方法制备为药学上可接受的盐的形式,包括其有机酸盐及无机酸盐,无机酸包括(但不限于)盐酸、硫酸、磷酸、二磷酸、氢溴酸、氢碘酸等,有机酸包括(但不限于)乙酸、甲磺酸、对甲苯磺酸、己二酸盐、马来酸、柠檬酸、富马酸、酒石酸、琥珀酸、苹果酸、樟脑酸、樟脑磺酸、烟酸、水杨酸、草酸、乳酸等。
在另一方面,本发明还提供式(I)化合物的制备方法,包括但不限于:
(1)反应路线1:
其中,A、B、L、Q、X、Rm、Rn和n的定义如前文所述;
PG为保护基,选自:Cbz,Boc,Fmoc,Alloc,Teoc等;
LVG为离去基团,选自:-I、-Br、-Cl、MsO-、TfO-、TsO-等;
1)原料S1与原料S2反应生成化合物I-1;
2)化合物I-1发生氮氧化反应生成化合物I-2;
3)化合物I-2发生卤代反应生成化合物I-3;
4)化合物I-3与化合物PG-L-H反应后脱除保护基生成化合物I-4;
5)化合物I-4与中间体M1反应、脱Boc保护得到中间体I-5;
6)化合物I-5与试剂M2反应得到式(I)化合物;
(2)反应路线2:
其中,A、B、L、Q、X、Rm、Rn和n如权利要求1-9任一项所定义;制备化合物I-3的方法与反应路线1相同;所得化合物I-3与中间体M3直接反应得到I-5化合物,再与试剂M2反应得到式(I)化合物。
在另一方面,本发明还涉及式(I)化合物或其药学上可接受的盐在制备预防或治疗与menin-MLL蛋白相关疾病的药物中的用途。
具体的,所述与menin-MLL蛋白相关疾病指混合系白血病(MLL)、MLL-相关性白血病、MLL-关联性白血病、MLL-阳性白血病、MLL-诱导性白血病、重排型混合系白血病(MLL-r)、与MLL重排或MLL基因重排有关的白血病、急性白血病、慢性白血病、成淋巴细胞白血病、淋巴细胞性白血病、髓细胞性白血病、髓性白血病、儿童期白血病、急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、急性粒细胞性白血病、急性非淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、与治疗有关的白血病、骨髓增生异常综合征(MDS)、骨髓增殖性疾病(MPD)、骨髓增殖性瘤形成(MPN)、血浆细胞瘤、多发性骨髓瘤、脊髓发育不良、皮肤T细胞淋巴瘤、淋巴样瘤、多毛细胞白血病、白血病性脑膜炎、多发性骨髓瘤、霍奇金淋巴瘤,以及非霍奇金淋巴瘤(恶性淋巴瘤)。
本申请发现一类结构全新,具有如式(I)化合物所示结构的menin-MLL相互作用抑制剂,其具有较好的细胞抑制活性及良好的药代动力学性质,为新一代高效低毒的menin-MLL相互作用抑制剂。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
定义和一般性说明:
除非另有说明,本申请中所用的术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照本领域普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
本申请中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本申请的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“可进一步任选被取代”是指“取代”可以但不必须发生,该说明包括发生或不发生的情形,即,取代或未被取代的。
“烷基”指仅由碳原子和氢原子组成的饱和烃基,碳碳之间、碳氢之间均为单键相连,烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括但不限于甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基也可以是其他基团的一部分,所述其他基团可以是烷氧基、氰基烷基、氨基烷基、羟基烷基等。
“环烷基”指完全饱和的并且可以呈单环、桥环或螺环存在的碳环。除非另有指示,本文中的环烷基可为C3-C8,例如3元环、4元环、5元环、6元环、7元环或8元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基等。
“杂环基”指杂环烷基;杂环烷基指指包含至少一个杂原子的具有单个环或多个环(稠合、桥连、螺合)的饱和环或非芳香性的部分饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或多环环系,其包含1、2或3个选自N、O和S的环杂原子,其余的环原子是碳。
“芳基”指具有多个碳原子的芳烃基团。芳基通常是具有多个碳原子的单环、二环或三环芳基。此外,本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。
“杂芳基”是包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地包含一至三个杂原子。杂环芳基例如代表:吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基等。
“卤素”指氟、氯、溴或碘。
“氰基”指-CN。
“卤代烷基”指被一个或多个、优选1-5个(例如1个、2个、3个、4个或5个)卤素原子取代的如上定义的烷基。卤代烷基包括单卤代烷基、二卤代烷基、三卤代烷基、全卤代烷基等,如氯代甲基、二氯甲基、二氟甲基、二溴甲基、三氟甲基、2,2,2-三氟乙基、全氟乙基、2,2,2-三氟-1,1-二氯乙基等。
“烷氧基”指-O-烷基。
“卤代烷氧基”指被一个或多个、优选1-5个(例如1个、2个、3个、4个或5个)卤素原子取代的如上定义的烷氧基(-O-烷基)。
“氰基烷基”指烷基上一个氢原子被氰基取代。
“氨基烷基”指烷基上一个氢原子被氨基取代。
“羟基烷基”烷基上一个氢原子被羟基取代。
“Cm-n杂芳基”指含有其他杂原子的芳基,其中参与成环的碳原子和杂原子的个数可以是m-n个(n大于m,且二者为整数)。
在本文中,除非另有说明,使用的术语“Cm-Cn”是指由该术语修饰的该部分中具有m-n个碳原子(n大于m,且二者为整数)。例如,C1-C6表示其修饰的部分中具有1-6个碳原子,例如1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
“m-n元(杂)环烃基”指由该术语修饰的该部分中具有m-n个碳原子及参与成环的杂原子个数,杂原子可以是氮原子、硫原子、氧原子等(n大于m,且二者为整数)。例如,4-8元环烯烃表示其修饰的成环结构中具有4个碳原子、5个碳原子、6个碳原子、7个碳原子或者碳原子;4-10元杂环烃基表示其修饰的成环结构中所含碳原子及杂原子数量为4、5、6、7、8、9或者10。
在本申请中,当化学名称和结构式不一致时,应当以结构式所示为准,除非如上下文可以推断化学名称而非结构式是正确的。
化合物的结构是通过质谱(MS)或核磁共振(1HNMR)来确定的。
核磁共振氢谱(1HNMR)的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲亚砜(DMSO),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
质谱(MS)的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Therm,型号:FinniganLCQ advantage MAX)进行。
薄层硅胶使用烟台黄海HSGF254或青岛GF254硅胶板。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在本发明的术语,“氮气保护”是指例如将反应瓶连接一个1L容积的氮气气球。
在本发明未给出特殊说明的情况下,本发明反应中提及的溶液是水溶液。
在本发明的术语“室温”是指温度处于10℃-25℃之间。
实施例1N-乙基-5-氟-N-异丙基-2-((4-(7-(((1r,4r)-4-(吡咯啉-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)苯甲酰胺(1)
合成路线:
步骤1:N-乙基-5-氟-N-异丙基-2-(嘧啶-5-基氧基)苯甲酰胺(1-1)
将N-乙基-5-氟-2-羟基-N-异丙基苯甲酰胺(12.54g,54.6mmol)、5-溴嘧啶(25.3g,156.0mmol)、碳酸铯(77.8g,234.0mmol)溶于无水DMF中,加热130℃反应16h。TLC检测(P/E=2/1)反应完成,冷却至室温,加水淬灭,乙酸乙酯萃取,饱和食盐水水洗,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂,柱层析纯化分离(P/E=8/1~2/1),得到黄色油状产品27.6g(收率:56.6%)。ESI-MS m/z:304.2[M+H]+。
步骤2:5-(2-(乙基(异丙基)氨基甲酰基)-4-氟苯氧基)嘧啶-1-氮氧化物(1-2)
将上述中间体1-1(27.2g,87.9mmol)溶于无水二氯甲烷中,冰浴下加入m-CPBA(46.46g,263.8mmol),室温反应过夜,LC/MS检测反应完毕,反应液用饱和亚硫酸钠溶液洗涤1次,饱和碳酸氢钠溶液洗涤2次,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂,得到黄色油状物粗品24.1g(收率:83.3%)。ESI-MS m/z:320.2[M+H]+。
步骤3:2-((4-氯嘧啶-5-基)氧基)-N-乙基-5-氟-N-异丙基苯甲酰胺(1-3)
将上述中间体1-2(23.8g,73.1mmol)溶于氯仿中,冰浴下加入三乙胺(15.7ml,109.6mmol)、三氯氧磷(12.5ml,131.6mmol),油浴加热70℃反应8h,TLC检测反应进程,待反应完毕,加入饱和碳酸氢钠水溶液调节pH为8,加乙酸乙酯萃取,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂。柱层析纯化分离(P/E=2/1)得到黄色油状物产品15.8g(收率:62.2%)。ESI-MS m/z:338.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.31(s,1H),7.42–7.36(m,3H),3.76-3.70(m,1H),3.42-3.35(m,1H),3.22-3.15(m,1H),1.17–1.09(m,6H),1.02(td,J=7.1,5.0Hz,3H).
步骤4:2-(5-(2-(乙基(异丙基)氨基甲酰基)-4-氟苯氧基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(1-4)
将上述中间体1-3(15.7g,45.6mmol)溶于异丙醇,加入DIPEA(16.3ml,91.3mmol),2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯(11.6g,50.2mmol),加热70℃反应16h,TLC检测反应完毕,加水稀释,乙酸乙酯萃取,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂得到黄色油状物粗品23.2g(收率:93.5%)。ESI-MS m/z:528.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.73(s,1H),7.34–7.20(m,2H),7.03(dd,J=8.9,4.4Hz,1H),3.90–3.81(m,4H),3.77-3.70(m,1H),3.43-3.37(m,1H),3.26-3.16(m,5H),1.66-1.62(m,4H),1.38(s,9H),1.19–0.96(m,9H).
步骤5:2-((4-(2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基苯甲酰胺(1-5)
将上述中间体1-4(22.1g,41mmol)溶于二氯甲烷(400ml)中,加入三氟乙酸(30ml),室温反应2h,LC/MS检测反应完毕,用饱和碳酸钠溶液调节pH到8~9,加饱和盐水洗涤,补加二氯甲烷萃取,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂得到黄色油状物粗品18.6g,直接用于下一步。ESI-MS m/z:428.2[M+H]+。
步骤6:((1r,4r)-4-((2-(5-(2-(乙基(异丙基)氨基甲酰基)-4-氟苯氧基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)环己基)甲酸叔丁酯(1-6)
将上述中间体1-5(18.6g,42.6mmol),((1r,4r)-4-((叔丁氧羰基)氨基)环己基)-4-甲基苯磺酸甲酯(33.4g,85.4mmol),碳酸钾(15.0g,106.8mmol),碘化钾(0.72g,4.3mmol),溶于乙腈中,80℃反应12h。LC/MS检测反应完毕,加饱和盐水洗涤,乙酸乙酯萃取,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂,柱层析纯化分离(D/M=20/1),得到产品13.6g(收率:48.4%)。ESI-MS m/z:639.2[M+H]+。
步骤7:2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7)
将上述中间体1-6(13.2g,20.3mmol)溶于二氯甲烷(400ml)中,加入三氟乙酸(15ml),室温反应2h,LC/MS检测反应完毕,用饱和碳酸钠溶液调节pH到8~9,加饱和盐水洗涤,补加二氯甲烷萃取,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂得到黄色油状物粗品10.8g,直接用于下一步。ESI-MS m/z:539.3[M+H]+。
步骤8:N-乙基-5-氟-N-异丙基-2-((4-(7-(((1r,4r)-4-(吡咯啉-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)苯甲酰胺(1)
将上述中间体1-7(220mg,0.40mmol)、三乙胺(0.15mL,1.0mmol),溶于无水二氯甲烷中,冰浴冷却、搅拌下滴加入吡咯啉-1-磺酰氯(138mg,0.80mmol),保持室温反应12h。LC/MS检测反应完毕,加饱和盐水淬灭、洗涤,二氯甲烷萃取,有机层加无水硫酸钠干燥,过滤,旋蒸回收溶剂,中压制备(fiash)纯化分离,得到产品92.0mg(收率:33.2%)。ESI-MS m/z:672.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.68(s,1H),7.20(dd,J=9.1,6.9Hz,2H),7.16(m,1H),6.99(d,J=6.7Hz,1H),3.83(m,4H),3.79(m,1H),3.34(m,2H),2.95(m,1H),2.85-2.67(m,4H),2.39(d,J=6.2Hz,2H),2.21(m,4H),1.97(d,J=7.0Hz,2H),1.93–1.84(m,4H),1.73(m,2H),1.66(m,4H),1.26–1.15(m,4H),1.14(m,7H),0.95(m,3H).
实施例2 N-乙基-5-氟-N-异丙基-2-((4-(7-(((1r,4r)-4-(哌啶-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)苯甲酰胺(2)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基苯甲酰胺(1-7),与哌啶-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=686.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.68(s,1H),7.20(dd,J=9.0,6.7Hz,2H),7.17(m,1H),6.96(m,1H),3.81(s,4H),3.72(m,1H),3.36(m,2H),2.94(m,1H),2.86-2.77(m,4H),2.32(m,2H),2.23(m,4H),1.96(m,2H),1.90(m,4H),1.70(m,2H),1.64-1.50(m,6H),1.28–1.18(m,4H),1.14-0.93(m,10H).
实施例3 2-((4-(7-(((1r,4r)-4-(吖啶-1-磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基苯甲酰胺(3)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与吖啶-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=658.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.68(s,1H),7.20(m,2H),7.16(m,1H),6.97(d,J=6.6Hz,1H),3.80(m,4H),3.78(m,1H),3.35-3.18(m,4H),3.31(m,2H),2.92(m,1H),2.29(d,J=6.4Hz,2H),2.20(m,4H),2.14(m,2H),1.92(d,J=7.0Hz,2H),1.72(m,2H),1.65(m,4H),1.25-1.14(m,4H),1.13(m,7H),0.88(m,3H).
实施例4 2-((4-(7-(((1r,4r)-4-(3-氰基-吖啶-1-磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基苯甲酰胺(4)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与1-氯磺酰基-3-氰基环丁氨反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=683.3[M+H]+;
实施例5 N-乙基-5-氟-2-((4-(7-(((1r,4r)-4-((3-氟-吖啶)-1-磺酰胺基)环己基)甲基)-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-异丙基苯甲酰胺(5)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与3-氟-吖啶-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=676.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.67(s,1H),7.21(dd,J=8.9,6.7Hz,2H),7.19(m,1H),6.99(d,J=6.6Hz,1H),3.98(m,1H),3.81(m,4H),3.76(m,1H),3.65-3.58(m,4H),3.34(m,2H),2.91(m,1H),2.28(d,J=6.4Hz,2H),2.19(m,4H),1.93(d,J=7.0Hz,2H),1.70(m,2H),1.63(m,4H),1.24-1.14(m,4H),1.12-0.92(m,10H).
实施例6 N-乙基-5-氟-2-((4-(7-(((1r,4r)-4-(((R)-3-氟-吡咯啉)-1-磺酰胺基)环己基)甲基)-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-异丙基苯甲酰胺(6)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与(R)-3-氟吡咯烷-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=690.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.67(s,1H),7.21(dd,J=9.0,6.9Hz,2H),7.16–7.11(m,1H),6.98(d,J=6.6Hz,1H),3.84(m,4H),3.78(m,1H),3.40(m,1H),3.33(m,2H),2.96-2.82(m,5H),2.40(d,J=6.4Hz,2H),2.24(m,4H),1.98(d,J=7.0Hz,2H),1.84(m,2H),1.71(m,2H),1.62(m,4H),1.26–1.13(m,11H),0.95(m,3H).
实施例7 N-乙基-5-氟-N-异丙基-2-((4-(7-(((1r,4r)-4-((4-甲基哌嗪)-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)苯甲酰胺(7)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与4-甲基-1-哌嗪磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=701.3[M+H]+;
实施例8 2-((4-(7-(((1r,4r)-4-((3,3-二氟吡咯啉)-1-磺酰胺)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基苯甲酰胺(8)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与3,3-二氟吡咯啉-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=708.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.68(s,1H),7.20(dd,J=9.1,6.8Hz,2H),7.17–7.11(m,1H),6.99(d,J=6.6Hz,1H),3.82(m,4H),3.76–3.60(m,1H),3.48(t,J=13.2Hz,2H),3.34(t,J=7.3Hz,2H),3.25(s,2H),2.98(s,1H),2.39(m,2H),2.21(br-s,4H),1.99(d,J=7.0Hz,2H),1.93–1.84(m,2H),1.73(d,J=13.2Hz,2H),1.66(t,J=5.2Hz,4H),1.26–1.15(m,6H),1.14-0.98(m,6H),0.85(m,2H).
实施例9 N-乙基-5-氟-N-异丙基-2-((4-(7-(((1r,4r)-4-((3-甲基吡咯啉)-1-磺酰胺)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)苯甲酰胺(9)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与3-甲基吡咯啉-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=686.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.67(s,1H),7.20(dd,J=9.0,6.8Hz,2H),7.18(m,1H),6.98(d,J=6.6Hz,1H),3.82(s,4H),3.78(m,1H),3.34(m,2H),2.91(m,1H),2.84-2.62(m,4H),2.37(d,J=6.2Hz,2H),2.20(m,4H),1.98(d,J=7.0Hz,2H),1.74(m,2H),1.67-1.41(m,7H),1.26–1.19(m,4H),1.14-1.09(m,7H),0.95-0.87(m,6H).
实施例10 2-((4-(7-(((1r,4r)-4-((3,3-二氟氮杂环丁烷基)-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基苯甲酰胺(10)
参考实施例1的制备方法,制备得到中间体2-((4-(7-(((1r,4r)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-5-氟-N-异丙基本甲酰胺(1-7),与3,3-二氟氮杂环丁烷-1-磺酰氯反应,并通过实施例1中所述的步骤制备纯化。ESI-MS:m/z=694.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.68(s,1H),7.21(dd,J=9.0,6.8Hz,2H),7.18–7.12(m,1H),6.98(d,J=6.6Hz,1H),3.92-3.87(m,4H),3.81(s,4H),3.77(m,1H),3.32(m,2H),2.91(m,1H),2.28(m,2H),2.20(m,4H),1.93(d,J=7.0Hz,2H),1.71(m,2H),1.64(m,4H),1.26-1.17(m,4H),1.10-1.03(m,7H),0.97(m,3H).
实施例11 3-((4-(7-(((1r,4r)-4-((3,3-二氟吡咯啉)-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺
合成路线
步骤1:3-甲氧基噻吩-2-羧酸甲酯
将3-羟基噻吩-2-羧酸甲酯(7.91g,50.01mmol),溶于100mL丙酮中,加入碳酸钾(20.70g,150.00mmol)和碘甲烷(21.15g,150.00mmol)加热50℃反应16h.TLC检测(PE/EA=10/1)反应完,将丙酮旋干,加入50mL水,100mL乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,旋干,得到(6.51g,75.31%)白色固体。LC/MS:173.0[M+H]+。
步骤2:3-甲氧基噻吩-2-羧酸
将3-甲氧基噻吩-2-羧酸甲酯(6.51g,37.85mmol),溶于50mL甲醇和10mL水的混合溶剂中,加入氢氧化钾(4.86g,86.78mmol)加热60℃反应3h.TLC检测(PE/EA=10/1)反应完,将甲醇旋干,加入2N盐酸溶液调PH值到3~4直到有大量白色固体析出,过滤,加入50mL甲苯带水旋干,得到(5.51g,91.97%)白色固体。LC/MS:159.0[M+H]+。
步骤3:N-乙基-N-异丙基-3-甲氧基噻吩-2-甲酰胺
将3-甲氧基噻吩-2-羧酸(5.51g,34.87mmol),溶于75mL二氯甲烷中,加入N,N-二异丙基乙胺(6.75g,52.31mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(15.90g,41.84mmol),室温搅拌反应0.5h.加入N-乙基丙烷-2-胺(6.07g,69.74mmol),25℃反应16h,TLC检测(PE/EA=3/1)反应完,旋干,柱层析(P/E=8/1~2/1),得到(5.11g,63.01%)淡黄色油状物。LC/MS:228.1[M+H]+。
步骤4:N-乙基-3-羟基-N-异丙基噻吩-2-甲酰胺
将N-乙基-N-异丙基-3-甲氧基噻吩-2-甲酰胺(5.11g,22.51mmol),溶于10mL氢碘酸溶液中,100℃反应6h,TLC检测(PE/EA=3/1)反应完,加入饱和碳酸氢钠溶液调PH=7,50mL二氯甲烷萃取三次,合并有机相,旋干,柱层析(P/E=8/1~2/1),得到(4.51g,93.96%)淡黄色油状物。LC/MS:214.1[M+H]+。
步骤5:N-乙基-N-异丙基-3-(嘧啶-5-氧基)噻吩-2-甲酰胺
将N-乙基-3-羟基-N-异丙基噻吩-2-甲酰胺(1.79g,8.35mmol)5-溴嘧啶(3.98g,25.05mmol),碳酸铯(8.16g,25.05mmol),溶于无水DMF中,加热130℃反应16h.TLC检测(P/E=2/1)反应完,加水淬灭,乙酸乙酯萃取,饱和食盐水水洗,无水硫酸钠干燥,过滤,旋干,柱层析(P/E=8/1~2/1),得到(1.21g,49.59%)白色固体。LC/MS:292.1[M+H]+。
步骤6:5-((2-(乙基(异丙基)氨基甲酰基)噻吩-3-基)氧代)嘧啶-1-氧化物
将N-乙基-N-异丙基-3-(嘧啶-5-氧基)噻吩-2-甲酰胺(1.21g,4.14mmol),溶于无水二氯甲烷中,冰浴下加入m-CPBA(2.86g,15.5mmol),室温反应过夜,LC/MS检测反应完,反应液用饱和亚硫酸钠溶液洗一次,饱和碳酸氢钠溶液洗两次,无水硫酸钠干燥,过滤,旋干。得到(0.96g,98%)黄色油状物。LC/MS:308.1[M+H]+
步骤7:3-((4-氯嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺
将5-((2-(乙基(异丙基)氨基甲酰基)噻吩-3-基)氧代)嘧啶-1-氧化物(0.96g,3.13mmol),溶于氯仿中,冰浴下加入三乙胺(0.65ml,4.69mmol),三氯氧磷(0.5ml,5.32mmol),加热70℃反应8h,TLC检测反应完,加入饱和碳酸氢钠溶液调节PH为8,乙酸乙酯萃取,无水硫酸钠干燥,过滤,旋干。PTLC(P/E=2/1)得到(0.450g,45.0%)黄色油状物。LC/MS:326.1[M+H]+
步骤8:叔丁基2-(5-((2-(乙基(异丙基)氨基甲酰基)噻吩-3-基)氧代)嘧啶-4-基)-二氮杂螺[3.5]壬烷-7-甲酸酯
将3-((4-氯嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺(0.15g,0.46mmol),溶于异丙醇中,加入DIPEA(0.162ml,0.93mmol),4-氨基哌啶-1-羧酸叔丁酯(93mg,0.46mmol),加热70℃反应16h,TLC检测反应完,直接旋干,PTLC(D/M=20/1)得到(0.25g,99.1%)黄色油状物。LC/MS:516.2[M+H]+
步骤9:3-((4-(2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺
将叔丁基2-(5-((2-(乙基(异丙基)氨基甲酰基)噻吩-3-基)氧代)嘧啶-4-基)-二氮杂螺[3.5]壬烷-7-甲酸酯(0.25g,0.46mmol),溶于二氯甲烷(4ml)中,加入三氟乙酸(2ml),室温反应2h,LC/MS检测反应完,直接旋干。得到黄色油状物,直接用于下一步。LC/MS:416.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.69(d,J=6.8Hz,1H),8.20(s,1H),7.63(s,1H),6.35(d,J=7.6Hz,1H),3.92(s,4H),3.78–3.60(m,1H),3.15-3.08(m,2H),2.87-2.77(m,4H),2.03-1.98(m,1H),1.58(t,J=5.6Hz,4H),1.12-0.98(m,7H),0.86(q,J=12.5Hz,2H).
步骤10:叔丁基(1s,4s)-4-((2-(5-((2-(乙基(异丙基)氨基甲酰基)噻吩-3-基)氧代)嘧啶-4-基)-2,7-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)环己基)氨基甲酸酯
将3-((4-(2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺(0.19g,0.46mmol),((1r,4r)-4-((叔丁氧基羰基)氨基)环己基)4-甲基苯磺酸甲酯(533mg,1.38mmol),碳酸钾(384mg,2.76mmol),碘化钾(7mg,0.046mmol),溶于乙腈中,80℃反应16h。LC/MS检测反应完,过滤无机盐,用二氯甲烷洗两次,旋干,PTLC(D/M=20/1)。得到(0.145g,50.4%)黄色油状物。LC/MS:627.3[M+H]+
步骤11:3-((4-(7-(((1s,4s)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺
将叔丁基(1s,4s)-4-((2-(5-((2-(乙基(异丙基)氨基甲酰基)噻吩-3-基)氧代)嘧啶-4-基)-2,7-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)环己基)氨基甲酸酯(0.145g,0.23mmol),溶于二氯甲烷(4ml)中,加入盐酸二氧六环(2ml),室温反应2h,LC/MS检测反应完,直接旋干。得到黄色油状物,直接用于下一步。LC/MS:527.3[M+H]+
步骤12:3-((4-(7-(((1r,4r)-4-((3,3-二氟吡咯烷)-1-磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺
将3-((4-(7-(((1s,4s)-4-氨基环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧代)-N-乙基-N-异丙基噻吩-2-甲酰胺(0.121g,0.23mmol),溶于无水二氯甲烷(2ml)中,加入三乙胺(0.2ml,1.38mmol),3,3二氟吡咯烷-1-磺酰氯(76mg,0.37mmol),室温反应16h,LC/MS检测反应完,直接旋干,flash反相制备,冻干,得到(78mg,52%)无色油状物。LC/MS:696.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.69(d,J=6.8Hz,1H),8.20(s,1H),7.63(s,1H),6.95(d,J=5.6Hz,1H),6.35(d,J=7.6Hz,1H),3.92(s,4H),3.78–3.60(m,1H),3.43(t,J=12.2Hz,2H),3.31(t,J=7.5Hz,3H),3.25(s,2H),2.97(s,1H),2.36(tt,J=14.2,7.1Hz,2H),2.22(t,J=5.5Hz,4H),2.03(d,J=7.2Hz,2H),1.92–1.84(m,2H),1.72(d,J=12.8Hz,2H),1.68(t,J=5.4Hz,4H),1.28–1.16(m,4H),1.12-0.98(m,7H),0.86(q,J=12.5Hz,2H).
参考实施例1~11的制备方法,完成其它实施例的制备。
生物实施例
试验例1细胞实验(MV4-11细胞增殖抑制实验)
通过CCK-8试剂测定细胞活力
第一天:细胞铺板
1)收集培养瓶中的MV4-11细胞悬液至15mL离心管中,将细胞悬液在1000rpm离心4min。
2)弃离心管中上清液,加入适量新鲜完全培养基(IMDM+10%FBS+1%P/S),重悬细胞。取20μL细胞液,加入20μL台盼蓝,CounterStar计数。
3)据活细胞密度和所需铺板细胞数量,计算所需细胞悬液体积和完全培养基体积。MV4-11细胞铺板密度为1×104个/孔,100μL/孔。
4)使用电动排枪吸取100μL上述细胞悬液加入96孔板中。空白对照孔加入150μL完全培养基。96孔板的周边孔加入适量体积的PBS,防止液体蒸发。96孔板放培养箱过夜培养。
第二天:化合物配制
1)取出用DMSO溶解的本申请的化合物以及阳性对照SNDX-5613,并进行梯度稀释(在96孔PCR板稀释,从左往右依次为A列、B列等,至J列)。
A列:初始浓度为10mM;
B列:取2μL A列溶液稀释到8μL DMSO中,得2000μM的终浓度;
C列:取2μL B列溶液稀释到8uL DMSO中,得400μM的终浓度;
D列:取2μL C列溶液稀释到8uL DMSO中,得80μM的终浓度;
E列:取2μL D列溶液稀释到8uL DMSO中,得16μM的终浓度;
F列:取2μL E列溶液稀释到8uL DMSO中,得3.2μM的终浓度;
G列:取2μL F列溶液稀释到8uL DMSO中,得0.64μM的终浓度;
H列:取2μL G列溶液稀释到8uL DMSO中,得0.128μM的终浓度;
I列:取2μL H列溶液稀释到8uL DMSO中,得0.0256μM的终浓度;
J列:取2μLI列溶液稀释到8uL DMSO中,得0.00512μM的终浓度;
采用低速离心机在1000rpm下离心1min。
2)3×化合物配制:(96孔细胞培养板稀释)
使用10μL手动排枪取中B~J列3μL到197μL完全培养基中,得到终浓度分别为:30000,6000,1200,240,48,9.6,1.92,0.384,0.0768nM的3×化合物溶液;取3μL DMSO到197μL完全培养基中作control用。将得到的96孔细胞培养板振荡器上500rpm,5min振荡。
化合物处理:
1)使用手动排枪,体积设置为50μL,吸取配置好的上述各浓度的3×化合物溶液加入到第一天过夜培养后的96孔板的对应孔中,每孔总培养体积为150ul。使96孔板中化合物的终浓度为10uM,2uM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM。将得到的96孔板在振荡器上以500rpm振荡10min。
2)将铺好的96孔板放到CO2培养箱中培养72小时。
结果检测(第五天):
1)使用排枪,体积设置为15μL,以15μL/孔的量向96孔细胞培养板加入CCK-8检测液。
2)将96孔细胞培养板放入CO2培养箱中,孵育4小时。
3)使用MD酶标仪读取450nm吸收值,计算抑制率,GraphPad计算IC50值。
本申请示例性化合物细胞增殖实验结果如表1所示。
表1:示例性化合物MV4-11细胞增殖抑制实验结果
试验结果表明,本申请化合物IC50值均小于100nM,表明本发明的化合物对MV4-11细胞有良好的抑制作用。
试验例2本申请示例性化合物抗肿瘤药效试验
目的:观察受试化合物对MV4-11白血病SCID小鼠皮下移植瘤生长的抑制作用。
方法:SCID小鼠皮下接种MV4-11细胞(5×106cells/mouse,1:1Matrigel),建立MV4-11小鼠移植瘤模型。待平均肿瘤体积约为80-120mm3,根据肿瘤体积大小采用随机区组法将荷瘤鼠分组,包括溶剂对照组、阳性对照组(25mg/kg)、实施例8(25mg/kg、50mg/kg、100mg/kg),实施例10(25mg/kg)、实施例11(25mg/kg)和实施例12(25mg/kg)为受试样品组,每天给药2次,每组8只。各组均采用灌胃给药,给药体积均为10mL/kg,连续给药21天,溶剂对照组给予空白溶剂(0.5%甲基纤维素溶液)。开始给予测试药物后每周两次测量肿瘤体积。实验结束后安乐死动物。
本申请示例性化合物动物体内药效结果如下表2所示。
表2:示例性化合物动物体内药效实验结果
本申请实施例8化合物各剂量组均表现出显著的体内抑瘤活性,呈剂量依赖关系,中、高剂量组均显示肿瘤消退(TGI=100.00%),最低起效剂量低于25mg/kg。对比SNDX-5613对照组,同等剂量(25mg/kg,BID)灌胃给药条件下,实施例8、实施例10、实施例11、实施例12化合物肿瘤抑制作用优于SNDX-5613对照组(P<0.01)。
要理解的是,上文的详述和附随实施例仅是示例性的,且不应被视为限制本发明的范围,该范围仅由所附权利要求及其对等物规定。本领域技术人员容易看出对所公开的实施方案的各种变动和修改。可以在不背离其精神和范围的情况下作出这样的变动和修改,包括但不限于与本发明的化学结构、取代基、衍生物、中间体、合成法、制剂和/或使用方法相关的那些。本文中引用的所有出版物、专利和专利申请出于各种目的全文经此引用并入本文。
Claims (14)
1.式(Ⅰ)化合物、其光学异构体或其药学上可接受的盐:
其中:
A选自C6-C10芳基或C4-10杂芳基,所述芳基、杂芳基可独立的被R1、R2或R3取代;
B选自C4-C8环烷基、C6-10芳基或C5-10杂芳基,所述环烷基、芳基或杂芳基可独立的被Rb1或Rb2取代;
L选自C3-C10的杂单环胺、并环胺、桥环胺或螺环胺;
Q选自-C(Rq1Rq2)-、-C(=O)-、-S(=O)-或-S(=O)2-;
X选自-O-、-CRx1Rx2或-NRx1Rx2;
Rx1、Rx2各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rq1、Rq2各自独立地选自H或C1-C6烷基;
Rb1、Rb2各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C3卤代烷基;
R1、R2、R3各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、-C(O)NR1aR2a、-S(O)NR1aR2a、-S(O)2NR1aR2a、-C(O)R1a、-S(O)2R1a、-NR1aS(O)R2a、-NR1aS(O)2R2a、-NR1aC(O)R2a、C6-C10芳基、5-7元杂芳基、C3-C8环烷基或3-8元杂环基,其中C6-C10芳基、5-7元杂芳基、C3-C8环烷基、3-8元杂环基可任选地被一个或多个-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C6卤代烷基取代;R1a、R2a在每次出现时各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;R1b、R2b在每次出现时各自独立地选自H或C1-C6烷基;
n为1、2、3或4。
2.如权利要求1所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,
A选自C6-C10芳基或5-10元杂芳基,所述芳基、杂芳基可独立的被R1、R2或R3取代;
B选自C4-C8环烷基、C6-C10芳基或5-10元杂芳基,所述环烷基、芳基或杂芳基可独立的被Rb1或Rb2取代;
L选自4-10元的杂单环胺、并环胺、桥环胺或螺环胺;
Q选自-C(Rq1Rq2)-、-C(=O)-、-S(=O)-或-S(=O)2-;
X选自-O-、-CRx1Rx2或-NRx1Rx2;
Rx1、Rx2各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rq1、Rq2各自独立地选自H或C1-C6烷基;
Rb1、Rb2各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C3卤代烷基;
R1、R2、R3各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、-C(O)NR1aR2a、-S(O)NR1aR2a、-S(O)2NR1aR2a、-C(O)R1a、-S(O)2R1a、-NR1aS(O)R2a、-NR1aS(O)2R2a、-NR1aC(O)R2a、C6-C10芳基、5-10元杂芳基、C3-C8环烷基或4-8元杂环烷基,其中C6-C10芳基、5-10元杂芳基、C3-C8环烷基、4-8元杂环烷基可任选地被一个或多个-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C6卤代烷基取代;R1a、R2a在每次出现时各自独立地选自H、C1-C6烷基、C3-C6环烷基或4-6元杂环烷基;
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;R1b、R2b在每次出现时各自独立地选自H或C1-C6烷基;
n为1、2、3或4。
3.如权利要求1或2所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,A选自取代或未取代的苯基、萘基、噻吩或吡啶。
4.如权利要求3所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,所述式(Ⅰ)化合物或其光学异构体具有式Ia、Ib、Ic、Id所示的结构,
B选自C4-C8环烷基、C6-C10芳基或5-10元杂芳基,所述环烷基、芳基或杂芳基可独立的被Rb1或Rb2取代;
L选自4-10元的杂单环胺、并环胺、桥环胺或螺环胺;
Q选自-C(Rq1Rq2)-、-C(=O)-、-S(=O)-或-S(=O)2-;
X选自-O-、-CRx1Rx2或-NRx1Rx2;
Rx1、Rx2各自独立地选自H、C1-C6烷基或C3-C6环烷基;
Rq1、Rq2各自独立地选自H或C1-C6烷基;
Rb1、Rb2各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C3卤代烷基;
R1、R2、R3各自独立地选自H、-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、-C(O)NR1aR2a、-S(O)NR1aR2a、-S(O)2NR1aR2a、-C(O)R1a、-S(O)2R1a、-NR1aS(O)R2a、-NR1aS(O)2R2a、-NR1aC(O)R2a、C6-C10芳基、5-10元杂芳基、C3-8环烷基或4-8元杂环烷基,其中C6-C10芳基、5-10元杂芳基、C3-C8环烷基、4-8元杂环烷基可任选地被一个或多个-OH、卤素、氰基、C1-C6烷基、C1-C3烷氧基或C1-C6卤代烷基取代;R1a、R2a在每次出现时各自独立地选自H、C1-C6烷基、C3-C6环烷基或4-6元杂环烷基;
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;R1b、R2b在每次出现时各自独立地选自H或C1-C6烷基;
n为1、2、3或4。
6.如权利要求1-4任一项权利要求所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,B选自C4-C8环烷基。
8.如权利要求1所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,Q为-CH2-。
9.如权利要求1所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,
Rm、Rn独立地选自H、-OH、卤素、氰基、氨基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、C1-C3氰基烷基、C1-C3氨基烷基、C1-C3羟基烷基、-C(O)NR1bR2b或-NR1bC(O)R2b;
优选地,Rm、Rn独立地选自H、-OH、F、Cl、氰基、氨基、甲基、乙基、甲氧基、三氟甲基、三氟甲氧基、C1-C3氰基烷基、C1-C3羟基烷基或-C(O)NH2。
10.如权利要求1所述的式(I)化合物、其光学异构体或其药学上可接受的盐,其特征在于,
n为1、2或3。
12.一种制备如权利要求1-10任一项所述式(I)化合物及其光学异构体的方法,其特征在于,包括如下步骤:
(1)反应路线1:
1)原料S1与原料S2反应生成化合物I-1;
2)化合物I-1发生氮氧化反应生成化合物I-2;
3)化合物I-2发生卤代反应生成化合物I-3;
4)化合物I-3与化合物PG-L-H反应后脱除保护基生成化合物I-4;
5)化合物I-4与中间体M1反应、脱Boc保护得到中间体I-5;
6)化合物I-5与试剂M2反应得到式(I)化合物;
其中,PG为保护基,LVG为离去基团,A、B、L、Q、X、Rm、Rn和n如权利要求1-10任一项所定义;
(2)反应路线2:
制备化合物I-3的方法与反应路线1相同;所得化合物I-3与中间体M3直接反应得到化合物I-5,再与试剂M2反应得到式(I)化合物;
其中,A、B、L、Q、X、Rm、Rn和n如权利要求1-10任一项所定义。
13.如权利要求1-11任一项所述的化合物、其光学异构体或其药学上可接受的盐在制备预防或治疗与menin-MLL蛋白相关疾病的药物中的用途。
14.如权利要求13所述的用途,其特征在于,所述与menin-MLL蛋白相关疾病包含混合系白血病(MLL)、MLL-相关性白血病、MLL-关联性白血病、MLL-阳性白血病、MLL-诱导性白血病、重排型混合系白血病(MLL-r)、与MLL重排或MLL基因重排有关的白血病、急性白血病、慢性白血病、成淋巴细胞白血病、淋巴细胞性白血病、髓细胞性白血病、髓性白血病、儿童期白血病、急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、急性粒细胞性白血病、急性非淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、与治疗有关的白血病、骨髓增生异常综合征(MDS)、骨髓增殖性疾病(MPD)、骨髓增殖性瘤形成(MPN)、血浆细胞瘤、多发性骨髓瘤、脊髓发育不良、皮肤T细胞淋巴瘤、淋巴样瘤、多毛细胞白血病、白血病性脑膜炎、多发性骨髓瘤、霍奇金淋巴瘤以及非霍奇金淋巴瘤(恶性淋巴瘤)。
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