CN115348963B - 吡啶并嘧啶类化合物及其应用 - Google Patents
吡啶并嘧啶类化合物及其应用 Download PDFInfo
- Publication number
- CN115348963B CN115348963B CN202280001130.XA CN202280001130A CN115348963B CN 115348963 B CN115348963 B CN 115348963B CN 202280001130 A CN202280001130 A CN 202280001130A CN 115348963 B CN115348963 B CN 115348963B
- Authority
- CN
- China
- Prior art keywords
- substituted
- compound
- hyt
- alkyl
- cycloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了一种具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,及其应用。本发明涉及的化合物可以高效、高选择性地降解细胞中的AKT3蛋白,而对AKT1/2无影响,从而能够显著抑制AKT3高表达介导的肿瘤细胞增殖,可用于制备与AKT3蛋白异常表达相关的癌症和其它相关疾病的治疗药物。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类吡啶并嘧啶类化合物及其应用。
背景技术
AKT(AK mouse plus Transforming or Thymoma),又称蛋白激酶B(Proteinkinase B,PKB),是一种分子量约为57kD的丝氨酸/苏氨酸蛋白激酶,该家族包含AKT1、AKT2和AKT3三种亚型。AKT各亚型的功能和组织学分布存在诸多异同,其异常表达与多种疾病的发生、发展密切相关。AKT1广泛存在于多种组织,包括心脏,肝脏,肌肉等;AKT2主要分布于胰岛素敏感的组织中,如骨骼肌和脂肪组织等;AKT3主要分布于大脑、心脏和肾脏等组织。AKT1在大约40%的乳腺癌和卵巢癌以及超过50%的前列腺癌中表达增强;AKT2在40%的肝癌和57%的结直肠癌存在过表达;AKT2缺失会导致高血糖症、2-型糖尿病和葡萄糖摄取障碍;AKT1和AKT2的过表达还与卵巢癌对紫杉醇耐药有关;AKT3的高表达存在于乳腺癌,前列腺癌和部分Osimertinib耐药的非小细胞肺癌中。因此,选择性调控AKT各亚型蛋白可能对相关疾病的治疗起到积极作用。
AKT是一类重要的肿瘤治疗靶点。目前已有多个AKT的激酶抑制剂进入临床试验阶段,且表现出良好的抗肿瘤效果。然而,这些抑制剂对AKT的各个亚型蛋白缺乏选择性,无差别的抑制可能存在一定的临床毒副作用。另外,与传统靶向药物类似,长时间的药物治疗可能导致病人对AKT抑制剂产生耐药,进而减弱疗效。此外,AKT蛋白具有激酶功能和非激酶功能,单纯的抑制激酶功能可能难以彻底发挥抗肿瘤效应。靶向降解完整的AKT3蛋白不仅能够抑制其激酶功能,更能调控其非激酶功能,进而发挥更强的抗肿瘤效果。
因此,开发合成能够选择性降解AKT3蛋白的小分子降解剂对开发AKT3介导的相关疾病的治疗药物具有重要意义。
发明内容
针对上述问题,本发明提供了一类新的吡啶并嘧啶类化合物,这类新的吡啶并嘧啶类化合物能够高活性的选择性降解AKT3蛋白,能够抑制多种肿瘤细胞的增殖,可用于治疗与AKT3蛋白相关的疾病以及肿瘤。
具体技术方案包括如下:
具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子:
其中:
E选自:氢,C1-C15烷基,取代的C1-C15烷基,C3-C15环烷基,取代的C3-C15环烷基,3-15元杂环烷基,取代的3-15元杂环烷基;
L不存在或者为由如下基团中的一个或多个组成的连接单元:亚烷基,醚基,硫醚基,酯基,胺基,酰胺基,杂芳基,环烷基,杂环烷基,-N=N-;
Y选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-;
Z选自:不存在或者-O-,-NH-,-N(C1-C6烷基)-,-NHCO-,-CH2-,-S-,-CO-,-SO-;
R1选自:氢,C1-C6烷基,卤素或卤素取代的C1-C6烷基;
R2选自:C3-C15环烷基,取代的C3-C15环烷基,3-15元杂环烷基,取代的3-15元杂环烷基,C6-C10芳基,取代的C6-C10芳基,5-10元杂芳基,取代的5-10元杂芳基;
R3为:其中,B通过共价键与Y连接;
A选自:-NH-,-NHR-;R选自:C6-C10芳基,取代的C6-C10芳基,5-10元杂芳基,取代的5-10元杂芳基;
B不存在或者选自:C3-C15环烷基,取代的C3-C15环烷基,3-15元杂环烷基,取代的3-15元杂环烷基,3-15元杂环烷酮基,R8取代的3-15元杂环烷酮基,C3-C12环烷基取代的胺基,3-12元杂环烷基取代的胺基,
在其中一些实施例中,E选自:氢,C1-C8烷基,R5取代的C1-C8烷基,C3-C12环烷基,R6取代的C3-C12环烷基,3-12元杂环烷基,R6取代的3-12元杂环烷基;
R5选自:卤素,C3-C12环烷基,C1-C3烷基取代的C3-C12环烷基,卤素取代的C3-C12环烷基;
R6选自:卤素,C1-C6烷基,卤素取代的C1-C6烷基。
在其中一些实施例中,E选自:氢,C1-C6烷基,R5取代的C1-C6烷基,C3-C10环烷基,R6取代的C3-C10环烷基;
R5选自:卤素,C6-C10环烷基,甲基取代的C6-C10环烷基,卤素取代的C6-C10环烷基;
R6选自:卤素,C1-C3烷基。
在其中一些实施例中,E选自:氢,环丙基,
其中x为0-3的整数,y为0-3的整数。
在其中一些实施例中,L选自:
其中n,m分别独立地为0-14的整数。
在其中一些实施例中,L选自: 其中n为0-7的整数,m为0-3的整数。
在其中一些实施例中,L选自: 或者L不存在,其中n为2-7的整数。
在其中一些实施例中,Y选自:-CH2-,-CO-,-O-,或者Y不存在;Z选自:-NHCO-,-NH-,或者Z不存在。
在其中一些实施例中,R1选自:氢,卤素,C1-C3烷基。
在其中一些实施例中,R2选自:C5-C10环烷基,R9取代的C5-C10环烷基,5-10元杂环烷基,R9取代的5-10元杂环烷基,C6-C10芳基,R9取代的C6-C10芳基,5-10元杂芳基,R9取代的5-10元杂芳基,5-10元杂芳酮基,R9取代的5-10元杂芳酮基;
R9选自:氨基,-N(C1-C6烷基)2,卤素,C1-C6烷基,C1-C6烷氧基,卤素取代的C1-C6烷基,卤素取代的C1-C6烷氧基,-NH(R4),-N(R4)2,-O(R4),-C=O-NH(R4),-C=O-NH(C3-C6环烷基),R10取代的C1-C6烷基,C3-C10环烷基,3-10元杂环烷基,R10取代的C3-C10环烷基,R10取代的3-10元杂环烷基,-NH(R4)取代的3-10元杂环烷基,5-10元杂芳基,-COR11;
R4选自:不存在或为氢,氨基,酯基,羧基,羟基,巯基,砜基,亚砜基,C1-C15烷基,R10取代的C1-C15烷基,C3-C15环烷基,3-15元杂环烷基,R10取代的C3-C15环烷基,R10取代的3-15元杂环烷基,-COR11;
R10选自:C1-C6烷基,氨基取代的C1-C6烷基,C3-C6环烷基,二甲胺基取代的C1-C6烷基,3-6元杂环烷基,二甲胺基,C1-C3烷氧基取代的C1-C6烷基,羟基取代的C1-C6烷基,C1-C6烷基取代的3-6元杂环烷基,C1-C6烷基酰基,羟基,C1-C6烷基取代的C3-C6环烷基,二甲氨乙基取代的5-6元杂环烷基,C1-C6烷氧基;
R11选自:乙烯基,C1-C6烷基,氨基取代的C1-C6烷基,C3-C6环烷基,氨基取代的C3-C6环烷基,卤素取代的C3-C6环烷基,3-6元杂环烷基,C1-C6烷基取代的3-6元杂环烷基,二甲胺基取代的C1-C6烷基,二甲胺乙基取代的5-6元杂环烷基。
在其中一些实施例中,R2选自:
苯基,
其中,R4选自:
H,
在其中一些实施例中,R2选自:C5-C8环烷基,R9取代的C5-C8环烷基,5-8元杂环烷基,R9取代的5-8元杂环烷基,苯基,R9取代的苯基,5-6元杂芳基,R9取代的5-6元杂芳基;
R9选自:H,二甲胺基,氨基,卤素,C1-C3烷基,C1-C3烷氧基,卤素取代的C1-C3烷基,卤素取代的C1-C3烷氧基,-NH(R4),-N(R4)2,-OR4,-C=O-NH(环丙基),R10取代的C1-C3烷基,C3-C6环烷基,3-6元杂环烷基,R10取代的C3-C6环烷基,R10取代的3-6元杂环烷基,-NH(R4)取代的3-6元杂环烷基,-COR11;
R4选自:H,C1-C6烷基,R10取代的C1-C6烷基,C3-C6环烷基,3-6元杂环烷基,R10取代的C3-C6环烷基,R10取代的3-6元杂环烷基,-CH2R11,-COR11;
R10选自:C1-C3烷基,二甲胺基,C3-C6环烷基,3-6元杂环烷基,C1-C3烷基取代的3-6元杂环烷基,C1-C3烷基取代的C3-C6环烷基;
R11选自:乙烯基,C1-C4烷基,C3-C6环烷基,卤素取代的C3-C6环烷基。
在其中一些实施例中,R2选自:C5-C6环烷基,R9取代的C5-C6环烷基,5-6元杂环烷基,R9取代的5-6元杂环烷基,苯基,R9取代的苯基;
R9选自:H、二甲胺基,氨基,C1-C3烷基,-NH(R4),-OR4,-C=O-NH(环丙基),R10取代的C1-C3烷基,C3-C6环烷基,5-6元杂环烷基,R10取代的C3-C6环烷基,R10取代的5-6元杂环烷基,-COR11;
R4选自:H,C1-C3烷基,R10取代的C1-C3烷基,C3-C6环烷基,5-6元杂环烷基,R10取代的C3-C6环烷基,R10取代的5-6元杂环烷基,-CH2R11,-COR11;
R10选自:C1-C3烷基,C3-C6环烷基;
R11选自:乙烯基,C1-C4烷基,C3-C6环烷基。
在其中一些实施例中,R2选自:
其中,R9选自:H,二甲胺基,C1-C3烷基,-NH(R4),-OR4,-COR11;
R4选自:H,甲基哌啶基,-CH2R11,-COR11;R11选自:乙烯基,C1-C4烷基,环丙基,环丁基,环戊基。
在其中一些实施例中,A选自:-NH-,-NHR-;R选自:苯基,R7取代的苯基,6元杂芳基,R7取代的6元杂芳基;
R7选自:C1-C6烷基,C3-C6环烷基,卤素,C1-C6烷氧基,卤素取代的C1-C6烷氧基,氘代C1-C6烷氧基,卤素取代的C1-C6烷基,氰基取代的C1-C6烷基,氘代C1-C6烷基,三氟甲基取代的C3-C6环烷基,C1-C6烷基取代的C3-C6环烷基,羟基,氨基,-SO(C1-C6烷基),-S(O)2(C1-C6烷基),C1-C6烷硫基;
B不存在或者选自:C3-C12环烷基,R8取代的C3-C12环烷基,3-12元杂环烷基,R8取代的3-12元杂环烷基,3-12元杂环烷酮基,R8取代的3-12元杂环烷酮基,C3-C12环烷基取代的胺基,3-12元杂环烷基取代的胺基,
R8选自:C1-C6烷基,C3-C12环烷基,3-12元杂环烷基,胺基,氰基取代的C1-C6烷基,卤素,C1-C6烷氧基,卤素取代的C1-C6烷基,羟基,氨基。
在其中一些实施例中,A选自:
-NH-,
B不存在或选自:
在其中一些实施例中,A选自:-NH-,-NHR-;R选自:苯基,6元杂芳基,R7取代的苯基,R7取代的6元杂芳基;
R7选自:C1-C3烷基,卤素,C1-C3烷氧基,卤素取代的C1-C3烷氧基,卤素取代的C1-C3烷基,氰基取代的C1-C3烷基;
B不存在或者选自:C4-C12环烷基,R8取代的C4-C12环烷基,4-12元杂环烷基,R8取代的4-12元杂环烷基,
R8选自:C1-C3烷基,C4-C6环烷基,4-6元杂环烷基,氰基取代的C1-C3烷基,卤素,C1-C3烷氧基,卤素取代的C1-C3烷基。
在其中一些实施例中,A选自:-NH-,-NHR-;R选自:苯基,6元含氮杂芳基,R7取代的苯基,R7取代的6元含氮杂芳基;
R7选自:C1-C3烷氧基;
B不存在或者选自:C4-C8环烷基,R8取代的C4-C10环烷基,4-10元杂环烷基,R8取代的4-10元杂环烷基,
R8选自:C1-C3烷基,C1-C3烷氧基。
在其中一些实施例中,R3选自:
本发明还提供了上述吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子的应用。包括如下技术方案:
上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备AKT3蛋白降解剂中的应用。
上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗与AKT3蛋白异常表达相关的疾病的药物中的应用。
在其中一些实施例中,所述与AKT3蛋白异常表达相关的疾病包括:肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症。
上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗肿瘤或防止肿瘤术后复发的药物中的应用。
在其中一些实施例中,所述肿瘤为:非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、肝癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病、皮肤鳞癌。
本发明还提供了一种AKT3蛋白降解剂。包括如下技术方案:
一种AKT3蛋白降解剂,其活性成分含有上所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明还提供了一种治疗和/或预防肿瘤或防止肿瘤术后复发的药物组合物。包括如下技术方案:
一种治疗和/或预防肿瘤或防止肿瘤术后复发的药物组合物,由活性成分和药学上可接受的载体或者辅料制备得到,所述活性成分包括上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明提供了一类结构新颖的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,该类化合物可以高效、高选择性地降解细胞中的AKT3蛋白,而对AKT1/2无影响,从而能够显著抑制AKT3高表达介导的肿瘤细胞增殖,可用于制备与AKT3蛋白异常表达相关的疾病以及多种肿瘤的治疗药物。
附图说明
图1为化合物ZX-HYT-11对H1975,PC-9,H1299和A549细胞中AKT1/2/3的降解活性。
具体实施方式
本发明所述化合物中,当任何变量(例如R4、R5等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
本文所用术语“环烷基”指环原子由碳原子组成的饱和或部分不饱和的单环、双环或多环环状烃基,双环或多环包括螺环、稠环和桥环。例如:“环烷基”包括但不限于以下基团:环丙基、环丁基、环戊基、环己基、 等。
本文所用术语“烷氧基”指具有-O-烷基结构的基团,如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
本文所用术语“杂环烷基”指饱和或部分不饱和的单环、双环或多环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,双环或多环包括螺环、稠环和桥环。例如:吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基、 等,及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。
本文所用术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环,该芳香环可以是单环、双环或者多环,例如包括但不限于:喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基等;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂芳基的连接可通过碳原子或通过杂原子实现。
本文所用术语“杂芳酮基”指含有1个或多个环羰基并且含有1个或多个选自O、N或S的杂原子的芳香环,该芳香环可以是单环、双环或者多环,例如包括但不限于: 等。杂芳酮基的连接可通过碳原子或通过杂原子实现。
本文所用术语“杂环烷酮基”指含有一个或多个环羰基的饱和或部分不饱和的单环、双环或多环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,双环或多环包括螺环、稠环和桥环,例如包括但不限于: 杂环烷酮基的连接可通过碳原子或通过杂原子实现
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
本发明提供了一种具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物:
其中:
E选自:氢,C1-C15烷基,取代的C1-C15烷基,C3-C15环烷基,取代的C3-C15环烷基,3-15元杂环烷基,取代的3-15元杂环烷基;
L不存在或者为由如下基团中的一个或多个组成的连接单元:亚烷基,醚基,硫醚基,酯基,胺基,酰胺基,杂芳基,环烷基,杂环烷基,-N=N-;
Y选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-;
Z选自:不存在或者-O-,-NH-,-N(C1-C6烷基)-,-NHCO-,-CH2-,-S-,-CO-,-SO-;
R1选自:氢,C1-C6烷基,卤素或卤素取代的C1-C6烷基;
R2选自:C3-C15环烷基,取代的C3-C15环烷基,3-15元杂环烷基,取代的3-15元杂环烷基,C6-C10芳基,取代的C6-C10芳基,5-10元杂芳基,取代的5-10元杂芳基;
R3为:其中,B通过共价键与Y连接;
A选自:-NH-,-NHR-;R选自:C6-C10芳基,取代的C6-C10芳基,5-10元杂芳基,取代的5-10元杂芳基;
B不存在或者选自:C3-C15环烷基,取代的C3-C15环烷基,3-15元杂环烷基,取代的3-15元杂环烷基,3-15元杂环烷酮基,R8取代的3-15元杂环烷酮基,C3-C12环烷基取代的胺基,3-12元杂环烷基取代的胺基,
本发明包括式Ⅰ化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式Ⅰ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
在一个实施方案中,本申请提供了一种利用具有式Ⅰ的化合物及其药学上可接受的盐治疗人或其它哺乳动物与AKT3蛋白异常表达相关的肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等疾病。
在一个实施方案中,本申请的化合物及其药学上可接受的盐可以用于预防和/或治疗非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病等肿瘤,或者用于防止肿瘤术后复发。
药物代谢物及前药
本发明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,也包含在本发明的权利要求中。
药物组合物
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体或者辅料。
本发明所述的“活性成分”是指本发明所述的式I化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明所述的“活性成分”和药物组合物可用作AKT3蛋白降解剂,可用于制备预防和/或治疗肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等的药物。
“安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体或者辅料”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
药学上可以接受的载体或者辅料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。
在另一优选例中,本发明式I化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中,本发明式I化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:
(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;
(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;
(c)保湿剂,例如,甘油;
(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;
(e)缓溶剂,例如石蜡;
(f)吸收加速剂,例如,季胺化合物;
(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;
(h)吸附剂,例如,高岭土;和
(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他治疗药物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
联合用药
式Ⅰ化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式和剂量保持不变,而同时或随后服用式Ⅰ化合物。当式Ⅰ化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I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时的剂量较低。
可以与式Ⅰ化合物进行药物联用的药物或活性成分包括但不局限为:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体、JAK抑制剂等。
在一个实施方案中,可以与式Ⅰ化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
本发明的有益之处在于:
(1)提供一种结构新颖的吡啶并嘧啶类化合物。
(2)该类化合物可以高效、高选择性地降解细胞中的AKT3蛋白,而对AKT1/2无影响,可以有效抑制多种肿瘤细胞的生长,可用于制备抗肿瘤药物。
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(NewYork: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技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中的原料可以从商业途径获得,或者通过本领域已知的方法制备,或根据本文所述方法制备。
化合物的结构通过核磁共振(1H-NMR)和/或质谱(MS)来确定。NMR测定是用BrukerAV-400型核磁共振仪,测定溶剂为氘代氯仿(CDCl3)或氘代二甲亚砜(DMSO-D6),TMS为内标。MS的测定用LCQAD-40000型质谱仪。柱层析采用200-300目硅胶(青岛海洋化工厂生产)。
实施例1:N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)乙氧基)乙氧基)乙氧基)乙基))哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-01)
步骤一:合成(3-((5-溴-2-氯嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯(3a)
将5-溴-2,4-二氯嘧啶(1)(0.45g,2.0mmol)和(3-氨基苯基)氨基甲酸叔丁酯(2a)(0.42g,2.0mmol)依次溶于N,N-二甲基甲酰胺(DMF)(10mL)溶液中,随后加入碳酸钾(0.55g,4.0mmol)。将悬浮液在室温条件下搅拌过夜。TLC监测反应完全后,向反应液中加入50mL冰水,有大量白色沉淀生成。减压抽滤,分别用冰水和无水乙醚洗涤(3×20mL)滤饼。待滤饼抽干后,将其加入10mL丙酮中打浆,再次减压抽滤,将所得滤饼干燥,得到较纯白色固体化合物3a(0.67g,收率84.2%)。MS(ESI),m/z:399.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.78(s,1H),7.45(d,1H,J=7.2Hz),7.32-7.28(m,2H),7.03(dd,1H,J=1.2,8.0Hz),6.56(s,1H),1.53(s,9H).
步骤二:合成(3-(2-氯-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)氨基甲酸叔丁酯(4a)
将化合物3a(2.57g,6.43mmol)和巴豆酸(5.54g,64.3mmol)置于250mL的两口圆底烧瓶中,在氩气保护条件下加入无水四氢呋喃(40mL)和N,N-二异丙基乙胺(11.2mL)。将混合物搅拌均匀后,置换氩气三次。再次加入二(氰基苯)二氯化钯(II)(0.12g,5%)和三(邻甲基苯基)磷(96mg,5%),并置换氩气三次。然后将混合液缓慢升温至70℃。用TLC检测原料3a反应完全后,加入1.5mL乙酸酐。并将反应液加热至80℃继续搅拌8小时。TLC检测反应完全后,减压蒸除大部分有机溶剂,将残余物用100mL乙酸乙酯稀释。分别用1N HCl(3×100mL)和饱和氯化钠溶液(2×100mL)洗涤有机层,分离出的有机相经无水硫酸钠干燥后,浓缩并通过柱色谱纯化(石油醚/乙酸乙酯=2:1洗脱),得到白色固体化合物4a(0.71g,收率30%)。MS(ESI),m/z:387.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.10(s,1H),7.51–7.38(m,3H),6.89(dt,J=7.4,1.7Hz,1H),6.73(d,J=1.4Hz,1H),2.53(d,J=1.3Hz,3H),1.47(s,9H).
步骤三:合成N-(3-(2-氯-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(5)
向化合物4a(0.50g,1.29mmol)的DCM(10mL)溶液中加入TFA(2mL),在室温条件下搅拌0.5小时,待反应完全后,减压蒸除有机溶剂。将所得残余物溶于10mL乙腈,并向该溶液中依次加入无水碳酸钾(0.36g,2.58mmol)和丙烯酰氯(0.17g,1.94mmol),并在室温条件下继续搅拌0.5小时。待TLC监测反应完全后,蒸干有机溶剂并加入冰水50mL,室温条件下继续搅拌1小时并减压抽滤,滤饼用无水丙酮(2×25mL)洗涤。滤饼干燥后得白色固体中间体5(0.41g,收率93%)。该粗品中间体无需纯化即可用于下一步反应。MS(ESI),m/z:341.0[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 10.69(br,1H),9.11(s,1H),7.78(d,J=8.22Hz,1H),7.71(br,1H),7.49(t,J=7.92Hz,1H),7.00(d,J=7.63Hz,1H),6.74(s,1H),6.56(dd,J=10.27,16.92Hz,1H),6.26(d,J=16.82Hz,1H),5.76(d,J=10.17Hz,1H),2.55(s,3H).
步骤四:合成叔丁基4-(4-((8-(3-丙烯酰胺基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-乙氧基苯基)哌嗪-1-羧酸酯(7)
将化合物5(0.68g,2mmol),化合物6(0.67g,2.2mmol)加入25mL仲丁醇,并往混合液中滴加催化量三氟乙酸。在氩气保护下,将反应液加热至95℃并搅拌过夜。TLC检测反应完全后,将混合物冷却至室温,减压蒸除有机溶剂。将残留物通过柱色谱分离纯化(氯仿/甲醇=25:1洗脱),得到黄色固体化合物7(1.11g,收率92%)。MS(ESI),m/z:612.1[M+H]+.1HNMR(400MHz,DMSO-d6)δ10.35(s,1H),8.81(s,1H),8.14(s,1H),7.90(d,J=8.2Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.1Hz,1H),7.28(d,J=8.9Hz,1H),6.98(ddd,J=7.9,2.0,1.0Hz,1H),6.56(d,J=2.5Hz,1H),6.50–6.38(m,1H),6.33(d,J=1.3Hz,1H),6.30–6.21(m,1H),6.03(s,1H),5.77(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.51–3.40(m,4H),3.05–2.89(m,4H),2.46(s,3H),1.44(s,9H).
步骤五:合成N-(3-(2-((2-甲氧基-4-(哌嗪-1-基)苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(8)
向化合物7(1.22g,2mmol)的DCM(20mL)溶液中加入TFA(3mL),并将所得溶液在室温下搅拌0.5小时。TLC监测反应完全后,蒸除有机溶剂,将所得粗产物经柱色谱纯化(氯仿/甲醇/氨水=25:1:0.1洗脱),得到黄色固体产物8(0.91g,收率90%)。MS(ESI),m/z:510.3[M-H]-.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.90(s,1H),8.82(s,1H),8.18(s,1H),7.90(d,J=8.3Hz,1H),7.56–7.45(m,2H),7.31(d,J=8.8Hz,1H),7.00(dd,J=7.9,2.0Hz,1H),6.60(d,J=2.6Hz,1H),6.45(dd,J=16.9,10.1Hz,1H),6.35–6.23(m,2H),6.06(s,1H),5.77(dd,J=10.1,2.1Hz,1H),3.79(s,3H),3.24(s,8H),2.48–2.44(m,3H)
步骤六:合成N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)乙氧基)乙氧基)乙氧基)乙基))哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-01)
将化合物8(0.20g,0.39mmol),2-(2-(2-(2-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)乙氧基)乙氧基)4-甲基苯磺酸乙酯10a(0.23g,0.47mmol)和无水碳酸钾(0.11g,0.8mmol)依次加入DMF(10mL)中,将反应体系升温至90℃搅拌过夜。TLC检测反应完全后,冷却至室温,并向体系中加入饱和氯化钠溶液(50mL),并用乙酸乙酯(40mL)萃取。用无水硫酸钠干燥并浓缩有机相,将所得粗产物通过柱色谱法纯化(三氯甲烷/甲醇=30/1洗脱),得黄色固体目标化合物ZX-HYT-01(0.21g,收率66%)。HRMS(ESI)for C46H58N8O6Na[M+Na]+:calcd,841.4377;found,841.4372.HPLC analysis:MeOH-H2O(97:3),RT=4.747min,98.07%purity.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.81(s,1H),8.12(s,1H),7.89(d,J=8.1Hz,1H),7.72(t,J=5.7Hz,1H),7.57(t,J=2.1Hz,1H),7.51(t,J=8.1Hz,1H),7.27(d,J=8.9Hz,1H),6.98(dd,J=7.8,2.0Hz,1H),6.56–6.49(m,1H),6.49–6.39(m,1H),6.37–6.21(m,2H),6.00(s,1H),5.77(dd,J=10.0,2.1Hz,1H),3.78(s,3H),3.60–3.49(m,6H),3.42(t,J=5.9Hz,2H),3.19(q,J=5.9Hz,2H),3.02(s,4H),2.63–2.52(m,6H),2.46(s,3H),1.91(s,3H),1.83(s,2H),1.70–1.61(m,3H),1.60–1.50(m,9H).13C NMR(101MHz,DMSO)δ170.52,163.73,162.63,157.05,156.73,147.43,140.39,137.52,132.15,129.97,127.66,124.52,120.13,119.20,116.98,106.60,100.06,70.15,69.99,69.65,56.15,53.52,50.47,49.12,42.54,38.82,36.93,32.61,28.52,17.48.
实施例2:N-(3-(2-((4-(4-(6-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)己基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-02)
化合物ZX-HYT-02的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和6-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)-4-甲基苯磺酸己酯(0.21g,0.47mmol)为原料,经亲核取代反应得到呈黄色固体的化合物ZX-HYT-02(0.18g,收率59%)。HRMS(ESI)forC46H58N8O4Na[M+Na]+:calcd,809.4479;found,809.4473.HPLC analysis:MeOH-H2O(97:3),RT=5.260min,98.05%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J=8.2Hz,1H),7.65(t,J=5.6Hz,1H),7.59–7.55(m,1H),7.51(t,J=8.0Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.9,2.1,1.0Hz,1H),6.52(d,J=2.5Hz,1H),6.49–6.39(m,1H),6.37–6.21(m,2H),6.00(s,1H),5.77(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.09–2.95(m,6H),2.48–2.43(m,6H),2.30(t,J=7.3Hz,2H),1.91(d,J=5.0Hz,3H),1.81(s,2H),1.69–1.63(m,3H),1.61–1.54(m,9H),1.49–1.43(m,2H),1.42–1.36(m,2H),1.33–1.27(m,4H).13C NMR(101MHz,DMSO)δ170.22,163.72,162.64,157.06,156.73,147.44,140.39,137.52,132.16,129.98,127.63,124.52,120.12,119.20,116.97,106.60,100.06,58.24,56.14,53.17,50.60,49.14,42.62,38.67,36.94,32.62,29.65,28.52,27.11,26.84,26.70,17.48.
实施例3:N-(3-(2-((4-(4-(8-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-03)
化合物ZX-HYT-03的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和8-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基-4-甲基苯磺酸酯(0.20g,0.47mmol)为原料,经亲核取代得到呈黄色固体的化合物ZX-HYT-03(0.17g,收率55%)。HRMS(ESI)forC48H62N8O4Na[M+Na]+:calcd,837.4792;found,837.4786.HPLC analysis:MeOH-H2O(97:3),RT=5.925min,98.11%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J=8.0Hz,1H),7.63(t,J=5.6Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.0Hz,1H),7.27(d,J=8.9Hz,1H),6.98(dd,J=8.0,2.0Hz,1H),6.52(d,J=2.5Hz,1H),6.49–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.79–5.74(m,1H),3.78(s,3H),3.12–2.94(m,6H),2.49–2.43(m,6H),2.31(q,J=8.5,7.4Hz,2H),1.91(s,3H),1.81(s,2H),1.71–1.62(m,3H),1.61–1.52(m,9H),1.48–1.42(m,2H),1.41–1.35(m,2H),1.33–1.21(m,11H).13C NMR(101MHz,DMSO)δ170.15,163.71,162.57,156.97,156.77,147.32,140.41,137.53,132.22,130.11,129.89,127.45,124.48,120.19,119.20,116.99,106.75,106.61,100.08,58.32,56.17,53.20,50.61,49.22,42.64,42.59,38.69,36.98,36.93,32.62,29.64,29.43,29.15,28.57,28.52,27.36,26.87,26.76,17.44.
实施例4:N-(3-(2-((4-(4-(10-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)癸基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-04)
化合物ZX-HYT-04的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和10-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)4-甲基苯磺酸癸酯(0.24g,0.47mmol)为原料,经亲核取代反应得到呈黄色固体的化合物ZX-HYT-04(0.19g,收率59%)。HRMS(ESI)forC50H66N8O4Na[M+Na]+:calcd,865.5105;found,865.5099.HPLC analysis:MeOH-H2O(97:3),RT=6.906min,97.22%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.96–7.82(m,1H),7.63(t,J=5.6Hz,1H),7.58–7.54(m,1H),7.51(t,J=8.0Hz,1H),7.27(d,J=8.9Hz,1H),6.98(dd,J=7.7,1.9Hz,1H),6.52(d,J=2.5Hz,1H),6.44(dd,J=16.9,10.1Hz,1H),6.35–6.21(m,2H),6.00(s,1H),5.79–5.74(m,1H),3.78(s,3H),3.01(q,J=6.3Hz,6H),2.46(s,6H),2.35–2.23(m,2H),1.93–1.87(m,3H),1.80(s,2H),1.66(d,J=12.2Hz,3H),1.61–1.52(m,9H),1.45(d,J=6.6Hz,2H),1.41–1.35(m,2H),1.32–1.23(m,13H).13CNMR(101MHz,DMSO)δ170.18,163.71,162.63,157.04,156.73,147.42,140.39,137.52,132.17,129.97,127.61,124.51,120.13,119.20,116.97,106.60,100.06,58.30,56.14,55.37,53.15,50.59,49.13,42.62,38.66,36.94,32.61,29.64,29.48,29.46,29.43,29.17,28.53,27.42,26.87,26.67,17.48.
实施例5:N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-05)
化合物ZX-HYT-05的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基4-甲基苯磺酸酯(0.25g,0.47mmol)为原料,经亲核取代反应得到呈黄色固体的化合物ZX-HYT-05(0.18g,收率54%)。HRMS(ESI)for C52H70N8O4Na[M+Na]+:calcd,893.5418;found,893.5412.HPLC analysis:MeOH-H2O(95:5),RT=9.127min,97.17%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J=8.2Hz,1H),7.62(t,J=5.7Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.0Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.9,2.0,1.0Hz,1H),6.52(d,J=2.5Hz,1H),6.44(dd,J=16.9,10.1Hz,1H),6.33(d,J=1.3Hz,1H),6.26(dd,J=17.0,2.1Hz,1H),6.00(s,1H),5.76(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.09–2.94(m,6H),2.49–2.41(m,7H),2.30(t,J=7.4Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.66(d,J=12.1Hz,3H),1.58(s,2H),1.56–1.52(m,7H),1.50–1.42(m,2H),1.40–1.33(m,2H),1.31–1.21(m,16H).13C NMR(101MHz,DMSO)δ170.14,163.69,162.61,157.01,156.73,147.37,140.41,137.52,132.19,129.95,127.55,124.50,120.24,120.14,119.19,116.98,106.65,106.58,100.02,58.36,56.13,53.22,50.59,49.22,42.62,38.66,36.95,32.61,29.64,29.54,29.52,29.48,29.43,29.19,28.54,27.47,26.88,26.77,17.48.
实施例6:N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十四烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-06)
化合物ZX-HYT-06的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和14-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)4-甲基苯磺酸十四烷基酯(0.26g,0.47mmol)为原料,经亲核取代反应得到呈黄色固体的化合物ZX-HYT-06(0.15g,收率43%)。HRMS(ESI)for C54H74N8O4Na[M+Na]+:calcd,921.5731;found,921.5725.HPLCanalysis:MeOH-H2O(95:5),RT=14.347min,98.68%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J=8.1Hz,1H),7.62(t,J=5.6Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.1Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.8,2.0,1.0Hz,1H),6.51(d,J=2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,6H),2.49–2.40(m,7H),2.30(t,J=7.4Hz,2H),1.90(s,3H),1.80(s,2H),1.69–1.61(m,3H),1.60–1.53(m,9H),1.50–1.41(m,2H),1.40–1.33(m,2H),1.32–1.20(m,20H).13C NMR(101MHz,DMSO)δ170.22,163.72,162.64,157.04,156.72,147.44,140.39,137.51,132.15,129.97,127.62,124.51,120.12,119.20,116.96,106.60,100.04,58.29,56.51,56.14,53.15,50.59,49.12,42.60,38.65,36.93,32.61,29.60,29.51,29.48,29.43,29.40,29.15,28.53,27.41,26.84,26.65,18.99,17.47.
实施例7:N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-07)
向化合物8(0.15g,0.29mmol)的DMF(10mL)溶液中加入12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二酸9(0.12g,0.29mmol),HATU(0.17g,0.43mmol)和碳酸钾(82mg,0.58mmol),并将反应体系在室温下搅拌0.5小时。TLC监测待反应完全后,向反应体系加入乙酸乙酯(20mL)稀释,再分别用饱和氯化钠溶液(1×30mL)和水(3×30mL)洗涤有机层。经无水硫酸钠干燥和浓缩后得到的残余物通过柱色谱纯化(三氯甲烷/甲醇=30/1洗脱),得到黄色固体状化合物ZX-HYT-07(0.13g,收率51%)。HRMS(ESI)for C52H68N8O5Na[M+Na]+:calcd,907.5210;found,907.5205.HPLC analysis:MeOH-H2O(95:5),RT=6.582min,100.00%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J=8.2Hz,1H),7.62(t,J=5.7Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.0Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.9,2.0,1.0Hz,1H),6.52(d,J=2.5Hz,1H),6.44(dd,J=16.9,10.1Hz,1H),6.33(d,J=1.3Hz,1H),6.26(dd,J=17.0,2.1Hz,1H),6.00(s,1H),5.76(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.09–2.94(m,6H),2.49–2.41(m,7H),2.30(t,J=7.4Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.66(d,J=12.1Hz,3H),1.58(s,2H),1.56–1.52(m,7H),1.50–1.42(m,2H),1.40–1.33(m,2H),1.31–1.21(m,16H).13C NMR(101MHz,DMSO)δ174.77,171.05,170.10,163.66,162.59,157.04,156.70,147.38,140.39,137.52,132.20,129.97,127.61,124.51,120.88,120.15,119.21,117.05,107.22,106.64,100.82,56.15,50.57,50.02,49.59,45.24,42.61,41.25,38.65,36.93,35.58,32.71,32.61,29.65,29.54,29.51,29.45,29.42,29.32,29.21,28.52,26.90,25.60,25.34,17.50.
实施例8:N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙酰胺(ZX-HYT-08)
第一步:1-(3-甲氧基-4-硝基苯基)哌嗪(12)
依次将5-氟-2-硝基苯甲醚11(3.00g,17.5mmol),哌嗪(7.53g,87.5mmol)和无水碳酸钾(3.63g,26.3mmol)加入乙腈(50mL)中,将混合液在80℃的条件下搅拌6小时。TLC监测,待反应完全后,减压蒸除有机溶剂。将所得残余物加入20mL蒸馏水中并搅拌1小时,减压抽滤,将所得滤饼再次加入40mL无水乙醚中,继续搅拌1小时后减压抽滤,用冰的无水乙醚(3×20mL)洗涤滤饼。经干燥后的滤饼即为较纯的化合物12(3.95g,收率95%)。MS(ESI),m/z:238.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.21(s,2H),7.97–7.87(m,1H),6.69–6.58(m,2H),3.93(s,3H),3.70–3.63(m,4H),3.28–3.19(m,4H).
第二步:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(3-甲氧基-4-硝基苯基)哌嗪-1-基)十二烷基)乙酰胺(13)
将化合物12(0.95g,4mmol),碳酸钾(0.83g,6mmol)和12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基4-甲基苯磺酸酯(2.34g,4.4mmol)依次加入DMF(30mL)中,并将混合液在80℃下加热搅拌过夜。待反应完全后冷却至室温。再将反应液加入50mL饱和氯化钠水溶液中,用乙酸乙酯萃取,分离有机相。有机相经无水硫酸钠干燥后浓缩。剩下的残余物通过柱色谱纯化(三氯甲烷/甲醇=100/1洗脱),得到黄色油状的目标化合物13(2.05g,收率86%)。MS(ESI),m/z:619.3[M+Na]+.1H NMR(400MHz,DMSO-d6)δ7.88(d,J=9.4Hz,1H),7.62(t,J=5.6Hz,1H),6.58(dd,J=9.5,2.5Hz,1H),6.52(d,J=2.6Hz,1H),3.91(s,3H),3.42(t,J=5.1Hz,4H),3.00(q,J=6.5Hz,2H),2.45(t,J=5.1Hz,4H),2.33–2.25(m,2H),1.94–1.86(m,3H),1.80(s,2H),1.65(dt,J=12.2,2.9Hz,3H),1.56(dd,J=12.7,2.3Hz,9H),1.44(t,J=7.2Hz,2H),1.36(t,J=6.5Hz,2H),1.26–1.20(m,16H).
第三步:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(14)
向化合物13(2.98g,5mmol)的甲醇溶液中加入钯碳(0.55g),用氢气置换3次。将反应液在室温条件下搅拌过夜。待反应完全后,减压抽滤,取滤液并蒸干。所得无色油状液体即为化合物14(2.8g,收率99%)。由于该化合物在空气中极易被氧化,故无需纯化直接用于下一步。MS(ESI),m/z:567.4[M+H]+.
第四步:叔丁基(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)氨基甲酸酯(15a)
将中间体14(1.13g,2mmol)和化合物4a(0.72g,2mmol)快速加入30mL仲丁醇中,并滴加一滴TFA。用氩气置换3次,并将反应液在95℃的条件下搅拌过夜。TLC监测反应完全后,冷却至室温,减压蒸除反应液中的有机溶剂。将所得残余物通过柱色谱纯化(三氯甲烷/甲醇=50/1洗脱),得黄色固体状化合物15a(1.11g,收率61%)。MS(ESI),m/z:917.5[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.64(s,1H),7.85(s,1H),7.63(s,1H),7.37(t,J=7.9Hz,1H),6.85(ddd,J=8.1,2.4,0.9Hz,1H),6.69(ddd,J=7.8,2.0,0.9Hz,1H),6.61(t,J=2.1Hz,1H),6.48(d,J=2.5Hz,1H),6.39(d,J=1.3Hz,1H),6.21(s,1H),5.36(s,1H),3.85(s,3H),3.81(s,1H),3.25(td,J=7.2,5.8Hz,2H),3.14(t,J=5.0Hz,4H),2.64(t,J=5.0Hz,4H),2.47(d,J=1.2Hz,3H),2.45–2.39(m,2H),1.99(p,J=3.1Hz,3H),1.92(s,2H),1.72(dt,J=12.2,3.1Hz,3H),1.65(dd,J=10.9,2.5Hz,9H),1.52(dq,J=20.4,6.8,6.3Hz,4H),1.36–1.26(m,16H).
第五步:N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙酰胺(ZX-HYT-08)
向装有化合物15a(0.25g,0.27mmol)的圆底烧瓶中加入10mL的DCM和0.50mL的TFA,将该反应体系在室温条件下搅拌0.5小时。待反应完全后,减压蒸除有机溶剂。将所得残余物直接溶于5mL无水乙腈,并向该溶液中依次加入无水碳酸钾(0.14g,1.01mmol)和丙酰氯(0.04g,0.43mmol),再将反应液于室温条件下搅拌1小时,TLC监测,待反应完全后,蒸干有机溶剂。所得残余物直接拌硅胶并通过柱色谱纯化(三氯甲烷/甲醇=30/1洗脱),得到黄色粉末状化合物ZX-HYT-08(0.18g,收率78%)。HRMS(ESI)for C52H72N8O4Na[M+Na]+:calcd,895.5574;found,895.5569.HPLC analysis:MeOH-H2O(97:3),RT=8.712min,95.41%purity.1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.79(s,1H),8.09(s,1H),7.79(d,J=8.0Hz,1H),7.62(t,J=5.8Hz,1H),7.53–7.41(m,2H),7.27(d,J=8.8Hz,1H),6.92(d,J=7.8Hz,1H),6.52(s,1H),6.31(s,1H),6.01(s,1H),3.78(s,3H),3.10–2.94(m,6H),2.45(m,5H),2.37–2.25(m,4H),1.90(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.61–1.51(m,9H),1.48–1.41(m,2H),1.41–1.33(m,2H),1.32–1.21(m,18H),1.07(t,J=7.5Hz,3H).13C NMR(101MHz,DMSO)δ172.54,170.10,162.60,157.00,156.75,147.32,140.79,137.45,130.11,129.79,123.85,120.27,119.70,118.79,116.98,106.68,106.57,100.04,58.35,56.13,53.25,50.59,49.26,42.62,38.65,36.96,32.61,30.05,29.65,29.57,29.54,29.52,29.48,29.43,29.19,28.54,27.46,26.88,26.77,17.47,10.08.
实施例9:N-(12-(4-(4-((8-(3-乙酰氨基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)-2-((3R,5R,7R)-金刚烷-1-基)乙酰胺(ZX-HYT-09)
与ZX-HYT-08的合成方法类似,以化合物15a(0.25g,0.27mmol)和乙酰氯(0.04g,0.51mmol)为原料,经两步反应即可得到黄色粉末状目标化合物ZX-HYT-09(0.11g,收率47%)。HRMS(ESI)for C51H71N8O4[M+H]+:calcd,859.5598;found,859.5593.HPLCanalysis:MeOH-H2O(97:3),RT=9.171min,98.91%purity.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.80(s,1H),8.13(s,1H),7.76(d,J=8.0Hz,1H),7.63(t,J=5.7Hz,1H),7.55–7.42(m,2H),7.27(d,J=8.8Hz,1H),7.02–6.90(m,1H),6.56(s,1H),6.32(s,1H),6.05(s,1H),3.79(s,3H),3.20–2.93(m,3H),2.49–2.41(m,6H),2.05(s,4H),1.95–1.87(m,3H),1.80(s,2H),1.75–1.61(m,4H),1.61–1.44(m,11H),1.42–1.02(m,22H).13C NMR(101MHz,DMSO)δ170.14,168.91,162.60,157.00,156.73,147.33,140.74,137.44,129.76,123.96,120.63,119.69,118.81,117.02,106.87,106.62,100.29,57.54,56.18,52.51,50.59,48.30,42.62,38.66,36.95,32.61,29.65,29.53,29.50,29.47,29.44,29.33,29.20,28.69,28.55,27.17,26.90,25.66,24.52,17.47.
实施例10:N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)异丁酰胺(ZX-HYT-10)
与ZX-HYT-08的合成方法类似,以化合物15a(0.25g,0.27mmol)和异丁酰氯(0.04g,0.37mmol)为原料,经两步反应即可得到黄色粉末状目标化合物ZX-HYT-10(0.16g,收率67%)。HRMS(ESI)for C53H74N8O4Na[M+Na]+:calcd,909.5731;found,909.5725.HPLCanalysis:MeOH-H2O(97:3),RT=8.363min,98.82%purity.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.2Hz,1H),7.62(t,J=5.6Hz,1H),7.56–7.42(m,2H),7.27(d,J=8.8Hz,1H),6.93(dd,J=7.8,1.9Hz,1H),6.53(d,J=2.5Hz,1H),6.32(s,1H),6.02(s,1H),3.78(s,3H),3.14–2.91(m,6H),2.59(p,J=6.9Hz,2H),2.49–2.23(m,7H),1.91(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.61–1.52(m,9H),1.50–1.41(m,2H),1.40–1.34(m,2H),1.33–1.18(m,17H),1.11–1.05(m,6H).13C NMR(101MHz,DMSO)δ178.31,175.78,170.12,162.60,157.00,156.75,147.33,140.86,137.45,129.79,123.88,120.31,119.83,118.94,116.98,106.68,106.56,100.04,58.21,56.13,53.14,50.59,49.11,42.62,42.46,38.65,36.96,35.43,33.59,32.61,29.65,29.52,29.45,29.43,29.19,28.54,27.40,26.88,26.61,19.93,19.90,19.38,17.47.
实施例11:N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-11)
与ZX-HYT-08的合成方法类似,以化合物15a(0.25g,0.27mmol)和环丙甲酰氯(0.04g,0.38mmol)为原料,经两步反应即可得到黄色粉末状目标化合物ZX-HYT-11(0.15g,收率63%)。HRMS(ESI)for C53H72N8O4Na[M+Na]+:calcd,907.5574;found,907.5569.HPLCanalysis:MeOH-H2O(95:5),RT=10.249min,100%purity.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J=8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J=2.5Hz,1H),6.32(d,J=1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J=13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.32–1.15(m,18H),0.88–0.75(m,6H).13C NMR(101MHz,DMSO)δ176.01,172.17,170.08,162.58,157.02,156.73,147.32,140.77,137.47,129.85,123.83,119.68,118.75,116.99,106.72,106.57,100.12,56.15,53.19,50.58,49.20,42.62,38.64,36.95,32.61,29.65,29.51,29.45,29.42,29.18,28.53,27.41,26.87,17.48,15.04,12.87,8.16,7.64.
实施例12:N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)新戊酰胺(ZX-HYT-12)
与ZX-HYT-08的合成方法类似,以化合物15a(0.25g,0.27mmol)和新戊酰氯(0.04g,0.33mmol)为原料,经两步反应即可得到黄色粉末状目标化合物ZX-HYT-12(0.18g,收率73%)。HRMS(ESI)for C54H76N8O4Na[M+Na]+:calcd,923.5887;found,923.5882.HPLCanalysis:MeOH-H2O(97:3),RT=10.083min,97.50%purity.1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.81(s,1H),8.10(s,1H),7.91(d,J=7.8Hz,1H),7.62(t,J=5.7Hz,1H),7.56(t,J=2.0Hz,1H),7.46(t,J=8.0Hz,1H),7.28(d,J=8.9Hz,1H),6.93(dt,J=7.9,1.2Hz,1H),6.52(d,J=2.5Hz,1H),6.40–6.26(m,1H),6.02(s,1H),3.78(s,3H),3.11–2.94(m,6H),2.49–2.42(m,7H),2.36–2.25(m,2H),1.91(t,J=3.4Hz,3H),1.80(s,2H),1.70–1.62(m,3H),1.61–1.52(m,9H),1.49–1.42(m,2H),1.40–1.33(m,2H),1.33–1.23(m,18H),1.23–1.18(m,9H).13C NMR(101MHz,DMSO)δ179.87,177.00,170.12,162.63,157.01,156.76,147.34,140.89,137.28,129.57,123.96,120.60,120.24,119.79,116.95,106.73,106.54,99.97,58.31,56.13,53.23,50.59,49.25,42.62,38.65,38.18,36.95,32.61,29.64,29.53,29.51,29.46,29.42,29.18,28.54,27.58,27.48,27.43,26.87,26.74,17.48.
实施例13:N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环己烷甲酰胺(ZX-HYT-13)
与ZX-HYT-08的合成方法类似,以化合物15a(0.25g,0.27mmol)和环己甲酰氯(0.05g,0.35mmol)为原料,经两步反应即可得到黄色粉末状目标化合物ZX-HYT-13(0.13g,收率52%)。HRMS(ESI)for C56H78N8O4Na[M+Na]+:calcd,949.6044;found,949.6038.HPLCanalysis:MeOH-H2O(97:3),RT=12.082min,96.21%purity.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.80(s,1H),8.10(s,1H),7.78(d,J=8.2Hz,1H),7.62(t,J=5.7Hz,1H),7.54(t,J=2.0Hz,1H),7.46(t,J=8.1Hz,1H),7.27(d,J=8.9Hz,1H),6.91(ddd,J=7.8,2.0,1.0Hz,1H),6.52(d,J=2.5Hz,1H),6.32(d,J=1.3Hz,1H),6.01(s,1H),3.78(s,3H),3.11–2.95(m,6H),2.50–2.40(m,6H),2.36–2.24(m,3H),1.90(s,3H),1.85–1.70(m,6H),1.68–1.62(m,4H),1.60–1.52(m,8H),1.50–1.44(m,2H),1.41–1.33(m,4H),1.32–1.13(m,21H).13C NMR(101MHz,DMSO)δ174.86,170.11,162.61,157.02,156.74,147.34,140.92,137.43,130.12,129.78,123.79,120.27,119.72,118.83,116.99,106.68,106.57,100.04,58.30,56.14,53.25,50.59,49.29,45.34,42.62,38.64,36.95,32.61,29.64,29.60,29.53,29.50,29.48,29.42,29.18,28.54,27.43,26.87,26.77,25.86,25.65,17.47.
实施例14:N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-14)
与ZX-HYT-08的合成方法类似,以化合物14(1.13g,2mmol),化合物4b(0.72g,2mmol)和丙烯酰氯(0.03g,0.38mmol)为原料,经三步反应即可得到黄色粉末状目标化合物ZX-HYT-14(0.21g,收率86%)。HRMS(ESI)for C52H70N8O4Na[M+Na]+:calcd,893.5418;found,893.5412.HPLC analysis:MeOH-H2O(97:3),RT=10.934min,96.59%purity.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.79(s,1H),8.07(s,1H),7.85(m,2H),7.62(t,J=5.7Hz,1H),7.26–7.17(m,3H),6.58–6.46(m,2H),6.38–6.28(m,2H),5.96(s,1H),5.81(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.04–2.91(m,6H),2.45(s,3H),2.41(s,4H),2.28(t,J=7.3Hz,2H),1.90(s,3H),1.80(s,2H),1.69–1.62(m,3H),1.59–1.52(m,9H),1.47–1.41(m,2H),1.40–1.33(m,2H),1.32–1.22(m,16H).13C NMR(101MHz,DMSO)δ170.21,163.68,162.78,157.00,156.90,147.24,139.19,132.48,132.22,129.86,127.38,120.46,120.19,117.00,106.61,99.72,58.30,56.11,53.23,50.60,49.03,42.61,38.67,36.94,32.61,29.63,29.54,29.52,29.49,29.44,29.19,28.54,27.44,26.88,26.77,17.43.
实施例15:N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-15)
与ZX-HYT-08的合成方法类似,以化合物14(1.13g,2mmol),化合物4b(0.72g,2mmol)和环丙甲酰氯(0.04g,0.38mmol)为原料,经三步反应即可得到黄色粉末状目标化合物ZX-HYT-15(0.21g,收率86%)。HRMS(ESI)for C53H72N8O4Na[M+Na]+:calcd,907.5574;found,907.5569.HPLC analysis:MeOH-H2O(97:3),RT=9.243min,96.18%purity.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.79(s,1H),8.07(s,1H),7.80–7.71(m,2H),7.63(t,J=5.7Hz,1H),7.27–7.14(m,3H),6.53(d,J=2.6Hz,1H),6.31(d,J=1.4Hz,1H),5.99(s,1H),3.79(s,3H),3.16–2.92(m,6H),2.49–2.23(m,6H),1.93–1.83(m,4H),1.80(s,2H),1.69–1.61(m,3H),1.60–1.52(m,9H),1.48(s,2H),1.41–1.19(m,20H),0.92–0.79(m,4H).13C NMR(101MHz,DMSO)δ172.24,170.20,162.81,157.01,156.93,147.21,139.50,131.85,129.74,120.42,120.04,117.05,106.65,100.03,58.03,56.17,53.03,50.59,48.83,42.61,38.65,36.94,32.61,29.62,29.49,29.41,29.17,28.53,27.32,26.86,26.42,17.44,14.96,7.68.
实施例16:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-乙基苯基)-5-甲基-7-氧代-7,8-二氢-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-16)
第一步:5-溴-2-氯-N-(3-乙基苯基)嘧啶-4-胺(3c)
将化合物5-溴-2,4-二氯嘧啶(4.9g,21.5mmol),3-乙基苯胺(2.6g,21.5mmol)和碳酸钾(5.9g,43mmol)依次加入60mL DMF中,并在室温条件下反应6小时。TLC监测,待反应完全后,将反应体系加入200mL冰水中,有大量白色固体生成。减压抽滤,并用冰水洗涤滤饼。抽干的滤饼置于50mL丙酮中室温搅拌2小时打浆,减压抽滤,取滤饼。即得白色中间体3c(6.5g,收率92%)。MS(ESI),m/z:312.1[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.30(s,1H),7.53–7.48(m,1H),7.40(t,J=2.5Hz,1H),7.33(td,J=7.8,2.9Hz,1H),7.28(s,1H),7.06(dt,J=8.2,1.9Hz,1H),2.70(qd,J=7.7,2.8Hz,2H),1.29(t,J=7.7,3.0Hz,3H).
第二步:2-氯-8-(3-乙基苯基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(3-4c)
将化合物3c(2.19g,7.01mmol),巴豆酸(6.04g,70.1mmol),二(氰基苯)二氯化钯(II)(0.13g,5%)和三(邻甲基苯基)磷(104mg,5%)置于250mL的两口圆底烧瓶中,置换3~5次氩气,用注射器加入无水四氢呋喃(45mL)和N,N-二异丙基乙胺(12mL)后,再次置换氩气三次。然后将反应体系于70℃搅拌6小时。用TLC检测,待原料3c反应完全后,加入5mL乙酸酐,并将反应液加热至80℃继续搅拌8小时。TLC检测反应完全后,减压蒸除大部分有机溶剂,将残余物用100mL乙酸乙酯稀释。分别用1N HCl(3×100mL)和饱和氯化钠溶液(2×100mL)洗涤有机层,分离出的有机相经无水硫酸钠干燥后,浓缩并通过柱色谱纯化(石油醚/乙酸乙酯=3:1洗脱),得到白色固体化合物4c(1.66g,收率80%)。MS(ESI),m/z:300.2[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),7.49(dd,J=9.0,7.3Hz,1H),7.38–7.32(m,1H),7.08–7.01(m,2H),6.73–6.67(m,1H),2.76(q,J=7.6Hz,2H),2.56(s,3H),1.30(t,J=7.6Hz,3H).
第三步:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-乙基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-16)
将化合物4c(0.31g,1mmol),2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(0.57g,1mmol)和催化量的三氟乙酸依次加入20mL仲丁醇中,并在90℃的温度下,搅拌反应10小时。TLC监测反应完全后,减压蒸除有机溶剂,所得残余物经柱色谱(三氯甲烷/甲醇=30:1)分离,得到目标化合物ZX-HYT-16(0.24g,收率29%)。HRMS(ESI)for C51H72N7O3[M+H]+:calcd,830.5618;found,830.5622.HPLCanalysis:MeOH-H2O(97:3),RT=13.173min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.05(s,1H),7.61(t,J=5.7Hz,1H),7.46(t,J=7.7Hz,1H),7.37(d,J=7.8Hz,1H),7.16(d,J=8.7Hz,1H),7.10(s,1H),7.06(d,J=7.8Hz,1H),6.52(s,1H),6.30(s,1H),5.93(s,1H),3.77(s,3H),3.08–2.95(m,6H),2.67(q,J=7.6Hz,2H),2.49–2.38(m,7H),2.29(t,J=7.4Hz,2H),1.90(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.60–1.51(m,9H),1.48–1.41(m,2H),1.39–1.34(m,2H),1.30–1.16(m,19H).13C NMR(101MHz,DMSO)δ170.07,162.72,156.88,147.13,145.34,137.26,129.51,128.68,127.72,126.70,120.39,117.07,106.60,100.19,58.38,56.14,53.27,50.59,49.34,42.63,38.64,36.96,32.61,29.65,29.51,29.47,29.42,29.18,28.55,28.42,27.46,26.88,26.79,17.44,15.88.
实施例17:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-氨基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-17)
将中间体14(1.13g,2mmol),化合物4a(0.72g,2mmol)和催化量的三氟乙酸依次加入30mL的仲丁醇中,并在95℃的温度下搅拌反应10小时。TLC监测反应完全后,减压蒸除有机溶剂。残余物用柱色谱纯化(三氯甲烷/甲醇=50/1洗脱)。纯化后的中间体再次溶于DCM(8mL)和TFA(0.50mL)中,室温搅拌反应0.5小时,蒸干有机溶剂,残余物经柱色谱分离得黄色粉末状化合物ZX-HYT-17(0.13g,收率54%)。HRMS(ESI)for C49H68N8O3Na[M+Na]+:calcd,839.5312;found,839.5307.HPLC analysis:MeOH-H2O(97:3),14.595min,100%purity.1HNMR(400MHz,DMSO-d6)δ8.77(s,1H),8.04(s,1H),7.63(t,J=5.6Hz,1H),7.45(d,J=8.9Hz,1H),7.17(t,J=7.9Hz,1H),6.70(dd,J=8.1,2.3Hz,1H),6.55(d,J=2.5Hz,1H),6.40(t,J=2.1Hz,1H),6.38–6.33(m,1H),6.28(d,J=1.4Hz,1H),6.14(s,1H),5.26(s,2H),3.80(s,3H),3.06(t,J=5.0Hz,4H),3.00(q,J=6.5Hz,2H),2.51–2.48(m,4H),2.43(s,3H),2.38–2.25(m,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.60–1.53(m,9H),1.45(q,J=6.9,6.2Hz,2H),1.36(q,J=6.5,6.0Hz,2H),1.30–1.23(m,16H).13CNMR(101MHz,DMSO)δ170.11,162.63,156.84,156.81,150.26,146.96,137.84,130.12,129.81,120.54,117.12,116.29,114.57,113.78,107.13,106.53,100.12,58.32,56.16,53.24,50.59,49.30,46.16,42.62,38.65,36.96,32.61,29.65,29.52,29.47,29.43,29.18,28.54,27.45,26.88,26.71,17.42.
实施例18:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(3-甲氧基-4-((5-甲基-8-(3-((1-甲基哌-4-基)氨基)苯基)-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-18)
将化合物ZX-HYT-17(200mg,0.24mmol),1-甲基哌啶-4-酮(27mg,0.24mmol),三乙酰氧基硼氢化钠(0.25g,1.2mmol)和催化量的冰乙酸置于20mL超干甲苯中,氩气保护下,将反应体系置于40℃的温度下,搅拌反应2小时。TLC监测,待反应完全后,蒸干有机溶剂,所得残余物直接拌硅胶柱层析(三氯甲烷/甲醇=25:1洗脱),纯化后得黄色目标化合物ZX-HYT-18(0.16mg,收率73%)。HRMS(ESI)for C55H80N9O3[M+H]+:calcd,914.6384;found,914.6379.HPLC analysis:MeOH-H2O(97:3),RT=13.264min,99.75%purity.1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.03(s,1H),7.63(t,J=5.7Hz,1H),7.42(d,J=8.9Hz,1H),7.22(t,J=7.9Hz,1H),6.72(d,J=7.7Hz,1H),6.54(d,J=2.5Hz,1H),6.43(t,J=2.2Hz,1H),6.34(dd,J=7.4,1.9Hz,1H),6.28(s,1H),6.05(s,1H),5.70(d,J=7.7Hz,1H),3.79(s,3H),3.05–2.97(m,6H),2.79(s,3H),2.49–2.46(m,4H),2.44(s,3H),2.31(t,J=7.4Hz,3H),2.23(s,3H),2.16(s,2H),1.96–1.85(m,6H),1.80(s,2H),1.68–1.62(m,3H),1.58–1.51(m,9H),1.46–1.42(m,2H),1.39–1.34(m,2H),1.30–1.21(m,16H).13C NMR(101MHz,DMSO)δ170.19,162.67,156.83,149.34,147.02,138.08,130.03,117.14,115.99,113.36,111.76,106.92,106.55,100.20,58.30,56.18,55.35,54.28,53.24,50.59,49.39,45.85,42.61,38.65,36.94,32.61,31.73,29.61,29.48,29.39,29.15,28.53,27.42,26.84,26.73,17.40.
实施例19:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-((环丙基甲基)氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-19)
与化合物ZX-HYT-18的合成方法类似,以化合物ZX-HYT-17(0.20g,0.24mmol)和环丙烷甲醛(17mg,0.24mmol)为原料制得黄色固体化合物ZX-HYT-19(0.18g,收率86%)。HRMS(ESI)for C53H75N8O3[M+H]+:calcd,871.5962;found,871.5957.HPLC analysis:MeOH-H2O(97:3),RT=11.992min,97.65%purity.1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.02(s,1H),7.61(t,J=5.7Hz,1H),7.43(d,J=8.8Hz,1H),7.23(t,J=7.9Hz,1H),6.72(d,J=8.2Hz,1H),6.54(d,J=2.5Hz,1H),6.44(d,J=2.2Hz,1H),6.37(dd,J=7.4,1.9Hz,1H),6.29(s,1H),6.07(s,1H),5.86(t,J=5.5Hz,1H),3.80(s,3H),3.08–2.97(m,5H),2.89(d,J=6.3Hz,2H),2.49–2.40(m,7H),2.35–2.26(m,2H),1.94–1.86(m,3H),1.80(s,2H),1.70–1.62(m,3H),1.60–1.57(m,2H),1.56–1.52(m,7H),1.49–1.43(m,2H),1.39–1.33(m,2H),1.30–1.21(m,16H),1.04(hept,J=5.8Hz,2H),0.43(dt,J=8.5,3.0Hz,2H),0.17(t,J=4.8Hz,2H).13C NMR(101MHz,DMSO)δ170.09,162.63,156.84,150.61,146.94,137.97,129.89,117.17,116.08,113.05,111.55,106.92,106.56,100.17,56.18,53.23,50.59,49.35,48.11,42.63,38.64,36.96,32.61,29.64,29.50,29.45,29.41,29.17,28.54,27.41,26.87,17.41,11.03,4.02,3.93.
实施例20:N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环戊基)环丙烷甲酰胺(ZX-HYT-20)
第一步:N-((1R,3S)-3-((5-溴-2-氯嘧啶-4-基)氨基)环戊基)环丙烷甲酰胺(26a)
将化合物5-溴-2,4-二氯嘧啶(0.91g,4mmol),N-((1R,3S)-3-((5-溴-2-氯嘧啶-4-基)氨基)环戊基)环丙烷甲酰胺(0.67g,4mmol)和碳酸钾(0.57g,8mmol)依次加入25mLDMF中,并在室温条件下反应6小时。TLC监测,待反应完全后,将反应体系加入40mL冰水中,有大量白色固体生成。减压抽滤,并用冰水洗涤滤饼。抽干的滤饼置于15mL丙酮中室温搅拌2小时打浆,减压抽滤,取滤饼。即得白色中间体26a(0.96g,收率67%)。MS(ESI),m/z:359.6[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.34(d,J=7.3Hz,1H),7.23(s,1H),5.67(p,J=9.4,8.9Hz,1H),4.17–4.04(m,1H),2.31–2.21(m,2H),2.02–1.92(m,2H),1.89–1.79(m,2H),1.63–1.54(m,1H),0.81–0.62(m,4H).
第二步:N-((1R,3S)-3-(2-氯-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环戊基)环丙烷甲酰胺(27a)
将化合物26a(1.92g,5.35mmol),巴豆酸(4.61g,70.1mmol),二(氰基苯)二氯化钯(II)(0.14g,5%)和三(邻甲基苯基)磷(114mg,5%)置于250mL的两口圆底烧瓶中,置换3~5次氩气,用注射器加入无水四氢呋喃(30mL)和N,N-二异丙基乙胺(5mL)后,再次置换氩气三次。然后将反应体系于70℃搅拌6小时。用TLC检测,待原料26a反应完全后,加入5mL乙酸酐,并将反应液加热至80℃继续搅拌8小时。TLC检测反应完全后,减压蒸除大部分有机溶剂,将残余物用100mL乙酸乙酯稀释。分别用1N HCl(3×100mL)和饱和氯化钠溶液(2×100mL)洗涤有机层,分离出的有机相经无水硫酸钠干燥后,浓缩并通过柱色谱纯化(石油醚/乙酸乙酯=2:1洗脱),得到白色固体化合物27a(0.87g,收率47%)。MS(ESI),m/z:347.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.24(d,J=7.4Hz,1H),6.63(d,J=1.5Hz,1H),5.77(p,J=9.4,8.9Hz,1H),4.18–4.05(m,1H),2.46(s,3H),2.25–2.15(m,2H),2.07–1.97(m,2H),1.95–1.85(m,2H),1.61–1.52(m,1H),0.69–0.59(m,4H).
第三步:N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环戊基)环丙烷甲酰胺(ZX-HYT-20)
将化合物27a(0.17g,0.5mmol),化合物14(0.28g,0.5mmol)和催化量的三氟乙酸依次加入10mL仲丁醇中,并在90℃的温度下,搅拌反应10小时。TLC监测反应完全后,减压蒸除有机溶剂,残余物经柱色谱(三氯甲烷/甲醇=35:1)分离,得到目标化合物ZX-HYT-20(0.13g,收率30%)。HRMS(ESI)for C52H77N8O4[M+H]+:calcd,877.6068;found,877.6062.HPLC analysis:MeOH-H2O(95:5),13.792min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.62(s,1H),8.16(s,1H),7.62(t,J=5.6Hz,1H),7.51(d,J=8.6Hz,1H),6.63(d,J=2.5Hz,1H),6.51(dd,J=8.8,2.5Hz,1H),6.16(d,J=1.3Hz,1H),5.84(s,1H),4.08(q,J=7.8Hz,1H),3.79(s,3H),3.14(t,J=4.8Hz,4H),3.00(q,J=6.5Hz,2H),2.51–2.45(m,6H),2.35(s,3H),2.33–2.19(m,4H),2.04–1.87(m,4H),1.86–1.72(m,4H),1.69–1.61(m,3H),1.60–1.52(m,9H),1.50–1.41(m,2H),1.40–1.32(m,2H),1.32–1.17(m,16H),0.75–0.53(m,4H).13C NMR(101MHz,DMSO)δ172.23,170.08,163.06,160.29,157.37,155.88,153.16,149.92,146.19,119.63,117.24,107.10,106.87,100.36,58.38,55.93,53.27,50.57,50.14,49.89,49.18,42.60,38.62,36.94,34.09,32.60,31.65,29.65,29.53,29.49,29.43,29.19,28.51,27.46,26.88,26.78,25.90,17.19,14.15,12.89,8.19,6.67,6.62.
实施例21:(1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基环己烷-1-羧酰胺(ZX-HYT-21)
与化合物ZX-HYT-20的合成方法类似,以化合物14(0.28g,0.5mmol)和N-(((1R,3S)-3-氨基环己基)环丙烷甲酰胺(0.18g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-21(0.13g,收率29%)。HRMS(ESI)for C53H79N8O4[M+H]+:calcd,891.6224;found,891.6219.HPLC analysis:MeOH-H2O(95:5),RT=11.542min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.82–8.44(m,2H),7.82–7.08(m,3H),6.65(s,1H),6.52(d,J=8.7Hz,1H),6.12(s,1H),5.41–4.88(m,1H),3.78(s,3H),3.16(s,4H),3.00(q,J=6.4Hz,2H),2.71–2.53(m,4H),2.44–2.21(m,7H),2.17–1.94(m,2H),1.90(s,3H),1.80(s,2H),1.71–1.61(m,4H),1.59–1.51(m,10H),1.50–1.42(m,3H),1.39–1.33(m,2H),1.30–1.18(m,19H),0.60–0.51(m,2H),0.38–0.28(m,2H).13C NMR(101MHz,DMSO)δ175.49,170.09,157.15,128.32,128.23,115.89,107.36,106.56,100.65,100.56,100.49,58.25,55.50,53.17,52.03,50.58,48.92,44.47,42.62,38.64,36.95,32.61,29.64,29.49,29.42,29.17,28.54,27.75,27.38,26.87,25.49,22.67,17.13,6.16,6.05.
实施例22:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-((S)-1-(环丙烷羰基)哌啶-3-基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-22)
与化合物ZX-HYT-20的合成方法类似,以化合物14(0.28g,0.5mmol)和(S)-(3-氨基哌啶-1-基)(环丙基)甲酮(0.15g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-22(0.13g,收率29%)。HRMS(ESI)for C52H77N8O4[M+H]+:calcd,877.6068;found,877.6067.HPLC analysis:MeOH-H2O(97:3),11.956min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.70(s,1H),7.61(t,J=5.6Hz,1H),7.09(s,1H),6.61(s,1H),6.48(s,1H),6.14(s,1H),5.35–4.74(m,1H),4.50–3.76(m,4H),3.73(s,3H),3.14(s,4H),3.00(q,J=6.4Hz,2H),2.50–2.39(m,4H),2.38–2.29(m,5H),2.00–1.86(m,4H),1.80(s,3H),1.69–1.61(m,4H),1.59–1.52(m,10H),1.48–1.42(m,3H),1.39–1.34(m,2H),1.29–1.21(m,16H),0.77–0.55(m,4H).13CNMR(101MHz,DMSO)δ171.40,171.11,170.08,157.36,155.90,146.49,119.19,115.82,107.01,106.57,100.16,58.34,55.75,53.27,50.58,48.98,47.11,43.60,42.62,38.65,36.95,32.60,29.65,29.51,29.47,29.42,29.18,28.55,27.45,26.88,26.73,25.48,17.16,10.89,7.28,7.15.
实施例23:N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环己基)环丙烷甲酰胺(ZX-HYT-23)
与化合物ZX-HYT-20的合成方法类似,以化合物14(0.28g,0.5mmol)和(1R,3S)-3-氨基-N-环丙基环己烷-1-羧酰胺(0.18g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-23(0.26g,收率58%)。HRMS(ESI)for C53H79N8O4[M+H]+:calcd,891.6224;found,891.6219.HPLC analysis:MeOH-H2O(95:5),RT=11.070min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.63(s,1H),8.09(s,1H),7.62(t,J=5.6Hz,1H),6.66(d,J=2.5Hz,1H),6.55(d,J=8.8Hz,1H),6.10(s,1H),5.33(s,1H),3.79(s,3H),3.67(s,1H),3.17(s,4H),3.00(q,J=6.5Hz,2H),2.68–2.51(m,4H),2.43–2.24(m,6H),1.90(s,3H),1.83–1.71(m,4H),1.69–1.61(m,4H),1.61–1.52(m,10H),1.51–1.41(m,4H),1.40–1.32(m,3H),1.31–1.17(m,18H),0.68–0.54(m,4H).13C NMR(101MHz,DMSO)δ171.87,170.09,157.18,145.86,120.00,117.81,116.08,107.22,106.72,100.51,58.20,55.90,52.99,50.58,48.86,48.13,42.62,38.64,36.95,34.95,32.60,32.41,29.64,29.49,29.41,29.17,28.54,27.38,27.31,26.87,24.13,17.12,14.03,6.57.
实施例24:2-(((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-24)
与化合物ZX-HYT-20的合成方法类似,以化合物14(0.28g,0.5mmol)和环戊胺(0.13g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-24(0.21g,收率53%)。HRMS(ESI)forC48H72N7O3[M+H]+:calcd,794.5697;found,794.5699.HPLC analysis:MeOH-H2O(97:3),14.410min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.73–8.63(m,2H),7.61(t,J=5.6Hz,1H),7.31(d,J=8.7Hz,1H),6.62(d,J=2.5Hz,1H),6.49(dd,J=8.7,2.5Hz,1H),6.12(s,1H),5.60(s,1H),3.74(s,3H),3.18–3.09(m,4H),3.00(q,J=6.4Hz,2H),2.51–2.42(m,4H),2.36–2.26(m,5H),2.19–2.08(m,2H),1.90(s,3H),1.80(s,2H),1.69–1.61(m,4H),1.60–1.52(m,12H),1.48–1.42(m,3H),1.40–1.32(m,3H),1.29–1.22(m,16H).13C NMR(101MHz,DMSO)δ170.08,163.14,160.65,157.19,155.91,154.16,150.52,145.91,126.66,119.56,116.67,107.18,106.80,100.38,58.38,55.82,53.24,52.51,50.58,49.27,42.62,38.64,36.96,32.61,29.64,29.49,29.45,29.40,29.17,28.54,27.66,27.45,26.87,26.75,25.07,17.14.
实施例25:N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)苯基)氨基)-5-甲基-7-氧杂吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-25)
将化合物28a(0.27g,0.5mmol),化合物21(0.18g,0.5mmol)和催化量的三氟乙酸依次加入10mL仲丁醇中,并在95℃的温度下,搅拌反应10小时。TLC监测反应完全后,减压蒸除有机溶剂,残余物经柱色谱(三氯甲烷/甲醇=45:1)分离,得到目标化合物ZX-HYT-25(0.25g,收率52%)。HRMS(ESI)for C52H71N8O3[M+H]+:calcd,855.5649;found,855.5644.1HNMR(400MHz,DMSO-d6)δ10.40(s,1H),9.83(s,1H),8.82(s,1H),7.86(d,J=8.3Hz,1H),7.61(t,J=5.7Hz,1H),7.52–7.43(m,2H),7.19(d,J=8.4Hz,2H),6.93(d,J=7.8Hz,1H),6.55(d,J=8.3Hz,2H),6.30(s,1H),3.05–2.93(m,6H),2.49–2.39(m,7H),2.30(t,J=7.3Hz,2H),1.90(s,3H),1.82–1.74(m,3H),1.68–1.63(m,3H),1.59–1.52(m,9H),1.47–1.41(m,2H),1.39–1.34(m,2H),1.30–1.22(m,16H),0.83–0.74(m,4H).13C NMR(101MHz,DMSO)δ172.18,170.09,162.61,158.77,156.91,156.73,147.36,146.73,140.86,137.68,132.24,129.93,123.84,119.72,118.75,116.73,115.74,106.23,58.35,53.27,50.59,49.31,42.63,38.65,36.96,32.61,29.65,29.52,29.48,29.43,29.19,28.54,27.45,26.88,26.78,17.46,15.03,7.72,7.60.
实施例26:N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-26)
与化合物ZX-HYT-25的合成方法类似,以化合物21(0.18g,0.5mmol)和化合物28b(0.28g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-26(0.14g,收率33%)。HRMS(ESI)forC53H73N8O3[M+H]+:calcd,869.5806;found,869.5800.HPLC analysis:MeOH-H2O(95:5),RT=6.397min,96.91%purity.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.84(s,1H),8.76(s,1H),7.65(dd,J=11.6,7.0Hz,2H),7.49(s,1H),7.38(t,J=8.1Hz,1H),7.15–7.03(m,1H),6.86(d,J=7.8Hz,1H),6.64(s,1H),6.42(s,1H),6.26(s,1H),3.00(q,J=6.3Hz,6H),2.51–2.39(m,7H),2.30(t,J=7.3Hz,2H),2.10(s,3H),1.91(s,3H),1.85–1.75(m,3H),1.71–1.62(m,3H),1.61–1.51(m,9H),1.50–1.42(m,2H),1.40–1.34(m,2H),1.32–1.21(m,16H),0.89–0.69(m,4H).13C NMR(101MHz,DMSO)δ172.15,170.08,162.70,157.06,156.72,147.27,140.56,137.23,129.56,129.20,123.92,119.68,118.52,117.42,116.50,112.99,106.37,58.40,53.27,50.59,49.14,42.62,38.64,36.96,32.61,29.65,29.52,29.48,29.43,29.18,28.54,27.46,26.88,26.79,18.84,17.48,15.04,7.67.
实施例27:N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)氧基)乙氧基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-27)
与化合物ZX-HYT-25的合成方法类似,以化合物21(0.18g,0.5mmol)和化合物28c(0.27g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-27(0.22g,收率51%)。HRMS(ESI)forC51H69N6O6[M+H]+:calcd,861.5279;found,861.5273.HPLC analysis:MeOH-H2O(90:10),RT=7.673min,100%purity.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.82(s,1H),8.19(s,1H),7.74(d,J=8.2Hz,1H),7.64(t,J=5.7Hz,1H),7.53(t,J=2.0Hz,1H),7.47(t,J=8.0Hz,1H),7.31(d,J=8.9Hz,1H),6.93(dd,J=7.8,2.0Hz,1H),6.55(d,J=2.6Hz,1H),6.33(s,1H),6.03(s,1H),4.01(t,J=4.6Hz,2H),3.78(s,3H),3.70–3.63(m,2H),3.44(t,J=6.6Hz,2H),2.99(q,J=6.4Hz,2H),2.46(s,3H),1.94–1.86(m,3H),1.83–1.74(m,3H),1.68–1.61(m,3H),1.58–1.47(m,11H),1.38–1.19(m,18H),0.85–0.71(m,4H).13C NMR(101MHz,DMSO)δ172.20,170.09,162.56,157.06,156.72,147.31,140.75,137.47,129.80,123.87,121.49,119.76,118.81,117.13,106.70,104.65,99.36,70.87,69.09,67.72,56.29,50.58,42.62,38.65,36.94,32.60,29.68,29.64,29.53,29.51,29.44,29.38,29.18,28.53,26.88,26.14,17.47,15.03,7.69,7.63.
实施例28:N-(3-(2-((4-((12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)氧基)-2-甲氧基苯基)氨基)-5-甲基-7-氧嘧啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-28)
与化合物ZX-HYT-25的合成方法类似,以化合物21(0.18g,0.5mmol)和化合物28d(0.25g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-28(0.24g,收率59%)。HRMS(ESI)forC49H65N6O5[M+H]+:calcd,817.5016;found,817.5011.HPLC analysis:MeOH-H2O(95:5),RT=9.932min,95.18%purity.1H NMR(400MHz,DMSO-d6)δ10.43–10.34(m,1H),8.86–8.75(m,1H),8.14(s,1H),7.76(d,J=8.2Hz,1H),7.60(d,J=6.2Hz,1H),7.51(d,J=2.6Hz,1H),7.46(td,J=8.1,2.5Hz,1H),7.31(dd,J=8.8,2.5Hz,1H),6.93(d,J=7.8Hz,1H),6.51(s,1H),6.32(s,1H),6.04(s,1H),3.87(q,J=5.7Hz,2H),3.78(s,3H),2.99(td,J=7.1,3.3Hz,2H),2.45(s,3H),1.90(s,3H),1.83–1.75(m,3H),1.71–1.61(m,5H),1.60–1.51(m,9H),1.43–1.32(m,5H),1.31–1.21(m,13H),0.84–0.72(m,4H).13C NMR(101MHz,DMSO)δ172.18,170.10,162.57,157.06,156.72,147.31,140.75,137.47,129.80,123.87,121.31,119.74,118.82,117.11,106.68,104.55,99.29,67.98,56.27,50.59,42.62,38.65,36.94,32.61,29.65,29.51,29.45,29.29,29.23,29.19,28.54,26.89,26.05,17.46,15.01,7.64.
实施例29:N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-金刚烷-1-基)乙基)氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-29)
第一步:N-(3-(2-((4-(4-(12-(1,3-二氧代异吲哚-2-基-基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(31)
将化合物29(0.26mg,0.5mmol),化合物30a(0.20g,0.5mmol)和无水碳酸钾(0.14g,1mmol)置于DMF(8mL)中,并在70℃的温度下搅拌反应7小时,TLC检测,待反应完全后,加入100mL乙酸乙酯中。相继用饱和食盐水(2×40mL),蒸馏水(3×40mL)洗涤有机层,分离、干燥并蒸干有机层,所得残余物经柱色谱纯化(三氯甲烷/甲醇=45:1洗脱),得黄色粉末状化合物31(0.31g,收率76%)。HRMS(ESI)for C49H59N8O5[M+H]+:calcd,839.4608;found,839.4602.HPLC analysis:MeOH-H2O(95:5),RT=9.870min,100%purity.1HNMR(400MHz,DMSO-d6)δ10.37(s,1H),8.78(s,1H),8.07(s,1H),7.83(s,5H),7.56–7.40(m,2H),7.26(d,J=8.9Hz,1H),6.91(s,1H),6.51(s,1H),6.30(s,1H),6.01(s,1H),3.77(s,3H),3.58–3.51(m,2H),3.02(s,4H),2.48–2.36(m,7H),2.28(s,2H),1.81–1.69(m,2H),1.60–1.53(m,2H),1.46–1.40(m,2H),1.32–1.17(m,15H),0.83–0.71(m,4H).
第二步:N-(3-(2-((4-(4-(12-氨基十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(32)
将化合物31(0.84mg,1mmol)和80%的水合肼(2mL)置于40mL无水乙醇中,并在70℃的温度下搅拌反应3小时,TLC检测,待反应完全后,减压蒸干有机溶剂,残余物置于50mLDCM中,充分搅拌后抽滤,滤液蒸干后柱层析(三氯甲烷/甲醇=10:1洗脱),得黄色固体状化合物32(0.67g,收率94%)。HRMS(ESI)for C41H57N8O3[M+H]+:calcd,709.4554;found,709.4548.HPLC analysis:MeOH-H2O(95:5),RT=7.589min,97.81%purity.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.78(s,1H),8.08(s,1H),7.81(s,1H),7.56–7.38(m,2H),7.27(d,J=8.9Hz,1H),6.91(d,J=7.8Hz,1H),6.52(s,1H),6.31(s,1H),6.01(s,1H),3.78(s,3H),3.03(s,6H),2.49–2.38(m,7H),2.29(t,J=7.4Hz,2H),1.78(d,J=9.6Hz,1H),1.45(s,3H),1.31–1.20(m,17H),0.85–0.70(m,4H).
第三步:N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-金刚烷-1-基)乙基)氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-29)
将化合物32(177mg,0.25mmol),金刚烷乙醛(45mg,0.25mmol),三乙酰氧基硼氢化钠(0.27g,1.25mmol)和催化量的冰乙酸置于20mL超干甲苯中,氩气保护下,将反应体系置于40℃的温度下,搅拌反应2小时。TLC监测,待反应完全后,蒸干有机溶剂,所得残余物直接拌硅胶柱层析(三氯甲烷/甲醇=15:1洗脱),得黄色固体目标化合物ZX-HYT-29(0.12mg,收率55%)。HRMS(ESI)for C52H73N8O3[M+H]+:calcd,857.5806;found,857.5801.HPLCanalysis:MeOH-H2O(97:3),RT=6.096min,99.17%purity.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.80(s,1H),8.09(s,1H),7.81(d,J=8.2Hz,1H),7.51–7.42(m,2H),7.27(d,J=8.9Hz,1H),6.92(dd,J=7.7,2.0Hz,1H),6.53(d,J=2.5Hz,1H),6.32(s,1H),6.02(s,1H),3.78(s,3H),3.03(t,J=4.8Hz,4H),2.50–2.42(m,11H),2.30(t,J=7.4Hz,2H),1.93–1.86(m,3H),1.81–1.73(m,1H),1.70–1.62(m,3H),1.62–1.55(m,3H),1.45(s,8H),1.38(t,J=6.9Hz,2H),1.33–1.22(m,17H),1.21–1.16(m,2H),0.82–0.74(m,4H).13C NMR(101MHz,DMSO)δ172.17,162.58,157.00,156.75,147.31,140.79,137.47,129.84,123.82,119.69,118.74,116.99,106.70,106.56,100.07,58.34,56.15,53.28,50.01,49.29,44.49,44.15,42.62,37.12,31.86,29.87,29.80,29.47,28.52,27.43,27.32,26.79,17.47,15.03,7.70,7.62.
实施例30:N-(3-(2-((2-甲氧基-4-(4-辛基哌嗪-1-基)苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-30)
将化合物29(0.13mg,0.25mmol),化合物30b(48mg,0.25mmol)和无水碳酸钾(69mg,0.5mmol)置于DMF(5mL)中,并在70℃的温度下搅拌反应7小时,TLC检测,待反应完全后,加入30mL乙酸乙酯中。相继用饱和食盐水(2×20mL),蒸馏水(3×20mL)洗涤有机层,分离、干燥并蒸干有机层,所得残余物经柱色谱纯化(三氯甲烷/甲醇=50:1洗脱),得黄色粉末状目标化合物ZX-HYT-30(0.11g,收率69%)。HRMS(ESI)for C37H48N7O3[M+H]+:calcd,638.3819;found,638.3813.HPLC analysis:MeOH-H2O(95:5),RT=6.803min,98.91%purity.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.80(s,1H),8.10(s,1H),7.80(d,J=8.0Hz,1H),7.51–7.42(m,2H),7.27(d,J=8.9Hz,1H),6.92(d,J=8.2Hz,1H),6.53(d,J=2.5Hz,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.03(t,J=4.8Hz,4H),2.50–2.43(m,7H),2.31(t,J=7.4Hz,2H),1.82–1.73(m,1H),1.46(s,2H),1.30–1.23(m,10H),0.90–0.85(m,3H),0.82–0.74(m,4H).13C NMR(101MHz,DMSO)δ172.19,162.60,157.02,156.75,147.33,140.79,137.48,129.86,123.83,120.30,119.68,118.73,116.99,106.70,106.57,100.08,58.35,56.15,53.27,49.28,31.76,29.44,29.20,27.46,26.79,22.57,17.46,15.03,14.44,7.69,7.62.
实施例31:N-(3-(2-((2-甲氧基-4-(4-辛基哌嗪-1-基)苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-31)
将化合物29(0.53mg,1mmol),化合物30c(0.34g,1mmol)和无水碳酸钾(0.28g,2mmol)置于DMF(10mL)中,并在70℃的温度下搅拌反应7小时,TLC检测,待反应完全后,加入50mL乙酸乙酯中。相继用饱和食盐水(2×50mL),蒸馏水(3×50mL)洗涤有机层,分离、干燥并蒸干有机层,残余物经柱色谱纯化(三氯甲烷/甲醇=50:1洗脱)后,直接溶于30mL无水乙醇并滴加1mL的80%水合肼。将反应体系于40℃的温度下,搅拌反应2小时,待反应完全后,蒸干有机溶剂。残余物与50mL DCM充分搅拌后,减压抽滤,滤液蒸干后经柱层析纯化(三氯甲烷/甲醇=10:1洗脱),得黄色固体状化合物ZX-HYT-31(0.57g,收率88%)。HRMS(ESI)forC37H49N8O3[M+H]+:calcd,653.3928;found,653.3934.HPLC analysis:MeOH-H2O(95:5),RT=7.852min,97.44%purity.1HNMR(400MHz,DMSO-d6)δ10.41(s,1H),8.79(s,1H),8.10(s,1H),7.80(d,J=8.1Hz,1H),7.53–7.41(m,2H),7.27(d,J=8.9Hz,1H),6.95–6.87(m,1H),6.52(d,J=2.5Hz,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.03(d,J=5.4Hz,4H),2.56–2.52(m,1H),2.50–2.46(m,5H),2.45(s,3H),2.30(t,J=7.4Hz,2H),1.78(qd,J=7.0,5.2Hz,1H),1.45(t,J=7.3Hz,2H),1.36(t,J=6.8Hz,2H),1.32–1.24(m,10H),0.83–0.74(m,4H).13C NMR(101MHz,DMSO)δ172.24,162.63,157.02,156.73,147.39,140.77,137.46,129.88,123.83,120.25,119.66,118.75,116.97,106.69,106.57,100.06,58.36,56.15,53.26,49.25,41.77,33.00,29.48,29.44,27.42,26.83,26.77,17.46,15.03,7.72,7.62.
实施例32:(1R,3R,5S,7R)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)-3,5-二甲基金刚烷-1-羧酰胺(ZX-HYT-32)
将化合物ZX-HYT-31(0.13mg,0.2mmol),(1R,3R,5S,7R)-3,5-二甲基金刚烷-1-羧酸(42mg,0.2mmol),HATU(91mg,0.24mmol)和DIPEA(52mg,0.4mmol)置于乙腈(6mL)中,并在室温条件下搅拌反应1小时,TLC检测,待反应完全后,蒸干有机溶剂,残余物拌硅胶蒸干直接柱色谱分离(三氯甲烷/甲醇=50:1洗脱)得黄色粉末状目标化合物ZX-HYT-32(93mg,收率55%)。HRMS(ESI)for C50H67N8O4[M+H]+:calcd,843.5285;found,843.5280.HPLCanalysis:MeOH-H2O(95:5),6.693min,99.44%purity.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.79(s,1H),8.09(s,1H),7.80(d,J=8.2Hz,1H),7.50–7.42(m,2H),7.31(t,J=5.6Hz,1H),7.27(d,J=8.9Hz,1H),6.91(d,J=7.9Hz,1H),6.52(d,J=2.6Hz,1H),6.31(s,1H),6.01(s,1H),3.78(s,3H),3.09–2.97(m,6H),2.50–2.46(m,4H),2.45(s,3H),2.30(t,J=7.5Hz,2H),2.03(p,J=3.2Hz,1H),1.77(td,J=7.2,3.7Hz,1H),1.60–1.53(m,2H),1.51–1.41(m,3H),1.40–1.34(m,5H),1.33(s,1H),1.30–1.22(m,11H),1.14–1.05(m,2H),0.82–0.75(m,10H).13C NMR(101MHz,DMSO)δ176.90,172.21,162.61,157.00,156.73,147.36,140.77,137.46,129.86,123.83,120.29,119.67,118.75,116.97,106.72,106.57,100.07,58.35,56.15,53.23,50.80,49.21,45.51,42.89,42.17,38.93,37.91,31.17,30.92,29.53,29.37,29.34,29.18,27.35,26.70,17.46,15.03,7.72,7.63.
实施例33:N-(3-(2-((4-(4-(8-(3,3-二甲基丁二酰胺基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-33)
与化合物ZX-HYT-32的合成方法类似,以化合物ZX-HYT-31(0.13mg,0.2mmol)和3,3-二甲基丁酸(23mg,0.2mmol)为原料,经过酰胺缩合即得化合物ZX-HYT-33(60mg,收率40%)。HRMS(ESI)for C43H59N8O4[M+H]+:calcd,751.4659;found,751.4654.HPLCanalysis:MeOH-H2O(90:10),6.793min,98.37%purity.1HNMR(400MHz,DMSO-d6)δ10.38(s,1H),8.79(s,1H),8.09(s,1H),7.80(d,J=7.6Hz,1H),7.67(t,J=5.5Hz,1H),7.52–7.42(m,2H),7.27(d,J=8.8Hz,1H),6.92(d,J=7.9Hz,1H),6.52(d,J=2.5Hz,1H),6.36–6.28(m,1H),6.02(s,1H),3.78(s,3H),3.08–2.98(m,6H),2.50–2.46(m,4H),2.45(s,3H),2.30(t,J=7.4Hz,2H),1.93(s,2H),1.82–1.73(m,1H),1.45(t,J=7.2Hz,2H),1.38(q,J=6.6Hz,2H),1.32–1.21(m,8H),0.95(s,9H),0.83–0.73(m,4H).13C NMR(101MHz,DMSO)δ172.18,170.98,162.58,157.00,156.74,147.31,140.78,137.48,129.85,123.83,120.27,119.68,118.74,116.99,106.71,106.56,100.07,58.36,56.15,53.28,49.37,49.28,38.70,30.82,30.16,29.67,29.44,29.21,27.39,26.89,26.78,17.46,15.04,7.71,7.62.
实施例34:N-(8-(4-(4-((8-(3-(环丙烷甲酰胺基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)-4,4-二氟环己烷-1-羧酰胺(ZX-HYT-34)
与化合物ZX-HYT-32的合成方法类似,以化合物ZX-HYT-31(0.13mg,0.2mmol)和4,4-二氟环己烷-1-羧酸(33mg,0.2mmol)为原料,经过酰胺缩合即得化合物ZX-HYT-34(73mg,收率46%)。HRMS(ESI)for C44H57F2N8O4[M+H]+:calcd,799.4471;found,799.4465.HPLCanalysis:MeOH-H2O(97:3),RT=4.194min,99.49%purity.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.80(s,1H),8.10(s,1H),7.86–7.74(m,2H),7.50–7.43(m,2H),7.27(d,J=8.9Hz,1H),6.92(d,J=7.8Hz,1H),6.53(d,J=2.5Hz,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.08–2.98(m,6H),2.49–2.46(m,4H),2.45(s,3H),2.30(t,J=7.4Hz,2H),2.21(t,J=11.8Hz,1H),2.08–1.98(m,2H),1.86–1.71(m,5H),1.61(t,J=11.9Hz,2H),1.49–1.42(m,2H),1.41–1.35(m,2H),1.31–1.23(m,8H),0.82–0.75(m,4H).13C NMR(101MHz,DMSO)δ173.95,172.18,162.58,156.99,156.74,147.32,140.77,137.47,129.84,124.20,123.82,120.26,119.67,118.73,116.98,106.70,106.56,100.07,58.36,56.14,53.27,49.27,41.49,38.79,32.97,32.73,32.50,29.53,29.42,29.19,27.39,26.78,26.17,26.08,17.46,15.04,7.69,7.63.
实施例35:(3R,5R,7R)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)金刚烷-1-羧酰胺(ZX-HYT-35)
与化合物ZX-HYT-32的合成方法类似,以化合物ZX-HYT-31(0.13mg,0.2mmol)和(3R,5R,7R)-金刚烷-1-羧酸(36mg,0.2mmol)为原料,经过酰胺缩合即得化合物ZX-HYT-35(74mg,收率45%)。HRMS(ESI)for C48H63N8O4[M+H]+:calcd,815.4972;found,815.4967.HPLC analysis:MeOH-H2O(95:5),5.824min,100%purity.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.79(s,1H),8.09(s,1H),7.80(s,1H),7.53–7.41(m,2H),7.28(dd,J=12.6,7.2Hz,2H),6.91(d,J=7.9Hz,1H),6.58–6.48(m,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.09–2.97(m,6H),2.47(d,J=19.2Hz,7H),2.34–2.26(m,2H),1.95(s,3H),1.75(t,J=6.2Hz,7H),1.70–1.58(m,6H),1.45(s,2H),1.38(t,J=6.6Hz,2H),1.33–1.20(m,8H),0.89–0.70(m,4H).13C NMR(101MHz,DMSO)δ177.08,172.16,162.57,157.00,156.73,147.31,140.76,137.46,129.83,129.76,123.81,119.66,118.72,116.97,116.84,106.69,106.55,100.13,100.06,58.38,56.14,53.28,49.28,38.90,36.65,29.59,29.41,29.21,28.15,27.39,26.78,26.72,17.46,15.07,15.03,7.71,7.70.
实施例36:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(3-甲氧基-4-((5-甲基-7-氧代-8-苯基-7,8))-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-36)
化合物ZX-HYT-36的合成方法参照实施例16。HRMS(ESI)for C49H68N7O3[M+H]+:calcd,803.5384;found,803.5379.HPLC analysis:MeOH-H2O(95:5),RT=11.983min,99.29%purity.1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.07(s,1H),7.61(t,J=5.6Hz,1H),7.53(dq,J=14.0,7.3Hz,3H),7.27(d,J=7.3Hz,2H),7.17(d,J=8.8Hz,1H),6.52(s,1H),6.31(s,1H),5.97(s,1H),3.77(s,3H),3.08–2.94(m,6H),2.50–2.37(m,7H),2.31(t,J=7.8Hz,2H),1.90(s,3H),1.80(s,2H),1.69–1.62(m,3H),1.60–1.52(m,9H),1.45(t,J=7.2Hz,2H),1.37(t,J=6.7Hz,2H),1.29–1.22(m,16H).13C NMR(101MHz,DMSO)δ170.08,162.70,156.92,156.85,147.20,137.25,129.55,129.52,128.33,120.30,117.02,106.75,106.60,100.14,79.66,58.33,56.12,53.24,50.59,49.28,42.63,38.65,36.96,32.61,29.65,29.51,29.48,29.43,29.18,28.55,27.45,26.88,26.74,17.46.
实施例37:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-((S)-1-(环丙烷羰基)吡咯烷-3-基))-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-37)
化合物ZX-HYT-37的合成方法参照实施例20。HRMS(ESI)for C51H75N8O4[M+H]+:calcd,863.5911;found,863.5906.HPLC analysis:MeOH-H2O(97:3),9.734min,100%purity.1H NMR(400MHz,Methanol-d4)δ8.70(s,1H),7.24(s,1H),6.67(s,1H),6.58(d,J=6.0Hz,1H),6.19(s,1H),5.75(s,1H),5.39(s,1H),3.80(s,3H),3.27–3.20(m,4H),3.14(t,J=6.9Hz,2H),2.81(d,J=30.8Hz,1H),2.66(t,J=5.0Hz,4H),2.52(s,1H),2.46–2.35(m,5H),2.23–2.11(m,1H),1.95(s,3H),1.91(s,2H),1.74(d,J=12.3Hz,3H),1.67(s,2H),1.63(d,J=2.9Hz,7H),1.59–1.54(m,2H),1.51–1.45(m,2H),1.38–1.25(m,16H),0.90–0.78(m,1H),0.55–0.44(m,2H),0.18–0.03(m,2H).13C NMR(101MHz,DMSO)δ171.17,170.09,163.11,157.46,155.88,150.21,150.05,146.67,131.96,125.70,125.40,119.48,116.53,107.01,100.18,58.39,55.92,53.31,50.58,50.31,49.18,48.95,42.61,38.65,36.95,32.59,29.63,29.49,29.17,28.54,27.45,26.86,17.19,14.00,12.41,11.86,7.64,7.41.
实施例38:N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-金刚烷-1-基)乙氧基)十二烷基)氧基)乙氧基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-38)
化合物ZX-HYT-38的合成方法参照实施例27。HRMS(ESI)for C51H75N8O4[M+H]+:calcd,847.5248;found,847.5351.HPLC analysis:MeOH-H2O(97:3),4.685min,100%purity.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.81(s,1H),8.18(s,1H),7.80–7.66(m,1H),7.54(t,J=2.1Hz,1H),7.47(t,J=8.0Hz,1H),7.32(d,J=8.9Hz,1H),6.93(d,J=7.8Hz,1H),6.55(d,J=2.5Hz,1H),6.33(s,1H),6.03(s,1H),4.07–3.95(m,2H),3.78(s,3H),3.71–3.63(m,2H),3.45–3.42(m,2H),3.36–3.32(m,2H),3.27(t,J=6.4Hz,2H),2.45(s,3H),1.88(s,2H),1.77(p,J=6.4Hz,1H),1.61(q,J=12.0Hz,4H),1.54–1.37(m,8H),1.31–1.17(m,23H),0.87–0.81(m,2H),0.79–0.77(m,4H).13C NMR(101MHz,DMSO)δ172.22,162.59,157.09,156.69,147.36,140.74,137.46,130.12,129.84,123.86,121.43,119.71,118.78,117.10,106.68,104.53,99.27,70.83,70.36,69.07,67.66,66.26,56.26,43.73,42.59,37.04,31.79,31.74,29.68,29.56,29.52,29.48,29.45,29.37,29.33,29.26,29.22,28.48,26.19,26.13,22.59,17.49,15.03,14.45,7.74,7.66.
实施例39:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-((环丁基甲基)氨基)苯基)-5-甲基-7)-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-39)
化合物ZX-HYT-39的合成方法参照实施例19。HRMS(ESI)for C54H77N8O3[M+H]+:calcd,885.6119;found,885.6114.HPLC analysis:MeOH-H2O(97:3),13.507min,100%purity.1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.01(s,1H),7.61(t,J=5.9Hz,1H),7.43(d,J=8.8Hz,1H),7.22(t,J=8.0Hz,1H),6.69(d,J=8.2Hz,1H),6.54(s,1H),6.42(s,1H),6.35(d,J=7.7Hz,1H),6.28(s,1H),6.05(s,1H),5.72(t,J=5.7Hz,1H),3.79(s,3H),3.09–2.95(m,8H),2.60–2.52(m,2H),2.50–2.45(m,4H),2.43(s,3H),2.29(t,J=7.4Hz,2H),2.00(q,J=8.0Hz,2H),1.90(s,3H),1.85–1.77(m,4H),1.73–1.65(m,3H),1.65–1.61(m,2H),1.59–1.56(m,2H),1.56–1.52(m,6H),1.47–1.41(m,2H),1.39–1.34(m,2H),1.30–1.21(m,16H).13C NMR(101MHz,DMSO)δ170.12,162.63,156.82,150.68,146.95,137.95,129.90,120.56,117.16,115.92,113.01,111.30,106.86,106.55,100.17,58.32,56.17,53.27,50.59,49.42,49.25,42.62,38.64,36.95,34.72,32.61,29.63,29.49,29.45,29.40,29.16,28.54,27.42,26.86,26.76,26.17,18.42,17.41.
实施例40:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-(环丙基甲氧基)苯基)-5-甲基-7-氧代-))7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-40)
化合物ZX-HYT-40的合成方法参照实施例16。HRMS(ESI)for C53H73N7O4[M+H]+:calcd,872.5797;found,872.5789.1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.08(s,1H),7.61(t,J=5.7Hz,1H),7.44(t,J=8.1Hz,1H),7.28(d,J=8.8Hz,1H),7.08(dd,J=8.4,2.6Hz,1H),6.86(t,J=2.2Hz,1H),6.81(dd,J=7.6,1.9Hz,1H),6.54(d,J=2.5Hz,1H),6.30(d,J=1.4Hz,1H),6.00(s,1H),3.86–3.73(m,5H),3.10–2.94(m,6H),2.50–2.40(m,7H),2.30(s,2H),1.95–1.85(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.60–1.52(m,9H),1.49–1.42(m,2H),1.37(t,J=6.7Hz,2H),1.30–1.23(m,17H),0.53(dt,J=10.2,3.0Hz,2H),0.28(dt,J=6.1,3.0Hz,2H).13C NMR(101MHz,DMSO)δ170.08,162.59,159.85,156.88,156.81,147.13,138.33,130.22,121.48,117.06,115.85,114.49,106.60,100.18,72.76,58.34,56.13,53.25,50.59,49.32,42.63,38.64,36.96,32.61,29.65,29.51,29.47,29.42,29.18,28.54,27.44,26.87,17.44,10.57,3.54.
实施例41:N-((1R,3S,5R,7S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)金刚烷-1-基)环丙烷甲酰胺(ZX-HYT-41)
化合物ZX-HYT-41的合成方法参照实施例16。HRMS(ESI)for C57H82N8O4[M+H]+:calcd,943.6532;found,943.6541.1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.15(s,1H),8.79(s,1H),8.08(s,1H),7.64(t,J=5.7Hz,1H),6.53(d,J=2.6Hz,1H),6.31(d,J=1.4Hz,1H),5.99(s,1H),3.79(s,3H),3.16–2.92(m,6H),2.49–2.23(m,6H),1.93–1.83(m,4H),1.80(s,2H),1.69–1.61(m,6H),1.60–1.52(m,9H),1.48(s,2H),1.41–1.19(m,32H),1.02–0.79(m,4H).
实施例42:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(8-(环丙烷羰基)-8-氮杂双环[3.2.1]辛烷))3-基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-42)
化合物ZX-HYT-42的合成方法参照实施例16。HRMS(ESI)for C54H78N8O4[M+H]+:calcd,903.6224;found,903.6231.HPLC analysis:MeOH-H2O(97:3),12.782min,100%purity.1HNMR(400MHz,DMSO-d6)δ8.73(s,1H),8.37(s,1H),7.61(t,J=5.7Hz,2H),6.65(d,J=2.5Hz,1H),6.57(d,J=8.9Hz,1H),6.15(s,1H),5.31(s,1H),4.65–4.47(m,2H),3.81(s,3H),3.23–3.07(m,4H),3.00(q,J=6.5Hz,2H),2.69–2.52(m,4H),2.38–2.26(m,5H),2.22–2.13(m,2H),1.90(s,4H),1.80(s,2H),1.68–1.62(m,3H),1.59–1.52(m,8H),1.50–1.44(m,2H),1.39–1.33(m,2H),1.30–1.21(m,22H),0.84–0.74(m,2H),0.71–0.60(m,2H).13C NMR(101MHz,DMSO)δ170.36,170.09,162.97,157.33,146.18,107.72,106.90,100.54,58.19,56.09,53.19,51.44,50.58,48.96,42.62,38.64,36.95,33.32,32.60,32.35,31.76,31.13,30.93,29.64,29.48,29.41,29.17,28.54,27.37,26.87,23.32,22.57,18.30,17.19,14.42,11.72,7.21,7.15,6.53.
实施例43:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4–((8-(3-(二甲基氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-43)
化合物ZX-HYT-43的合成方法参照实施例16。HRMS(ESI)for C51H72N8O3[M+H]+:calcd,845.5806;found,845.5797.HPLC analysis:MeOH-H2O(95:5),RT=12.901min,99.52%purity.1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.03(s,1H),7.61(t,J=5.7Hz,1H),7.40–7.30(m,2H),6.85(dd,J=8.4,2.5Hz,1H),6.62(t,J=2.2Hz,1H),6.54(d,J=2.5Hz,1H),6.50(dd,J=7.5,1.8Hz,1H),6.29(s,1H),5.98(s,1H),3.79(s,3H),3.09–2.97(m,6H),2.90(s,6H),2.50–2.46(m,4H),2.44(s,3H),2.32(d,J=8.7Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.65(d,J=12.2Hz,3H),1.58(s,2H),1.56–1.54(m,6H),1.45(t,J=7.1Hz,2H),1.36(q,J=6.5,5.9Hz,2H),1.32–1.23(m,17H).13C NMR(101MHz,DMSO)δ170.07,162.68,156.91,156.77,151.82,146.91,138.12,129.87,120.57,117.20,116.85,113.36,112.11,106.62,100.22,58.33,56.16,55.38,53.24,50.59,49.32,42.63,38.65,36.96,32.61,29.65,29.51,29.46,29.43,29.19,28.55,27.44,26.88,26.72,17.41.
实施例44:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-((氮杂环丁烷-3-基甲基)氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-44)
化合物ZX-HYT-44的合成方法参照实施例17。HRMS(ESI)for C53H75N9O3[M+H]+:calcd,886.6071;found,886.6066.HPLC analysis:MeOH-H2O(95:5),RT=8.652min,98.25%purity.1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.79(s,1H),8.69(s,1H),8.13(s,1H),7.64(t,J=5.7Hz,1H),7.45(d,J=8.8Hz,1H),7.25(t,J=8.0Hz,1H),6.72(d,J=8.3Hz,1H),6.64(d,J=2.5Hz,1H),6.50–6.39(m,2H),6.30(s,1H),6.06(s,1H),3.95(s,2H),3.81(s,3H),3.76–3.64(m,4H),3.57(s,2H),3.30–3.23(m,4H),3.13(s,4H),3.04–2.89(m,5H),2.45(s,3H),1.90(s,3H),1.80(s,2H),1.70–1.61(m,4H),1.60–1.51(m,8H),1.40–1.34(m,2H),1.33–1.19(m,16H).13C NMR(101MHz,DMSO)δ170.15,162.64,158.69,158.40,156.89,156.81,150.09,147.02,138.15,129.96,121.57,119.19,117.24,116.80,116.21,112.57,112.28,107.27,106.71,100.91,56.31,55.97,51.27,50.58,49.41,46.70,45.42,42.61,38.65,36.94,32.61,31.46,29.64,29.49,29.41,29.27,29.16,28.97,28.52,26.88,26.49,23.66,17.42.
实施例45:2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-(氮杂环丁烷-3-基氨基)苯基)-5-甲基-7-氧-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-45)
化合物ZX-HYT-45的合成方法参照实施例17。HRMS(ESI)for C52H73N9O3[M+H]+:calcd,872.5915;found,872.5926.HPLC analysis:MeOH-H2O(95:5),RT=4.763min,98.21%purity.1HNMR(400MHz,DMSO-d6)δ8.76(s,1H),8.01(s,1H),7.61(s,1H),7.43–7.32(m,1H),7.23(s,1H),6.67–6.57(m,1H),6.53(s,1H),6.46–6.22(m,4H),6.03(s,1H),4.18(s,1H),3.94–3.64(m,7H),3.06–2.96(m,6H),2.48–2.35(m,7H),2.29(s,2H),1.89(s,3H),1.79(s,2H),1.67–1.61(m,3H),1.59–1.50(m,9H),1.47–1.41(m,2H),1.38–1.34(m,2H),1.29–1.17(m,16H).13C NMR(101MHz,DMSO)δ170.11,162.61,156.82,148.94,147.00,138.05,130.10,120.51,117.14,113.44,111.57,106.87,106.55,100.11,58.40,56.16,54.58,54.44,53.29,50.59,49.35,47.79,42.62,38.65,36.95,32.60,29.64,29.51,29.42,29.18,28.54,27.48,26.88,26.80,17.41.
实施例46:N-((1S,4S)-4-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环己基)环丙烷甲酰胺(ZX-HYT-46)
化合物ZX-HYT-46的合成方法参照实施例20。HRMS(ESI)for C53H78N8O4[M+H]+:calcd,891.6219;found,891.6223.1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.51(s,1H),7.48(t,J=5.9Hz,1H),7.07(d,J=7.5Hz,1H),6.91(d,J=11.5Hz,1H),6.76(dd,J=7.5,1.5Hz,1H),6.45(q,J=1.1Hz,1H),6.31(d,J=1.6Hz,1H),4.11(p,J=7.0Hz,1H),3.86(s,3H),3.59(dp,J=11.4,7.0Hz,1H),3.27(t,J=7.1Hz,4H),3.07(td,J=7.1,5.9Hz,2H),2.63(t,J=7.1Hz,4H),2.50–2.41(m,4H),2.38(t,J=7.1Hz,2H),2.28(s,2H),2.10(s,3H),1.78–1.70(m,2H),1.70–1.54(m,15H),1.54–1.48(m,5H),1.41–1.38(m,4H),1.34–1.18(m,14H),1.00–0.86(m,4H).
实施例47:N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-47)
化合物ZX-HYT-47的合成方法参照实施例8。HRMS(ESI)for C49H64N8O4[M+H]+:calcd,829.5123;found,829.5135.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J=8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J=2.5Hz,1H),6.32(d,J=1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J=13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,3H),1.69–1.62(m,4H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.32–1.15(m,10H),0.88–0.75(m,4H).
实施例48:N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)新戊酰胺(ZX-HYT-48)
化合物ZX-HYT-48的合成方法参照实施例8。HRMS(ESI)for C50H68N8O4[M+H]+:calcd,845.5436;found,845.5441.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.80(s,1H),8.11(s,1H),7.91(d,J=8.2Hz,1H),7.64(t,J=5.6Hz,1H),7.55(t,J=2.1Hz,1H),7.46(t,J=8.1Hz,1H),7.28(d,J=8.9Hz,1H),6.93(dd,J=7.7,2.0Hz,1H),6.52(d,J=2.5Hz,1H),6.32(s,1H),6.03(s,1H),3.78(s,3H),3.15–3.04(m,4H),3.01(q,J=6.5Hz,2H),2.71–2.52(m,4H),2.48–2.38(m,5H),1.90(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.58–1.53(m,9H),1.51–1.43(m,2H),1.41–1.35(m,2H),1.30–1.25(m,8H),1.21(s,9H).
实施例49:N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙酰胺(ZX-HYT-49)
化合物ZX-HYT-49的合成方法参照实施例8。HRMS(ESI)for C48H64N8O4[M+H]+:calcd,817.5123;found,817.5134.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.80(s,1H),8.10(s,1H),7.82–7.75(m,1H),7.63(t,J=5.7Hz,1H),7.51–7.43(m,2H),7.26(d,J=8.9Hz,1H),6.96–6.89(m,1H),6.53(d,J=2.6Hz,1H),6.35–6.29(m,1H),6.01(s,1H),3.78(s,3H),3.10–2.96(m,6H),2.49–2.41(m,7H),2.36–2.25(m,4H),1.91(s,3H),1.80(s,2H),1.70–1.62(m,3H),1.60–1.52(m,9H),1.49–1.43(m,2H),1.40–1.35(m,2H),1.31–1.23(m,8H),1.07(t,J=7.5Hz,3H).
实施例50:N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-50)
化合物ZX-HYT-50的合成方法参照实施例8。HRMS(ESI)for C41H47N7O4[M+H]+:calcd,702.3702;found,702.3713.1H NMR(600MHz,DMSO-d6)δ10.39(s,1H),8.81(s,1H),8.14(s,1H),7.80(s,1H),7.54–7.41(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.78(p,J=6.3Hz,1H),1.69–1.60(m,12H),0.82–0.73(m,4H).
实施例51:N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)乙基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-51)
化合物ZX-HYT-51的合成方法参照实施例8。HRMS(ESI)for C43H52N8O4[M+H]+:calcd,745.4184;found,745.4191.1H NMR(600MHz,DMSO-d6)δ10.40(s,1H),8.80(s,1H),8.11(s,1H),7.79(s,1H),7.61(t,J=5.7Hz,1H),7.54–7.42(m,2H),7.28(d,J=8.9Hz,1H),6.93(dt,J=8.1,1.6Hz,1H),6.53(d,J=2.5Hz,1H),6.32(s,1H),6.00(s,1H),3.79(s,3H),3.20(q,J=6.4Hz,2H),3.09–2.98(m,4H),2.57–2.52(m,4H),2.46(s,3H),2.40(t,J=6.6Hz,2H),1.91(s,3H),1.86–1.82(m,2H),1.78(tt,J=7.3,3.7Hz,1H),1.69–1.64(m,3H),1.60–1.56(m,9H),0.80–0.74(m,4H).
实施例52:N-(3-(2-((4-(4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)丁基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-52)
化合物ZX-HYT-52的合成方法参照实施例8。HRMS(ESI)for C45H56N8O4[M+H]+:calcd,773.4497;found,773.4485.1H NMR(600MHz,DMSO-d6)δ10.39(s,1H),8.81(s,1H),8.14(s,1H),7.81(s,1H),7.71(s,1H),7.50–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.95–6.91(m,1H),6.56(s,1H),6.33(s,1H),6.02(s,1H),3.79(s,3H),3.18–2.86(m,8H),2.64–2.51(m,6H),2.46(s,3H),1.95–1.90(m,3H),1.83(s,2H),1.80–1.76(m,1H),1.69–1.63(m,3H),1.61–1.52(m,9H),1.46–1.40(m,2H),0.83–0.75(m,4H).
实施例53:N-(3-(2-((4-(4-(6-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)己基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-53)
化合物ZX-HYT-53的合成方法参照实施例8。HRMS(ESI)for C47H60N8O4[M+H]+:calcd,801.4810;found,801.4823.1H NMR(600MHz,DMSO-d6)δ10.40(s,1H),8.81(s,1H),8.17(s,1H),7.91(s,1H),7.76(s,1H),7.50–7.45(m,2H),7.19(d,J=8.8Hz,1H),6.95–6.93(m,1H),6.57(s,1H),6.34(s,1H),6.12(s,1H),3.79(s,3H),3.18–2.86(m,8H),2.64–2.51(m,8H),2.46(s,3H),1.95–1.90(m,3H),1.83(s,2H),1.80–1.76(m,1H),1.69–1.63(m,3H),1.61–1.52(m,9H),1.48–1.37(m,4H),0.83–0.75(m,4H).
实施例54:N-(3-(2-((4-(4-(10-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)癸基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-54)
化合物ZX-HYT-54的合成方法参照实施例8。HRMS(ESI)for C51H68N8O4[M+H]+:calcd,857.5436;found,857.5441.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=5.7Hz,1H),7.57–7.41(m,2H),7.28(d,J=8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J=2.5Hz,1H),6.32(d,J=1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J=13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.31–1.11(m,14H),0.88–0.75(m,6H).
实施例55:N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十四烷基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-55)
化合物ZX-HYT-55的合成方法参照实施例8。HRMS(ESI)for C55H76N8O4[M+H]+:calcd,913.6062;found,913.6062.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J=8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J=2.5Hz,1H),6.32(d,J=1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J=13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.32–1.12(m,22H),0.88–0.75(m,6H).
实施例56:N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-56)
化合物ZX-HYT-56的合成方法参照实施例8。HRMS(ESI)for C40H45N7O4[M+H]+:calcd,688.3606;found,688.3673..1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J=8.1Hz,1H),7.62(t,J=5.6Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.1Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.8,2.0,1.0Hz,1H),6.51(d,J=2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,4H),2.49–2.40(m,4H),2.41(s,3H),2.30-2.12(m,2H),1.79–1.61(m,3H),1.42–1.20(m,12H).
实施例57:N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)乙基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-57)
化合物ZX-HYT-57的合成方法参照实施例8。HRMS(ESI)for C42H50N8O4[M+H]+:calcd,731.4028;found,731.4031.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J=8.1Hz,1H),7.62(t,J=5.6Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.1Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.8,2.0,1.0Hz,1H),6.51(d,J=2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,4H),2.49–2.40(m,4H),2.41(s,3H),2.30-2.12(m,4H),1.69–1.61(m,3H),1.60–1.53(m,4H),1.32–1.20(m,10H).
实施例58:N-(3-(2-((4-(4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)丁基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-58)
化合物ZX-HYT-58的合成方法参照实施例8。HRMS(ESI)for C44H54N8O4[M+H]+:calcd,759.4341;found,759.4356.
1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J=8.1Hz,1H),7.62(t,J=5.6Hz,1H),7.56(t,J=2.0Hz,1H),7.51(t,J=8.1Hz,1H),7.27(d,J=8.9Hz,1H),6.98(ddd,J=7.8,2.0,1.0Hz,1H),6.51(d,J=2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J=10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,6H),2.49–2.40(m,7H),2.30(t,J=7.4Hz,2H),1.90(s,3H),1.69–1.61(m,3H),1.60–1.53(m,3H),1.50–1.41(m,2H),1.32–1.20(m,10H).
实施例59:N-(3-(2-((4-(4-(8-(2-((1S,3R,5S,7R)-3,5-二甲基金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-59)
化合物ZX-HYT-59的合成方法参照实施例32。HRMS(ESI)for C51H68N8O4[M+H]+:calcd,857.5442;found,857.5436.HPLC analysis:MeOH-H2O(85:15),RT=13.264min,96.02%purity.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.79(s,1H),8.14(s,1H),7.81(d,J=7.9Hz,1H),7.66(t,J=5.7Hz,1H),7.50–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.92(dd,J=7.9,2.0Hz,1H),6.55(d,J=2.5Hz,1H),6.32(s,1H),6.04(s,1H),3.78(s,3H),3.12(q,J=7.4Hz,4H),3.01(q,J=6.4Hz,2H),2.82(s,2H),2.52–2.37(m,7H),2.02–1.95(m,1H),1.83(s,1H),1.77(p,J=6.2Hz,1H),1.54(s,1H),1.41–1.34(m,3H),1.28–1.26(m,7H),1.25–1.23(m,8H),1.20–1.16(m,3H),1.13–1.07(m,2H),1.03–0.98(m,1H),0.86–0.62(m,10H).13C NMR(101MHz,DMSO)δ172.23,170.21,162.60,157.03,156.74,147.36,140.72,137.48,129.84,123.89,119.74,118.84,117.04,106.89,106.63,100.37,56.22,54.03,52.51,51.10,49.88,48.94,43.18,42.29,41.21,38.62,34.20,31.32,31.01,29.63,29.58,29.32,29.13,27.05,26.87,18.53,17.46,17.23,15.05,12.99,7.73,7.63.
实施例60:(1S,2R,4S)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)双环[2.2.1]庚-5-烯-2-羧酰胺(ZX-HYT-60)
化合物ZX-HYT-60的合成方法参照实施例32。HRMS(ESI)for C45H56N8O4[M+H]+:calcd,773.4503;found,773.4497.HPLC analysis:MeOH-H2O(97:3),RT=4.703min,98.47%purity.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.87(s,1H),9.27(s,1H),8.81(s,1H),8.17(s,1H),7.78(d,J=8.0Hz,1H),7.56(t,J=5.7Hz,1H),7.48–7.44(m,1H),7.32(d,J=8.8Hz,1H),6.93(d,J=7.8Hz,1H),6.61(s,1H),6.33(s,1H),6.10(dd,J=5.7,3.0Hz,1H),5.82–5.76(m,1H),3.80(s,3H),3.76–3.70(m,1H),3.60–3.55(m,1H),3.14–3.08(m,8H),3.04–3.00(m,1H),2.98–2.92(m,2H),2.82–2.74(m,2H),2.45(s,3H),1.79(t,J=6.1Hz,1H),1.73–1.67(m,2H),1.38–1.35(m,1H),1.32–1.29(m,3H),1.27–1.24(m,3H),1.20–1.16(m,7H),0.83–0.74(m,4H).13C NMR(101MHz,DMSO)δ173.07,172.27,162.57,157.06,156.73,147.34,140.71,137.48,137.28,132.58,129.81,123.93,119.82,118.92,117.12,107.10,106.70,100.79,56.30,51.27,49.85,46.67,46.15,46.11,43.77,42.56,38.91,29.68,28.93,28.84,26.73,26.46,17.47,15.03,9.04,7.65.
实施例61:(1R,2R,4S)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)双环[2.2.1]庚烷-2-羧酰胺(ZX-HYT-61)
化合物ZX-HYT-61的合成方法参照实施例32。HRMS(ESI)for C45H58N8O4[M+H]+:calcd,775.4659;found,775.4654.HPLC analysis:MeOH-H2O(95:5),4.929min,96.20%purity.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.78(s,1H),8.08(s,1H),7.81(d,J=7.9Hz,1H),7.70–7.58(m,1H),7.53–7.42(m,2H),7.27(d,J=8.9Hz,1H),6.91(d,J=7.9Hz,1H),6.52(s,1H),6.30(s,1H),6.02(s,1H),3.78(s,3H),3.11–2.93(m,7H),2.59–2.53(m,1H),2.49–2.45(m,4H),2.44–2.40(m,4H),2.29(t,J=7.4Hz,2H),2.22–2.09(m,2H),1.85–1.68(m,2H),1.60–1.53(m,1H),1.49–1.42(m,4H),1.40–1.35(m,3H),1.29–1.24(m,9H),0.82–0.75(m,4H).13C NMR(101MHz,DMSO)δ175.06,173.17,172.21,162.60,156.97,156.73,147.32,140.79,137.47,130.11,129.85,123.82,120.28,119.68,118.75,116.98,106.72,106.56,100.04,58.37,56.14,53.27,49.27,46.87,46.33,41.94,41.04,38.98,38.95,37.06,36.29,35.86,33.79,31.13,29.81,29.73,29.65,29.44,29.31,29.21,28.86,27.39,27.03,26.82,26.78,24.32,17.45,15.04,7.71,7.63.
实施例62:N-(3-(2-((4-(4-(8-(环丙烷甲酰胺基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d)]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-62)
化合物ZX-HYT-62的合成方法参照实施例32。HRMS(ESI)for C41H52N8O4[M+H]+:calcd,721.4184;found,721.4192.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J=8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J=2.5Hz,1H),6.32(d,J=1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.33(s,3H),1.94–1.87(m,3H),1.69–1.62(m,2H),1.61–1.52(m,9H),1.52–1.44(m,2H),0.88–0.75(m,8H).
实施例63:N-(8-(4-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基))氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)环己烷甲酰胺(ZX-HYT-63)
化合物ZX-HYT-63的合成方法参照实施例32。HRMS(ESI)for C44H58N8O4[M+H]+:calcd,763.4654;found,763.4661.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J=8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J=2.5Hz,1H),6.32(d,J=1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.33(s,3H),1.94–1.87(m,3H),1.69–1.62(m,2H),1.61–1.52(m,11H),1.52–1.44(m,4H),0.88–0.75(m,10H).
实施例64:N-((3S,5S,7S)-金刚烷-1-基)-4-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-甲酰胺(ZX-HYT-64)
将化合物29(0.13mg,0.25mmol),1-异氰基金刚烷(44mg,0.25mmol)和三乙胺(38mg,0.38mmol)置于无水乙醇(5mL)中,并在25℃的温度下搅拌反应1小时,TLC检测,待反应完全后,蒸干反应液,所得残余物经柱色谱纯化(三氯甲烷/甲醇=40:1洗脱),得黄色粉末状目标化合物ZX-HYT-64(0.17g,收率97%)。HRMS(ESI)for C40H46N8O4[M+H]+:calcd,703.3715;found,703.3721.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.80(s,1H),8.11(s,1H),7.87–7.76(m,1H),7.52–7.42(m,2H),7.28(d,J=8.9Hz,1H),6.98–6.85(m,1H),6.61–6.52(m,1H),6.32(s,1H),6.04(s,1H),5.77(s,1H),3.80(s,3H),3.45–3.36(m,4H),3.02–2.93(m,4H),2.46(s,3H),2.05–1.98(m,3H),1.98–1.91(m,6H),1.82–1.74(m,1H),1.67–1.57(m,6H),0.82–0.75(m,4H).
实施例65:N-(3-(2-((4-(4-((3R,5R,7R)-金刚烷-1-羰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-65)
化合物ZX-HYT-65的合成方法参照实施例32。HRMS(ESI)for C40H45N7O4[M+H]+:calcd,688.3606;found,688.3611.HRMS(ESI)for C40H46N8O4[M+H]+:calcd,703.3715;found,703.3723.1H NMR(600MHz,DMSO-d6)δ10.39(s,1H),8.81(s,1H),8.13(s,1H),7.81(s,1H),7.53–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.89(m,1H),6.62–6.52(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.77–3.69(m,4H),3.08–2.96(m,4H),2.46(s,3H),2.01(s,3H),1.98–1.90(m,6H),1.78(p,J=6.2,5.4Hz,1H),1.76–1.67(m,6H),0.84–0.75(m,4H).
实施例66:2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-(4-甲基-2-氧代哌嗪-1-基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-66)
化合物ZX-HYT-66的合成方法参照实施例18。MS(ESI),m/z:731.6[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.07(s,1H),8.48(s,1H),7.87(t,J=1.5Hz,1H),7.53(d,J=7.5Hz,1H),7.26(t,J=7.5Hz,1H),7.09(dd,J=24.7,7.5Hz,2H),6.74(dd,J=7.5,1.5Hz,1H),6.58(q,J=0.9Hz,1H),6.30(d,J=1.5Hz,1H),3.94–3.85(m,5H),3.68(t,J=7.0Hz,4H),3.51(s,2H),3.32(t,J=7.1Hz,4H),2.69(t,J=7.1Hz,2H),2.47(d,J=1.1Hz,3H),2.39(s,3H),2.34(s,2H),2.00(p,J=7.0Hz,3H),1.69–1.58(m,12H).
实施例67:N-(3-(2-((6-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基吡啶-3-基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-67)
化合物ZX-HYT-67的合成方法参照实施例32。HRMS(ESI)for C40H46N8O4[M+H]+:calcd,703.3715;found,703.3723.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.79(s,1H),8.34(s,1H),7.77–7.66(m,1H),7.50–7.40(m,3H),6.90(d,J=7.8Hz,1H),6.30(s,1H),5.86(s,1H),3.80(s,3H),3.66–3.53(m,4H),3.42–3.36(m,4H),2.45(s,3H),2.16(s,2H),1.97–1.89(m,3H),1.82–1.73(m,1H),1.70–1.57(m,12H),0.83–0.70(m,4H).
实施例68:N-((3S,5S,7S)-金刚烷-1-基)-4-(5-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-6-甲氧基吡啶-2-基)哌嗪-1-甲酰胺(ZX-HYT-68)
化合物ZX-HYT-68的合成方法参照实施例65。HRMS(ESI)for C39H45N9O4[M+H]+:calcd,704.3667;found,704.3653.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.79(s,1H),8.32(s,1H),7.78–7.70(m,1H),7.50–7.40(m,3H),6.90(d,J=7.8Hz,1H),6.30(s,1H),5.83(s,1H),5.76(s,1H),3.80(s,3H),3.45–3.35(m,8H),2.45(s,3H),2.05–1.98(m,3H),1.98–1.90(m,6H),1.82–1.74(m,1H),1.68–1.56(m,6H),0.83–0.73(m,4H).
实施例69:N-(3-(2-((6-(4-((3R,5R,7R)-金刚烷-1-羰基)哌嗪-1-基)-2-甲氧基吡啶-3-基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-69)
化合物ZX-HYT-69的合成方法参照实施例32。HRMS(ESI)for C39H44N8O4[M+H]+:calcd,689.3558;found,689.3562.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.79(s,1H),8.33(s,1H),7.81–7.66(m,1H),7.50–7.40(m,3H),6.91(d,J=7.8Hz,1H),6.31(s,1H),5.86(s,1H),3.81(s,3H),3.75–3.65(m,4H),3.33–3.33(m,4H),2.45(s,3H),2.05–1.98(m,3H),1.98–1.91(m,6H),1.81–1.63(m,7H),0.84–0.71(m,4H).
实施例70:N-(3-(2-((6-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-4-甲氧基吡啶-3-基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-70)
化合物ZX-HYT-70的合成方法参照实施例32。HRMS(ESI)for C40H46N8O4[M+H]+:calcd,703.3715;found,703.3723.1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.72(s,1H),8.52(s,1H),7.83(s,1H),7.66–7.56(m,1H),7.46(s,1H),7.36(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例71:N-((3S,5S,7S)-金刚烷-1-基)-4-(5-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-4-甲氧基吡啶-2-基)哌嗪-1-甲酰胺(ZX-HYT-71)
化合物ZX-HYT-71的合成方法参照实施例65。HRMS(ESI)for C39H45N9O4[M+H]+:calcd,704.3667;found,704.3653.1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.72(s,1H),8.50(s,1H),7.82(s,1H),7.63–7.55(m,1H),7.47(s,1H),7.37(s,1H),6.85(s,1H),6.30(s,1H),6.27(s,1H),5.74(s,1H),3.73(s,3H),3.45–3.35(m,8H),2.42(s,3H),2.06–1.99(m,3H),1.99–1.93(m,6H),1.82–1.74(m,1H),1.65–1.58(m,6H),0.84–0.74(m,4H).
实施例72:N-(3-(2-((6-(4-((3R,5R,7R)-金刚烷-1-羰基)哌嗪-1-基)-4-甲氧基吡啶-3-基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-72)
化合物ZX-HYT-72的合成方法参照实施例32。HRMS(ESI)for C39H44N8O4[M+H]+:calcd,689.3558;found,689.3562.1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.72(s,1H),8.52(s,1H),7.84(s,1H),7.66–7.54(m,1H),7.46(s,1H),7.37(s,1H),6.84(s,1H),6.34–6.24(m,2H),3.78–3.65(m,7H),3.49–3.39(m,4H),2.42(s,3H),2.05–1.88(m,9H),1.80–1.63(m,7H),0.82–0.73(m,4H).
实施例73:N-(3-(2-((4-((2-(2-((3R,5R,7R)-金刚烷-1-基)-N-甲基乙酰氨基)乙基)(甲基)氨基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-73)
化合物ZX-HYT-73的合成方法参照实施例32。HRMS(ESI)for C41H49N7O4[M+H]+:calcd,704.3919;found,704.3923.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.79(s,1H),8.34(s,1H),7.77–7.66(m,1H),7.50–7.40(m,3H),6.90(d,J=7.8Hz,1H),6.30(s,1H),5.86(s,1H),3.80(s,3H),3.67(s,3H),3.42–3.36(m,4H),3.16(s,3H),2.45(s,3H),2.16(s,2H),1.97–1.89(m,3H),1.82–1.72(m,1H),1.71–1.58(m,12H),0.85–0.73(m,4H).
实施例74:2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-((4-甲基哌嗪-1-基)甲基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-74)
化合物ZX-HYT-74的合成方法参照实施例18。MS(ESI),m/z:730.9[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.49(s,1H),7.81(p,J=1.3Hz,1H),7.42(dt,J=7.5,1.5Hz,1H),7.34(t,J=7.5Hz,1H),7.13(dddd,J=7.5,2.6,1.7,1.1Hz,1H),7.07(d,J=7.5Hz,1H),6.74(dd,J=7.5,1.5Hz,1H),6.58(q,J=0.9Hz,1H),6.30(d,J=1.5Hz,1H),3.87(s,3H),3.68(t,J=7.0Hz,4H),3.54(t,J=1.0Hz,2H),3.32(t,J=7.1Hz,4H),3.02(t,J=7.1Hz,4H),2.49–2.43(m,7H),2.33(d,J=8.8Hz,5H),2.00(s,3H),1.67–1.57(m,12H).
实施例75:2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-8-(4-氟-3-((4-甲基哌嗪-1-基)甲基)苯基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-75)
化合物ZX-HYT-75的合成方法参照实施例18。MS(ESI),m/z:748.9[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.78(s,1H),7.85(dq,J=4.9,1.1Hz,1H),7.41(ddd,J=7.5,4.9,1.5Hz,1H),7.27–7.18(m,1H),7.07(d,J=7.5Hz,1H),6.74(dd,J=7.5,1.5Hz,1H),6.58(q,J=0.9Hz,1H),6.30(d,J=1.5Hz,1H),3.89(s,3H),3.67(t,J=7.0Hz,4H),3.61(d,J=1.1Hz,2H),3.31(t,J=7.1Hz,4H),2.59(td,J=6.9,0.8Hz,4H),2.48–2.42(m,7H),2.33(d,J=9.0Hz,5H),2.10(s,3H),1.69–1.51(m,12H).
实施例76:2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-((4-甲基哌嗪-1-基)甲基)-4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-76)
化合物ZX-HYT-76的合成方法参照实施例18。MS(ESI),m/z:798.9[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.49(s,1H),7.60–7.54(m,2H),7.42(dd,J=7.4,1.5Hz,1H),7.07(d,J=7.5Hz,1H),6.74(dd,J=7.5,1.5Hz,1H),6.58(q,J=0.9Hz,1H),6.30(d,J=1.5Hz,1H),3.89(s,2H),3.81–3.64(m,6H),3.31(t,J=7.1Hz,4H),2.67(td,J=7.0,0.8Hz,4H),2.49–2.42(m,7H),2.34(d,J=10.2Hz,4H),2.16(s,3H),1.67–1.57(m,12H).
实施例77:3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-(1-甲基氮杂环丁烷-3-基)苯甲酰胺(ZX-HYT-77)
化合物ZX-HYT-77的合成方法参照实施例18。MS(ESI),m/z:730.9[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.09(s,1H),8.68(s,1H),8.29(t,J=1.5Hz,1H),7.79(d,J=9.5Hz,1H),7.71(dt,J=7.3,1.5Hz,1H),7.52(dt,J=7.5,1.5Hz,1H),7.41(t,J=7.5Hz,1H),7.07(d,J=7.5Hz,1H),6.74(dd,J=7.5,1.5Hz,1H),6.59(q,J=1.0Hz,1H),6.30(d,J=1.5Hz,1H),4.14(dp,J=9.5,7.0Hz,1H),3.87(s,3H),3.68(t,J=7.0Hz,4H),3.32(t,J=7.1Hz,4H),3.16(dd,J=12.4,7.0Hz,2H),2.94(dd,J=12.4,7.1Hz,2H),2.47(d,J=1.1Hz,3H),2.34(s,2H),2.24(s,3H),1.98(s,3H),1.69–1.50(m,12H).
实施例78:4-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-(1-甲基氮杂环丁烷-3-基)吡啶酰胺(ZX-HYT-106)
化合物ZX-HYT-78的合成方法参照实施例18。MS(ESI),m/z:732.3[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.75(d,J=1.5Hz,1H),8.48(s,1H),8.43(d,J=7.5Hz,1H),8.33(dd,J=7.4,1.5Hz,1H),7.99(d,J=10.3Hz,1H),7.07(d,J=7.5Hz,1H),6.74(dd,J=7.5,1.5Hz,1H),6.58(q,J=1.0Hz,1H),6.30(d,J=1.5Hz,1H),4.14(dp,J=9.5,7.0Hz,1H),3.87(s,3H),3.68(t,J=7.0Hz,4H),3.32(t,J=7.1Hz,4H),3.16(dd,J=12.4,7.0Hz,2H),2.94(dd,J=12.4,7.1Hz,2H),2.47(d,J=1.1Hz,3H),2.34(s,2H),2.24(s,3H),1.98(s,3H),1.69–1.50(m,12H).
实施例79:5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-氟-N-(1-甲基氮杂环丁烷-3-基)苯甲酰胺(ZX-HYT-79)
化合物ZX-HYT-79的合成方法参照实施例18。MS(ESI),m/z:749.3[M+H]+.1H NMR(600MHz,Chloroform-d)δ8.65(s,1H),8.01(dd,J=6.9,2.7Hz,1H),7.76(s,1H),7.45–7.27(m,3H),6.81(dd,J=12.2,3.2Hz,1H),6.44(s,1H),6.37(s,1H),6.05(s,1H),3.84(s,3H),3.82–3.78(m,4H),3.72–3.67(m,4H),3.51-3.16(m,4H),2.93(tq,J=7.2,3.6Hz,1H),2.62(s,3H),2.46(s,3H),2.20(s,2H),2.00–1.97(m,3H),1.72–1.65(m,12H).
实施例80:5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-(1-甲基氮杂环丁烷-3-基)-2-(三氟甲基)苯甲酰胺(ZX-HYT-80)
化合物ZX-HYT-80的合成方法参照实施例18。MS(ESI),m/z:799.3[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.07(s,1H),8.48(s,1H),8.02(d,J=1.5Hz,1H),7.67(d,J=7.4Hz,1H),7.56(dd,J=7.5,1.6Hz,1H),7.32(d,J=9.7Hz,1H),7.07(d,J=7.5Hz,1H),6.74(dd,J=7.5,1.5Hz,1H),6.57(q,J=0.9Hz,1H),6.30(d,J=1.5Hz,1H),4.31-4.14(m,1H),3.86(s,2H),3.68(t,J=7.0Hz,4H),3.32(t,J=7.1Hz,4H),3.17(dd,J=12.5,7.0Hz,2H),2.95(dd,J=12.4,7.0Hz,2H),2.47(d,J=1.1Hz,3H),2.34-2.25(m,4H),2.12(s,3H),1.7–1.57(m,12H).
实施例81:N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)-1-氨基环丙烷-1-甲酰胺(ZX-HYT-81)
化合物ZX-HYT-81的合成方法参照实施例18。MS(ESI),m/z:717.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.80(s,1H),8.13(s,1H),7.87(s,1H),7.60(s,1H),7.48(t,J=8.1Hz,1H),7.28(d,J=8.8Hz,1H),6.95(d,J=7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H),1.21–1.09(m,2H),0.93–0.80(m,2H).
实施例82:N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)-2-氨基乙酰胺(ZX-HYT-82)
化合物ZX-HYT-82的合成方法参照实施例18。MS(ESI),m/z:691.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.81(s,1H),8.11(s,1H),7.87(s,1H),7.60(s,1H),7.48(t,J=8.1Hz,1H),7.28(d,J=8.8Hz,1H),6.95(d,J=7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),4.12(s,2H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例83:N-(3-(2-((4-(4-(((3R,5R,7R)-金刚烷-1-基)甲基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基)-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-83)
将化合物29(0.13g,0.25mmol),1-金刚烷甲醛(0.041g,0.025mmol)和氰基硼氢化钠(0.032g,0.5mmol)依次加入10mL二氯甲烷中。室温条件下搅拌2h。TLC检测,反应完全后蒸干反应液。剩下的固体残余物经柱层析纯化(三氯甲烷/甲醇=40:1洗脱),得黄色粉末状目标化合物ZX-HYT-83(0.11g,收率65%)。HRMS(ESI)for C40H47N7O3[M+H]+:calcd,674.3813;found,674.3824.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.79(p,J=6.3Hz,1H),1.72–1.61(m,12H),0.87–0.71(m,4H).
实施例84:N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-84)
化合物ZX-HYT-84的合成方法参照实施例83。HRMS(ESI)for C41H49N7O3[M+H]+:calcd,688.3970;found,688.3981.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.26(s,2H),1.95(s,3H),1.79(p,J=6.4Hz,1H),1.72–1.63(m,14H),0.88–0.70(m,4H).
实施例85:N-(3-(2-((4-(((3S,5S,7S)-金刚烷-1-基)氨基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-)d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-85)
化合物ZX-HYT-85的合成方法参照实施例25。HRMS(ESI)for C35H38N6O3[M+H]+:calcd,591.7355;found,591.9362.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),5.83(s,1H),3.80(s,3H),2.46(s,3H),1.95(s,3H),1.79(p,J=6.4Hz,1H),1.74–1.63(m,12H),0.88–0.71(m,4H).
实施例86:N-(3-(2-((4-((3R,5R,7R)-金刚烷-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶)-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-86)
化合物ZX-HYT-86的合成方法参照实施例25。HRMS(ESI)for C35H37N5O3[M+H]+:calcd,576.2969;found,576.2971.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),2.46(s,3H),1.95(s,3H),1.79(p,J=6.4Hz,1H),1.74–1.63(m,12H),0.88–0.71(m,4H).
实施例87:N-((3S,5S,7S)-金刚烷-1-基)-1-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)氮杂环丁烷-3-甲酰胺(ZX-HYT-87)
化合物ZX-HYT-87的合成方法参照实施例25。HRMS(ESI)for C39H43N7O4[M+H]+:calcd,674.3449;found,674.3452.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.77(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J=8.0Hz,1H),7.16(d,J=8.7Hz,1H),6.93(d,J=7.8Hz,1H),6.31–6.26(m,2H),5.93(s,1H),5.62(s,1H),3.97(s,3H),3.77–3.59(m,4H),2.44(s,3H),1.93–1.86(m,3H),1.81–1.73(m,2H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例88:N-(5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-氟苯基)-2-氨基乙酰胺(ZX-HYT-88)
化合物ZX-HYT-88的合成方法参照实施例18。MS(ESI),m/z:709.8[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.91(s,1H),8.18(s,1H),7.87(s,1H),7.60(s,1H),7.4(d,J=7.8Hz,1H),6.98(d,J=7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),4.12(s,2H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例89:N-(((3R,5R,7R)-金刚烷-1-基)甲基)-1-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-甲酰胺(ZX-HYT-89)
化合物ZX-HYT-89的合成方法参照实施例25。HRMS(ESI)for C42H49N7O4[M+H]+:calcd,716.3919;found,716.3921.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.80(s,1H),8.10(s,1H),7.84–7.75(m,1H),7.70–7.63(m,1H),7.51–7.42(m,2H),7.26(d,J=8.8Hz,1H),6.92(d,J=7.9Hz,1H),6.53(s,1H),6.31(s,1H),6.03(s,1H),3.78(s,3H),3.67–3.56(m,2H),2.81–2.75(m,2H),2.64–2.54(m,2H),2.45(s,3H),2.37–2.28(m,1H),1.97–1.87(m,3H),1.82–1.53(m,11H),1.49–1.37(m,6H),0.83–0.71(m,4H).
实施例90:N-(3-(2-((4-(5-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)-2,5-二氮杂双环)[2.2.2]辛烷-2-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-90)
化合物ZX-HYT-90的合成方法参照实施例25。HRMS(ESI)for C43H49N7O4[M+H]+:calcd,728.9175;found,728.9182.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.76(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J=8.0Hz,1H),7.16(d,J=8.7Hz,1H),6.93(d,J=7.8Hz,1H),6.32–6.22(m,2H),5.62(s,1H),3.98–3.87(m,4H),3.77–3.59(m,5H),3.29–3.22(m,2H),2.44(s,3H),1.93–1.86(m,3H),1.85–1.73(m,5H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例91:N-(3-(2-((4-(6-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)-2,6-二氮杂螺[3.3]庚-2-基))-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-91)
化合物ZX-HYT-91的合成方法参照实施例25。HRMS(ESI)for C42H47N7O4[M+H]+:calcd,714.3762;found,714.3774.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.76(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J=8.0Hz,1H),7.16(d,J=8.7Hz,1H),6.93(d,J=7.8Hz,1H),6.32–6.22(m,2H),5.62(s,1H),3.98–3.87(m,4H),3.77–3.59(m,5H),3.29–3.22(m,2H),2.44(s,3H),1.93–1.86(m,3H),1.85–1.73(m,3H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例92:N-(3-(2-((4-(2-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)-2,7-)二氮杂螺[3.5]壬-7-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-92)
化合物ZX-HYT-92的合成方法参照实施例25。HRMS(ESI)for C44H51N7O4[M+H]+:calcd,742.4075;found,742.4082.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.76(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J=8.0Hz,1H),7.16(d,J=8.7Hz,1H),6.93(d,J=7.8Hz,1H),6.32–6.22(m,2H),5.62(s,1H),3.98–3.87(m,7H),3.77–3.59(m,4H),3.29–3.22(m,2H),2.44(s,3H),1.93–1.86(m,3H),1.85–1.73(m,5H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例93:N-(3-(2-((4-(5-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-93)
化合物ZX-HYT-93的合成方法参照实施例25。HRMS(ESI)for C43H49N7O4[M+H]+:calcd,728.3919;found,728.3919.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.81(s,1H),8.14(s,1H),7.80(s,1H),7.54–7.41(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.81-1.74(m,1H),1.69–1.53(m,14H),0.82–0.73(m,4H).
实施例94:N-(5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-氟苯基)环丙烷甲酰胺(ZX-HYT-94)
化合物ZX-HYT-94的合成方法参照实施例20。HRMS(ESI)for C41H46FN7O4[M+H]+:calcd,720.3668;found,720.3673.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.82(s,1H),8.51(s,1H),7.83(s,1H),7.67–7.56(m,1H),7.42(s,1H),7.31(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例95:N-(5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-(三氟甲基)苯基)环丙烷甲酰胺(ZX-HYT-95)
化合物ZX-HYT-95的合成方法参照实施例20。HRMS(ESI)for C42H46F3N7O4[M+H]+:calcd,770.3636;found,770.3641.1H NMR(600MHz,DMSO-d6)δ10.19(s,1H),8.77(s,1H),8.51(s,1H),7.88(s,1H),7.68–7.55(m,1H),7.41(s,1H),7.30(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例96:N-(4-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)吡啶-2-基)环丙烷甲酰胺(ZX-HYT-96)
化合物ZX-HYT-96的合成方法参照实施例20。HRMS(ESI)for C40H46N8O4[M+H]+:calcd,703.3715;found,703.3723.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.77(s,1H),8.51(s,1H),7.88(s,1H),7.68–7.59(m,1H),7.31(s,1H),7.21(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例97:2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-8-(3-((环丙基甲基)氨基)苯基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-97)
化合物ZX-HYT-97的合成方法参照实施例18。HRMS(ESI)for C41H49N7O3[M+H]+:calcd,688.3970;found,688.3965.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.81(s,1H),8.14(s,1H),7.80(s,1H),7.54–7.41(m,2H),7.29(d,J=8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.24(dd,J=7.0,5.9Hz,2H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.71–1.60(m,1H),1.69–1.60(m,12H),0.82–0.73(m,4H).
实施例98:2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-吗啉代苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-98)
化合物ZX-HYT-98的合成方法参照实施例18。HRMS(ESI)for C43H54N8O3[M+H]+:calcd,731.4392;found,731.4395.1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.09(s,1H),7.37(t,J=8.0Hz,1H),7.29(d,J=8.8Hz,1H),7.07(d,J=8.5Hz,1H),6.85(d,J=2.3Hz,1H),6.69–6.63(m,1H),6.57(d,J=2.5Hz,1H),6.29(s,1H),5.99(s,1H),3.77(s,3H),3.68(t,J=4.9Hz,4H),3.62(dq,J=11.0,5.4,5.0Hz,4H),3.10(q,J=5.0Hz,4H),3.04–2.94(m,4H),2.43(s,3H),2.14(t,J=4.5Hz,2H),1.91(s,3H),1.67–1.54(m,12H).
实施例99:N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-5-(三氟甲基)苯基)-2-氨基乙酰胺(ZX-HYT-99)
化合物ZX-HYT-99的合成方法参照实施例18。MS(ESI),m/z:759.8[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.91(s,1H),8.18(s,1H),7.90(s,1H),7.78(s,1H),7.4(d,J=7.8Hz,1H),6.98(d,J=7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),4.12(s,2H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例100:5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基-2-氟苯甲酰胺(ZX-HYT-100)
化合物ZX-HYT-100的合成方法参照实施例18。MS(ESI),m/z:720.4[M+H]+.1H NMR(600MHz,Chloroform-d)δ8.65(s,1H),8.01(dd,J=6.9,2.7Hz,1H),7.76(s,1H),7.45–7.27(m,3H),6.81(dd,J=12.2,3.2Hz,1H),6.44(s,1H),6.37(s,1H),6.05(s,1H),3.84(s,3H),3.82–3.78(m,2H),3.72–3.67(m,2H),3.06(dt,J=14.9,4.9Hz,4H),2.93(tq,J=7.2,3.6Hz,1H),2.46(s,3H),2.20(s,2H),2.00–1.97(m,3H),1.72–1.65(m,12H),0.91–0.86(m,2H),0.65–0.61(m,2H).
实施例101:8-(3-(1H-咪唑-1-基)苯基)-2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-yl)-2-甲氧基苯基)氨基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-101)
化合物ZX-HYT-101的合成方法参照实施例18。MS(ESI),m/z:685.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.91(s,1H),8.18(s,1H),7.87(s,1H),7.72(s,1H),7.46–7.59(m,2H),7.4(d,J=7.8Hz,1H),7.18(s,1H),6.98(d,J=7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例102:4-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基吡啶酰胺(ZX-HYT-102)
化合物ZX-HYT-102的合成方法参照实施例18。MS(ESI),m/z:703.3[M+H]+.1H NMR(600MHz,Chloroform-d)δ8.72(d,J=5.1Hz,1H),8.68(s,1H),8.20(s,1H),8.11(d,J=3.9Hz,1H),7.42(dd,J=6.1,4.3Hz,1H),7.26(s,1H),6.43(s,1H),6.37(s,1H),3.84(s,3H),3.81(t,J=5.2Hz,2H),3.68(t,J=5.1Hz,2H),3.05(s,4H),2.98(dq,J=7.2,3.6Hz,1H),2.48(s,3H),2.20(s,2H),1.99(s,3H),1.73–1.65(m,12H),0.94–0.89(m,2H),0.72–0.67(m,2H).
实施例103:3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基苯甲酰胺(ZX-HYT-103)
化合物ZX-HYT-103的合成方法参照实施例18。MS(ESI),m/z:702.4[M+H]+.1H NMR(500MHz,Chloroform-d)δ8.63(s,1H),8.10–7.97(m,1H),7.83(s,1H),7.64(t,J=7.8Hz,1H),7.58(t,J=1.9Hz,1H),7.40(d,J=7.8Hz,1H),7.26(s,1H),6.50(d,J=3.2Hz,1H),6.41(d,J=2.6Hz,1H),6.35(d,J=1.4Hz,1H),6.02(s,1H),3.83(s,3H),3.82–3.76(m,2H),3.73–3.64(m,2H),3.12–2.99(m,4H),2.84(tq,J=7.2,3.7Hz,1H),2.45(s,3H),2.21(s,2H),2.03–1.90(m,3H),1.77–1.54(m,12H),0.85–0.74(m,2H),0.59–0.45(m,2H).
实施例104:5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基-2-(三氟甲基)苯甲酰胺(ZX-HYT-104)
化合物ZX-HYT-104的合成方法参照实施例18。MS(ESI),m/z:770.2[M+H]+.1H NMR(600MHz,Chloroform-d)δ8.66(s,1H),7.90(d,J=8.2Hz,1H),7.80(s,1H),7.52–7.45(m,2H),7.21(s,1H),6.49–6.40(m,1H),6.37(s,1H),6.15(s,1H),5.90(s,1H),3.85(s,3H),3.83–3.74(m,2H),3.71–3.64(m,2H),3.13–3.04(m,4H),2.83(q,J=3.6Hz,1H),2.48(s,3H),2.24–2.19(m,2H),1.99(s,3H),1.75–1.63(m,12H),0.84–0.78(m,2H),0.56–0.47(m,2H).
实施例105:化合物对H1975OR细胞中AKT3蛋白水平的影响
细胞株:非小细胞肺癌H1975-OR细胞株。该细胞株为Osimertinib耐药H1975细胞株,通过低剂量逐渐递加法培养获得。具体方法:将H1975细胞以60-70%汇合度铺于10cm培养皿中,添加50nM的Osimertinib于培养基中,待细胞状态稳定后,逐渐将Osimertinib浓度加倍培养至3μM。经基因检测,获得的耐药细胞株(H1975-OR)相对于原H1975细胞株存在AKT3显著高表达。
使用常规Western Blot(免疫印迹法)进行检测,具体如下。将H1975-OR细胞按一定数量种于96孔板,培养箱内贴壁培养过夜后,加入一定浓度的化合物作用24小时。用带有蛋白酶和磷酸酶抑制剂的1×SDS裂解缓冲液裂解细胞。通过SDS-PAGE分离细胞裂解物,并转移至PVDF膜上。然后,在室温下,将PCDF膜取出浸于封闭液(含0.5%Tween-20的5%BSATBS溶液)中封闭处理1小时,然后在4℃下与对特定的一抗孵育过夜。用TBST洗涤印迹,并在室温下与辣根过氧化物酶(HRP)标记的二抗孵育2小时。最后用ECLplus荧光检测试剂(Thermo Scientific,Waltham,MA)进行蛋白显影,并使用Amersham Imager 600系统(GE,America)进行拍照。检测结果使用ImageJ软件分别进行灰度处理,得到灰度值G(Density),使用以下公式计算蛋白最大降解率(Maximal degradation rate,Dmax):Dmax=1-(Gmax-Gmin)/Gmax×100%,其中,Gmax=空白对照组Density(目的蛋白条带)/Density(对应GAPDH);Gmin为化合物处理组观察到目标蛋白降解最大值时的Density(目的蛋白条带)/Density(对应GAPDH)。所得结果以Dmax(%)呈现,如表1所示。
表1化合物诱导H1975-OR细胞中AKT1、AKT2和AKT3蛋白降解的能力
实施例106:化合物ZX-HYT-11对其他肿瘤细胞中AKT1/2/3蛋白的影响
将肿瘤细胞(H1975,PC-9,H1299和A549)分别与不同给定浓度的化合物ZX-HYT-11一起孵育24小时,然后使用实施例105所述的免疫印迹法分析AKT1/2/3的蛋白水平。结果显示(图1),化合物ZX-HYT-11能选择性地降解上述细胞中的AKT3蛋白,而对AKT1/2无影响,进一步表明:该化合物降解AKT3蛋白的有效性和普适性。
实施例107:化合物对肿瘤细胞的增殖抑制活性
将肿瘤细胞(见表2-表5)接种于完全培养基中的96孔板中(2000-3000个/孔)。孵育过夜后,用不同浓度(0.000508~10μM)的化合物分别处理细胞72小时。用CCK-8(CellCounting Kit 8,Dojindo Laboratories,Kumamoto,Japan)实验评估细胞增殖情况。使用GraphPad Prism 5.0软件(GraphPad Software,La Jolla,CA)通过浓度响应曲线拟合计算半数最大抑制浓度(IC50)值。每个IC50值均表示为平均值±SD。结果如表2-5所示。
表2化合物对多种肿瘤细胞的增殖抑制活性
表3化合物对PC-9等肿瘤细胞的增殖抑制活性
表4化合物对MDA-MB-231等肿瘤细胞的增殖抑制活性
表5化合物对A549等肿瘤细胞的增殖抑制活性
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (23)
1.具有式(I)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体:
其中:
E选自:R5取代的C1-C8烷基,C3-C12环烷基,R6取代的C3-C12环烷基;R5选自:C3-C12环烷基,C1-C3烷基取代的C3-C12环烷基,卤素取代的C3-C12环烷基;R6选自:卤素,C1-C6烷基,卤素取代的C1-C6烷基;
L不存在或者选自:其中各n分别独立地为0-14的整数;
Y选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-;
Z选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-,-SO-;
R1选自:C1-C6烷基;
R2选自:
其中,R9选自:H,二甲胺基,C1-C3烷基,-NH(R4),-OR4,-COR11;
R4选自:H,甲基哌啶基,-CH2R11,-COR11;R11选自:乙烯基,C1-C4烷基,环丙基,环丁基,环戊基;
R3为:其中,B通过共价键与Y连接;
A选自:-NHR-;R选自:R7取代的苯基,R7取代的6元杂芳基;
R7选自:C1-C6烷氧基,C1-C6烷硫基;
B不存在或者选自:C3-C12环烷基,R8取代的C3-C12环烷基,3-12元杂环烷基,R8取代的3-12元杂环烷基,
R8选自:C1-C6烷基。
2.根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,E选自:R5取代的C1-C6烷基,C3-C10环烷基,R6取代的C3-C10环烷基;
R5选自:C6-C10环烷基,甲基取代的C6-C10环烷基,卤素取代的C6-C10环烷基;
R6选自:卤素,C1-C3烷基。
3.具有式(I)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体:
其中:
E选自:环丙基, 其中x为0-3的整数,y为0-3的整数;
L不存在或者选自:其中各n分别独立地为0-14的整数;
Y选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-;
Z选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-,-SO-;
R1选自:C1-C6烷基;
R2选自:
其中,R9选自:H,二甲胺基,C1-C3烷基,-NH(R4),-OR4,-COR11;
R4选自:H,甲基哌啶基,-CH2R11,-COR11;R11选自:乙烯基,C1-C4烷基,环丙基,环丁基,环戊基;
R3为:其中,B通过共价键与Y连接;
A选自:-NHR-;R选自:R7取代的苯基,R7取代的6元杂芳基;
R7选自:C1-C6烷氧基,C1-C6烷硫基;
B不存在或者选自:C3-C12环烷基,R8取代的C3-C12环烷基,3-12元杂环烷基,R8取代的3-12元杂环烷基,
R8选自:C1-C6烷基。
4.根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,L选自:其中n为0-7的整数。
5.根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,L选自:或者L不存在,其中n为2-7的整数。
6.根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,Y选自:-CH2-,-CO-,-O-,或者Y不存在;Z选自:-NHCO-,-NH-,或者Z不存在。
7.根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R1选自:C1-C3烷基。
8.具有式(I)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体:
其中:
E选自:R5取代的C1-C8烷基,C3-C12环烷基,R6取代的C3-C12环烷基;R5选自:C3-C12环烷基,C1-C3烷基取代的C3-C12环烷基,卤素取代的C3-C12环烷基;R6选自:卤素,C1-C6烷基,卤素取代的C1-C6烷基;
L不存在或者选自:其中各n分别独立地为0-14的整数;
Y选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-;
Z选自:不存在或者-O-,-NH-,-NHCO-,-CH2-,-S-,-CO-,-SO-;
R1选自:C1-C6烷基;
R2选自:
苯基,
其中,R4选自:
R3为:其中,B通过共价键与Y连接;
A选自:-NHR-;R选自:R7取代的苯基,R7取代的6元杂芳基;
R7选自:C1-C6烷氧基,C1-C6烷硫基;
B不存在或者选自:C3-C12环烷基,R8取代的C3-C12环烷基,3-12元杂环烷基,R8取代的3-12元杂环烷基,
R8选自:C1-C6烷基。
9.根据权利要求1-8任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,A选自:
B不存在或选自:
10.根据权利要求1-8任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,A选自:-NHR-;R选自:R7取代的苯基,R7取代的6元杂芳基;
R7选自:C1-C3烷氧基;
B不存在或者选自:C4-C12环烷基,R8取代的C4-C12环烷基,4-12元杂环烷基,R8取代的4-12元杂环烷基,
R8选自:C1-C3烷基。
11.根据权利要求10所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,A选自:-NHR-;R选自:R7取代的苯基,R7取代的6元含氮杂芳基;
R7选自:C1-C3烷氧基;
B不存在或者选自:C4-C8环烷基,R8取代的C4-C10环烷基,4-10元杂环烷基,R8取代的4-10元杂环烷基,
R8选自:C1-C3烷基。
12.根据权利要求11所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R3选自:
13.吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,所述化合物选自:
14.权利要求1-13任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体在制备AKT3蛋白降解剂中的应用。
15.权利要求1-13任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗与AKT3蛋白异常表达相关的疾病的药物中的应用。
16.根据权利要求15所述的应用,其特征在于,所述与AKT3蛋白异常表达相关的疾病包括:肿瘤、心血管疾病、糖尿病、肌营养不良症、帕金森症、阿尔茨海默症。
17.根据权利要求16所述的应用,其特征在于,所述心血管疾病包括高血压。
18.权利要求1-13任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体在制备治疗肿瘤的药物中的应用,所述肿瘤为与AKT3蛋白异常表达相关的肿瘤。
19.根据权利要求18所述的应用,其特征在于,所述肿瘤为:恶性黑色素瘤、前列腺癌、肾癌、肝癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病、皮肤鳞癌。
20.根据权利要求19所述的应用,其特征在于,所述肺癌为非小细胞肺癌。
21.权利要求1-13任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体在制备治疗肿瘤的药物中的应用,其特征在于,所述肿瘤为:结肠癌、胰腺癌、白血病、皮肤鳞癌。
22.一种AKT3蛋白降解剂,其特征在于,其活性成分含有权利要求1-13任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体。
23.一种治疗肿瘤的药物组合物,其特征在于,由活性成分和药学上可接受的载体或者辅料制备得到,所述活性成分包括权利要求1-13任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110251924 | 2021-03-08 | ||
CN2021102519249 | 2021-03-08 | ||
PCT/CN2022/079597 WO2022188755A1 (zh) | 2021-03-08 | 2022-03-07 | 吡啶并嘧啶类化合物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115348963A CN115348963A (zh) | 2022-11-15 |
CN115348963B true CN115348963B (zh) | 2024-04-19 |
Family
ID=83227417
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280001130.XA Active CN115348963B (zh) | 2021-03-08 | 2022-03-07 | 吡啶并嘧啶类化合物及其应用 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20240132492A1 (zh) |
EP (1) | EP4310084A1 (zh) |
JP (1) | JP2024508901A (zh) |
KR (1) | KR20230148235A (zh) |
CN (1) | CN115348963B (zh) |
AU (1) | AU2022234998B2 (zh) |
WO (1) | WO2022188755A1 (zh) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1422268A (zh) * | 2000-03-06 | 2003-06-04 | 沃尼尔·朗伯公司 | 5-烷基吡啶并[2,3-d]嘧啶酪氨酸激酶抑制剂 |
WO2006021547A1 (de) * | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim International Gmbh | Pteridinone als plk (polo like kinase) inhibitoren |
WO2012065019A2 (en) * | 2010-11-12 | 2012-05-18 | Exelixis, Inc. | Pyridopyrimidinone inhibitors of p13k alpha |
WO2014079232A1 (zh) * | 2012-11-22 | 2014-05-30 | 中国科学院广州生物医药与健康研究院 | 7-氧代吡啶并嘧啶类化合物及其药用组合物和应用 |
WO2014134308A1 (en) * | 2013-03-01 | 2014-09-04 | Amgen Inc. | Substituted 7-oxo-pyrido [2, 3-d] pyrimidines and their use for the treatment of egfr / erbb2 related disorders |
CN107840846A (zh) * | 2016-09-19 | 2018-03-27 | 郑州泰基鸿诺医药股份有限公司 | 一种含嘧啶环的化合物、egfr抑制剂及其应用 |
WO2018233620A1 (zh) * | 2017-06-21 | 2018-12-27 | 江苏恒瑞医药股份有限公司 | SERD与CDK4/6抑制剂、PI3K/mTOR通路抑制剂的用途 |
CN109305967A (zh) * | 2017-07-28 | 2019-02-05 | 中国科学院上海药物研究所 | 新型嘧啶并杂环类化合物及制备方法和用途 |
CN111297867A (zh) * | 2020-03-31 | 2020-06-19 | 黄泳华 | 含有吡啶基氨基吡啶并嘧啶衍生物的组合物在制备用于治疗乳腺癌的药物中的用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2006121990A (ru) * | 2003-11-21 | 2007-12-27 | Эррэй Биофарма Инк. (Us) | Ингибиторы протеинкиназ акт |
-
2022
- 2022-03-07 EP EP22766278.0A patent/EP4310084A1/en active Pending
- 2022-03-07 WO PCT/CN2022/079597 patent/WO2022188755A1/zh active Application Filing
- 2022-03-07 JP JP2023553413A patent/JP2024508901A/ja active Pending
- 2022-03-07 KR KR1020237032389A patent/KR20230148235A/ko active Pending
- 2022-03-07 CN CN202280001130.XA patent/CN115348963B/zh active Active
- 2022-03-07 AU AU2022234998A patent/AU2022234998B2/en active Active
-
2023
- 2023-09-06 US US18/462,373 patent/US20240132492A1/en active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1422268A (zh) * | 2000-03-06 | 2003-06-04 | 沃尼尔·朗伯公司 | 5-烷基吡啶并[2,3-d]嘧啶酪氨酸激酶抑制剂 |
WO2006021547A1 (de) * | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim International Gmbh | Pteridinone als plk (polo like kinase) inhibitoren |
WO2012065019A2 (en) * | 2010-11-12 | 2012-05-18 | Exelixis, Inc. | Pyridopyrimidinone inhibitors of p13k alpha |
WO2014079232A1 (zh) * | 2012-11-22 | 2014-05-30 | 中国科学院广州生物医药与健康研究院 | 7-氧代吡啶并嘧啶类化合物及其药用组合物和应用 |
WO2014134308A1 (en) * | 2013-03-01 | 2014-09-04 | Amgen Inc. | Substituted 7-oxo-pyrido [2, 3-d] pyrimidines and their use for the treatment of egfr / erbb2 related disorders |
CN107840846A (zh) * | 2016-09-19 | 2018-03-27 | 郑州泰基鸿诺医药股份有限公司 | 一种含嘧啶环的化合物、egfr抑制剂及其应用 |
WO2018233620A1 (zh) * | 2017-06-21 | 2018-12-27 | 江苏恒瑞医药股份有限公司 | SERD与CDK4/6抑制剂、PI3K/mTOR通路抑制剂的用途 |
CN109305967A (zh) * | 2017-07-28 | 2019-02-05 | 中国科学院上海药物研究所 | 新型嘧啶并杂环类化合物及制备方法和用途 |
CN111297867A (zh) * | 2020-03-31 | 2020-06-19 | 黄泳华 | 含有吡啶基氨基吡啶并嘧啶衍生物的组合物在制备用于治疗乳腺癌的药物中的用途 |
Non-Patent Citations (7)
Title |
---|
A novel drug discovery concept for tuberculosis: Inhibition of bacterial and host cell signalling;Rita Sz´ekely,et al;《Immunology Letters》;第116卷(第2期);225-231 * |
An Improved Process for the Preparation of a Covalent Kinase Inhibitor through a C-N Bond-Forming SNAr Reaction;Andrew T. Parsons,et al;《Org. Process Res. Dev.》;第22卷;898-902 * |
C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR T790M mutant;Tianfeng Xu, et al;《Med. Chem. Commun.》;第6卷(第9期);1693-1697 * |
Characterization of the Novel Broad-Spectrum Kinase Inhibitor CTx-0294885 As an Affinity Reagent for Mass Spectrometry-Based Kinome Profiling;Luxi Zhang, et al;《J. Proteome Res.》;第12卷(第7期);3104-3116 * |
Signalling Inhibitors Against Mycobacterium tuberculosis – Early Days of a New Therapeutic Concept in Tuberculosis;B. Hegymegi-Barakonyi,et al;《Current Medicinal Chemistry》;第15卷(第26期);2760-2770 * |
Tianfeng Xu, et al.C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR T790M mutant.Med. Chem. Commun..2015,第6卷(第9期),第1693-1697页. * |
Trypanosoma brucei Glycogen Synthase Kinase-3, A Target for Anti-Trypanosomal Drug Development: A Public-Private Partnership to Identify Novel Leads;Richard O. Oduor,et al;《PLoS Neglected Tropical Diseases》;第5卷(第4期);e1017(1-9) * |
Also Published As
Publication number | Publication date |
---|---|
CN115348963A (zh) | 2022-11-15 |
KR20230148235A (ko) | 2023-10-24 |
JP2024508901A (ja) | 2024-02-28 |
EP4310084A1 (en) | 2024-01-24 |
WO2022188755A1 (zh) | 2022-09-15 |
AU2022234998B2 (en) | 2025-04-10 |
AU2022234998A1 (en) | 2023-10-12 |
US20240132492A1 (en) | 2024-04-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101885722B (zh) | 杂环炔苯类化合物及其药用组合物和应用 | |
CN106458930B (zh) | 2-氨基嘧啶类化合物及其药物组合物和应用 | |
TW202128653A (zh) | 作為parp7抑制劑的嗒酮 | |
CN103012399B (zh) | 7-氧代吡啶并嘧啶类化合物及其药用组合物和应用 | |
CN107406417A (zh) | 4H‑吡咯并[3,2‑c]吡啶‑4‑酮衍生物 | |
CN110914267B (zh) | 嘧啶并吡啶酮或者吡啶并吡啶酮类化合物及其应用 | |
WO2022253283A1 (zh) | 一类蛋白激酶降解剂及其用途 | |
KR20190104632A (ko) | 트라이사이클릭 자이라제 억제제 | |
EP3019493A1 (de) | Modifizierte bet-proteininhibitorische dihydrochinoxalinone und dihydropyridopyrazinone | |
CN110305161A (zh) | 2-氨基嘧啶类化合物及其应用 | |
EP2807162B1 (de) | Substituierte phenylimidazopyrazole und ihre verwendung | |
CN117642408A (zh) | 含硒杂环类化合物及其药用组合物和应用 | |
ES2863925T3 (es) | Derivados de 3-(pirimidinamina 4,5-sustituida)fenilo deuterados y aplicaciones de los mismos | |
CN115348963B (zh) | 吡啶并嘧啶类化合物及其应用 | |
AU2019241374B2 (en) | Quinoline or quinazoline compound and application thereof | |
DE102017005091A1 (de) | Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one | |
CN112851667B (zh) | 含氮并杂环类化合物及其药用组合物和应用 | |
CN101298427B (zh) | 二芳基脲类化合物及其应用 | |
CN103570731A (zh) | 嘧啶并三环或嘧啶并四环类化合物及其药用组合物和应用 | |
CN117917402A (zh) | 异吲哚酰胺类化合物及其药物组合物和应用 | |
WO2024213160A1 (zh) | 一类PIKfyve蛋白激酶降解剂及其用途 | |
CN116924976A (zh) | 一类二芳杂环胺化合物、及其制法和药物组合物与用途 | |
EA042574B1 (ru) | Соединение на основе хинолина или хиназолина и его применение |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |