CN112142745B - 一种酪蛋白激酶1ε抑制剂、药物组合物及其应用 - Google Patents
一种酪蛋白激酶1ε抑制剂、药物组合物及其应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Abstract
本发明公开了一种新颖的抑制酪蛋白激酶1ε(CK1ε)活性的取代的吡唑并嘧啶类化合物及其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物及其在制备治疗从酪蛋白激酶1ε(CK1ε)活性的抑制中获益的疾病、障碍或病症药物中的应用。本发明化合物对CK1ε激酶和OCI‑LY10细胞、Karpas299细胞具有抑制活性,并在OCI‑LY10皮下异种模型中,表现出良好的抗肿瘤活性,与BTK抑制剂联用显示出优异的协同抗肿瘤活性,本发明化合物具有较好的药代动力学性质,可应用于在单独或与其他药物联合应用治疗从酪蛋白激酶1ε活性的抑制中获益的疾病、障碍或病症,包括癌症、自身免疫性疾病等。
Description
技术领域
本发明属于医药领域,具体是涉及一种取代的吡唑并嘧啶类酪蛋白激酶1ε抑制剂、药物组合物及其应用。
背景技术
蛋白激酶在信号转导中发挥着重要作用,可通过磷酸化底物蛋白介导胞内信号转导,是一类重要的药物靶标。酪蛋白激酶1(CK1)属于丝氨酸-苏氨酸激酶家族,在哺乳动物中存在七种亚型:ɑ、β、γ1、γ2、γ3、δ和ε。这些亚型参与了Wnt信号转导、昼夜节律、细胞信号转导、膜转运、DNA复制、DNA损伤和RNA代谢,可以调节机体功能。
CK1的磷酸化底物参与了多种细胞内调控。如抑癌因子p53和癌基因MDM2均为控制细胞异常生长的重要蛋白质,同时也为CK1的底物。CK1激酶的亚型(主要为CK1ε和CK1δ)与p53磷酸化、p53的稳定与活化、p53-MDM2相互作用等有十分重要的相关性。同时,还与细胞分裂时形成中心体、纺锤体继而调控蛋白质的合成,或与TRAIL(肿瘤坏死因子相关凋亡诱导配体)及FAS的细胞凋亡相关。
酪蛋白激酶1ε(CK1ε)是CK1家族中的一个重要亚型,是各种细胞生长和存活过程的关键调节剂,除了在调节昼夜节律中具有重要作用,在癌症的发生和发展中同样重要。例如,通过药物抑制或shRNA-介导切除CK1ε后可以阻碍多种癌症的生长和生存,包括胰腺癌、肉瘤、乳腺癌、直肠癌、卵巢癌、白血病等。研究表明,由于CK1基因缺乏底物特异性,CK1ε调节肿瘤生长和生存的作用机制尚不清楚,可能与Akt、MYC、β-连环蛋白等(Varghese等人,Scientific Reports,2018,8:13621)。
Wnt信号通路可调控细胞增殖过程,该通路的一些突变可导致各种癌症,包括皮肤癌、肝癌、脑瘤、结肠癌等。CK1可通过磷酸化β-连环蛋白促进其降解。CK1ε还可通过磷酸化Tcf3来调节Wnt信号通路,磷酸化的Tcf3可与β-连环蛋白结合促进其降解(Knippschild等,Cellular Signalling,2005,17:675–689)。
目前已报道多类CK1激酶抑制剂的结构,如1)PF-4800567,为一类取代的吡唑并嘧啶类化合物,为选择性的CK1ε抑制剂(IC50=32nM;Walton等,J Pharmacol Exp Ther.2009,330(2):430-9);2)PF-670462,为一类取代的咪唑-5-基嘧啶类化合物,为选择性的CKIε/CKIδ抑制剂(IC50值分别为7.7nM和14nM;Badura等,J Pharmacol Exp Ther.2007,322(2):730-8);3)CK1-IN-1,为一类咪唑-5-基吡啶类化合物,为多靶点抑制剂,对CKIδ、CKIε、p38σMAPK的IC50值分别为15nM、16nM和73nM(WO2015119579A1)。
另外,CK1ε作为调节Wnt信号通路的重要组成部分,可以驱动慢性淋巴细胞白血病(CLL)的发生与发展。CK1ε在CLL患者中显著上调,通过抑制CK1ε从而阻断CLL的发展,且不会影响BCR相关通路;另外,CK1ε还可增强BCR通路BTK抑制剂ibrutinib的体内外抗肿瘤活性。因此,CK1ε也是重要的抗肿瘤靶标(Janovska等人,Blood,2019,11:1206~1218)。
因此,开发具有抑制CK1ε功能的药物,将在多种疾病如癌症和自身免疫性疾病中发挥重要的治疗作用。
发明内容
本发明的目的在于提供一种新颖的抑制酪蛋白激酶1ε(CK1ε)活性的取代的吡唑并嘧啶类化合物及其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物。
本发明还提供了一种包括上述化合物及其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物的药物组合物。
本发明同时提供了一种上述化合物及其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物用于制备治疗从酪蛋白激酶1ε(CK1ε)活性的抑制中获益的疾病、障碍或病症药物中的应用。
本发明采用如下的技术方案:
本发明所提供的CK1ε抑制剂,其具有通式I的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物;
其中:
R1为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、卤素、氰基、氨基、硝基或羟基;
m为1~4的整数;m大于1时多个R1相互独立,可以不相同,也可以相同;
R2为H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C5-C12芳基;
R3为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、卤素、氰基、氨基、硝基或羟基;
X为CR4或N;
R4为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、卤素、氰基、氨基或羟基;
B选自取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的3至10元杂环烷基、取代或未取代的C5-C12芳基、取代或未取代5至12元杂芳基。
作为一种优选的方案,所述R3和R4不同时为H。
更进一步地,本发明优选的化合物具有通式II-A、II-B或II-C的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物;
其中:R1、m、R2、R3、X、R4、B的定义如通式I中所定义;
R5为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、取代或未取代的C1-C6羟烷基、取代或未取代的C1-C6卤代羟烷基、卤素、氰基、氨基、硝基或羟基;
o为1~5的整数;
R6和R6’独立选自H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、卤素、氰基、氨基或羟基,或,R6和R6’成三到六元环烷基或杂环烷基;
n为不存在或0、1、2;其中:
当n为不存在时,即Y和Z不成环时,Y为CR7R7’或NR8;Z为CHR7R7’、OH、NHR8;Y和Z中的R7相互独立,可以相同,也可以不同;同样的Y和Z中的R7’相互独立,可以相同,也可以不同;
当n为0、1、2时,Y为CH或N;Z为CR7R7’、O或NR8;
R7和R7’独立选自H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的3至10元杂环烷基、卤素、氰基、氨基或羟基;或,R7和R7’成三到六元环烷基或杂环烷基;
R8为H、烷基(优选取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基)、取代或未取代的C3-C10环烷基、取代或未取代的3至10元杂环烷基、-C(O)-R9、-S(O)2-R10;
R9为取代或未取代的C1-C6烷基、取代或未取代的C1-C6环烷基;
R10为取代或未取代的C1-C6烷基、取代或未取代的C1-C6环烷基。
更进一步地,本发明优选的化合物具有通式III-A、III-B或III-C的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物;
其中,R1、R2、R3、R4、R5、R6、R6’、Y、Z、n的定义如通式II-A、II-B、II-C中所定义。
更进一步地,本发明优选的化合物具有通式IV-A、IV-B或IV-C的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物;
其中:
R1选自H、取代或未取代的C1-C6烷基、卤素;
m选自1~4的整数;
R2选自甲基、乙基、异丙基、环丙基;
R5选自H、取代或未取代的C1-C6烷基、卤素;
o选自1~4的整数;
R6、R6’选自H、取代或未取代的C1-C6烷基、卤素;
Y选自N或CH;
Z选自CH2、O、NR8;
R8选自H、取代或未取代的C1-C6烷基、-C(O)-R9;
R9选自取代或未取代的C1-C6烷基。
更进一步地,本发明优选的化合物具有通式V-A、V-B或V-C的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物;
其中:R1、m、R5和Z的定义如通式IV-A、IV-B、IV-C中所定义;R2为甲基或乙基、异丙基。
作为优选,本发明优选的化合物具有通式V-A、V-B或V-C的结构,其中:
R1选自H、卤素(优选Cl、F);
R2选自甲基、乙基、异丙基、环丙基、苯基;
m为1、2、3;
R3选自F、Cl、CN、H;
X为C、N、CH。
作为优选的方案,B为苯基、吡啶基(进一步优选为3位基,即:吡啶-3-基)、卤素取代的吡啶基(进一步优选Cl、F取代的吡啶基;优选为3位基,即:Cl、F取代的吡啶-3-基)、环己基、哌啶基(进一步优选为4位基(即哌啶-4-基)、1位(即哌啶-1-基))、N-乙酰基哌啶基(进一步优选为4位基,即N-乙酰基哌啶-4-基),N-(2-三氟乙基)取代的哌啶基(进一步优选为4位基,即N-(2-三氟乙基)取代的哌啶-4-基)、吗啉基(进一步优选为N位基、C位基)、哌嗪基(进一步优选为N位基)、二甲基(进一步优选为C位二甲基取代基)取代的哌嗪基(进一步优选为N位基)、三氟甲基取代(进一步优选为C位三氟甲基取代基)的哌嗪基(进一步优选为N位基)、三氟乙基取代(进一步优选为N位三氟乙基取代基)的哌嗪基(优选为N位基)、甲基取代(进一步优选为N位甲基取代基)的哌嗪基(进一步优选为N位基)、乙酰基取代(进一步优选为N位乙酰基取代基)的哌嗪基(进一步优选为N位基)、3-甲氧基丙基、2-(四氢呋喃-2-基)乙基。
作为优选,所述CK1ε抑制剂优选为以下具体化合物:
及上式化合物的立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物。
作为优选,所述CK1ε抑制剂优选为以下化合物之一:
作为优选,所述化合物为如下化合物:
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-1)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-1a)
(R)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-1b)
2-(1-(4-氨基-3-(2,3-二氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-2)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-2a)
(R)-2-(1-(4-氨基-3-(2,3-二氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-2b)
2-(1-(4-氨基-3-(4-乙氧基-2,3-二氟苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-3)
2-(1-(4-氨基-3-(4-环丙氧基-2,3-二氟苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-4)
2-(1-(4-氨基-3-(3-氯-2-氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-5)
3-(4-氨基-1-(1-(4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)-2-氟-6-甲氧基苯腈(II-A-6)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮(II-A-7)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮(II-A-7a)
(R)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮(II-A-7b)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(II-A-8)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(II-A-8a)
(R)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(II-A-8b)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(II-A-9)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-8-氟-3-苯基喹唑啉-4(3H)-酮(II-A-10)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5,8-二氟-3-苯基喹唑啉-4(3H)-酮(II-A-11)
2-(1-(4-氨基-3-(2,6-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-12)
2-(1-(4-氨基-3-(2-氟-6-甲氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-13)
2-(1-(4-氨基-3-(2-氟-6-异丙氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-14)
2-(1-(4-氨基-3-(2-氟-6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮(II-A-15)
2-(1-(4-氨基-3-(2,3-二氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(II-A-16)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(吡啶-3-基)喹唑啉-4(3H)-酮(II-B-1)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(吡啶-3-基)喹唑啉-4(3H)-酮(II-B-2)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(吡啶-3-基)喹唑啉-4(3H)-酮(II-B-2a)
(R)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(吡啶-3-基)喹唑啉-4(3H)-酮(II-B-2b)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(5-氟吡啶-3-基)喹唑啉-4(3H)-酮(II-B-3)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-环己基喹唑啉-4(3H)-酮(II-C-1)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(哌啶-4-基)喹唑啉-4(3H)-酮(II-C-2)
3-(1-乙酰哌啶-4-基)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯代喹唑啉-4(3H)-酮(II-C-3)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(1-(2,2,2-三氟乙基)哌啶-4-基)喹唑啉-4(3H)-酮(II-C-4)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(哌啶-1-基)喹唑啉-4(3H)-酮(II-C-5)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-吗啉喹唑啉-4(3H)-酮(II-C-6)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(哌嗪-1-基)喹唑啉-4(3H)-酮(II-C-7)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(3,3-二甲基哌嗪-1-基)喹唑啉-4(3H)-酮(II-C-8)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(3-(三氟甲基)哌嗪-1-基)喹唑啉-4(3H)-酮(II-C-9)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(4-(2,2,2-三氟乙基)哌嗪-1-基)喹唑啉-4(3H)-酮(II-C-10)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(4-甲基哌嗪-1-基)喹唑啉-4(3H)-酮(II-C-11)
3-(4-乙酰哌嗪-1-基)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯代喹唑啉-4(3H)-酮(II-C-12)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-(3-甲氧基丙基)喹唑啉-4(3H)-酮(II-C-13)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(3-甲氧基丙基)喹唑啉-4(3H)-酮(II-C-14)
2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-(2-(四氢呋喃-2-基)乙基)喹唑啉-4(3H)-酮(II-C-15)
或其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物。
作为优选,所述化合物为如下化合物:
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮盐酸盐(II-D-1)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮硫酸盐(II-D-2)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮对甲苯磺酸盐(II-D-3)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮甲烷磺酸盐(II-D-4)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮盐酸盐(II-D-5)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮硫酸盐(II-D-6)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮磷酸盐(II-D-7)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮对甲苯磺酸盐(II-D-8)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮甲烷磺酸盐(II-D-9)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮柠檬酸盐(II-D-10)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮丁二酸盐(II-D-11)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮-L-苹果酸盐(II-D-12)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮-D-苹果酸盐(II-D-13)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮-L-酒石酸盐(II-D-14)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮苯甲酸盐(II-D-15)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮马来酸盐(II-D-16)
(S)-2-(1-(4-氨基-3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮草酸盐(II-D-17)
或其立体异构体或其立体异构体混合物或溶剂合物。
本发明还提供了通式化合物I的制备方法,所述方法包括以下三种方法:
1)方法一:3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(化合物5)与化合物4在碱的作用下进行烷基化反应生成化合物10,然后与化合物7通过偶联反应得到通式化合物I:
第一步反应中,反应溶剂除DMF外,还可以选择THF,MeCN,DMSO等。化合物4与化合物5的摩尔比约为1:(1~3),进一步优选为1:(1~2)。碱可选择为碳酸钾、碳酸铯、碳酸钠等,碱与化合物5的摩尔比约为(1~5):1,进一步优选为(1.5~2.5):1。反应温度为室温-60℃。
第二步反应中,化合物10与化合物7在碱(碳酸钠、碳酸钾)、催化剂(钯催化剂等)存在下进行。催化剂优选为四三苯基膦钯等。化合物10与化合物7的摩尔比为1:(1~3),进一步优选为1:(1~2)。碱与化合物10的摩尔比为1:(1~4),进一步优选为1:(2~3)。催化剂的加入量为化合物10摩尔量的0.05~1.0%。反应溶剂为有机溶剂二氧六环、四氢呋喃、N,N-二甲基甲酰胺等与水的混合溶剂等,体积比例为(2-10):1,进一步优选为(2-5):1。反应温度为80~120℃。
选用该方法时,作为优选,所述R2优选为C1~C5的烷基(优选为甲基、乙基、异丙基、丙基、环丙基)、苯基,所述R3优选为H、卤素(优选为F),X为C-卤素(优选为C-Cl、C-F等)、C-CN、CH、N。
2)方法二:3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(化合物5)在碱的作用下,与三苯基氯甲烷反应生成化合物6,然后与化合物7通过偶联反应生成化合物8,脱保护后在碱的作用下与化合物4发生烷基化反应生成通式化合物I:
该方法中,步骤一中,三苯基氯甲烷与化合物5的摩尔比为(1~5):1,优选为(1.5~2.5):1;该步骤中,可以加入碱(优选为碳酸钾、碳酸铯),其与化合物5的摩尔比为(1~8):1,优选为(2~5):1。反应温度为60~100℃。
步骤二中,化合物6与化合物7在碱(碳酸钠、碳酸钾)、催化剂(钯催化剂等)存在下进行。催化剂优选为四三苯基膦钯等。化合物6与化合物7的摩尔比为1:(1~3),进一步优选为1:(1~2)。碱与化合物6的摩尔比为(1~4):1,进一步优选为(2~3):1。催化剂的加入量为化合物6摩尔量的0.05~1.0%。反应溶剂为有机溶剂二氧六环、四氢呋喃、N,N-二甲基甲酰胺等与水的混合溶剂等,体积比例为(2-10):1,进一步优选为(2-5):1。反应温度为80~120℃。
步骤三中,反应过程中,加入TFA和三异丙基硅烷,反应溶剂可以为二氯甲烷、氯仿等。TFA与化合物8的摩尔比为(2~8):1,进一步优选为(3~6):1。三异丙基硅烷与化合物8的摩尔比为(2~8):1,进一步优选为(3~6):1。
步骤四中,反应溶剂除DMF外,还可以选择THF,MeCN,DMSO等。化合物9与化合物4的摩尔比约为1:(1~3),进一步优选为1:(1~2)。反应过程中可以加入碱,碱可选择为碳酸钾、碳酸铯、碳酸钠等,碱与化合物9的摩尔比约为(1~5):1,进一步优选为(1.5~2.5):1。反应温度为室温-60℃。
该方法中,作为优选,R1为卤素(优选为一个或多个Cl、一个或多个F或者上述两者的组合);R2为C1~C5(甲基、乙基、异丙基等);R3为H和卤素等。B优选为苯基、卤素(Cl、F)取代或者无取代的吡啶基、哌啶基、甲基取代哌嗪基、Boc取代的哌啶基、N杂哌啶基、烷基取代哌嗪基、三氟甲基取代的哌嗪基、三氟甲基取代的烷基取代哌嗪基、乙酰基取代的哌嗪基、取代丙基、丙基、取代乙基等。
3)方法三(手性化合物的合成):
该方法首先采用手性的D-乳酸甲酯和L-乳酸甲酯,通过多步反应生成(R)-12或(S)-12,后分别与中间体9在膦配体和偶氮二羧酸酯的作用下,发生Mitsunobu反应得到(S)-I或(R)-I。
该Mitsunobu反应的反应溶剂可以为THF、二氯甲烷、甲苯、乙腈、DMF等,与中间体9的体积比为(2~10):1,优选为(2~5):1;膦配体可选三苯基膦、三叔丁基膦,与中间体9的摩尔比为(1~4):1,优选为(1.5~3):1;偶氮二羧酸酯可选DEAD、DIAD,与中间体9的摩尔比为(1~4):1,优选为(1.5~3):1。反应温度为15~30度,优选为室温。
选用该方法时,作为优选,所述R2优选为C1~C5的烷基(优选为甲基、乙基、异丙基、丙基、环丙基)、苯基,所述R3优选为H、卤素(优选为F),X为C-卤素(优选为C-Cl、C-F等)、C-CN、CH、N。
本发明的另外一个目的是提供如下化合物9所示的中间体以及用于制备从酪蛋白激酶1ε活性的抑制中获益的疾病、障碍或病症药物中的用途:
其中,
R2为H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C5-C12芳基;R2优选为甲基、乙基、异丙基、环丙基;
R3为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、卤素、氰基、氨基、硝基或羟基;R3优选为F、Cl、CN、H;;
X为CR4或N;
R4为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6卤代烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6卤代烷氧基、卤素、氰基、氨基或羟基;R4优选为氟;
作为一种优选的方案,所述R3和R4不同时为H。
X优选为CF、N、CH。
作为优选,化合物9所示的中间体优选为下式所示化合物:
R2选自甲基、乙基、异丙基、环丙基。
术语说明:
本发明所用术语“芳基”是由芳环去掉一个H得到,所述芳环是指5到12个碳原子的全碳单环或稠合多环基团,具有完全共轭的π电子系统。芳环的非限制性实例有:苯环、萘环和蒽环。芳环可以是无取代或取代的。芳环的取代基选自卤素(优选为氟、氯、溴、碘)、氰基、硝基、氨基、羟基、C1-C6烷基(优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等)、C1-C6羟烷基(优选为羟甲基、羟乙基、羟丙基、羟异丙基等)、C1-C6烷氧基(优选为甲氧基、乙氧基、丙氧基、异丙基氧基、丁氧基、异丁基氧基、仲丁基氧基、叔丁基氧基等)、卤代C1-C6烷基(优选为卤代甲基、卤代乙基、卤代丙基、卤代异丙基、卤代丁基、卤代异丁基、卤代仲丁基、卤代叔丁基等)、卤代C1-C6羟烷基(优选为卤代羟甲基、卤代羟乙基、卤代羟丙基、卤代羟异丙基等)、卤代C1-C6烷氧基(优选为卤代甲氧基、卤代乙氧基、卤代丙氧基、卤代异丙基氧基、卤代丁氧基、卤代异丁基氧基、卤代仲丁基氧基、卤代叔丁基氧基等)、C3-C6环烷基(优选为环丙基、环戊基、环己基等)、卤代C3-C6环烷基(优选为卤代环丙基、卤代环戊基、卤代环己基等)、3至10元杂环基(优选为四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基等);芳环的取代,可以是单取代(比如邻位、间位、对位取代),也可以是双取代或者三取代等。
本发明所用术语“杂芳基”指5到12个环原子的不饱和的环基团,具有完全共轭的π电子系统,相当于上述“芳基”中一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环,也可以是双环,即通过两个环稠合而成。具体的杂环芳基(杂芳基)可以是:吡啶基、嘧啶基、吡嗪基、异恶唑基、异噻唑基、吡唑基、噻唑基、恶唑基和咪唑基等。杂环芳基可以是无取代或取代的。杂环芳基的取代基选自卤素、氰基、硝基、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、3至10元杂环基。
本发明所用术语“烷基”是指一个具有一至六个碳原子的直链饱和单价烃基或一个具有三至六个碳原子的支链饱和的单价烃基,优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等。烷基可以是无取代或单取代或多取代,多取代时取代基可以相同也可以不同;烷基的取代基选自卤素、硝基、羟基、C1-C6烷基、C1-C6烷氧基、C3-C10环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基。
本发明所用术语“羟烷基”是指-烷基-OH,其中烷基如上所定义。本发明所用“羟烷基”的实例包括但不限于羟甲基、羟乙基、羟丙基、羟异丙基等。“羟烷基”还包括取代羟烷基,其取代基可为卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基。
本发明所用术语“烷氧基”是指-O-烷基基团,其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。“烷氧基”还包括取代烷氧基,其取代基可为卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基。
本发明所用术语“环烷基”是指具有三个至十个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的环饱和单价烃基,优选为环丙基、环丁基、环戊基、环己基等,其中一个或两个碳原子可以由一个氧代基团替代。该环烷基可以是无取代或取代的,其取代基选自卤素、硝基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基。
本发明所用术语“杂环基”是指具有三个至十个环原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的环基,具有一个及以上的选自N、O、S的杂原子,包括但不仅限于 该杂环基可以是无取代或取代的,其取代基选自卤素、硝基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基。
本发明所用术语“烯基”指由碳和氢原子组成,含至少一个双键且具有2至10个碳原子的直链或支链的烃链基团(即C2-C10烯基),包括但不限于乙烯基、烯丙基、丁-1-烯基、戊-1-烯基、戊-1,4-二-烯基等。烯基可被一个或者多个取代基取代,所述取代基独立为烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、环烷基、卤代环烷基、杂环烷基、芳基、杂芳基、羟基、卤素、氰基、硝基。
本发明所用术语“炔基”指由碳和氢原子组成,含至少一个叁键且具有2至10个碳原子的直链或支链的烃链基团(即C2-C10炔基),包括但不限于乙炔基、丙炔基、丁炔基、戊炔基和己炔基等。炔基可被一个或者多个取代基取代,所述取代基独立为烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、环烷基、卤代环烷基、杂环烷基、芳基、杂芳基、羟基、卤素、氰基、硝基。
本发明所用术语“卤素”指氟、氯、溴、碘,优选氟、氯或溴。
本发明所用术语“卤代”指被同一个原子或不同原子被卤素取代,可以取代一次也可以取代多次,如二取代或三取代。
本发明所用术语“卤代烷基”是指被卤素(优选为氟、氯、溴、碘)取代的烷基基团,其中烷基如上所定义。“卤代烷基”可被卤素取代一次或多次。
本发明所用术语“卤代羟烷基”是指被卤素(优选为氟、氯、溴、碘)取代的羟烷基基团,其中羟烷基如上所定义。“卤代羟烷基”可被卤素取代一次或多次。
本发明所用术语“卤代烷氧基”是指被卤素(优选为氟、氯、溴、碘)取代的烷氧基基团,其中烷氧基如上所定义。“卤代烷氧基”可被卤素取代一次或多次。
本发明所用术语“卤代环烷基”是指被卤素(优选为氟、氯、溴、碘)取代的环烷基基团,其中环烷基如上所定义。“卤代环烷基”可被卤素取代一次或多次。
本发明所用术语“m”优选1、2;比如可以为两个相同的R1或者两个不相同的R1。以R1为F、Cl为例,当m为2时,可以是两个不同取代位置的Cl,或者是两个不同取代位置的F,或者是两个不同取代位置Cl和F的组合。
本发明所用术语“n”优选不存在、1、2。
本发明所用术语“o”优选1、2、3。
本发明式I、式II-A~II-C、式IIIA~IIIC、式IVA~IVC、式VA~VC所述化合物,*C具有手性,其构型是R-构型或S-构型,或者R-构型和S-构型的混合物。作为进一步优选,其构型为S型。
本发明所用术语“溶剂合物”是指由溶质(例如:本发明的通式I~通式V-A~V-C化合物)和溶剂形成的可变化学计量的复合物。为了本发明的目的,所述溶剂不能干扰溶质的生物学活性。合适的溶剂的实例包括但不限于水、甲醇、乙醇和乙酸。优选使用的溶剂为药学可接受溶剂。合适的药学可接受溶剂包括但不限于水、乙醇和乙酸。更优选地,所用溶剂为水。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述化合物的盐。所述的盐可以是有机酸盐、无机酸盐等,所述的有机酸盐包括枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐、柠檬酸盐、丁二酸盐、酒石酸盐、马来酸盐、苯甲酸盐等;所述的无机酸盐包括氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。例如,与低级烷基磺酸,如甲磺酸(甲烷磺酸),三氟甲磺酸等可形成甲磺酸盐(甲烷磺酸盐)、三氟甲磺酸盐;与芳基磺酸,如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐;与有机羧酸,如乙酸,富马酸,酒石酸,草酸,马来酸,苹果酸,琥珀酸或柠檬酸等可形成相应的盐;与氨基酸,如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸,如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸),硝酸,碳酸,硫酸或磷酸等也可形成相应的盐。
本发明的第二个目的是提供一种药物组合物,包括上述任意一项技术方案所述的化合物中的一种或多种。本发明所述的药物组合物可以是上述任意一项技术方案所述的化合物中的一种或多种与其他化合物组成,或者上述任意一项技术方案所述的化合物中的一种或多种组成。
另一方面,本发明提供的是使用本文公开的通式I~通式V-A~V-C所述的化合物及其立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物来抑制酪蛋白激酶1ε(CK1ε)活性或者治疗从酪蛋白激酶1ε(CK1ε)活性的抑制中获益的疾病、障碍或病症。
在进一步优选的方案中,本发明提供的是通过给予有需要的受治疗者一种含有治疗有效量的至少一种化合物的组合物、从而抑制所述受治疗者的酪蛋白激酶1ε活性的方法,其中所述化合物的结构式为通式I~通式V-A~V-C化合物。
在一些实施方式中,所述有需要的受治疗者罹患癌症,所述癌症包括血液肿瘤和实体瘤,例如B细胞淋巴瘤、多发性骨髓瘤、白血病、肺癌、乳腺癌、前列腺癌、膀胱癌、卵巢癌、胰腺癌、肉瘤、结肠癌、肾癌、肝癌、黑色素瘤、脑部肿瘤。
在进一步的实施方式中,所述有需要的受治疗者罹患B细胞淋巴瘤,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)/白血病或淋巴瘤样肉芽肿病。
在进一步的实施方式中,所述有需要的受治疗者罹患自身免疫性疾病,例如类风湿关节炎、系统性红斑狼疮、多发性硬化、炎性肠炎、克罗恩氏病、结肠炎、自身免疫性溶血性贫血、强直性脊柱炎、天疱疮、荨麻疹、哮喘、视神经炎、银屑病、慢性阻塞性气道疾病、皮炎、秃头症。
在进一步的实施方式中,所述有需要的受治疗者罹患T细胞淋巴瘤,例如外周T细胞淋巴瘤、间变性大细胞淋巴瘤、结外NK/T细胞淋巴瘤、皮肤外周T细胞淋巴瘤、T幼淋巴细胞白血病、血管免疫母细胞T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、肝脾T细胞淋巴瘤、肠道T细胞淋巴瘤、乳房植入物相关间变性大细胞淋巴瘤、T大颗粒淋巴细胞白血病。
本发明还提供本发明所述的化合物或其可药用盐在制备CK1ε抑制剂中的应用,特别是在制备治疗细胞增生疾病中的应用。所述的细胞增生疾病包括癌症。换言之,本发明还提供通式I~通式V-A~V-C所述的化合物、立体异构体或其立体异构体混合物或其药学上可接受的盐或溶剂合物单独或和其他药物联合使用在治疗增生类疾病(如癌症)中的应用。能和本发明所提供的化合物或其可药用盐联合使用的抗肿瘤药包括但并非限定至少一种以下种类:有丝分裂抑制剂(如长春碱、长春地辛和长春瑞宾);微管蛋白分解抑制剂(如泰素));烷基化试剂(如顺铂、卡铂、环磷酰胺、苯丁酸氮芥和苯达莫丝汀);抗代谢物(如5-氟尿嘧啶、替加氟、甲氨蝶呤、阿糖胞苷和羟基脲);可插入抗生素(如阿雷素、丝裂霉素和争光霉素);酶(如天门冬氨酶);拓朴异构酶抑制剂(如依托伯苷和喜树碱);生物反应调节剂(如干扰素);免疫调节剂(如来那度胺);BTK抑制剂(如伊布替尼、阿卡替尼);Bcl-2抑制剂(如Venetoclax);anti-CD20单抗(如利妥昔单抗、奥法木单抗、阿妥珠单抗);mTOR抑制剂(如雷帕霉素、AZD8055)、mTORC1抑制剂(如依维莫司、坦罗莫司)、AKT抑制剂(如MK-2206、GSD690693)、PI3K抑制剂(如Idelalisib、Duvelisib);蛋白酶体抑制剂(如硼替佐米、卡非佐米、伊沙佐米);EGFR抑制剂(如厄洛替尼、吉非替尼、奥西替尼)、VEGFR抑制剂(索拉菲尼、卡博替尼、瑞乏替尼、乐伐替尼、阿帕替尼)、CDK抑制剂(如帕博西尼、瑞博西尼)、PD-1/PD-L1抑制剂(帕博利珠单抗、纳武利尤单抗、特瑞普利单抗、信迪利单抗)。
本发明还涉及所述化合物或药物组合物与放射治疗组合使用治疗细胞增生疾病的方法。给与放射治疗的技术是本领域已知的,这些技术能够在本申请所述的联合治疗中使用。
本发明的化合物还可以与一种或多种类固醇抗炎药、非类固醇抗炎药或免疫选择性抗炎衍生物以及其组合物联合使用。
本申请人前期专利文献中报道了一类BTK不可逆抑制剂及其光学异构体或其药学上可接受的盐或溶剂合物(专利申请号:201710998664.5),其中17a为代表化合物。通过对本申请化合物的进一步研究,我们发现,本申请化合物与BTK抑制剂联用显示出优异的协同抗肿瘤活性。
本发明发明人通过实验证实,本发明化合物具有强效的体外CK1ε激酶和体外抗肿瘤细胞抑制活性;在OCI-LY10皮下异种模型中,本发明化合物单药显示出良好的抗肿瘤效果、与BTK抑制剂联用显示出优异的协同抗肿瘤活性;本发明化合物具有较好的药代动力学性质,可应用于在单独或与其他药物联合应用治疗从酪蛋白激酶1ε活性的抑制中获益的疾病、障碍或病症,包括癌症、自身免疫性疾病等。
具体实施方式
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
实施例1:中间体4的合成
步骤1:在250mL反应瓶内加入化合物1(117mmol)和40mL DMF,于0℃下搅拌溶解,然后缓慢滴加丙酰氯(121mmol),滴毕后有大量白色固体析出,继续保温反应1h后加入200mL水,搅拌1h后过滤、烘干得固体产物中间体2。
步骤2:在100mL反应瓶内加入中间体2(10mmol)、H2N-B(20mmol)、甲苯20mL,在室温搅拌下滴加PCl3(10mmol),滴加完毕后升温至110℃回流过夜。TLC检测反应完成后,用乙酸乙酯和水萃取,干燥,浓缩后粗品经硅胶柱层析纯化得到产物中间体3。
步骤3:在100mL反应瓶内加入中间体3(8mmol)、醋酸钠(11.2mmol)、冰醋酸20mL,在室温下搅拌,然后缓慢滴加溴素(8mmol);滴加完毕继续在室温下反应约3小时,TLC检测基本反应完全;加入硫代硫酸钠水溶液搅拌15分钟,然后用乙酸乙酯和水萃取,干燥,浓缩后的粗品硅胶柱层析纯化得产物中间体4。
使用上述中间体4的合成路线和所述方法制备下列化合物:
为了描述方便,化合物1定义为:R1取代的2-氨基苯甲酸;
2-(1-溴乙基)-3-苯基喹唑啉-4(3H)-酮;3步反应,总收率55%;LC-MS(ESI-MS):329[M+H]+;1H NMR(400MHz,CDCl3)δ8.34(d,J=8.0Hz,1H),7.91–7.76(m,2H),7.71–7.49(m,5H),7.22(dt,J=7.3,2.9Hz,1H),4.62(q,J=6.7Hz,1H),2.10(d,J=6.7Hz,3H).
2-(1-溴乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮,3步反应,总收率49%;LC-MS(ESI-MS):363[M+H]+;1H NMR(500MHz,CDCl3)δ7.71(dd,J=8.2,1.2Hz,1H),7.64(dd,J=14.4,6.3Hz,1H),7.62–7.48(m,5H),7.20–7.13(m,1H),4.52(q,J=6.7Hz,1H),2.03(t,J=7.2Hz,3H).
2-(1-溴乙基)-5-氟-3-苯基喹唑啉-4(3H)-酮,3步反应,总收率28%;LC-MS(ESI-MS):347[M+H]+;1H NMR(500MHz,CDCl3)δ7.73(dd,J=13.5,8.1Hz,1H),7.57(dd,J=22.5,6.9Hz,5H),7.16(t,J=9.0Hz,2H),4.52(q,J=6.6Hz,1H),2.02(d,J=6.7Hz,3H).
2-(1-溴乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮,3步反应,总收率39%;LC-MS(ESI-MS):347[M+H]+.
2-(1-溴乙基)-5-氯-8-氟-3-苯基喹唑啉-4(3H)-酮,3步反应,总收率26%;LC-MS(ESI-MS):381[M+H]+.
2-(1-溴乙基)-5,8-二氟-3-苯基喹唑啉-4(3H)-酮,3步反应,总收率20%;LC-MS(ESI-MS):365[M+H]+.
2-(1-溴乙基)-3-(吡啶-3-基)喹唑啉-4(3H)-酮,3步反应,总收率36%;;LC-MS(ESI-MS):330[M+H]+.
2-(1-溴乙基)-5-氯-3-(吡啶-3-基)喹唑啉唑啉-4(3H)-酮,3步反应,总收率33%;LC-MS(ESI-MS):364[M+H]+.
2-(1-溴乙基)-5-氯-3-(5-氟吡啶-3-基)喹唑啉-4(3H)-酮,3步反应,总收率35%;LC-MS(ESI-MS):382[M+H]+.
2-(1-溴乙基)-3-(3-甲氧基丙基)喹唑啉-4(3H)-酮,3步反应,总收率45%;LC-MS(ESI-MS):325[M+H]+.
2-(1-溴乙基)-5-氯-3-(3-甲氧基丙基)喹唑啉-4(3H)-酮,3步反应,总收率46%;LC-MS(ESI-MS):359[M+H]+.
2-(1-溴乙基)-5-氯-3-(2-(四氢呋喃-2-基)乙基)喹唑啉-4(3H)-酮,3步反应,总收率30%;LC-MS(ESI-MS):385[M+H]+.
2-(1-溴乙基)-5-氯-3-环已基喹唑啉-4(3H)-酮,3步反应,总收率18%;LC-MS(ESI-MS):369[M+H]+.
2-(1-溴乙基)-5-氯-3-(哌啶-1-基)喹唑啉-4(3H)-酮,3步反应,总收率36%;LC-MS(ESI-MS):370[M+H]+.
2-(1-溴乙基)-5-氯-3-吗啉喹唑啉-4(3H)-酮,3步反应,总收率40%;LC-MS(ESI-MS):372[M+H]+.
4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)哌嗪-1-羧酸叔丁酯,3步反应,总收率28%;LC-MS(ESI-MS):471[M+H]+.
4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)-2-(三氟甲基)哌嗪-1-羧酸叔丁酯,3步反应,总收率36%;LC-MS(ESI-MS):539[M+H]+.
4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)-2,2-二甲基哌嗪-1-羧酸叔丁酯,3步反应,总收率31%;LC-MS(ESI-MS):499[M+H]+.
4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)哌啶-1-羧酸叔丁酯,3步反应,总收率15%;LC-MS(ESI-MS):470[M+H]+.
实施例2:中间体9的合成
步骤1:在100ml反应瓶中分别加入化合物5(5g,19mmol),三苯基氯甲烷(10.7g,38mmol),碳酸钾(10.6g,76mmol)和50mL DMF,然后加热至80℃反应约24h后,经TLC检测反应完毕,降至室温,加入乙酸乙酯和水,过滤除掉不溶物,分离乙酸乙酯层,经减压浓缩后的粗品,经硅胶柱层析纯化得到6.75g产物中间体6,收率73%。
步骤2:在500ml反应瓶中分别加入中间体6(18mmol),化合物7(27mmol),碳酸钾(54mmol),四三苯基膦钯(0.9mmol),二氧六环135ml,水45ml;在搅拌下升温至100℃反应14h后,经TLC检测反应完毕,降至室温,反应液经硅藻土过滤,乙酸乙酯漂洗滤饼,回收滤液加入100ml水和300ml乙酸乙酯萃取,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,粗品经硅胶柱层析纯化,得到产物中间体8;
步骤3:在100ml反应瓶中分别加入中间体8(3.85mmol),二氯甲烷30ml,再加入1.15ml TFA(15.4mmol)和3.1ml三异丙基硅烷(15.4mmol),在室温下反应18h后,经TLC检测反应完毕后直接减压旋蒸溶剂至近干,加入20ml MTBE,在室温下打浆2h后过滤得目标产物中间体9。
使用上述中间体9的合成路线和所述方法制备下列化合物:
化合物7中共轭环上碳原子位置定义如下:
3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺,3步反应,总收率55%;LC-MS(ESI-MS):278[M+H]+.
3-(2,3-二氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺,3步反应,总收率42%;LC-MS(ESI-MS):306[M+H]+.
3-(3-氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺,3步反应,总收率58%;LC-MS(ESI-MS):260[M+H]+.
3-(3-氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺,3步反应,总收率55%;LC-MS(ESI-MS):288[M+H]+.
实施例4:中间体10的合成
在500ml反应瓶中分别加入3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(5.2g,20mmol),碳酸钾(4.2g,30mmol)和100mL DMF,在室温搅拌下加入化合物4(8.6g,26mmol),室温反应约12h后经TLC检测反应完毕,加入乙酸乙酯和水萃取,水洗3次,分离乙酸乙酯层,无水硫酸钠干燥后经减压浓缩后的粗品,经硅胶柱层析纯化得到白色产物中间体10。
2-(1-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-3-苯基喹唑啉-4(3H)-酮;收率83%。LC-MS(ESI-MS):510[M+H]+.
实施例5:中间体(R)-12a~(R)-12d的合成
步骤1:在1000ml反应瓶中加入(R)-(+)-乳酸甲酯(20g,192mmol)和400mL甲基叔丁基醚,在室温搅拌下加入溴化苄(36g,211mmol)和氧化银(44g,192mmol),在室温下反应约20小时,TLC检测反应完成;反应液通过硅藻土过滤,滤饼用甲基叔丁醚洗涤,滤液减压浓缩之后硅胶柱层析纯化得到无色油状产物(R)-2-(苄氧基)丙酸甲酯29.8g,收率80%。手性纯度ee%:99.0%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间10.12min(对映异构体保留时间8.07min)。1H NMR(500MHz,CDCl3)δ7.44–7.27(m,5H),4.69(d,J=11.7Hz,1H),4.46(d,J=11.7Hz,1H),4.07(q,J=6.8Hz,1H),3.76(s,3H),1.44(d,J=6.9Hz,3H).
步骤2:在反应瓶中加入(R)-2-(苄氧基)丙酸甲酯(11g,57mmol)和甲醇100mL,然后在搅拌下加入氢氧化锂(2.1g,85mmol),室温反应约5h,TLC监测反应完毕;加入0.1N盐酸水溶液中和至中性,减压浓缩除去大部分甲醇,然后加入乙酸乙酯和水萃取,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化,得到无色油状产物(R)-2-(苄氧基)丙酸8.0g,收率78%。1H NMR(500MHz,CDCl3)δ7.45–7.28(m,5H),4.72(d,J=11.6Hz,1H),4.53(d,J=11.6Hz,1H),4.12(q,J=6.9Hz,1H),1.50(d,J=6.9Hz,3H).
步骤3:在反应瓶中加入取代的2-氨基-苯甲酸(19mmol)、(R)-2-(苄氧基)丙酸(4.0g,22mmol)、亚磷酸三苯酯(23g,76mmol)和吡啶50mL,反应混合物加热至60℃下搅拌反应2小时,然后将B-NH2(38mmol)加入到反应体系,继续加热至70℃下搅拌反应约12小时,TLC监测反应完毕后降至室温,减压浓缩除去大部分吡啶;加入乙酸乙酯,用2M硫酸氢钾水溶液洗3次,乙酸乙酯层分离后用无水硫酸钠干燥、减压浓缩,所得残留物硅胶柱层析纯化得到白色固体产物中间体(R)-11。
步骤4:在反应瓶中加入(R)-11(5.4mmol)和二氯甲烷50mL,降温至-10℃,滴加浓度为2M的三溴化硼二氯甲烷溶液28mL;滴加完毕升温至室温反应约2h,TLC检测反应完毕,反应瓶置于冰浴中加水淬灭反应,然后加入二氯甲烷萃取;分离二氯甲烷层后无水硫酸钠干燥,减压浓缩所得残留物硅胶柱层析纯化,得到白色固体产物(R)-12。
使用上述中间体(R)-12的合成路线和所述方法制备下列化合物:
(R)-2-(1-羟基乙基)-3-苯基喹唑啉-4(3H)-酮,1.4g,最后一步收率为97%。LC-MS(ESI-MS):267[M+H]+.
(R)-5-氯-2-(1-羟基乙基)-3-苯基喹唑啉-4(3H)-酮,1.6g,最后一步收率为98%。手性纯度ee%:98.5%,chiral-HPLC在反相CHIRALPAK IG-3柱上测定,保留时间52.7min。1H NMR(500MHz,CDCl3)δ7.70–7.62(m,2H),7.60–7.52(m,3H),7.52–7.49(m,1H),7.32(dd,J=7.5,2.2Hz,1H),7.27–7.23(m,1H),4.45(q,J=6.4Hz,1H),1.24(d,J=6.4Hz,3H).LC-MS(ESI-MS):301[M+H]+.
(R)-5-氟-2-(1-羟基乙基)-3-苯基喹唑啉-4(3H)-酮,1.5g,最后一步收率为98%。LC-MS(ESI-MS):285[M+H]+.
(R)-5-氯-2-(1-羟基乙基)-3-(吡啶-3-基)喹唑啉-4(3H)-酮,1.5g,最后一步收率为92%。LC-MS(ESI-MS):302[M+H]+.
实施例6:中间体(S)-12a~(S)-12d的合成
参照实施例5的中间体(R)-12的制备方法,采用(S)-(-)-乳酸甲酯作为起始原料,制备下列化合物:
(S)-2-(1-羟基乙基)-3-苯基喹唑啉-4(3H)-酮,1.4g,最后一步收率为97%。LC-MS(ESI-MS):267[M+H]+.
(S)-5-氯-2-(1-羟基乙基)-3-苯基喹唑啉-4(3H)-酮,1.5g,最后一步收率为93%。手性纯度ee%:98.5%,chiral-HPLC在反相CHIRALPAK IG-3柱上测定,保留时间43.7min。LC-MS(ESI-MS):301[M+H]+.
(S)-5-氟-2-(1-羟基乙基)-3-苯基喹唑啉-4(3H)-酮,1.4g,最后一步收率为91%。LC-MS(ESI-MS):285[M+H]+.
(S)-5-氯-2-(1-羟基乙基)-3-(吡啶-3-基)喹唑啉-4(3H)-酮,1.5g,最后一步收率为92%。LC-MS(ESI-MS):302[M+H]+.
实施例7:目标化合物II-A-1~II-A-6、II-A-12~II-A-15的合成
在50ml反应瓶中分别加入化合物10(2.0mmol)、中间体7(3.0mmol)、碳酸钾(4.0mmol)、四三苯基膦钯(0.02mmol),溶剂二氧六环9ml,水3ml;然后在搅拌下升温至100℃反应约14h,经TLC检测反应完全,降至室温,反应液用硅藻土过滤,乙酸乙酯洗涤;滤液加入20ml水和50ml乙酸乙酯萃取,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,粗品经硅胶柱层析纯化,得到白色固体产物。
目标化合物II-A-1(R2=CH3,R3=H,X=CF):白色固体产物,0.76g,收率为72%。1HNMR(500MHz,CDCl3)δ8.27(d,J=7.9Hz,1H),8.04(s,1H),7.89–7.72(m,2H),7.61–7.40(m,2H),7.31(d,J=7.7Hz,1H),7.21(t,J=7.5Hz,1H),7.16(t,J=7.4Hz,1H),6.90(t,J=7.7Hz,1H),6.85(t,J=7.9Hz,1H),6.54(d,J=7.7Hz,1H),6.03(q,J=6.5Hz,1H),5.45(brs,2H),3.94(s,3H),1.93(d,J=6.7Hz,3H).LC-MS(ESI-MS):526[M+H]+.
目标化合物II-A-2(R2=CH(CH3)2,R3=H,X=CF):白色固体产物,0.78g,收率为70%。LC-MS(ESI-MS):554[M+H]+.
目标化合物II-A-3(R2=CH2CH3,R3=H,X=CF):白色固体产物,0.68g,收率为63%。1H NMR(500MHz,CDCl3)δ8.27(d,J=7.8Hz,1H),8.04(s,1H),7.92–7.73(m,2H),7.49(dt,J=18.2,7.7Hz,2H),7.31(d,J=7.8Hz,1H),7.17(dt,J=14.7,7.3Hz,2H),6.89(t,J=7.6Hz,1H),6.83(t,J=7.6Hz,1H),6.53(d,J=7.9Hz,1H),6.03(q,J=6.7Hz,1H),5.38(brs,2H),4.16(q,J=6.9Hz,2H),1.92(d,J=6.7Hz,3H),1.48(t,J=7.0Hz,3H).LC-MS(ESI-MS):540[M+H]+.
目标化合物II-A-4(R2=环丙基,R3=H,X=CF):白色固体产物,0.41g,收率为37%。1H NMR(500MHz,CDCl3)δ8.27(d,J=7.9Hz,1H),8.03(s,1H),7.80(ddd,J=11.6,9.6,4.3Hz,2H),7.55–7.45(m,2H),7.31(d,J=7.3Hz,1H),7.24–7.13(m,2H),6.89(t,J=7.7Hz,1H),6.53(d,J=7.9Hz,1H),6.03(q,J=6.7Hz,1H),5.49(brs,2H),3.87(ddd,J=9.0,5.9,3.1Hz,1H),1.93(t,J=6.0Hz,3H),0.89–0.82(m,4H).LC-MS(ESI-MS):552[M+H]+.
目标化合物II-A-5(R2=CH3,R3=H,X=CCl):白色固体产物,0.44g,收率为41%。LC-MS(ESI-MS):542[M+H]+.
目标化合物II-A-6(R2=CH3,R3=H,X=CCN):白色固体产物,0.42g,收率为39%。LC-MS(ESI-MS):533[M+H]+.
目标化合物II-A-12(R2=CH3,R3=6-氟,X=CH):白色固体产物,0.36g,收率为34%。1H NMR(500MHz,CDCl3)δ8.27(d,J=8.0Hz,1H),8.03(s,1H),7.91–7.71(m,2H),7.63–7.41(m,2H),7.31(d,J=7.6Hz,1H),7.24–7.18(m,1H),7.15(dd,J=14.5,7.0Hz,1H),6.89(dd,J=11.1,4.4Hz,1H),6.85(t,J=7.4Hz,1H),6.54(d,J=8.1Hz,1H),6.03(q,J=6.7Hz,1H),5.49(brs,2H),3.94(s,3H),1.92(d,J=6.7Hz,3H).LC-MS(ESI-MS):526[M+H]+.
目标化合物II-A-13(R2=CH3,R3=H,X=N):白色固体产物,0.75g,收率为74%。LC-MS(ESI-MS):509[M+H]+.
目标化合物II-A-14(R2=CH(CH3)2,R3=H,X=N):白色固体产物,0.72g,收率为67%。1H NMR(500MHz,CDCl3)δ8.27(dd,J=7.9,0.9Hz,1H),8.03(s,1H),7.89–7.75(m,2H),7.54–7.49(m,1H),7.47(td,J=7.7,1.2Hz,1H),7.31(d,J=7.9Hz,1H),7.16(t,J=7.5Hz,1H),6.96–6.87(m,1H),6.67(d,J=8.2Hz,1H),6.51(d,J=8.0Hz,1H),6.02(q,J=6.7Hz,1H),5.60(brs,2H),5.33–5.22(m,1H),4.06(t,J=6.7Hz,1H),1.92(d,J=6.8Hz,3H),1.36(dd,J=6.2,3.0Hz,6H).LC-MS(ESI-MS):537[M+H]+.
目标化合物II-A-15(R2=Ph,R3=H,X=N):白色固体产物,0.82g,收率为72%。1HNMR(500MHz,CDCl3)δ8.27(d,J=7.7Hz,1H),8.04(s,1H),7.96(t,J=8.8Hz,1H),7.81(dt,J=15.0,7.4Hz,2H),7.51(t,J=6.9Hz,1H),7.47(t,J=7.9Hz,1H),7.43(t,J=7.9Hz,2H),7.36–7.23(m,2H),7.16(d,J=7.6Hz,3H),6.90(t,J=7.7Hz,1H),6.86(d,J=8.1Hz,1H),6.50(d,J=7.8Hz,1H),6.03(q,J=6.6Hz,1H),5.46(brs,2H),1.92(d,J=6.7Hz,3H).LC-MS(ESI-MS):571[M+H]+.
实施例8:目标化合物II-A-7~II-A-11的合成
在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4d]嘧啶-4-胺(1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入中间体4(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到目标产物。
目标化合物II-A-7(R1=5-氯):白色固体产物,0.48g,收率85%。1H NMR(500MHz,CDCl3)δ8.05(s,1H),7.73(d,J=8.1Hz,1H),7.64(t,J=8.0Hz,1H),7.51(d,J=7.8Hz,1H),7.47(t,J=7.6Hz,1H),7.29(d,J=7.9Hz,1H),7.22(dd,J=11.8,4.4Hz,1H),7.16(t,J=7.4Hz,1H),6.93–6.84(m,2H),6.53(d,J=8.0Hz,1H),6.00(q,J=6.7Hz,1H),5.33(brs,2H),3.96(s,3H),1.90(d,J=6.7Hz,3H).LC-MS(ESI-MS):560[M+H]+.
目标化合物II-A-8(R1=5-氟):白色固体产物,0.36g,收率66%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.71(dd,J=13.5,8.1Hz,1H),7.61(d,J=8.2Hz,1H),7.47(t,J=7.6Hz,1H),7.29(d,J=8.1Hz,1H),7.21(t,J=7.9Hz,1H),7.15(t,J=9.3Hz,2H),6.87(dd,J=17.1,8.6Hz,2H),6.52(d,J=8.0Hz,1H),6.00(q,J=6.6Hz,1H),5.31(brs,2H),3.95(s,3H),1.90(d,J=6.7Hz,3H).LC-MS(ESI-MS):544[M+H]+.
目标化合物II-A-9(R1=6-氟):白色固体产物,0.38g,收率70%。LC-MS(ESI-MS):544[M+H]+.
目标化合物II-A-10(R1=5-氯-8-氟):白色固体产物,0.34g,收率58%。LC-MS(ESI-MS):578[M+H]+.
目标化合物II-A-11(R1=5,8-二氟):白色固体产物,0.37g,收率65%。LC-MS(ESI-MS):562[M+H]+.
实施例9:目标化合物II-A-16的合成
在20mL反应瓶中加入3-(2,3-二氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9b,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入中间体4c(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到目标产物II-A-16,0.36g,收率63%。1H NMR(500MHz,DMSO)δ7.87(brs,2H),7.60(brs,2H),7.47–7.28(m,2H),7.24–7.02(m,3H),6.79(brs,1H),6.31(brs,1H),5.90(brs,1H),4.71(brs,1H),1.71(s,3H),1.31(s,6H).LC-MS(ESI-MS):572[M+H]+.
实施例10:目标化合物II-B-1~II-B-3的合成
在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入中间体4(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到目标产物。
目标产物II-B-1(R1=H,R5=H):白色固体产物,0.37g,收率71%。LC-MS(ESI-MS):527[M+H]+.
目标产物II-B-2(R1=5-氯,R5=H):白色固体产物,0.36g,收率65%。1H NMR(500MHz,CDCl3)δ8.58(d,J=2.3Hz,0.5H),8.39(d,J=3.6Hz,0.5H),8.30(d,J=4.3Hz,0.5H),8.08(d,J=11.6Hz,1H),7.81–7.72(m,1.5H),7.67(td,J=8.1,3.9Hz,1.5H),7.58–7.50(m,1H),7.38(dd,J=8.0,4.9Hz,0.5H),7.29–7.23(m,0.5H),7.20(t,J=7.3Hz,0.5H),6.92–6.79(m,2H),5.99(q,J=6.7Hz,0.5H),5.90(q,J=6.8Hz,0.5H),5.39(brs,2H),3.95(d,J=2.0Hz,3H),1.91(t,J=6.1Hz,3H).LC-MS(ESI-MS):561[M+H]+.
目标产物II-B-3(R1=5-氯,R5=5-氟):白色固体产物,0.35g,收率60%。1H NMR(500MHz,CDCl3)δ8.43(s,0.6H),8.26(d,J=2.6Hz,0.6H),8.16(d,J=2.5Hz,0.6H),8.12(s,1H),7.77(d,J=8.1Hz,1H),7.69(td,J=8.0,1.3Hz,1H),7.63–7.52(m,1.4H),7.46–7.41(m,0.4H),7.25–7.18(m,1H),6.88(dd,J=14.2,7.0Hz,1H),6.69–6.57(m,0.7H),5.97(dq,J=24.5,6.7Hz,1.3H),5.33(d,J=24.5Hz,2H),3.96(d,J=3.3Hz,3H),2.11–1.76(m,3H).LC-MS(ESI-MS):579[M+H]+.
实施例11:目标化合物II-C-1、II-C-5、II-C-6的合成
在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入中间体4(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到目标产物。
目标产物II-C-1(Y=CH,Z=CH2):白色固体产物,0.41g,收率72%。1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.65(d,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.45(d,J=7.7Hz,1H),7.18(t,J=7.4Hz,1H),6.84(t,J=7.9Hz,1H),6.36(q,J=6.5Hz,1H),5.66(brs,2H),4.00–3.86(m,1H),3.93(s,3H),2.73(qd,J=12.5,3.4Hz,1H),2.47(qd,J=12.7,3.4Hz,1H),1.99(d,J=6.5Hz,3H),1.86–1.77(m,1H),1.66(d,J=12.0Hz,1H),1.44(d,J=12.8Hz,1H),1.37(d,J=13.0Hz,1H),1.29(dd,J=16.7,6.7Hz,1H),1.16–1.05(m,1H),0.43(d,J=11.6Hz,1H),0.11(dd,J=26.0,13.0Hz,1H).LC-MS(ESI-MS):566[M+H]+.
目标产物II-C-5(Y=N,Z=CH2):白色固体产物,0.40g,收率71%。1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.59(dt,J=6.7,3.3Hz,1H),7.54(t,J=7.9Hz,1H),7.43(dd,J=7.7,1.1Hz,1H),7.25–7.17(m,1H),6.84(dd,J=11.8,4.3Hz,1H),6.53(q,J=6.9Hz,1H),5.54(brs,2H),4.02–3.90(m,1H),3.94(s,3H),3.88–3.72(m,1H),2.98(d,J=10.3Hz,1H),2.26(d,J=9.9Hz,1H),1.95(d,J=6.9Hz,3H),1.78–1.68(m,3H),1.58–1.45(m,1H),1.29(d,J=14.7Hz,1H),1.22–1.06(m,1H),0.45(dtd,J=12.9,9.0,4.0Hz,1H).LC-MS(ESI-MS):567[M+H]+.
目标产物II-C-6(Y=N,Z=O):白色固体产物,0.31g,收率55%。1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.57(d,J=8.1Hz,1H),7.51(t,J=8.0Hz,1H),7.39(d,J=6.9Hz,1H),7.13(dd,J=11.7,4.7Hz,1H),6.78(t,J=7.4Hz,1H),6.48(q,J=6.9Hz,1H),5.36(brs,2H),4.18(td,J=11.2,3.1Hz,1H),4.05(dd,J=14.4,7.3Hz,1H),4.03–3.96(m,1H),3.87(s,3H),3.80(d,J=10.3Hz,1H),3.65(dd,J=11.4,9.2Hz,1H),3.37(d,J=10.8Hz,1H),2.77(d,J=10.6Hz,1H),2.40(dd,J=11.4,9.2Hz,1H),1.87(d,J=6.9Hz,3H).LC-MS(ESI-MS):569[M+H]+.
实施例12:目标化合物II-C-2的合成
步骤1:在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)哌啶-1-羧酸叔丁酯(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.46g中间体13,收率69%。
步骤2:在20mL反应瓶中加入中间体13(0.6mmol),二氯甲烷6mL,然后加入1mL三氟乙酸,在室温下反应约12小时,经TLC检测反应基本完全,加入水和二氯甲烷萃取,有机相用饱和碳酸氢钠水溶液洗,分离二氯甲烷层,无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化后得到0.27g目标产物:化合物II-C-2,收率80%。LC-MS(ESI-MS):567[M+H]+.
实施例13:目标化合物II-C-3的合成
在20mL反应瓶中加入化合物II-C-2(0.3mmol),二氯甲烷6mL,然后加入醋酸(0.3mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.6mmol);在室温反应约3h,TLC检测反应完毕,加入水和二氯甲烷萃取,分离有机相无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化得到151mg白色产物:化合物II-C-3,收率83%。LC-MS(ESI-MS):609[M+H]+.
实施例14:目标化合物II-C-4的合成
在20mL反应瓶中加入化合物II-C-2(0.3mmol),四氢呋喃4mL,然后加入三氟甲基碘乙烷(0.3mmol),碳酸钾(0.6mmol);在室温下反应约2h,TLC检测反应完成;加入水淬灭,然后用乙酸乙酯萃取,有机相无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到101mg类白色产物:化合物II-C-4,收率52%。LC-MS(ESI-MS):649[M+H]+.
实施例15:目标化合物II-C-7的合成
步骤1:在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)哌嗪-1-羧酸叔丁酯(4p,1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.42g中间体14,收率63%。
步骤2:在20mL反应瓶中加入中间体14(0.6mmol),二氯甲烷6mL,然后加入1mL三氟乙酸,在室温下反应约12小时,经TLC检测反应基本完全,加入水和二氯甲烷萃取,有机相用饱和碳酸氢钠水溶液洗,分离二氯甲烷层,无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化后得到0.28g目标产物:化合物II-C-7,收率82%。1H NMR(500MHz,DMSO)δ9.11(s,3H),8.32(s,1H),7.78(t,J=7.9Hz,1H),7.67(d,J=8.1Hz,1H),7.59(d,J=8.0Hz,1H),7.20(t,J=7.9Hz,1H),7.05(t,J=8.1Hz,1H),6.44(dd,J=13.3,6.8Hz,1H),4.04–3.89(m,2H),3.88(s,3H),3.45(d,J=11.7Hz,2H),3.02(t,J=11.5Hz,1H),2.85(d,J=11.3Hz,1H),1.89(d,J=11.1Hz,1H),1.72(d,J=6.5Hz,3H),1.42(t,J=10.8Hz,1H).LC-MS(ESI-MS):567[M+H]+.
实施例16:目标化合物II-C-8的合成
步骤1:在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)-2,2-二甲基哌嗪-1-羧酸叔丁酯(4r,1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.38g中间体15,收率55%。
步骤2:在20mL反应瓶中加入中间体15(0.6mmol),二氯甲烷6mL,然后加入1mL三氟乙酸,在室温下反应约12小时,经TLC检测反应基本完全,加入水和二氯甲烷萃取,有机相用饱和碳酸氢钠水溶液洗,分离二氯甲烷层,无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化后得到0.28g目标产物:化合物II-C-8,收率79%。LC-MS(ESI-MS):596[M+H]+.
实施例17:目标化合物II-C-9的合成
步骤1:在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入4-(2-(1-溴乙基)-5-氯-4-氧代喹唑啉-3(4H)-基)-2-(三氟甲基)哌嗪-1-羧酸叔丁酯(4q,1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.36g中间体16,收率49%。
步骤2:在20mL反应瓶中加入中间体16(0.6mmol),二氯甲烷6mL,然后加入1mL三氟乙酸,在室温下反应约12小时,经TLC检测反应基本完全,加入水和二氯甲烷萃取,有机相用饱和碳酸氢钠水溶液洗,分离二氯甲烷层,无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化后得到0.28g目标产物:化合物II-C-9,收率75%。LC-MS(ESI-MS):636[M+H]+.
实施例18:目标化合物II-C-10的合成
在20mL反应瓶中加入化合物II-C-7(0.5mmol),四氢呋喃5mL,然后加入三氟甲基碘乙烷(0.5mmol),碳酸钾(1.0mmol);在室温下反应约2h,TLC检测反应完成;加入水淬灭,然后用乙酸乙酯萃取,有机相无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到172mg类白色产物:化合物II-C-10,收率53%。LC-MS(ESI-MS):650[M+H]+.
实施例19:目标化合物II-C-11的合成
在20mL反应瓶中加入化合物II-C-7(0.5mmol),四氢呋喃5mL,然后加入碘甲烷(0.45mmol),碳酸钾(1.0mmol);在室温下反应约2h,加入水淬灭,然后用乙酸乙酯萃取,有机相无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到125mg类白色目标产物:化合物II-C-11,收率43%。1H NMR(500MHz,CDCl3)δ8.44(s,1H),7.60(d,J=7.9Hz,1H),7.55(t,J=7.8Hz,1H),7.43(d,J=7.5Hz,1H),7.19(t,J=7.6Hz,1H),6.84(t,J=7.8Hz,1H),6.50(dd,J=13.2,6.6Hz,1H),5.51(brs,2H),4.23(t,J=10.4Hz,1H),4.06(t,J=10.1Hz,1H),3.94(s,3H),2.84(dd,J=33.7,10.2Hz,2H),2.40(d,J=11.5Hz,2H),2.17(s,3H),2.08(d,J=9.6Hz,2H),1.94(d,J=6.6Hz,3H).LC-MS(ESI-MS):582[M+H]+.
实施例20:目标化合物II-C-12的合成
在20mL反应瓶中加入化合物II-C-7(0.3mmol),二氯甲烷6mL,然后加入醋酸(0.3mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.6mmol);在室温反应约3h,TLC检测反应完毕,加入水和二氯甲烷萃取,分离有机相无水硫酸钠干燥后减压浓缩,所得残留物经硅胶柱层析纯化得到155mg白色产物II-C-12,收率85%。LC-MS(ESI-MS):610[M+H]+.
实施例21:化合物II-C-13的合成
在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入2-(1-溴乙基)-3-(3-甲氧基丙基)喹唑啉-4(3H)-酮(4j,1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.35g固体产物:化合物II-C-13,收率67%。LC-MS(ESI-MS):522[M+H]+.
实施例22:化合物II-C-14的合成
在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入2-(1-溴乙基)-5-氯-3-(3-甲氧基丙基)喹唑啉-4(3H)-酮(4k,1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.36g固体产物:化合物II-C-14,收率65%。1H NMR(500MHz,DMSO)δ8.30(s,1H),7.72(t,J=7.5Hz,1H),7.57(dd,J=28.8,7.5Hz,2H),7.18(s,1H),7.08(d,J=7.2Hz,1H),6.40(d,J=5.7Hz,1H),4.06–3.75(m,2H),3.84(s,3H),3.05(s,3H),2.96(brs,2H),1.85–1.76(m,5H).LC-MS(ESI-MS):556[M+H]+.
实施例23:化合物II-C-15的合成
在20mL反应瓶中加入3-(2,3-二氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9a,1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入2-(1-溴乙基)-5-氯-3-(2-(四氢呋喃-2-基)乙基)喹唑啉-4(3H)-酮(4l,1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到0.30g固体产物:化合物II-C-15,收率52%。LC-MS(ESI-MS):582[M+H]+.
实施例24:目标化合物II-A-1a和II-A-1b的合成
在反应瓶中加入中间体9a(10mmol)、(R)-12a或(S)-12a(20mmol)、三苯基膦(5.3g,20mmol)和四氢呋喃50mL,降温至0℃,滴加偶氮二甲酸二异丙酯(3.9mL,20mmol);滴加完毕升温至室温反应约6h,TLC检测反应完毕;减压浓缩除去大部分四氢呋喃,所得残留物硅胶柱层析纯化,得到白色固体产物。
目标化合物II-A-1a:3.1g,收率58%;手性纯度ee%:97.8%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间13.86min。LC-MS(ESI-MS):526[M+H]+.
目标化合物II-A-1b:2.9g,收率55%;手性纯度ee%:98.2%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间17.24min。LC-MS(ESI-MS):526[M+H]+.
实施例25:目标化合物II-A-2a和II-A-2b的合成
在反应瓶中加入中间体9b(10mmol)、(R)-12a或(S)-12a(20mmol)、三苯基膦(5.3g,20mmol)和四氢呋喃50mL,降温至0℃,滴加偶氮二甲酸二异丙酯(3.9mL,20mmol);滴加完毕升温至室温反应约6h,TLC检测反应完毕;减压浓缩除去大部分四氢呋喃,所得残留物硅胶柱层析纯化,得到白色固体产物。
目标化合物II-A-2a:3.1g,收率56%;手性纯度ee%:98.2%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间14.10min。LC-MS(ESI-MS):554[M+H]+.
目标化合物II-A-2b:3.0g,收率54%;手性纯度ee%:97.8%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间16.90min。LC-MS(ESI-MS):554[M+H]+.
实施例26:目标化合物II-A-7a和II-A-7b的合成
在反应瓶中加入中间体9a(10mmol)、(R)-12b或(S)-12b(20mmol)、三苯基膦(5.3g,20mmol)和四氢呋喃50mL,降温至0℃,滴加偶氮二甲酸二异丙酯(3.9mL,20mmol);滴加完毕升温至室温反应约6h,TLC检测反应完毕;减压浓缩除去大部分四氢呋喃,所得残留物硅胶柱层析纯化,得到白色固体产物。
目标化合物II-A-7a:3.1g,收率55%;手性纯度ee%:98.6%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间12.09min。LC-MS(ESI-MS):560[M+H]+.
目标化合物II-A-7b:3.0g,收率54%;手性纯度ee%:98.1%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间19.90min。LC-MS(ESI-MS):560[M+H]+.
实施例27:目标化合物II-A-8a和II-A-8b的合成
在反应瓶中加入中间体9a(10mmol)、(R)-12c或(S)-12c(20mmol)、三苯基膦(5.3g,20mmol)和四氢呋喃50mL,降温至0℃,滴加偶氮二甲酸二异丙酯(3.9mL,20mmol);滴加完毕升温至室温反应约6h,TLC检测反应完毕;减压浓缩除去大部分四氢呋喃,所得残留物硅胶柱层析纯化,得到白色固体产物。
目标化合物II-A-8a:3.1g,收率57%;手性纯度ee%:98.7%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间12.75min。LC-MS(ESI-MS):544[M+H]+.
目标化合物II-A-8b:3.0g,收率55%;手性纯度ee%:98.2%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间18.99min。LC-MS(ESI-MS):544[M+H]+.
实施例28:目标化合物II-B-2a和II-B-2b的合成
在反应瓶中加入中间体9a(10mmol)、(R)-12d或(S)-12d(20mmol)、三苯基膦(5.3g,20mmol)和四氢呋喃50mL,降温至0℃,滴加偶氮二甲酸二异丙酯(3.9mL,20mmol);滴加完毕升温至室温反应约6h,TLC检测反应完毕;减压浓缩除去大部分四氢呋喃,所得残留物硅胶柱层析纯化,得到白色固体产物。
目标化合物II-B-2a:2.7g,收率48%;手性纯度ee%:98.0%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间13.42min。LC-MS(ESI-MS):561[M+H]+.
目标化合物II-B-2b:2.6g,收率46%;手性纯度ee%:97.8%,chiral-HPLC在正相CHIRALCEL OD-H柱上测定,保留时间23.15min。LC-MS(ESI-MS):561[M+H]+.
实施例29:化合物II-D-1~II-D-4的合成
将化合物II-A-1a(231mg,0.4mmol)加入烧瓶,加入6mL异丙醇,搅拌,加入无机酸或有机酸(0.44mmol),加热至回流,搅拌反应1h,缓慢冷却至室温,脱溶,过滤并收集固体,常温真空干燥,得到固体产物。
化合物II-D-1:加入的酸为盐酸(0.44mmol)。终产物II-D-1为白色固体,241mg,收率98.1%。LC-MS(ESI-MS):526[M+H]+.
化合物II-D-2:加入的酸为硫酸(0.44mmol)。终产物II-D-2为白色固体,250mg,收率99.5%。LC-MS(ESI-MS):526[M+H]+.
化合物II-D-3:加入的酸为一水合对甲苯磺酸(84mg,0.44mmol)。终产物II-D-3为白色固体,273mg,收率91%。1H NMR(400MHz,DMSO)δ8.17(s,1H),7.84(t,J=8.0Hz,1H),7.76(dd,J=8.2,1.1Hz,1H),7.65(dd,J=12.9,5.1Hz,2H),7.50–7.43(m,3H),7.37–7.25(m,1H),7.22–7.04(m,4H),6.93(dd,J=11.1,4.3Hz,1H),6.44(d,J=8.2Hz,1H),5.99(q,J=6.6Hz,1H),3.93(s,3H),2.29(s,3H),1.78(d,J=6.7Hz,3H)。LC-MS(ESI-MS):526[M+H]+.
化合物II-D-4:加入的酸为甲烷磺酸(29μL,0.44mmol)。终产物II-D-4为白色固体,260mg,收率96.5%。LC-MS(ESI-MS):526[M+H]+.
实施例30:化合物II-D-5~II-D-17的合成
将化合物II-A-7a(0.4mmol)加入烧瓶,加入6mL异丙醇,搅拌,加入无机酸或有机酸(0.44mmol),加热至回流,搅拌反应1h,缓慢冷却至室温,脱溶,过滤并收集固体,常温真空干燥,得到固体产物。
化合物II-D-5:加入的酸为盐酸(0.44mmol)。终产物II-D-5为白色固体,233mg,收率99.5%。1H NMR(500MHz,DMSO)δ8.04(s,1H),7.84(t,J=8.0Hz,1H),7.75(d,J=8.2Hz,1H),7.64(d,J=7.9Hz,2H),7.46(t,J=7.7Hz,1H),7.29(t,J=7.7Hz,1H),7.20–7.05(m,2H),6.87(t,J=7.7Hz,1H),6.37(d,J=8.0Hz,1H),5.95(q,J=6.6Hz,1H),3.92(s,3H),1.75(d,J=6.6Hz,3H)。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-6:加入的酸为硫酸(0.44mmol)。终产物II-D-6为类白色固体,244mg,收率99.5%。1H NMR(500MHz,DMSO)δ8.06(s,1H),7.84(t,J=8.0Hz,1H),7.75(d,J=8.1Hz,1H),7.64(d,J=7.8Hz,2H),7.46(t,J=7.7Hz,1H),7.30(t,J=7.5Hz,1H),7.22–7.06(m,2H),6.88(t,J=7.7Hz,1H),6.38(d,J=8.1Hz,1H),5.96(q,J=6.6Hz,1H),3.92(s,3H),1.75(d,J=6.6Hz,3H)。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-7:加入的酸为磷酸(0.44mmol)。终产物II-D-7为类白色固体,207mg,收率78.6%。1H NMR(500MHz,DMSO)δ7.88(s,1H),7.83(t,J=8.0Hz,1H),7.75(d,J=8.1Hz,1H),7.61(dd,J=13.8,7.9Hz,2H),7.43(t,J=7.6Hz,1H),7.24(t,J=7.6Hz,1H),7.10(dd,J=12.8,7.5Hz,2H),6.81(t,J=7.7Hz,1H),6.31(d,J=7.8Hz,1H),5.90(q,J=6.6Hz,1H),3.91(s,3H),1.72(d,J=6.6Hz,3H)。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-8:加入的酸为一水合对甲苯磺酸(84mg,0.44mmol)。终产物II-D-8为类白色固体,268mg,收率91.5%。1H NMR(400MHz,DMSO)δ8.20–8.05(m,2H),7.97–7.87(m,1H),7.82(d,J=7.9Hz,1H),7.68(d,J=8.0Hz,1H),7.65–7.56(m,1H),7.54–7.39(m,3H),7.34–7.24(m,1H),7.20–7.01(m,3H),6.93(dd,J=11.1,4.3Hz,1H),6.42(d,J=8.0Hz,1H),6.05(q,J=6.6Hz,1H),3.92(s,3H),2.29(s,3H),1.80(d,J=6.6Hz,3H)。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-9:加入的酸为甲烷磺酸(29μL,0.44mmol)。终产物II-D-9为类白色固体,262mg,收率99.5%。1H NMR(500MHz,DMSO)δ8.14(s,1H),7.84(t,J=8.0Hz,1H),7.75(d,J=8.1Hz,1H),7.65(t,J=7.7Hz,2H),7.47(t,J=7.6Hz,1H),7.31(t,J=8.1Hz,1H),7.15(dt,J=16.3,7.8Hz,2H),6.92(t,J=7.5Hz,1H),6.41(d,J=7.8Hz,1H),5.97(t,J=6.6Hz,1H),3.93(s,3H),2.36(s,3H),1.77(d,J=6.6Hz,3H)。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-10:加入的酸为柠檬酸(85mg,0.44mmol)。终产物II-D-10为类白色固体,206mg,收率68.5%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-11:加入的酸为丁二酸(52mg,0.44mmol)。终产物II-D-11为类白色固体,198mg,收率73.1%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-12:加入的酸为L-苹果酸(66mg,0.44mmol)。终产物II-D-12为类白色固体,213mg,收率76.7%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-13:加入的酸为D-苹果酸(59mg,0.44mmol)。终产物II-D-13为类白色固体,201mg,收率72.4%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-14:加入的酸为L-酒石酸(66mg,0.44mmol)。终产物II-D-14为类白色固体,209mg,收率73.6%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-15:加入的酸为苯甲酸(54mg,0.44mmol)。终产物II-D-15为类白色固体,202mg,收率74%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-16:加入的酸为马来酸(51mg,0.44mmol)。终产物II-D-16为类白色固体,220mg,收率81.5%。LC-MS(ESI-MS):560[M+H]+.
化合物II-D-17:加入的酸为草酸(55mg,0.44mmol)。终产物II-D-17为类白色固体,216mg,收率83.1%。LC-MS(ESI-MS):560[M+H]+.
实施例31:化合物A和B的合成
在50ml反应瓶中分别加入化合物10(2.0mmol)、化合物7(3.0mmol)、碳酸钾(4.0mmol)、四三苯基膦钯(0.02mmol),溶剂二氧六环9ml,水3ml;然后在搅拌下升温至100℃反应约14h,经TLC检测反应完全,降至室温,反应液用硅藻土过滤,乙酸乙酯洗涤;滤液加入20ml水和50ml乙酸乙酯萃取,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,粗品经硅胶柱层析纯化,得到白色固体产物。
化合物A(R2=CH(CH3)2):0.67g,收率63%。H NMR(500MHz,CDCl3)δ8.27(dt,J=11.9,5.8Hz,1H),8.05(s,1H),7.80(ddd,J=11.3,9.6,4.4Hz,2H),7.55–7.49(m,1H),7.47(td,J=7.7,1.1Hz,1H),7.37(dd,J=11.5,2.0Hz,1H),7.31(d,J=7.6Hz,2H),7.16(t,J=7.5Hz,1H),7.07(t,J=8.4Hz,1H),6.89(td,J=7.8,1.1Hz,1H),6.50(d,J=8.3Hz,1H),6.00(q,J=6.7Hz,1H),5.55(brs,2H),4.60(dq,J=12.1,6.1Hz,1H),1.91(t,J=8.9Hz,3H),1.38(dt,J=7.0,3.5Hz,6H).LC-MS(ESI-MS):536[M+H]+.
化合物B(R2=环丙基):0.49g,收率46%。1H NMR(500MHz,CDCl3)δ8.28(d,J=7.9Hz,1H),8.06(s,1H),7.88–7.76(m,2H),7.50(dt,J=15.1,7.2Hz,2H),7.36(ddd,J=25.8,18.5,8.0Hz,4H),7.17(t,J=7.4Hz,1H),6.89(t,J=7.6Hz,1H),6.50(d,J=7.8Hz,1H),6.00(q,J=6.7Hz,1H),5.51(s,2H),3.91–3.81(m,1H),1.92(d,J=6.7Hz,3H),0.92–0.78(m,4H).LC-MS(ESI-MS):534[M+H]+.
实施例32:化合物C的合成
在20mL反应瓶中加入中间体9c(1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入中间体4b(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到固体产物C,,0.42g,收率78%。1H NMR(500MHz,DMSO)δ7.92(brs,1H),7.89–7.80(m,1H),7.77(d,J=7.6Hz,1H),7.62(dd,J=16.6,7.6Hz,2H),7.48–7.40(m,2H),7.37(d,J=8.1Hz,1H),7.30(d,J=8.5Hz,1H),7.11(d,J=6.9Hz,1H),6.86(d,J=7.2Hz,1H),6.34(d,J=6.8Hz,1H),5.91(d,J=6.3Hz,1H),3.89(s,3H),1.74(d,J=6.1Hz,3H).LC-MS(ESI-MS):544[M+H]+.
实施例33:化合物D的合成
在20mL反应瓶中加入中间体9d(1.0mmol)和5mL DMF,在室温下搅拌溶解,然后依次加入中间体4c(1.1mmol)和碳酸钾(2.0mmol),升温至40℃反应约15小时;TLC检测反应完毕后,加入乙酸乙酯萃取,水洗,分离乙酸乙酯层,无水硫酸钠干燥后减压浓缩,所得残留物硅胶柱层析纯化得到固体产物D,0.32g,收率58%。1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.71(td,J=8.2,5.4Hz,1H),7.61(d,J=8.2Hz,1H),7.46(t,J=7.7Hz,1H),7.37(dd,J=11.4,1.9Hz,1H),7.30(dd,J=13.9,8.5Hz,2H),7.15(dd,J=15.6,8.0Hz,2H),7.07(dd,J=17.1,8.8Hz,1H),6.88(t,J=7.7Hz,1H),6.49(d,J=7.9Hz,1H),5.96(q,J=6.7Hz,1H),5.56(brs,2H),4.60(dq,J=12.0,6.0Hz,1H),1.89(d,J=6.8Hz,3H),1.39(dd,J=6.0,2.5Hz,6H).LC-MS(ESI-MS):554[M+H]+.
实施例34:CK1ε激酶活性测定
本发明化合物的体外CK1ε激酶抑制活性测定方法:
(1)准备1×激酶基础缓冲液和反应停止缓冲液:
—1×激酶基础缓冲液:50mM HEPES,pH 7.5;0.0015%Brij-35;
—反应停止缓冲液:100mM HEPES,pH 7.5;0.015%Brij-35;0.2%CoatingReagent#3;50mM EDTA。
(2)待测化合物的配制:
—DMSO配制50×(“n×”表示稀释倍,下同)化合物储备液(10mM,DMSO),得到的储备液I待用;在96孔板中加入100μl储备液I,按5倍浓度梯度稀释的方法稀释每个化合物样品,至10个浓度并保证每孔中药物溶液体积为10μl,同时加入100μl DMSO作为空白对照组,以及不加酶底物的阴性对照组;
—再另外准备一块96孔板,取10μl上述化合物
加入90μl 1×激酶基础缓冲液,混匀10min,得到混合液。
(3)待测板准备:
—取上述配制的96孔板中混合液5μl至384孔板,每个化合物两个复孔;
—配制2.5×激酶溶液,加入相应1×激酶基础缓冲液;
—配制2.5×多肽溶液,在1×激酶基础缓冲液中加入FAM标记的多肽和ATP;
—在待测384孔板中加入10μl的2.5×激酶溶液,室温放置10min,继而加入10μl的2.5×多肽溶液,28℃下反应1h后加入25μl反应停止缓冲液。
—Caliper程序读板,并利用数据获得相应化合物抑制激酶的IC50值,测试结果见表1。
表1部分化合物对CK1ε的抑制活性
*:数据来源于文献值:WO2017079558A1。
表1中数据表明,本发明得到的所有化合物对CK1ε均有明显的抑制活性,同时,本发明得到的所有化合物对CK1ε的抑制活性均明显优于化合物CUX-031723(专利文献公开号:WO2017079558A1,CK1ε的IC50为9.362μM),以及化合物A~D(4-氨基-二取代苯基-1H-吡唑[3,4-d]嘧啶-1-基类化合物。其中手性化合物II-A-1a、II-A-2a、II-A-7a、II-A-8a、II-B-2a对CK1ε抑制的IC50分别达到了108、88、45、60和202nM。化合物II-A-2、II-A-4、II-A-7分别与化合物A、B、C相比,CK1ε抑制活性分别提高了12、12、7.2倍;II-A-16分别与化合物D和CUX-031773相比,CK1ε抑制活性分别提高了12.9和93.6倍,说明本发明化合物在吡唑并[3,4-d]嘧啶-1-基部分,取代基苯环上的2位氟原子对提高CK1ε抑制活性十分重要。说明本发明化合物具有进一步的应用前景。
实施例35:体外抗肿瘤细胞活性测试
选用弥漫性巨型B细胞淋巴瘤(OCI-LY10)细胞株对所合成的化合物进行了体外抗肿瘤活性的测定:
药物配制方法:将药物溶于DMSO中制成10mM的储备液,并按一定比例稀释得到7个不同浓度(测试浓度100×)。
肿瘤细胞体外培养:培养基:IMDM+胎牛血清将所选取的OCI-LY10细胞于37℃、5%CO2细胞培养箱中孵育,待细胞密度长到70~90%时传代(贴壁细胞用Duck’s EDTA消化后传代),用于以后实验所需。在96孔板上种入4000个/200μL/孔,于37℃、5%CO2细胞培养箱中孵育过夜。每孔加入化合物2μL,终浓度为10μM、2.5μM、0.625μM、0.15625μM,0.039063μM,0.0097656μM,0.0024414μM共同于37℃、5%CO2细胞培养箱中孵育72小时,以DMSO(2%)为对照组。72小时后,加入20μL CCK-8溶液,置于37℃、5%CO2细胞培养箱中4小时。用加了相应量细胞培养液和CCK-8溶液但没有加入细胞的孔作为空白对照。用酶标仪在450nm测定吸光度(OD值),所得数据用于计算IC50,测试结果见表2。
细胞抑制率的计算公式为:细胞抑制率%=[(对照组OD值-空白组OD值)-(用药组OD值-空白组OD值)]/(对照细胞OD值-空白组OD值)×100%,用CalcuSyn软件计算求得半数抑制浓度(IC50)。
表2部分化合物对OCI-LY10的抑制活性
结果表明,在细胞水平上,所测试化合物对OCI-LY10细胞株表现出明显的肿瘤细胞增殖抑制活性(IC50<0.31μM),均显著优于化合物D,其中化合物II-A-7的IC50达到了22nM,相较化合物C提高了123倍。进一步说明本发明化合物在4-氨基吡唑[3,4-d]嘧啶-1-基部分,取代基苯环上的2位氟原子对提高肿瘤细胞抑制活性十分重要。进一步说明本发明化合物具广阔的抗肿瘤应用前景。
实施例36:体外抗肿瘤细胞活性测试
选用人间变性大细胞淋巴瘤(Karpas299)细胞株对所合成的化合物进行了体外抗肿瘤活性的测定:
药物配制方法:将药物溶于DMSO中制成10mM的储备液,并按一定比例稀释得到7个不同浓度(测试浓度100×)。
肿瘤细胞体外培养:RPMI-1640+胎牛血清,将所选取的Karpas299细胞于37℃、5%CO2细胞培养箱中孵育。在96孔板上种入4000个/100μL/孔,于37℃、5%CO2细胞培养箱中孵育过夜。每孔加入化合物5μL,终浓度为10μM、2.5μM、0.625μM、0.15625μM,0.039063μM,0.0097656μM,0.0024414μM共同于37℃、5%CO2细胞培养箱中孵育72小时,以DMSO(0.1%)为对照组。72小时后,将CellTiter-Glo缓冲液和反应底物从冰箱中取出,平衡至室温后将缓冲液倒入装有底物的棕色瓶中,上下颠倒使底物粉末充分溶解。将细胞在显微镜下观察,将细胞培养板放置室温中平衡30分钟。将配制好的CellTiter-Glo加入96孔板中,每孔100μl。在振板机上混匀10分钟,然后常温静置10min。在孔板底部贴上白色封膜,Enspire微孔板检测仪检测各孔化学发光信号,所得数据用于计算IC50,测试结果见表3。
细胞抑制率的计算公式为:细胞抑制率%=[(对照组OD值-空白组OD值)-(用药组OD值-空白组OD值)]/(对照细胞OD值-空白组OD值)×100%,用CalcuSyn软件计算求得半数抑制浓度(IC50)。
表3部分化合物对Karpas299的抑制活性
结果表明,在细胞水平上,所测试化合物对Karpas299细胞株表现出明显的肿瘤细胞增殖抑制活性(IC50<1μM),进一步说明本发明化合物具广阔的抗肿瘤应用前景。
实施例37:OCI-LY10异位接种SCID小鼠转移瘤模型的体内药效学研究
(1)实验方法
OCI-LY10细胞培养于含20%FBS的IMDM培养基,维持在5%CO2的37℃饱和湿度培养箱中。收集对数生长期OCI-LY10细胞,重悬于含50%Matrigel的IMDM基础培养基中,调整细胞浓度至5×107/mL。在无菌条件下,接种0.1mL细胞悬液至小鼠右侧背部皮下,接种浓度为5×106/0.1mL/mouse。在肿瘤体积达到150mm3左右时,将动物按肿瘤体积随机分组,使各组肿瘤体积差异小于均值的10%,分组当日记为Day 0,并按照动物体重开始给药。给药期间,个别动物体重与Day 0相比下降超过15%(BWL≥15%),将做停药处理,直至动物体重恢复后(BWL<15%),恢复给药。实验期间每周2次测定动物体重和肿瘤体积,每日观察记录动物临床症状。
(2)评价指标
肿瘤体积的疗效用相对肿瘤增值率T/C评价,T/C(%)计算公式为TRTV/CRTV×100%,其中TRTV为治疗组RTV,CRTV为阴性对照组RTV。相对肿瘤体积(relative tumorvolume,RTV)计算公式为:Vt/V0,其中V0为分组时的肿瘤体积,Vt为每一次测量时的肿瘤体积。根据NMPA指导原则,T/C≤40%,认为此药有效。
肿瘤重量的疗效用TGI评价,瘤重抑制率(TGI)%=(TWc-TWT)/TWc×100%,TWc:对照组瘤重,TWT:治疗组瘤重。根据NIH指导原则,TGI≥58%,认为此药有效。
(3)实验结果
给药期间,小鼠体重均表现良好,且实验期间未观测到药物相关动物死亡及其他明显药物相关毒副反应。最后一次给药结束,量取瘤体积后,取瘤并称重,结果见表4和表5:
表4受试物在人弥漫大B细胞淋巴瘤OCI-LY10异种移植瘤模型中对肿瘤体积和瘤重的影响(N=5)
表5受试物在人弥漫大B细胞淋巴瘤OCI-LY10异种移植瘤模型中对肿瘤体积和瘤重的影响(N=5)
表4和表5结果显示测试化合物单用组和联用组的T/C均小于40%、TGI均大于58%(表4和表5),表现出很好的抑瘤效果。特别是与BTK抑制剂17a(专利申请号:201710998664.5)联合给药的治疗组的抑瘤效果显著:1)II-A-1+17a:T/C为17.49%,TGI为83.96%;2)II-A-7+17a:T/C为16.59%,TGI为86.34%;3)II-A-1a+17a:T/C为10.40%,TGI为88.06%;4)II-A-7a+17a:T/C为7.52%,TGI为90.82%。因此,本发明涉及的化合物,具有广阔的抗肿瘤前景。
实施例38:大鼠生物利用度研究
实验方法:
以SD大鼠为实验动物,灌胃给药10mg/kg,尾静脉注射给药1mg/kg。灌胃给药取血时间点:给药前及给药后0.25、0.5、1、2、4、6、8、和24h;静脉给药取血时间点:给药前及给药后0.0833、0.25、0.5、1、2、4、6、8和24h。取全血0.3mL,于2000g离心10min后分离血浆0.1mL,采用LC-MS/MS法进行样品分析。
绝对生物利用度的计算方法为:F=(AUCPO/DosePO)/(AUCIV/DoseIV)×100%
表6大鼠口服给药后主要药动学参数汇总
在大鼠考察了化合物游离态(II-A-7a)和化合物药学上可接受的盐(II-D-6)在大鼠体内的药代动力学性质,表6的结果表明,本发明的化合物可口服吸收;而药学上可接受的盐可提高游离态化合物的体内暴露量,生物利用度显著提高(3.7倍),可改善药物的口服吸收。因此,本发明涉及的化合物可通过口服吸收给药用于疾病的治疗。
Claims (19)
1.一种化合物,其特征在于,具有通式I的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐;
其中:
R1为H、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素、氰基、氨基、硝基或羟基;
m为1~4的整数;m大于1时多个R1相互独立,可以不相同,也可以相同;
R2为H、C1-C6烷基、C3-C10环烷基、C5-C12芳基,其中上述烷基、环烷基、芳基可以是无取代或取代的,取代基选自C1-C6烷基、C1-C6烷氧基、3至10元杂环基、卤素、硝基、氨基或羟基;
X为CR4或N;
R4为H、卤素;
R3为H、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素、氨基、硝基或羟基;
其中,R4为H时,R3选自卤素;R4为卤素时,R3为H、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素、氨基、硝基或羟基;
B选自C1-C6烷基、C3-C10环烷基、3至10元杂环烷基、C5-C12芳基、5至12元杂芳基,其中上述烷基、环烷基、杂环烷基、芳基、杂芳基可以是无取代或取代的,所述烷基的取代基选自C1-C6烷基、C1-C6烷氧基、3至10元杂环基、卤素、硝基、氨基或羟基;所述环烷基、杂环烷基、芳基、杂芳基的取代基选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6羟烷基、C1-C6卤代羟烷基、3至10元杂环基、卤素、硝基、氨基或羟基。
2.根据权利要求1所述的化合物,其特征在于,具有通式II-A、II-B或II-C的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐;
其中:
R5为H、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6羟烷基、C1-C6卤代羟烷基、卤素、氨基、硝基或羟基;
o为1~5的整数;
R6和R6’独立选自H、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素、氨基或羟基;
n为2;
Y为CH或N;Z为CR7R7’、O或NR8;
R7和R7’独立选自H、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素、氨基或羟基;
R8为H、C1-C6烷基。
6.根据权利要求1所述的化合物,其特征在于,式I中*标注的C为R构型或S构型。
9.根据权利要求1~8任一项所述的化合物,其特征在于,*标注的C为S构型。
10.一种药物组合物,其特征在于,包括权利要求1至9中任意一项所述的化合物中的一种或多种。
11.一种如权利要求1至9任意一项所述化合物在制备单独或与其他药物联合应用治疗从酪蛋白激酶1ε活性的抑制中获益的疾病、障碍或病症药物中的应用。
12.如权利要求11所述的应用,所述其他药物选择下列药物中的一种或多种:抗肿瘤药物、抗炎剂、免疫抑制剂。
13.如权利要求11所述的应用,其特征在于,所述疾病选自B细胞淋巴瘤、多发性骨髓瘤、白血病、肺癌、乳腺癌、前列腺癌、膀胱癌、卵巢癌、胰腺癌、肉瘤、结肠癌、肾癌、肝癌、黑色素瘤、脑部肿瘤、类风湿关节炎、系统性红斑狼疮、多发性硬化、炎性肠炎、自身免疫性溶血性贫血、强直性脊柱炎、天疱疮、荨麻疹、哮喘、视神经炎、银屑病、慢性阻塞性气道疾病、皮炎、秃头症。
14.如权利要求13所述的应用,其特征在于,所述B细胞淋巴瘤包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、脾边缘区淋巴瘤、浆细胞性骨髓瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病或淋巴瘤样肉芽肿病。
15.如权利要求11所述的应用,其特征在于,所述疾病选自T细胞淋巴瘤。
16.如权利要求15所述的应用,其特征在于,所述T细胞淋巴瘤包括外周T细胞淋巴瘤、间变性大细胞淋巴瘤、结外NK/T细胞淋巴瘤、皮肤外周T细胞淋巴瘤、T幼淋巴细胞白血病、血管免疫母细胞T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、肝脾T细胞淋巴瘤、肠道T细胞淋巴瘤、乳房植入物相关间变性大细胞淋巴瘤、T大颗粒淋巴细胞白血病。
17.如权利要求12所述的应用,所述抗肿瘤药物包括如下药物中的一种或多种个:有丝分裂抑制剂、微管蛋白分解抑制剂、烷基化试剂、抗代谢物、可插入抗生素、酶、拓朴异构酶抑制剂、生物反应调节剂、免疫调节剂、BTK抑制剂、Bcl-2抑制剂、anti-CD20单抗、mTOR抑制剂、mTORC1抑制剂、AKT抑制剂、PI3K抑制剂、蛋白酶体抑制剂、EGFR抑制剂、VEGFR抑制剂、CDK抑制剂、PD-1/PD-L1抑制剂。
18.如权利要求12所述的应用,所述抗肿瘤药物为BTK抑制剂。
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CN112830927A (zh) * | 2021-03-04 | 2021-05-25 | 山西科灜科技有限公司 | 一种嘌呤喹唑啉酮衍生物及其制备方法 |
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