CN115109048B - 一种(杂)芳基酰胺类化合物 - Google Patents
一种(杂)芳基酰胺类化合物 Download PDFInfo
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- CN115109048B CN115109048B CN202210953698.3A CN202210953698A CN115109048B CN 115109048 B CN115109048 B CN 115109048B CN 202210953698 A CN202210953698 A CN 202210953698A CN 115109048 B CN115109048 B CN 115109048B
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- -1 aryl amide compound Chemical class 0.000 title claims abstract description 173
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
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- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 238000006467 substitution reaction Methods 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 18
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
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- 230000002062 proliferating effect Effects 0.000 claims description 6
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
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- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 239000000243 solution Substances 0.000 description 11
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- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 7
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
本发明属于医药化学领域，涉及式I所示的一类能抑制Abelson蛋白(Abl1)、Abelson相关蛋白(Abl2)和相关的嵌合蛋白质、特别是Bcr‑Abl1的酪氨酸激酶酶活性的(杂)芳基酰胺类化合物或其药学上可接受的立体异构体、或其晶型、药学上可接受的盐、水合物或溶剂合物，以及这些化合物的制备方法、含有这些化合物的药物组合物，和这些化合物或组合物在药物制备中的应用。本发明的化合物具有更好的Bcr‑Abl激酶抑制活性和药效学性能，可用于在受试者中治疗和/或预防Bcr‑Abl导致的疾病。
Description
技术领域
本发明涉及医药技术领域，特别是涉及一种能抑制Abelson蛋白(Abl1)、Abelson相关蛋白(Abl2)和相关的嵌合蛋白质、特别是Bcr-Abl1的酪氨酸激酶酶活性的(杂)芳基酰胺类化合物，包含它们的药物组合物，及其制备方法和用途。
背景技术
已知的(杂)芳基酰胺类化合物是一类Bcr-Abl激酶抑制活性化合物，是Bcr-Abl酪氨酸激酶的变构抑制剂。Bcr-Abl融合基因是由人造血干细胞中9号和22号染色体之间的相互易位，费城染色体(Ph)上Bcr和Abl1基因融合导致的。其表达出的酪氨酸激酶使一系列调节细胞生长、分化、死亡的信号通路被异常激活，引起细胞增殖、黏附和生存性质的改变，进而导致多种肿瘤的产生，因此抑制Bcr-Abl酪氨酸激酶可有效抑制肿瘤生长。
(杂)芳基酰胺类结构化合物如ABL001(又名Asciminib，化学名为(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺)，是诺华制药公司研发的Abl1激酶变构抑制剂，靶向Abl1的变构位点肉豆蔻酰口袋而致其失活，与ATP竞争性Bcr-Abl酪氨酸激酶抑制剂联用可有效预防ATP竞争抑制剂和/或变构抑制剂应用的抗药性的出现。已证明ABL-001与第二代Bcr-Abl抑制剂尼洛替尼联用，在小鼠模型中可以起到根治CML的效果。诺华正在开发ABL001与多个ATP竞争性Bcr-Abl抑制剂联用的治疗方案，包括伊马替尼、尼洛替尼和达沙替尼。该药物已于2021在美国上市。
TGRX-678是塔吉瑞制药公司研发的中国首个且研发进展最快的***Bcr-Abl1变构抑制剂，也是全球第二款Bcr-Abl1变构抑制剂，临床前体内外研究结果显示，与ABL001相比TGRX-678对Bcr-AblT315I细胞的活性和选择性更高，口服生物利用度更佳，动物体内安全性也优于ABL001。
然而，本领域仍需要开发对Bcr-Abl激酶有抑制活性、或更好药效学性能的化合物。
发明内容
本发明的目的是提供一类新型的具有Bcr-Abl激酶抑制活性和更好药效学性能的(杂)芳基酰胺类化合物或其药学上可接受的立体异构体、或其晶型、药学上可接受的盐、水合物或溶剂合物，可用于在受试者中治疗/或预防Bcr-Abl导致的疾病。
本发明还提供所述(杂)芳基酰胺类化合物及其中间体的制备方法。
本发明还提供了药物组合物，其包含至少一种本发明的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物，和药学上可接受的赋形剂。
本发明还提供了本发明化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物或本发明所述药物组合物用于制备药物的用途。
对此，本发明采用的技术方案如下：
本发明的第一方面中，提供了如式(I)所示的化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
其中，Y选自CH或N；
R1独立地选自氢、卤素、腈基、羟基，可以为单、双或多取代；R2选自-CF2-Y1；
Y1选自氢、氯、氟、甲基、二氟甲基和三氟甲基；
Z选自化学键、O和S(O)0-2；或者-Z-R2一起表示-SF5；
Het是吡咯烷基；其中所述吡咯烷基被1个或多个Ra基团取代；
Ra选自氢、羟基、甲基、卤素、甲氧基、羟基-甲基、氨基、甲基-氨基、氨基-甲基、三氟甲基、氰基和氨基-羰基；
Link为脲、硫脲、
R3为其中X1-X9独立地选自CRc或N，且X6，X7，X8和X9中的一个为母核连接的C原子，X10选自O、S或NRb，X11选自O、S、NRb或C(Rc)2；
m为0、1、2、3或4；
n为0、1、2、3、4、5、6或7；
Rb独立地选自氢、乙酰基、C1-6烷基或C1-6卤代烷基；
R和Rc独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6羟基代烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；
或者相同原子或相邻原子上的两个R基团可以一起形成C3-7环烷基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；
所述的卤素为F，Cl，或Br。
在某些优选的实施方案中，公开了式(II)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
其中，R1独立地选自氢、卤素、腈基、羟基，可以为单、双或多取代；
Ra独立地选自氢、羟基、卤素、腈基、羧基，可以为单、双或多取代；
Link为脲、硫脲、
R3为
其中X1-X9独立地选自CRc或N，且X6,X7,X8和X9中的一个为母核连接的C原子，X10选自O、S或NRb，X11选自O、S、NRb或C(Rc)2；
m为0、1、2、3或4；
n为0、1、2、3、4、5、6或7；
Rb独立地选自氢、乙酰基、C1-6烷基或C1-6卤代烷基；
R和Rc独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6羟基代烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；
在或者相同原子或相邻原子上的两个R基团可以一起形成C3-7环烷基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；
所述的卤素为F，Cl，或Br。
进一步的，所述R1独立地选自氢和卤素；Ra独立地选自氢和羟基；
Link为脲、硫脲、
Rb独立地选自氢、乙酰基、C1-3烷基或C1-3卤代烷基；
R和Rc独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-3烷基、C1-3卤代烷基、C1-3羟基代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基；
或者相同原子或相邻原子上的两个R基团可以一起形成C3-7环烷基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基。
在某些优选的实施方案中，公开了式(III)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
其中，Ra独立地选自氢和羟基；
Link为脲、硫脲、
R3选自任选被一个、两个或三个R取代的以下基团：
Rb独立地选自氢、乙酰基或C1-3烷基；
R独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-3烷基、C1-3卤代烷基、C1-3羟基代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基、C3-7杂环烷基、C6-10芳基或C5-10杂芳基。
进一步的，所述Ra为羟基；
Link为硫脲、
R独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-3烷基、C1-3卤代烷基、C1-3羟基代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基。
在某些更优选的实施方案中，本发明的(杂)芳基酰胺类化合物是如下表1中的任一化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
表1为本发明的部分化合物
在又一方面本发明提供如式(XI)所述的化合物及其中间体的制备方法，包括如下步骤：
(1)制备中间体(V)：将2-氨基-5-甲基吡啶(IV)溶解于浓硫酸中，冰浴条件下加入体积比为1：1的浓硫酸和浓硝酸的混酸溶液，加热至55℃，反应液倒入碎冰中再加入亚硝酸钠，冰浴搅拌，得到中间体(V)；
(2)制备中间体(VI)：将2-羟基-5-甲基-3-硝基吡啶(V)加入反应瓶中，加入三氯氧磷，加热回流8小时，得到中间体(VI)；
(3)制备中间体(VII)：将2-氯-5-甲基-3-硝基吡啶(VI)溶解于浓硫酸中，冰浴条件下分批加入重铬酸钾，室温搅拌16h，得到中间体(VII)；
(4)制备中间体(VIII)：将6-氯-5-硝基烟酸(VII)溶解于无水DCM中，加入二氯亚砜(SOCl2)，加热搅拌反应4小时，真空干燥，加入无水DCM溶解，再加入相应取代的苯胺，室温搅拌反应得到中间体(VIII)；
(5)制备中间体(IX)：将中间体(VIII)溶解于无水DMSO中，加入N,N-二异丙基乙胺(DIEA)和相应取代的吡咯烷，加热反应得到中间体(IX)；
(6)制备中间体(X)：将中间体(IX)溶解于无水MeOH中，加入钯碳(Pd/C)，在H2条件下加热反应得到中间体(X)；
(7)制备目标产物(XI)：
缩合反应，具体步骤为，将中间体(X)溶解于无水乙腈中，加入各种取代的酰氯，再加入三乙胺(TEA)，室温搅拌1h，得到目标产物(XI)；
或加成反应，具体步骤为，将中间体(X)溶解于无水甲醇中，加入各种取代的环烷基酮，加热搅拌反应得到目标产物(XI)；
或还原胺化反应，具体步骤为，将中间体(X)溶解于无水甲醇中，加入各种取代的环烷基酮，加热搅拌反应2小时，再加入氰基硼氢化钠(NaBH3CN)，加热反应得到目标产物(XI)；
或加成反应，具体步骤为，将中间体(X)溶解于无水乙醇中，加入各种取代的异硫氰酸酯和TEA，80℃搅拌4h，得到目标产物(XI)；
或缩合反应，具体步骤为，将中间体(X)溶解于N,N-二甲基甲酰胺中，加入各种取代的羧酸，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和DIEA，室温搅拌18小时，得到目标产物(XI)。
在又一方面，本发明提供了一种药物组合物，其含有本发明的任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物，和药学上可接受的赋形剂。所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂、注射剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
本发明提供了含有本发明化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物以及药物组合物在制备用于在受试者中治疗和/或预防Bcr-Abl导致的疾病的药物中的应用。
在本发明的具体实施方案中，所述Bcr-Abl导致的疾病为增殖性疾病，其选自：实体瘤、肉瘤、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病。在本发明具体实施方案中，所述Bcr-Abl导致的疾病为转移的浸润性癌、病毒感染或CNS障碍。
药理实验显示，本发明的化合物可以对人慢性髓性白血病细胞系K562，KBM5产生良好的抗增殖作用，可用于制备治疗慢性粒细胞白血病、急性粒细胞白血病等癌症的药物，具有良好的应用前景。
具体实施方式
提供以下实施例以便为领域技术人员提供如何实施、制备和评估本文请求保护的方法和化合物的完整公开和说明，旨在仅仅示例本发明而非限制本发明的范围。
本发明中化合物的结构是通过质谱(MS)和/或核磁共振(1HNMR)设备来确定的。
合成方法
本发明化合物可按照本领域常规方法，并使用合适的试剂、原料和本领域技术人员已知的纯化方法制备。下面更具体地描述本发明化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
通常，在制备中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)进行。反应时间通常为0.1～60小时，优选0.5～24小时。
实施例1制备(R,E)-5-(((5-溴噻吩-2-基)亚甲基)氨基)-N-(4-(氯二氟甲氧基) 苯基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物1)
步骤1：2-羟基-5-甲基-3-硝基吡啶(化合物1b)的合成。
向反应瓶中加入300mL浓硫酸，冰浴下加入2-氨基-5-甲基吡啶(1a，60.0g，554.8mmol)，70mL浓硫酸和浓硝酸混酸(V:V＝1:1),室温搅拌1h，后加热至55℃搅拌2h。反应液倒入冰水中，冰浴下分批加入77g亚硝酸钠，保温搅拌4h，产生大量黄色固体。抽滤，滤饼干燥，得黄色固体45.2g，收率：52.9％。
步骤2：2-氯-5-甲基-3-硝基吡啶(化合物1c)的合成。
向反应瓶中加入2-羟基-5-甲基-3-硝基吡啶(1b，45.2g，272.5mmol)，750mL三氯氧磷，加热回流8h。反应液减压浓缩后倒入碎冰中，有大量黄色固体析出，抽滤，洗涤干燥后得产物42.1g，收率：89.5％。
步骤3：6-氯-5-硝基烟酸(化合物1d)的合成。
向反应瓶中加入2-氯-5-甲基-3-硝基吡啶(1c，42.1g，197.4mmol)，500mL浓硫酸溶解，室温搅拌，分批加入重铬酸钾(92.3g，313.8mmol)，室温搅拌16h。将反应液倒入碎冰中，搅拌降温，乙酸乙酯萃取3次，合并有机相，减压浓缩，重结晶得产物36.72g，收率：74.3％。
步骤4：6-氯-N-(4-(氯二氟甲氧基)苯基)-5-硝基烟酰胺(化合物1e)的合成。
向反应瓶中加入6-氯-5-硝基烟酸(1d，36.53g，180.35mmol)，加入二氯亚砜(SOCl2，550mL)，80℃搅拌反应4小时，真空干燥，加入500mL无水DCM溶解，再加入4-(氯二氟甲氧基)苯胺(34.91g，180.35mmol)，室温搅拌反应1小时，减压浓缩得产物52.13g，收率：76.4％。
步骤5：(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-硝基烟酰胺(化合物1f)的合成。
向反应瓶中加入化合物1e(52.06g，137.6mmol)和(R)-3羟基吡咯烷(12.00g，137.6mmol)，加入400mL无水DMSO，加入DIEA(35.57g，275.3mmol)，加热至100℃搅拌反应2小时，加入过量水稀释，乙酸乙酯萃取3遍，合并有机相，饱和氯化钠溶液洗涤，减压浓缩，经硅胶柱层析纯化得产物45.73g，收率：77.4％。
步骤6：(R)-5-氨基-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物1g)的合成
向反应瓶中加入化合物1f(45.7g，106.5mmol)、钯碳(Pd/C,2g)及300mL无水MeOH，H2置换，40℃搅拌反应12小时，抽滤，滤液减压浓缩得产物33.4g，收率：78.63％。
步骤7：(R,E)-5-(((5-溴噻吩-2-基)亚甲基)氨基)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1)烟酰胺(化合物1)的合成
向反应瓶中加入化合物1g(200mg，0.5mmol)，5-溴噻吩-2-甲醛(190mg，1mmol)、甲酸(2.3mg，0.05mmol)及3mL无水甲醇，50℃加热搅拌2小时。经硅胶柱层析和反相柱层析纯化得产物61.6mg，收率：21.4％。LC-MS(ESI):m/z＝570.99；1H-NMR(300MHz,DMSO-d6)δ10.18(s,1H),8.75(s,1H),8.62(d,J＝2.1Hz,1H),7.90-7.85(m,2H),7.82(d,J＝2.2Hz,1H),7.54(d,J＝3.9Hz,1H),7.40(d,J＝3.9Hz,1H),7.38-7.33(m,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.81-3.78(m,3H),3.68(s,1H),1.98-1.82(m,2H)。
实施例2制备(R,E)-5-(((5-溴呋喃-2-基)亚甲基)氨基)-N-(4-(氯二氟甲氧基)
苯基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物2)
参照实施例1的方法，将5-溴噻吩-2-甲醛替换成5-溴-2-呋喃甲醛，最终制得产物72.8mg，收率：26.2％。LC-MS(ESI):m/z＝555.02[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.61(d,J＝2.1Hz,1H),8.41(s,1H),7.87(d,J＝9.1Hz,2H),7.75(d,J＝2.2Hz,1H),7.35(d,J＝8.6Hz,2H),7.21(d,J＝3.5Hz,1H),6.89(d,J＝3.5Hz,1H),4.94(d,J＝3.3Hz,1H),4.33(s,1H),3.88-3.75(m,3H),3.66-3.62(m,1H),1.96-1.82(m,2H)。
实施例3制备(R,E)-N-(4-(氯二氟甲氧基)苯基)-5-(((5-(羟甲基)呋喃-2-基)亚
甲基)氨基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物3)
参照实施例1的方法，将5-溴噻吩-2-甲醛替换成5-羟甲基糠醛，最终得产物80.0mg，收率：31.6％。LC-MS(ESI):m/z＝507.12[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.14(s,1H),8.59(d,J＝2.1Hz,1H),8.41(s,1H),7.91-7.84(m,2H),7.71(d,J＝2.2Hz,1H),7.38-7.31(m,2H),7.12(d,J＝3.4Hz,1H),6.56(d,J＝3.4Hz,1H),5.48(t,J＝5.8Hz,1H),4.93(d,J＝3.3Hz,1H),4.51(d,J＝5.8Hz,2H),4.32(s,1H),3.79-3.76(m,3H),3.65-3.62(m,1H),1.98-1.80(m,2H)。
实施例4制备(R,E)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-
(((5-甲氧基吡啶-3-基)亚甲基)氨基)烟酰胺(化合物4)
参照实施例1的方法，将5-溴噻吩-2-甲醛替换成5-甲氧基-吡啶-3-甲醛，最终得产物49.0mg，收率：18.9％。LC-MS(ESI):m/z＝518.14[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.20(s,1H),8.76(s,1H),8.70(d,J＝1.6Hz,1H),8.65(d,J＝2.1Hz,1H),8.46(d,J＝2.9Hz,1H),7.90(s,1H),7.87(s,1H),7.83(d,J＝2.1Hz,2H),7.36(d,J＝8.6Hz,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.92(s,3H),3.85-3.81(m,3H),3.70-3.67(m,1H),1.97-1.81(m,2H)。
实施例5制备(R,E)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-
((吡啶-4-基亚甲基)氨基)烟酰胺(化合物5)
参照实施例1的方法，将5-溴噻吩-2-甲醛替换成4-吡啶甲醛，最终得产物39.3mg，收率：16.1％。LC-MS(ESI):m/z＝488.13[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.21(s,1H),8.81-8.77(m,2H),8.75(s,1H),8.67(d,J＝2.2Hz,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝1.3Hz,3H),7.85(d,J＝1.7Hz,1H),7.41-7.31(m,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.86-3.81(m,3H),3.70-3.65(m,1H),1.99-1.84(m,2H)。
实施例6制备(R,E)-5-(((6-溴吡啶-3-基)亚甲基)氨基)-N-(4-(氯二氟甲氧基)
苯基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物6)
参照实施例1的方法，将5-溴噻吩-2-甲醛替换成5-溴吡啶-3-甲醛，制得化合物6。LC-MS(ESI):m/z＝566.04[M+H]+。
实施例7制备(R,E)-N-(4-(氯二氟甲氧基)苯基)-5-((2-羟基-5-硝基亚苄基)氨
基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物7)
参照实施例1的方法，将5-溴噻吩-2-甲醛替换成5-硝基水杨醛，制得化合物7。LC-MS(ESI):m/z＝548.12[M+H]+。
实施例8制备(R)-5-(((5-溴噻吩-2-基)甲基)氨基)-N-(4-(氯二氟甲氧基)苯
基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物8)
向反应瓶中加入化合物1g(200mg，0.5mmol)，5-溴噻吩-2-甲醛(190mg，1mmol)、甲酸(2.3mg，0.05mmol)及3mL无水甲醇，50℃加热搅拌2小时，加入氰基硼氢化钠(NaBH3CN,128mg，2mmol)，室温搅拌反应1小时，加水稀释，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液洗涤，减压浓缩，经硅胶柱层析纯化得产物113.4mg，收率：39.6％。LC-MS(ESI):m/z＝573.02[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.13(s,1H),8.21(d,J＝1.9Hz,1H),7.90-7.81(m,2H),7.33-7.29(m,2H),7.21(d,J＝2.0Hz,1H),7.08(d,J＝3.7Hz,1H),6.95(d,J＝3.7Hz,1H),5.64(t,J＝5.5Hz,1H),4.93(d,J＝3.6Hz,1H),4.47(d,J＝5.4Hz,2H),4.37(d,J＝3.7Hz,1H),3.88-3.68(m,2H),3.47-3.42(m,1H),3.30-3.25(m,1H),2.05-1.77(m,2H)。
实施例9制备(R)-5-(((5-溴呋喃-2-基)甲基)氨基)-N-(4-(氯二氟甲氧基)苯
基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物9)
参照实施例8的方法，将5-溴噻吩-2-甲醛替换成5-溴-2-呋喃甲醛，制得化合物9。LC-MS(ESI):m/z＝557.04[M+H]+。
实施例10制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(((5-(羟甲基)呋喃-2-基)甲
基)氨基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物10)
参照实施例8的方法，将5-溴噻吩-2-甲醛替换成5-羟甲基糠醛，最终得产物35.0mg，收率：13.7％。LC-MS(ESI):m/z＝509.16[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.19(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.3Hz,2H),7.27(d,J＝2.0Hz,1H),6.20(s,2H),5.30(t,J＝5.8Hz,1H),5.17(t,J＝5.7Hz,1H),4.91(d,J＝3.7Hz,1H),4.36(s,2H),4.34(s,2H),3.74-3.70(m,2H),3.49-3.39(m,1H),3.31-3.26(m,1H),2.04-1.74(m,2H)。
实施例11制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-
(((5-甲氧基吡啶-3-基)甲基)氨基)烟酰胺(化合物11)
参照实施例8的方法，将5-溴噻吩-2-甲醛替换成5-甲氧基-吡啶-3-甲醛，最终得产物64.0mg，收率：24.6％。LC-MS(ESI):m/z＝520.15[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.12(s,1H),8.23(d,J＝1.7Hz,1H),8.18-8.13(m,2H),7.88-7.80(m,2H),7.39-7.35(m,1H),7.32-7.26(m,2H),7.10(d,J＝2.0Hz,1H),5.55(t,J＝5.7Hz,1H),4.93(d,J＝3.6Hz,1H),4.36(s,3H),3.81(s,5H),3.49-3.45(m,1H),3.33-3.28(m,1H),2.05-1.79(m,2H)。
实施例12制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-((吡
啶-4-基甲基)氨基)烟酰胺(化合物12)
参照实施例8的方法，将5-溴噻吩-2-甲醛替换成4-吡啶甲醛，最终得产物55.0mg，收率：22.4％。LC-MS(ESI):m/z＝490.16[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.11(s,1H),8.52(d,J＝5.0Hz,2H),8.18(d,J＝1.9Hz,1H),7.82(d,J＝2.1Hz,1H),7.80(d,J＝2.3Hz,1H),7.42-7.37(m,2H),7.31(d,J＝8.7Hz,2H),6.95(d,J＝2.0Hz,1H),5.66(t,J＝5.7Hz,1H),4.94(d,J＝3.5Hz,1H),4.40-4.36(m,3H),3.92-3.73(m,2H),3.52-3.48(m,2H),2.06-1.80(m,2H)。
实施例13制备(R)-5-(((6-溴吡啶-3-基)甲基)氨基)-N-(4-(氯二氟甲氧基)苯
基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物13)
参照实施例8的方法，将5-溴噻吩-2-甲醛替换成5-溴吡啶-3-甲醛，最终得产物127.5mg，收率：44.9％。LC-MS(ESI):m/z＝568.06[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.12(s,1H),8.43(d,J＝2.5Hz,1H),8.19(d,J＝2.0Hz,1H),7.88-7.80(m,2H),7.76-7.72(m,1H),7.63-7.58(m,1H),7.32-7.28(m,2H),7.06(d,J＝2.0Hz,1H),5.58(d,J＝5.7Hz,1H),4.92(d,J＝3.6Hz,1H),4.36(d,J＝5.6Hz,3H),3.84-3.73(m,2H),3.49-3.45(m,1H),3.33-3.29(m,1H),2.07-1.74(m,2H)。
实施例14制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-((2-羟基-5-硝基苄基)氨基)-
6-(3-羟基吡咯烷-1-基)烟酰胺(化合物14)
参照实施例8的方法，将5-溴噻吩-2-甲醛替换成5-硝基水杨醛，最终得产物98.0mg，收率：35.7％。LC-MS(ESI):m/z＝550.13[M+H]+；1H-NMR(300MHz,DMSO-d6)δ11.44(s,1H),10.14(s,1H),8.18(d,J＝1.9Hz,1H),8.11(d,J＝2.9Hz,1H),8.05(d,J＝8.9Hz,1H),7.81(d,J＝9.1Hz,2H),7.31(d,J＝8.6Hz,2H),7.08-6.94(m,2H),5.61(s,1H),4.97(s,1H),4.36(d,J＝19.7Hz,3H),3.84-3.80(m,2H),3.52-3.49(m,1H),3.33-3.28(m,1H),2.09-1.77(m,2H)。
实施例15制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(2-
硝基苯甲酰氨基)烟酰胺(化合物15)
向反应瓶中加入邻硝基苯甲酸(84mg，0.5mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU，228mg，0.6mmol)，N,N-二异丙基乙胺(DIEA，129mg，1mmol)及3mLDMF，室温搅拌1小时，加入化合物1g(200mg，0.5mmol)，室温搅拌4小时，加水稀释，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液洗涤，减压浓缩，经硅胶柱层析纯化得产物36.0mg，收率：13.16％。LC-MS(ESI):m/z＝548.12[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.36(s,1H),10.30(d,J＝1.8Hz,1H),8.73(d,J＝2.1Hz,1H),8.15-8.11(m,1H),7.99(d,J＝2.2Hz,1H),7.92-7.87(m,3H),7.82-7.76(m,2H),7.39-7.32(m,2H),5.01-4.97(m,1H),4.37(s,1H),3.82-3.71(m,3H),3.55-3.48(m,1H),2.00-1.83(m,2H)。
实施例16制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(噻
吩-2-甲酰胺基)烟酰胺(化合物16)
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参照实施例15的方法，将邻硝基苯甲酸替换成噻吩-2-甲酸,最终制得产物37.0mg，收率：14.5％。LC-MS(ESI):m/z＝509.11[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.18(s,1H),10.17(s,1H),8.72(d,J＝2.3Hz,1H),8.06-7.94(m,2H),7.94-7.81(m,3H),7.46-7.33(m,2H),7.25-7.21(m,1H),4.99(d,J＝3.3Hz,1H),4.32-4.28(m,1H),3.70-3.67(m,3H),3.55-3.43(m,1H),1.98-1.74(m,2H)。
实施例17制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(呋喃-2-甲酰氨基)-6-(3-羟
基吡咯烷-1-基)烟酰胺(化合物17)
参照实施例15的方法，将邻硝基苯甲酸替换成糠酸，最终制得产物69.0mg，收率：28.0％。LC-MS(ESI):m/z＝493.12[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.19(s,1H),10.10(s,1H),8.71(d,J＝2.3Hz,1H),7.95(m,2H),7.90-7.87(m,2H),7.39-7.28(m,3H),6.71(dd,J＝3.5,1.8Hz,1H),4.99(d,J＝3.3Hz,1H),4.32-4.29(m,1H),3.76-3.62(m,3H),3.47-3.42(m,1H),1.97-1.77(m,2H)。
实施例18制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)吡啶酰胺(化合物18)
参照实施例15的方法，将邻硝基苯甲酸替换成2-吡啶甲酸，最终制得产物59.0mg，收率：23.4％。LC-MS(ESI):m/z＝504.14[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.20(s,1H),8.80-8.67(m,2H),8.15-8.11(m,1H),8.08-8.06(m,1H),8.05-8.00(m,1H),7.94-7.84(m,2H),7.69-7.64(m,1H),7.34-7.31(m,2H),4.95(d,J＝3.4Hz,1H),4.29-4.25(m,1H),3.79-3.62(m,3H),3.47-3.42(m,1H),1.96-1.72(m,2H)。
实施例19制备N-{4-[(氯二氟甲基)氧基]苯基}-4-[(3R)-3-羟基四氢-1H-吡咯-
1-基]-3-[(吡啶-4-基羰基)氨基]苯甲酰胺(化合物19)
参照实施例15的方法，将邻硝基苯甲酸替换成异烟酸，制得化合物19。LC-MS(ESI):m/z＝504.15[M+H]+。
实施例20制备(R)-5-(5-溴烟酰胺)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯
烷-1-基)烟酰胺(化合物20)
参照实施例15的方法，将邻硝基苯甲酸替换成5-溴烟酸，制得化合物20。LC-MS(ESI):m/z＝582.03[M+H]+。
实施例21制备(R)-5-(2-溴烟酰胺)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯
烷-1基)烟酰胺(化合物21)
参照实施例15的方法，将邻硝基苯甲酸替换成2-溴烟酸，制得化合物21。LC-MS(ESI):m/z＝582.03[M+H]+。
实施例22制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(4-
硝基苯甲酰氨基)烟酰胺(化合物22)
参照实施例15的方法，将邻硝基苯甲酸替换成2-溴烟酸，最终制得产物23.0mg，收率：8.4％。LC-MS(ESI):m/z＝548.13[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.52(s,1H),10.22(s,1H),8.74(d,J＝2.2Hz,1H),8.44-8.38(m,2H),8.27-8.21(m,2H),7.99(d,J＝2.2Hz,1H),7.92-7.85(m,2H),7.39-7.30(m,2H),4.98(d,J＝3.3Hz,1H),4.30(d,J＝4.9Hz,1H),3.78-3.61(m,3H),3.53-3.44(m,1H),1.95-1.76(m,2H)。
实施例23制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(3-
(4-硝基苯基)硫脲基)烟酰胺(化合物23)
向反应瓶中加入异硫代氰基4-硝基苯酯(108mg，0.6mmol)，三乙胺(TEA，101mg，1mmol)，化合物1g(200mg，0.5mmol)和2mL无水乙醇，80℃搅拌4小时。减压浓缩，经硅胶柱层析纯化得产物162.3mg，收率：56.1％。LC-MS(ESI):m/z＝579.23[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.62(s,1H),10.16(s,1H),9.75(s,1H),8.72(d,J＝2.2Hz,1H),8.30-8.16(m,2H),7.95(d,J＝5.5Hz,2H),7.91-7.70(m,3H),7.41-7.28(m,2H),5.01(d,J＝3.3Hz,1H),4.35(s,1H),3.76-3.72(m,3H),3.55-3.51(m,1H),1.96-1.84(m,2H)。
实施例24制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(3-
(吡啶-3-基)硫脲基)烟酰胺(化合物24)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成3-吡啶基异硫氰酸酯，最终制得产物92.9mg，收率：34.7％。LC-MS(ESI):m/z＝535.22[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.15(s,1H),9.63(s,2H),8.72(d,J＝2.2Hz,1H),8.60(s,1H),8.36-8.32(m,1H),7.97(s,2H),7.94-7.86(m,2H),7.37-3.34(m,3H),4.38(s,1H),3.75-3.71(m,4H),3.57-3.52(m,1H),2.03-1.83(m,3H)。
实施例25制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(3-
(对甲苯基)硫脲基)烟酰胺(化合物25)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成对甲苯异硫氰酸酯，最终制得产物215.6mg，收率：78.8％。LC-MS(ESI):m/z＝548.12[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.14(s,1H),9.68(s,1H),9.28(s,1H),8.68(d,J＝2.2Hz,1H),7.91(d,J＝3.5Hz,2H),7.87(d,J＝2.2Hz,1H),7.36(d,J＝1.2Hz,1H),7.35-7.29(m,3H),7.16(d,J＝8.1Hz,2H),5.01(d,J＝3.3Hz,1H),4.36(s,1H),3.84-3.68(m,3H),3.55-3.51(m,1H),2.29(s,3H),1.99-1.80(m,2H)。
实施例26制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(3-
苯基硫脲基)烟酰胺(化合物26)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成硫代异氰酸苯酯，最终制得产物48.8mg，收率：18.3％。LC-MS(ESI):m/z＝534.14[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.15(s,1H),9.79(s,1H),9.37(s,1H),8.69(d,J＝2.3Hz,1H),7.93(s,1H),7.91-7.85(m,2H),7.47(d,J＝7.9Hz,2H),7.38(s,1H),7.37-7.34(m,2H),7.33-7.28(m,1H),7.21-7.13(m,1H),5.02(d,J＝3.3Hz,1H),4.36(s,1H),3.76-3.72(m,3H),3.56-3.51(m,1H),2.00-1.80(m,2H)。
实施例27制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(3-(4-氰基苯基)硫脲基)-6-
(3-羟基吡咯烷-1-基)烟酰胺(化合物27)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成4-氰基苯基异硫氰酸酯，最终制得产物59.9mg，收率：21.5％。LC-MS(ESI):m/z＝559.11[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.23(s,1H),10.16(s,1H),9.68(s,1H),8.80-8.65(m,1H),7.94(s,1H),7.89(d,J＝2.2Hz,1H),7.89-7.83(m,2H),7.79-7.74(m,3H),7.39-7.30(m,2H),5.01(d,J＝3.3Hz,1H),4.35(s,1H),3.75-3.71(m,3H),3.55-3.51(m,1H),1.96-1.82(m,2H)。
实施例28制备(R)-5-(3-(3,5-双(三氟甲基)苯基)硫脲基)-N-(4-(氯二氟甲氧
基)苯基)-6-(3-羟基吡咯烷-1-基)烟酰胺(化合物28)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成3,5-双(三氟甲基)苯基异硫氰酯，最终制得产物196.3mg，收率：58.7％。LC-MS(ESI):m/z＝670.08[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.61(s,1H),10.15(s,1H),9.74(s,1H),8.74(d,J＝2.2Hz,1H),8.29(d,J＝19.2Hz,2H),7.99(s,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝2.1Hz,1H),7.84(s,1H),7.41-7.30(m,2H),5.02(d,J＝3.2Hz,1H),4.37(s,1H),3.76-3.71(m,3H),3.56-3.51(m,1H),2.00-1.84(m,2H)。
实施例29制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(3-(4-氟苯基)硫脲基)-6-(3-
羟基吡咯烷-1-基)烟酰胺(化合物29)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成4-氟苯基异硫氰酸酯，最终制得产物81.9mg，收率：29.7％。LC-MS(ESI):m/z＝552.10[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.14(s,1H),9.67(s,1H),9.40(s,1H),8.69(d,J＝2.2Hz,1H),7.93(s,1H),7.92-7.85(m,2H),7.44(s,2H),7.35-7.31(m,2H),7.18-7.14(m,2H),5.02(d,J＝3.3Hz,1H),4.36(s,1H),3.75-3.71(m,3H),3.55-3.51(m,1H),1.98-1.82(m,2H)。
实施例30制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(3-
(4-(三氟甲基)苯基)硫脲基)烟酰胺(化合物30)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成4-(三氟甲基)异硫氰酸苯酯，最终制得产物162.5mg，收率：54.0％。LC-MS(ESI):m/z＝602.10[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.37(s,1H),10.23(s,1H),10.16(s,1H),9.62(s,1H),8.71(d,J＝2.2Hz,1H),7.95(s,1H),7.92-7.85(m,2H),7.78(s,1H),7.70(d,J＝8.5Hz,2H),7.44-7.24(m,2H),5.01(d,J＝3.3Hz,1H),4.36(s,1H),3.84-3.70(m,3H),3.56-3.51(m,1H),2.00-1.79(m,2H)。
实施例31制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(3-(3,5-二氯苯基)硫脲基)-
6-(3-羟基吡咯烷-1-基)烟酰胺(化合物31)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成3,5-二氯异硫氰酸苯酯，得到化合物31。LC-MS(ESI):m/z＝602.03[M+H]+。
实施例32制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(3-
(4-甲氧基苯基)硫脲基)烟酰胺(化合物32)
参照实施例23的方法，将异硫代氰基4-硝基苯酯替换成4-甲氧基苯基异硫氰酸酯，得到化合物32。LC-MS(ESI):m/z＝548.15[M+H]+。
实施例33制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-6-氟吡啶酰胺(化合物33)
参照实施例15的方法，将邻硝基苯甲酸替换成2-氟吡啶-6-羧酸,最终制得产物40.0mg，收率：15.3％。LC-MS(ESI):m/z＝522.11[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.19(s,1H),8.70(d,J＝2.3Hz,1H),8.25(t,J＝7.9Hz,1H),8.09(d,J＝2.1Hz,1H),7.98(d,J＝2.3Hz,1H),7.90-7.86(m,2H),7.58-7.49(m,1H),7.42-7.30(m,2H),4.95(d,J＝3.3Hz,1H),4.29(s,1H),3.67-3.61(m,3H),3.46-3.42(m,1H),1.93-1.75(m,2H)。
实施例34制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-5-氟吡啶酰胺(化合物34)
参照实施例15的方法，将邻硝基苯甲酸替换成5-氟-2-吡啶羧酸,最终制得产物53.0mg，收率：20.3％。LC-MS(ESI):m/z＝522.12[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.52(s,1H),10.19(s,1H),8.76(d,J＝2.8Hz,1H),8.70(d,J＝2.4Hz,1H),8.22-8.16(m,1H),7.99-7.94(m,2H),7.94-7.84(m,2H),7.34(d,J＝8.5Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.64(m,3H),3.46-3.42(m,1H),1.98-1.68(m,2H)。
实施例35制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-3-氟吡啶酰胺(化合物35)
参照实施例15的方法，将邻硝基苯甲酸替换成3-氟吡啶-2-羧酸,最终制得产物128.0mg，收率：49.12％。LC-MS(ESI):m/z＝522.11[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.22(s,1H),8.71(d,J＝2.3Hz,1H),8.59-8.57(m,1H),7.99-7.96(m,1H),7.97-7.92(m,1H),7.91-7.85(m,2H),7.77-7.73(m,1H),7.38-7.32(m,2H),4.97(d,J＝3.3Hz,1H),4.31(s,1H),3.73-3.65(m,3H),3.50-3.45(m,1H),1.95-1.79(m,2H)。
实施例36制备(R)-5-(2-溴异烟酰胺)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡
咯烷-1-基)烟酰胺(化合物36)
参照实施例15的方法，将邻硝基苯甲酸替换成2-溴-4-吡啶羧酸,最终制得化合物36。LC-MS(ESI):m/z＝582.03[M+H]+。
实施例37制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(6-
(三氟甲基)烟酰胺基)烟酰胺(化合物37)
参照实施例15的方法，将邻硝基苯甲酸替换成6-三氟甲基烟酸,最终制得化合物37。LC-MS(ESI):m/z＝572.11[M+H]+。
实施例38制备(R)-2,6-二氯-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-
(3-羟基吡咯烷-1-基)吡啶-3-基)烟酰胺(化合物38)
参照实施例15的方法，将邻硝基苯甲酸替换成2,6-二氯烟酸,最终制得化合物38。LC-MS(ESI):m/z＝572.05[M+H]+。
实施例39制备(R)-3,5-二氯-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-
(3-羟基吡咯烷-1-基)吡啶-3-基)吡啶酰胺(化合物39)
参照实施例15的方法，将邻硝基苯甲酸替换成1H-苯并咪唑-2-甲酸,最终制得产物78.0mg，收率：27.3％。LC-MS(ESI):m/z＝572.03[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.27(s,1H),8.77(d,J＝2.0Hz,1H),8.73(d,J＝2.3Hz,1H),8.46(d,J＝2.0Hz,1H),7.96(d,J＝2.4Hz,1H),7.92-7.86(m,2H),7.38-7.31(m,2H),4.98(d,J＝3.3Hz,1H),4.34(s,1H),3.79-3.71(m,3H),3.52-3.47(m,1H),1.95-1.83(m,2H)。
实施例40制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-6-羟基吡啶甲酰胺(化合物40)
参照实施例15的方法，将邻硝基苯甲酸替换成6-羟基吡啶-2-羧酸,最终制得化合物40。LC-MS(ESI):m/z＝520.12[M+H]+。
实施例41制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)嘧啶-2-甲酰胺(化合物41)
参照实施例15的方法，将邻硝基苯甲酸替换成嘧啶-2-羧酸,最终制得化合物41。LC-MS(ESI):m/z＝505.12[M+H]+。
实施例42制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)吡嗪-2-甲酰胺(化合物42)
参照实施例15的方法，将邻硝基苯甲酸替换成2-甲酸吡嗪,最终制得化合物42。LC-MS(ESI):m/z＝505.13[M+H]+。
实施例43制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)嘧啶-4-甲酰胺(化合物43)
参照实施例15的方法，将邻硝基苯甲酸替换成4-嘧啶甲酸,最终制得化合物43。LC-MS(ESI):m/z＝505.12[M+H]+。
实施例44制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(烟
酰胺)烟酰胺(化合物44)
参照实施例15的方法，将邻硝基苯甲酸替换成烟酸,最终制得化合物44。LC-MS(ESI):m/z＝504.12[M+H]+。
实施例45制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(异
烟酰胺)烟酰胺(化合物45)
参照实施例15的方法，将邻硝基苯甲酸替换成异烟酸,最终制得化合物45。LC-MS(ESI):m/z＝504.13[M+H]+。
实施例46制备(R)-5-溴-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟
基吡咯烷-1-基)吡啶-3-基)-2-(甲硫基)嘧啶-4-甲酰胺(化合物46)
参照实施例15的方法，将邻硝基苯甲酸替换成5-溴-2-(甲巯基)-4-嘧啶甲酸,最终制得产物96.0mg，收率：30.5％。LC-MS(ESI):m/z＝629.02[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.29(s,1H),9.02(s,1H),8.74(d,J＝2.2Hz,1H),7.94(d,J＝2.3Hz,1H),7.91-7.86(m,2H),7.35(d,J＝8.7Hz,2H),5.00(d,J＝3.3Hz,1H),4.35(s,1H),3.78-3.74(m,3H),3.57-3.52(m,1H),2.60(s,3H),1.99-1.83(m,2H)。
实施例47制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-5-甲基吡嗪-2-甲酰胺(化合物47)
参照实施例15的方法，将邻硝基苯甲酸替换成5-甲基嘧啶-2-羧酸,最终制得产物89.0mg，收率：34.3％。LC-MS(ESI):m/z＝519.13[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.61(s,1H),10.20(s,1H),9.15(d,J＝1.4Hz,1H),8.73(d,J＝1.4Hz,1H),8.71(d,J＝2.3Hz,1H),7.99(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.37-7.32(m,2H),4.95(s,1H),4.27(s,1H),3.73-3.64(m,3H),3.46-3.41(m,1H),2.65(s,3H),1.94-1.75(m,2H)。
实施例48制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(环丙烷甲酰胺基)-6-(3-羟基
吡咯烷-1-基)烟酰胺(化合物48)
向反应瓶中加入化合物1g(200mg，0.5mmol)，三乙胺(TEA，50.7mg，0.75mmol)，环丙基甲酰氯(104.9mg，1mmol)和3mL无水乙腈。室温搅拌2小时，经硅胶柱层析纯化得产物23.3mg，收率：9.9％。LC-MS(ESI):m/z＝467.12[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.40(s,1H),8.64(d,J＝2.3Hz,1H),7.91-7.85(m,2H),7.83(d,J＝2.3Hz,1H),7.34-7.31(m,2H),4.97(d,J＝3.3Hz,1H),4.32(s,1H),3.73-3.56(m,3H),3.41(m,1H),3.24-3.17(m,1H),2.31-2.08(m,4H),2.05-1.69(m,2H)。
实施例49制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(环丁烷甲酰胺基)-6-(3-羟基
吡咯烷-1-基)烟酰胺(化合物49)
参照实施例48的方法，将环丙基甲酰氯替换成环丁基甲酰氯,最终制得产物53.0mg，收率：22.0％。LC-MS(ESI):m/z＝481.15[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.82(s,1H),8.64(s,1H),7.87(d,J＝9.9Hz,3H),7.34(d,J＝8.5Hz,2H),5.00(d,J＝2.9Hz,1H),4.35(s,1H),3.70-3.65(m,3H),3.45(d,J＝11.8Hz,1H),3.24-3.18(m,1H),2.31-2.08(m,4H),2.05-1.76(m,4H)。
实施例50制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(环戊烷甲酰胺基)-6-(3-羟基
吡咯烷-1-基)烟酰胺(化合物50)
参照实施例48的方法，将环丙基甲酰氯替换成环戊基甲酰氯,最终制得产物130.0mg，收率：52.6％。LC-MS(ESI):m/z＝495.16[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.19(d,J＝4.1Hz,1H),9.52(d,J＝3.6Hz,1H),8.64(dt,J＝3.9,2.3Hz,1H),7.89-7.85(m,3H),7.35(d,J＝9.2Hz,2H),5.00-4.97(m,1H),4.34(s,1H),3.69(d,J＝9.0Hz,3H),3.44(d,J＝11.6Hz,1H),2.79-2.72(m,1H),1.97-1.80(m,4H),1.79-1.62(m,4H),1.61-1.50(m,2H)。
实施例51制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(环己烷甲酰胺基)-6-(3-羟基
吡咯烷-1-基)烟酰胺(化合物51)
参照实施例48的方法，将环丙基甲酰氯替换成环己基甲酰氯,最终制得产物18.0mg，收率：7.3％。LC-MS(ESI):m/z＝509.18[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.20(d,J＝4.2Hz,1H),9.44(d,J＝4.1Hz,1H),8.69-8.60(m,1H),7.86-7.83(m,2H),7.77(q,J＝2.4Hz,1H),7.38-7.30(m,2H),4.97(s,1H),4.33(s,1H),3.67(d,J＝13.2Hz,3H),3.43(d,J＝11.7Hz,1H),2.34(s,1H),1.94-1.58(m,8H),1.47-1.12(m,4H)。
实施例52制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(环庚烷甲酰胺基)-6-(3-羟基
吡咯烷-1-基)烟酰胺(化合物52)
参照实施例48的方法，将环丙基甲酰氯替换成环庚基甲酰氯,最终制得化合物52。LC-MS(ESI):m/z＝523.17[M+H]+。
实施例53制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(四
氢-2H-吡喃-4-甲酰胺基)烟酰胺(化合物53)
参照实施例15的方法，将邻硝基苯甲酸替换成四氢吡喃-4-甲酸,最终制得产物92.0mg，收率：36.0％。LC-MS(ESI):m/z＝511.16[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.20(s,1H),9.53(s,1H),8.65(d,J＝2.3Hz,1H),7.90-7.84(m,2H),7.79(d,J＝2.2Hz,1H),7.34(d,J＝8.8Hz,2H),4.98(d,J＝3.2Hz,1H),4.34(s,1H),3.97-3.88(m,2H),3.65-3.61(m,3H),3.47-3.38(m,1H),3.32-3.27(m,2H),2.66-2.54(m,1H),1.90-1.64(m,6H)。
实施例54制备N-(4-(氯二氟甲氧基)苯基)-6-((R)-3-羟基吡咯烷-1-基)-5-(四
氢呋喃-2-甲酰胺基)烟酰胺(化合物54)
参照实施例48的方法，将环丙基甲酰氯替换成四氢呋喃-2-甲酰氯,最终制得产物55.0mg，收率：22.17％。LC-MS(ESI):m/z＝497.13[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.19(s,1H),9.55(d,J＝2.7Hz,1H),8.66(d,J＝2.2Hz,1H),7.91-7.86(m,2H),7.83(t,J＝2.9Hz,1H),7.34(d,J＝8.8Hz,2H),4.99(t,J＝3.0Hz,1H),4.41-4.37(m,1H),4.33(s,1H),4.06-3.94(m,1H),3.84-3.80(m,1H),3.72-3.61(m,3H),3.45(t,J＝11.2Hz,1H),2.23-2.18(m,1H),2.01-1.93(m,1H),1.89-1.75(m,4H)。
实施例55制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-6-甲基吡啶酰胺(化合物55)
参照实施例15的方法，将邻硝基苯甲酸替换成6-甲基-2-吡啶甲酸,最终制得产物128.0mg，收率：49.5％。LC-MS(ESI):m/z＝518.14[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.42(s,1H),10.21(s,1H),8.69(d,J＝2.3Hz,1H),8.12(d,J＝2.2Hz,1H),7.95(d,J＝1.9Hz,1H),7.94(s,1H),7.92-7.87(m,2H),7.56-7.52(m,1H),7.34(d,J＝10.8Hz,2H),4.96(d,J＝3.4Hz,1H),4.30(s,1H),3.71-3.67(m,3H),3.47-3.43(m,1H),2.62(s,3H),1.98-1.76(m,2H)。
实施例56制备N-{4-[(氯二氟甲基)氧基]苯基}-4-[(3R)-3-羟基四氢-1H-吡咯-
1-基]-3-[(1H-吡咯-2-基羰基)氨基]苯甲酰胺(化合物56)
参照实施例15的方法，将邻硝基苯甲酸替换成吡咯-2-羧酸,最终制得化合物56。LC-MS(ESI):m/z＝492.13[M+H]+。
实施例57制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(5-羟基呋喃-2-甲酰胺基)-6-
(3-羟基吡咯烷-1-基)烟酰胺(化合物57)
参照实施例15的方法，将邻硝基苯甲酸替换成5-羟基呋喃-2-羧酸,最终制得化合物57。LC-MS(ESI):m/z＝509.11[M+H]+。
实施例58制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(5-氯呋喃-2-甲酰胺)-6-(3-
羟基吡咯烷-1-基)烟酰胺(化合物58)
参照实施例15的方法，将邻硝基苯甲酸替换成5-氯-2-糠酸,最终制得产物72.0mg，收率：27.3％。LC-MS(ESI):m/z＝527.06[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.18(d,J＝3.0Hz,2H),8.71(d,J＝2.3Hz,1H),7.94(d,J＝2.3Hz,1H),7.90-7.85(m,2H),7.41(d,J＝3.6Hz,1H),7.35(d,J＝8.8Hz,2H),6.78(d,J＝3.6Hz,1H),4.98(d,J＝3.2Hz,1H),4.32(s,1H),3.67-3.62(m,3H),3.45-3.40(m,1H),1.96-1.79(m,2H)。
实施例59制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(呋喃-3-甲酰胺基)-6-(3-羟
基吡咯烷-1-基)烟酰胺(化合物59)
参照实施例15的方法，将邻硝基苯甲酸替换成3-糠酸,最终制得化合物59。LC-MS(ESI):m/z＝493.11[M+H]+。
实施例60制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(噻
吩-3-甲酰胺基)烟酰胺(化合物60)
参照实施例15的方法，将邻硝基苯甲酸替换成3-噻吩甲酸,最终制得化合物60。LC-MS(ESI):m/z＝509.09[M+H]+。
实施例61制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(5-
甲基噻吩-2-甲酰胺)烟酰胺(化合物61)
参照实施例15的方法，将邻硝基苯甲酸替换成5-甲基-2-噻吩甲酸,最终制得产物67.0mg，收率：25.6％。LC-MS(ESI):m/z＝523.08[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.19(s,1H),10.05(s,1H),8.70(d,J＝2.3Hz,1H),7.96(d,J＝2.3Hz,1H),7.90-7.86(m,2H),7.77(d,J＝3.7Hz,1H),7.34-7.31(m,2H),6.94-6.92(m,1H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.68-3.63(m,3H),3.47-3.41(m,1H),2.51(s,3H),1.93-1.79(m,2H)。
实施例62制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(5-氯噻吩-2-甲酰胺)-6-(3-
羟基吡咯烷-1-基)烟酰胺(化合物62)
参照实施例15的方法，将邻硝基苯甲酸替换成2-氯噻吩-5-甲酸，最终制得产物79.0mg，收率：29.1％。LC-MS(ESI):m/z＝543.04[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.29(s,1H),10.19(s,1H),8.71(d,J＝2.2Hz,1H),7.98(d,J＝2.3Hz,1H),7.89-7.86(m,2H),7.85(d,J＝4.2Hz,1H),7.35(d,J＝8.7Hz,2H),7.31(d,J＝4.1Hz,1H),4.99(d,J＝3.2Hz,1H),4.32(s,1H),3.76-3.60(m,3H),3.48-3.41(m,1H),1.92-1.81(m,2H)。
实施例63制备(R)-5-(4-溴噻吩-2-甲酰胺基)-N-(4-(氯二氟甲氧基)苯基)-6-
(3-羟基吡咯烷-1-基)烟酰胺(化合物63)
参照实施例15的方法，将邻硝基苯甲酸替换成4-溴噻吩-2-甲酸，最终制得化合物63。LC-MS(ESI):m/z＝586.98[M+H]+。
实施例64制备(R)-5-(5-溴噻吩-2-甲酰胺基)-N-(4-(氯二氟甲氧基)苯基)-6-
(3-羟基吡咯烷-1-基)烟酰胺(化合物64)
参照实施例15的方法，将邻硝基苯甲酸替换成5-溴-2-羧基噻吩，最终制得产物54.0mg，收率：18.4％。LC-MS(ESI):m/z＝586.99[M+H]+；1H-NMR(400MHz,DMSO-d6)δ10.27(s,1H),10.19(s,1H),8.71(d,J＝2.3Hz,1H),7.98(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.80(d,J＝4.0Hz,1H),7.40(d,J＝4.0Hz,1H),7.37-7.32(m,2H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.73-3.62(m,3H),3.46-3.42(m,1H),1.92-1.80(m,2H)。
实施例65制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)噻唑-2-甲酰胺(化合物65)
参照实施例15的方法，将邻硝基苯甲酸替换成噻唑-2-甲酸，最终制得产物79.0mg，收率：31.0％。LC-MS(ESI):m/z＝510.08[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.64(s,1H),10.19(s,1H),8.72(d,J＝2.3Hz,1H),8.15(q,J＝3.1Hz,2H),7.99(d,J＝2.3Hz,1H),7.92-7.84(m,2H),7.39-7.31(m,2H),4.97(d,J＝3.3Hz,1H),4.30(s,1H),3.74-3.66(m,3H),3.49-3.42(m,1H),1.95-1.78(m,2H)。
实施例66制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-2-甲基噻唑-5-甲酰胺(化合物66)
参照实施例15的方法，将邻硝基苯甲酸替换成2-甲基噻唑-5-羧酸，最终制得化合物66。LC-MS(ESI):m/z＝524.09[M+H]+。
实施例67制备(R)-2-溴-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟
基吡咯烷-1-基)吡啶-3-基)噻唑-5-甲酰胺(化合物67)
参照实施例15的方法，将邻硝基苯甲酸替换成2-溴-4-噻唑羧酸，最终制得产物74.0mg，收率：25.2％。LC-MS(ESI):m/z＝587.98[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.31(s,1H),10.18(s,1H),8.70(d,J＝2.3Hz,1H),8.46(s,1H),7.93(d,J＝2.2Hz,1H),7.91-7.86(m,2H),7.39-7.29(m,2H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.73-3.60(m,3H),3.45-3.41(m,1H),1.95-1.77(m,2H)。
实施例68制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯 烷-1-基)吡啶-3-基)异噁唑-5-甲酰胺(化合物68)
参照实施例15的方法，将邻硝基苯甲酸替换成异唑-5-羧酸，最终制得产物53.0mg，收率：21.5％。LC-MS(ESI):m/z＝494.11[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.70(s,1H),10.20(s,1H),8.86(d,J＝1.9Hz,1H),8.73(d,J＝2.3Hz,1H),8.00(d,J＝2.2Hz,1H),7.93-7.83(m,2H),7.35-7.31(m,1.0Hz,2H),7.27(d,J＝2.0Hz,1H),4.99(d,J＝3.3Hz,1H),4.32(s,1H),3.66-3.61(m,3H),3.46-3.41(m,1H),1.97-1.79(m,2H)。
实施例69制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-
吡唑-4-甲酰胺)烟酰胺(化合物69)
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参照实施例15的方法，将邻硝基苯甲酸替换成1H-吡唑-4-甲酸，最终制得化合物69。LC-MS(ESI):m/z＝493.12[M+H]+。
实施例70制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-
吡唑-3-甲酰胺)烟酰胺(化合物70)
参照实施例15的方法，将邻硝基苯甲酸替换成吡唑-3-甲酸，最终制得化合物70。LC-MS(ESI):m/z＝493.12[M+H]+。
实施例71制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1-
甲基-1H-吡唑-4-甲酰胺基)烟酰胺(化合物71)
参照实施例15的方法，将邻硝基苯甲酸替换成1-甲基吡唑-4-甲酸，最终制得化合物71。LC-MS(ESI):m/z＝507.14[M+H]+。
实施例72制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1-
甲基-1H-咪唑-4-甲酰胺基)烟酰胺(化合物72)
参照实施例15的方法，将邻硝基苯甲酸替换成1-甲基-4-咪唑甲酸，最终制得化合物72。LC-MS(ESI):m/z＝507.13[M+H]+。
实施例73制备(R)-5-(苯并[b]噻吩-2-甲酰胺基)-N-(4-(氯二氟甲氧基)苯基)-
6-(3-羟基吡咯烷-1-基)烟酰胺(化合物73)
参照实施例15的方法，将邻硝基苯甲酸替换成苯并噻吩-2-羧酸，最终制得产物67.0mg，收率：24.0％。LC-MS(ESI):m/z＝559.09[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.48(s,1H),10.22(s,1H),8.74(d,J＝2.3Hz,1H),8.30(s,1H),8.12-8.06(m,1H),8.04(s,1H),8.02(d,J＝2.2Hz,1H),7.92-7.85(m,2H),7.55-7.45(m,2H),7.39-7.28(m,2H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.78-3.65(m,J＝4.1Hz,3H),3.51-3.45(m,1H),2.00-1.74(m,2H)。
实施例74制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-1H-吲哚-2-甲酰胺(化合物74)
参照实施例15的方法，将邻硝基苯甲酸替换成2-吲哚甲酸，最终制得产物78.0mg，收率：28.8％。LC-MS(ESI):m/z＝542.12[M+H]+；1H-NMR(400MHz,DMSO-d6)δ11.77(s,1H),10.22(s,1H),10.17(s,1H),8.73(d,J＝2.3Hz,1H),8.03(d,J＝2.2Hz,1H),7.94-7.85(m,2H),7.68(d,J＝8.0Hz,1H),7.47-7.42(m,1H),7.37-7.34(m,3H),7.23-7.19(m,1H),7.08-7.05(m,1H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.71-3.67(m,3H),3.50-3.45(m,1H),1.90-1.80(m,2H)。
实施例75制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-1H-吲唑-3-甲酰胺(化合物75)
参照实施例15的方法，将邻硝基苯甲酸替换成吲唑-3-羧酸，最终制得产物46.0mg，收率：16.9％。LC-MS(ESI):m/z＝543.13[M+H]+；1H-NMR(300MHz,DMSO-d6)δ13.79(s,1H),10.20(d,J＝5.5Hz,2H),8.71(d,J＝2.3Hz,1H),8.19(m,1H),8.03(d,J＝2.3Hz,1H),7.92-7.88(m,2H),7.68-7.62(m,1H),7.46-7.42(m,1H),7.37-7.32(m,2H),7.29-7.26(m,1H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.74-3.71(m,3H),3.58-3.48(m,1H),1.94-1.77(m,2H)。
实施例76制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-1H-苯并[d]咪唑-2-甲酰胺(化合物76)
参照实施例15的方法，将邻硝基苯甲酸替换成1H-苯并咪唑-2-甲酸，最终制得产物37.0mg，收率：13.6％。LC-MS(ESI):m/z＝543.13[M+H]+；1H-NMR(300MHz,DMSO-d6)δ13.46(s,1H),10.78(s,1H),10.21(s,1H),8.73(d,J＝2.2Hz,1H),8.01(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.82(d,J＝7.8Hz,1H),7.59(d,J＝7.8Hz,1H),7.38-7.32(m,4H),4.95(d,J＝3.4Hz,1H),4.29(s,1H),3.75-3.69(m,3H),3.51-3.46(m,1H),1.92-1.78(m,2H)。
实施例77制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(5-羟基烟酰胺)-6-(3-羟基吡
咯烷-1-基)烟酰胺(化合物77)
参照实施例15的方法，将邻硝基苯甲酸替换成5-羟基烟酸，最终制得化合物77。LC-MS(ESI):m/z＝520.12[M+H]+。
实施例78制备(R)-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟基吡咯
烷-1-基)吡啶-3-基)-4-氟吡啶酰胺(化合物78)
参照实施例15的方法，将邻硝基苯甲酸替换成5-氟-2-吡啶羧酸，最终制得产物57.0mg，收率：21.8％。LC-MS(ESI):m/z＝522.11[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.53(s,1H),10.19(s,1H),8.76(d,J＝2.8Hz,1H),8.70(d,J＝2.2Hz,1H),8.22-8.20(m,1H),8.01-8.98(m,2H),7.91-7.86(m,2H),7.34(d,J＝8.8Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.65(m,3H),3.46-3.42(m,1H),1.96-1.74(m,2H)。
实施例79制备(R)-4-氯-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟
基吡咯烷-1-基)吡啶-3-基)吡啶酰胺(化合物79)
参照实施例15的方法，将邻硝基苯甲酸替换成4-氯-2-吡啶甲酸，最终制得产物88.0mg，收率：32.7％。LC-MS(ESI):m/z＝538.08[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.65(s,1H),10.20(s,1H),8.75-8.71(m,1H),8.71(d,J＝2.3Hz,1H),8.14-8.11(m,1H),8.00(d,J＝2.3Hz,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝1.3Hz,2H),7.34-7.31(m,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.62(m,3H),3.47(s,1H),1.93-1.77(m,2H)。
实施例80制备(R)-N-(4-(氯二氟甲氧基)苯基)-5-(2-氯异烟酰胺)-6-(3-羟基吡
咯烷-1-基)烟酰胺(化合物80)
参照实施例15的方法，将邻硝基苯甲酸替换成2-氯异烟酸，最终制得产物93.0mg，收率：34.6％。LC-MS(ESI):m/z＝538.07[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.56(s,1H),10.22(s,1H),8.74(d,J＝2.2Hz,1H),8.67-8.65(m,1H),8.02-8.00(m,1H),7.99(d,J＝2.3Hz,1H),7.92-7.90(m,1H),7.90-7.86(m,2H),7.39-7.28(m,3H),4.97(d,J＝3.2Hz,1H),4.31(s,1H),3.65-3.62(m,3H),3.44-3.41(m,1H),1.92-1.80(m,2H)。
实施例81制备(R)-3-氯-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟
基吡咯烷-1-基)吡啶-3-基)吡啶酰胺(化合物81)
参照实施例15的方法，将邻硝基苯甲酸替换成3-氯-2-吡啶甲酸，最终制得产物48.0mg，收率：17.8％。LC-MS(ESI):m/z＝538.08[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.41(s,1H),10.27(s,1H),8.72(d,J＝2.3Hz,1H),8.66-8.63(m,1H),8.13-8.11(m,1H),7.96(d,J＝2.2Hz,1H),7.89(d,J＝9.1Hz,2H),7.64-7.61(m,1H),7.35-7.32(m,2H),4.99(d,J＝3.3Hz,1H),4.34(s,1H),3.77-3.72(m,,3H),3.54-3.50(m,1H),1.97-1.82(m,2H)。
实施例82制备(R)-6-溴-N-(5-((4-(氯二氟甲氧基)苯基)氨基甲酰基)-2-(3-羟
基吡咯烷-1-基)吡啶-3-基)吡啶酰胺(化合物82)
参照实施例15的方法，将邻硝基苯甲酸替换成6-溴-2-吡啶羧酸，最终制得产物65.0mg，收率：22.4％。LC-MS(ESI):m/z＝582.03[M+H]+；1H-NMR(300MHz,DMSO-d6)δ10.45(s,1H),10.19(s,1H),8.70(d,J＝2.3Hz,1H),8.14-8.11(m,1H),8.03-8.00(m,2H),8.00-7.93(m,1H),7.91-7.85(m,2H),7.34(m,2H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.74-3.64(m,3H),3.45-3.41(m,1H),1.95-1.79(m,2H)。
实施例83制备(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(6-
甲基烟酰胺)烟酰胺(化合物83)
参照实施例15的方法，将邻硝基苯甲酸替换成6-甲基烟酸，最终制得化合物83。LC-MS(ESI):m/z＝518.13[M+H]+。
生物活性测试
实施例84体外肿瘤细胞(K562，KBM5)抗增殖活性实验
1.以K562，KBM5人慢性髓性白血病细胞系进行实验，在1640+10％FBS(Gibco)完全培养基，置于37℃，5％CO2，95％湿度中悬浮培养。
2.以下是一般实验方法：取对数生长的K562和KBM5细胞，离心后，获得细胞沉淀，加入新鲜培养基重悬，台盘蓝染色计数，将细胞稀释到合适浓度，取50uL细胞分别种于96孔板中，3000个/孔，细胞板置于二氧化碳培养箱中过夜培养；制备待测化合物母液，所有化合物的DMSO母液为10mM，保存于-80℃，并分装使用。根据所需工作浓度，用培养基稀释化合物母液至合适浓度，取50uL待测化合物溶液加入细胞孔，且每个待测化合物设置三复孔；将细胞板置于二氧化碳培养箱中继续培养3天。
3.终点读板：每孔10uL Cell Counting Kit-8试剂，室温孵育2-4小时，酶标仪在450nm处读取吸光值，并计算细胞生长抑制效率。
4.数据处理
使用GraphPad Prism 9.0软件分析数据，利用非线性S曲线回归拟合数据得出剂量-效应曲线，并由此计算IC50值。细胞存活率(％)＝{(OD待测药-OD培养液对照)/(OD细胞对照-OD培养液对照)}×100％。
实施例中对细胞的体外抗增殖活性初筛结果归纳于下表2。
表2实施例化合物初筛的细胞毒性作用
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如表2所示，实验结果表明，本发明的化合物均具有一定的抗肿瘤细胞(K562/KBM5)增殖活性。其中，化合物16，33，35和67对于K562和KBM5表现出显著的抗增殖活性。由以上实施例可知，本发明的(杂)芳基酰胺类的部分化合物可以对人慢性髓性白血病细胞系K562，KBM5产生良好的抗增殖作用，可用于制备治疗慢性粒细胞白血病、急性粒细胞白血病等癌症的药物。
尽管已经示出了和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。
Claims (10)
1.一种如式I所示的化合物：
或其药学上可接受的盐、立体异构体，其中：
Y选自CH或N；
R1独立地选自氢、卤素、腈基、羟基，可以为单、双或多取代；
R2选自-CF2-Y1；
Y1选自氢、氯、氟、甲基、二氟甲基和三氟甲基；
Z选自化学键、O和S(O)0-2；
或者-Z-R2一起表示-SF5；
Het是吡咯烷基；其中所述吡咯烷基被1个或多个Ra基团取代；
Ra选自氢、羟基、甲基、卤素、甲氧基、羟基-甲基、氨基、甲基-氨基、氨基-甲基、三氟甲基、氰基和氨基-羰基；
Link为硫脲、
R3选自任选被一个、两个或三个R取代的以下基团：
Rb独立地选自氢、乙酰基、C1-6烷基或C1-6卤代烷基；
R独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-3烷基、C1-3卤代烷基、C1-3羟基代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基；
所述的卤素为F，Cl，或Br。
2.根据权利要求1所述的化合物，其具有式(II)：
或其药学上可接受的盐、立体异构体，其中：
R1独立地选自氢、卤素、腈基、羟基，可以为单、双或多取代；
Ra独立地选自氢、羟基、卤素、腈基、羧基，可以为单、双或多取代；Link为硫脲、
R3如权利要求1所述。
3.根据权利要求2所述的化合物，其中：
所述R1独立地选自氢和卤素；
Ra独立地选自氢和羟基；
Link为硫脲、
Rb独立地选自氢、乙酰基、C1-3烷基或C1-3卤代烷基。
4.根据权利要求1所述的化合物，其具有式(III)：
或其药学上可接受的盐、立体异构体，其中：
Ra独立地选自氢和羟基；
Link为硫脲、
R3选自任选被一个、两个或三个R取代的以下基团：
Rb独立地选自氢、乙酰基或C1-3烷基；
R如权利要求1所述。
5.根据权利要求4所述的化合物，其特征在于，
所述Ra为羟基；
Link为硫脲、
R独立地选自氢、卤素、腈基、硝基、羟基、醛基、羧基、乙酰胺基、乙氧羰基、氨基酰基、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-3烷基、C1-3卤代烷基、C1-3羟基代烷基、C1-3烷氧基、C1-3烷硫基、C1-3卤代烷氧基。
6.根据权利要求2-5任一项所述的化合物、或其药学上可接受的盐、立体异构体，所述化合物选自：
7.一种药物组合物，其含有权利要求1-6中任一项的化合物或其药学上可接受的盐、立体异构体，和药学上可接受的赋形剂。
8.如权利要求1-6中任一项的化合物或其药学上可接受的盐、立体异构体或如权利要求7所述的药物组合物在制备用于在受试者中治疗和/或预防Bcr-Abl导致的疾病的药物中的应用。
9.根据权利要求8所述的应用，其中所述Bcr-Abl导致的疾病为增殖性疾病，其选自：实体瘤、肉瘤、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病。
10.根据权利要求8所述的应用，其中所述Bcr-Abl导致的疾病为转移的浸润性癌、病毒感染或CNS障碍。
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