CN114555597A - 异柠檬酸脱氢酶(idh)抑制剂 - Google Patents
异柠檬酸脱氢酶(idh)抑制剂 Download PDFInfo
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- CN114555597A CN114555597A CN202080070986.3A CN202080070986A CN114555597A CN 114555597 A CN114555597 A CN 114555597A CN 202080070986 A CN202080070986 A CN 202080070986A CN 114555597 A CN114555597 A CN 114555597A
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- Prior art keywords
- ethyl
- pyridin
- pyrrolo
- amino
- dihydro
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- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 title description 111
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 title description 111
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 236
- 150000003839 salts Chemical class 0.000 claims abstract description 88
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 37
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 156
- 125000000217 alkyl group Chemical group 0.000 claims description 137
- -1 cyano, nitro, carboxy, carbamoyl Chemical group 0.000 claims description 110
- 125000003342 alkenyl group Chemical group 0.000 claims description 108
- 125000000304 alkynyl group Chemical group 0.000 claims description 99
- 125000000623 heterocyclic group Chemical group 0.000 claims description 90
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 79
- 150000002367 halogens Chemical class 0.000 claims description 79
- 125000001072 heteroaryl group Chemical group 0.000 claims description 77
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 70
- 125000003545 alkoxy group Chemical group 0.000 claims description 68
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 claims description 20
- 230000002401 inhibitory effect Effects 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
公开了抑制α‑KG转化为D‑2‑HG的化合物、其药学上可接受的盐、水合物、溶剂合物或立体异构体,以及包含所述化合物的药物组合物。所述化合物和所述药物组合物可有效地治疗IDH相关疾病,包括癌症。
Description
发明领域
本公开涉及抑制α-酮戊二酸(α-KG)转化为例如D-2-HG的2-羟戊二酸(2-HG)的化合物、包含所述化合物作为活性成分的药物组合物和所述化合物在制造用于治疗与α-KG转化为D-2-HG相关的疾病的药剂中的用途。
背景技术
异柠檬酸脱氢酶(IDH)为用于三羧酸(TCA)循环中的细胞呼吸的必需酶,其催化异柠檬酸的氧化脱羧,产生α-酮戊二酸(α-ketoglutarate,α-KG)和CO2。在人体内,IDH以三种同功型存在:IDH3催化柠檬酸循环的第三步骤,同时在线粒体中将NAD+转化为 NADH。同功型IDH1和IDH2催化柠檬酸循环的情形之外的相同反应且使用NADP+而非 NAD+作为辅因子。其分别定位到细胞溶质和过氧物酶体或线粒体。
IDH1中的特定突变已发现于若干脑肿瘤中,包括星形细胞瘤、少突神经胶质瘤和多形性胶质母细胞瘤,其中在几乎所有继发性胶质母细胞瘤的病例中发现突变,其从较低级别神经胶质瘤发展,但很少在原发性多形性胶质母细胞瘤中。肿瘤具有IDH1-R132X突变的神经胶质瘤患者的存活期较长[“对人类多形性胶质母细胞瘤的综合基因组分析(Anintegrated genomic analysis of human glioblastoma multiforme)”,帕森斯(Parsons),D.w.,等人,《科学(Science)》,(2008);“对脑肿瘤中的IDH1密码子132突变的分析(Analysis of the IDH1 codon 132mutation in brain tumors)”,巴尔斯(Balss),J.,等人,《神经病理学报 (Acta Neuropathol)》,(2008);布里克(Bleeker),F.E.,等人,“残基p.R132(IDH1(R132)) 的IDH1突变经常发生在高级别神经胶质瘤中而非其它实体肿瘤中(IDH1 mutations at residue p.R132(IDH1(R132))occur frequently in high-gradegliomas but not in other solid tumors)”,《人类突变(Hum Mutat)》,(2009)]。IDH1和IDH2突变发生在p53突变和1p/19q 染色体丢失之前,且被认为是神经胶质瘤发生的第一现象[“IDH1突变是星形细胞瘤和少突胶质细胞瘤的发展中的早期现象(IDH1 mutations areearly events in the development of astrocytomas and oligodendrogliomas)”,渡边(Watanabe),T.,等人,《美国病理学杂志(Am J Pathol)》,(2009);“II级和III级神经胶质瘤中的突变景观和克隆架构(Mutational landscape and clonal architecture ingrade II and III gliomas)”,铃木(Suzuki),H.,等人,《自然遗传学(Nat Genet)》,(2015);“弥漫性较低级别神经胶质瘤的全面综合基因组分析(Comprehensive,Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas)”,布拉特(Brat),D.J.,等人, 《新英格兰医学杂志(N Engl J Med)》,(2015)]。此外,在高达20%的细胞遗传学正常的急性髓性白血病(AML)中发现IDH2和IDH1的突变[“通过对急性髓性白血病基因组进行测序发现的复发突变(Recurring mutations found by sequencing an acutemyeloid leukemia genome)”,马迪斯(Mardis),E.R.,等人,《新英格兰医学杂志》,(2009);“IDH2突变对细胞遗传学正常的急性髓性白血病的预后影响(Prognostic impact of IDH2mutations in cytogenetically normal acute myeloid leukemia)”,托(Thol),F.,等人,《血液(Blood)》, (2010);“编码IDH1和IDH2的基因中的获得性突变均为急性髓性白血病的复发性异常:患病率和预后值(Acquired mutations in the genes encoding IDH1and IDH2 both are recurrent aberrations in acute myeloid leukemia:prevalenceand prognostic value)”,阿巴斯(Abbas), S.,等人,《血液》,(2010);“IDH1突变在年轻成人急性髓性白血病患者中的预后意义取决于FLT3/ITD状态(The prognosticsignificance of IDH1 mutations in younger adult patients with acute myeloidleukemia is dependent on FLT3/ITD status)”,格林(Green),C.L.,等人,《血液》,(2010);“IDH1突变在6.6%的1414名AML患者中检测到且与60岁以下成人的中危核型和不良预后以及未突变NPM1状态相关(IDH1 mutations are detected in 6.6%of 1414 AMLpatients and are associated with intermediate risk karyotype and unfavorableprognosis in adults younger than 60years and unmutated NPM1 status)”,施尼特格(Schnittger),S.,等人, 《血液》,(2010);“成人新发急性髓性白血病的基因组和表观基因组景观(Genomic and epigenomic landscapes of adult de novo acute myeloidleukemia)”,《新英格兰医学杂志》, (2013)]。在其它类型的癌症中也报告了IDH突变,包括75%的软骨肉瘤[“IDH1和IDH2 突变是中心软骨肉瘤以及中心和骨膜软骨瘤的常见现象,但在其它间叶组织肿瘤中不常见 (IDH1 and IDH2 mutations are frequent events incentral chondrosarcoma and central and periosteal chondromas but not in othermesenchymal tumours)”,艾美瑞(Amary),M.F.,等人,《病理学杂志(J Pathol)》,(2011);“奥利埃病和马富西综合征由IDH1和IDH2的体细胞嵌合突变引起(Ollier disease andMaffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2)”,艾美瑞(Amary),M.F.,等人,《自然遗传学》,(2011)]、 10%至23%的肝内胆管癌[“通过广泛的肿瘤基因分型鉴定胆管癌中异柠檬酸脱氢酶IDH1 和IDH2的频繁突变(Frequentmutation of isocitrate dehydrogenase IDH1 and IDH2 in cholangiocarcinomaidentified through broad-based tumor genotyping)”,博格(Borger),D.R., 等人,《肿瘤学家(Oncologist)》,(2012);“异柠檬酸脱氢酶1和2的突变经常发生在肝内胆管癌中且与成胶质细胞瘤共享高甲基化靶标(Mutations in isocitrate dehydrogenase 1and2occur frequently in intrahepatic cholangiocarcinomas and sharehypermethylation targets with glioblastomas)”,王(Wang),P.,等人,《癌基因(Oncogene)》,(2012)],和一些血管免疫母细胞性T细胞淋巴瘤和黑色素瘤患者[“人类乳腺癌和结肠直肠癌的共有编码序列(The consensus coding sequences of human breastand colorectal cancers)”,索布洛姆(Sjoblom), T.,等人,《科学》,(2006)]。到目前为止,IDH1和IDH2为人类癌症中最频繁突变的新陈代谢酶基因。
这些上述突变导致对酶活性至关重要的氨基酸残基(IDH1上的R132、IDH2上的R140 或R172)发生变化,且因此损害了由IDH酶进行的从异柠檬酸到α-KG的催化作用。与此同时,这些IDH突变体获得了将α-KG转化为D-2-HG的新形态催化活性。在具有上述IDH 突变的肿瘤细胞中,D-2-HG累积到非常高的水平,并抑制依赖于α-KG的酶的功能。这导致DNA和组蛋白的高甲基化状态,从而导致不同的基因表达,其可以激活致癌基因和灭活肿瘤抑制基因。最终,这可能导致以上所公开的癌症类型[“人类乳腺癌和结肠直肠癌的共有编码序列”,索布洛姆,T.,等人,《科学》,(2006)]。
因此,需要研发抑制α-KG转化为D-2-HG的过程的抑制剂。
发明内容
在一个方面中,本公开提供一种式(I)化合物:
或其药学上可接受的盐,其中:
Z1和Z2独立地选自C和N;
X选自由以下组成的组:芳基、杂芳基或饱和或部分不饱和杂环基,所述芳基、杂芳基或饱和或部分不饱和杂环基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、烷氧基、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基;
Y选自由以下组成的组:空、键、-CR5R6-、-O(CH2)n-、-N(Ra)-、-S-、-S(=O)-、-S(=O)2-、 -C(O)-和-C(O)N(Rb)-;
W选自由以下组成的组:空、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个R7取代;
R1选自由以下组成的组:烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基和烷氧基;
R2选自由以下组成的组:卤素、羟基、氰基和硝基;
R3选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
R4选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、烷氧基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、氰基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基;
R7独立地选自由以下组成的组:卤素、羟基、氰基、硝基、烷氧基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基、-NRcRd和-C(O)Re,其中所述烷氧基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、烷基、卤代烷基、烷氧基、饱和或部分不饱和环烷基、-C(O)N(Rc)(Rd);
Ra、Rb、Rc和Rd各自独立地选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
Re选自由以下组成的组:烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
m为0、1或2;且
n为0、1或2。
在另一方面中,本公开提供一种式(Ia)化合物:
或其药学上可接受的盐,其中R1为任选地被一个或多个独立地选自由以下组成的组的基团取代的烷基:卤素、羟基、氰基、硝基和烷氧基,R2、X、Y、W和m如上文所定义。
在又一方面中,本公开提供一种式(Ib)化合物:
或其药学上可接受的盐,其中R1为任选地被一个或多个独立地选自由以下组成的组的基团取代的烷基:卤素、羟基、氰基、硝基和烷氧基,R8为卤素,q为1或2,R2、X、 Y、W和m如上文所定义。
在另一方面中,本公开提供一种式(Ic)化合物:
或其药学上可接受的盐,其中R2、R8、Y、W、m和q如上文所定义。
在又一方面中,本公开提供一种式(Id)化合物:
或其药学上可接受的盐,其中R2、Y、W和m如上文所定义。
在再另一方面中,本公开提供一种式(Ie)化合物:
或其药学上可接受的盐,其中R2、Y、W和m如上文所定义。
在另一方面中,本公开提供一种药物组合物,其包含式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物或其药学上可接受的盐,和至少一种药学上可接受的赋形剂。
在又一方面中,本公开提供一种治疗与α-KG转化为D-2-HG相关的疾病的方法,其包括向个体施用治疗有效量的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物或其药学上可接受的盐,或本公开的药物组合物。
在另一方面中,本公开提供一种抑制α-KG转化为D-2-HG的方法,其通过使用式(I)、 (Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物或其药学上可接受的盐或本公开的药物组合物进行。
在又一方面中,本公开提供一种抑制突变型IDH、野生型IDH或上述两者的方法,其通过使用式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物或其药学上可接受的盐或本公开的药物组合物进行。
附图说明
图1显示由野生型和突变型IDH1/2催化的代表性反应。
具体实施方式
现将详细参考本发明的某些实施例,在随附结构和化学式中说明所述实施例的实例。尽管将结合所列举的实施例描述本发明,但应理解,其并不旨在将本发明限制于那些实施例。相反地,本发明旨在覆盖可包括在由权利要求书限定的本发明的范围内的所有替代方案、修改和等效物。所属领域的技术人员将认识到许多方法和材料与本文中所描述的方法或材料类似或等效,所述方法和材料可以用于实践本发明。本发明决不限制于所描述的方法和材料。如果所结合的文献和类似材料中的一者或多者与本申请不同或矛盾,包括但不限于所定义的术语、术语用法、所描述的技术等,那么以本申请为准。
应了解,为清楚起见而在分开的实施例的上下文中描述的本公开的某些特征也可组合提供于单个实施例中。相反地,为简洁起见,在单个实施例的上下文中描述的本公开的各种特征也可以分开提供或以任何合适的子组合提供。
定义
下文更详细描述特定官能团和化学术语的定义。出于本公开的目的,根据元素周期表, CAS版本,《化学和物理学手册(Handbook of Chemistry and Physics)》,第75版,内封面来识别化学元素,且一般如其中所描述来定义特定官能团。另外,有机化学的一般原理以及特定官能性部分和反应性描述于《有机化学(Organic Chemistry)》,托马斯·索雷尔(Thomas Sorrell),大学科学书籍(University Science Books),索萨利托(Sausalito),1999;史密斯(Smith)和马奇(March),《马奇高等有机化学(March's Advanced OrganicChemistry)》,第5版,约翰·威利父子公司(John Wiley&Sons,Inc.),纽约(New York),2001;拉洛克(Larock),《综合有机转化(Comprehensive Organic Transformations)》,VCH出版公司(VCH Publishers,Inc.),纽约,1989;卡拉瑟斯(Carruthers),《一些现代有机合成方法(Some Modern Methods of Organic Synthesis)》,第3版,剑桥大学出版社(Cambridge University Press),剑桥(Cambridge),1987中;其中每一者的全部内容以引用的方式并入本文中。
在本公开的多处,描述了连接取代基。在结构明确需要连接基团的情况下,关于所述基团所列的马库什变量(Markush variable)应理解为连接基团。举例来说,如果结构需要连接基团且所述变量的马库什组定义列举“烷基”,那么应理解,所述“烷基”表示连接亚烷基。
如本文中所使用,术语“取代的”,无论前面是否有术语“任选地”,都意指指定部分的一个或多个氢被合适的取代基置换。应理解,“取代”或“被取代”包括以下隐含的限制条件:所述取代与被取代的原子的容许价态一致,并且取代产生稳定或化学上可行的化合物,例如不会通过重排、环化、消除等而自发地进行转化的化合物。除非另外指示,否则“任选地被取代的”基团可以在基团的每一可取代位置处具有合适的取代基,并且当任何既定结构中的一个以上位置可以被一个以上选自规定基团的取代基取代时,在每一位置处取代基可以是相同或不同的。所属领域的技术人员应理解,适当时,取代基本身可以被取代。除非具体陈述为“未被取代的”,否则提及本文中的化学部分应理解为包括被取代的变量。举例来说,提及“芳基”基团或部分隐含地包括被取代和未被取代的变量两者。
当连到取代基的键显示与连接环中的两个原子的键交叉时,那么所述取代基可以键结于所述环上的任何原子。当所列取代基未指示所述取代基键结到给定式化合物的其余部分的原子时,那么所述取代基可经由所述式中的任何原子键结。取代基和/或变量的组合为可容许的,但仅在这类组合产生稳定化合物时。
当任何变量(例如Ri)在化合物的任何成分或式中出现超过一次时,其在每次出现时的定义独立于其在其它每次出现时的定义。因此,举例来说,如果基团显示为被0至2个Ri部分取代,那么所述基团可任选地被最多两个Ri部分取代,并且Ri在每次出现时独立地选自Ri的定义。而且,取代基和/或变量的组合为可容许的,但仅在这类组合产生稳定化合物时。
如本文中所使用,术语“Ci-j”指示碳原子数的范围,其中i和j为整数,并且碳原子数的范围包括端点(即i和j)和介于其间的每个整数点,并且其中j大于i。举例来说, C1-6指示一至六个碳原子的范围,包括一个碳原子、两个碳原子、三个碳原子、四个碳原子、五个碳原子和六个碳原子。在一些实施例中,术语“C1-12”指示1至12,尤其1至10,尤其1至8,尤其1至6,尤其1至5,尤其1至4,尤其1至3或尤其1至2个碳原子。
不论作为另一术语的一部分还是独立地使用,如本文中所使用,术语“烷基”是指饱和直链或分支链烃基。术语“Ci-j烷基”是指具有i至j个碳原子的烷基。在一些实施例中,烷基含有1至12个碳原子。在一些实施例中,烷基含有1至11个碳原子。在一些实施例中,烷基含有1至11个碳原子、1至10个碳原子、1至9个碳原子、1至8个碳原子、1 至7个碳原子、1至6个碳原子、1至5个碳原子、1至4个碳原子、1至3个碳原子或1 至2个碳原子。烷基的实例包括但不限于甲基、乙基、1-丙基(正丙基)、2-丙基(异丙基)、 1-丁基(正丁基)、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)、2-甲基-2-丙基(叔丁基)、 1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基 -1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基 -3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基等。“C1-12烷基”的实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基。“C1-6烷基”的实例为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基等。
所述烷基可任选地被取代基取代,该取代基独立地置换所述烷基的一个或多个碳上的一个或多个氢原子。这类取代基的实例可包括但不限于卤素、羟基、氰基、硝基、叠氮基、酰基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、烷氧基、卤代烷基、卤代烷氧基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基芳基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷基硫基羰基、磷酸酯基、膦酸基、亚膦酸基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨甲酰基和脲基)、甲脒基、亚氨基、巯基、烷基硫基、芳基硫基、硫代羧酸酯基、硫酸酯基、烷基磺酰基、磺酸酯基、氨磺酰基、磺酰氨基、芳基、杂芳基、饱和或部分不饱和环烷基或饱和或部分不饱和杂环基。如下文所描述的烯基、炔基、芳基、杂芳基、饱和或部分不饱和环烷基和饱和或部分不饱和杂环基也可类似地被取代。
不论作为另一术语的一部分还是独立地使用,如本文中所使用,术语“烯基”是指具有至少一个碳-碳双键的直链或分支链烃基,其可任选地独立地被本文中所描述的一个或多个取代基取代,并且包括具有“顺”和“反”取向,或替代地“E”和“Z”取向的基团。在一些实施例中,烯基含有2至12个碳原子。在一些实施例中,烯基含有2至11个碳原子。在一些实施例中,烯基含有2至11个碳原子、2至10个碳原子、2至9个碳原子、2 至8个碳原子、2至7个碳原子、2至6个碳原子、2至5个碳原子、2至4个碳原子、2 至3个碳原子,并且在一些实施例中,烯基含有2个碳原子。烯基的实例包括但不限于乙烯基(ethylenyl或vinyl)、丙烯基、丁烯基、戊烯基、1-甲基-2丁-1-基、5-己烯基等。
不论作为另一术语的一部分还是独立地使用,如本文中所使用,术语“炔基”是指具有至少一个碳-碳三键的直链或分支链烃基,其可任选地独立地被本文中所描述的一个或多个取代基取代。在一些实施例中,烯基含有2至12个碳原子。在一些实施例中,炔基含有2至11个碳原子。在一些实施例中,炔基含有2至11个碳原子、2至10个碳原子、2至 9个碳原子、2至8个碳原子、2至7个碳原子、2至6个碳原子、2至5个碳原子、2至4 个碳原子、2至3个碳原子,并且在一些实施例中,炔基含有2个碳原子。炔基的实例包括但不限于乙炔基、1-丙炔基、2-丙炔基等。
不论作为另一术语的一部分还是独立地使用,如本文中所使用,术语“烷氧基(alkoxy 或alkoxyl)”是指如先前所定义的通过氧原子附接到母体分子的烷基。术语“Ci-j烷氧基”意指烷氧基的烷基部分具有i至j个碳原子。在一些实施例中,烷氧基含有1至12个碳原子。在一些实施例中,烷氧基含有1至11个碳原子。在一些实施例中,烷氧基含有1至11个碳原子、1至10个碳原子、1至9个碳原子、1至8个碳原子、1至7个碳原子、1至6 个碳原子、1至5个碳原子、1至4个碳原子、1至3个碳原子或1至2个碳原子。“C1-12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)、叔丁氧基、新戊氧基、正己氧基等。
不论作为另一术语的一部分还是独立地使用,如本文中所使用,术语“芳基”或“芳香族”是指具有总共5至20个环成员的单环和多环系统,其可任选地独立地被本文中所描述的一个或多个取代基取代,其中系统中的至少一个环是芳香族且其中系统中的每一环含有3至12个环成员。“芳基”的实例包括但不限于苯基、联苯基、萘基、蒽基等,其可带有一个或多个取代基。如本文中所使用,其中芳环与一个或多个额外环稠合的基团也包括在术语“芳基”的范围内。在多环系统的情况下,仅需要一个环为芳香族(例如,2,3-二氢吲哚),但所有环均可为芳香族(例如,喹啉)。第二环也可以是稠合的或桥连的。多环芳基的实例包括但不限于苯并呋喃基、茚满基、邻苯二甲酰亚胺基(phthalimidyl)、萘酰亚胺基(naphthimidyl)、啡啶基(phenanthridinyl)或四氢萘基等。芳基可在一个或多个环位置处任选地被如本文中所描述的一个或多个取代基取代。
如本文中所使用,术语“环烷基”、“碳环基”和“碳环”可互换,且不论作为另一术语的一部分还是独立地使用,是指可任选地独立地被本文中所描述的一个或多个取代基取代的单价、饱和或部分不饱和或完全不饱和单环和多环系统,其中所有环原子为碳且含有至少三个成环碳原子。在一些实施例中,环烷基可含有3至12个成环碳原子、3至10个成环碳原子、3至9个成环碳原子、3至8个成环碳原子、3至7个成环碳原子、3至6个成环碳原子、3至5个成环碳原子、4至12个成环碳原子、4至10个成环碳原子、4至9 个成环碳原子、4至8个成环碳原子、4至7个成环碳原子、4至6个成环碳原子、4至5 个成环碳原子。环烷基可为饱和或部分不饱和的。环烷基可任选地独立地被本文中所描述的一个或多个取代基取代。在一些实施例中,环烷基可为饱和的环状烷基。在一些实施例中,环烷基可为在其环系统中含有至少一个双键或三键的不饱和环状烷基。
在一些实施例中,环烷基可为饱和或不饱和单环碳环系统,其实例包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1- 烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。
在一些实施例中,环烷基可为饱和或不饱和多环(例如,双环和三环)碳环系统,其可布置为稠环、螺环或桥环系统。如本文中所使用,术语“稠环”是指具有共享两个相邻原子的两个环的环系统,术语“螺环”是指具有通过一个单个共同原子连接的两个环的环系统,且术语“桥环”是指具有共享三个或更多个原子的两个环的环系统。稠合碳环基的实例包括但不限于萘基、苯并芘基、蒽基、苊基、茀基等。螺碳环基的实例包括但不限于螺[5.5]十一烷基、螺戊二烯基、螺[3.6]癸基等。桥连碳环基的实例包括但不限于双环[1,1,1] 戊烯基、双环[2,2,1]庚烯基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.3.1]壬基、双环[3.3.3]十一烷基等。
如本文中所使用,术语“氰基”是指-CN。
如本文中所使用,术语“卤代”或“卤素”是指选自氟(fluorine或fluoro)、氯(chlorine 或chloro)、溴(bromine或bromo)和碘(iodine或iodo)的原子。
如本文中所使用,术语“卤代烷基”是指由一个或多个卤素原子取代的烷基,该一个或多个卤素原子独立地置换所述烷基的一个或多个碳上的一个或多个氢原子。
如本文中所使用,术语“杂烷基”是指烷基,其碳原子中的至少一者被选自N、O、S或P的杂原子置换。杂烷基可以是碳基或杂原子基(即,杂原子可出现在基团的中间中或末端处),且可任选地独立地被本文中所描述的一个或多个取代基取代。术语“杂烷基”涵盖烷氧基和杂烷氧基。
如本文中所使用,术语“杂烯基”是指烯基,其碳原子中的至少一者被选自N、O、S或P的杂原子置换。杂烯基可以是碳基或杂原子基(即,杂原子可出现在基团的中间中或末端处),且可任选地独立地被本文中所描述的一个或多个取代基取代。
如本文中所使用,术语“杂炔基”是指炔基,其碳原子中的至少一者被选自N、O、S或P的杂原子置换。杂炔基可以是碳基或杂原子基(即,杂原子可出现在基团的中间中或末端处),且可任选地独立地被本文中所描述的一个或多个取代基取代。
如本文中所使用,术语“杂原子”是指氮、氧、硫或磷,且包括任何氧化形式的氮或硫和任何季铵化形式的碱性氮。
不论作为另一术语的一部分还是独立地使用,如本文中所使用,术语“杂芳基”是指除碳原子之外还具有一个或多个杂原子且可任选地独立地被本文中所描述的一个或多个取代基取代的芳基。杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚嗪基、嘌呤基、萘啶基、苯并呋喃基和蝶啶基。杂芳基还包括杂芳环与一个或多个芳基、环脂肪族基或杂环基环稠合的基团,其中附接基团或附接点位于杂芳环上。非限制性实例包括吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、啡嗪基、啡噻嗪基、啡噁嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。在一些实施例中,术语“5至10 元杂芳基”是指具有1至3个独立地选自氮、氧、硫或磷的杂原子的5至6元杂芳基环,或具有1至4个独立地选自氮、氧、硫或磷的杂原子的8至10元双环杂芳基环。在某些实施例中,术语“5至12元杂芳基”是指具有1至3个独立地选自氮、氧、硫或磷的杂原子的5至6元杂芳基环,或具有1至4个独立地选自氮、氧、硫或磷的杂原子的8至12元双环杂芳基环。
如本文中所使用,术语“杂环”或“杂环基”是指饱和、部分不饱和或完全不饱和碳环基,其中一个或多个环原子为独立地选自氧、硫、氮、磷等的杂原子,其余环原子为碳,其中一个或多个环原子可任选地独立地被一个或多个取代基取代。在一些实施例中,杂环基为饱和杂环基。在一些实施例中,杂环基为在其环系统中具有一个或多个双键的不饱和杂环基。在一些实施例中,杂环基可含有任何氧化形式的碳、氮、硫或磷和任何季铵化形式的碱性氮。“杂环基”还包括其中杂环基与饱和、部分不饱和或完全不饱和(即,芳香族) 的碳环或杂环稠合的基团。在可能的情况下,杂环基可为碳连接的或氮连接的。在一些实施例中,杂环为碳连接的。在一些实施例中,杂环为氮连接的。举例来说,衍生自吡咯的基团可为吡咯-1-基(氮连接)或吡咯-3-基(碳连接)。此外,衍生自咪唑的基团可为咪唑- 1-基(氮连接)或咪唑-3-基(碳连接)。
在一些实施例中,术语“3至12元杂环基”是指具有1至3个独立地选自氮、氧或硫的杂原子的3至12元饱和或部分不饱和的单环或多环杂环系统。稠环、螺环和桥环系统也包括在本定义范围内。单环杂环基的实例包括但不限于氧杂环丁烷基、1,1-二氧代硫杂环丁烷基吡咯烷基、四氢呋喃基、四氢噻吩基、吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、三唑基、噁唑基、噻唑基、哌啶基(piperidyl)、哌嗪基、吗啉基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、吡啶酮基、嘧啶酮基、吡嗪酮基、嘧啶酮基、哒嗪酮基、吡咯烷基、三嗪酮基等。稠合杂环基的实例包括但不限于苯基稠环或吡啶基稠环,例如喹啉基、异喹啉基、喹喔啉基、喹嗪基、喹唑啉基、氮杂吲哚嗪基、蝶啶基、色烯基(chromenyl)、异色烯基、吲哚基、异吲哚基、吲哚嗪基、吲唑基、嘌呤基、苯并呋喃基、异苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噻唑基、咔唑基、吩嗪基、吩噻嗪基、啡啶基、咪唑[1,2-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、[1,2,3]三唑并[4,3-a]吡啶基等。螺杂环基的实例包括但不限于螺吡喃基、螺噁嗪基等。桥连杂环基的实例包括但不限于吗啡烷基(morphanyl)、六亚甲基四胺基、3-氮杂-双环[3.1.0]己烷、8-氮杂-双环[3.2.1]辛烷、1-氮杂-双环[2.2.2]辛烷、 1,4-二氮杂双环[2.2.2]辛烷(DABCO)等。
如本文中所使用,术语“羟基(hydroxyl或hydroxy)”是指-OH基团。
如本文中所使用,术语“硝基”是指-NO2基团。
如本文中所使用,术语“部分不饱和”是指包括至少一个双键或三键的基团。术语“部分不饱和的”意图涵盖具有多个不饱和位点的环,但并不意图包括芳香族(即,完全不饱和的)部分。
除非另外说明,否则“IDH”或“野生型IDH”是指催化异柠檬酸转化为α-KG的正常IDH酶。示例性正常IDH酶包括:
人IDH1蛋白(NCBI登录号:O75874.2,SEQ ID NO:1)
人IDH2蛋白(NCBI登录号:P48735.2,SEQ ID NO:2)
如本文中所使用,术语“IDH突变”是指IDH酶的任何突变,所述突变使得“IDH突变体”、“突变型IDH”或“突变的IDH”能够催化α-KG转化为D-2-HG。在一些实施例中,“突变型IDH”催化α-KG转化为D-2-HG以及异柠檬酸转化为α-KG。这类突变包括但不限于IDH1中的R132H、R132C、R132G、R132L、R132S;或IDH2中的R172K、 R172M、R172W。
化合物
在一个方面中,本公开提供一种式(I)化合物:
或其药学上可接受的盐,其中:
Z1和Z2独立地选自C和N;
X选自由以下组成的组:芳基、杂芳基或饱和或部分不饱和杂环基,所述芳基、杂芳基或饱和或部分不饱和杂环基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、烷氧基、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基;
Y选自由以下组成的组:空、键、-CR5R6-、-O(CH2)n-、-N(Ra)-、-S-、-S(=O)-、-S(=O)2-、 -C(O)-和-C(O)N(Rb)-;
W选自由以下组成的组:空、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个R7取代;
R1选自由以下组成的组:烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基和烷氧基;
R2选自由以下组成的组:卤素、羟基、氰基和硝基;
R3选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
R4选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、烷氧基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、氰基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基;
R7独立地选自由以下组成的组:卤素、羟基、氰基、硝基、烷氧基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基、-NRcRd和-C(O)Re,其中所述烷氧基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、烷基、卤代烷基、烷氧基、饱和或部分不饱和环烷基、-C(O)N(Rc)(Rd);
Ra、Rb、Rc和Rd各自独立地选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
Re选自由以下组成的组:烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
m为0、1或2;且
n为0、1或2。
在一些实施例中,Z1为N。
在一些实施例中,Z1为C。
在一些实施例中,Z2为N。
在一些实施例中,Z2为C。
在一些实施例中,Z1为N且Z2为N。
在一些实施例中,Z1为N且Z2为C。
在一些实施例中,X为芳基、杂芳基或饱和或部分不饱和杂环基,其中的每一者任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基和烷基。
在一些实施例中,X选自由以下组成的组:被卤素取代的芳基、未被取代的杂芳基、被卤素取代的杂芳基、被烷基取代的杂芳基或被卤素取代的饱和或部分不饱和杂环基。
在一些实施例中,Y选自由以下组成的组:键、-CR5R6-、-O(CH2)n-、-N(Ra)-、-C(O)-和-C(O)N(Rb)-。
在一些实施例中,n为0或1。在一些实施例中,n为0。在一些实施例中,n为1。
在一些实施例中,W为空、3至10元饱和或部分不饱和环烷基、3至10元饱和或部分不饱和杂环基、3至10元芳基和3至10元杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个R7取代。
在一些实施例中,W为空。
在一些实施例中,W选自由以下组成的组:
其中的每一者任选地被一个或多个R7取代。
在一些实施例中,R1选自由以下组成的组:烷基、烯基和炔基,其中所述烷基、烯基和炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基和烷氧基。
在一些实施例中,R1为任选地被一个或多个独立地选自由以下组成的组的基团取代的烷基:卤素、羟基、氰基、硝基和烷氧基。
在一些实施例中,R1为任选地被一个或多个独立地选自由以下组成的组的基团取代的烷基:卤素、羟基和烷氧基。
在一些实施例中,R1为任选地被一个或多个独立地选自由以下组成的组的基团取代的乙基:氟、羟基和甲氧基。
在一些实施例中,R2为卤素。在一些实施例中,R2为氟、氯或溴。在一些实施例中,R2为氟或氯。在一些实施例中,R2为氟。
在一些实施例中,m为0、1或2。在一些实施例中,m为0或1。在一些实施例中, m为0。在一些实施例中,m为1。
在一些实施例中,R2为卤素且m为0、1或2。在一些实施例中,R2为氟或氯且m为 0、1或2。在一些实施例中,R2为氟或氯且m为0或1。在一些实施例中,R2为氟且m为 0或1。
在一些实施例中,R3选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
在一些实施例中,R3为氢或烷基。在一些实施例中,R3为氢。
在一些实施例中,R4选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
在一些实施例中,R4为烷基。在一些实施例中,R4为甲基、乙基、丙基或丁基。
在一些实施例中,R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、氰基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基。
在一些实施例中,R5和R6各自独立地选自氢、卤素、羟基和烷基。在一些实施例中,R5和R6为氢。
在一些实施例中,R7选自由以下组成的组:卤素、羟基、氰基、烷氧基、烷基、烯基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基、-NRcRd和-C(O)Re,其中所述烷氧基、烷基、烯基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、烷基、卤代烷基、烷氧基、饱和或部分不饱和环烷基、-C(O)N(Rc)(Rd)。
在一些实施例中,R7选自由以下组成的组:卤素、羟基、氰基、烷氧基、烷基、烯基、卤代烷基和饱和或部分不饱和环烷基,其中所述烷氧基、烷基、烯基、卤代烷基和饱和或部分不饱和环烷基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、卤代烷基和烷氧基。
在一些实施例中,Ra、Rb、Rc和Rd各自独立地选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
在一些实施例中,Ra、Rb、Rc和Rd各自独立地选自由氢和烷基组成的组。
在一些实施例中,Re选自由以下组成的组:饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。在一些实施例中,Re为饱和或部分不饱和环烷基。
在另一方面中,本公开提供一种式(Ia)化合物:
其中R1为任选地被一个或多个独立地选自由以下组成的组的基团取代的烷基:卤素、羟基、氰基、硝基和烷氧基,R2、X、Y、W和m如上文所定义。
在另一方面中,本公开提供一种式(Ic)化合物:
或其药学上可接受的盐,其中R2、R8、Y、W、m和q如上文所定义。
在又一方面中,本公开提供一种式(Id)化合物:
或其药学上可接受的盐,其中R2、Y、W和m如上文所定义。
在再另一方面中,本公开提供一种式(Ie)化合物:
或其药学上可接受的盐,其中R2、Y、W和m如上文所定义。
在又一方面中,本公开提供一种式(I)化合物或其药学上可接受的盐,所述化合物选自由以下组成的组:
本文所提供的化合物参考通用化学式和具体化合物来进行描述。此外,本公开的化合物可以许多不同形式或衍生物存在,其全部在本公开的范围内。这些不同形式或衍生物包括例如互变异构体、立体异构体、外消旋混合物、区位异构体、盐、前药、溶剂化形式、不同的晶体形式或多晶型物以及活性代谢物。
本公开的化合物可包括一个或多个不对称中心,并且因此可以各种立体异构形式存在,例如对映异构体和/或非对映异构体。因此,本发明化合物和其组合物可呈个别对映异构体、非对映异构体或几何异构体形式,或可呈立体异构体的混合物形式。在某些实施例中,本公开的化合物是对映纯化合物。在某些实施例中,提供对映异构体或非对映异构体的混合物。
术语“对映异构体”是指化合物的为彼此的不可重叠的镜像的两种立体异构体。术语“非对映异构体”是指不是彼此的镜像的一对光学异构体。非对映异构体具有不同物理特性,例如熔点、沸点、光谱特性和反应性。
此外,如本文中所描述,某些化合物可具有一个或多个双键,除非另外指示,否则其可以Z或E异构体形式存在。另外,本公开涵盖呈基本上不含其它异构体的个别异构体形式且替代地呈多种异构体的混合物(例如,对映异构体的外消旋混合物)形式的化合物。除上文所提及的化合物本身以外,本公开还涵盖包括一种或多种化合物的组合物。
如本文中所使用,术语“异构体”包括任何和所有的几何异构体和立体异构体。举例来说,如在本发明的范围内,“异构体”包括顺式和反式异构体、E-异构体和Z-异构体、R-对映异构体和S-对映异构体、非对映异构体、(D)-异构体、(L)-异构体、其外消旋混合物以及其其它混合物。举例来说,在一些实施例中,可以提供基本上不含一种或多种对应立体异构体并且也可以称作“立体化学富集”的立体异构体。
当特定对映异构体为优选的时,在一些实施例中其可提供为基本上不含相对对映异构体,并且还可称作“光学富集”。如本文中所使用,“光学富集”意指化合物由显著较大比例的一种对映异构体构成。在某些实施例中,化合物由至少约90重量%的优选对映异构体构成。在其它实施例中,化合物由至少约95重量%、98重量%或99重量%的优选对映异构体构成。优选对映异构体可以通过所属领域的技术人员已知的任何方法从外消旋混合物中分离,所述方法包括对掌性高压液相色谱(HPLC)和对掌性盐的形成和结晶,或通过不对称合成制备。参见例如,雅克(Jacques)等人,《对映异构体、外消旋体和拆分(Enantiomers,Racemates and Resolutions)》(威立国际科学(Wiley Interscience),纽约,1981);威伦(Wilen), S.H.,等人,《四面体(Tetrahedron)》33:2725(1977);伊莱尔(Eliel),E.L.《碳化合物的立体化学(Stereochemistry of Carbon Compounds)》(麦格劳-希尔(McGraw-Hill),NY, 1962);威伦,S.H.《拆分剂和光学分辨率的表格(Tables of Resolving Agentsand Optical Resolutions)》第268页(E.L.伊莱尔编,美国诺特丹大学出版社(Univ.ofNotre Dame Press), 诺特丹(Notre Dame),印第安纳州(IN)1972)。
本公开的化合物还可以不同互变异构形式存在,并且所有此类形式涵盖在本公开的范围内。术语“互变异构体”或“互变异构形式”是指可经由低能垒相互转化的不同能量的结构异构体。举例来说,质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移进行的相互转化,例如酮-烯醇、酰胺-亚胺酸、内酰胺-内酰亚胺、亚胺-烯胺异构化和环状形式,其中质子可占据杂环系统的两个或更多个位置(例如1H-咪唑和3H-咪唑、1H- 1,2,4-三唑、2H-1,2,4-三唑和4H-1,2,4-三唑、1H-异吲哚和2H-异吲哚以及1H-吡唑和2H-吡唑)。价互变异构体包括通过一些成键电子的重组而进行的相互转化。互变异构体可处于平衡状态或通过适当取代而空间锁定成一种形式。除非另外说明,否则通过名称或结构识别为一种特定互变异构形式的本公开的化合物意图包括其它互变异构形式。
本公开的化合物还包括前药、活性代谢衍生物(活性代谢物)、活性中间物和其药学上可接受的盐。
如本文中所使用,术语“前药”是指当在生理条件下代谢时或当通过溶剂分解转化时产生所需活性化合物的化合物或其药学上可接受的盐。前药包括但不限于活性化合物的酯、酰胺、氨基甲酸酯、碳酸酯、酰脲、溶剂合物或水合物。典型地,前药无活性或活性小于活性化合物,但可以提供有利的处置、使用和/或代谢特性中的一者或多者。举例来说,一些前药是活性化合物的酯;在代谢期间,酯基裂解以产生活性药物。此外,一些前药被酶活化以产生活性化合物,或是在进一步化学反应后产生活性化合物的化合物。前药可以在单个步骤中由前药形式发展为活性形式,或可以具有一种或多种本身可以具有活性或可以无活性的中间形式。前药的制备和使用论述于T.樋口(T.Higuchi)和V.斯黛拉(V. Stella),“作为新颖递送系统的前药(Pro-drugs as Novel Delivery Systems)”,《美国化学学会会议论文集(A.C.S.Symposium Series)》第14卷,以及《药物设计中的生物可逆载体(Bioreversible Carriers in Drug Design)》,爱德华B.罗奇(Edward B.Roche)编,美国医药协会和培格曼出版社(American Pharmaceutical Association and PergamonPress),1987,二者特此以全文引用的方式并入。
如本文中所使用,术语“代谢物”(例如活性代谢物)与如上文所描述的前药重叠。因此,所述代谢物是药理学活性化合物或进一步代谢为药理学活性化合物的化合物,所述药理学活性化合物是由个体身体内的代谢过程产生的衍生物。举例来说,这类代谢物可由使施用的化合物或盐或前药氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱酯化、酶裂解等产生。其中,活性代谢物是所述药理学活性的衍生化合物。对于前药,前药化合物一般无活性或活性比代谢产物低。对于活性代谢物,母体化合物可以是活性化合物或可以是无活性前药。
前药和活性代谢物可以使用所属领域中已知的常规技术鉴别。参见例如贝尔托利尼 (Bertolini)等人,1997,《药物化学杂志(J Med Chem)》40:2011-2016;珊(Shan)等人,《药学杂志(J Pharm Sci)》86:756-757;巴格肖(Bagshawe),1995,《药物开发研究(DrugDevRes)》34:220-230;韦穆特(Wermuth),同上。
如本文中所使用,术语“活性中间物”是指合成过程中的中间化合物,其呈现与最终合成的化合物相同或基本上相同的生物活性。
本公开的化合物可调配成药学上可接受的盐或呈药学上可接受的盐形式。除非另有说明,否则本文提供的化合物包括此类化合物的药学上可接受的盐。
如本文中所使用,术语“药学上可接受的”指明所述物质或组合物在化学和/或毒理学上与包括调配物的其它成分和/或用其治疗的个体相容。
如本文中所使用,除非另外指示,否则术语“药学上可接受的盐”包括保留指定化合物的游离酸和碱的生物有效性并且在生物学上或其它方面并非不合需要的盐。所考虑的药学上可接受的盐形式包括但不限于单盐、双盐、三盐、四盐等。药学上可接受的盐在对其进行施用的量和浓度下是无毒的。这类盐的制备可以通过改变化合物的物理特征而不妨碍其发挥其生理作用来促进药理学使用。物理特性中的有用改变包括降低熔点以促进透粘膜施用和增加溶解度以促进使用更高浓度的药物。
药学上可接受的盐包括酸加成盐,例如含有以下的酸加成盐:硫酸盐、氯化物、盐酸盐、富马酸盐、马来酸盐、磷酸盐、氨基磺酸盐、乙酸盐、柠檬酸盐、乳酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎尼酸盐。药学上可接受的盐可以由例如以下的酸获得:盐酸、马来酸、硫酸、磷酸、氨基磺酸、乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、富马酸和奎尼酸。
当存在酸性官能团(例如羧酸或苯酚)时,药学上可接受的盐还包括碱加成盐,例如含有以下的碱加成盐:苄星(benzathine)、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙醇胺、叔丁胺、乙二胺、葡甲胺、普鲁卡因、铝、钙、锂、镁、钾、钠、铵、烷基胺和锌。举例来说,参见《雷明顿氏药物科学(Remington's Pharmaceutical Sciences)》,第19 版,马克出版公司(Mack Publishing Co.),宾夕法尼亚州伊斯顿(Easton,PA),第2卷,第 1457页,1995;斯塔尔(Stahl)和韦穆特(Wermuth)的“药用盐手册:特性、选择和使用 (Handbook ofPharmaceutical Salts:Properties,Selection,and Use)”,威立-VCH(Wiley-VCH), 德国魏因海姆(Weinheim,Germany),2002。这类盐可以使用适当对应碱制备。
药学上可接受的盐可以通过标准技术制备。举例来说,化合物的游离碱形式可以溶解于合适的溶剂(例如含有适当酸的水溶液或水-醇溶液)中,并且接着通过蒸发溶液来加以分离。因此,如果特定化合物是碱,那么期望的药学上可接受的盐可以通过所属领域中可用的任何合适方法制备,例如,用例如盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸处理游离碱,或用例如乙酸、马来酸、琥珀酸、杏仁酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖基酸(例如葡糖醛酸或半乳糖醛酸)、α-羟基酸(例如柠檬酸或酒石酸)、氨基酸(例如天冬氨酸或谷氨酸)、芳香族酸(例如苯甲酸或肉桂酸)、磺酸(例如对甲苯磺酸或乙磺酸)等有机酸处理游离碱。
类似地,如果特定化合物是酸,那么期望的药学上可接受的盐可通过任何合适方法制备,例如,用无机或有机碱处理游离酸,所述无机或有机碱例如胺(伯、仲或叔)、碱金属氢氧化物或碱土金属氢氧化物等。合适盐的说明性实例包括:有机盐,其衍生自氨基酸(例如L-甘氨酸、L-赖氨酸和L-精氨酸),氨,伯胺、仲胺和叔胺,以及环胺(例如羟乙基吡咯烷、哌啶、吗啉或哌嗪);以及无机盐,其衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂。
还应理解,本公开的化合物可以非溶剂化形式、溶剂化形式(例如水合形式)和固体形式(例如晶体或多晶形式)存在,并且本公开意图涵盖所有这类形式。
如本文中所使用,术语“溶剂合物”或“溶剂化形式”是指含有化学计量或非化学计量量的溶剂的溶剂加成形式。一些化合物处于结晶固态时倾向于捕获固定摩尔比率的溶剂分子,从而形成溶剂合物。如果溶剂是水,那么所形成的溶剂合物是水合物;并且如果溶剂是醇,那么所形成的溶剂合物是醇化物。水合物通过将一个或多个水分子与一个分子物质组合而形成,其中水将其分子状态保持为H2O。形成溶剂合物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
如本文中所使用,术语“晶体形式”、“结晶形式”、“多晶形式”和“多晶型物”可互换使用,并且意指化合物(或其盐或溶剂合物)可以不同的晶体堆积排列方式结晶的晶体结构,所有这些晶体结构具有相同的元素组成。不同的晶体形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光学和电学特性、稳定性以及溶解性。重结晶溶剂、结晶速率、存储温度和其它因素可使一种晶体形式占主导地位。化合物的多晶型物可以通过在不同条件下结晶来制备。
本公开还意图包括化合物中的原子的所有同位素。原子的同位素包括具有相同原子数但质量数不同的原子。举例来说,除非另外说明,否则本公开的化合物中的氢、碳、氮、氧、磷、硫、氟、氯、溴或碘意指还包括其同位素,例如但不限于1H、2H、3H、11C、12C、13C、14C、14N、15N、16O、17O、18O、31P、32P、32S、33S、34S、36S、17F、19F、35Cl、37Cl、79Br、81Br、127I和131I。在一些实施例中,氢包括氕、氘和氚。在一些实施例中,碳包括12C 和13C。
化合物的合成
在实例中的合成流程中说明本文提供的化合物(包括其药学上可接受的盐)的合成。本文提供的化合物可使用任何已知的有机合成技术制备且可根据多种可能的合成途径中的任一种合成,且因此,这些流程只是说明性的且不打算限制可用于制备本文提供的化合物的其它可能的方法。此外,所述流程中的步骤是为了更好地说明且可在适当时改变。出于研究和可能提交给管理机构的目的,实例中的化合物实施例是在中国合成。
用于制备本公开的化合物的反应可在合适的溶剂中进行,所述溶剂可由有机合成领域的技术人员容易地选择。合适的溶剂可以在反应进行的温度下,例如在从溶剂的冷冻温度到溶剂的沸腾温度范围内的温度下基本上不与起始材料(反应物)、中间物或产物反应。给定反应可以在一种溶剂或超过一种溶剂的混合物中进行。取决于特定反应步骤,用于特定反应步骤的合适溶剂可以由所属领域的技术人员进行选择。
本公开的化合物的制备可涉及各种化学基团的保护和脱保护。对保护和脱保护的需求和对适当的保护基团的选择可以由所属领域的技术人员容易地确定。保护基团的化学性质可见于例如T.W.格林(T.W.Greene)和P.G.M.伍兹(P.G.M.Wuts),《有机合成中的保护基团(Protective Groups in Organic Synthesis)》,第3版,威利父子公司(Wiley&Sons,Inc.),纽约(1999),其以全文引用的方式并入本文中。
可以根据所属领域中已知的任何合适方法监测反应。举例来说,可通过光谱手段,例如核磁共振光谱(例如1H或13C)、红外光谱、分光光度法(例如UV-可见光)、质谱,或通过色谱法,例如高效液相色谱(HPLC)、液相色谱-质谱(LCMS)或薄层色谱(TLC) 来监测产物形成。所属领域的技术人员可通过多种方法,包括高效液相色谱(HPLC)(“制备型LC-MS纯化:改进的化合物特异性方法优化(Preparative LC-MS Purification:Improved CompoundSpecific Method Optimization)”,卡尔F.布卢姆(Karl F.Blom),布莱恩·格拉斯(Brian Glass),理查德·斯帕克斯(Richard Sparks),安德鲁P.库姆斯(AndrewP.Combs), 《组合化学杂志(J.Combi.Chem.)》,2004,6(6),874-883,其以全文引用的方式并入本文中) 和正相二氧化硅色谱来纯化化合物。
出于说明性目的以下显示用于制备本公开的化合物的通用合成途径以及关键中间物。有关个别反应步骤的详细说明,请参见下文的实例部分。所属领域的技术人员将理解,可以使用其它合成路径来合成本发明的化合物。尽管在流程中描述了特定的起始材料和试剂,并在下文进行了讨论,但也可以轻松取代其它起始材料和试剂,以提供多种衍生物和/或反应条件。另外,通过下文所描述的方法制备的许多化合物可以根据本公开使用所属领域的技术人员熟知的常规化学反应来进一步修改。
可如流程A至D中所显示合成式(I)化合物。
通用流程A:合成式(I)化合物
通用流程B:合成式(I)化合物
通用流程C:合成式(I)化合物
通用流程D:合成式(I)化合物
化合物的用途
在一方面中,式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)化合物或其药学上可接受的盐可抑制α-KG转化为D-2-HG。
在一些实施例中,本公开的化合物可抑制异柠檬酸转化为α-KG。在一些实施例中,本公开的化合物可抑制α-KG转化为D-2-HG以及异柠檬酸转化为α-KG。在一些实施例中,本公开的化合物可选择性地抑制α-KG转化为D-2-HG,但不抑制异柠檬酸转化为α-KG。
在另一方面中,式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)化合物或其药学上可接受的盐可抑制突变型IDH。在一些实施例中,式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)化合物或其药学上可接受的盐可抑制野生型IDH。在一些实施例中,式 (I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)化合物或其药学上可接受的盐可抑制突变型IDH和野生型IDH两者。在一些实施例中,式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)化合物或其药学上可接受的盐可选择性地抑制突变型IDH,但不抑制野生型IDH。
在一些实施例中,本公开的化合物抑制IC50值为0.01至1000μM、0.01至500μM、0.01至100μM、0.01至80μM、0.01至50μM、0.01至40μM、0.01至30μM或0.01至 20μM、0.01至10μM、0.01至5μM或0.01至1μM、0.01至0.5μM、0.01至0.1μM或 0.01至0.05μM的野生型IDH和/或突变型IDH。
如本文中所使用,术语“选择性地抑制突变型IDH”意指所提供的化合物在本文中所描述的至少一个检定中抑制突变型IDH超过野生型IDH。在一些实施例中,本公开的化合物对突变型IDH的选择性比野生型IDH高至少2至500倍。在一些实施例中,本公开的化合物对突变型IDH的选择性比野生型IDH高至少2倍、5倍、10倍、20倍、30倍、40 倍、50倍、60倍、70倍、80倍、90倍、100倍、200倍、300倍、400倍或至少500倍。
药物组合物
本公开提供包含本文中所公开的至少一种化合物的药物组合物。在一些实施例中,药物组合物包含多于一种本文中所公开的化合物。在一些实施例中,药物组合物包含一种或多种本文中所公开的化合物和药学上可接受的载剂。
药学上可接受的载剂是本领域中的常规药物载剂,其可以按药学领域中众所周知的方式制备。在一些实施例中,本文中所公开的化合物可与药学上可接受的载剂混合以制备药物组合物。
如本文中所使用,短语“药学上可接受的”是指在合理的医学判断范围内,适合与人类和动物的组织接触使用,而不会产生过量毒性、刺激性、过敏反应或其它问题或并发症,并与合理的效益/风险比相称的化合物、材料、组合物和/或剂型。在一些实施例中,药学上可接受的化合物、材料、组合物和/或剂型是指被管理机构(例如美国食品和药物管理局(U.S.Food and Drug Administration)、中国食品和药物管理局(China Food and DrugAdministration)或欧洲药物管理局(European Medicines Agency))批准或公认药典(例如美国药典(U.S.Pharmacopoeia)、中国药典(China Pharmacopoeia)或欧洲药典(European Pharmacopoeia))中所列的可用于动物且特别是人类的那些化合物、材料、组合物和/或剂型。
如本文中所使用,术语“药学上可接受的载剂”是指将本文提供的化合物从一个位置、体液、组织、器官(内部或外部)或身体的一部分载运或运输至另一位置、体液、组织、器官或身体的一部分所涉及的药学上可接受的材料、组合物或媒剂,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。药学上可接受的载剂可以是能够用于动物组织接触,而无过量毒性或不良作用的媒剂、稀释剂、赋形剂或其它材料。示例性药学上可接受的载剂包括糖、淀粉、纤维素、麦芽、黄芪胶、明胶、林格氏溶液(Ringer's solution)、海藻酸、等渗生理盐水、缓冲剂等。可用于本公开中的药学上可接受的载剂包括所属领域中一般已知的那些载剂,例如以引用的方式并入本文中的《雷明顿药物科学(Remington PharmaceuticalSciences)》,马克出版公司(Mack Pub.Co.),新泽西州(New Jersey)(1991) 中公开的载剂。
可充当药学上可接受的载剂的材料的一些实例包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素和其衍生物,例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8) 赋形剂,例如可可脂和栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)乙二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇和聚乙二醇;(12)酯,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原质水;(17)等渗生理盐水;(18)林格氏溶液;(19)醇,例如乙醇和丙醇;(20)磷酸盐缓冲溶液;以及(21)药物调配物中使用的其它无毒相容物质,例如丙酮。
药物组合物可视需要含有药学上可接受的辅助物质以接近生理条件,例如pH值调节剂和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
药物组合物的形式取决于多种标准,包括但不限于施用途径、疾病程度或待施用的剂量。
药物组合物可调配成经口、经鼻、经直肠、经皮、静脉内或肌肉内施用。根据期望的施用途径,药物组合物可以调配成片剂、胶囊、丸剂、糖衣药丸、散剂、颗粒剂、药囊、扁囊剂、口含锭、悬浮液、乳液、溶液、糖浆、气雾剂(呈固体形式或在液体介质中)、喷雾剂、油膏、糊浆、乳霜、洗剂、凝胶剂、贴片、吸入剂或栓剂形式。
药物组合物可以经调配,以便在通过采用所属领域中已知的程序向患者施用之后,提供活性成分的快速、持续或延迟释放。在一些实施例中,药物组合物调配成持续释放形式。如本文中所使用,术语“持续释放形式”是指活性剂从药物组合物释放以使得其变得在较长时间段(延长释放)内或在某一位置(控制释放)可供个体,主要在个体的胃肠道内生物吸收。在一些实施例中,延长时间段可以是约1小时至24小时、2小时至12小时、3小时至8小时、4小时至6小时、1至2天或更长时间。在某些实施例中,延长时间段是至少约4小时、至少约8小时、至少约12小时或至少约24小时。药物组合物可以调配成片剂形式。举例来说,活性剂的释放速率不仅可以通过活性剂溶解于胃肠液中且随后独立于pH 自片剂或丸剂扩散而控制,而且还受片剂崩解和溶蚀的物理过程影响。在一些实施例中,“控制释放的医学应用(Medical Applications of Controlled Release)”,兰格(Langer)和怀斯(Wise)(编),CRC出版社(CRC Pres.),佛罗里达州波卡拉顿(Boca Raton,Florida) (1974);“控制性药物生物利用率(Controlled Drug Bioavailability)”,《药品设计和性能(Drug ProductDesign and Performance)》,什莫伦(Smolen)和波耳(Ball)(编),威立(Wiley), 纽约(1984);蓝吉(Ranger)和佩帕斯(Peppas),1983,《高分子科学-高分子化学评述(JMacromol.Sci.Rev.Macromol Chem.)》23:61中所公开的聚合材料可以用于持续释放;还参见利维(Levy)等人,1985,《科学(Science)》228:190;迪兰(During)等人,1989,《神经病学年评(Ann.Neurol.)》25:351;霍华德(Howard)等人,1989,《神经外科杂志(J.Neurosurg.)》71:105。以上参考文献以全文引用的方式并入本文中。
在某些实施例中,药物组合物包括约0.01mg至约1000mg的本文提供的化合物(例如约0.01mg至约10mg、约0.1mg至约10mg、约1mg至约10mg、约5mg至约10mg、约5mg至约20mg、约5mg至约30mg、约5mg至约40mg、约5mg至约50mg、约10 mg至约100mg、约20mg至约100mg、约30mg至约100mg、约40mg至约100mg、约50mg至约100mg、约50mg至约200mg、约50mg至约300mg、约50mg至约400 mg、约50mg至约500mg、约100mg至约200mg、约100mg至约300mg、约100mg 至约400mg、约100mg至约500mg、约200mg至约500mg、约300mg至约500mg、约400mg至约500mg、约500mg至约1000mg、约600mg至约1000mg、约700mg至约1000mg、约800mg至约1000mg或约900mg至约1000mg)。每天每位个体的合适剂量可以是约5mg至约500mg,优选地是约5mg至约50mg、约50mg至约100mg或约 50mg至约500mg。
在某些实施例中,药物组合物可调配成单位剂型,每一剂量含有约0.01mg至约10mg、约0.1mg至约10mg、约1mg至约10mg、约5mg至约10mg、约5mg至约20mg、约5mg至约30mg、约5mg至约40mg、约5mg至约50mg、约10mg至约100mg、约 20mg至约100mg、约30mg至约100mg、约40mg至约100mg、约50mg至约100mg、约50mg至约200mg、约50mg至约300mg、约50mg至约400mg、约50mg至约500 mg、约100mg至约200mg、约100mg至约300mg、约100mg至约400mg、约100mg 至约500mg、约200mg至约500mg、约300mg至约500mg、约400mg至约500mg、约500mg至约1000mg、约600mg至约1000mg、约700mg至约1000mg、约800mg至约1000mg或约900mg至约1000mg的本文中所公开的化合物。术语“单位剂型”是指适用作人类个体和其它哺乳动物的单位剂量的物理离散单元,每个单元含有与合适的药物载剂结合的经计算以产生所期望的治疗作用的预定量的活性材料。
在一些实施例中,药物组合物包含本文中所公开的一种或多种化合物作为第一活性成分,且进一步包含第二活性成分。第二活性成分可以是所属领域中已知的任何抗癌剂。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(例如,伊马替尼、吉非替尼、硼替佐米、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、伏立诺他、拉帕替尼、坦西莫司、尼罗替尼、依维莫司、帕唑帕尼、曲妥珠单抗、贝伐单抗、西妥昔单抗、雷珠单抗、哌加他尼、帕尼单抗等)、有丝分裂抑制剂(例如,紫杉醇、长春新碱、长春碱等)、烷化剂(例如,顺铂、环磷酰胺、苯丁酸氮芥、卡莫司汀等)、抗代谢物(例如,甲氨蝶呤、5-FU等)、嵌入抗癌剂(例如,放线菌素、蒽环霉素、博莱霉素、丝裂霉素-C等)、拓扑异构酶抑制剂(例如,伊立替康、拓扑替康、替尼泊苷等)、免疫治疗剂(例如,白细胞介素、干扰素等)和抗激素剂(例如,他莫昔芬、雷洛昔芬等)。在一些实施例中,第二活性剂为以下中的一者或多者:依鲁替尼、维奈妥拉、甲磺酸伊马替尼、盐酸尼罗替尼、伯舒替尼、达沙替尼、依托泊苷、磷酸氟达拉滨、普纳替尼、硫酸长春新碱、甲氨蝶呤、环磷酰胺、洛莫司汀、替尼泊苷、替莫唑胺、福莫司汀、卡莫司汀、贝伐单抗、毕西巴尼、氟尿嘧啶、美法仑、盐酸依西他滨。
治疗方法
本公开提供一种治疗与IDH相关的疾病的方法,其包括向个体施用有效量的本文中所公开的一种或多种化合物或药学上可接受的盐或药物组合物。
如本文中所使用,术语“个体”是指生物体、组织或细胞。个体可包括用于医学目的的人类个体,例如现有病况或疾病的诊断和/或治疗或用于预防病况或疾病发作的预防性治疗,或用于医学、兽医学目的或发育目的的动物个体。个体还可包括来自组织培养、细胞培养、器官复制、干细胞生产等的样品材料。合适的动物个体包括哺乳动物和禽类。如本文中所使用,术语“哺乳动物”包括但不限于灵长类动物,例如人类、猴、猿等;牛科动物,例如牛、公牛等;绵羊(ovine),例如绵羊(sheep)等;山羊(caprine),例如山羊(goat) 等;猪科动物,例如猪、肉猪等;马科动物,例如马、驴、斑马等;猫科动物,包括野猫和家猫;犬科动物,包括狗;兔类动物,包括兔子、野兔等;以及啮齿动物,包括小鼠、大鼠等。如本文中所使用,术语“禽类”包括但不限于鸡、鸭、鹅、鹌鹑、火鸡和雉。在一些实施例中,个体为哺乳动物或哺乳动物细胞。在一些实施例中,个体为人类或人类细胞。人类个体包括但不限于胎儿、新生儿、婴儿、青少年和成年个体。此外,“个体”可包括罹患或疑似罹患病况或疾病的患者。因此,术语“个体”和“患者”在本文中可互换使用。个体还可指实验室中或生物加工培养物中的细胞或细胞集合,以进行活力、分化、标志物产生、表达等测试。
如本文中所使用,术语活性剂或药物递送装置的“有效量”是指引发所需生物反应所必需的量。如所属领域的普通技术人员将理解,药剂或装置的有效量可以取决于如所需的生物学端点、待递送的药剂、囊封基质的组成、目标组织等因素而变化。
在一些实施例中,经由肠胃外途径或非肠胃外途径施用本文中所公开的一种或多种化合物或其药学上可接受的盐或药物组合物。在一些实施例中,一种或多种化合物或其药学上可接受的盐或药物组合物是经口、经肠、经颊、经鼻、鼻内、经粘膜、经表皮、透皮、经皮、经眼、肺、舌下、经直肠、经阴道、经表面、皮下、静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、表皮下、关节内、囊下、蛛网膜下、脊椎内或胸骨内施用。
本文中所公开的化合物可以呈纯形式、与其它活性成分组合或呈本公开的药物组合物形式施用。在一些实施例中,本文中所公开的化合物可以与所属领域中已知的一种或多种抗癌剂组合同时或依序向有需要的个体施用。在一些实施例中,施用是一天一次、一天两次、一天三次或每两天一次、每三天一次、每四天一次、每五天一次、每六天一次、一周一次进行。
在某些实施例中,本公开提供本公开的化合物、其药学上可接受的盐或药物组合物在制造用于治疗与α-KG转化为D-2-HG相关的疾病的药剂中的用途。在某些实施例中,本公开提供本公开的化合物、其药学上可接受的盐或药物组合物在制造用于治疗与突变型IDH相关的疾病的药剂中的用途。
在某些实施例中,与α-KG转化为D-2-HG相关的疾病为与突变型IDH相关的疾病,包括癌症。
确切地说,癌症包括但不限于白血病、成胶质细胞瘤、黑色素瘤、软骨肉瘤、胆管癌、骨肉瘤、淋巴瘤、肺癌、腺瘤、骨髓瘤、肝细胞癌、肾上腺皮质癌、胰腺癌、乳腺癌、前列腺癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、子宫颈癌、脑癌、食道癌、骨癌、睾丸癌、皮肤癌、肾癌、间皮瘤、神经母细胞瘤、甲状腺癌、头颈癌、食道癌、眼癌、前列腺癌、鼻咽癌或口腔癌。在一些实施例中,癌症为白血病、成胶质细胞瘤或胆管癌。
本公开中的化合物、其药学上可接受的盐和其药物组合物可用于预防或治疗与α-KG 转化为D-2-HG相关的疾病或病况中的任一者在哺乳动物中(尤其人类中)的发作或发展。在一些实施例中,本公开中的化合物、其药学上可接受的盐和其药物组合物可用于预防或治疗与突变型IDH相关的疾病或病况中的任一者在哺乳动物中(尤其人类中)的发作或发展。
在这类情形下,本公开还提供一种筛选适合于单独使用本公开的化合物、其药学上可接受的盐或药物组合物或与其它成分(例如第二活性成分,例如抗癌剂)组合治疗的患者的方法。方法包括对来自患者的肿瘤样本进行测序以及检测患者中的D-2-HG的累积或检测患者中的IDH的突变状态。
实例
以下进一步阐明本公开的通用方法。本公开的化合物可通过所属领域中已知的方法制备。以下说明本公开的优选化合物的详细制备方法。然而,这些决不限制本公开的化合物的制备方法。
合成实例
以下实例中的化合物的结构是通过核磁共振(NMR)或/和质谱(ESI)表征。NMR位移(δ)是以10-6(ppm)为单位给出。1H-NMR光谱记录于具有四甲基硅烷(TMS)作为内标的VarianMercury VX 400光谱仪上的二甲亚砜-d6(DMSO-d6)或CDCl3中。
使用Agilent 1260-6230TOF LC-MS质谱仪进行ESI-HRMS测量。
使用Phenomen C18柱(4.6mm×150mm,0.4μm)在Agilent 1200LC上进行高效液相色谱(HPLC)测量。
使用Yantai Huanghai HSGF254硅胶板进行薄层色谱。用于薄层色谱(TLC)的硅胶板为0.15mm至0.2mm。通过TLC分离和纯化产物所使用的硅胶板为0.4mm至0.5mm。
经纯化色谱柱使用硅胶作为载体(200至300目,由烟台黄海公司(YantaiHuanghai co.)产生)。
本公开的已知起始材料可通过使用或根据所属领域中已知的方法合成,或可购自阿法埃莎(Alfa Aesar)、兰开斯特(Langcaster)、TCI、奥德里奇(Aldrich)、毕得医药(Bepharm) 和思阔化学(Scochem)。
除非另外说明,否则实例中的反应都是在氩气或氮气环境下进行。氩气或氮气环境是指反应烧瓶连接到体积约1L的氩气或氮气球。氢化通常在真空下进行,用氢气填充,且重复三次。除非另外说明,否则实例中的反应温度是环境温度,即20℃至30℃。
实例中的反应进展通过TLC监测。用于反应的洗脱剂系统包括二氯甲烷-甲醇系统和石油醚-乙酸乙酯系统。根据化合物的不同极性调节溶剂的体积比。
用于纯化化合物的柱色谱的洗脱系统以及TLC的洗脱剂系统包括二氯甲烷-甲醇系统和石油醚-乙酸乙酯系统。根据化合物的不同极性调节溶剂的体积比。可添加少量碱性或酸性试剂,例如三乙胺和乙酸,以进行调节。
在以下实例和本文其它地方使用的缩写词为:
实例1
2-乙基-4-[[(1S)-1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙基]氨基]-3H-吡咯并[3,4-c]吡啶-1-酮(1)
根据通用流程A制备此化合物。具体地说,流程如下列出。
流程1:
步骤1. 1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙酮(1b)
向1-甲基吲唑-5-醇(1a,1g,6.75mmol)、1-(3,4-二氟苯基)乙酮(1.16g,7.42mmol) 和18-冠醚-6(178mg,0.67mmol)于DMSO(20mL)中的混合物中添加K2CO3(1.87g,13.5mmol)。接着在N2环境下将混合物在120℃下搅拌1h。将混合物倒入水(150mL) 中并用EtOAc(2×50mL)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤,浓缩,以获得残余物。使残余物悬浮于石油醚(60mL)中并搅拌30min。形成灰白色固体。固体经过滤,收集且在真空中干燥,得到呈灰白色固体的1-[3-氟-4-(1-甲基吲唑- 5-基)氧基-苯基]乙酮(1b,1.7g,88.6%产率)。
1H NMR(400MHz,CDCl3)δ:7.95(s,1H),7.81(dd,J=2.0,11.6Hz,1H),7.65(d,J=8.8 Hz,1H),7.44(d,J=8.8Hz,1H),7.39(d,J=2.0Hz,1H),7.21(dd,J=2.4,8.8Hz,1H),6.88(t, J=8.4Hz,1H),4.12(s,3H),2.58(s,3H)。LC-MS:(ESI)m/z:284.9[M+H]。
步骤2.N-[1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]亚乙基]-2-甲基-丙烷-2-亚磺酰胺(1c)
向1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙酮(1b,1.7g,5.98mmol)和(S)-2-甲基丙烷-2-亚磺酰胺(1.09g,8.97mmol)于无水THF(30mL)中的混合物中添加Ti(OEt)4(2.73 g,11.96mmol)。接着在N2环境下将混合物在70℃下搅拌16h。在搅拌下将混合物倒入水 (100mL)和EtOAc(100mL)的混合物中。在将混合物搅拌15min之后,过滤混合物。分离滤液的有机层,且用EtOAc(100mL)萃取水层。合并的有机层用盐水(100mL)洗涤,用Na2SO4干燥且过滤。滤液经浓缩且在真空中干燥,得到呈棕色油状物的N-[1-[3-氟 -4-(1-甲基吲唑-5-基)氧基-苯基]亚乙基]-2-甲基-丙烷-2-亚磺酰胺(1c,2.3g,81.9%产率),其将直接用于下一步骤。
LC-MS:(ESI)m/z:387.8[M+H]。
步骤3.(S)-N-((S)-1-(3-氟-4-((1-甲基-1H-吲唑-5-基)氧基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(1d)
在-50℃下向N-[1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]亚乙基]-2-甲基-丙烷-2-亚磺酰胺(1c,2.3g,5.94mmol)于THF(40mL)和H2O(0.8mL)中的溶液中逐份添加NaBH4(674mg,17.81mmol)。在将混合物在-50℃下搅拌2h之后,将混合物升温到25℃并搅拌1h。将混合物倒入水(100mL)中并用EtOAc(2×80mL)萃取。合并的有机层用盐水(100 mL)洗涤,用Na2SO4干燥,过滤且浓缩以获得残余物。残余物通过硅胶上的急骤色谱(石油醚/EtOAc=1:1(v/v))纯化,得到呈淡黄色油状物的(S)-N-((S)-1-(3-氟-4-((1-甲基-1H-吲唑-5-基)氧基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(1d,2.0g,82%产率)。
1H NMR(400MHz,CDCl3)δ:7.90(s,1H),7.39(d,J=8.8Hz,1H),7.25(d,J=2.0Hz,1H),7.22(d,J=2.0Hz,1H),7.20-7.18(m,1H),7.05(d,J=8.8Hz,1H),6.96-6.90(m,1H),4.53 (q,J=6.4Hz,1H),4.09(s,3H),3.42(br s,1H),1.52(d,J=6.4Hz,3H),1.25(s,9H)。LC-MS: (ESI)m/z:389.9[M+H]。
步骤4.(1S)-1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙胺(1e)
向(S)-N-((S)-1-(3-氟-4-((1-甲基-1H-吲唑-5-基)氧基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺 (1d,2.0g,5.13mmol)于MeOH(20mL)中的混合物中逐滴添加HCl/二噁烷(4M,5 mL)。接着将混合物在25℃下搅拌2h。将混合物倒入水(100mL)中且用固体Na2CO3碱化至pH=9。接着用EtOAc(2×50mL)萃取混合物。合并的有机层用盐水(50mL)洗涤且用Na2SO4干燥。接着将其过滤,浓缩且在真空中干燥,得到呈棕色油状物的(1S)-1-[3-氟 -4-(1-甲基吲唑-5-基)氧基-苯基]乙胺(1e,1.5g,粗),其将直接用于下一步骤。
LC-MS:(ESI)m/z:286.8[M+H]。
步骤5. 2-氟吡啶-4-羰酰氯(A-1b)
向2-氟吡啶-4-甲酸(A-1a,10g,70.87mmol)于SOCl2(39mL,537.6mmol)中的溶液中逐滴添加DMF(0.6mL,7.8mmol)。将混合物在80℃下搅拌1h。反应混合物经浓缩且用DCM(2×100mL)共蒸发,得到呈黄色油状物的2-氟吡啶-4-羰酰氯(A-1b,13g, 98.8%产率,86%纯度),其不经纯化即用于下一步骤。
步骤6.N-乙基-2-氟-吡啶-4-甲酰胺(A-1c)
在0℃至4℃下向乙胺(6.9g,84.09mmol,HCl盐)和K2CO3(33.9g,245.3mmol) 于THF(150mL)和H2O(75mL)中的溶液中添加2-氟吡啶-4-羰酰氯(A-1b,13g,70.07 mmol,86%纯度)。将混合物在0℃至4℃下搅拌2h。混合物用水(75mL)稀释且静置2 min。分离有机层。水层用EtOAc(3×50mL)萃取。合并的有机层用盐水(75mL)洗涤,用Na2SO4干燥,过滤且浓缩以获得棕色油状物。残余物通过急骤硅胶色谱(ISCO;80g SepaFlash二氧化硅急骤柱,0%至40%乙酸乙酯/石油醚梯度的洗脱剂,80mL/min)纯化,得到呈淡黄色固体的N-乙基-2-氟-吡啶-4-甲酰胺(A-1c,6.6g,56.2%产率)。
1H NMR(400MHz,CDCl3)δ:8.31(d,J=5.2Hz,1H),7.51-7.48(m,1H),7.30-7.27(m,1H),6.50(br s,1H),3.55-3.45(m,2H),1.26(t,J=7.2Hz,3H)。
步骤7. 2-乙基-4-氟-3-羟基-3H-吡咯并[3,4-c]吡啶-1-酮(A-1d)
在N2环境下,在-65℃下向N-乙基-2-氟-吡啶-4-甲酰胺(A-1c,6.6g,39.42mmol)于 THF(200mL)中的溶液中逐滴添加LDA(2M于THF中,45mL)。将混合物在-65℃下搅拌30min。接着添加DMF(16mL,208mmol)。将混合物在-65℃下再搅拌1h。混合物用饱和NH4Cl溶液(100mL)淬灭且用水(70mL)稀释。混合物用EtOAc(3×50mL) 萃取。合并的有机层用盐水(75mL)洗涤,用Na2SO4干燥,过滤且浓缩以获得呈黄色固体的2-乙基-4-氟-3-羟基-3H-吡咯并[3,4-c]吡啶-1-酮(A-1d,9.3g,98.9%产率,82%纯度),其不经纯化即用于下一步骤。
1H NMR(400MHz,CDCl3)δ:8.37-8.35(m,1H),7.52(dd,J=2.4,4.8Hz,1H),6.05(s,1H),4.34(br s,1H),3.82-3.74(m,1H),3.54-3.46(m,1H),1.29(t,J=7.2Hz,3H)。
步骤8. 2-乙基-4-氟-3H-吡咯并[3,4-c]吡啶-1-酮(A-1)
在0℃下向2-乙基-4-氟-3-羟基-3H-吡咯并[3,4-c]吡啶-1-酮(A-1d,9.3g,39mmol, 82%纯度)于TFA(30mL)和DCM(80mL)中的溶液中添加Et3SiH(16mL,100.17mmol)。接着将溶液在25℃下搅拌16h。将混合物缓慢添加到搅拌的饱和NaHCO3溶液(800mL)中且接着用DCM(3×200mL)萃取。合并的有机层用盐水(200mL)洗涤,用 Na2SO4干燥,过滤且浓缩以获得黄色油状物。残余物通过急骤硅胶色谱(ISCO;80g SepaFlash二氧化硅急骤柱,0%至40%乙酸乙酯/石油醚梯度的洗脱剂,60mL/min)纯化,得到呈白色固体的2-乙基-4-氟-3H-吡咯并[3,4-c]吡啶-1-酮(A-1,6.3g,90.8%产率)。
1H NMR(400MHz,CDCl3)δ:8.38-8.34(m,1H),7.64(dd,J=2.8,4.8Hz,1H),4.49(s,2H),3.72(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H)。
步骤9. 2-乙基-4-[[(1S)-1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙基]氨基]-3H-吡咯并 [3,4-c]吡啶-1-酮(1)
在N2环境下,将粗(1S)-1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙胺(1e,300mg,1.05 mmol)、2-乙基-4-氟-3H-吡咯并[3,4-c]吡啶-1-酮(A-1,758mg,4.21mmol)和DIPEA(544 mg,4.21mmol)于NMP(4mL)中的混合物在180℃下搅拌8h。将反应混合物倒入水(30mL)中并用EtOAc(2×30mL)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以获得残余物。残余物通过硅胶上的急骤色谱(EtOAc)纯化,得到呈无色胶状物的粗2-乙基-4-[[(1S)-1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙基]氨基]-3H-吡咯并 [3,4-c]吡啶-1-酮,其通过制备型HPLC(柱:DuraShell 150×25mm×5μm;移动相:水(0.05%HCl v/v)-ACN;相B%:22%至52%;流动速率:25mL/min)进一步纯化,得到呈蓝色固体的2-乙基-4-[[(1S)-1-[3-氟-4-(1-甲基吲唑-5-基)氧基-苯基]乙基]氨基]-3H-吡咯并[3,4-c] 吡啶-1-酮(1,122.0mg,23.7%产率,HCl盐)。
1H NMR(400MHz,CD3OD)δ:7.98-7.91(m,2H),7.58(d,J=8.8Hz,1H),7.42(dd,J=2.0,11.6Hz,1H),7.26(d,J=8.8Hz,1H),7.24-7.19(m,3H),7.03(t,J=8.4Hz,1H),5.15(q,J =6.4Hz,1H),4.75-4.57(m,2H),4.07(s,3H),3.72(q,J=7.2Hz,2H),1.74(d,J=6.4Hz,3H), 1.32(t,J=7.2Hz,3H)。LC-MS:(ESI)m/z:446.1[M+H]。
合成化合物2至化合物64
一般来说,根据通用流程A中描述的程序制备表1中的化合物2至化合物64。合成方法与实例1类似。化合物2至化合物64的数据在本文中显示于下表1中。
表1.
实例2 2-乙基-4-[[(1S)-1-[3-氟-4-[[2-(三氟甲基)-4-吡啶基]氧基]苯基]乙基]氨基]-3H-吡咯并[3,4-c]吡啶-1-酮(65)
流程2:
步骤1. 6-羟基-5-甲基-嘧啶-4-甲酸乙酯(2)
在20℃下向2-甲基-3-氧代-丁二酸二乙酯(1,30g,148.4mmol)于EtOH(350mL) 中的混合物中添加EtONa(16.15g,237.4mmol)和甲脒乙酸酯(21.6g,207.7mmol)。接着在N2环境下,将混合物在90℃下搅拌16h。向混合物添加2N HCl以调节pH=7,接着向混合物添加水(200mL)并用EtOAc(3×200mL)萃取。有机层经收集且用盐水(200 mL)洗涤,用Na2SO4干燥,过滤且在真空中浓缩以获得呈棕色油状物的残余物。残余物通过用(石油醚:EtOAc=1:3)洗脱的硅胶上的柱色谱纯化,得到呈黄色固体的6-羟基-5- 甲基-嘧啶-4-甲酸乙酯(2,6.0g,19.5%产率)。
1H NMR(400MHz,CD3OD)δ:8.09(s,1H),4.40(q,J=7.2Hz,2H),2.20(s,3H),1.39(t, J=7.2Hz,3H)。LC-MS:(ESI)m/z:182.9[M+H]。
步骤2. 6-氯-5-甲基-嘧啶-4-甲酸乙酯(3)
向6-羟基-5-甲基-嘧啶-4-甲酸乙酯(2,1.0g,5.49mmol)于EtOAc(50mL)中的溶液中缓慢添加草酰二氯(1.44mL,16.47mmol),随后添加DMF(84μL,1.1mmol)。接着在N2环境下,将混合物在80℃下搅拌2h。冷却混合物且添加冰水(50mL),并用EtOAc (3×60mL)萃取。有机层经收集且用盐水(60mL)洗涤,用Na2SO4干燥,过滤且在真空中浓缩以获得呈棕色油状物的残余物。残余物通过用(石油醚:EtOAc=4:1(v/v))洗脱的硅胶上的柱色谱纯化,得到呈黄色油状物的6-氯-5-甲基-嘧啶-4-甲酸乙酯(3,0.73g, 61.2%产率)。
1H NMR(400MHz,CD3OD)δ:8.85(s,1H),4.45(q,J=7.2Hz,2H),2.50(s,3H),1.41(t, J=6.8Hz,3H)。LC-MS:(ESI)m/z:200.8[M+H]。
步骤3 5-(溴甲基)-6-氯-嘧啶-4-甲酸乙酯(4)
向6-氯-5-甲基-嘧啶-4-甲酸乙酯(3,0.73g,3.64mmol)、AIBN(60mg,0.36mmol)、NBS(1.62g,9.10mmol)的混合物中溶解1,2-二氯乙烷(30mL),且在N2环境下将混合物在100℃下搅拌12h。向混合物添加水(50mL)并用EtOAc(3×50mL)萃取。有机层经收集且用盐水(50mL)洗涤,用Na2SO4干燥,过滤且在真空中浓缩,得到呈棕色油状物的5-(溴甲基)-6-氯-嘧啶-4-甲酸乙酯(4,1.23g,粗制的)。
1H NMR(400MHz,CD3OD)δ:8.99(s,1H),4.54-4.48(m,2H),2.69(s,2H),1.46-1.42(m, 3H)。LC-MS:(ESI)m/z:278.9[M+H]。
步骤4 4-氯-6-乙基-5H-吡咯并[3,4-d]嘧啶-7-酮(5)
向5-(溴甲基)-6-氯-嘧啶-4-甲酸乙酯(4,1.18g,4.22mmol)、乙胺盐酸盐(1.03g,12.66mmol)于MeCN(40mL)中的溶液中添加K2CO3(1.17g,8.44mmol),且在N2环境下将混合物在25℃下搅拌6h。向混合物添加水(50mL)并用EtOAc(3×50mL)萃取。有机层经收集且用盐水(50mL)洗涤,用Na2SO4干燥,过滤且在真空中浓缩以获得呈棕色油状物的残余物。残余物经由硅胶上的急骤色谱(石油醚/EtOAc=1:1)纯化,得到呈棕色固体的4-氯-6-乙基-5H-吡咯并[3,4-d]嘧啶-7-酮(5,0.31g,29.7%产率)。
1H NMR(400MHz,CD3OD)δ:9.15(s,1H),4.66(s,2H),3.75(q,J=7.6Hz,2H),1.32(t, J=7.2Hz,3H)。LC-MS:(ESI)m/z:197.9[M+H]。
步骤5 6-乙基-4-[[(1S)-1-[3-氟-4-(4-甲基苯氧基)苯基]乙基]氨基]-5H-吡咯并[3,4-d]嘧啶 -7-酮(65)
向4-氯-6-乙基-5H-吡咯并[3,4-d]嘧啶-7-酮(5,0.08g,0.4mmol)和(1S)-1-[3-氟-4-(4- 甲基苯氧基)苯基]乙胺(129mg,0.53mmol)于二噁烷(4mL)中的混合物中添加DIPEA (262mg,2.02mmol),且将所得混合物在80℃下搅拌4h。将混合物冷却到室温且用水(20 mL)稀释,用EtOAc(3×20mL)萃取。有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以获得残余物。残余物通过制备型HPLC(柱:DuraShell 150×25mm×5μm;移动相:[水(0.05%HCl)-ACN];B%:41%至61%,10min)纯化,得到呈灰白色固体的6- 乙基-4-[[(1S)-1-[3-氟-4-(4-甲基苯氧基)苯基]乙基]氨基]-5H-吡咯并[3,4-d]嘧啶-7-酮(65,30.3mg,18.2%产率)。
1H NMR(400MHz,CD3OD)δ:8.78(s,1H),7.35(dd,J=2.0,11.2Hz,1H),7.23(d,J=8.4 Hz,1H),7.14(d,J=8.0Hz,2H),7.01(t,J=8.0Hz,1H),6.81(d,J=8.4Hz,2H),5.68(q,J= 7.2Hz,1H),4.56(s,2H),3.70(q,J=7.2Hz,2H),2.30(s,3H),1.69(d,J=6.8Hz,3H),1.31(t, J=7.6Hz,3H)。LC-MS:(ESI)m/z:407.2[M+H]。
合成化合物66和化合物67
一般来说,根据通用流程B中描述的程序制备表2中的化合物66和化合物67。合成方法与实例2类似。化合物66和化合物67的数据在本文中显示于下表2中。
表2.
实例3.
2-乙基-4-[[(1S)-1-[3-氟-4-[4-(三氟甲基)苯基]苯基]乙基]氨基]-3H-吡咯并[3,4-c]吡啶-1- 酮(68)
根据通用流程C制备此化合物。具体地说,流程如下列出。
流程3:
步骤1. 4-溴-3-氟-N-甲氧基-N-甲基-苯甲酰胺(C-1b)
在0℃下向4-溴-3-氟-苯甲酸(C-1a,150g,0.68mol)于DCM(1L)和DMF(3mL,0.039mol)中的混合物中逐滴缓慢添加(COCl)2(66mL,0.75mol)。将反应物在25℃至 30℃下搅拌12h。将混合物冷却到0℃至5℃,且接着添加N-甲氧基甲胺盐酸盐(100g, 1.03mol),随后缓慢添加TEA(400mL,2.87mol)。将反应物在25℃至30℃下再搅拌2 h。过滤混合物且用DCM(2×200mL)洗涤滤饼。混合物用水(800mL)稀释并用DCM (3×300mL)萃取。合并的有机层用1.0M HCl溶液(2×500mL)、盐水(500mL)洗涤,用Na2SO4干燥,过滤且浓缩。将所得油状物在干冰/EtOH浴中冷却直到形成固体为止。混合物用石油醚(100mL)稀释且接着过滤。滤饼经收集且干燥,得到呈灰白色固体的4-溴 -3-氟-N-甲氧基-N-甲基-苯甲酰胺(C-1b,170g,94.7%产率)。
1H NMR(400MHz,CDCl3)δ:7.60(dd,J=6.8,8.4Hz,1H),7.50(dd,J=2.0,8.8Hz,1H), 7.41(dd,J=1.6,8.4Hz,1H),3.55(s,3H),3.36(s,3H)。LC-MS:(ESI)m/z:261.9/263.9[M+H]。
步骤2. 1-(4-溴-3-氟-苯基)乙酮(C-1c)
在氮气环境下,在0℃至5℃下向4-溴-3-氟-N-甲氧基-N-甲基-苯甲酰胺(C-1b,170 g,0.65mol)于THF(1.5L)中的溶液中添加MeMgBr(3M于醚中,325mL)。将反应物在0℃至5℃下搅拌3h。混合物用饱和NH4Cl溶液(1L)在0℃至10℃下淬灭且混合物用EtOAc(3×600mL)萃取。合并的有机层用盐水(500mL)洗涤,用Na2SO4干燥,过滤且浓缩。将所得油状物在干冰-EtOH浴中冷却直到形成固体为止。混合物用石油醚(100 mL)稀释且接着过滤。固体经收集且干燥,得到呈灰白色固体的1-(4-溴-3-氟-苯基)乙酮 (C-1c,121g,85.9%产率)。
1H NMR(400MHz,CDCl3)δ:7.72-7.64(m,2H),7.61(dd,J=2.0,8.4Hz,1H),2.59(s,3H)。
步骤3.(S)-N-[1-(4-溴-3-氟-苯基)亚乙基]-2-甲基-丙烷-2-亚磺酰胺(C-1d)
将1-(4-溴-3-氟-苯基)乙酮(C-1c,121g,0.56mol.)、2-甲基丙烷-2-亚磺酰胺(81g, 0.67mol)和Ti(OEt)4(255g,1.12mol)于THF(1L)中的混合物在80℃下搅拌8h。将混合物倒入水(1L)中且接着用EtOAc(600mL)稀释。过滤混合物且用EtOAc(2×600 mL)洗涤滤饼。分离有机层,且用EtOAc(2×600mL)萃取水层。合并的有机层用盐水 (800mL)洗涤,用Na2SO4干燥,过滤且浓缩,得到呈黄色油状物的(S)-N-[1-(4-溴-3-氟-苯基)亚乙基]-2-甲基-丙烷-2-亚磺酰胺(C-1d,170g,95.2%产率)。
1H NMR(400MHz,CDCl3)δ:7.68-7.59(m,2H),7.53(dd,J=1.6,8.4Hz,1H),2.75(s,3H),1.33(s,9H)。
步骤4.N-[(1S)-1-(4-溴-3-氟-苯基)乙基]-2-甲基-丙烷-2-亚磺酰胺(C-1e)
在-60℃至-40℃下向(S)-N-[1-(4-溴-3-氟-苯基)亚乙基]-2-甲基-丙烷-2-亚磺酰胺(C-1d, 160g,0.5mol)于THF(1L)和水(20mL)中的混合物中逐份添加NaBH4(56.7g,1.50 mol)。将反应物在-60℃至-40℃下搅拌3h。将混合物倒入饱和NH4Cl溶液(2L)中,且混合物用EtOAc(3×800mL)萃取。合并的有机层用盐水(800mL)洗涤,用Na2SO4干燥,过滤且浓缩。将所得油状物溶解于石油醚(300mL)中且在15℃至20℃下放置12h。白色沉淀物经收集,用石油醚(2×50mL)洗涤且干燥,得到呈白色固体的所需产物(66 g)。滤液在真空中浓缩,且残余物通过柱色谱(SiO2,石油醚/乙酸乙酯=5/1至3:1)纯化,得到呈白色固体的纯产物(103g)。总共获得呈白色固体的N-[(1S)-1-(4-溴-3-氟-苯基)乙基]- 2-甲基-丙烷-2-亚磺酰胺(C-1e,103g,64%产率)。
1H NMR(400MHz,CDCl3)δ:7.52(dd,J=7.2,8.0Hz,1H),7.14(dd,J=2.0,9.2Hz,1H), 7.04(dd,J=2.0,8.4Hz,1H),4.55-4.48(m,1H),3.41(d,J=2.4Hz,1H),1.50(d,J=6.4Hz, 3H),1.24(s,9H)。LC-MS:(ESI)m/z:323.7[M+H]。
步骤5.(1S)-1-(4-溴-3-氟-苯基)乙胺(C-1f)
在20℃至25℃下向N-[(1S)-1-(4-溴-3-氟-苯基)乙基]-2-甲基-丙烷-2-亚磺酰胺(C-1e, 50g,155.17mmol)于中MeOH(250mL)中的溶液中添加HCl/二噁烷(4M,80mL),且将反应物搅拌2h。溶剂在真空中浓缩且残余物用水(300mL)稀释。混合物用EtOAc (3×150mL)萃取。弃去有机层。用饱和NaHCO3溶液将水层调节至pH=7至8。混合物用EtOAc(3×150mL)萃取。合并的有机层用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩,得到呈无色胶状物的(1S)-1-(4-溴-3-氟-苯基)乙胺(C-1f,30.1g,89%产率)。
1H NMR(400MHz,CDCl3)δ:7.48(dd,J=7.2,8.0Hz,1H),7.16(dd,J=2.0,10.0Hz,1H),7.02(dd,J=2.0,8.0Hz,1H),4.11(q,J=6.4Hz,1H),1.36(d,J=6.8Hz,3H)。LC-MS:(ESI)m/z:200.7/202.7[M+H]。
步骤6. 4-[[(1S)-1-(4-溴-3-氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(C-1)
将(1S)-1-(4-溴-3-氟-苯基)乙胺(C-1f,20g,91.72mmol)、2-乙基-4-氟-3H-吡咯并[3,4- c]吡啶-1-酮(A-1,50g,277.5mmol)和DIPEA(48mL,275.58mmol)于NMP(100mL) 中的混合物在170℃下搅拌6h。将混合物倒入水(800mL)中且接着用EtOAc(5×300mL) 萃取。合并的有机层用盐水(500mL)洗涤,用Na2SO4干燥,过滤且浓缩。残余物通过柱色谱(SiO2,石油醚/乙酸乙酯=3/1至1:1)纯化,得到呈灰白色固体的4-[[(1S)-1-(4-溴-3- 氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(C-1,25g,72.1%产率)。
1H NMR(400MHz,CDCl3)δ:8.20(d,J=5.2Hz,1H),7.48(dd,J=7.2,8.4Hz,1H),7.17 (dd,J=2.0,9.6Hz,1H),7.08(dd,J=2.0,8.0Hz,1H),7.06(d,J=4.8Hz,1H),5.36(quin,J= 6.8Hz,1H),4.41(d,J=6.8Hz,1H),4.30-4.20(m,2H),3.68(q,J=7.2Hz,2H),1.58(d,J= 6.8Hz,3H),1.28(t,J=7.2Hz,3H)。LC-MS:(ESI)m/z:377.8/379.8[M+H]。
步骤7. 4-[[(1S)-1-[4-(环戊烯-1-基)-3-氟-苯基]乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶 -1-酮(35a)
在N2环境下,将4-[[(1S)-1-(4-溴-3-氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶- 1-酮(C-1,100mg,0.26mmol)、2-(环戊烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷(51 mg,0.26mmol)、Pd(dppf)Cl2.CH2Cl2(22mg,0.026mmol)和DIPEA(92μL,0.53mmol) 于1,4-二噁烷(1mL)和H2O(1mL)中的混合物在85℃下搅拌2h。将反应混合物添加到H2O(100mL)中,用EtOAc(3×30mL)萃取。合并的有机相用无水Na2SO4干燥,浓缩以获得减压下的粗产物。粗产物通过硅胶色谱(石油醚/EtOAc=3/1(v/v))纯化,以获得呈黄色油状物的4-[[(1S)-1-[4-(环戊烯-1-基)-3-氟-苯基]乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(35a,50mg,51.6%产率)。
LC-MS:(ESI)m/z:366.1[M+H]。
步骤8. 4-[[(1S)-1-(4-环戊基-3-氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮 (35)
在H2环境(15psi)下,将4-[[(1S)-1-[4-(环戊烯-1-基)-3-氟-苯基]乙基]氨基]-2-乙基- 3H-吡咯并[3,4-c]吡啶-1-酮(35a,50mg,0.14mmol)和Pd/C(5mg,10重量%)于MeOH (10mL)中的混合物在25℃下搅拌20min。反应混合物经过滤以获得滤液。接着去除溶剂,以获得减压下的粗产物。粗产物通过制备型HPLC(柱:Boston Prime C18 150×30mm×5μm;移动相:[水(0.05%氢氧化氨v/v)-ACN];B%:65%至85%,9min)纯化,以获得呈白色固体的4-[[(1S)-1-(4-环戊基-3-氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(35,26.1mg,51.9%产率)。
1H NMR(400MHz,CDCl3)δ:8.24(d,J=5.2Hz,1H),7.24-7.19(m,1H),7.11(d,J=8.0 Hz,1H),7.08-7.02(m,2H),5.38(q,J=6.8Hz,1H),4.37(d,J=7.2Hz,1H),4.28-4.16(m,2H), 3.67(q,J=7.2Hz,2H),3.21(q,J=8.2Hz,1H),2.10-1.99(m,2H),1.86-1.76(m,J=5.2Hz, 2H),1.71-1.64(m,4H),1.59(d,J=6.8Hz,3H),1.27(t,J=7.2Hz,3H)。LC-MS:(ESI)m/z: 368.2[M+H]。
实例4.
2-[4-[4-[(1S)-1-[(2-乙基-1-氧代-3H-吡咯并[3,4-c]吡啶-4-基)氨基]乙基]-2-氟-苯基]-2-吡啶基]-2-甲基-丙腈(69)
根据通用流程C制备此化合物。具体地说,流程如下列出。
流程4:
步骤1. 4-[[(1S)-1-(4-溴-3-氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(C- 2)
在20℃下向4-[[(1S)-1-(4-溴-3-氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮 (C-1,0.05g,0.13mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)- 1,3,2-二氧杂硼戊烷(134mg,0.53mol)于DMSO(2mL)中的混合物中添加KOAc(26 mg,0.26mmol)。将混合物通过N2吹扫3次且添加Pd(dppf)Cl2.CH2Cl2(10.8mg,0.013 mmol)。接着将混合物通过N2再次吹扫3次,且在N2环境下,在100℃下搅拌2h。将反应混合物(与另一批含50mg C-1的二噁烷、另一批含50mg C-1的DMF组合)添加水 (20mL),并用EtOAc(3×20mL)萃取。有机层经收集且用盐水(20mL)洗涤,用Na2SO4干燥,过滤且在真空中浓缩以获得呈棕色油状物的残余物。残余物通过用(石油醚:EtOAc =1:1)洗脱的硅胶上的柱色谱纯化,得到呈棕色胶状物的2-乙基-4-[[(1S)-1-[3-氟-4-(4,4,5,5- 四甲基-1,3,2-二氧杂硼戊环-2-基)苯基]乙基]氨基]-3H-吡咯并[3,4-c]吡啶-1-酮(C-2,0.1g,59.3%产率)。
1H NMR(400MHz,CDCl3)δ:8.18(d,J=5.2Hz,1H),7.71(dd,J=6.8,7.6Hz,1H),7.18 (d,J=7.6Hz,1H),7.09-7.04(m,2H),5.35(t,J=6.8Hz,1H),4.96-4.36(m,1H),4.31-4.17(m, 2H),3.67(dq,J=3.2,7.2Hz,2H),1.35(s,12H),1.30-1.26(m,6H)。LC-MS:(ESI)m/z:426.2 [M+H]。
步骤2. 2-(4-碘-2-吡啶基)-2-甲基-丙酰胺(62a)
将2-(4-碘-2-吡啶基)-2-甲基-丙腈(61b,150mg,0.55mmol.)于浓缩H2SO4(2mL)中的混合物在20℃至25℃下搅拌12h。将混合物倒入水(20mL)中且用饱和NaHCO3溶液调节至pH=8。混合物用EtOAc(3×30mL)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩,得到呈白色固体的2-(4-碘-2-吡啶基)-2-甲基-丙酰胺(62a, 145mg,90.7%产率)。
1H NMR(400MHz,CDCl3)δ:8.25(d,J=5.6Hz,1H),7.80(dd,J=0.4,1.6Hz,1H),7.59 (dd,J=1.6,5.2Hz,1H),6.62(br s,1H),5.32(br s,1H),1.64(s,6H)。LC-MS:(ESI)m/z:290.7 [M+Na]。
步骤3. 2-[4-[4-[(1S)-1-[(2-乙基-1-氧代-3H-吡咯并[3,4-c]吡啶-4-基)氨基]乙基]-2-氟-苯基]-2-吡啶基]-2-甲基-丙酰胺(69)
在氮气环境下,向2-(4-碘-2-吡啶基)-2-甲基-丙酰胺(62a,60mg,0.21mmol)、2-乙基-4-[[(1S)-1-[3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯基]乙基]氨基]-3H-吡咯并 [3,4-c]吡啶-1-酮(C-2,100mg,0.24mmol)和Na2CO3(44mg,0.42mmol)于二噁烷(2 mL)和水(0.5mL)中的混合物中添加Pd(dppf)Cl2.CH2Cl2(9mg,0.011mmol)。将反应物在90℃至100℃下搅拌2h。混合物用EtOAc(20mL)稀释且通过硅藻土过滤。滤液经蒸发,且残余物通过制备型HPLC(柱:DuraShell 150×25mm×5μm;移动相:[水(0.05%氢氧化氨v/v)-ACN];B%:14%至54%,10min)纯化,得到呈白色固体的2-[4-[4-[(1S)- 1-[(2-乙基-1-氧代-3H-吡咯并[3,4-c]吡啶-4-基)氨基]乙基]-2-氟-苯基]-2-吡啶基]-2-甲基-丙酰胺(69,47.2mg,49.5%产率)。
1H NMR(400MHz,CDCl3)δ:8.64(d,J=5.2Hz,1H),8.22(d,J=4.8Hz,1H),7.56(s,1H),7.42(t,J=8.0Hz,1H),7.38-7.34(m,1H),7.30(dd,J=1.6,8.0Hz,1H),7.23(dd,J=1.6, 12.0Hz,1H),7.08(d,J=5.2Hz,1H),6.82(br s,1H),5.45(quin,J=7.2Hz,1H),5.29(br s, 1H),4.44(d,J=7.2Hz,1H),4.32-4.23(m,2H),3.69(q,J=7.2Hz,2H),1.70(s,6H),1.67-1.63 (m,3H),1.30(t,J=7.2Hz,3H)。LC-MS:(ESI)m/z 462.1[M+H]。
合成化合物70至化合物165
一般来说,根据通用流程C制备表3中的化合物70至化合物165。合成方法与实例3或实例4类似。化合物70至化合物139和化合物141至化合物165的数据如下显示在表3 中。
表3.
实例5:
3-[2-[[(1S)-1-(3-氟-4-苯氧基-苯基)乙基]氨基]-4-吡啶基]苯甲腈(166)
根据通用流程D制备此化合物。具体地说,流程如下列出。
流程4:
步骤1. 3-(2-氟吡啶-4-基)苯甲腈(166b)
在氮气环境下向2-氟-4-碘吡啶(166a,1.2g,5.38mmol)于1,2-二甲氧乙烷(20mL)中的溶液中添加(3-氰基苯基)硼酸(166a1,0.87g,5.92mmol)、Pd(PPh3)4(186mg,0.16mmol)和Na2CO3水溶液(2mol/L,6mL)。将反应混合物在80℃下加热12h。反应混合物用乙酸乙酯(100mL)和水(30mL)稀释。分离的水层用乙酸乙酯(2×50mL)萃取。合并的有机层用盐水洗涤,用硫酸钠干燥,过滤且浓缩。残余物用乙酸乙酯(10mL)稀释并搅拌30min。固体通过过滤分离且干燥以获得3-(2-氟吡啶-4-基)苯甲腈(166b,0.69g,产率64.0%)。
1H NMR(400MHz,DMSO-d6)δ:8.41(s,1H),8.37(d,J=5.2Hz,1H),8.23(d,J=8.0Hz, 1H),8.00(d,J=7.6Hz,1H),7.82-7.73(m,2H),7.68(s,1H)。LC-MS:(ESI)m/z:199.1[M+H]。
步骤2. 3-[2-[[(1S)-1-(3-氟-4-苯氧基-苯基)乙基]氨基]-4-吡啶基]苯甲腈(166)
将(S)-1-(3-氟-4-苯氧基苯基)乙胺盐酸盐(166b1,200mg,0.72mmol)添加到饱和NaHCO3溶液(10mL)中,且将混合物在室温下搅拌30min。接着混合物用EtOAc萃取三次。合并的有机层用盐水洗涤,用硫酸钠干燥,过滤且浓缩以获得游离碱(S)-1-(3-氟-4-苯氧基苯基)乙胺,其用于下一步骤。以上游离碱(S)-1-(3-氟-4-苯氧基苯基)乙胺和3-(2-氟吡啶-4-基)苯甲腈(166b,24mg,0.12mmol)经混合且在160℃下加热5h。在冷却到室温之后,粗产物通过制备型TLC纯化以获得3-[2-[[(1S)-1-(3-氟-4-苯氧基-苯基)乙基]氨基]-4-吡啶基] 苯甲腈(166,22mg,产率44.4%)。
1H NMR(400MHz,DMSO-d6)δ:8.18(d,J=5.2Hz,1H),7.76(s,1H),7.69-7.54(m,3H), 7.33-7.24(m,3H),7.14-6.95(m,5H),6.77(dd,J=5.6Hz,1H),6.36(s,1H),5.00-4.87(m,2H), 1.60(d,J=7.6Hz,3H)。LC-MS:(ESI)m/z:410.1[M+H]。
合成化合物167至化合物169
一般来说,表4中的化合物167至化合物169的合成方法与实例5类似。化合物167至化合物169的数据在本文中显示于下表4中。
表4.
实例6:
4-[[(1S)-1-[2,5-二氟-4-[2-(1-氟-1-甲基-乙基)-4-吡啶基]苯基]乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(102)
根据如下列出的流程5制备此化合物。
流程5:
步骤1. 2-(4-溴-2-吡啶基)丙-2-醇(2)
在N2环境下,在0℃至4℃下向4-溴吡啶-2-甲酸甲酯(1,5g,23.14mmol,1当量) 于THF(100mL)中的溶液中逐滴添加MeMgBr(3M,16.20mL,2.1当量)。接着将混合物在20℃至25℃下搅拌0.5hr。TLC(PE/EA=3/1,Rf=0.6)显示反应完成。混合物冷却到0℃至4℃且用饱和NH4Cl溶液(30mL)缓慢淬灭。混合物用水(50mL)稀释,用 EtOAc(50mL×2)萃取,用盐水(100mL)洗涤,用Na2SO4干燥,过滤,浓缩。残余物通过柱色谱(SiO2,石油醚/乙酸乙酯=95/5至85/15)纯化。获得呈淡黄色液体的2-(4-溴- 2-吡啶基)丙-2-醇(2,2.5g,49.99%产率)。
1H NMR(400MHz,CDCl3)δ:8.36(d,J=5.2Hz,1H),7.60-7.59(dd,J=0.4,2.0Hz,1H), 7.40-7.38(dd,J=2.0,5.2Hz,1H),4.57(s,1H),1.56(s,9H)。
步骤2. 4-溴-2-(1-氟-1-甲基-乙基)吡啶(3)
在0℃至4℃下向2-(4-溴-2-吡啶基)丙-2-醇(2,1g,4.63mmol,1当量)于DCM(30mL)中的溶液中逐滴添加DAST(1.12g,6.94mmol,N/A,1.5当量)。接着将混合物在 0℃至4℃下搅拌1.5hr。TLC(PE/EA=3/1,Rf=0.8)显示反应完成。将混合物倒入饱和NaHCO3溶液(100mL)中,用DCM(30mL×2)萃取,用盐水(50mL)洗涤,用Na2SO4干燥,过滤,浓缩。残余物通过柱色谱(SiO2,石油醚/乙酸乙酯=98/2)纯化(LCMS:ES9778- 173-P1MA)。获得呈黄色液体的4-溴-2-(1-氟-1-甲基-乙基)吡啶(3,700mg,69.36%产率)。
1H NMR(400MHz,CDCl3)δ:8.36(d,J=5.2Hz,1H),7.75(t,J=1.2Hz,1H),7.38-7.36 (dd,J=2.0,5.2Hz,1H),1.70(d,J=22.0Hz,6H)。LC-MS:(ESI)m/z:218.1[M+H]+,tR=0.809 min。
步骤3. 4-[[(1S)-1-[2,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯基]乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(2A)
在N2环境下,将4-[[(1S)-1-(4-溴-2,5-二氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮(2B,2g,5.05mmol,1当量)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)-1,3,2-二氧杂硼戊烷(3.20g,12.62mmol,2.5当量)、Pd(dppf)Cl2.CH2Cl2(412.20 mg,504.76μmol,0.1当量)和KOAc(990.76mg,10.10mmol,2当量)于1,4-二噁烷(50mL)中的混合物在100℃下搅拌2小时。LCMS(ES9799-190-P1A)显示4-[[(1S)-1-(4- 溴-2,5-二氟-苯基)乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1-酮完全消耗且所需MS检测到一个主峰。TLC(PE/EtOAc=1/1)显示未检测到新点。去除溶剂以获得减压下的粗产物。粗产物通过硅胶柱(PE/EtOAc=1/1)纯化以获得呈黄色油状物的4-[[(1S)-1-[2,5-二氟-4- (4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯基]乙基]氨基]-2-乙基-3H-吡咯并[3,4-c]吡啶-1- 酮(2A,2.2g,粗制的),其由LCMS确认。LC-MS:(ESI)m/z:444.2[M+H]+,tR=0.817 min。
步骤4. 4-[[(1S)-1-[2,5-二氟-4-[2-(1-氟-1-甲基-乙基)-4-吡啶基]苯基]乙基]氨基]-2-乙基- 3H-吡咯并[3,4-c]吡啶-1-酮(102)
将4-[[(1S)-1-[2,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯基]乙基]氨基]-2- 乙基-3H-吡咯并[3,4-c]吡啶-1-酮(2A,200mg,451.17μmol,1当量)、4-溴-2-(1-氟-1-甲基 -乙基)吡啶(3,130mg,596.15μmol,1.32当量)、Pd(dppf)Cl2.CH2Cl2(37mg,45.31μmol, 0.1当量)、Na2CO3(100mg,943.49μmol,2.09当量)于二噁烷(6mL)和H2O(2mL) 中的混合物脱气并用N2吹扫3次,且接着在N2环境下将混合物在90℃下搅拌1hr。LCMS(ES9778-175-P1LA)显示反应完成。混合物经冷却且经由硅藻土过滤。硅藻土用EtOAc(50mL×2)洗涤。浓缩滤液。残余物通过制备型HPLC(柱:DuraShell 150×25mm×5μm;移动相:[水(0.05%氢氧化氨v/v)-ACN];B%:46%至66%,10min)纯化。获得呈浅黄色固体的4-[[(1S)-1-[2,5-二氟-4-[2-(1-氟-1-甲基-乙基)-4-吡啶基]苯基]乙基]氨基]-2-乙基-3H- 吡咯并[3,4-c]吡啶-1-酮(102,65.9mg,32.14%产率,100%纯度)。
LC-MS:(ESI)m/z:455.1[M+H]+,tR=3.687min。1H NMR(400MHz,MeOD)δ:8.53(d, J=5.2Hz,1H),8.03(d,J=5.2Hz,1H),7.69(s,1H),7.44-7.42(m,1H),7.33-7.24(m,2H),6.87 (d,J=5.2Hz,1H),5.57-5.52(q,J=6.8Hz,1H),4.52-4.41(m,2H),3.70-3.64(q,J=7.2Hz, 2H),1.68(d,J=22Hz,6H),1.60(d,J=7.2Hz,3H),1.30(t,J=7.2Hz,3H)。
生物检定
测试1:野生型IDH蛋白和突变型IDH蛋白的纯化
IDH1蛋白和IDH2蛋白的纯化
本公开提供用于在大肠杆菌中表达和纯化突变型和野生型重组IDH1和IDH2蛋白的方法。
将含有编码全长野生型或突变型IDH1蛋白(IDH1-R132H或IDH1-R132C)、缺失第一个N端40个氨基酸残基的部分IDH2蛋白、野生型或突变型(IDH2-R140Q或IDH2- R172K)的cDNA序列的pSJ3质粒转化到BL21菌株中,且IDH蛋白在0.5mM IPTG存在下在16℃下过夜表达。通过使用与表达蛋白稠合的六个串联组氨酸标签,IDH蛋白经由 Ni Sepharose 4B(购自GE生命科学(GE Lifescience))如用户手册中所描述而纯化。通过使用Amicon 3,000DaMWCO过滤器单元将洗脱的蛋白浓缩到TBS缓冲液中,并将最终蛋白产物在-80℃下存储在含有10%甘油的TBS溶液中。通过上海生工(Shanghai Sangon) 的布拉德福(Bradford)试剂盒进行蛋白浓度的定量。
测试2:化合物的IDH抑制和选择性的生物化学检定
本公开提供一种通过直接检测IDH酶活性而检测化合物的IDH抑制和选择性的生物化学检定方法。
图1显示由野生型和突变型IDH1/2催化的反应。在催化α-KG生成反应时,野生型IDH酶将NADP+转化为NADPH。在催化D-2-HG生成反应时,突变型IDH酶将NADPH 转化为NADP+。因此,野生型和突变型IDH1/2的活性可通过监测NADPH水平变化来测量,因为NADPH为萤光的(激发340nm,发射460nm)。通过监测反应中的NADPH水平的变化,可快速且有效地确定酶活性,还可检定化合物的IC50。
将测试化合物制备到DMSO中的50mM储备溶液中且在-20℃下存储。将每一测试化合物储备液进一步稀释以获得浓度分别为400μM、200μM、100μM、50μM、25μM、12.5 μM、6.25μM和3.125μM的100×储备溶液,以用于测试当天的最终用途(可调节100×储备溶液的浓度范围以覆盖特定测试化合物的所估计IC50)。
野生型IDH1的抑制:
为建立由野生型IDH1蛋白将异柠檬酸催化成α-KG的反应,纯化的野生型IDH1蛋白首先在20mM Tris-HCl pH7.5、150mM NaCl、10mM MgCl2、1mM DTT、0.05mg/ml BSA 和107μM异柠檬酸盐中稀释成2.7nM。将148μL 2.7nM野生型IDH1蛋白溶液与2μL DMSO(测试化合物的媒剂对照)或上述测试化合物的100×储备溶液混合,并在室温下培育1小时。含有148μL无酶溶液(20mM Tris-HCl pH7.5、150mM NaCl、10mM MgCl2、 1mM DTT、0.05mg/ml BSA和107μM异柠檬酸盐)和2μL DMSO的额外反应也设置为背景对照。接着通过添加在20mM Tris-HCl pH7.5、150mM NaCl、10mM MgCl2、1mM DTT和0.05mg/ml BSA中制备的50μL 200μM NADP+溶液来引发每一反应。BioTek Synergy H1微板读数仪(伯腾仪器公司(BioTekInstruments Inc.),美国威努斯基(Winooski, U.S.))用于监测每42秒NADPH荧光(激发340nm,发射460nm)15分钟。NADPH变化率根据荧光-时间曲线的线性相位而确定,且背景对照反应的结果用作背景减法以计算其它反应的净NADPH变化率。来自媒剂对照反应的净NADPH变化率用作100%酶活性,且因此可确定添加测试化合物的反应的相对酶活性。接着针对每一测试化合物绘制剂量反应曲线并计算对应IC50。IC50值用于评估每一测试化合物对IDH酶活性的抑制和选择性。
突变型IDH1(R132H或R132C)的抑制:
为了检定突变型IDH1蛋白的酶活性,在20mM Tris-HCl pH7.5、150mM NaCl、10 mMMgCl2、1mM DTT、0.05mg/ml BSA和1.33mMα-KG中制备25nM IDH1-R132C或 50nM IDH1-R132H蛋白溶液。将148μL 25nM IDH1-R132C或50nM IDH1-R132H蛋白溶液与2μL DMSO(测试化合物的媒剂对照)或上述测试化合物的100×储备溶液混合,并在室温下培育1小时。含有148μL无酶溶液(20mM Tris-HCl pH7.5、150mM NaCl、10 mM MgCl2、1mM DTT、0.05mg/mlBSA和1.33mMα-KG)和2μL DMSO的额外反应也设置为背景对照。接着通过添加在20mM Tris-HCl pH7.5、150mM NaCl、10mM MgCl2、 1mM DTT和0.05mg/ml BSA中制备的50μL 80μMNADPH溶液来引发每一反应。BioTek Synergy H1微板读数仪(伯腾仪器公司(BioTekInstruments Inc.),美国威努斯基(Winooski, U.S.))用于监测每42秒NADPH荧光(激发340nm,发射460nm)15分钟。NADPH变化率根据荧光-时间曲线的线性相位而确定,且背景对照反应的结果用作背景减法以计算其它反应的净NADPH变化率。来自媒剂对照反应的净NADPH变化率用作100%酶活性,且因此可确定添加测试化合物的反应的相对酶活性。接着针对每一测试化合物绘制剂量反应曲线并计算对应IC50。IC50值用于评估每一测试化合物对IDH酶活性的抑制和选择性。
测试3:化合物的IDH抑制和选择性的基于细胞的检定
本公开还提供一种基于细胞的方法,其用于检定化合物在人纤维瘤细胞系HT1080和胆管癌细胞系HCCC 9810中的IDH抑制和选择性,其分别具有内源性杂合IDH1 R132C 和R132H突变并累积D-2-HG。肿瘤衍生的IDH突变体失去其正常的产生α-KG的活性,并获得了产生D-2-HG的新活性。D-2-HG是一种在表达突变型IDH1或IDH2蛋白的肿瘤细胞中特别地增多的代谢物。在用有效IDH抑制剂治疗这种突变型IDH表达肿瘤细胞时, D-2-HG的合成被阻断,且D-2-HG浓度通过内源性D-2-HG脱氢酶催化的氧化反应降低。因此,本公开的化合物的IDH抑制活性和选择性可以通过细胞代谢物中的D-2-HG的降低来检定。
为了执行基于细胞的IDH抑制检定,将HT1080和HCCC 9810细胞(或其它具有不同IDH突变的细胞系)在补充有10%FBS的DMEM中培养。用各种不同浓度的本公开的化合物处理细胞。处理16小时后,去除培养基上清液,且用40%甲醇和40%乙腈水溶液 (预冷于-80℃)在4℃下萃取细胞代谢物1小时。收集所萃取上清液并经由高速离心去除细胞碎片。在Agilent LC-MS系统(型号:1290-6470)上分析所得代谢物萃取物的2-HG 和谷氨酸浓度。在HPLC上采用HILIC-Z柱(2.1mm×100mm,2.7μm)。移动相A为15 mM CH3COONH4和0.3%NH3·H2O水溶液。移动相B为90%MeCN/10%H2O溶剂中的15 mM CH3COONH4和0.3%NH3·H2O。使用19%溶剂A和81%溶剂B等度梯度法,流速为 0.3ml/min。D-2-HG在负离子喷雾模式下电离,且通过对m/z=147.0/128.9和147.0/85.1的质量跃迁对的多反应监测而进行检测。谷氨酸在离子喷雾模式下电离,且在m/z=146/102 和146/128的质量跃迁对的负极性多反应监测中检测到,且其水平用于标准化2-HG浓度。在不同浓度的每一测试化合物存在的情况下,细胞突变型IDH蛋白的活性可以由相对于阴性对照样品的D-2-HG浓度表示(即,细胞仅用DMSO处理),并且可以确定IC50值以评估每一测试化合物对IDH酶活性的抑制和选择性。
测试4:肝微粒体中的代谢稳定性检定
小鼠、大鼠(来自Xenotech)、狗、猴和人(来自康宁公司(Corning Inc.))的肝微粒体用于测试化合物的活体外代谢稳定性。所有肝微粒体在使用前在-60℃下存储。睾酮、双氯芬酸和普罗帕酮用作对照。
测试化合物或对照化合物中的每一者与0.5mg·mL-1小鼠、大鼠、狗、猴或人肝微粒体在PBS(100mM,pH 7.4)中与3mM MgCl2在37℃水浴中在1μM的预设初始浓度下共培育。通过将NADPH添加到1mM的最终浓度来引发反应。每一反应混合物的最终体积为0.2ml,且所有反应重复执行两次。在每一设定的时间点(0min、5min、15min、30min 和60min),将一小部分(例如,20μl)从反应系统转移到含有乙腈的冰冷内标(IS)中以淬灭反应并沉淀蛋白。在以3700rpm涡旋和离心10min后,将上清液注入LC-MS/MS以进行分析。
活体外微粒体清除率是基于确定每一化合物从其初始浓度消失的消除半衰期(T1/2)来估计的。计算每一化合物(测试或对照)与IS的峰面积比。标绘Ln(对照%)相对于培育时间(分钟)的曲线,且计算线性拟合线的斜率。药物消除速率常数k(min-1)、T1/2(分钟)和活体外内在清除率CLint(mL·min-1·mg-1蛋白)是根据以下等式计算:
k=-斜率
T1/2=0.693/k
CLint=k/Cprotein
其中Cprotein(mg·mL-1)为培育系统中的微粒体蛋白浓度。
测试5:活体内药物动力学检定
可经由经口或静脉内施用在ICR小鼠(雄性,6至8周,20.0至25.3g)中评估本公开的化合物的药物动力学特性。
ICR小鼠购自维通利华实验技术有限公司(Vital River Laboratory TechnologyCo.,Ltd.) (中国北京(Beijing,China)),饲养在带有无菌垫料的实心聚丙烯笼子中,保持在具有40%至70%湿度、20℃至25℃、10至20换气次数/小时的房间中,且在除研究活动需要中断以外的12小时明暗循环。给小鼠喂食来自上海SLAC实验动物有限公司(ShanghaiSLAC Laboratory Animal Co.,Ltd.)(中国上海(Shanghai,China))的无菌饲料和无菌水。所有动物在收到时都会接受检查并适应至少3天。根据整体健康状况、体重或其它适当的相关数据,仅选择看起来健康的那些进行研究。每一组中的个别动物由耳凹口识别。
小鼠在给药前禁食过夜,但始终可以自由饮水。给药前,对每只小鼠称重,并使用以下公式计算每只小鼠的实际剂量体积:
剂量体积(mL)=[标称剂量(mg·kg-1)/剂量浓度(mg·mL-1)]×动物体重(kg)
相应地记录实际体重和实际剂量体积。
对于每一测试组,使用九只小鼠,且不同组的小鼠分别以10mg·kg-1的单次口服剂量的测试化合物或2mg·kg-1的单次静脉内剂量的测试化合物给药。在预先确定的时间点,例如给药前或给药后5min、15min、30min、1h、2h、4h、8h、12h和24h,对血液样品进行取样并收集到含有EDTA-K2的试管中。在三个不连续时间点收集每只小鼠的血液样品,且每个时间点对三只小鼠进行取样。将收集的样品以5500rpm离心10min以获得血浆样品,随后通过LC-MS/MS对其进行分析。通过线性回归分析处理血浆中药物浓度对时间的数据。使用WinNonlin 8.0的非隔室模型计算所有药物动力学参数。
测试6:抑制IDH突变型细胞的锚定非依赖性生长
众所周知,不依赖锚定的细胞生长是癌细胞的基本特性。锚定非依赖性生长的能力与活体内肿瘤细胞的致瘤和转移潜能密切相关。
以前的工作表明,HT1080细胞中的突变型IDH1的缺失(具有内源性IDH1-R132C突变)对正常培养条件下的细胞增殖影响不大,但强烈抑制HT1080细胞的锚定非依赖性生长[“D-2-羟戊二酸对于维持含有突变型IDH的癌细胞的致癌特性至关重要,但对细胞生长为非必需的(D-2-hydroxyglutarate is essential for maintaining oncogenic propertyof mutant IDH-containing cancer cells but dispensable for cell growth)”,马(Ma),S.等人,《肿瘤靶点(Oncotarget)》,(2015)]。由于IDH1突变体经由2-HG促进肿瘤发生,因此锚定非依赖性生长(在软琼脂中形成细胞集落)也可用作一种方便且有价值的活体外检定以用于测量化合物在肿瘤抑制中的活性。
将具有内源性IDH1-R132X突变的肿瘤细胞系,例如HT1080(含有IDH1-R132C突变)或HCCC9810(含有IDH1-R132H突变)细胞接种在适当培养基(例如针对HT1080细胞或HCCC9810细胞具有10%FBS的DMEM)中的0.35%琼脂(顶部琼脂层)中,其中测试化合物或DMSO在适当培养基(例如针对HT1080细胞或HCCC9810细胞具有10% FBS的DMEM)中的0.65%琼脂的层(底部琼脂层)之上。在顶部琼脂层上方,添加具有测试化合物或DMSO的适当介质(例如,针对HT1080细胞或HCCC9810细胞具有10% FBS的DMEM)以保持琼脂层的水分。顶部琼脂层或上述介质中的测试化合物的最终浓度通常高于HT1080细胞中测试的IC50值。琼脂中的细胞将培养约4周,并且每周更换顶部琼脂层上方的具有测试化合物或DMSO的介质。在实验结束时,软琼脂板用结晶紫染色,且细胞集落在显微镜下成像以进行定量。具有测试化合物和DMSO的板之间的集落数的差反映了测试化合物对IDH突变型细胞的锚定非依赖性生长的抑制作用。
测试7:抑制HT1080异种接枝的小鼠肿瘤中的IDH突变体
为了测试测试化合物对肿瘤中的IDH突变体的抑制作用,首先将HT1080细胞皮下接种到BALB/c裸鼠中(每只小鼠五百万个HT1080细胞)。当HT1080肿瘤体积达到约200mm3时,将小鼠随机分组,且每组小鼠口服测试化合物。在给药前或给药后2小时、4小时、8 小时、12小时和24小时等不同时间点处死一组小鼠以供取血和HT1080肿瘤组织。在均质化和萃取后,通过LC-MS/MS确定肿瘤组织中的2-HG水平,且计算给药后不同时间点处的测试化合物对HT1080肿瘤中产生2-HG的IDH1-R132C突变型活性的抑制比率。
工作实例
实例1:化合物抑制IDH1 R132H和IDH1 R132C的活性
根据生物检定部分的测试2评估化合物的IDH抑制活性。对每一化合物的突变型IDH1 R132H和IDH1 R132C抑制的测试以三重态方式进行。代表性化合物对IDH1 R132H和IDH1 R132C的IC50值显示于表5中。如表5中所使用,“A”是指在IC50<0.1μM的情况下的对IDH1 R132H或IDH1 R132C的抑制活性;“B”是指在IC50为0.1μM至0.5μM的情况下的对IDH1R132H或IDH1 R132C的抑制活性;“C”是指在IC50为0.5μM至1μM 的情况下的对IDH1 R132H或IDH1 R132C的抑制活性;“D”是指在IC50>1μM的情况下的对IDH1 R132H或IDH1 R132C的抑制活性。
表5.代表性式(I)化合物的IDH1抑制活性
根据表5,其显示本公开的化合物展现对突变型IDH1的良好抑制。
实例2:化合物抑制基于细胞的检定中的IDH的活性
根据生物检定部分的测试3,在人纤维瘤细胞系HT1080中评估化合物的IDH抑制活性。对每一化合物的IDH抑制的测试以三重态方式进行。代表性化合物对IDH的IC50值显示于表6中。如表6中所使用,“A”是指在IC50<0.1μM的情况下的IDH抑制活性;“B”是指在IC50为0.1μM至0.5μM的情况下的IDH抑制活性;“C”是指在IC50为0.5 μM至1μM的情况下的IDH抑制活性;“D”是指在IC50>1μM的情况下的IDH抑制活性。
表6.基于细胞的检定中的代表性式(I)化合物的IDH抑制活性
如表6中所显示,本公开的化合物还展现基于细胞的检定中的对突变型IDH1的良好抑制。
上述描述仅被视为本公开的原理的说明。此外,由于许多修改和变化对于所属领域的技术人员来说将显而易见,所以并不期望将本发明限于如上文所描述而展示的确切构造和过程。因此,所有合适的修改和等效方案可以被视为属于由所附权利要求书限定的本发明的范围内。
词语“包括(comprise、comprising、include、including和includes)”在用于本说明书中和以下权利要求书中时预期指定所陈述的特征、整数、组件或步骤的存在,但其并不排除一个或多个其它特征、整数、组件、步骤或其群组的存在或添加。
序列表
<110> 浙江迈同生物医药有限公司
<120> 异柠檬酸脱氢酶(IDH)抑制剂
<130> 066521-8003CN01
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<170> PatentIn version 3.5
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<213> 智人
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Claims (31)
1.一种式(I)化合物:
或其药学上可接受的盐,其中:
Z1和Z2独立地选自C和N;
X选自由以下组成的组:芳基、杂芳基或饱和或部分不饱和杂环基,所述芳基、杂芳基或饱和或部分不饱和杂环基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、烷氧基、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基;
Y选自由以下组成的组:空、键、-CR5R6-、-O(CH2)n-、-N(Ra)-、-S-、-S(=O)-、-S(=O)2-、-C(O)-和-C(O)N(Rb)-;
W选自由以下组成的组:空、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个R7取代;
R1选自由以下组成的组:烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基和烷氧基;
R2选自由以下组成的组:卤素、羟基、氰基和硝基;
R3选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
R4选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、烷氧基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、氰基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基;
R7独立地选自由以下组成的组:卤素、羟基、氰基、硝基、烷氧基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基、-NRcRd和-C(O)Re,其中所述烷氧基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、烷基、卤代烷基、烷氧基、饱和或部分不饱和环烷基、-C(O)N(Rc)(Rd);
Ra、Rb、Rc和Rd各自独立地选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
Re选自由以下组成的组:烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基;
m为0、1或2;且
n为0、1或2。
2.根据权利要求1所述的式(I)化合物或其药学上可接受的盐,其中Z1为N。
3.根据权利要求1或2所述的式(I)化合物或其药学上可接受的盐,其中Z2为C。
4.根据权利要求1或2所述的式(I)化合物或其药学上可接受的盐,其中Z2为N。
5.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中X为芳基、杂芳基或饱和或部分不饱和杂环基,其中的每一者任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基和烷基。
6.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中X选自由以下组成的组:被卤素取代的芳基、未被取代的杂芳基、被卤素取代的杂芳基、被烷基取代的杂芳基或被卤素取代的饱和或部分不饱和杂环基。
7.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中Y选自由以下组成的组:键、-CR5R6-、-O(CH2)n-、-N(Ra)-、-C(O)-和-C(O)N(Rb)-。
8.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中W为空、3至10元饱和或部分不饱和环烷基、3至10元饱和或部分不饱和杂环基、3至10元芳基和3至10元杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个R7取代。
10.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中R1选自由以下组成的组:烷基、烯基和炔基,其中所述烷基、烯基和炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基和烷氧基。
11.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中R2为卤素。
12.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中R3选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
13.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中R4选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
14.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、氰基、烷基、烯基、炔基、杂烷基、杂烯基、杂炔基、饱和和部分不饱和环烷基、饱和和部分不饱和杂环基、芳基和杂芳基。
15.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中R7选自由以下组成的组:卤素、羟基、氰基、烷氧基、烷基、烯基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基、-NRcRd和-C(O)Re,其中所述烷氧基、烷基、烯基、卤代烷基、饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基、杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、烷基、卤代烷基、烷氧基、饱和或部分不饱和环烷基、-C(O)N(Rc)(Rd)。
16.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中Ra、Rb、Rc和Rd各自独立地选自由以下组成的组:氢、烷基、烯基、炔基、杂烷基、杂烯基和杂炔基,其中所述烷基、烯基、炔基、杂烷基、杂烯基和杂炔基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
17.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中Re选自由以下组成的组:饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基、芳基和杂芳基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、羟基、氰基、硝基、羧基、氨甲酰基、烷基、烯基、炔基和烷氧基。
18.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中m为0或1。
19.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中n为0或1。
25.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中Y为键或-O-。
26.根据前述权利要求所述的式(I)化合物或其药学上可接受的盐,其中W选自由以下组成的组:饱和或部分不饱和环烷基、饱和或部分不饱和杂环基和杂芳基,其中所述饱和或部分不饱和环烷基、饱和或部分不饱和杂环基和杂芳基任选地被一个或多个R7取代,其中R7独立地选自由以下组成的组:卤素、烷氧基、烷基、烯基、卤代烷基和饱和或部分不饱和环烷基,其中所述烷氧基、烷基、烯基、卤代烷基和饱和或部分不饱和环烷基任选地被一个或多个独立地选自由以下组成的组的基团取代:卤素、卤代烷基和烷氧基。
27.根据前述权利要求中任一项所述的化合物或其药学上可接受的盐,其中所述化合物选自由以下组成的组:
(S)-2-乙基-4-((1-(3-氟-4-((1-甲基-1H-吲唑-5-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-甲基-1H-吲哚-4-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-甲基-1H-吲哚-5-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-甲基-1H-吡唑-4-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-((2,3-二氢-1H-茚-2-基)氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((1S)-1-(4-((2,3-二氢-1H-茚-1-基)氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-((6-(叔丁基)吡啶-3-基)氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-异丙基-1H-吲哚-5-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-(2-羟乙基)-1H-吲哚-5-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-((1,2-二甲基-1H-吲哚-5-基)氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(R)-2-乙基-4-((1-(3-氟-4-苯氧基苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(吡啶-3-基氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(环己氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(环戊氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(3-氟-4-(对甲苯氧基)苯基)乙基)氨基)-2-(2-氟乙基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-(2,2-二氟乙基)-4-((1-(3-氟-4-(对甲苯氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-7-氟-4-((1-(3-氟-4-(对甲苯氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(环戊氧基)-3-氟苯基)乙基)氨基)-2-乙基-7-氟-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(对甲苯氧基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-((1-甲基-1H-吲哚-5-基)氧基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((1S)-1-(2,5-二氟-4-((3,3,5-三甲基环己基)氧基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((S)-1-(2,5-二氟-4-(((1R,5S)-3,3,5-三甲基环己基)氧基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((S)-1-(2,5-二氟-4-(((1S,5S)-3,3,5-三甲基环己基)氧基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-((2-(叔丁基)吡啶-4-基)氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((1S)-1-(4-((3,3-二氟环戊基)氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(氮杂环丁烷-3-基甲氧基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((1-甲基吲哚啉-5-基)氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(喹啉-4-基氧基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(甲基(苯基)氨基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(苯基氨基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(2-氟-4'-(三氟甲基)-[1,1'-联苯基]-4-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(2-(三氟甲基)吡啶-4-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(1-(叔丁基)-1,2,3,6-四氢吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(1-(叔丁基)哌啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-(2,2-二氟乙基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-(1,3-二氟丙-2-基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((S)-1-(4-(2-(叔丁基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-(2,3-二氟丙基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((S)-1-(4-(2-(叔丁基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-((R)-1-氟丙-2-基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,4'-二氟-3'-甲基-[1,1'-联苯基]-4-基)乙基)氨基)-2-乙基-7-氟-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-2,3-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-3,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4'-(叔丁基)-3-氟-[2,2'-联吡啶]-5-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(4-甲基-2'-(三氟甲基)-[3,4'-联吡啶]-6-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2'-(叔丁基)-[3,4'-联吡啶]-6-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(5-苯基嘧啶-2-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(5-(4-氟-3-甲基苯基)嘧啶-2-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(5-(2-氟-3-甲基苯基)嘧啶-2-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(5-(4-甲氧基苯基)嘧啶-2-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(4-氟-3-甲基苄基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-苄基-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-((2-(三氟甲基)吡啶-4-基)甲基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(5-(4-氟-3-甲基苄基)嘧啶-2-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-((4,4-二氟哌啶-1-基)甲基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(1-(2-(叔丁基)吡啶-4-基)-1H-咪唑-4-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-7-氟-4-((1-(1-(4-氟苯基)-1H-咪唑-4-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(R)-4-((1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(3-甲基-1H-吡唑-1-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-苯甲酰基-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-烟碱酰基苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-氯-N-环己基-4-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)苯甲酰胺;
(S)-4-((1-(2-(叔丁基)-5-氟吡啶-4-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-6-氯-3-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)喹啉-2(1H)-酮;
(S)-6-乙基-4-((1-(3-氟-4-(对甲苯氧基)苯基)乙基)氨基)-5H-吡咯并[3,4-d]嘧啶-7(6H)-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-3-氟苯基)乙基)氨基)-6-乙基-5H-吡咯并[3,4-d]嘧啶-7(6H)-酮;
(S)-4-((1-(2,4'-二氟-3'-甲基-[1,1'-联苯基]-4-基)乙基)氨基)-6-乙基-5H-吡咯并[3,4-d]嘧啶-7(6H)-酮;
(S)-4-((1-(4-环戊基-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-(4-(4-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)-2-氟苯基)吡啶-2-基)-2-甲基丙酰胺;
(S)-2-乙基-4-((1-(3-氟-4-(喹啉-4-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(1-甲基-1H-吲哚-5-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(2-氟-4'-甲基-[1,1'-联苯基]-4-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,4'-二氟-[1,1'-联苯基]-4-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(6-(三氟甲基)吡啶-3-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2,6-二甲基吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-环丁基吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(2-(1-羟基环丁基)吡啶-4-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(环丙基甲基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(2-氟-[1,1'-联苯基]-4-基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,4'-二氟-3'-甲基-[1,1'-联苯基]-4-基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(5-甲基吡啶-2-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-乙基-4-((1-(3-氟-4-(1-甲基-1H-吡唑-3-基)苯基)乙基)氨基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-(4-(4-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)-2-氟苯基)吡啶-2-基)-2-甲基丙腈;
4-(((1S)-1-(4-(2-(环丙基(羟基)甲基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(环丙烷羰基)吡啶-4-基)-3-氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(三氟甲基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-环丁基吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-环丙基吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(环丙基甲基)吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(1-甲基-1H-吡咯-3-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(氧杂环丁烷-3-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(3-羟基氧杂环丁烷-3-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-氯吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2'-氯-[2,4'-联吡啶]-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(3,3-二氟环丁基)吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-苯基吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-([2,3'-联吡啶]-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(5'-氯-[2,3'-联吡啶]-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-环戊基吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(2-氟丙-2-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(2-羟基丙-2-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)-5-氟吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(1,1,1-三氟-2-甲基丙-2-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(1,1-二氟乙基)吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(全氟乙基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(4-(叔丁基)吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(5-(叔丁基)吡啶-3-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(6-(叔丁基)嘧啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)嘧啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-6-甲基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-(4-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)-2,5-二氟苯基)异烟碱腈;
(S)-4-((1-(2,5-二氟-4-(4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)-5-甲氧基吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(6-(叔丁基)-3-甲氧基吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-(氟甲基)-4-(2-氟丙-2-基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-氟-4-(2-氟丙-2-基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-6-甲氧基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(6-氯-4-(三氟甲基)吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-甲基-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-(氟甲基)-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(1-(三氟甲基)环丙基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S,E)-4-((1-(2,5-二氟-4-(4-(1,1,1-三氟丁-2-烯-2-基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
4-(((1S)-1-(2,5-二氟-4-(4-(5-(三氟甲基)-4,5-二氢-1H-吡唑-5-基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-5-甲基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(4-(叔丁基氨基)-6-甲基吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(4-(叔丁氧基)-6-甲基吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-(2-氟丙-2-基)嘧啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(1-氟环丙基)-6-甲基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(2-(2-氟丙-2-基)-5-甲氧基吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-氟-4-(2-氟丙-2-基)-6-甲基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(3-氟-4-(2-氟丙-2-基)-6-甲基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-5-甲氧基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(5-氯-4-(2-氟丙-2-基)吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-氟-4-(2-氟丙-2-基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)-5-羟基吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-(氟甲基)-2-(2-氟丙-2-基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-(2-氟丙-2-基)-2-甲氧基嘧啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-甲氧基-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-甲氧基-2-(三氟甲基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-羟基-2-(三氟甲基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-(甲氧基甲氧基)-2-(三氟甲基)吡啶-4-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(1,1-二甲基-1,3-二氢呋喃并[3,4-c]吡啶-6-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-5-(甲氧基甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-5-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(6-(叔丁基)-5-甲氧基吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(4-(叔丁基)-5-甲氧基吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁氧基)-5-甲基吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(4-(叔丁氧基)-5-氯吡啶-2-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(5-(2-氟丙-2-基)-6-甲氧基哒嗪-3-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-2-(4-(4-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)-2,5-二氟苯基)吡啶-2-基)-2-甲基丙腈;
(S)-4-((1-(2,5-二氟-4-(6-氟-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-6-羟基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(6-羟基-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-(2-甲氧基乙基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(2-(叔丁基)吡啶-4-基)-2,5-二氟苯基)乙基)氨基)-2-(2-羟乙基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(4-(1-(叔丁基)-1H-咪唑-4-基)-2,5-二氟苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-5-(甲氧基甲氧基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-4-((1-(2,5-二氟-4-(4-(2-氟丙-2-基)-5-羟基吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;
(S)-6-(4-(1-((2-乙基-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)乙基)-2,5-二氟苯基)-4-(2-氟丙-2-基)烟碱腈;
(S)-4-((1-(2,5-二氟-4-(5-羟基-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮;以及
(S)-4-((1-(2,5-二氟-4-(5-甲氧基-4-(三氟甲基)吡啶-2-基)苯基)乙基)氨基)-2-乙基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮。
28.一种药物组合物,其包含根据前述权利要求中任一项所述的式(I)化合物或其药学上可接受的盐,和至少一种药学上可接受的赋形剂。
29.一种治疗特征在于患者中的D-2-HG累积的疾病的方法,其包括向个体施用治疗有效量的根据权利要求1至27中任一项所述的式(I)化合物或其药学上可接受的盐或根据权利要求28所述的药物组合物,其中所述疾病优选地为癌症。
30.一种抑制α-KG转化为D-2-HG的方法,其通过使用根据权利要求1至27中任一项所述的式(I)化合物或其药学上可接受的盐或根据权利要求28所述的药物组合物进行。
31.一种抑制突变型IDH、野生型IDH或上述两者的方法,其通过使用根据权利要求1至27中任一项所述的式(I)化合物或其药学上可接受的盐或根据权利要求28所述的药物组合物进行。
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WO2016171755A1 (en) * | 2015-04-21 | 2016-10-27 | Forma Therapeutics, Inc. | Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors |
WO2018010637A1 (en) * | 2016-07-14 | 2018-01-18 | Shanghai Meton Pharmaceutical Co., Ltd | Iso-citrate dehydrogenase (idh) inhibitor |
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WO2010139953A1 (en) * | 2009-06-04 | 2010-12-09 | Xention Limited | Compounds |
WO2016171755A1 (en) * | 2015-04-21 | 2016-10-27 | Forma Therapeutics, Inc. | Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors |
WO2018010637A1 (en) * | 2016-07-14 | 2018-01-18 | Shanghai Meton Pharmaceutical Co., Ltd | Iso-citrate dehydrogenase (idh) inhibitor |
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