WO2022089454A1 - 一种高活性Wnt通路抑制剂化合物 - Google Patents
一种高活性Wnt通路抑制剂化合物 Download PDFInfo
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- WO2022089454A1 WO2022089454A1 PCT/CN2021/126539 CN2021126539W WO2022089454A1 WO 2022089454 A1 WO2022089454 A1 WO 2022089454A1 CN 2021126539 W CN2021126539 W CN 2021126539W WO 2022089454 A1 WO2022089454 A1 WO 2022089454A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 317
- 230000000694 effects Effects 0.000 title claims abstract description 16
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 65
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
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- 229950011257 veliparib Drugs 0.000 description 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229950003081 volasertib Drugs 0.000 description 1
- SXNJFOWDRLKDSF-STROYTFGSA-N volasertib Chemical compound C1CN([C@H]2CC[C@@H](CC2)NC(=O)C2=CC=C(C(=C2)OC)NC=2N=C3N(C(C)C)[C@@H](C(N(C)C3=CN=2)=O)CC)CCN1CC1CC1 SXNJFOWDRLKDSF-STROYTFGSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000012447 xenograft mouse model Methods 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Images
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- C07D471/12—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 three hetero rings
- C07D471/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D471/14—Ortho-condensed systems
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Abstract
提供了一种具有式(I)结构的抑制Wnt通路活性的化合物、包含所述化合物的药物组合物以及所述化合物在预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病中的用途。
Description
本申请要求于2020年10月28日提交到中国专利局的发明名称为“一种高活性Wnt通路抑制剂化合物”的中国专利申请202011175894.X的优先权,其内容通过引用以整体并入本文。
本发明涉及一种杂环化合物,具体地涉及一种高活性的Wnt通路抑制剂及其用途。
Wnt/β-catenin信号转导通路是一条在生物进化中保守的通路。在正常的体细胞中,β-catenin只是作为一种细胞骨架蛋白在胞膜处与E-cadherin形成复合体对维持同型细胞的黏附、防止细胞的移动发挥作用。当Wnt信号通路未被激活时,细胞质内的β-catenin被磷酸化与APC、Axin和GSK3β等构成β-catenin降解复合物,启动泛素系统经蛋白酶体途径降解β-catenin,使细胞质内的β-catenin维持在较低水平。当细胞受到Wnt信号刺激时,Wnt蛋白与细胞膜上特异性受体Frizzled蛋白结合,激活后的Frizzled受体招募胞内Dishevelled蛋白,抑制GSK3β等蛋白形成的β-Catenin降解复合物的降解活性,稳定细胞质中游离状态的β-Catenin蛋白。胞浆中稳定积累的β-Catenin进入细胞核后结合LEF/TCF转录因子家族,启动下游靶基因(如c-myc、c-jun,Cyclin D1等)的转录。Wnt/β-catenin信号通路的过渡激活与多种癌症(包括结肠癌、胃癌、乳腺癌等)的发生密切相关。例如结直肠癌中广泛存在Wnt经典信号通路的异常激活和β-catenin蛋白的核内积聚现象,而通过抑制Wnt信号通路活性可以抑制结肠癌增殖。85%以上的结直肠癌中均存在APC的突变,突变后的APC阻断β-catenin磷酸化降解,诱导结直肠癌的发生。此外,Axin突变、β-catenin自身突变也可引起β-catenin的胞内聚集,活化Wnt/β-catenin通路。
发明内容
本发明提供了一种具有式(I)结构的抑制Wnt通路活性的化合物及药学上可接受的盐、同位素衍生物、立体异构体:
其中:---表示存在或者不存在;
R
1表示C
1-C
6烷基、C
3-C
6环烷基、C
6-C
10芳基、5-10元杂芳基,并且所述的R
1可以任意地被0、1、2、3个选自:氢、卤素、ORa、卤代(C
1-C
6)烷基、(C
3-C
6)环烷基、卤代(C
3-C
6)环烷基、氰基、SR
a、卤代(C
1-C
6)烷氧基、卤代(C
3-C
6)环烷氧基、卤代(C
1-C
6)烷基硫基、(C
3-C
6)环烷基氧基、(C
3-C
6)环烷基硫基、卤代(C
3-C
6)环烷硫基的取代基所取代;
X表示-(CR
aR
a’)
m-、-(CR
aR
a’)
m O(CR
aR
a’)
n-、-(CR
aR
a’)
m S(CR
aR
a’)
n-;
Cy表示C
6-C
10芳基或者5-10元杂芳基,并且其可以任意地被0、1、2、3个选自:氢、卤素、-ORa、(C
1-C
6)烷基、卤代(C
1-C
6)烷基、(C
3-C
6)环烷基、氰基、羟基(C
1-C
6)烷基;
R
2表示氢、(C
1-C
6)烷基、卤代(C
1-C
6)烷基、(C
3-C
6)环烷基、羟基(C
1-C
6)烷基;R
3和R
3’各自独立地表示氢,卤素、OR
a、(C
1-C
6)烷基、(C
3-C
6)环烷基、羟基(C
1-C
6烷基)、(C
1-C
6)烷氧基(C
1-C
6)烷基;
或者R
3和R
3’一起与与之相连的碳原子形成3-6元饱和或者不饱和的环,该环中还可以任意地含有1、2个选自O、S、N的杂原子;并且该环还可以任意地被0、1、2个卤素、羟基、C
1-C
6烷基所取代;
或者R
2、R
3或者R
2’、R
3一起与其相连的原子形成4-6元饱和或者不饱和的环,该环中还可以任意地含有1、2个选自O、S、N的杂原子;并且该环还可以任意地被0、1、2个卤素、羟基、C
1-C
6烷基所取代;
R
4和R
4’各自独立地表示氢、C
1-C
6烷基、C
3-C
6环烷基、羟基(C
1-C
6烷基)、卤代(C
1-C
6烷基)、(C
1-C
6)烷氧基(C
1-C
6)烷基;
或者R
4与R
4’一起形成=O;
R
T和R
T’各自独立地表示氢、C
1-C
6烷基、卤代(C
1-C
6烷基)、羟基C
1-C
6烷基、C
3-C
6环烷基、卤素、OR
a;
或者R
T和R
T’一起与与其相连的原子形成3-6元环;
其中,当---表示不存在时,A表示(CR
LR
L’)
p,其中R
L和R
L’各自独立地表示氢、C
1-C
6烷基、卤代(C
1-C
6烷基)、羟基(C
1-C
6烷基)、C
3-C
6环烷基、卤素、OR
a、或者R
L和R
L’一起与与其相连的碳原子形成3-6元环,该环中可以任意地含有0、1、2个选自O、S、N的杂原子,并且该环还可以任意地被0、1、2个卤素、羟基所取代;
其中,当---表示存在时,A表示CR
H,其中,R
H表示氢、C
1-C
6烷基、卤代(C
1-C
6烷基)、羟基(C
1-C
6烷基)、C
3-C
6环烷基、卤素、OR
a;
其中,R
a、R
a’各自独立地表示氢和C
1-C
6烷基;
其中m、n、p各自独立地表示0、1、2。
在一个实施方案中,其中X表示-O-、-CH
2-、-OCH
2或-CH
2CH
2-。
在一个实施方案中,其中Cy表示被0、1、2个选自(C
1-C
6)烷基、(C
3-C
6)环烷基、卤代(C
1-C
6烷基)、-OR
a、卤素、氰基、NR
aR
a’、羟基(C
1-C
6)烷基取代的吡唑基、吡啶基、吡嗪基、嘧啶基、咪唑基、苯基;其中,R
a、R
a’各自独立地表示氢和C
1-C
6烷基。
在一个实施方案中,其中R
1表示(C
1-C
6)烷基、(C
3-C
6)环烷基、(C
6-C
10)芳基、(5-10)元杂芳基,其任意地被0、1、2个选自卤素、OR
a、(C
1-C
6)烷基、卤代(C
1-C
6烷基)的取代基所取代;其中,R
a表示氢和C
1-C
6烷基。
在一个实施方案中,其中R
2表示氢或者(C
1-C
6)烷基。
在一个实施方案中,其中R
3和R
3’各自独立地表示氢或者(C
1-C
6)烷基。
在一个实施方案中,其中R
4与R
4’一起形成=O。
优选地,本发明的化合物具有如下结构:
特别注意的是,在本文中,当提及具有特定结构式的“化合物”时,一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。
本领域技术人员公知,一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式,它们都可以在一定条件下转化为所述化合物,因此,特别注意的是在本文中当提到一种化合物时,一般地还包括它的可药用盐,进而还包括其溶剂合物和水合物。
相似地,在本文中当提到一种化合物时,一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐可使用例如以下的无机酸或有机酸而形成:“可药用盐”是指这样的盐,在合理的医学判断范围内,其适用于接触人和较低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐,或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐,如下概述。例如,游离碱功能可以与合适的酸反应。此外,当本发明的化合物带有酸性部分,其合适的可药用盐可包括金属盐,例如碱金属盐(如钠盐或钾盐);和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如,盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如,醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环 戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、hernisulfate、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠、锂、钾、钙、镁等的盐。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的胺阳离子,例如,卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈),向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐。
本发明所述的前体或代谢物可以本领域公知的前体或代谢物,只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药,在合理的医学判断范围内,其适用于接触人和更低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物,例如通过在体内代谢,或本发明化合物的N-去甲基化。
本发明所述的“溶剂合物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中,例如当一个或多个溶剂分子纳入结晶固体的晶格中时,溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构,构型异构还可分为顺反 异构和旋光异构(即光学异构),构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象,常见的有烷烃和环烷烃类化合物的结构,如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心,每个不对称中心会产生两个光学异构体,本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在,其通过一个或多个双键位移而具有不同的氢的连接点。例如,酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等,均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是:氢同位素,
2H和
3H;碳同位素:
11C,
13C和
14C;氯同位素:
35Cl和
37Cl;氟同位素:
18F;碘同位素:
123I和
125I;氮同位素:
13N和
15N;氧同位素:
15O,
17O和
18O和硫同位素
35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘
3H和碳
13C,由于它们容易标记且方便检测,运用更为广泛。某些重同位素,比如重氢(
2H),的取代能增强代谢的稳定性,延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始,用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
本发明还提供了本发明化合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
此外,本发明提供了用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物,其包含本发明化合物作为活性成分。
此外,本发明提供了一种用于预防和/或治疗癌症、肿瘤、炎症性疾病、自 身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法,其包括向有此需要的哺乳动物施用本发明化合物。
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于,关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、盆腔炎性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。
癌症或肿瘤的代表性实例可包括但不限于,皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂 肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或免疫检查点抑制剂组合施用时,本发明化合物或其可药用盐可提供增强的抗癌作用。
用于治疗癌症或肿瘤的抗癌剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、PI3K抑制剂、CSF1R抑制剂、A2A和/或A2B受体拮抗剂、IDO抑制剂、抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体及抗CTLA-4抗体或其任意组合。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时,本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于,甾体药物(例如,强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如,依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如,他克莫司、吡美莫司等)和抗组胺药(例如,苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等),并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用,其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天,并且每天以单次或4次分次剂量,或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下,小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
除此之外,本发明还提供了一种预防和/或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法,其包括向有此需要的哺乳动物施用本发明的化合物或本发明的药物组合物。
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径、瘤内注射)的剂型,例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备:纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。在本发明的注射组合物中采用的载体的实例是水、盐溶液、葡萄糖溶液、葡萄糖样溶液(glucose-like solution)、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。
本发明描述示例性实施方案的过程中,本发明的其它特征将变得显而易见,给出所述实施方案用于说明本发明而不意欲成为其限制,以下实施例使用本发明 所公开的方法制备、分离和表征。
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物,可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解,分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。
图1显示了化合物11对人骨髓瘤细胞NCI-H929 SCID异种移植瘤肿瘤体积的影响。
术语
如果无另外说明,用于本发明申请,包括说明书和权利要求书中的术语,定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
在说明书和权利要求书中,给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明,否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C=C双键、C=N双键、环系统等的许多几何异构体,且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体,且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时,其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件,以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话,则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化 成盐;可将盐转化成游离化合物或另一种盐;可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在,其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是,可存在的所有互变异构体形式均包括在本发明内。
除非另有定义,本发明的取代基的定义是各自独立而非互相关联的,例如对于取代基中R
a(或者R
a’)而言,其在不同的取代基的定义中是各自独立的。具体而言,对于R
a(或者R
a’)在一种取代基中选择一种定义时,并不意味着该R
a(或者R
a’)在其他取代基中都具有该相同的定义。更具体而言,例如(仅列举非穷举)对于NR
aR
a’中,当R
a(或者R
a’)的定义选自氢时,其并不意味着在-C(O)-NR
aR
a’中,R
a(或者R
a’)必然为氢。
除非另有定义,否则当取代基被标注为“任选取代的”时,所述取代基选自例如以下取代基,诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO
2NH
2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH
2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基,例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如,“C
1-C
6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如,“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如,“C
2-C
6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C
1-C
6烷氧基”(或烷基氧基)意欲包括C
1、C
2、C
3、C
4、C
5、C
6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地,“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基;例如甲基-S-和乙基-S-。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C=O)。
术语“芳基”,单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分,是指具有总计5至12个环成员的单环、二环或三环的环系统,其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。在本发明的某些实施方案中,“芳基”是指芳族环系统,其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环系统中画出的虚线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C
3-C
8的环状烷基,包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C
3-C
8的环状烯基,包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或融合环的环状烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原 子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如,“卤代C
1-C
6烷氧基”意欲包括C
1、C
2、C
3、C
4、C
5、C
6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地,“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基;例如三氟甲基-S-和五氟乙基-S-。
本公开内容中,当提到一些取代基团时使用C
x1-C
x2的表述,这表示所述取代基团中的碳原子数可以是x1至x2个。例如,C
0-C
8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子,C
1-C
8表示所述基团含有1、2、3、4、5、6、7或8个碳原子,C
2-C
8表示所述基团含有2、3、4、5、6、7或8个碳原子,C
3-C
8表示所述基团含有3、4、5、6、7或8个碳原子,C
4-C
8表示所述基团含有4、5、6、7或8个碳原子,C
0-C
6表示所述基团含有0、1、2、3、4、5或6个碳原子,C
1-C
6表示所述基团含有1、2、3、4、5或6个碳原子,C
2-C
6表示所述基团含有2、3、4、5或6个碳原子,C
3-C
6表示所述基团含有3、4、5或6个碳原子。
本公开内容中,当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述,这表示该基团的环原子数可以是x1至x2个。例如,所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环,其环原子数可以是3、4、5、6、7、8、9、10、11或12个;3-6元环表示该环状基团可以是3、4、5或6元环,其环原子数可以是3、4、5或6个;3-8元环表示该环状基团可以是3、4、5、6、7或8元环,其环原子数可以是3、4、5、6、7或8个;3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环,其环原子数可以是3、4、5、6、7、8或9个;4-7元环表示该环状基团可以是4、5、6或7元环,其环原子数可以是4、5、6或7个;5-8元环表示该环状基团可以是5、6、7或8元环,其环原子数可以是5、6、7或8个;5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环,其环原子数可以是5、6、7、8、9、10、11或12个;6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环,其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子,例如选自N、O和S的杂原子。当所述环是杂环时,所述杂环可以含有1、 2、3、4、5、6、7、8、9、10或更多个环杂原子,例如选自N、O和S的杂原子。
本公开内容中,一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
术语“杂芳基”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环,其为完全不饱和的、部分不饱和的,且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子;且包括任何以下多环基团,其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR,其中R为H或如果被定义,则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的,则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地,当杂环中S和O原子的总数超过1时,则这些杂原子彼此不相邻。优选地,杂环中S和O原子的总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎 宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构,例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”;其中本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系,或为一个二环杂环烷基体系,同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S、P的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基融合到一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成;后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物,该环中至少含一个选自O、N、S原子。可分为二环桥环杂环及多环桥杂环。
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃,该环中至少含一个选自O、N、S原子。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代,条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C=C、C=N或N=N)。
在本发明化合物上存在氮原子(例如胺)的情形下,可通过使用氧化剂(例如 mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此,所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时,其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此,例如如果显示基团取代有0-3个R,则所述基团可任选地取代有至多三个R基团,且在每次出现时R独立地选自R的定义。此外,取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外,术语“治疗有效量”意指这样的量:与未接受上述量的相应受试者相比,所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用,或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果,例如减轻、减少、调节、改善或消除,或改善其症状。
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/或剂型:在合理医学判断的范围内,其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症,并与合理的益处/风险比相称。
本文使用的短语“药用载体”意指药用物质、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质,其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺 乳动物)的介质,包括(即)佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂,这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”,如本文所用,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“癌症”,如本文所用,指一种不能控制的细胞的异常生长,并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于,实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语,如本文所用,指将几种所选的治疗药物给一个病人用药,以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”,如本文所用,指预期的结果能够在效价或是持续时间方面都有增加或延长。因此,在增强药物的治疗效果方面,术语“能增强”指药物在系统中有提高或延长效价或持续时间的能力。本文所用的“增效值”,指在理想的系统中,能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于,哺乳类:人、非人灵长类如猩猩、猿及猴类;农业动物如牛、马、山羊、绵羊、猪;家畜如兔、狗;实验动物包括啮齿类,如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于,鸟、鱼等。在一优选例中,所选哺乳动物是人。
术语“治疗”、“治疗过程”或“疗法”如本文所用,包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善或预防潜在代谢综合症;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或预防和/或治疗由疾病或症状引起的征兆。
如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或 情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药,可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于,口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外,仅作举例说明,肠道外给药,包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。
在一方面,此处描述的化合物给药方式是局部的而不是全身性的给药方式。在特定的具体实施例中,长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外,在另一具体化实施例中,药物通过靶向药物给药系统来给药。例如,由器官特异性抗体包裹的脂质体。在这种具体实施例中,所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本发明还提供药用组合物,其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物,和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途,例如口服,诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液;经舌下;含服;经肠胃外,诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式);经鼻,包括向鼻膜给药,诸如通过吸入喷雾;局部,诸如以乳膏剂或软膏剂形式;或经直肠,诸如以栓剂形式;或经瘤内注射。它们可单独给药,但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括,但不限于:所调配活性剂的类型和性质;含有活性剂的组合物所要给药的受试者;组合物的预期给药途径;及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂,上述其它成分出于本领域技术人员公知的各种原因包括于制剂中,例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源,例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。
当然,本发明化合物的剂量方案取决于已知因素而有所变化,诸如具体药剂的药效学特性及其给药模式和途径;接受者的物种、年龄、性别、健康状况、医学病状和重量;症状的性质和程度;同时治疗的种类;治疗频率;给药途径、患者的肾和肝功能及期望效应。根据一般指导,当用于指定效应时,各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天,优选地为约0.01mg/天至约1000mg/天,且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间,静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药,或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中,以组合物的总重量计,活性成分通常将以约0.1-95重量%的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60目网筛,并包装成1号明胶胶囊。
典型的可注射制剂可如下制备:以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用,将瓶内容物与2mL生理盐水混合,以产生可注射制剂。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地,本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径,通过本领域技术人员已知的常规方法来将本发的化合 物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平,从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素,包括所用的本发明的特定化合物或其酯、盐或酰胺的活性;给药路径;给药时间;所用的特定化合物的排泄速率;吸收速率和程度;治疗的持续时间;与所用的特定化合物组合使用的其它药物、化合物和/或物质;所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如,为了达到所期望的治疗效果,医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量,并逐步增加剂量直至实现所期望的效果。通常,合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常,口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话,有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药,任选地呈单位剂型形式。在本发明的某些方面中,服药为每天一次给药。
虽然本发明化合物可单独给药,但优选以药物制剂(组合物)形式给予化合物。试剂盒/产品包装
为了用于上述适应症的治疗,试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成,容器盒可被划分成多格,以容纳一种或多种容器,如管形瓶、试管及类似物等,每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子,管形瓶,注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲,容器可装有一种或多种在此所述的化合物,化合物可能以药物组分形式存在,也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶,瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物,及本文中所述的使用方法的说明、标签或操作 说明。
一个典型的试剂盒可包括一种或多种容器,为适应商业推广和使用者对化合物使用的需求,每个容器装有一种或多种材料(如试剂,也可以是浓缩的母液,和/或器械)。这些材料包括但不局限于缓冲液,稀释液,滤器,针头,注射器,输送器,包,容器,瓶和/或试管,附有内容清单和/或使用说明书,内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上;标签也可出现在装有多种容器的容器盒或运输盒内,如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明,诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤,均有可能以任意一种组合存在,除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的,例如是指在100毫升的溶液中溶质的重量。除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例
通用过程
未包括制备途径时,本发明所用原料与试剂均为已知产品,可以按照本领域已知 的方法合成,或者可通过购买市售产品获得。使用的市售试剂均不需进一步纯化。室温是指20-30℃。
反应实施例中无特殊说明,反应均在氮气氛下进行。氮气氛是指反应瓶连接一个约1L的氮气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。氢气氛是指反应瓶连接一个约1L的氢气气球。
本发明化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10
-6(ppm)的单位给出。NMR的测定是用(Bruker Ascend
TM 500型)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS)。以下简写用于NMR信号的多重性:s=单峰,brs=宽峰,d=二重峰,t=三重峰,m=多重峰。耦合常数以J值列出,以Hz测量。
LC-MS的测定使用Thermo液质联用仪(UltiMate 3000+MSQ PLUS)。HPLC的测定使用Thermo高压液相色谱仪(UltiMate 3000)。反相制备色谱使用Thermo(UltiMate 3000)反相制备色谱仪。快速柱层析使用艾杰尔(FS-9200T)自动过柱机,硅胶预装柱使用三泰
预装柱。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
实施例1
(S)-4,5-二甲基-2-(((1-((6-(三氟甲基)吡啶-3-yl)甲基)-1H-吡唑-4-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物1由以下步骤制备:
第一步:将6-三氟甲基-3-吡啶甲醇1a(4.0g,22.58mmol)溶于二氯甲烷(20mL)中,在冰浴条件下滴加氯化亚砜(26.87g,225.83mmol,16.38mL),加完后反应升至室温,并在55℃条件下搅拌过夜。反应液浓缩得到粗品黄色的油状物1b(4.4g,收率99%)。ESI-MS(m/z):196.5[M+H]
+。
第二步:将化合物1b(4.4g,22.48mmol),化合物1c(1.8g,18.73mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(6.47g,46.83mmol),在室温条件下搅拌过夜。反应液用乙酸乙酯稀释,依次用水和饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到黄色固体1d(4.5g,收率94%)。ESI-MS(m/z):256.4[M+H]
+。
第三步:将化合物1d(4.5g,17.63mmol)和盐酸羟胺(1.73g,26.45mmol)溶于乙醇(20mL)中,在室温条件下搅拌过夜。向反应液中加入锌粉(4.58g,70.53mmol)和醋酸(50mL)加热至70℃反应过夜。反应结束后,减压蒸掉大部分的溶剂,残余物用2N的氢氧化钠调节pH值为11-12,过滤。滤液用二氯甲烷萃取三次,有机相合并,无水硫酸钠干燥,过滤浓缩得到黄色油状物1e(3.5g,收率77%)。ESI-MS(m/z):257.6[M+H]
+。
第四步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.7g,8.50mmol)和(S)-2-(甲基氨基)丙酸甲酯盐酸盐1g(1.70g,11.05mmol)溶解于四氢呋喃(40mL)中,加入三乙胺(2.58g,25.50mmol,3.53mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析纯化,得到黄色油状物1h(1.1g,收率46%)。ESI-MS(m/z):281[M+H]
+。
第五步:将化合物1h(1.1g,3.92mmol)溶解于四氢呋喃(20mL)中,加入盐酸水溶液(6N,0.65mL)和二氧化铂(88mg,0.39mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析纯化,得到白色固体1i(900mg,收率90%)。ESI-MS(m/z):253[M+H]
+。
第六步:将化合物1i(300mg,1.19mmol),化合物1e(395mg,1.54mmol),Pd
2(dba)
3(217mg,0.23mmol),t-BuONa(342mg,3.56mmol)和X-Phos(113mg,0.23mmol)分散于甲苯(10mL)中,反应体系置换氮气后加热至100℃反应16小时,LCMS监测反应结束。反应液浓缩,残余物通过硅胶柱层析纯化,得到的粗品再通过制备HPLC纯化得到白色固体1(143mg,收率25%)。ESI-MS(m/z):473.2[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.61(s,1H),8.13(s,1H),7.86(d,J=8.0Hz,1H),7.82(dd,J=8.0,1.5Hz,1H),7.74(s,1H),7.41(s,1H),6.67(t,J=5.5Hz 1H),5.43(s,2H),4.28-4.16(m,2H),4.10(q,J=7.0Hz,1H),4.04-3.96(m,1H),3.30-3.20(m,1H),2.93(s,3H),2.54-2.50(m,2H),1.95-1.85(m,1H),1.84-1.70(m,1H),1.21(d,J=7.0Hz,3H)。
实施例2
(R)-4,5-二甲基-2-(((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
用(S)-2-(甲基氨基)丙酸甲酯盐酸盐替换实施例1中第四步的(R)-2-(甲基氨基)丙 酸甲酯盐酸盐1g,用类似的方法和反应步骤,可以得到化合物2。ESI-MS(m/z):473.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.63(s,1H),8.17(s,1H),7.89(d,J=8.0Hz,1H),7.85(d,J=8.5Hz,1H),7.77(s,1H),7.44(s,1H),6.69(t,J=5.0Hz,1H),5.46(s,2H),4.33-4.18(m,2H),4.12(q,J=7.0Hz,1H),4.07-4.00(m,1H),3.31-3.24(m,1H),2.95(s,3H),2.56-2.52(m,2H),1.98-1.90(m,1H),1.85-1.75(m,1H),1.23(d,J=6.5Hz,3H)。
实施例3
6-甲基-4-(((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)氨基)-7,8-二氢-3,5,6,9a-四氮杂苯并[cd]薁-9(6H)-酮
化合物3由以下步骤制备:
第一步:将化合物3a(5.0g,26.59mmol),三乙胺(5.38g,53.19mmol)和4-二甲氨基吡啶(324mg,2.66mmol)溶于二氯甲烷(50mL),室温下滴加二碳酸二叔丁酯(6.38g,29.25mmol),并搅拌过夜,LCMS监测反应结束。反应液浓缩,残余物通过硅胶柱层析纯化,得到化合物3b(5.3g,收率69%)。ESI-MS(m/z):288.4[M+H]
+。
第二步:将化合物3b(1.0g,3.48mmol),3-(甲氨基)丙酸乙酯3c(0.55g,4.2mmol)和N,N-二异丙基乙胺(1.35g,10.4mmol)溶于四氢呋喃(10mL)中,在50℃条件下搅拌过夜,TLC监测反应结束。反应液浓缩,残余物通过硅胶柱层析纯化,得到无色油状物3d(1.33g,收率100%)。ESI-MS(m/z):383.2[M+H]
+。第三步:将化合物3d(1.3g,3.40mmol),化合物1e(1.04g,4.07mmol)溶于正丁醇(5mL)中,加入三氟乙酸(0.13mL,1.7mmol),反应液用微波加热至150℃反应5小时,LCMS监测反应结束。反应液浓缩,残余物通过硅胶柱层析纯化,得到褐色固体3e和3f的混合物(0.8g),直接用于下一步反应。ESI-MS(m/z):503.3[M+H]
+,531.3[M+H]
+。
第四步:将上一步产物(300mg)溶于四氢呋喃(5mL)中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.18mL,1.2mmol),氮气保护下在70℃反应16小时,LCMS监测反应结束。反应液浓缩,残余物通过制备HPLC制备得到白的固体3(4mg)。ESI-LCMS(m/z):457.2[M+H]
+;
1HNMR(500MHz,DMSO-d
6)δ8.63(s,1H),7.90-7.82(m,3H),7.78(s,1H),7.44(s,1H),6.64(t,J=6.1Hz,1H),6.47(d,J=3.7Hz,1H),5.45(s,2H),4.32(d,J=6.1Hz,2H),3.68-3.61(m,2H),3.16(s,3H),3.14-3.09(m,2H)。
实施例4,5和6
6,7-二甲基-4-(((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)氨基)-7,8-二氢-3,5,6,9a-四氮杂苯并[cd]薁-9(6H)-酮
(R)-6,7-二甲基-4-(((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)氨基)-7,8-二氢-3,5,6,9a-四氮杂苯并[cd]薁-9(6H)-酮
(S)-6,7-二甲基-4-(((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)氨基)-7,8-二氢-3,5,6,9a-四氮杂苯并[cd]薁-9(6H)-酮
化合物4,5和6由以下步骤制备:
第一步:将化合物3b(1.0g,3.5mmol)和3-(甲氨基)丁酸乙酯4a(0.6g,4.2mmol)溶解在四氢呋喃(10mL)中,加入N,N-二异丙基乙胺(1.35g,10.4mmol)。50℃反应过夜,TLC监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得到黄色固体4b(1.22g,收率89%)。ESI-MS(m/z):397.3[M+H]
+。
第二步:将化合物4b(1.17g,2.9mmol)溶于正丁醇(5mL)中,加入三氟乙 酸(0.2mL,2.9mmol),体系用微波加热至150℃反应5h,LCMS监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得褐色固体4c和4d的混合物(1.1g),直接用于下一步反应。ESI-MS(m/z):517.2[M+H]
+,545.5[M+H]
+。
第三步:将上一步得到的4c和4d混合物(320mg)溶于四氢呋喃(5mL)中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.18mL,1.2mmol)。70℃搅拌过夜,LC-MS监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得白色固体4(110mg,收率38%)。ESI-MS(m/z):471.0[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.61(s,1H),7.88-7.81(m,3H),7.76(s,1H),7.43(s,1H),6.64(br s,1H),6.44(d,J=3.6Hz,1H),5.43(s,2H),4.30(d,J=5.9Hz,2H),3.96-3.88(m,1H),3.37(d,J=16.1Hz,1H),3.16(s,3H),3.00(dd,J=16.0,6.7Hz,1H),1.10(d,J=6.8Hz,3H)。
第四步:消旋体化合物4(102mg)用手性柱拆分得到化合物5(P1,50mg)和化合物6(P2,40mg)。
化合物5:手性柱保留时间=5.62min(ICH column,HEP:IPA(0.1%DEA)=60:40);ESI-MS(m/z):471.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.63(s,1H),7.89-7.83(m,3H),7.78(s,1H),7.44(s,1H),6.64(t,J=6.1Hz,1H),6.45(d,J=3.6Hz,1H),5.45(s,2H),4.31(d,J=6.0Hz,2H),3.98-3.89(m,1H),3.38(d,J=15.9Hz,1H),3.18(s,3H),3.02(dd,J=16.0,6.7Hz,1H),1.12(d,J=6.8Hz,3H)。
化合物6:手性柱保留时间=6.24min(ICH column,HEP:IPA(0.1%DEA)=60:40);ESI-MS(m/z):471.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.63(s,1H),7.89-7.83(m,3H),7.78(s,1H),7.45(s,1H),6.64(t,J=5.7Hz,1H),6.46(d,J=3.6Hz,1H),5.45(s,2H),4.32(d,J=6.0Hz,2H),3.98-3.87(m,1H),3.38(d,J=16.0Hz,1H),3.18(s,3H),3.02(dd,J=16.0,6.7Hz,1H),1.12(d,J=6.8Hz,3H)。
实施例7
(S)-4,5-二甲基-2-(((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物7由以下步骤制备:
第一步:将1H-吡唑-4-甲醛1c(5g,52.04mmol)溶于N,N-二甲基甲酰胺(20mL)中,依次加入Cs
2CO
3(33.91g,104.07mmol)和2,2,2-三氟乙基三氟甲烷磺酸酯(18.12g,78.05mmol)。室温反应4小时后,TLC显示原料转化完全。反应液用乙酸乙酯稀释,饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩得到化合物7a(8.0g),直接用于下一步反应。
第二步:将上一步得到的化合物7a(8.0g)溶于乙醇(20mL)中,加入盐酸羟胺(6.24g,89.83mmol),反应液室温搅拌过夜。反应液浓缩,得到粗品肟,重新溶解于醋酸(50mL)中,加入锌粉(17.47g,267.18mmol)。反应液在60℃反应2小时,LC-MS监测反应已转化完全。将反应液冷却至室温,加入乙酸乙酯稀释,用NaOH溶液(2N)碱化至pH=10。将混合物过滤,滤液浓缩得化合物7b(4.5g),直接用于下一步反应。
第三步:将化合物1i(200mg,0.79mmol),化合物7b(212mg,1.19mmol),Pd
2(dba)
3(144mg,0.15mmol),t-BuONa(228mg,2.37mmol)和X-Phos(75mg,0.15mmol)分散于甲苯(10mL),反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析纯化,得到的粗品再通过制备HPLC纯化得到白色固体7(71mg,收率22%)。ESI-MS(m/z):396.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.13(s,2H),7.67(s,1H),7.46(s,1H),6.74(t,J=5.0Hz,1H),5.03(q,J=9.0Hz,2H),4.30-4.17(m,2H), 4.11(q,J=7.0Hz,1H),4.04-3.96(m,1H),3.29-3.21(m,1H),2.94(s,3H),2.53-2.50(m,2H),1.96-1.88(m,1H),1.86-1.75(m,1H),1.21(d,J=7.0Hz,3H)。
实施例8
(S)-4,5-二甲基-2-(((6-(三氟甲氧基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物8由以下步骤制备:
第一步:将化合物1i(80mg,0.31mmol),6-(三氟甲氧基)吡啶-3-甲胺盐酸盐8a(94mg,0.41mmol),Pd
2(dba)
3(57mg,0.063mmol),X-Phos(30mg,0.063mmol)和t-BuONa(91mg,0.094mmol)分散于甲苯(5mL)中,体系置换氮气后加热至100℃反应16小时,LCMS检测反应完全。反应液浓缩,残余物用制备HPLC纯化得白色固体8(28mg,收率22%)。ESI-MS(m/z):409.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.31(d,J=2.5Hz,1H),8.20(s,1H),7.95(dd,J=8.5,2.5Hz,1H),7.24(d,J=8.5Hz,1H),7.12(t,J=6.0Hz,1H),4.48-4.36(m,2H),4.12(q,J=7.0Hz,1H),4.08-3.97(m,1H),3.33-3.23(m,1H),2.92(s,3H),1.99-1.88(m,1H),1.86-1.73(m,1H),1.23(d,J=7.0Hz,3H)。
实施例9
6,7-二甲基-4-(((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)甲基)氨基)-7,8-二氢-3,5,6,9a-四氮杂苯并[cd]薁-9(6H)-酮
化合物9由以下步骤制备:
第一步:将化合物4b(1.2g,3.0mmol)和化合物7b(0.65g,3.63mmol)溶于正丁醇(5mL)中,加入三氟乙酸(0.2mL,2.9mmol),反应液用微波加热至150℃反应5小时,LC-MS监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得褐色固体9a和9b混合物(0.95g),直接用于下一步反应。ESI-MS(m/z):440.3[M+H]
+,468.2[M+H]
+。
第二步:将9a和9b(300mg)溶于四氢呋喃(5mL)中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.20mL,1.4mmol)。70℃搅拌过夜,LC-MS监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得白色固体9(130mg)。ESI-MS(m/z):394.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ7.87(d,J=3.7Hz,1H),7.70(s,1H),7.50(s,1H),6.72(br s,1H),6.46(d,J=3.6Hz,1H),5.05(q,J=9.2Hz,2H),4.33(d,J=6.1Hz,2H),3.97-3.93(m,1H),3.39(d,J=15.9Hz,1H),3.20(s,3H),3.02(dd,J=16.1,6.7Hz,1H),1.12(d,J=6.9Hz,3H)。
实施例10
6-甲基-4-(((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)甲基)氨基)-7,8-二氢-3,5,6,9a-四氮杂苯并[cd]薁-9(6H)-酮
化合物10由以下步骤制备:
第一步:将化合物3d(500mg,1.3mmol)和7b(0.28g,1.57mmol))溶于正丁醇(4mL)中,加入三氟乙酸(0.1mL,1.3mmol),反应液用微波加热至150℃反应5小时,LC-MS监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得褐色固体10a和10b混合物(420mg),直接用于下一步反应。ESI-MS(m/z):426.3[M+H]
+,454.2[M+H]
+。
第二步:将10a和10b(420mg)溶于四氢呋喃(5mL)中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.29mL,2.0mmol)。70℃搅拌过夜,LC-MS监测反应完全。反应液浓缩,残余物用硅胶柱层析纯化得白色固体10(50mg,两步反应收率10%)。ESI-MS(m/z):380.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ7.87(d,J=3.7Hz,1H),7.70(s,1H),7.50(s,1H),6.71(br s,1H),6.48(d,J=3.7Hz,1H),5.05(q,J=9.2Hz,2H),4.33(d,J=6.1Hz,2H),3.73-3.62(m,2H),3.18(s,3H),3.16-3.08(m,2H)。
实施例11
(S)-4,5-二甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物11由以下步骤制备:
第一步:将6-(三氟甲基)吡啶-3-醇11a(1.0g,6.13mmol)溶于二甲亚砜(10mL)中,加入碳酸铯(2.0g,6.13mmol),室温搅拌30分钟后加入2-氟吡啶-5-甲醛11b(1.53g,12.26mmol),反应混合物继续搅拌2小时后终止反应。反应液用乙酸乙酯稀释,依次用水和饱和食盐水洗涤,有机相无水硫酸钠干燥,过滤浓缩,残余物通过硅胶柱层析纯化得到产物11c(1.5g,收率91%)。
1HNMR(500MHz,DMSO-d6)δ10.04(s,1H),8.79-8.70(m,2H),8.37(dd,J=8.6,2.3Hz,1H),8.05(d,J=1.0Hz,2H),7.42(d,J=8.6Hz,1H)。
第二步:将化合物11c(1.53g,5.70mmol)溶于乙醇(5mL),加入盐酸羟胺(792mg,11.41mmol),室温搅拌过夜。反应液浓缩得到粗品肟,重新溶解于醋酸(5mL)中,加入锌粉(1.94g,29.66mmol),室温搅拌2小时,LCMS检测反应完全。反应混合物过滤,滤液浓缩除去大部分醋酸,加乙酸乙酯稀释,然后用NaOH溶液(2N)碱化至pH=11。混合物过滤,滤液浓缩得到化合物11d(1.3g),直接用于下一步反应。ESI-MS(m/z):270.5[M+H]
+。
第二步:将化合物11d(383mg),化合物1i(300mg,1.19mmol),Pd
2(dba)
3(217mg,0.23mmol),t-BuONa(342mg,3.56mmol)和X-Phos(113mg,0.23mmol)分散于甲苯(10mL)中,体系置换氮气后加热至100℃反应16小时,LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析纯化,得到粗品再通过制备HPLC纯化得到化合物11(20mg,收率3%)。ESI-MS(m/z):486.4[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.17(s,1H),8.14(d,J=2.2Hz,1H),7.98(d,J=8.6Hz,1H),7.92-7.86(m,2H),7.18(d,J=8.4Hz,1H),7.06(br s,1H),4.40-4.30(m,2H),4.12(q,J=6.8Hz,1H),4.05-3.99(m,1H),3.26(d,J=3.2Hz,1H),2.94(s,3H),1.96-1.88(m,1H),1.85-1.76(m,1H),1.24(d,J=6.8Hz,3H)。
实施例12
(S)-2-(((6-(3,3-二氟环丁氧基)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物12由以下步骤制备:
第一步:将3,3-二氟环丁醇12a(572mg,5.30mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸铯(3.98g,12.23mmol)和2-氟吡啶-5-甲醛11b(0.51g,4.08mmol),搅拌3小时后结束反应。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析得到化合物12b(0.55g,收率63%)。
第二步:将化合物12b(0.55g,2.58mmol)溶于乙醇(20mL),加入盐酸羟胺(358mg,5.16mmol),室温搅拌过夜。反应液浓缩得到粗品肟,重新溶解于醋酸(10mL)中,加入锌粉(997mg,15.25mmol),60℃搅拌3小时,LCMS检测反应完全。反应混合物过滤,滤液浓缩除去大部分醋酸,加乙酸乙酯稀释,冰浴下用NaOH溶液(2N)碱化至pH=11。混合物过滤,滤液浓缩得到化合物12c(0.3g),直接用于下一步反应。
第三步:将化合物12c(135mg),化合物1i(80mg,0.31mmol),Pd
2(dba)
3(57mg,0.063mmol),t-BuONa(91mg,0.94mmol)和X-Phos(30mg,0.063mmol)分散于甲苯(10mL)中,反应体系置换氮气后加热至100℃反应5小时。LCMS监测反应结束,反应液浓缩,残余物通过制备型薄层层析纯化,得到粗品再通过制备HPLC纯化得到化合物12(8mg,收率5%)。ESI-MS(m/z):431.2[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.23(br s,1H),8.10(s,1H),7.70(dd,J=8.4,2.0Hz,1H),7.00(br s,1H),6.80(d,J=8.4Hz,1H),5.12-5.03(m,1H),4.40-4.25(m,2H),4.15-4.10(m,1H),4.05-4.00(m,1H),3.31-3.25(m,1H),3.20-3.07(m,2H),2.94(s,3H),2.70-2.60(m,2H),1.97-1.88(m,1H),1.84-1.76(m,1H),1.23(d,J=6.7Hz,3H)。
实施例13
(S)-4,5-二甲基-2-(((1-(3-(三氟甲基)苄基)-1H-吡唑-4-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物13由以下步骤制备:
第一步:将4-(Boc-氨甲基)吡唑13b(0.3g,1.52mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入3-三氟甲基氯苄13a(443mg,2.28mmol)和碳酸铯(1.49g,4.56mmol),室温搅拌4小时后终止反应。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到化合物13c(0.51g,收率94%)。ESI-MS(m/z):356.5[M+H]
+。
第二步:将化合物13c(0.51g,1.44mmol)溶于二氧六环(5mL),加入4N盐酸二氧六环溶液(1mL),反应液在室温搅拌过夜,LCMS检测反应完全。反应液浓缩得到化合物13d(0.36g)。
第三步:将化合物13d(393mg),化合物1i(300mg,1.19mmol),Pd
2(dba)
3(217mg,0.23mmol),t-BuONa(342mg,3.56mmol)和S-Phos(97mg,0.23mmol)分散于甲苯(20mL)中,反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过制备型薄层层析纯化,得到粗品再通过制备HPLC纯化得到化合物13(200mg,收率35%)。ESI-MS(m/z):472.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.17(s,1H),7.73(s,1H),7.65(d,J=7.6Hz,1H),7.61-7.55(m,2H),7.50(d,J=7.7Hz,1H),7.42(s,1H),6.69(br s,1H),5.38(s,2H),4.30-4.18(m,2H),4.12(q,J=6.7Hz,1H),4.07-4.00(m,1H),3.31-3.24(m,1H),2.95(s,3H),2.57-2.52(m,2H),1.97-1.89(m,1H),1.86-1.75(m, 1H),1.23(d,J=6.7Hz,3H)。
实施例14
(S)-2-(((1-(4-氟苯乙基)-1H-吡唑-4-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
用4-氟溴乙基苯替换实施例13中第一步的3-三氟甲基氯苄13a,用类似的方法和反应步骤,可以得到化合物14。ESI-MS(m/z):436.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.13(s,1H),7.43(s,1H),7.33(s,1H),7.14-7.09(m,2H),7.04-6.98(m,2H),6.59(br s,1H),4.22(t,J=7.2Hz,2H),4.17(dd,J=11.7,6.1Hz,2H),4.14-4.08(m,1H),4.03-3.98(m,1H),3.29-3.22(m,1H),3.01(t,J=7.2Hz,2H),2.92(s,3H),2.55–2.50(m,2H),1.95-1.87(m,1H),1.83-1.74(m,1H),1.21(d,J=6.8Hz,3H)。
实施例15
(S)-2-(((1-(4-氟苄基)-1H-吡唑-4-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
用4-氟氯苄替换实施例13中第一步的3-三氟甲基氯苄13a,用类似的方法和反应步骤,可以得到化合物15。ESI-MS(m/z):422.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.12(s,1H),7.63(s,1H),7.36(s,1H),7.27-7.22(m,2H),7.15-7.10(m,2H),6.66(br s,1H),5.22(s,2H),4.25-4.16(m,2H),4.10(q,J=6.7Hz,1H),4.03-3.97(m,1H),3.29-3.22(m,1H),2.93(s,3H),2.53-2.49(m,2H),1.95-1.86(m, 1H),1.83-1.72(m,1H),1.21(d,J=6.8Hz,3H)。
实施例16
(S)-4,5-二甲基-2-(((6-((4-(三氟甲基)苄基)氧基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物16由以下步骤制备:
第一步:将2-羟基-5-吡啶甲醛16a(0.5g,4.06mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入碳酸铯(3.97g,12.18mmol)和4-(三氟甲基)苄基氯16b(1.03g,5.28mmol),反应液室温搅拌过夜。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得化合物16c(0.91g,收率79%)。ESI-MS(m/z):282.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ9.62(s,1H),8.80(d,J=2.4Hz,1H),7.83(dd,J=9.5,2.4Hz,1H),7.74(d,J=8.2Hz,2H),7.55(d,J=8.1Hz,2H),6.56(d,J=9.5Hz,1H),5.30(s,2H)。
第二步:将化合物16c(0.91g,3.24mmol)溶于乙醇(20mL)中,加入盐酸 羟胺(449mg,6.47mmol),室温搅拌过夜。反应混合物中继续加入锌粉(993mg,15.19mmol)和浓盐酸(0.5mL),室温反应0.5小时后终止反应。将反应液用氨水碱化至pH=11,加入乙酸乙酯稀释,饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩得化合物16d(0.72g),直接用于下一步反应。ESI-MS(m/z):282.3[M+H]
+。
第三步:将化合物16d(290mg),化合物1i(200mg,0.79mmol),Pd
2(dba)
3(144mg,0.15mmol),t-BuONa(228mg,2.37mmol)和S-Phos(64mg,0.15mmol)分散于甲苯(20mL)中,反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过制备型薄层层析纯化,得到粗品再通过制备HPLC纯化得到化合物16(175mg,收率44%)。ESI-MS(m/z):499.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.24(s,1H),7.82(d,J=1.8Hz,1H),7.75-7.71(m,2H),7.66-7.62(t,2H),7.57(dd,J=9.3,2.3Hz,1H),7.02(br s,1H),6.51(d,J=9.3Hz,1H),5.26(s,2H),4.26-4.15(m,3H),4.13-4.07(m,1H),3.37-3.30(m,1H),2.97(s,3H),2.57-2.50(m,2H),2.02-1.94(m,1H),1.90-1.81(m,1H),1.29(d,J=6.8Hz,3H)。
实施例17
(S)-4,5-二甲基-2-(((6-((3-(三氟甲基)苄基)氧基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
用3-(三氟甲基)苄基氯13a替换实施例16中第一步的4-(三氟甲基)苄基氯16b,用类似的方法和反应步骤,可以得到化合物17。ESI-MS(m/z):499.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.25(s,1H),7.82(d,J=1.8Hz,1H),7.75-7.71(m,2H),7.66-7.62(m,2H),7.57(dd,J=9.3,2.3Hz,1H),7.02(br s,1H),6.51(d,J=9.3Hz,1H),5.26(s,2H),4.26-4.15(m,3H),4.13-4.07(m,1H),3.37-3.30(m,1H),2.97(s,3H),2.57-2.50(m,2H),2.02-1.94(m,1H),1.90-1.81(m,1H),1.29(d,J=6.8Hz,3H)。
实施例18
(S)-2-(((2-(Cyclopropyl甲基)pyrimidin-5-yl)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物18由以下步骤制备:
第一步:将化合物18a(65mg,0.40mmol),化合物1i(100mg,0.40mmol),Pd
2(dba)
3(36mg,0.04mmol),t-BuONa(114mg,1.19mmol)和S-Phos(32mg,0.079mmol)分散于甲苯(10mL),反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过制备性薄层层析,得到粗品再通过Prep-HPLC制备得到白色固体18(52mg,收率34%)。ESI-MS(m/z):380.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.66(s,2H),8.14(s,1H),7.09(br s,1H),4.42-4.29(m,2H),4.12(q,J=6.7Hz,1H),4.05-3.96(m,1H),3.31-3.23(m,1H),2.93(s,3H),2.71(d,J=7.0Hz,2H),2.55-2.51(m,2H),1.96-1.88(m,1H),1.84-1.74(m,1H),1.22(d,J=6.8Hz,3H),1.19-1.09(m,1H),0.47-0.38(m,2H),0.24-0.14(m,2H)。
实施例19
(S)-4,6-二甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
化合物19由以下步骤制备:
第一步:将化合物19a(200mg,1.06mmol)和19b(808mg,3.19mmol)溶于N,N-二甲基甲酰胺(5mL)中,加入Cs
2CO
3(1.39g,4.26mmol),反应液升温至100℃反应2小时,LCMS监测反应完全。反应液用水稀释,乙酸乙酯提取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得白色固体19c(200mg,收率60%)。ESI-MS(m/z):253.5[M-55]
+。
第二步:将化合物19c(200mg,0.64mmol)溶于二氧六环(5mL)中,加入浓盐酸(118mg,0.098mL),反应液在室温搅拌1小时,LCMS监测反应完全。反应液减压浓缩得化合物19d(135mg,收率99%)。ESI-MS(m/z):209.7[M+1]
+。第三步:将化合物19d(135mg,0.64mmol)溶于THF(3mL)中,冰浴下加入NaH(77mg,1.92mmol),搅拌5分钟后加入碘甲烷(137mg,0.97mmol),继续搅拌半小时后LCMS监测反应完全。反应液用水稀释,乙酸乙酯提取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得到化合物19e(60mg,收率41%)。ESI-MS(m/z):223.6[M+H]
+。
第四步:将化合物19e(60mg,0.26mmol)和1e(103mg,0.40mmol)溶于正丁醇(5mL)中,加入三氟乙酸(153mg,1.35mmol),反应液用微波加热至150℃ 反应4小时,LCMS监测反应完全。反应液浓缩,残余物用制备HPLC纯化得化合物19(20mg,收率16%)。ESI-MS(m/z):443.6[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(s,1H),8.18(s,1H),7.92-7.81(m,3H),7.49(s,1H),7.28(s,1H),6.09(s,1H),5.47(s,2H),4.36(d,J=5.4Hz,2H),4.18(dd,J=12.3,3.9Hz,1H),4.07(dd,J=12.4,2.9Hz,1H),3.99(s,1H),3.11(s,3H),1.24(d,J=6.5Hz,3H)。
实施例20
(S)-4,6-二甲基-N-((6-(3,3,3-三氟丙基)吡啶-3-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
化合物20由以下步骤制备:
第一步:将化合物19e(81mg,0.36mmol)和20a(112mg,0.55mmol)溶于正丁醇(3mL)中,加入三氟乙酸(41mg,0.36mmol),反应液用微波加热至150℃反应3小时,LCMS监测反应完全。反应液浓缩,残余物用制备HPLC纯化得化合物20(101mg,收率70%)。ESI-MS(m/z):391.4[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.54(d,J=1.8Hz,1H),8.21(s,1H),7.73(dd,J=8.0,2.2Hz,1H),7.51(d,J=2.4Hz,1H),7.32(d,J=8.0Hz,1H),6.18(d,J=2.7Hz,1H),4.57(d,J=5.8Hz,2H),4.43-4.35(m,1H),3.81(dd,J=12.9,4.1Hz,1H),3.50(dd,J=12.9,8.6Hz,1H),3.17(s,3H),2.95(dd,J=9.2,6.7Hz,2H),2.75-2.63(m,2H),1.45(d,J=6.4Hz,3H)。
实施例21
(S)-8-(二氟甲基)-4,6-二甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
化合物21由以下步骤制备:
第一步:氮气保护下,将化合物19e(0.6g,2.69mmol)溶于无水THF(10mL)中,冷却至-70℃,滴加正丁基锂(6.7mL,1.6M,10.78mmol),继续搅拌15分钟后加入N,N-二甲基甲酰胺(787mg,10.78mmol)。反应液在-70℃反应2小时后加入饱和氯化铵水溶液(2mL)终止反应。反应混合物用乙酸乙酯稀释,饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得化合物21a(0.3g,收率44%)。ESI-MS(m/z):251.5[M+H]
+。
第二步:将化合物21a(0.45g,1.80mmol)溶于二氯甲烷(10mL)中,冰浴下滴加二乙胺基三氟化硫DAST(1.2mL),然后升至室温搅拌3小时。反应液加入饱和碳酸氢钠水溶液(2mL)淬灭,二氯甲烷稀释,饱和食盐水洗涤。有机相无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得化合物21b(0.25g,收率51%)。ESI-MS(m/z):273.4[M+H]
+。
第三步:将化合物21b(100mg,0.36mmol),化合物1e(122mg,0.47mmol),Pd
2(dba)
3(67mg,0.073mmol),t-BuONa(105mg,1.10mmol)和X-Phos(34mg,0.073mmol)分散于甲苯(3mL),反应体系置换氮气后加热至100℃反应16小 时。LCMS监测反应结束,反应液浓缩,残余物首先通过硅胶柱层析,得到粗品再通过Prep-HPLC纯化得到化合物21(55mg,收率30%)。ESI-MS(m/z):493.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(s,1H),8.21(s,1H),7.87-7.83(m,2H),7.80(s,1H),7.47(s,1H),7.26(t,J=53.7Hz,1H),6.39(s,1H),5.45(s,2H),4.74-4.68(m,1H),4.31(d,J=5.8Hz,2H),3.76(dd,J=12.6,3.7Hz,1H),3.46(dd,J=12.6,2.2Hz,1H),3.09(s,3H),1.29(d,J=6.5Hz,3H)。
实施例22
(S)-8-(二氟甲基)-4,5-二甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
化合物22由以下步骤制备:
第一步:将化合物19a(5.0g,26.59mmol),22a(7.57g,31.91mmol)和18-冠 -6(2.11g,7.98mmol)溶于二氧六环(50mL)中,加入碳酸钾(11.03g,79.78mmol),反应体系加热至50℃反应16小时。LCMS监测反应结束。反应液用乙酸乙酯稀释,分别用水和饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩。残余物用乙酸乙酯/石油醚(1/1)打浆得到灰色固体22b(8克,粗品),直接用于下一步反应。ESI-MS(m/z):345.4[M+H]
+。
第二步:将化合物22b(5.0g,粗品)溶于二氯甲烷(30mL)中,加入盐酸二氧六环溶液(4N,18.1mL),反应液室温搅拌16小时,LCMS监测反应完全。反应液过滤,收集滤饼,减压干燥得到化合物22c的盐酸盐(4.0g,粗品),直接用于下一步反应。ESI-MS(m/z):245.6[M+H]
+。
第三步:将化合物22c的盐酸盐(4.0g,粗品)溶于二氧六环(50mL)和N,N-二甲基甲酰胺(5mL)的混合液中,加入N,N-二异丙基乙胺(1.84g,14.21mmol),反应液升温至100℃反应16小时,LCMS监测反应完全。反应液浓缩,残余物用乙酸乙酯稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得到黄色固体22d(1.6g)。ESI-MS(m/z):209.6[M+H]
+。
第四步:将化合物22d(2.1g,10.06mmol)溶于无水N,N-二甲基甲酰胺(15mL)中,冰浴下分批加入NaH(401mg,含量60%,10.06mmol),反应混合物搅拌30分钟后加入碘甲烷(1.43g,10.06mmol,0.93mL)。反应液升至室温,搅拌16小时后LCMS监测反应完全。反应液用乙酸乙酯稀释,依次用水和饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到黄色固体22e(2.0g,收率89%)。ESI-MS(m/z):223.5[M+H]
+。
第五步:氮气保护下,化合物22e(200mg,0.89mmol)溶于无水四氢呋喃(8mL)中,反应液冷却至-70℃,滴加正丁基锂溶液(2.5M,1.8mL),搅拌30分钟后加入N,N-二甲基甲酰胺(262mg,3.59mmol)。反应混合物在-70℃继续搅拌3小时后缓慢升至室温。反应液用稀盐酸(1N)淬灭后,加入乙酸乙酯稀释,依次用水和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得化合物22f(150mg,收率66%)。ESI-MS(m/z):251.5[M+H]
+。第六步:将化合物22f(150mg,0.59mmol)溶于二氯甲烷(5mL)中,冰浴下滴加二乙胺基三氟化硫DAST(192mg,1.20mmol,0.16mL),然后升至室温搅 拌5小时。反应液加入饱和碳酸氢钠水溶液(2mL)淬灭,二氯甲烷稀释,饱和食盐水洗涤。有机相无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得到白色固体22g(150mg,收率73%)。ESI-MS(m/z):273.4[M+H]
+。
第七步:将化合物22g(110mg,0.40mmol),化合物1e(134mg,0.52mmol),Pd
2(dba)
3(73mg,0.08mmol),t-BuONa(116mg,1.21mmol)和X-Phos(38mg,0.08mmol)分散于甲苯(4mL),反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过Prep-HPLC纯化得到化合物22(35mg,收率17%)。ESI-MS(m/z):493.2[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(s,1H),7.91-7.82(m,2H),7.79(s,1H),7.46(s,1H),7.22(t,J=53.5Hz,1H),6.45-6.29(m,2H),5.45(s,2H),4.30(d,J=6.0Hz,2H),4.20(dd,J=12.5,3.5Hz,1H),4.09(dd,J=12.5,3.5Hz,1H),3.99-3.88(m,1H),3.05(s,3H),1.23(d,J=6.5Hz,3H)。
实施例23
(S)-4-异丙基-6-甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
化合物23由以下步骤制备:
第一步:将化合物19e(0.2g,0.95mmol)溶于无水N,N-二甲基甲酰胺(5mL)中,冰浴下分批加入NaH(115mg,含量60%,2.87mmol),反应混合物搅拌5分钟后加入碘代异丙烷(211mg,1.25mmol,0.12mL)。反应液升至室温,搅拌3小时后LCMS监测反应完全。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩。残余物通过硅胶柱层析纯化得到化合物23a (185mg,收率76%)。ESI-MS(m/z):251.5[M+H]
+。
第二步:将化合物23a(100mg,0.39mmol),化合物1e(132mg,0.51mmol),Pd
2(dba)
3(73mg,0.08mmol),t-BuONa(115mg,1.20mmol)和X-Phos(38mg,0.08mmol)分散于甲苯(5mL),反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过Prep-HPLC纯化得到化合物23(31mg,收率16%)。ESI-MS(m/z):471.2[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.63(s,1H),8.26(s,1H),7.88-7.80(m,2H),7.77(s,1H),7.45(s,1H),7.29(d,J=2.7Hz,1H),6.51(br s,1H),6.03(d,J=2.7Hz,1H),5.44(s,2H),4.85-4.79(m,1H),4.29(d,J=5.8Hz,2H),4.25-4.20(m,1H),3.66(dd,J=12.6,3.5Hz,11H),3.25-3.20(m,1H),1.41(d,J=6.4Hz,3H),1.19-1.14(m,6H)。
实施例24
(R)-5-(甲氧基甲基)-4-甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-6,6-d2-2-胺
化合物24由以下步骤制备:
第一步:氮气保护下,将SOCl
2(1.72g,14.47mmol,1.05mL)溶解于无水二氯甲烷(100mL)中,反应液冷却至-70℃后,滴加咪唑(2.63g,38.60mmol)和三乙胺(2.93g,28.95mmol,4.01mL)的无水二氯甲烷溶液(10mL)。反应剧烈放热,控制反应液内温在-40℃以下。滴加完毕后,反应液重新冷却至-70℃搅拌10分钟,继续滴加化合物24a(2.0g,9.65mmol)的无水二氯甲烷溶液(10mL)。反应混合物缓慢升至室温搅拌过夜。反应液用二氯甲烷稀释,加入0.5M的柠檬酸水溶液,分出有机相。得到的有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到化合物24b(2.43g,粗品),直接用于下一步反应。
第二步:将上一步得到的化合物24b(2.43g)溶于乙腈(55mL)和水(25mL)的混合溶液中,冰浴下依次加入三氯化钌(99mg,0.47mmol)和高碘酸钠(4.10g,19.19mmol)。反应混合物室温搅拌3小时后终止反应。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到化合物24c(2.2g,粗品),直接用于下一步反应。
第三步:将化合物19a(1.3g,6.91mmol),22a(2.23g)和18-冠-6(91mg,0.34mmol)溶于二氧六环(20mL)中,加入碳酸钾(2.87g,20.74mmol),反应体 系加热至60℃反应16小时,LCMS监测反应结束。反应液用乙酸乙酯稀释,分别用水和饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到化合物24d(2.6克,粗品),直接用于下一步反应。ESI-MS(m/z):377.5[M+H]
+。
第四步:将化合物24d(1.65g,粗品)溶于二氧六环(10mL)中,加入浓盐酸(1.33mL),反应液室温搅拌3小时,LCMS监测反应完全。反应液浓缩得到化合物24e的盐酸盐(1.2g,粗品),直接用于下一步反应。ESI-MS(m/z):277.4[M+H]
+。
第五步:将化合物24e的盐酸盐(1.3g,粗品)溶于二氧六环(20mL)和N,N-二甲基甲酰胺(2mL)的混合液中,加入N,N-二异丙基乙胺(2.68g,20.73mmol,3.43mL),反应液升温至100℃反应16小时,LCMS监测反应完全。反应液浓缩,残余物用乙酸乙酯稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得到化合物24f(0.56g)。ESI-MS(m/z):241.5[M+H]
+。
第六步:将化合物24f(0.1g,0.41mmol)溶于无水N,N-二甲基甲酰胺(5mL)中,冰浴下加入NaH(49mg,含量60%,1.22mmol),反应混合物搅拌5分钟后加入碘甲烷(70mg,0.49mmol)。反应液升至室温,搅拌3小时后LCMS监测反应完全。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩。残余物通过硅胶柱层析纯化得到化合物24g(50mg,收率47%)。ESI-MS(m/z):255.5[M+H]
+。
第七步:将化合物24g(100mg,0.39mmol)和1e(100mg,0.39mmol)溶于正丁醇(3mL)中,加入三氟乙酸(134mg,1.18mmol),反应液用微波加热至150℃反应3小时,LCMS监测反应完全。反应液浓缩,残余物用制备HPLC纯化得化合物24(43mg,收率23%)。ESI-MS(m/z):475.4[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.65(s,1H),8.23(s,1H),7.90-7.84(m,3H),7.52(s,1H),7.37(s,1H),6.14(s,1H),5.48(s,2H),4.47-4.36(m,2H),4.17-4.14(m,1H),3.57(dd,J=10.0,5.6Hz,1H),3.46(dd,J=9.8,7.3Hz,1H),3.30-3.26(m,6H)。
实施例25
(R)-6-(甲氧基甲基)-4,8-二甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
化合物25由以下步骤制备:
第一步:氮气保护下,将SOCl
2(2.26g,19.00mmol,1.38mL)溶解于无水二氯甲烷(50mL)中,反应液冷却至-70℃后,滴加咪唑(3.98g,58.47mmol)和三乙胺(2.96g,29.23mmol,4.05mL)的无水二氯甲烷溶液(10mL)。反应剧烈放热,控制反应液内温在-40℃以下。滴加完毕后,反应液重新冷却至-70℃搅拌10分钟,继续滴加化合物25a(3.0g,14.62mmol)的无水二氯甲烷溶液(10mL)。反应混合物缓慢升至室温搅拌过夜。反应液用二氯甲烷稀释,加入0.5M的柠檬酸水溶液,分出有机相。得到的有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到化合物25b(3.6g),直接用于下一步反应。第二步:将上一步得到的化合物25b(3.6g)溶于乙腈(50mL),加入三氯化钌(99mg,0.47mmol),然后冰浴下滴加高碘酸钠水溶液(4.10g,19.19mmol,溶 于50mL水)。滴加完毕后反应混合物升至室温搅拌4小时。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到化合物25c(3.5g,两步反应收率46%)。
1HNMR(500MHz,DMSO-d6)δ5.14-5.06(m,1H),4.13-4.06(m,1H),3.85-3.78(m,1H),3.73-3.65(m,2H),3.31(s,3H),1.47(s,9H)。第三步:将化合物19a(2.0g,10.64mmol),25c(3.70g,13.83mmol)和18-冠-6(281mg,1.06mmol)溶于二氧六环(50mL)中,加入碳酸钾(4.41g,31.91mmol),反应体系加热至80℃反应16小时,LCMS监测反应结束。反应液用乙酸乙酯稀释,分别用水和饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到化合物25d(3.8克,粗品),直接用于下一步反应。ESI-MS(m/z):375.4[M+H]
+。第四步:将上一步得到的化合物25d(3.8g)溶于二氯甲烷(40mL)中,加入盐酸二氧六环溶液(4N,12.66mL),反应液室温搅拌16小时,LCMS监测反应完全。反应液浓缩得到化合物25e的盐酸盐(3.0g,粗品),直接用于下一步反应。ESI-MS(m/z):275.5[M+H]
+。
第五步:将化合物25e的盐酸盐(3.6g,粗品)溶于二氧六环(50mL)和N,N-二甲基甲酰胺(5mL)的混合液中,加入N,N-二异丙基乙胺(7.47g,57.77mmol,9.57mL),反应液升温至90℃反应16小时,LCMS监测反应完全。反应液浓缩,残余物用乙酸乙酯稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得到化合物25f(0.84g)。ESI-MS(m/z):239.6[M+H]
+。
第六步:将化合物25f(150mg,0.62mmol)溶于无水N,N-二甲基甲酰胺(2mL)中,冰浴下加入NaH(75mg,含量60%,1.89mmol),反应混合物搅拌30分钟后加入碘甲烷(133mg,0.94mmol)。反应液升至室温,搅拌3小时后LCMS监测反应完全。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩。残余物通过硅胶柱层析纯化得到化合物25g(130mg,收率81%)。ESI-MS(m/z):253.5[M+H]
+。
第七步:氮气保护下,化合物25g(130mg,0.51mmol)溶于无水四氢呋喃(3mL)中,反应液冷却至-70℃,滴加正丁基锂溶液(2.5M,0.82mL),搅拌30分钟后加入碘甲烷(292mg,2.06mmol)。反应混合物在-70℃继续搅拌1小时后缓慢升至室温。反应液用饱和氯化铵水溶液淬灭后,加入乙酸乙酯稀释,依次用水和饱 和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩得到化合物25h(100mg,粗品)。ESI-MS(m/z):267.4[M+H]
+。
第八步:将化合物25h(100mg,粗品),化合物1e(124mg,0.48mmol),Pd
2(dba)
3(68mg,0.074mmol),t-BuONa(108mg,1.12mmol)和X-Phos(35mg,0.074mmol)分散于甲苯(5mL),反应体系置换氮气后加热至100℃反应16小时。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析纯化得到粗品,再通过Prep-HPLC纯化得到化合物25(13mg)。ESI-MS(m/z):487.4[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.65(s,1H),8.29(br s,1H),7.88(d,J=8.0Hz,1H),7.84(d,J=8.0Hz,1H),7.78(s,1H),7.45(s,1H),6.33(br s,1H),5.80(s,1H),5.45(s,2H),4.63(s,1H),4.29(d,J=6.0Hz,2H),3.57(s,2H),3.43(dd,J=9.5,7.0Hz,1H),3.34-3.30(m,1H),3.24(s,3H),3.01(s,3H),2.33(s,3H)。
实施例26
8,8-二氟-6-甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-6,7,8,9-四氢-3,5,6,9a-四氮杂苯并[cd]薁-4-胺
化合物26由以下步骤制备:
第一步:室温下将化合物19a(400mg,2.13mmol)和三苯基膦(1.67g,6.38mmol)溶于无水四氢呋喃(15mL)中,氮气保护下依次加入N,N-二异丙基乙胺(1.37g,10.64mmol)和偶氮二甲酸二异丙酯(1.29g,6.38mmol,1.25mL)。搅拌30分钟后,继续滴加化合物26a(898mg,4.26mmol)的无水四氢呋喃溶液(5mL)。反应混合物升温至70℃反应16小时后终止反应。反应液浓缩,残余物硅胶柱层析纯化得化合物26b(500mg,收率61%)。ESI-MS(m/z):325.4[M-55]
+。
第二步:将化合物26b(500mg,1.31mmol)溶于二氯甲烷(5mL)中,加入盐酸二氧六环溶液(4N,1.64mL),反应液室温搅拌16小时,LCMS监测反应完全。反应液过滤,收集滤饼,减压干燥得到化合物26c的盐酸盐(360mg,收率86%)。
第三步:将化合物26c的盐酸盐(360mg,1.13mmol)溶于二氧六环(5mL)和N,N-二甲基甲酰胺(1mL)的混合液中,加入N,N-二异丙基乙胺(732mg,5.67mmol),反应液升温至100℃反应4小时,LCMS监测反应完全。反应液浓缩,残余物用乙酸乙酯稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化得到白色固体26d(250mg,收率90%)。ESI-MS(m/z):245.5[M+H]
+。
第四步:将化合物26d(300mg,1.23mmol)溶于无水N,N-二甲基甲酰胺(5mL)中,冰浴下分批加入NaH(122mg,含量60%,3.07mmol),反应混合物搅拌15分钟后加入碘甲烷(261mg,1.84mmol,0.17mL)。反应液升至室温,搅拌4小时后LCMS监测反应完全。反应液用乙酸乙酯稀释,饱和食盐水洗涤,有机相 用无水硫酸钠干燥,过滤浓缩得到化合物26e(290mg,收率91%)。ESI-MS(m/z):259.5[M+H]
+。
第五步:将化合物26e(100mg,0.38mmol)和1e(148mg,0.57mmol)溶于正丁醇(4mL)中,加入三氟乙酸(44mg,0.38mmol),反应液用微波加热至150℃反应6小时,LCMS监测反应完全。反应液浓缩,残余物用制备HPLC纯化得化合物26(17mg,收率9%)。ESI-MS(m/z):479.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(s,1H),7.90-7.80(m,3H),7.52-7.40(m,2H),6.26(d,J=2.5Hz,1H),5.46(s,2H),4.73(t,J=12.0Hz,2H),4.37(d,J=6.0Hz,2H),4.17(t,J=12.0Hz,2H),3.26(s,3H)。
实施例27
(R)-4,6-二甲基-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-5,6-二氢-4H-吡咯并[3,2,1-de]蝶啶-2-胺
用(S)-1-(BOC-氨基)-2-丙醇甲烷磺酸酯替换实施例19中第一步的(R)-1-(BOC-氨基)-2-丙醇甲烷磺酸酯19b,用类似的方法和反应步骤,可以得到化合物27。ESI-MS(m/z):443.6[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ12.19(br s,1H),8.64(s,1H),8.34(br s,1H),7.92-7.83(m,3H),7.53(s,1H),7.44(d,J=2.5Hz,1H),6.20(s,1H),5.49(s,2H),4.44(s,2H),4.29-4.06(m,3H),3.22(s,3H),1.29(d,J=6.5Hz,3H)。
实施例28
(R)-N-((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)-7a,8,10,11-四氢-7H-[1,4]噁嗪并[3,4-h]吡咯并[3,2,1-de]蝶啶-2-胺
化合物28由以下步骤制备:
第一步:室温下将化合物19a(300mg,1.60mmol)和三苯基膦(1.26g,4.79mmol)溶于无水四氢呋喃(10mL)中,氮气保护下依次加入N,N-二异丙基乙胺(1.03g,7.98mmol)和偶氮二甲酸二异丙酯(967mg,4.79mmol,0.94mL)。搅拌30分钟后,继续滴加化合物28a(866mg,3.99mmol)的无水四氢呋喃溶液(5mL)。反应混合物升温至70℃反应16小时后终止反应。反应液浓缩,残余物硅胶柱层析纯化得化合物28b(200mg,收率32%)。ESI-MS(m/z):331.4[M-55]
+。
第二步:将化合物28b(200mg,0.51mmol)溶于二氯甲烷(2mL)中,加入盐酸二氧六环溶液(4N,1.29mL),反应液室温搅拌16小时,LCMS监测反应完全。反应液浓缩得到化合物28c(100mg,粗品),直接用于下一步反应。ESI-MS(m/z):251.5[M+H]
+。
第三步:将化合物28c(100mg)和1e(122mg,0.47mmol)溶于正丁醇(4mL)中,加入三氟乙酸(45mg,0.39mmol),反应液用微波加热至150℃反应5小时, LCMS监测反应完全。反应液浓缩,残余物用制备HPLC纯化得化合物28(13mg)。ESI-MS(m/z):471.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ12.19(s,1H),8.63(s,1H),8.36(br s,1H),8.01-7.79(m,3H),7.65-7.44(m,2H),6.23(s,1H),5.48(s,2H),4.56-4.40(m,3H),4.29-4.25(m,1H),4.13-4.02(m,3H),3.93-3.82(m,1H),3.62-3.52(m,2H),3.24-3.17(m,1H)。
实施例59(W284)
(S)-4,5-二甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物59由以下步骤制备:
第一步:将化合物59a(2g,12.69mmol)和N-甲基-N-甲氧基胺盐酸盐(1.86g,19.04mmol)溶于二氯甲烷(20mL)中,加入EDCI(3.65g,19.04mmol)、HOBt(2.57g,19.04mmol)和N,N-二异丙基丙胺(4.92g,38.08mmol)。反应在室温下搅拌12小时。LCMS监测反应结束。反应液加水稀释,乙酸乙酯萃取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=5/1)得到无色油状液体59b(2.2g,收率86%)。ESI-MS(m/z):201.4[M+H]
+。
第二步:将化合物59c(371mg,1.64mmol)溶于干燥的四氢呋喃(10mL)中,反应体系置换氮气后在-78℃下搅拌5分钟。将正丁基锂(0.72mL,2.5M,1.79mmol)滴加入反应液中,反应液在-78℃下搅拌30分钟。随后,将化合物59b(300mg,1.50mmol,溶解于1mL干燥的四氢呋喃)加入反应液中。反应液在-78℃下搅拌2小时。待反应体系恢复至室温,反应液用饱和氯化铵水溶液淬灭,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=10/1)得到白色固体化合物59d(80mg,收率19%)。ESI-MS(m/z):287.2[M+H]
+;
1H NMR(500MHz,CDCl
3)δ9.43(s,1H),8.68(d,J=2.2Hz,1H),8.61(d,J=6.7Hz,1H),8.20(d,J=8.4Hz,1H),7.94(dd,J=8.4,2.2Hz,1H),7.83(d,J=8.1Hz,1H)。
第三步:将化合物59d(200mg,0.70mmol)溶于甲醇(8mL),在0℃下缓慢加入硼氢化钠(40mg,1.05mmol),反应液在0℃下继续搅拌反应4小时。LCMS监测反应结束。反应用饱和氯化铵水溶液淬灭,随后用乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=5/1)得到化合物59e(201mg,收率99%)。ESI-MS(m/z):289.2[M+H]
+。
第四步:将化合物59e(100mg,0.35mmol)溶于干燥的四氢呋喃(5mL)中,随后在0℃下加入氢化钠(24mg,含量60%,0.6mmol),反应液在0℃下搅拌半小时。然后依次加入二硫化碳(80mg,1.05mmol)和碘甲烷(148mg,1.05 mmol),反应在0℃下继续搅拌2小时。LCMS监测反应结束。反应液用0℃的饱和氯化铵水溶液淬灭,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=10/1)得到化合物59f(98mg,收率75%)。ESI-MS(m/z):379.1[M+H]
+。
第五步:将化合物59f(98mg,0.26mmol)和三丁基氢化锡(150mg,0.52mmol)溶于甲苯(5mL)中,加入偶氮二异丁腈(5mg,0.03mmol)。反应体系置换氮气后在80℃下搅拌12小时。LCMS监测反应结束。将反应液滴加入冰水中淬灭,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=10/1)得到化合物59g(40mg,收率57%)。ESI-MS(m/z):273.2[M+H]
+。
第六步:将化合物59g(40mg,0.15mmol)溶于N-甲基吡咯烷酮(3mL)中,加入氰化锌(35mg,0.30mmol)、Pd
2(dba)
3(27mg,0.03mmol)和S-Phos(12mg,0.03mmol),反应体系置换氮气后在微波条件下,150℃搅拌2小时。LCMS监测反应结束。反应液硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=10/1)得到白色固体59h(21mg,收率55%)。ESI-MS(m/z):264.4[M+H]
+。
第七步:将化合物59h(21mg,0.08mmol)溶于甲醇(5mL)和氨水(1mL)中,加入Raney Nickel(0.5mL,水混悬液),反应体系置换氢气后在室温下搅拌12小时。LCMS监测反应结束。反应液硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(二氯甲烷/甲醇=5/1)得到化合物59i(20mg,收率94%)。ESI-MS(m/z):268.3[M+H]
+。
第八步:将化合物59i(20mg,0.08mmol)和化合物1i(13mg,0.05mmol)溶于正丁醇(3mL)中,加入对甲苯磺酸一水合物(9mg,0.05mmol),反应液在微波条件下,160℃搅拌3小时。待反应液冷却至室温,反应液减压浓缩,残余物用制备HPLC纯化得到白色固体化合物59(9mg,收率25%)。ESI-MS(m/z): 484.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.70(s,1H),8.44(s,1H),7.94(d,J=7.8Hz,1H),7.82(s,1H),7.67(dd,J=7.9,1.6Hz,1H),7.31(d,J=7.9Hz,1H),7.02(br s,1H),4.43-4.30(m,2H),4.19(s,2H),4.10(q,J=6.7Hz,1H),4.02-3.97(m,1H),3.31-3.22(m,3H),2.90(s,3H),1.93-1.87(m,1H),1.83-1.74(m,1H),1.21(d,J=6.8Hz,3H)。
根据以上实施例描述的合成路线和中间体的合成方法,得到了以下实施例化合物。
实施例91(W221)
(S)-4,5-二甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物91由以下步骤制备:
第一步:将2-(三氟甲基)嘧啶-5-醇91a(1.0g,6.09mmol),6-氟-烟腈91b(1.01g,7.31mmol)和碳酸铯(3.97g,12.19mmol)溶解于DMF(10mL)中,在80℃ 条件下搅拌过夜。LCMS监测反应结束。反应液用乙酸乙酯稀释,依次用水和饱和食盐水洗涤,有机相通过无水硫酸钠干燥,浓缩后通过硅胶柱层析纯化(石油醚/乙酸乙酯=5/1),得到黄色油状物91c(1.3g,收率80%)。
第二步:将化合物91c(1.3g,4.88mmol)和Raney Nickel(0.5mL,水混悬液)溶解分散于甲醇(2mL)和氨水(0.2mL)中,用氢气球抽换气,室温条件下搅拌过夜。LCMS监测反应结束,反应液用甲醇稀释,硅藻土滤层抽滤,有机相浓缩,得到黄色油状物91d(700mg,收率53%)。ESI-MS(m/z):271.3[M+H]
+。
第三步:将化合物1i(150mg,593umol),化合物91d(192mg,712umol)和一水对甲苯磺酸(11mg,59umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体91(68mg,收率23%)。ESI-MS(m/z):487.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ9.03(s,2H),8.12(d,J=2.3Hz,1H),7.92(dd,J=8.4,2.4Hz,1H),7.22(d,J=8.5Hz,1H),7.05(br s,1H),4.45-4.32(m,2H),4.11(q,J=6.8Hz,1H),4.03-3.97(m,1H),3.35-3.22(m,2H),2.92(s,3H),2.52-2.48(m,2H),1.95-1.88(m,1H),1.84-.75(m,1H),1.22(d,J=6.8Hz,3H)。
实施例92(W232)
(S)-4,5-二甲基-2-(((6-((3-(三氟甲基)-1H-吡唑-1-基)甲基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物92由以下步骤制备:
第一步:将3-(三氟甲基)吡唑92a(89mg,0.66mmol)和3-氰基-6-氯甲基吡啶92b(100mg,0.66mmol)溶于N,N-二甲基甲酰胺(5mL)中,加入碳酸钾(181mg,1.31mmol),反应液在室温下反应6小时。LCMS监测反应结束。反应液用饱和氯化钠水溶液稀释,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=10/3)得到棕色液体化合物92c(142mg,收率86%)。ESI-MS(m/z):253.2[M+H]
+。
第二步:将化合物92c(142mg,0.56mmol)溶于甲醇(9mL)和氨水(1mL)中,加入Raney Nickel(0.5mL,水混悬液),反应体系置换氢气后在室温下搅拌12小时。反应液硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(二氯甲烷/甲醇=5/1)得到无色油状液体92d(79mg,收率55%)。ESI-MS(m/z):257.3[M+H]
+。
第三步:将化合物92d(80mg,0.31mmol)和化合物1i(53mg,0.21mmol)溶于正丁醇(3mL)中,加入对甲苯磺酸一水合物(40mg,0.21mmol),反应液在微波条件下,160℃搅拌3小时。待反应液冷却至室温,反应液减压浓缩,残余物用反相制备HPLC纯化得到白色固体化合物92(19mg,收率13%)。ESI-MS(m/z):473.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.49(d,J=1.7Hz,1H),8.07(d,J=1.2Hz,1H),7.72(dd,J=8.0,2.1Hz,1H),7.14(d,J=8.0Hz,1H),7.04(t,J=5.7Hz,1H),6.74(d,J=2.2Hz,1H),5.48(s,2H),4.46-4.32(m,2H),4.10(q,J=6.8Hz,1H),4.04-3.96(m,1H),3.40-3.23(m,3H),2.90(s,3H),1.96-1.87(m, 1H),1.85-1.74(m,1H),1.21(d,J=6.8Hz,3H)。
实施例93(W223)
(S)-4,5-二甲基-2-(((1-(4,4,4-三氟丁基)-1H-吡唑-4-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物93由以下步骤制备:
第一步:将1,1,1-三氟-4-碘丁烷93a(289mg,1.22mmol),4-(BOC-氨甲基)吡唑13b(200mg,1.01mmol),和碳酸铯(660mg,2.03mol)溶于N,N-二甲基甲酰胺(10mL)之中,反应液在室温下搅拌12个小时。反应结束后,将反应液过滤,滤液浓缩后得到粗品。粗品经过硅胶柱层析纯化(石油醚/乙酸乙酯=3/1)得到白色固体目标化合物93b(230mg,收率73%)。ESI-MS(m/z):308.4[M+H]
+。
第二部:将化合物93b(200mg,650ummol)溶于二氯甲烷(10mL)之中,向上述反应溶液之中加入盐酸-二氧六环溶液(1M,3.25mL),反应液在室温下搅拌6个小时。反应结束后,将反应液浓缩后得白色固体目标产物93c(134mg),直接用于下一步反应。ESI-MS(m/z):208.3[M+H]
+。
第三步:将化合物93c(103mg,从第二步得到),1i(126mg,0.5mmol),和对甲苯磺酸一水合物(9mg,50ummol)溶于正丁醇(4mL)之中,反应液在微波160摄氏度条件下反应2个小时。反应结束后,将反应液通过反相制备HPLC纯化得到白色固体目标化合物93(25mg,两步反应收率9%)。ESI-MS(m/z):424.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ7.58(s,1H),7.37(s,1H),6.60(t,J=6.0Hz,1H),4.26-4.17(m,2H),4.10(t,J=6.9Hz,3H),4.04-3.99(m,1H),3.30-3.23(m,2H),2.95(s,3H),2.54-2.49(m,2H),2.23-2.12(m,2H),1.95-1.91(m,2H),1.82-1.78(m,1H),1.22(d,J=6.7Hz,3H)。
实施例94(W252)
(S)-4,5-二甲基-2-(((6-((5-(三氟甲基)吡啶-2-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物94由以下步骤制备:
第一步:将化合物94a(52mg,0.23mmol)和94b(25mg,0.21mmol)溶于二甲基亚砜(2mL)中,加入碘化亚铜(4mg,0.021mol),无水磷酸钾(88mg, 0.42mol)和2,2,6,6-四甲基-3,5-庚二酮(8mg,0.042mol)。反应体系置换氮气后加热至100℃搅拌2小时。待反应完全后,加水淬灭反应,水相用乙酸乙酯萃取。合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯=10/1)得到白色固体94c(50mg,收率90%)。ESI-MS(m/z):266.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.79(d,J=2.5Hz,1H),8.77-8.73(m,1H),8.49-8.44(m,1H),8.41-8.38(m,1H),7.50(t,J=8.5Hz,2H)。
第二步:将化合物94c(50mg,0.19mmol)溶于甲醇(10mL)和氨水(1mL)的混合溶液中,加入雷尼镍(0.1mL,水混悬液),混合物在氢气氛围下室温搅拌16小时。反应完全后,用硅藻土过滤,滤饼用甲醇洗,浓缩滤液得到白色固体94d(45mg,收率88%)。ESI-MS(m/z):270.3[M+H]
+。
第三步:将化合物94d(45mg,0.17mmol)和1i(36mg,0.14mmol)溶于1,4-二氧六环(5mL)中,加入Pd
2(dba)
3(15mg,0.017mol),Sphos(14mg,0.034mol)和碳酸铯(109mg,0.34mol)。反应体系置换氮气后加热至100℃搅拌16小时。待反应液冷却至室温,反应液用硅藻土过滤,滤液浓缩。残余物用反相制备HPLC纯化得到白色固体94(6mg,收率7%)。ESI-MS(m/z):486.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.61-8.59(m,1H),8.29-8.23(m,2H),7.92-7.86(m,1H),7.31(d,J=8.5Hz,1H),7.17(d,J=8.5Hz,1H),7.13-7.05(m,1H),4.49-4.35(m,2H),4.17-4.08(m,1H),4.05-3.98(m,1H),3.29-3.24(m,1H),2.94(s,3H),2.55-2.50(m,2H),1.97-1.88(m,1H),1.85-1.73(m,1H),1.23(d,J=7.0Hz,3H)。
实施例95(W253)
(S)-2-(((6-(二氟(6-(三氟甲基)吡啶-3-基)甲基)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物95由以下步骤制备:
第一步:将化合物59d(80mg,0.28mmol)溶于二氯甲烷(2mL)中,反应体系在0℃下缓慢滴加二乙胺基三氟化硫(2.44g,15.14mmol),反应液在0℃下搅拌4小时。LCMS监测反应结束。将反应液滴加入饱和碳酸氢钠水溶液中,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=5/1)得到白色固体95a(83mg,收率96%)。ESI-MS(m/z):309.0[M+H]
+。
第二步:将化合物95a(83mg,0.27mmol)溶于N-甲基吡咯烷酮(3mL)中,加入氰化锌(63mg,0.54mmol)、Pd
2(dba)
3(50mg,0.05mmol)和S-Phos(22mg,0.05mmol),反应体系置换氮气后在微波条件下,150℃搅拌2小时。反应液冷至室温后用硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=10/1)得到白色固体95b(66mg,收率82%)。ESI-MS(m/z):300.1[M+H]
+。
第三步:将化合物95b(66mg,0.22mmol)溶于甲醇(5mL)和氨水(1mL)中,加入Raney Nickel(0.5mL,水混悬液),反应体系置换氢气后在室温下搅拌12小时。反应液硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(二氯甲烷/甲醇=10/1)得到无色油状液体95c(66mg,收率99%)。ESI-MS(m/z):304.2 [M+H]
+。
第四步:将化合物95c(66mg,0.22mmol)和化合物1i(37mg,0.15mmol)溶于正丁醇(3mL)中,加入对甲苯磺酸一水合物(25mg,0.15mmol),反应液在微波条件下,160℃搅拌3小时。待反应液冷却至室温,反应液减压浓缩,残余物用反相制备HPLC纯化得到白色固体化合物95(8mg,收率9%)。ESI-MS(m/z):520.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ9.01(s,1H),8.59(s,1H),8.31(d,J=7.7Hz,1H),8.06(d,J=8.2Hz,1H),7.97(d,J=9.4Hz,1H),7.90(d,J=8.1Hz,1H),7.13(t,J=5.8Hz,1H),4.52-4.38(m,2H),4.11(q,J=6.7Hz,1H),4.04-3.96(m,1H),3.31-3.24(m,1H),2.89(s,3H),2.52-2.47(m,2H),1.95-1.86(m,1H),1.83-1.73(m,1H),1.21(d,J=6.8Hz,3H)。
实施例96(W256)
(S)-2-(((6-(4-氟苯甲基)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物96由以下步骤制备:
第一步:将化合物96a(1.0g,7.0mmol),Boc
2O(2.29g,10.52mmol)和N,N-二异丙基乙胺(1.81g,14.03mmol,2.44mL)溶解于二氯甲烷(10mL)中,在室温条件下搅拌过夜。LCMS监测反应结束。反应液用二氯甲烷稀释,依次用水和饱和氯化铵溶液,饱和碳酸氢钠水溶液洗涤,有机相通过无水硫酸钠干燥,过滤浓缩后得到无色油状物96b(1.6g,收率94%)。ESI-MS(m/z):243.3[M+H]
+。
第二步:将化合物96b(200mg,824umol),4-氟苄基硼酸频哪醇酯96c(194mg,824umol),Pd(t-Bu
3P)
2(42mg,82umol)和碳酸钾(227mg,1.65mmol)分散于1,4-二氧六环(5mL)和水(0.5mL)中,反应体系置换氮气后加热至100℃搅拌过夜。LCMS监测反应结束。反应液用乙酸乙酯稀释,依次用水和饱和食盐水洗涤,有机相通过无水硫酸钠干燥,过滤浓缩后通过硅胶柱层析纯化(石油醚/乙酸乙酯=2/1),得到黄色油状物96d(180mg,收率69%)。ESI-MS(m/z):317.5[M+H]
+。
第三步:将化合物96d(180mg,568umol)和盐酸1,4-二氧六环溶液(4M,0.5mL)溶解于二氯甲烷(2mL)中,在室温条件下搅拌过夜。LCMS监测反应结束。反应液浓缩得到黄色固体96e(140mg,收率97%)。ESI-MS(m/z):217.5[M+H]
+。
第四步:将化合物1i(50mg,197umol),化合物96e(64mg,296umol)和一水对甲苯磺酸(4mg,19umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体95(28mg,收率33%)。ESI-MS(m/z):433.5[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.44(d,J=2.2Hz,1H),7.64(dd,J=8.0,2.2Hz,1H),7.28(dd,J=8.3,5.6Hz,2H),7.20(d,J=7.9Hz,1H),7.09(t,J=8.8Hz,2H),7.02(s,1H),4.42-4.31(m,2H),4.11(q,J=6.8Hz,1H),4.03-3.97(m,3H),3.28-3.24(m,1H),2.92(s,3H),2.55-2.48(m,2H),1.94-1.87(m,1H),1.83-1.76(m,1H),1.22(d,J=6.8Hz,3H)。
实施例97(W312)
(S)-2-(((6-((2-环丙基嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10- 四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物97由以下步骤制备:
第一步:将化合物97a(800mg,6.13mmol),化合物97b(748mg,6.13mmol)和碳酸铯(2.40g,7.35mmol)溶于N,N-二甲基甲酰胺(15mL)之中,反应液在室温下搅拌12个小时。反应结束后,将反应液过滤,滤液浓缩后得到粗品。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯=3/1)得到目标化合物97c(950mg,收率66%)。ESI-MS(m/z):233.2[M+H]
+。
第二步:将中间体97c(500mg,2.15mmol),环丙基硼酸(923mg,10.75mmol),1,1-双(二苯基膦)二荗铁二氯化钯(314mg,429ummol)和碳酸钾(549mg,4.30mmol)溶于1,4-二氧六环(10mL)与水(2mL)的混合溶液之中,反应体系置换氮气后加热至100℃反应4个小时。反应结束后,将反应液用硅藻土过滤,滤液浓缩后得到粗品。粗品经过硅胶柱层析纯化(石油醚/乙酸乙酯=3/1)得到目标化合物97d(290mg,收率56%)。ESI-MS(m/z):239.4[M+H]
+。
第三步:将中间体97d(100mg,419ummol)和Raney Nickel(0.1mL,水混悬液)溶于甲醇(10mL)和氨水(1mL)的混合溶液之中,反应液在氢气氛围下室 温搅拌12个小时。反应结束后,将反应液过滤,滤液浓缩后得到粗品97e(101mg),直接用于下一步反应。ESI-MS(m/z):243.5[M+H]
+。
第四步:将中间体97e(101mg,从第三步得到),中间体1i(106mg,419umol)和对甲苯磺酸一水合物(8mg,42ummol)溶于正丁醇(4mL)之中,反应液在微波160℃条件下反应2个小时。反应结束后,将反应液通过反相制备HPLC纯化得到目标产物97(34mg,两步反应收率17%)。ESI-MS(m/z):459.5[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.55(s,2H),8.06(d,J=2.5Hz,1H),7.85(dd,J=8.0,2.5Hz,1H),7.10(d,J=8.5Hz,1H),7.01(br s,1H),4.40-4.30(m,2H),4.11(q,J=7.0Hz,1H),4.03-3.98(m,1H),3.30-3.25(m,2H),2.93(s,3H),2.53-2.48(m,2H),2.26-2.21(m,1H),1.93-1.78(m,2H),1.23(d,J=7.0Hz,3H),1.07-0.96(m,4H)。
实施例98(W188)
(S)-2-(((6-((4,4-二氟环己基)氧代)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用4,4-二氟环己烷-1-醇替换实施例12中第一步的3,3-二氟环丁烷-1-醇12a,用类似的方法和反应步骤,可以得到化合物98。ESI-MS(m/z):459.2[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.09(d,J=2.3Hz,1H),7.66(dd,J=8.6,2.4Hz,1H),6.98(br s,1H),6.74(d,J=8.4Hz,1H),5.15(br s,1H),4.40-4.24(m,2H),4.11(q,J=6.7Hz,1H),4.06-3.98(m,1H),3.32-3.24(m,1H),2.94(s,3H),2.55-2.48(m,2H),2.10-1.72(m,10H),1.22(d,J=6.7Hz,3H)。
实施例99(W193)
(S)-4,5-二甲基-2-(((6-((5-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物99由以下步骤制备:
第一步:将5-(三氟甲基)吡啶-3-酚99a(500mg,3.07mmol)和6-氯-3-氰基吡啶99b(509mg,3.68mmol)溶解于N,N-二甲基甲酰胺(10mL)中,加入碳酸铯(2.0g,6.14mmol),在80℃条件下搅拌过夜。LCMS监测反应结束。反应液用乙酸乙酯稀释,依次用水,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=5/1)纯化,得到无色油状物99c(600mg,收率73%)。ESI-MS(m/z):266.0[M+H]
+。
第二步:将中间体99c(550mg,2.07mmol)溶解于甲醇(2mL)中,依次加入雷尼镍(0.5mL,水混悬液)和氨水(0.2mL),体系通过氢气球抽换气,并在氢气球条件下搅拌过夜。LCMS监测反应结束,反应液用甲醇稀释,抽滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到白色固体99d(400mg,收率71%)。ESI-MS(m/z):270.3[M+H]
+。
第三步:将化合物1i(50mg,197umol),化合物99d(79mg,296umol)和一水对甲苯磺酸(4mg,19umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白 色固体99(19mg,收率20%)。ESI-MS(m/z):486.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.83(d,J=1.8Hz,1H),8.76(d,J=2.6Hz,1H),8.15-8.08(m,2H),7.88(dd,J=8.4,2.4Hz,1H),7.15(d,J=8.4Hz,1H),7.04(br s,1H),4.46-4.32(m,2H),4.11(q,J=6.7Hz,1H),4.07-3.99(m,1H),3.31-3.24(m,1H),2.93(s,3H),2.55-2.51(m,2H),1.96-1.88(m,1H),1.87-1.73(m,1H),1.22(d,J=6.8Hz,3H)。
实施例100(W239)
(S)-4,5-二甲基-2-(((6-((2-(三氟甲基)吡啶-4-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用2-(三氟甲基)吡啶-4-酚替换实施例99中第一步的5-(三氟甲基)吡啶-3-酚99a,用类似的方法和反应步骤,可以得到化合物100。ESI-MS(m/z):486.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.71(d,J=5.6Hz,1H),8.24(d,J=2.4Hz,1H),7.93(dd,J=8.4,2.4Hz,1H),7.63(d,J=2.3Hz,1H),7.42(dd,J=5.6,2.3Hz,1H),7.20(d,J=8.3Hz,1H),7.07(t,J=6.2Hz,1H),4.47-4.36(m,2H),4.12(q,J=6.8Hz,1H),4.05-3.98(m,1H),3.29-3.24(m,1H),2.93(s,3H),2.55-2.49(m,2H),1.96-1.88(m,1H),1.85-1.77(m,1H),1.23(d,J=6.7Hz,3H)。
实施例101(W213)
(S)-4,5-二甲基-2-((4-((6-(三氟甲基)吡啶-3-基)氧代)苯甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用4-羟基苯甲腈和5-氟-2-(三氟甲基)吡啶替换实施例99中第一步的5-(三氟甲基) 吡啶-3-酚99a和6-氯-3-氰基吡啶99b,用类似的方法和反应步骤,可以得到化合物101。ESI-MS(m/z):485.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.52(d,J=2.8Hz,1H),7.90-7.85(m,1H),7.50-7.45(m,1H),7.44-7.39(m,2H),7.18-7.11(m,2H),7.10-7.01(m,1H),4.50-4.35(m,2H),4.15-4.10(m,1H),4.06-3.97(m,1H),3.31-3.23(m,1H),2.93(s,3H),2.55-2.49(m,2H),1.98-1.87(m,1H),1.86-1.74(m,1H),1.23(d,J=6.4Hz,3H)。
实施例102(W214)
(S)-4,5-二甲基-2-(((6-((1-(2,2,2-三氟乙基)哌啶-4-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物102由以下步骤制备:
第一步:将化合物102a(500mg,2.48mmol)溶于N,N-二甲基甲酰胺(8mL)中,在0℃下加入氢化钠(105mg,含量60%,2.62mmol),反应液搅拌半小时。将化合物99b(344mg,2.48mmol)加入反应液中,反应液在0℃下继续搅拌2小时。LCMS监测反应结束。反应液用饱和氯化铵水溶液淬灭,乙酸乙酯萃取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯 化(石油醚/乙酸乙酯=5/1)得到白色固体102b(606mg,收率81%)。ESI-MS(m/z):304.3[M+H]
+。
第二步:将化合物102b(606mg,2.0mmol)溶于盐酸二氧六环(4M,5mL)中,反应液在室温下搅拌1小时。LCMS监测反应结束。将反应液浓缩得到化合物102c的粗品,直接用于下一步反应。ESI-MS(m/z):204.5[M+H]
+。
第三步:将上一步得到的化合物102c的粗品溶于N,N-二甲基甲酰胺(5mL)中,加入碳酸钾(502mg,3.63mmol)和三氟甲磺酸三氟乙酯(280mg,1.21mmol),反应液在室温下搅拌12小时。LCMS监测反应结束。反应液用饱和食盐水稀释,乙酸乙酯萃取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩,得到化合物102d的粗品,直接用于下一步反应。ESI-MS(m/z):286.4[M+H]
+。
第四步:将上一步得到的102d粗品溶于甲醇(9mL)和氨水(1mL)中,加入Raney Nickel(0.5mL,水混悬液),反应体系置换氢气后在室温下搅拌12小时。LCMS监测反应结束。反应液硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(二氯甲烷/甲醇=5/1)得到黄色油状液体102e(171mg,三步反应收率29%)。ESI-MS(m/z):290.4[M+H]
+。
第五步:将化合物102e(160mg,0.55mmol)和化合物1i(94mg,0.37mmol)溶于正丁醇(4mL),加入对甲苯磺酸一水合物(71mg,0.37mmol),反应液在微波条件下,160℃搅拌3小时。待反应液冷却至室温,反应液减压浓缩,残余物用反相制备HPLC纯化得到白色固体化合物102(20mg,收率7%)。ESI-MS(m/z):506.3[M+H]
+;
1H NMR(400MHz,DMSO)δ8.11-8.06(m,1H),7.68-7.62(m,1H),6.99(br s,1H),6.75-6.68(m,1H),5.21-4.92(m,1H),4.75-4.65(m,1.5H),4.38-4.22(m,2H),4.11(q,J=6.8Hz,1H),4.06-3.97(m,1H),3.76-3.66(m,1.5H),3.32-3.22(m,2H),3.21-3.13(m,1H),2.93(s,3H),2.88-2.79(m,1H),2.60-2.50(m,2H),2.00-1.88(m,3H),1.84-1.73(m,1H),1.70-1.50(m,2H),1.22(d,J=6.8Hz,3H)。
实施例103(W195)
(S)-4,5-二甲基-2-(((5-甲基-6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用6-(三氟甲基)吡啶-3-酚和6-氯-5-甲基-3-氰基吡啶替换实施例99中第一步的5-(三氟甲基)吡啶-3-酚99a和6-氯-3-氰基吡啶99b,用类似的方法和反应步骤,可以得到化合物103。ESI-MS(m/z):500.2[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.61(d,J=2.5Hz,1H),7.95(d,J=8.6Hz,1H),7.92(d,J=1.5Hz,1H),7.83(dd,J=8.6,2.5Hz,1H),7.75(d,J=1.5Hz,1H),7.02(t,J=5.6Hz,1H),4.40-4.29(m,2H),4.11(q,J=6.7Hz,1H),4.04-3.98(m,1H),3.29-3.22(m,1H),2.93(s,3H),2.55-2.49(m,2H),2.30(s,3H),1.93-1.86(m,1H),1.82-1.77(m,1H),1.22(d,J=6.8Hz,3H)。
实施例104(W198)
4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物104由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(0.70g,3.50mmol)和甘氨酸甲酯盐酸盐104a(0.66g,5.25mmol)溶解于四氢呋喃(10mL)中,加入N,N-二异丙基乙胺(1.36g,10.50mmol,1.83mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色油状物104b(0.70g,收率79%)。ESI-MS(m/z):275.3[M+Na]
+。
第二步:将化合物104b(0.70g,2.77mmol)溶解于四氢呋喃(30mL)中,加入盐酸水溶液(6M,0.46mL)和二氧化铂(62mg,0.28mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到灰色固体104c(0.35g,收率56%)。ESI-MS(m/z):225.5[M+H]
+。
第三步:将化合物104c(100mg,0.45mmol)和碘甲烷(94mg,0.67mmol)溶解在乙腈(2mL)中,加入碳酸铯(290mg,0.89mmol),在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到黄色固体104d(80mg,收率75%)。ESI-MS(m/z):239.5[M+H]
+。
第四步:将化合物104d(50mg,209umol),化合物11d(67mg,251umol)和一水对甲苯磺酸(4mg,21umol)溶解在正丁醇(2mL)中,在微波160℃的 条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体104(40mg,收率40%)。ESI-MS(m/z):472.2[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.63(d,J=2.7Hz,1H),8.12(d,J=2.5Hz,1H),7.97(d,J=8.6Hz,1H),7.89(dd,J=8.5,2.6Hz,1H),7.85(dd,J=8.5,2.6Hz,1H),7.17(dd,J=8.4,0.7Hz,1H),7.03(br s,1H),4.37(d,J=6.4Hz,2H),4.00(s,2H),3.73-3.62(m,2H),2.91(s,3H),2.53-2.47(m,2H),1.89-1.78(m,2H)。
实施例105(W199)
(S)-5-甲基-4-(甲基-d3)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物105由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(2.0g,3.5mmol)和L-丙氨酸甲酯盐酸盐105a(1.81g,13.0mmol)溶解于四氢呋喃(20mL)中,加入N,N-二异丙基乙胺(3.88g,30.0mmol,5.22mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色油状物105b(2.5g,收率93%)。ESI-MS(m/z):267.3[M+H]
+。
第二步:将化合物105b(2.5g,9.37mmol)溶解于四氢呋喃(30mL)中,加入盐酸水溶液(6M,1.56mL)和二氧化铂(212mg,0.94mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到灰色固体105c(0.8g,收率35%)。ESI-MS(m/z):239.5[M+H]
+。
第三步:将化合物105c(100mg,0.42mmol)和氘代碘甲烷(121mg,0.84mmol)溶解在乙腈(10mL)中,加入碳酸铯(273mg,0.84mmol),在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到白色固体105d(80mg,收率74%)。ESI-MS(m/z):256.3[M+H]
+。
第四步:将化合物105d(50mg,195umol),化合物11d(63mg,234umol)和一水对甲苯磺酸(4mg,19umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体105(33mg,收率34%)。MS(ESI):m/z 489.2[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.63(d,J=2.6Hz,1H),8.12(d,J=2.4Hz,1H),7.97(d,J=8.6Hz,1H),7.89(dd,J=8.5,2.6Hz,1H),7.85(dd,J=8.5,2.6Hz,1H),7.17(d,J=8.4Hz,1H),7.06(br s,1H),4.45-4.31(m,2H),4.11(q,J=6.8Hz,1H),4.04-3.96(m,1H),3.30-3.22(m,1H),2.62-2.50(m,2H),1.96-1.87(m,1H),1.84-1.73(m,1H),1.22(d,J=6.8Hz,3H)。
实施例106(W190)
(S)-5-(甲氧基甲基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物106由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(2g,10.00mmol)和O-甲基-L-丝氨酸甲酯盐酸盐106a(2.45g,15.00mmol)溶解于四氢呋喃(20mL)中,加入N,N-二异丙基乙胺(3.88g,30.00mmol,5.22mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色油状物106b(2.5g,收率84%)。ESI-MS(m/z):297.2[M+H]
+。
第二步:将化合物106b(2.5g,8.43mmol)溶解于四氢呋喃(30mL)中,加入盐酸水溶液(6N,1.40mL)和二氧化铂(191mg,0.84mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,硅藻土过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到灰色固体106c(2.0g,收率88%)。ESI-MS(m/z):269.3[M+H]
+。
第三步:将化合物106c(500mg,1.86mmol)和碘甲烷(343mg,2.42mmol)溶 解在乙腈(10mL)中,加入碳酸铯(1.21g,372mmol),在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到白色固体106d(350mg,收率66%)。ESI-MS(m/z):283.3[M+H]
+。
第四步:将化合物106d(50mg,176umol),化合物11d(71mg,265umol)和一水对甲苯磺酸(3mg,17umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体106(6mg,收率7%)。ESI-MS(m/z):516.2[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.63(d,J=2.7Hz,1H),8.13(d,J=2.4Hz,1H),7.97(d,J=8.6Hz,1H),7.89(dd,J=8.5,2.6Hz,2H),7.85(dd,J=8.5,2.6Hz,2H),7.17(d,J=8.4Hz,1H),6.99(br s,1H),4.45-4.32(m,2H),4.22(t,J=2.8Hz,1H),4.02-3.95(m,1H),3.71-3.60(m,2H),3.40-3.30(m,1H),3.15(s,3H),2.96(s,3H),2.55-2.47(m,2H),1.88(d,J=7.6Hz,1H),1.74(s,1H)。
实施例107(W192)
(S)-5-(羟甲基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物107由以下步骤制备:
第一步:将106d(250mg,0.88mmol)溶解于二氯甲烷(2mL)中,再0℃滴加三溴化硼(2.21g,8.84mmol,0.85mL),滴加完成后在0℃下反应两个小时。LCMS监测反应结束。反应液用碳酸氢钠溶液小心淬灭,二氯甲烷萃取,有机相饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩,残余物通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到白色固体107a(100mg,收率42%)。ESI-MS(m/z):269.3[M+H]
+。
第二步:将化合物107a(30mg,111umol),化合物11d(45mg,167umol)和一水对甲苯磺酸(2mg,11umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体107(9mg,收率17%)。ESI-MS(m/z):501.6[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.27(s,1H),8.13(d,J=2.5Hz,1H),7.97(d,J=8.6Hz,1H),7.89(dd,J=8.6,2.5Hz,2H),7.86(dd,J=8.6,2.5Hz,2H),7.17(d,J=8.4Hz,1H),6.95(br s,1H),4.44-4.30(m,2H),4.08-3.97(m,2H),3.76-3.65(m,2H),3.40-3.30(m,1H),2.96(s,3H),2.52-2.47(m,2H),1.92-1.86(m,1H),1.83-1.72(s,1H)。
实施例108(W207)
(S)-5-(羟甲基)-4-(甲基-d3)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物108由以下步骤制备:
第一步:将化合物106c(200mg,0.74mmol)和氘代碘甲烷(215mg,1.49mmol)溶解在乙腈(5mL)中,加入碳酸铯(485mg,1.49mmol),在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到黄色固体108a(200mg,收率94%)。ESI-MS(m/z):286.3[M+H]
+。
第二步:将108a(200mg,0.87mmol)溶解于二氯甲烷(2mL)中,在0℃滴加三溴化硼(2.19g,8.75mmol,0.84mL),滴加完成后在0℃下反应两个小时。LCMS监测反应结束。反应液用碳酸氢钠溶液小心淬灭,二氯甲烷萃取,合并的有机相无水硫酸钠干燥,过滤浓缩,残余物通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到白色固体108b(150mg,收率75%)。ESI-MS(m/z):272.3[M+H]
+。
第三步:将化合物108b(50mg,184umol),化合物11d(59mg,220umol)和一水对甲苯磺酸(3.5mg,18umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体108(41mg,收率44%)。ESI-MS(m/z):505.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=2.7Hz,1H),8.15(d,J=2.4Hz,1H),7.97(d,J=8.6Hz,1H),7.92(dd,J=8.4,2.5Hz,1H),7.87(dd,J=8.5,2.7Hz,1H),7.19(d,J=8.4Hz,1H),5.07(br s,1H),4.52-4.37(m,2H),4.14(s,1H),4.07-4.00(m,1H),3.80-3.68(m,2H),3.35-3.29(m,1H),2.56-2.50(m,2H),1.97-1.88(m,1H),1.82-1.71(m,1H)。\
实施例109(W220)
(S)-5-((R)-1-羟基乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物109由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.0g,5.0mmol)和L-苏氨酸甲酯盐酸盐109a(1.10g,6.5mmol)溶解于四氢呋喃(10mL)中,加入N,N-二异丙基乙胺(1.94g,15.0mmol,2.61mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色油状物109b(1.3g,收率87%)。ESI-MS(m/z):297.3[M+H]
+。
第二步:将化合物109b(1.3g,4.38mmol)溶解于四氢呋喃(20mL)中,加入盐酸水溶液(6M,0.73mL)和二氧化铂(99mg,0.44mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,硅藻土过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到灰色固体109c(0.4g,收率33%)。ESI-MS(m/z):269.3[M+H]
+。
第三步:将化合物109c(150mg,0.56mmol)和碘甲烷(118mg,0.84mmol)溶解在乙腈(3mL)中,加入碳酸铯(363mg,1.12mmol),在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到白色固体109d(100mg,收率63%)。ESI-MS(m/z):283.4[M+H]
+。
第四步:将化合物109d(50mg,176umol),化合物11d(57mg,212umol)和一水对甲苯磺酸(3.3mg,17umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体109(40mg,收率44%)。ESI-MS(m/z):516.3[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.19(s,1H),8.13(d,J=2.4Hz,1H),7.97(d,J=8.6Hz,1H),7.89(dd,J=8.5,2.5Hz,1H),7.86(dd,J=8.5,2.5Hz,2H),7.17(d,J=8.4Hz,1H),7.02(t,J=6.4Hz,1H),4.93(br s,1H),4.47-4.27(m,2H),4.17-4.06(m,1H),3.93-3.83(m,2H),3.17-3.10(m,1H),3.07(s,3H),2.52-247(m,2H),1.98-1.88(m,1H),1.82-1.68(m,1H),1.09(d,J=6.2Hz,3H)。
实施例110(W231)
(S)-5-((S)-1-羟基乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物110由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(3.0g,15.0mmol)和L-别苏氨酸甲酯盐酸盐110a(3.31g,19.5mmol)溶解于二氯甲烷(30mL)中,加入N,N-二异丙基乙胺(5.82g,45.0mmol,7.84mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色油状物110b(3.8g,收率85%)。ESI-MS(m/z):297.3[M+H]
+。
第二步:将化合物110b(1.5g,5.06mmol)溶解于四氢呋喃(20mL)中,加入盐酸水溶液(6N,0.84mL)和二氧化铂(114.80mg,0.51mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到灰色固体110c(0.5g,收率36%)。ESI-MS(m/z):269.5[M+H]
+。
第三步:将化合物110c(100mg,0.37mmol)和碘甲烷(79mg,0.56mmol)溶解在乙腈(3mL)中,加入碳酸铯(242mg,0.74mmol),在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到白色固体110d(80mg,收率76%)。ESI-MS(m/z):283.3[M+H]
+。
第四步:将化合物110d(50mg,176umol),化合物11d(57mg,212umol)和一水对甲苯磺酸(3.3mg,17umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得 到白色固体110(44mg,收率48%)。ESI-MS(m/z):516.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.65(d,J=2.7Hz,1H),8.17-8.13(m,1H),7.98(d,J=8.6Hz,1H),7.92(dd,J=8.4,2.5Hz,1H),7.87(dd,J=8.6,2.7Hz,1H),7.19(d,J=8.3Hz,1H),7.10-6.90(m,1H),5.05(d,J=4.8Hz,1H),4.52-4.34(m,2H),4.16-4.02(m,3H),3.25-3.17(m,1H),3.05(s,3H),2.55-2.47(m,2H),1.99-1.90(m,1H),1.80-1.70(m,1H),1.04(d,J=6.4Hz,3H)。
实施例111(W241)
(S)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-5,6,8a,9,10,11-六氢-4H,8H-吡啶并[3,2,1-脱]吡咯并[2,1-h]蝶啶-8-酮
化合物111由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.00g,5.00mmol)和L-脯氨酸甲酯盐酸盐111a(1.08g,6.50mmol)溶解于四氢呋喃(10mL)中,加入N,N-二异丙基乙胺(1.94g,15.00mmol,2.61mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色固体111b(1.20g,收率82%)。ESI-MS(m/z):293.2[M+H]
+。
第二步:将化合物111b(1.20g,4.10mmol)溶解于四氢呋喃(20mL)中,加入盐酸水溶液(6N,0.70mL)和二氧化铂(94mg,0.41mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到黄色固体111c(0.60g,收率55%)。ESI-MS(m/z):265.3[M+H]
+。
第三步:将化合物111c(50mg,188umol),化合物11d(67mg,251umol)和一水对甲苯磺酸(3.6mg,18umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体111(15mg,收率16%)。ESI-MS(m/z):498.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.13(d,J=2.3Hz,1H),7.98(d,J=8.6Hz,1H),7.90(dd,J=8.5,2.6Hz,1H),7.86(dd,J=8.5,2.6Hz,2H),7.17(d,J=8.4Hz,1H),7.06(t,J=6.4Hz,1H),4.44-4.32(m,2H),4.14-4.04(m,2H),3.62-3.54(m,1H),3.49-3.40(m,1H),3.25-3.16(m,1H),2.52-2.47(m,2H),2.26-2.20(m,1H),2.00-1.75(m,5H)。
实施例112(W242)
(8aS,10S)-10-羟基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-5,6,8a,9,10,11-六氢-4H,8H-吡啶并[3,2,1-脱]吡咯并[2,1-h]蝶啶-8-酮
化合物112由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.0g,5.0mmol)和顺式-4-羟基-L-脯氨酸甲酯盐酸盐112a(943mg,6.50mmol)溶解于四氢呋喃(10mL)中,加入N,N-二异丙基乙胺(1.94g,15.0mmol,2.61mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液浓缩,残余物通过硅胶柱层析(石油醚/乙酸乙酯=1/1)纯化,得到黄色固体112b(1.3g,收率84%)。ESI-MS(m/z):309.2[M+H]
+。
第二步:将化合物112b(1.3g,4.21mmol)溶解于四氢呋喃(10mL)中,加入盐酸水溶液(6N,0.70mL)和二氧化铂(95mg,0.42mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到白色固体112c(0.80g,收率67%)。ESI-MS(m/z):281.3[M+H]
+。
第三步:将化合物112c(50mg,178umol),化合物11d(57mg,213umol)和一水对甲苯磺酸(3.4mg,17umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体112(23mg,收率25%)。ESI-MS(m/z):514.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.13(d,J=2.3Hz,1H),7.97(d,J=8.6Hz,1H),7.89(dd,J=8.5,2.6Hz,1H),7.86(dd,J=8.5,2.6Hz,2H),7.17(d,J=8.4Hz,1H),7.06(t,J=4.3Hz,1H),5.14(br s,1H),4.45-4.29(m,4H),4.15-4.08(m,1H),3.80-3.70(m,1H),3.54-3.40(m,2H),3.25-3.17(m,1H),2.50-2.39(m,1H), 2.15-2.09(m,1H),2.04-1.89(m,2H),1.86-1.77(m,1H)。
实施例113(W247)
(S)-5-((S)-1-甲氧基乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物113由以下步骤制备:
第一步:将化合物110c(100mg,0.37mmol)溶解于四氢呋喃(2mL)中,加入碳酸银(431mg,1.86mmol),碳酸铯(242mg,0.74mmol)和碘甲烷(158mg,1.12mmol,69uL),在60℃氮气保护条件下搅拌16小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇=20/1)纯化,得到黄色油状物113a(60mg,收率54%)。ESI-MS(m/z):297.3[M+H]
+。
第二步:将化合物113a(60mg,202umol),化合物11d(65mg,242umol)和一水对甲苯磺酸(3.8mg,20umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体113(23mg,收率21%)。ESI-MS(m/z):530.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=2.7Hz,1H),8.14(d,J=2.5Hz,1H),7.97(d,J=8.5Hz,1H),7.91(dd,J=8.4,2.5Hz,1H),7.86(dd,J=8.6,2.7Hz,1H),7.18(d,J=8.4Hz,1H),7.01(br s,1H),4.39(d,J=6.2Hz,2H),4.31(d,J=1.9Hz,1H),4.12-4.03 (m,1H),3.75-3.68(m,1H),3.30-3.21(m,1H),3.20(s,3H),3.02(s,3H),2.52-2.47(m,2H),1.96-1.89(m,1H),1.80-1.70(m,1H),1.00(d,J=6.4Hz,3H)。
实施例114(W243)
(S)-5-((R)-1-甲氧基乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用中间体109c替换实施例113中第一步的110c,用类似的方法和反应步骤,可以得到化合物114。ESI-MS(m/z):530.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.15(d,J=2.3Hz,1H),7.97(d,J=8.6Hz,1H),7.92(dd,J=8.4,2.5Hz,1H),7.87(dd,J=8.6,2.7Hz,1H),7.18(d,J=8.4Hz,1H),7.06(br s,1H),4.45-4.33(m,2H),4.17-4.10(m,1H),4.07(d,J=4.8Hz,1H),3.60-3.51(m,1H),3.20-3.11(m,4H),3.07(s,3H),2.55-2.49(m,2H),2.02-1.93(m,1H),1.81-1.69(m,1H),1.08(d,J=6.4Hz,3H)。
实施例115(W244)
(S)-4-(2-甲氧基乙基)-5-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物115由以下步骤制备:
第一步:将氢化钠(84mg,含量60%,2.10mmol)溶于干燥DMF(1mL)中,0度下加入化合物105c(100mg,0.42mmol,溶于1mL DMF),氮气保护下,继续在0度搅拌1小时。再加入1-溴乙基甲基醚(117mg,0.84mmol),反应液继续在0度搅拌2小时。TLC监测反应结束,加水淬灭后,加入乙酸乙酯(2*20mL)萃取,有机相用无水硫酸钠干燥,过滤浓缩。残余物通过硅胶柱层析纯化(乙酸乙酯/石油醚=1/1到4/1)得到黄色固体115a(95mg,收率76%)。ESI-MS(m/z):297.3[M+H]
+。
第四步:将化合物115a(90mg,0.30mmol),化合物11d(81mg,0.30mol)和一水对甲苯磺酸(5.7mg,0.03mol)溶解在正丁醇(3mL)中,在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体115(23mg,收率15%)。ESI-MS(m/z):530.2[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.63(d,J=2.7Hz,1H),8.11(d,J=2.5Hz,1H),7.97(d,J=8.6Hz,1H),7.90-7.83(m,2H),7.18(d,J=8.4Hz,1H),7.08(br s,1H),4.48-4.28(m,2H),4.16(q,J=6.7Hz,1H),4.09-3.98(m,2H),3.30-3.15(m,5H),2.55-2.50(m,2H),1.99-1.89(m,1H),1.84-1.75(m,1H),1.23(d,J=6.8Hz,3H)。
实施例116(W249)
(S)-4-乙基-5-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用碘乙烷替换实施例105中第三步的氘代碘甲烷,用类似的方法和反应步骤,可以得到化合物116。ESI-MS(m/z):499.9[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.63(d,J=2.6Hz,1H),8.12(d,J=2.3Hz,1H),7.98(d,J=8.6Hz,1H),7.92-7.83(m,2H),7.18(d,J=8.4Hz,1H),7.06(br s,1H),4.45-4.31(m,2H),4.16(q,J=6.7Hz,1H),4.06-3.99(m,1H),3.89-3.77(m,1H),3.32-3.25(m,2H),3.15-3.07(m,1H),2.00-1.90(m,1H),1.86-1.74(m,1H),1.25(d,J=6.7Hz,3H),1.06(t,J=7.1Hz,3H)。
实施例117(W237)
(S)-5-异丙基-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-缬氨酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a,用类似的方法和反应步骤,可以得到化合物117。ESI-MS(m/z):514.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.14(d,J=2.4Hz,1H),7.98(d,J=8.5Hz,1H),7.91(dd,J=8.5,3.0Hz,1H),7.86(dd,J=8.5,3.0Hz,1H),7.18(d,J=8.3Hz,1H),7.02(br s,1H),4.45-4.33(m,2H),4.18-4.12(m,1H),3.99(d,J=3.8Hz,1H),3.22-3.15(m,1H),3.01(s,3H),2.55-2.49(m,2H),2.18-2.13(m,1H),2.01-1.93(m,1H),1.80-1.69(m,1H),0.94(d,J=7.0Hz,3H),0.75(d,J=6.9Hz,3H)。
实施例118(W279)
(S)-4-乙基-5-异丙基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-缬氨酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a,然后用碘乙烷替换第三步中的碘甲烷。用类似的方法和反应步骤,可以得到化合物118。ESI-MS(m/z):526.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.61(d,J=2.2Hz,1H),8.11(d,J=1.6Hz,1H),7.96(d,J=8.6Hz,1H),7.88(dd,J=8.4,2.0Hz,1H),7.83(dd,J=8.6,2.1Hz,1H),7.17(d,J=8.4Hz,1H),7.01(br s,1H),4.47-4.31(m,2H),4.17-4.11(m,1H),4.06-3.95(m,2H),3.35-3.26(m,2H),3.21-3.15(m,1H),3.10-3.00(m,1H),2.09-2.01(m,1H),1.99-1.93(m,1H),1.76-1.67(m,1H),1.02(t,J=6.7Hz,3H),0.93(d,J=6.9Hz,3H),0.74(d,J=6.8Hz,3H)。
实施例119(W255)
(S)-5-乙基-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-2-氨基丁酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a,用类似的方法和反应步骤,可以得到化合物119。ESI-MS(m/z):500.0[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.6Hz,1H),8.12(d,J=2.3Hz,1H),7.96(d,J=8.5Hz,1H),7.89(dd,J=8.5,2.5Hz,2H),7.85(dd,J=8.5,2.5Hz,2H),7.16(d,J=8.4Hz,1H),7.00(t,J=6.3Hz,1H),4.43-4.31(m,2H),4.15-4.10(m,1H),4.07-4.00(m,1H),3.30-3.25(m,1H),2.94(s,3H),2.55-2.49(m,2H),1.99-1.89(m,1H),1.85-1.70(m,3H),0.68(t,J=7.4Hz,3H)。
实施例120(W265)
(S)-5-环丙基-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-环丙基甘氨酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a,用类似的方法和反应步骤,可以得到化合物120。ESI-MS(m/z):512.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.5Hz,1H),8.13(d,J=2.3Hz,1H),7.96(d,J=8.6Hz,1H),7.90(dd,J=8.5,2.4Hz,1H),7.85(dd,J=8.7,2.6Hz,1H),7.17(d,J=8.4Hz,1H),7.07(br s,1H),4.46-4.29(m,2H),4.14-4.06(m,1H),3.47(d,J=8.7Hz,1H),3.20-3.12(m,1H),3.01(s,3H),2.54-2.49(m,2H),2.00-1.90(m,1H),1.84-1.72(m,1H),0.93-0.83(m,1H),0.56-0.47(m,2H),0.45-0.31(m,2H)。
实施例121(W266)
(S)-4-乙基-5-((S)-1-羟基乙基)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物121由以下步骤制备:
第一步:将化合物110c(230mg,0.86mmol)溶于乙腈(5mL)中,加入碳酸铯(557mg,1.71mmol)和碘乙烷(200mg,1.28mmol),反应液在50℃下搅拌 12小时。反应液用饱和食盐水稀释,乙酸乙酯萃取。有机相用无水硫酸钠干燥,过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯=2/1)得到化合物121a(265mg,收率70%)。ESI-MS(m/z):297.2[M+H]
+。
第二步:将化合物11d(65mg,0.24mmol)和化合物121a(48mg,0.16mmol)溶于正丁醇(5mL)中,加入对甲苯磺酸一水合物(28mg,0.16mmol),反应液在微波条件下,160℃搅拌3小时。待反应液冷却至室温,反应液减压浓缩,残余物用反相制备HPLC纯化得到白色固体化合物119(8mg,收率6%)。ESI-MS(m/z):530.5[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.2Hz,1H),8.12(d,J=1.6Hz,1H),7.96(d,J=8.6Hz,1H),7.89(dd,J=8.4,2.0Hz,1H),7.84(dd,J=8.6,2.1Hz,1H),7.17(d,J=8.4Hz,1H),6.94(br s,1H),5.01(d,J=4.8Hz,1H),4.49-4.27(m,2H),4.13-4.05(m,2H),4.04-3.95(m,2H),3.24-3.14(m,2H),2.50-2.43(m,2H),1.95-1.87(m,1H),1.79-1.66(m,1H),1.06-0.99(m,6H)。
实施例122(W272)
(S)-5-(2-羟基丙烷-2-基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用(S)-2-氨基-3-羟基-3-甲基丁酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a,用类似的方法和反应步骤,可以得到化合物122。ESI-MS(m/z):530.3[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.60(d,J=3.0Hz,1H),8.11(d,J=2.0Hz,1H),7.96-7.92(m,1H),7.91-7.87(m,1H),7.85-7.80(m,1H),7.16-7.12(m,1H),7.01-6.94(m,1H),4.68(s,1H),4.46-4.30(m,2H),4.17-4.11(m,1H),3.86(s,1H),3.09(s,3H),3.08-3.03(m,1H),2.58-2.52(m,2H),2.00-1.89(m,1H),1.77-1.66(m,1H),1.15(s,3H),0.91(s,3H)。
实施例123(W276)
(8aS,9S)-9-羟基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-5,6,8a,9,10,11-六氢-4H,8H-吡啶并[3,2,1-脱]吡咯并[2,1-h]蝶啶-8-酮
用反-3-羟基-L-脯氨酸甲酯盐酸盐替换实施例112中第一步的顺式-4-羟基-L-脯氨酸112a,用类似的方法和反应步骤,可以得到化合物123。ESI-MS(m/z):514.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.5Hz,1H),8.11(d,J=2.3Hz,1H),7.96(d,J=8.6Hz,1H),7.88(dd,J=8.5,2.5Hz,2H),7.85(dd,J=8.5,2.5Hz,2H),7.15(d,J=8.4Hz,1H),7.05(t,J=6.3Hz,1H),5.27(d,J=5.0Hz,1H),4.43-4.32(m,3H),4.15-4.06(m,1H),3.74(d,J=6.4Hz,1H),3.65-3.55(m,1H),3.46-3.35(m,1H),3.24-3.13(m,1H),2.52-2.45(m,2H),2.13-2.04(m,1H),1.99-1.87(m,1H),1.85-1.67(m,2H)。
实施例124(W278)
(S)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-5,6,8a,9,11,12-六氢-4H,8H-[1,4]氧杂联氮基[3,4-h]吡啶并[3,2,1-脱]蝶啶-8-酮
用(S)-3-吗啉甲酸甲酯盐酸盐替换实施例111中第一步的L-脯氨酸甲酯盐酸盐111a,用类似的方法和反应步骤,可以得到化合物124。ESI-MS(m/z):514.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.5Hz,1H),8.12(d,J=2.3 Hz,1H),7.96(d,J=8.6Hz,1H),7.88(dd,J=8.4,2.5Hz,2H),7.85(dd,J=8.4,2.5Hz,2H),7.16(d,J=8.5Hz,1H),7.13(br s,1H),4.38(d,J=6.3Hz,2H),4.24-4.19(m,1H),4.13-4.09(m,2H),3.90-3.85(m,2H),3.48-3.37(m,3H),2.86-2.76(m,1H),2.55-2.48(m,2H),1.93-1.75(m,2H)。
实施例125(W281)
(S)-4-乙基-5-((R)-1-羟基乙基)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用中间体109c替换实施例121中第一步的110c,用类似的方法和反应步骤,可以得到化合物125。ESI-MS(m/z):530.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.5Hz,1H),8.12(d,J=2.5Hz,1H),7.96(d,J=8.5Hz,1H),7.89(dd,J=8.0,2.0Hz,1H),7.84(dd,J=9.0,2.5Hz,1H),7.17(d,J=8.5Hz,1H),6.99(br s,1H),4.87(d,J=5.5Hz,1H),4.50-4.40(m,1H),4.36-4.28(m,1H),4.20-4.10(m,2H),3.92(d,J=4.5Hz,1H),3.86-3.77(m,1H),3.18-3.05(m,2H),2.55-2.43(m,2H),2.00-1.90(m,1H),1.80-1.70(m,1H),1.05(d,J=6.5Hz,3H),0.99(t,J=7.5Hz,1H)。
实施例126(W308)
(R)-5-((S)-1-氟乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物126由以下步骤制备:
第一步:将化合物109(30mg,58umol)溶于二氯甲烷(2mL)中,在0℃冰浴下加入二乙胺基三氟化硫(19mg,116umol),混合物在0℃搅拌2小时。待反应完全后,加水淬灭反应,水相用乙酸乙酯萃取。合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用反向制备HPLC分离得到白色固体化合物126(4.5mg,收率15%)。ESI-MS(m/z):518.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.6Hz,1H),8.12(d,J=2.3Hz,1H),7.96(d,J=8.6Hz,1H),7.88(dd,J=8.5,2.5Hz,1H),7.85(dd,J=8.5,2.5Hz,1H),7.16(d,J=8.4Hz,1H),7.08(br s,1H),5.16-4.96(m,1H),4.45-4.31(m,3H),4.13-4.05(m,1H),3.31-3.20(m,1H),3.02(s,3H),2.55-2.47(m,2H),1.97-1.89(m,1H),1.80-1.68(m,1H),1.30-1.20(m,3H)。
实施例127(W280)
(S)-4-甲基-5-苯基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-苯甘氨酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a,用类似的方法和反应步骤,可以得到化合物127。ESI-MS(m/z):548.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.63(d,J=2.6Hz,1H),8.14(d,J=2.3 Hz,1H),7.96(d,J=8.6Hz,1H),7.91(dd,J=8.3,2.4Hz,1H),7.85(dd,J=8.6,2.6Hz,1H),7.40-7.29(m,3H),7.25-7.15(m,3H),7.12(br s,1H),5.19(s,1H),4.47-4.35(m,2H),4.06-3.99(m,1H),3.40-3.30(m,1H),2.83(s,3H),2.60-2.50(m,2H),1.98-1.91(m,1H),1.84-1.72(m,1H)。
实施例128(W263)
(S)-4,5-二甲基-2-(((6-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用5-羟基-1-甲基-3-三氟甲基-1H-吡唑替换实施例99中第一步的5-(三氟甲基)吡啶-3-酚99a,用类似的方法和反应步骤,可以得到化合物128。ESI-MS(m/z):489.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.15(d,J=2.3Hz,1H),7.90(dd,J=8.4,2.3Hz,1H),7.18(d,J=8.4Hz,1H),7.05(t,J=5.5Hz,1H),6.53(s,1H),4.47-4.31(m,2H),4.10(q,J=6.8Hz,1H),4.05-3.96(m,1H),3.69(s,3H),3.30-3.23(m,1H),2.92(s,3H),2.52-2.47(m,2H),1.95-1.85(m,1H),1.83-1.72(m,1H),1.22(d,J=6.8Hz,3H)。
实施例129(W369)
(S)-4,5-二甲基-2-(((6-((1-甲基-5-(三氟甲基)-1H-吡唑-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用3-羟基-1-甲基-5-三氟甲基-1H-吡唑替换实施例99中第一步的5-(三氟甲基)吡啶-3-酚99a,用类似的方法和反应步骤,可以得到化合物129。ESI-MS(m/z):489.3 [M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.13(d,J=2.3Hz,1H),7.84(dd,J=8.4,2.4Hz,1H),7.08-7.02(m,2H),6.71(s,1H),4.43-4.31(m,2H),4.12(q,J=6.8Hz,1H),4.05-3.99(m,1H),3.89(s,3H),3.33-3.23(m,2H),2.94(s,3H),2.01-1.90(m,1H),1.86-1.73(m,1H),1.24(d,J=6.7Hz,3H)。
实施例130(W354)
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物130由以下步骤制备:
第一步:将三氟乙酰乙酸乙酯130a(1.7g,9.21mmol)和环丙基肼盐酸盐130b(1.0g,9.21mmol)溶于20mL乙醇中,80℃反应过夜。反应液浓缩,残余物加入石油醚打浆,过滤得棕色固体化合物130c(800mg,收率45%)。ESI-MS(m/z):193.2[M+H]
+。
第二步:将化合物130c(300mg,1.56mmol)和化合物97b(229mg,1.87mmol)溶于10mL乙腈中,加入碳酸铯(763mg,2.34mmol),室温反应过夜,LCMS监测原料反应完全。反应液加入乙酸乙酯稀释,分别用水和饱和食盐水洗涤,有 机相用无水硫酸钠干燥,过滤浓缩,残余物用硅胶柱层析纯化得无色油状物化合物130d(350mg,收率76%)。ESI-MS(m/z):295.3[M+H]
+。
第三步:将化合物130d(350mg,1.19mmol)溶于30mL甲醇中,加入雷尼镍(0.5mL,水混悬液),3mL氨水,氢气氛下室温反应过夜,LCMS监测原料反应完全。反应液用硅藻土过滤,甲醇洗涤滤饼,滤液浓缩得浅灰色油化合物130e(350mg,收率98%)。ESI-MS(m/z):299.1[M+H]
+。
第四步:将化合物1i(50mg,0.2mmol)和化合物130e(77mg,0.25mmol)溶于正丁醇(2mL)中,加入一水对甲苯磺酸(3.7mg,0.02mmol),微波条件下160℃反应3小时,LCMS监测原料反应完全。反应液直接通过反向制备HPLC纯化得白色固体化合物130(45mg,收率44%)。ESI-MS(m/z):515.4[M+H]
+;
1H NMR(500MHz,DMSO-d
6)δ12.92(br s,1H),8.23(d,J=2.3Hz,1H),7.97(dd,J=8.4,2.4Hz,1H),7.26(d,J=8.4Hz,1H),6.55(s,1H),4.62-4.51(m,2H),4.32(q,J=6.9Hz,1H),4.04-3.94(m,1H),3.48(dt,J=7.4,3.8Hz,1H),3.33-3.28(m,1H),3.06(s,3H),2.64(t,J=6.3Hz,2H),2.03-1.94(m,1H),1.90-1.78(m,1H),1.37(d,J=6.9Hz,3H),1.07-1.02(m,2H),0.99-0.86(m,2H)。
实施例131(W366)
(S)-4,5-二甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)硫代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用6-三氟甲基-吡啶-3-硫醇替换实施例99中第一步的5-(三氟甲基)吡啶-3-酚99a,用类似的方法和反应步骤,可以得到化合物131。ESI-MS(m/z):501.7[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.79(s,1H),8.41(d,J=2.2Hz,1H),8.18(d,J=8.2Hz,1H),7.94(d,J=8.2Hz,1H),7.72(dd,J=8.2,2.2Hz,1H),7.36(d,J=8.2 Hz,1H),7.05(t,J=6.4Hz,1H),4.46-4.31(m,2H),4.11(q,J=7.0Hz,2H),4.04-3.98(m,1H),3.32-3.23(m,2H),2.91(s,3H),2.56-2.47(m,2H),1.97-1.89(m,1H),1.86-1.74(m,1H),1.23(d,J=6.7Hz,3H)。
实施例132(W383)
(S)-5-((甲氧基-d3)甲基)-4-(甲基-d3)-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物132由以下步骤制备:
第一步:将化合物106c(1.0g,3.72mmol)和碳酸铯(2.43g,7.44mmol)溶于乙腈(10mL)中,加入氘代碘甲烷(701mg,4.84mmol)。反应液在室温下搅拌反应12小时。反应液加水稀释,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩,得到黄色固体132a(693mg,收率65%)。ESI-MS(m/z):286.3[M+H]
+。
第二步:将化合物132a(200mg,0.7mmol)溶于二氯甲烷(10mL)中,在0℃ 下缓慢滴加三溴化硼(876mg,3.5mmol)。反应液在0℃下继续搅拌反应2小时。将反应液缓慢滴加至饱和碳酸氢钠水溶液中淬灭反应,乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩,得到化合物132b(108mg,收率58%)。ESI-MS(m/z):272.4[M+H]
+。
第三步:将化合物132b(108mg,0.4mmol)溶于乙腈(8mL)中,加入氧化银(461mg,1.99mmol)和氘代碘甲烷(115mg,0.8mmol)。反应液在50℃下搅拌反应12小时。反应液硅藻土过滤,滤液浓缩。残余物用硅胶柱层析纯化(二氯甲烷/甲醇=10/1)得到黄色液体132c(68mg,收率59%)。ESI-MS(m/z):289.4[M+H]
+。
第四步:将化合物91d(100mg,0.38mmol)和化合物132c(68mg,0.24mmol)溶于正丁醇(3mL)中,加入对甲苯磺酸一水合物(40mg,0.24mmol),反应液在微波条件下,160℃搅拌3小时。待反应液冷却至室温,反应液减压浓缩,残余物用反相制备HPLC纯化得到白色固体化合物140(21mg,收率10%)。ESI-MS(m/z):523.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ9.04(s,2H),8.14(s,1H),7.93(d,J=8.3Hz,1H),7.23(d,J=8.4Hz,1H),6.99(s,1H),4.45-4.31(m,2H),4.22(s,1H),4.01-3.92(m,1H),3.70-3.60(m,2H),3.40-3.30(m,1H),2.54-2.47(m,2H),1.95-1.84(m,1H),1.78-1.68(m,1H)。
实施例133(W377)
(S)-5-(羟甲基)-4,5-二甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物133由以下步骤制备:
第一步:将2,4-二氯吡啶并[3,2-d]嘧啶1f(4.0g,20.0mmol)和2-甲基-L-丝氨酸甲酯盐酸盐133a(4.07g,24.0mmol)溶解于二氯甲烷(30mL)中,加入N,N-二异丙基乙胺(7.75g,59.99mmol,10.45mL),在室温条件下搅拌过夜。LCMS监测反应结束,反应液用二氯甲烷稀释,分别用水和饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到白色固体133b(5.0g,收率84%)。ESI-MS(m/z):297.3[M+H]
+。
第二步:将化合物133b(5.0g,16.85mmol)溶解于四氢呋喃(50mL)中,加入盐酸水溶液(6M,5.62mL)和二氧化铂(382mg,1.69mmol),反应体系用氢气球置换氢气,在室温氢气球压力下搅拌48小时,LCMS监测反应结束。反应液用甲醇稀释,过滤,滤液浓缩得到白色固体133c(4.0g,收率88%)。ESI-MS(m/z):269.3[M+H]
+。
第三步:将化合物133c(1.5g,5.58mmol)和碘甲烷(1.58g,11.16mmol)溶解在乙腈(5mL)中,加入碳酸铯(3.64g,11.16mmol),反应混合物在室温条件下搅拌48小时。LCMS监测反应结束。反应液用乙酸乙酯稀释,过滤分别用水喝饱和食盐水洗涤,有机相无水硫酸钠干燥,过滤浓缩。残余物通过硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到黄色固体133d(1.1g,收率69%)。ESI-MS(m/z):283.3[M+H]
+。
第四步:将化合物133d(50mg,176umol),化合物11d(62mg,229umol)和一水对甲苯磺酸(3.3mg,17umol)溶解在正丁醇(2mL)中,在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体133(38mg,收率41%)。ESI-MS(m/z):516.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=2.6Hz,1H),8.14(d,J=2.3Hz,1H),7.97(d,J=8.6Hz,1H),7.91(dd,J=8.5,2.5Hz,2H),7.87(dd,J=8.5,2.5Hz,2H),7.18(d,J=8.4Hz,1H),6.92(t,J=7.5Hz,1H),5.06(t,J=5.5Hz,1H),4.47-4.32(m,2H),3.80-3.70(m,2H),3.69-3.61(m,1H),3.60-3.52(m,1H),2.96(s,3H),2.54-2.48(m,2H),1.92-1.75(m,2H),1.34(s,3H)。
实施例134(W380)
(S)-5-(羟甲基)-4,5-二甲基-2-(((2-((6-(三氟甲基)吡啶-3-基)氧代)嘧啶-5-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物134由以下步骤制备:
第一步:将2-氯嘧啶-5-甲醛134a(800mg,5.61mmol)溶于四氢呋喃(20mL),依次向反应液加入乙酸(0.5mL)和2,4-二甲氧基苄胺(985mg,5.89mmol),反应4小时醛134a完全转化为亚胺后,再加入氰基硼氢化钠(1.06g,16.84mmol)反应过夜。LCMS监测反应结束后,加入水淬灭反应,乙酸乙酯萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩有机相得到化合物134b。直接用于下一步反应。ESI-MS(m/z):294.3[M+H]
+。
第二步:将上述产物134b溶于二氯甲烷(15mL),向反应液加入三乙胺(1.21mL,8.71mmol),并在0℃下加入二叔丁基二碳酸酯(800mg,5.61mmol)。在室温下反应30分钟后,LCMS监测反应结束。加入水淬灭反应,二氯甲烷萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩,残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯=3/1)得到黄色油状液体134c(720mg,两步反应收率32%)。ESI-MS(m/z):394.2[M+H]
+。
第三步:将5-羟基-2-三氟甲基吡啶11a(328mg,2.01mmol)和叔丁醇钾(308mg,2.74mmol)溶于N-甲基吡咯烷酮(10mL),反应液在室温下搅拌一小时后向其加入化合物134c(720mg,1.83mmol),继续在80℃条件下反应24小时。LCMS监测反应结束后,加入水淬灭反应,乙酸乙酯萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩,残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯=3/1)得到黄色油状液体134d(638mg,收率67%)。ESI-MS(m/z):521.4[M+H]
+。
第四步:将134d(638mg,1.23mmol)溶于三氟乙酸(5mL),反应液在室温条件下搅拌30分钟。LCMS监测反应结束后,减压蒸馏除去三氟乙酸,加入1N的氢氧化钠水溶液将pH调为8,乙酸乙酯萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩有机相并通过硅胶柱层析纯化(石油醚/乙酸乙酯=3/1)得到黄色油状液体134e(145mg,收率43%)。ESI-MS(m/z):271.4[M+H]
+。
第五步:将化合物133d(45mg,159.16umol),化合物134e(52mg,191umol)和一水对甲苯磺酸(3mg,16umol)溶解在正丁醇(3mL)中,在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体134(27mg,收率33%)。ESI-MS(m/z):517.5[M+H]
+;
1H NMR(500MHz,DMSO-d
6)δ8.74(s,1H),8.65(s,2H),8.02(s,2H),6.94(t,J=6.1Hz,1H),5.06(t,J=5.5Hz,1H),4.36(d,J=6.2Hz,2H),3.77-3.71(m,1H),3.69(dd,J=11.3,5.7Hz,1H),3.65-3.59(m,1H),3.55(dd,J=11.4,5.4Hz,1H),2.96(s,3H),2.49-2.44(m,2H),1.89-1.77(m,2H),1.34(s,3H)。
实施例135(W382)
(S)-5-(羟甲基)-2-(((6-(2-(5-甲氧基-3-(三氟甲基)-1H-吡唑-1-基)乙氧基)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
实施例136(W381)
(S)-5-(羟甲基)-2-(((6-(2-(5-甲氧基-4-甲基-3-(三氟甲基)-1H-吡唑-1-基)乙氧基)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物135和136由以下步骤制备:
第一步:将三氟乙酰乙酸乙酯130a(508mg,6.68mmol)和135a(1.23g,6.68mmol)溶于乙醇(15mL),反应液在80℃搅拌16小时。LCMS监测反应结束后,减压蒸馏除去乙醇,再加入水和乙酸乙酯萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩有机相并通过硅胶柱层析(石油醚/乙酸乙酯=3/1)纯化得到白色固体135b(778mg,收率59%)。ESI-MS(m/z):197.5[M+H]
+。
第二步:将化合物135b(678mg,3.46mmol),6-氟-烟腈91b(422mg,3.46mmol)和碳酸铯(2.25g,6.91mmol)加入到N,N-二甲基甲酰胺(20mL)中,在80℃下反应5小时。LCMS监测反应结束后,减压蒸馏除去N,N-二甲基甲酰胺,再加入水和乙酸乙酯萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到白色固体135c(443mg,收率43%)。ESI-MS(m/z):299.3[M+H]
+。
第三步:在0℃、氮气氛围下将氢化钠(59mg,1.48mmol,含量60%)加入到化合物135c(221mg,0.74mmol)的四氢呋喃(10mL)溶液中,反应液在室温条件下搅拌一小时后,在0℃条件下向其加入碘甲烷(210mg,1.48mmol),继 续在室温下搅拌24小时。LCMS监测反应结束后,加入冰水淬灭反应,乙酸乙酯萃取,合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩有机相并通过硅胶柱层析(石油醚:乙酸乙酯=5:1)纯化得到无色油状液体135d和135d'混合物(100mg,135d比135d'约为4:1)。ESI-MS(m/z):313.3&327.3[M+H]
+。
第四步:将化合物135d和135d'混合物(100mg)溶于甲醇(10mL),依次向反应体系加入氨水(1mL)和雷尼镍(0.1mL,水混悬液),通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时,LCMS监测反应结束。反应液用甲醇稀释,抽滤,滤液浓缩得到棕色油状液体135e和135e'的混合物(81mg,135e比135e'约为4:1)。ESI-MS(m/z):317.3&331.4[M+H]
+。
第五步:将化合物133d(50mg,177umol),化合物135e和135e'的混合物(81mg)和一水对甲苯磺酸(3.3mg,18umol)溶解在正丁醇(3mL)中,在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化,得到白色固体135(27mg,收率23%)和副产物白色固体136。
化合物135:ESI-MS(m/z):563.3[M+H]
+;
1H NMR(500MHz,DMSO-d
6)δ8.08(d,J=2.3Hz,1H),7.65(dd,J=8.4,2.4Hz,1H),6.86-6.78(m,1H),6.68(d,J=8.5Hz,1H),6.19(s,1H),5.05(t,J=5.5Hz,1H),4.53(t,J=5.4Hz,2H),4.37-4.28(m,4H),3.85(s,3H),3.78-3.68(m,2H),3.67-3.58(m,1H),3.55(dd,J=11.2,5.3Hz,1H),2.96(s,3H),2.50-2.44(m,2H),1.89-1.78(m,2H),1.33(s,3H)。
化合物136:ESI-MS(m/z):577.4[M+H]
+;
1H NMR(500MHz,DMSO-d
6)δ8.09(d,J=2.3Hz,1H),7.66(dd,J=8.5,2.4Hz,1H),6.82(t,J=5.7Hz,1H),6.70(d,J=8.5Hz,1H),5.05(t,J=5.5Hz,1H),4.54(t,J=5.3Hz,2H),4.38-4.29(m,4H),3.90(s,3H),3.76-3.67(m,2H),3.65-3.59(m,1H),3.55(dd,J=11.3,5.4Hz,1H),2.96(s,3H),2.49-2.42(m,2H),2.03(s,3H),1.88-1.76(m,2H),1.33(s,3H)。
实施例137(W335)
(S)-2-(((6-((6-环丙基吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用6-溴吡啶-3-酚替换实施例97中第一步的2-氯-5-羟基嘧啶97a,用类似的方法和反应步骤,可以得到化合物137。ESI-MS(m/z):458.5[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.21(d,J=2.5Hz,1H),8.05(d,J=2.5Hz,1H),7.81(dd,J=8.5,2.5Hz,1H),7.43(dd,J=8.0,2.5Hz,1H),7.32(d,J=8.5Hz,1H),7.05-6.98(m,2H),4.39-4.29(m,2H),4.11(q,J=6.8Hz,1H),4.04-3.98(m,1H),3.32-3.22(m,1H),2.92(s,3H),2.55-2.47(m,2H),2.14-2.09(m,1H),1.95-1.90(m,1H),1.82-1.75(m,1H),1.22(d,J=6.8Hz,3H),0.96-0.85(m,4H)。
实施例138(W271)
(S)-4,5-二甲基-2-(((6-(4-(三氟甲基)苯甲基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用4-三氟甲基苄基硼酸频哪醇酯替换实施例96中第二步的4-氟苄基硼酸频哪醇酯96c,用类似的方法和反应步骤,可以得到化合物138。ESI-MS(m/z):483.5[M+H]
+;
1HNMR(500MHz,DMSO-d6)δ8.43(d,J=2.2Hz,1H),7.65(d,J=2,5Hz,1H),7.62(d,J=7.9Hz,2H),7.46(d,J=7.9Hz,2H),7.24(d,J=8.0Hz,1H),7.00(br s,1H),4.40-4.32(m,2H),4.13(s,2H),4.09(q,J=6.7Hz,1H),4.02-3.97(m,1H),3.35-3.25(m,2H),2.90(s,3H),2.55-2.45(m,2H),1.92-1.85(m,1H),1.82–1.72(m,1H),1.20(d,J=6.8Hz,3H)。
实施例139(W268)
(S)-5-(羟甲基)-4-甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用中间体91d替换实施例107中第二步的11d,可以得到化合物139。ESI-MS(m/z):503.1[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ9.04(s,2H),8.23(s,1H),8.13(d,J=2.3Hz,1H),7.93(dd,J=8.4,2.4Hz,1H),7.22(d,J=8.4Hz,1H),6.94(t,J=6.4Hz,1H),4.45-4.29(m,2H),4.07-3.98(m,2H),3.75-3.67(m,2H),3.35-3.30(m,1H),2.96(s,3H),2.52-2.46(m,2H),1.92-1.84(m,1H),1.82-1.71(m,1H)。
实施例140(W376)
(S)-5-(羟甲基)-4,5-二甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用中间体91d替换实施例133中第四步的11d,用类似的方法和反应步骤,可以得到化合物140。ESI-MS(m/z):517.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ9.06(s,2H),8.19(d,J=2.3Hz,1H),7.97(dd,J=8.5,2.3Hz,1H),7.28(d,J=8.4Hz,1H),5.26(br s,1H),4.50(d,J=5.9Hz,2H),3.87-3.78(m,1H),3.73-3.68(m,1H),3.65-3.54(m,2H),3.05(s,3H),2.58-2.49(m,2H),1.95-1.80(m,2H),1.41(s,3H)。
实施例141(W261)
(S)-5-((S)-1-羟基乙基)-4-(甲基-d3)-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
从中间体110c出发,用氘代碘甲烷替换实施例110中第四步碘甲烷,用可以得到化合物141。ESI-MS(m/z):519.3[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.5Hz,1H),8.11(d,J=2.0Hz,1H),7.95(d,J=9.0Hz,1H),7.89(dd,J=8.5,2.5Hz,1H),7.85(dd,J=8.5,2.5Hz,1H),7.16(d,J=8.5Hz,1H),6.93(br s,H),4.43-4.32(m,2H),4.11-4.02(m,3H),3.26-3.17(m,2H),2.53-2.45(m,2H),1.94-1.85(m,1H),1.80-1.70(m,1H),1.00(d,J=6.4Hz,3H)。
实施例142(W257)
(S)-5-((S)-1-羟基乙基)-4-甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用中间体91d替换实施例110中第四步的11d,可以得到化合物142。ESI-MS(m/z):517.4[M+H]
+;
1H NMR(500MHz,DMSO-d6)δ9.03(s,2H),8.13(d,J=2.3Hz,1H),7.93(dd,J=8.4,2.4Hz,1H),7.22(d,J=8.4Hz,1H),6.95(t,J=6.1Hz,1H),4.99(d,J=4.9Hz,1H),4.44-4.32(m,2H),4.12-4.01(m,3H),3.25-3.15(m,1H),3.02(s,3H),2.52-2.46(m,2H),1.95-1.86(m,1H),1.80-1.67(m,1H),1.00(d,J=6.4Hz,3H)。
根据以上实施例描述的合成路线和中间体的合成方法,得到了以下实施例化合物。
Wnt通路抑制剂生物学筛选和结果
试验例1:Colo205-LUC-TCF/LEF-M1报告细胞系构建
Colo205细胞系(中科院细胞库,Cat#TCHu102)购买于中科院细胞库,扩增传代培养后,于细胞的指数生长期,以lipo3000脂质体转染的方法,转染带有TCF/LEF转录因子驱动的萤光素酶报告质粒(Promega)。该质粒带有抗性基因,可以进行抗性筛选。转染在10cm培养皿中进行,使用无抗性的常规完全培养基。2天后,更换带有抗性的培养基,继续培养。之后每2天更换抗性培养基,并将悬浮细胞丢弃,原始培养基离心去除细胞和碎片后保留,作为适应性培养基。当细胞长满培养皿后,将细胞消化下来,计数,传代于96孔板,使每孔中含有的细胞数量平均为1.5个/孔,传代时使用适应培养基。其余细胞进行冻存。传代后培养4小时,让细胞贴壁,然后在显微镜下观察各孔的细胞数量。每孔仅1个细胞的孔进行标记,其为单克隆孔。而后正常培养,每2天更换培养基,并进行观察。前期单克隆细胞有继续生长的孔,进行2次标记,可更换为正常的带抗性培养基。当有单克隆孔长满96孔板板孔时,将其消化传代到24孔培养板,24孔板长满后,传代到1个96孔板和1个6孔板,96孔板细胞至少6孔,其中3孔加入已知的Wnt抑制剂,另外3孔不作处理。24h后,96孔板细胞加入萤光检测试剂,检测萤光强度。选择其中不处理时有萤光表达,且抑制后萤之光降低的细胞系,进一步培养。Colo205-LUC-TCF/LEF-M1细胞系为上述筛选出的细胞系之一,其生长曲线、细胞形态、细胞生长状态与原始Colo205细胞相似,且其加抑制剂处理和不处理的萤光信号之比在所有细胞系中属于较大的,比值在4h时 抑制时可达4-5倍,完全适用于后期的Wnt抑制剂的筛选。
试验例2:化合物对Colo205-LUC-TCF/LEF M1报告细胞系上抑制能力的检测Colo205-LUC-TCF/LEF M1细胞株为稳定转pGL4.49-LUC2-TCF/LEF载体的报告工具细胞,其β-catenin Wnt通路持续激活,加入抑制剂后,Wnt通路被抑制,载体上TCF/LEF顺式元件调控的萤火虫萤光素酶表达量下降,后续加入检测底物后,检测到的光信号相应下降,从而检测出化合物的抑制效果。
向96孔的细胞培养板,每孔中加入100uL,最高浓度20uM的化合物,化合物浓度做3倍梯度稀释。然后向各孔中接种10000个稳定转染过报告基因的colo205细胞和100uL培养基,同时做相应的阳性、阴性对照孔。将细胞放入细5%CO2胞培养箱,37℃培养4h,4小时后,去除培养液,向各孔添加含相应的萤火虫荧光素酶底物的试剂(Promega)100uL,测定荧光素酶报告基因的活性。用SpectraMax在全波长模式下读取发光强度。仅由DMSO处理的细胞的光信号强度为阳性对照,无细胞孔的光信号强度为阴性对照,计算各化合物的IC50的浓度。Colo 205报告基因检测数据汇总于表1。
表1
试验例3:化合物对Wnt突变细胞株(Colo205和DU4475)和非Wnt突变细胞株(Hela和RKO)的增殖抑制试验
试验中使用的细胞株为Wnt通路持续激活的,且其增殖为Wnt通路依赖型的Colo205和DU4475细胞系;而正常情况下Wnt通路不激活,且增殖不依赖于Wnt通路的HELA和RKO细胞系作为对照细胞系,判断本发明的化合物对于Wnt依赖的增殖的抑制作用不是由于其它非特异毒性造成的。
将培养于各自的培养基中的Colo205、Du4475、HELA和RKO细胞株在对数生长期时处理,收集细胞后制备成已知浓度的均匀的细胞悬液,然后向96孔细胞培养板中加入细胞悬液,使每孔中含有1000个细胞。放入5%CO2胞培养箱,37℃培养20-24h。第二天向各细胞培养孔中加入已经完全溶解的,3倍梯度稀释的化合物,使细胞培养孔中的最终最高浓度为20uM,继续培养96h。本试验使用Promega的细胞活性检测试验进行检测,细胞增殖越多,则最终的信号强度越强。检测仪器为SpectraMax,全波长模式。仅加入DMSO的孔作为阳性对照孔,未接种细胞的孔为阴性对照孔,计算各化合物对于Wnt持续激活或增殖依赖的细胞的增殖抑制的IC50值,以及对于Wnt未激活的或增殖不依赖的细胞的增殖抑制的IC50值,评估化合物对于Wnt通路的抑制作用和对于正常细胞的毒性作用(表2)。
表2
试验例4:化合物对NCI-H929和HepG2细胞株的增殖抑制试验
试验中使用的细胞株为Wnt通路持续激活的,且其增殖为Wnt通路依赖型的NCI-H929和HepG2细胞系;判断本发明的化合物对于Wnt依赖的增殖的抑制作用。
将培养于各自的培养基中的NCI-H929和HepG2细胞株在对数生长期时处理,收集细胞后制备成已知浓度的均匀的细胞悬液,然后向96孔细胞培养板中加入细胞悬液,使每孔中含有4000个细胞。放入5%CO2胞培养箱,37℃培养20-24h。第二天向各细胞培养孔中加入已经完全溶解的,3倍梯度稀释的化合物,使细胞培养孔中的最终最高浓度为20uM,继续培养96h。本试验使用Promega的细胞活性检测试验进行检测,细胞增殖越多,则最终的信号强度越强。检测仪器为SpectraMax,全波长模式。仅加入DMSO的孔作为阳性对照孔,未接种细胞的孔为阴性对照孔,计算各化合物对于Wnt持续激活或增殖依赖的细胞的增殖抑制的IC50值,以及对于Wnt未激活的或增殖不依赖的细胞的增殖抑制的IC50值,评估化合物对于Wnt通路的抑制作用和对于正常细胞的毒性作用(表3)。
化合物 | 抗增殖IC 50(nM) |
NCI-H929 | HepG2 | |
11(W176) | 55 | ND |
68(W49) | ND | 4.4 |
80(W104) | ND | 9.3 |
82(W107) | ND | 1.0 |
91(W221) | 65 | 35 |
103(W195) | ND | 68 |
105(W199) | 45 | 44 |
111(W241) | 94 | 40 |
114(W243) | 60 | 37 |
116(W249) | 17 | 69 |
117(W237) | 27 | 3.1 |
118(W279) | 83 | 16 |
119(W255) | 28 | 5.4 |
120(W265) | 55 | 18 |
126(W308) | 39 | 2.7 |
127(W280) | 75 | 42 |
128(W263) | 78 | 27 |
130(W354) | 19 | <0.5 |
146(W273) | 87 | 81 |
149(W285) | 41 | 11 |
150(W301) | 62 | 19 |
151(W332) | 26 | 9.8 |
152(W336) | 36 | 4.4 |
153(W293) | 37 | 19 |
160(W362) | 48 | 3.5 |
161(W269) | 22 | 16 |
162(W270) | 22 | 16 |
163(W325) | 31 | 7 |
164(W326) | 26 | 7.5 |
165(W286) | 31 | 11 |
166(W287) | 31 | 21 |
167(W289) | 28 | 6.8 |
168(W298) | 68 | 35 |
170(W368) | 94 | 31 |
172(W305) | 89 | 26 |
176(W296) | 40 | 27 |
177(W297) | 56 | 25 |
178(W333) | 60 | 23 |
179(W375) | 45 | 11 |
180(W386) | 82 | 40 |
181(W396) | 25 | 81 |
182(W395) | ND | 24 |
189(W306) | ND | 3.5 |
190(W317) | 6.4 | 2.1 |
192(W324) | 12 | 4 |
193(W342) | 24 | 1.2 |
195(W323) | 19 | 4 |
196(W344) | 54 | 1.2 |
198(W307) | ND | 2.3 |
199(W319) | 28 | 2 |
201(W360) | 51 | 14 |
202(W361) | 50 | 10 |
203(W372) | 95 | 8.2 |
204(W374) | 60 | 12 |
205(W379) | 67 | 5.6 |
206(W388) | 90 | 49 |
214(W392) | 82 | 9.6 |
230(W415) | ND | 50.8 |
231(W417) | ND | <0.5 |
232(W418) | ND | <0.5 |
234(W420) | ND | 66.2 |
238(W426) | ND | 25.8 |
试验例5:化合物11对NCI-H929小鼠Xenograft模型的肿瘤增长抑制试验本研究用人骨髓瘤细胞NCI-H929 SCID移植瘤模型对化合物11的体内抗肿瘤活性进行评价。
雌性SCID皮下接种人骨髓瘤细胞NCI-H929,建立NCI-H929 SCID移植瘤模型。待肿瘤生长至平均肿瘤体积为80mm
3左右后,根据肿瘤体积大小采用随机分组法将荷瘤鼠分为2组:溶剂处理对照组、30mg/kg化合物11组。化合物11口服给药,每天给药一次,给药周期21天,每隔一天测量肿瘤体积,Day 21称量体重和测量肿瘤体积(表4和图1)。
表4化合物11在NCI-H929 SCID异种移植瘤模型中对动物肿瘤大小的影响
***:与阴性对照组相比,P<0.001。
Claims (10)
- 一种具有式(I)结构的抑制Wnt通路活性的化合物及药学上可接受的盐、同位素衍生物、立体异构体:R 1表示C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基、5-10元杂芳基,并且所述的R 1可以任意地被0、1、2、3个选自:氢、卤素、ORa、卤代(C 1-C 6)烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基、氰基、SR a、卤代(C 1-C 6)烷氧基、卤代(C 3-C 6)环烷氧基、卤代(C 1-C 6)烷基硫基、(C 3-C 6)环烷基氧基、(C 3-C 6)环烷基硫基、卤代(C 3-C 6)环烷硫基的取代基所取代;X表示-(CR aR a’) m-、-(CR aR a’) mO(CR aR a’) n-、-(CR aR a’) mS(CR aR a’) n-;Cy表示C 6-C 10芳基或者5-10元杂芳基,并且其可以任意地被0、1、2、3个选自:氢、卤素、-ORa、(C 1-C 6)烷基、卤代(C 1-C 6)烷基、(C 3-C 6)环烷基、氰基、羟基(C 1-C 6)烷基;R 2表示氢、(C 1-C 6)烷基、卤代(C 1-C 6)烷基、(C 3-C 6)环烷基、羟基(C 1-C 6)烷基;R 3和R 3’各自独立地表示氢,卤素、OR a、(C 1-C 6)烷基、(C 3-C 6)环烷基、羟基(C 1-C 6烷基)、(C 1-C 6)烷氧基(C 1-C 6)烷基;或者R 3和R 3’一起与与之相连的碳原子形成3-6元饱和或者不饱和的环,该环中还可以任意地含有1、2个选自O、S、N的杂原子;并且该环还可以任意地被0、1、2个卤素、羟基、C 1-C 6烷基所取代;或者R 2、R 3或者R 2’、R 3一起与其相连的原子形成4-6元饱和或者不饱和的环,该环中还可以任意地含有1、2个选自O、S、N的杂原子;并且该环还可以任意地被0、1、2个卤素、羟基、C 1-C 6烷基所取代;R4和R4’各自独立地表示氢、C 1-C 6烷基、C 3-C 6环烷基、羟基(C 1-C 6烷基)、卤代(C 1-C 6烷基)、(C 1-C 6)烷氧基(C 1-C 6)烷基;或者R 4与R 4’一起形成=O;R T和R T’各自独立地表示氢、C 1-C 6烷基、卤代(C 1-C 6烷基)、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a;或者R T和R T’一起与与其相连的原子形成3-6元环;其中,当 表示不存在时,A表示(CR LR L’) p,其中R L和R L’各自独立地表示氢、C 1-C 6烷基、卤代(C 1-C 6烷基)、羟基(C 1-C 6烷基)、C 3-C 6环烷基、卤素、OR a、或者R L和R L’一起与与其相连的碳原子形成3-6元环,该环中可以任意地含有0、1、2个选自O、S、N的杂原子,并且该环还可以任意地被0、1、2个卤素、羟基所取代;其中,R a、R a’各自独立地表示氢和C 1-C 6烷基;其中m、n、p各自独立地表示0、1、2。
- 如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体,其中X表示-O-、-CH 2-、-OCH 2或-CH 2CH 2-。
- 如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体,其中Cy表示被0、1、2个选自(C 1-C 6)烷基、(C 3-C 6)环烷基、卤代(C 1-C 6烷基)、-OR a、卤素、氰基、NR aR a’、羟基(C 1-C 6)烷基取代的吡唑基、吡啶基、吡嗪基、嘧啶基、咪唑基、苯基;其中,R a、R a’各自独立地表示氢和C 1-C 6烷基。
- 如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体,其中R 1表示(C 1-C 6)烷基、(C 3-C 6)环烷基、(C 6-C 10)芳基、(5-10)元杂芳基,其任意地被0、1、2个选自卤素、OR a、(C 1-C 6)烷基、卤代(C 1-C 6烷基)的取代基所取代;其中,R a表示氢和C 1-C 6烷基。
- 如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体,其中R 2表示氢或者(C 1-C 6)烷基。
- 如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体,其中R 3和R 3’各自独立地表示氢或者(C 1-C 6)烷基。
- 如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体,其中R 4与R 4’一起形成=O。
- 药物组合物,包括权利要求1-8任一项所述的化合物以及药学上可接受的盐。
- 权利要求1-8任一项所述的化合物以及药学上可接受的盐、同位素衍生物、立体异构体以及权利要求9所述的药物组合物用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023005894A1 (zh) * | 2021-07-26 | 2023-02-02 | 杭州阿诺生物医药科技有限公司 | 一种Wnt通路抑制剂化合物 |
WO2023143546A1 (zh) * | 2022-01-30 | 2023-08-03 | 杭州阿诺生物医药科技有限公司 | Wnt通路抑制剂化合物 |
WO2023220433A1 (en) | 2022-05-12 | 2023-11-16 | Skyhawk Therapeutics, Inc. | Compositions useful for modulating splicing |
WO2024022365A1 (zh) * | 2022-07-28 | 2024-02-01 | 杭州阿诺生物医药科技有限公司 | 一种Wnt通路抑制剂化合物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104379583A (zh) * | 2012-06-15 | 2015-02-25 | 广州源生医药科技有限公司 | 作为wnt信号传导抑制剂的化合物、组合物及其应用 |
CN109310690A (zh) * | 2016-04-27 | 2019-02-05 | 萨穆梅德有限公司 | 异喹啉-3-基甲酰胺类及其制备和其用途 |
WO2020125759A1 (zh) * | 2018-12-21 | 2020-06-25 | 汇瀚医疗科技有限公司 | 作为wnt信号通路抑制剂的化合物及其医学应用 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104379583A (zh) * | 2012-06-15 | 2015-02-25 | 广州源生医药科技有限公司 | 作为wnt信号传导抑制剂的化合物、组合物及其应用 |
CN109310690A (zh) * | 2016-04-27 | 2019-02-05 | 萨穆梅德有限公司 | 异喹啉-3-基甲酰胺类及其制备和其用途 |
WO2020125759A1 (zh) * | 2018-12-21 | 2020-06-25 | 汇瀚医疗科技有限公司 | 作为wnt信号通路抑制剂的化合物及其医学应用 |
Non-Patent Citations (2)
Title |
---|
ALLEN L.V.JR ET AL.: "Remington: The Science and Practice of Pharmacy", vol. 2, 2012, PHARMACEUTICAL PRESS |
DATABASE ChemBank Registry; ANONYMOUS : " -5,6-Dihydro-4-methyl-N-(phenylmethyl)-4H-pyrrolo[3,2,1-de]pteridin-2-amine ", XP055925255, retrieved from STN * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023005894A1 (zh) * | 2021-07-26 | 2023-02-02 | 杭州阿诺生物医药科技有限公司 | 一种Wnt通路抑制剂化合物 |
WO2023143546A1 (zh) * | 2022-01-30 | 2023-08-03 | 杭州阿诺生物医药科技有限公司 | Wnt通路抑制剂化合物 |
WO2023220433A1 (en) | 2022-05-12 | 2023-11-16 | Skyhawk Therapeutics, Inc. | Compositions useful for modulating splicing |
WO2023220439A1 (en) | 2022-05-12 | 2023-11-16 | Skyhawk Therapeutics, Inc. | Compositions useful for modulating splicing |
WO2024022365A1 (zh) * | 2022-07-28 | 2024-02-01 | 杭州阿诺生物医药科技有限公司 | 一种Wnt通路抑制剂化合物 |
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CN117088876A (zh) | 2023-11-21 |
CN117088875A (zh) | 2023-11-21 |
CN116348469A (zh) | 2023-06-27 |
EP4238974A1 (en) | 2023-09-06 |
US20230390301A1 (en) | 2023-12-07 |
TW202216719A (zh) | 2022-05-01 |
CN117088877A (zh) | 2023-11-21 |
CN117088878A (zh) | 2023-11-21 |
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