CN113307794A - 1,3,5-三嗪衍生物及其使用方法 - Google Patents
1,3,5-三嗪衍生物及其使用方法 Download PDFInfo
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- CN113307794A CN113307794A CN202110544440.3A CN202110544440A CN113307794A CN 113307794 A CN113307794 A CN 113307794A CN 202110544440 A CN202110544440 A CN 202110544440A CN 113307794 A CN113307794 A CN 113307794A
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- Prior art keywords
- alkyl
- cycloalkyl
- phenyl
- hydroxy
- substitution
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- 238000000034 method Methods 0.000 title description 26
- 125000003363 1,3,5-triazinyl group Chemical class N1=C(N=CN=C1)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 claims abstract description 40
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 claims abstract description 37
- 230000035772 mutation Effects 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- -1 C2-6Alkenyl radical Chemical class 0.000 claims description 56
- 238000006467 substitution reaction Methods 0.000 claims description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 150000003254 radicals Chemical class 0.000 claims description 9
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 20
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
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- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- FNYGWXSATBUBER-UHFFFAOYSA-N n-cyclohexyl-2-(3-fluoro-n-[2-(2-methylimidazol-1-yl)acetyl]anilino)-2-(2-methylphenyl)acetamide Chemical compound CC1=NC=CN1CC(=O)N(C=1C=C(F)C=CC=1)C(C=1C(=CC=CC=1)C)C(=O)NC1CCCCC1 FNYGWXSATBUBER-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 description 4
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 150000000182 1,3,5-triazines Chemical class 0.000 description 3
- CCAWRGNYALGPQH-UHFFFAOYSA-N 1-[5-(cyclopropylsulfamoyl)-2-thiophen-3-ylphenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC=CC(NC(=O)NC=2C(=CC=C(C=2)S(=O)(=O)NC2CC2)C2=CSC=C2)=C1 CCAWRGNYALGPQH-UHFFFAOYSA-N 0.000 description 3
- GSSCQXYNRDFGAV-UHFFFAOYSA-N 2,4-dichloro-6-[6-(trifluoromethyl)pyridin-2-yl]-1,3,5-triazine Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(Cl)N=C(Cl)N=2)=N1 GSSCQXYNRDFGAV-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本申请涉及通式Ⅱ的化合物或其药学上可接受的盐或水合物、其制备方法及其药物组合物。所述通式Ⅱ的化合物具有异柠檬酸脱氢酶2(IDH2)抑制活性,能治疗IDH2突变诱发的癌症。
Description
本申请是基于申请日为2016年07月29日,申请号为201680043893.5,发明名称为“1,3,5-三嗪衍生物及其使用方法”的申请的分案申请。
相关申请的引用
本申请要求于2015年07月30日向中华人民共和国国家知识产权局提交的第201510459126.X号中国发明专利申请的权益,在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及医药领域,更具体而言涉及1,3,5-三嗪衍生物及其使用方法。
背景技术
IDH全称异柠檬酸脱氢酶,是细胞内三羧酸循环过程中最主要的关键酶,它们能够催化异柠檬酸氧化脱羧生成2-氧化戊二酸酯(即,a-酮戊二酸)。研究发现多种肿瘤(如神经胶质瘤、肉瘤、急性粒细胞白血病等)存在IDH突变,突变位点是位于催化中心的精氨酸残基(IDH1/R132H、IDH2/R140Q、IDH2/R172K)。突变后的IDH获得一种新的能力,即催化a-酮戊二酸(a-KG)转化为2-羟基戊二酸(2-HG)。研究表明,a-酮戊二酸与2-羟基戊二酸的结构相似,2-HG与a-KG竞争,由此降低了a-KG依赖性酶的活性,导致染色质高度甲基化,这种超甲基化被认为干扰了正常的细胞分化,导致未成熟细胞过度增殖,从而引发癌症。
2013年Agios Pharmaceuticals报道了IDH2/R140Q抑制剂AGI-6780(Science.2013,340,622-626)和IDH1/R132H抑制剂AGI-5198(Science.2013,340,626-630),以及WO2015017821公开了另一种IDH2/R140Q抑制剂AG-221。AGI-6780和AGI-5198能够分别抑制携带最常见IDH2和IDH1突变体的细胞中2-HG的生成。除能抑制2-HG生成,这些分子还诱导了培养物中异常增殖的人类癌细胞的分化。用AGI-6780治疗携带IDH2突变体的白血病细胞,用AGI-5198治疗携带IDH1突变体的神经胶质瘤细胞,均导致细胞中的成熟标记物表达增高。此外,研究人员证实不论是用AGI-5198处理细胞培养物,还是口服给药肿瘤移植小鼠,AGI-5198均可抑制神经胶质瘤细胞生长速率。
发明内容
一方面,本申请提供通式Ⅰ的化合物或其药学上可接受的盐或水合物:
其中,
环A选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环;
X1选自NH或O;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、含有1-2个选自N、O或S的杂原子的5-6元杂芳基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
R4和R5独立地选自H、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1,2或3。
另一方面,本申请提供通式Ⅱ的化合物或其药学上可接受的盐或水合物:
其中,
X1选自NH或O;
X2选自N或CH;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、CF3、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1,2或3。
另一方面,本申请提供了药物组合物,其包含治疗有效量的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。
另一方面,本申请提供了治疗由IDH2突变诱发的癌症的方法,所述方法包括给予有需要的个体通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
另一方面,本申请提供了通式Ⅰ或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
另一方面,本申请提供了用于治疗由IDH2突变诱发的癌症的通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
在本申请的一些实施方案中,所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
发明详述
在以下的说明中,包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而,相关领域的技术人员会认识到,不采用一个或多个这些具体的细节,而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求,在整个说明书和其后的权利要求书中,词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义,即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此,在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外,具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解,在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象,除非文中另外明确地规定。因此,例如提到的包括“催化剂”的反应包括一种催化剂,或两种或多种催化剂。还应当理解,术语“或”通常以其包括“和/或”的含义而使用,除非文中另外明确地规定。
定义
除非另有说明,本文所用的下列术语和短语具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而是应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。例如,乙基“任选”被卤素取代,指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解,对于包含一个或多个取代基的任何基团,不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的Cm-n指该部分中具有m-n个碳原子。例如,“C3-10环烷基”指该环烷基具有3-10个碳原子。“C0-6亚烷基”指该亚烷基具有0-6个碳原子,当亚烷基具有0个碳原子时,该基团为键。
本文中的数字范围是指给定范围中的各个整数。例如“C1-10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即=O)时,意味着两个氢原子被取代,酮取代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定,术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团),即碳和氢以外的原子或含有这些原子的原子团,杂原子独立地选自氧、氮、硫、磷、硅、锗、铝、硼。在出现两个或更多杂原子的实施方案中,所述两个或更多杂原子可彼此相同,或者所述两个或更多杂原子中的部分或全部彼此不同。
术语“卤素”或“卤代”是指氟、氯、溴或碘的任何基团。
术语“羟基”指-OH。
术语“氰基”指-CN。
术语“氨基”是指-NH2、-NH(烷基)和-N(烷基)2,氨基的具体例子包括但不限于-NH2、-NHCH3、-NHCH(CH3)2、-N(CH3)2、-NHC2H5、-N(CH3)C2H5等。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和脂肪烃基团,例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等。所述特定烷基包括其所有同分异构体形式,例如丙基包括-CH2CH2CH3、-CH(CH3)2,例如丁基包括-CH2CH2CH2CH3、-CH(CH3)(CH2CH3)、-C(CH3)3、-CH2CH(CH3)2。术语“C1-8烷基”指具有1-8个碳原子的烷基。术语“C1-6烷基”指具有1-6个碳原子的烷基。术语“C1-4烷基”指具有1-4个碳原子的烷基。术语“C1-3烷基”指具有1-3个碳原子的烷基。所述“烷基”、“C1-8烷基”、“C1-6烷基”、“C1-4烷基”或“C1-3烷基”可以是非取代的或是被一个或多个选自羟基、卤素或氨基的取代基取代。
术语“烯基”是指含有2至12个碳原子并且具有一个或多个双键的直链或支链的脂肪烃基。烯基的实例包括但不限于乙烯基、烯丙基、丙烯基、2-丁烯基以及3-己烯基。双键碳之一可任选地为烯基取代基的附接点。
术语“炔基”是指含有2至12个碳原子并且具有一个或多个三键的直链或支链的脂肪烃基。炔基的实例包括但不限于乙炔基、炔丙基以及3-己炔基。三键碳之一可任选地为炔基取代基的附接点。
术语“环烷基”是指仅由碳原子和氢原子组成的单环的饱和的脂肪烃基团,如C3-20环烷基,优选为C3-6环烷基,例如环丙基、环丁基、环戊基、环己基等。所述环烷基可以是非取代的或是被取代的,所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基等。
术语“烷氧基”是指-O-烷基基团。
术语“杂芳环”是指具有5-12个环原子的单环或稠合环,例如5、6、7、8、9、10、11或12个环原子,其中含有1、2、3或4个选自N、O、S的环原子,其余环原子为C,且具有完全共轭的π-电子体系。
术语“杂芳基”是指“杂芳环”分子去掉1个氢原子后余下的基团,杂芳基可以是非取代的或取代的,所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基等。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噻二唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并咪唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、***基、四唑基、三嗪基、喋啶基等。
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的载体”是指对有机体无明显刺激作用,而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成分一同给药的、有利于活性成分给药的惰性物质,包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息,可以参考Remington:The Science and Practice ofPharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要的载体、稀释剂和/或介质。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本申请中的口服剂型,药物组合物中的一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于个体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
术语“患者”或“个体”包括人和动物,例如,哺乳动物(如灵长类动物,牛,马,猪,狗,猫,小鼠,大鼠,兔,山羊,绵羊以及禽类等)。
通式化合物
一方面,本申请提供通式Ⅰ的化合物或其药学上可接受的盐或水合物:
其中,
环A选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环;
X1选自NH或O;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、含有1-2个选自N、O或S的杂原子的5-6元杂芳基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
R4和R5独立地选自H、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1,2或3。
在本申请的一个实施方案中,提供通式Ⅱ的化合物或其药学上可接受的盐或水合物:
其中,
X1选自NH或O;
X2选自N或CH;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、CF3、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1,2或3。
在本申请的一个实施方案中,优选通式Ⅱ的化合物或其药学上可接受的盐或水合物,其中
X1选自O;
X2选自N或CH;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并且可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、CF3、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1或2。
在本申请的一个实施方案中,优选通式Ⅱ的化合物或其药学上可接受的盐或水合物,其中X1为O;R1选自C1-6烷基,其可任选地被一个或多个R6取代;每个R6独立地选自羟基、苯基或C3-6环烷基。更优选地,R1选自甲基、乙基、丙基或丁基,并可任选地被1-2个R6取代;每个R6独立地选自羟基、苯基或环丙烷基。
在本申请的一个实施方案中,优选通式Ⅱ的化合物或其药学上可接受的盐或水合物,其中X1为O;R2选自苯基、吡啶基、苄基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基,并可任选地被1个或2个R7取代;每个R7独立地选自羟基、卤代C1-3烷基或C1-6烷基。更优选地,R2选自苯基、吡啶基、苄基、丙基、丁基、乙氧基,并可任选地被一个或多个R7取代;每个R7独立地选自羟基或三氟甲基。
在本申请的一个实施方案中,优选通式Ⅱ所示的化合物或其药学上可接受的盐或水合物,其中X1为O;n为0或1;R3为卤代C1-3烷基。更优选地,n为0或1;R3选自三氟甲基。
在本申请的一个实施方案中,优选下述化合物:
及其药学上可接受的盐或水合物。
作为通式Ⅰ或通式Ⅱ的化合物的药学上可接受的盐,例如,可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐,例如钠盐、钾盐等;碱土金属的盐,例如钙盐、镁盐、钡盐等;铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺等形成的盐。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。与碱性氨基酸形成的盐的非限制性实例包括但不限于与精氨酸、赖氨酸、鸟氨酸等形成的盐。与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、谷氨酸等形成的盐。
本申请的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本申请的通式Ⅰ或通式Ⅱ的化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本申请的范围之内。本申请的通式Ⅰ或通式Ⅱ的化合物可以以多晶型物或无定形形式存在。
本申请的通式Ⅰ或通式Ⅱ的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本申请的范围之内。
本申请中的消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明,用楔形键和虚线键表示一个立体中心的绝对构型。当本申请所述的通式Ⅰ或通式Ⅱ的化合物含有烯双键或其它几何不对称中心,除非另有规定,它们包括E和Z几何异构体。同样地,所有的互变异构形式均包括在本申请的范围之内。
本申请的通式Ⅰ或通式Ⅱ的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物也均包括在本申请的范围之内。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某一化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域技术人员已知的分步结晶法或色谱法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请的通式Ⅰ或通式Ⅱ的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。本申请的通式Ⅰ或通式Ⅱ的化合物的所有同位素组成的变换,无论放射性与否,都包括在本申请的范围之内。
药物组合物
另一方面,本申请提供了药物组合物,其包含通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。本申请的药物组合物可以进一步含有一种或多种另外的治疗剂。
本申请的药物组合物可通过将本申请的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物与适宜的药学上可接受的载体或赋形剂组合而制备,例如可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本申请的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物或其药物组合物的典型的给药途径包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
可以采用本领域技术人员已知的方法制备本申请的药物组合物,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药,可以通过将通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物与本领域技术人员熟知的药学上可接受的载体或赋形剂混合来配制该药物组合物。这些载体或赋形剂能使本申请的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如,可通过下述方法获得:将所述的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物与固体赋形剂混合,任选地碾磨所得的混合物,如果需要则加入其它合适的辅料,然后将该混合物加工成颗粒,得到了片剂或糖衣剂的核心。适合的辅料包括但不限于:粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊;滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸;乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙;二氧化硅;交联羧甲基纤维素钠、预胶化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据药剂领域中通常公知的方法任选地对糖衣剂的核心进行包衣,尤其使用肠溶包衣。
本申请的药物组合物还可适用于肠胃外给药,如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂,例如填充剂、缓冲剂或表面活性剂来制备适于肠胃外给药的剂型。
医药用途
另一方面,本申请提供了治疗由IDH2突变诱发的癌症的方法,所述方法包括给予有需要的个体通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
另一方面,本申请提供了通式Ⅰ或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
另一方面,本申请提供了用于治疗由IDH2突变诱发的癌症的通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
在本申请的一些实施方案中,所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
在本申请的一些实施方案中,所述的由IDH2突变诱发的癌症选自:成胶质细胞瘤(神经胶质瘤)、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)。在更具体的实施方案中,待治疗的癌症是神经胶质瘤、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、黑色素瘤、软骨肉瘤、或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)等,优选地包括急性骨髓性白血病(AML)或肉瘤。
本申请所述的通式Ⅰ或通式Ⅱ的化合物或其药学上可接受的盐或其药物组合物可以通过任何适用的途径和方法给药,例如通过口服或肠胃外(例如,静脉内)给药。本申请所述的通式Ⅰ或通式Ⅱ的化合物或其药学上可接受的盐或其药物组合物以治疗有效量给予所述有需要的个体。通式Ⅰ或通式Ⅱ化合物的给药剂量可以为从约0.0001到20mg/Kg体重/天,例如从0.001到10mg/Kg体重/天。
本申请的通式Ⅰ或通式Ⅱ化合物的给药频率由患者个体的需求决定,例如,每天1次或2次,或每天更多次。给药可以是间歇性的,例如,其中在若干天的期间内,患者接受通式Ⅰ或通式Ⅱ化合物的每日剂量,接着在若干天或更多天的期间,患者不接受通式Ⅰ或通式Ⅱ化合物的每日剂量。
制备
本申请的通式Ⅰ或通式Ⅱ的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方案以及本领域技术上人员所熟知的等同替换方式,优选的实施方案均包括但不限于本申请的实施例。
本申请的具体实施方案的化学反应是在合适的溶剂中完成的,所述的溶剂必须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的通式Ⅰ或通式Ⅱ的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本申请的通式Ⅱ的化合物可以由有机合成领域技术人员通过如下路线用本领域的标准方法来制备:
化合物1-1发生成酰化反应得到1-2;1-2与缩二脲反应得到1-3;1-3发生氯化反应得到1-4;1-4与R2基团取代的氨发生氨化反应得到1-5;1-5与R2-X1基团取代的氨发生氨化反应得到通式Ⅱ的化合物。
实施例
下面的具体实施例,其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制,而只是本发明的示例性说明和典型代表。本领域技术人员应该理解:还有形成本申请化合物的其它合成途径,下面提供的是非限制性的实施例。
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明,本申请使用的原料都是市场上直接买到未经进一步纯化直接使用的。
柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60PF254,0.25毫米)。手性化合物分离和对映体过量值(ee)测定使用Agilent LC 1200series(柱子:CHIRALPAK AD-H,毫米,5微米,30℃)。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定;液质连用(LC/MS)使用FINNIGAN Thermo LCQ Advantage MAX,Agilent LC 1200series(柱子:Waters SymmetryC18,毫米,5微米,35℃),采用ESI(+)离子模式。
实验部分
实施例1:4-(乙氧基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
步骤1:6-三氟甲基-吡啶-2-甲酸甲酯
氮气保护下,向2-溴-6-三氟甲基吡啶(1.48g,6.55mmol)的甲醇(50.0mL)溶液中依次加入醋酸钯(74.0mg,0.33mmol)、1,1'-双(二苯基膦)二茂铁(363.0mg,0.655mmol)和三乙胺(0.92g,9.8mmol)。该反应液在60℃、2个大气压的一氧化碳气氛下反应18小时。反应结束后,将反应液冷却到室温,过滤,滤液真空减压浓缩,所得残留物经硅胶柱色谱纯化得6-三氟甲基-吡啶-2-甲酸甲酯(0.9g,收率67.0%)。
步骤2:6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪-2,4(1H,3H)-二酮
氮气保护下,向乙醇钠(11.2g,165.0mmol)的乙醇(200mL)溶液中依次加入6-三氟甲基-吡啶-2-甲酸甲酯(10.0g,48.7mmol)和缩二脲(4.2g,40.7mmol)。将该混合物加热回流2小时后冷却到室温。将反应液真空减压浓缩,所得残留物倒入水中,用6mol/L盐酸溶液调节pH值到7,所得固体过滤,滤饼用水洗涤,干燥后得6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪-2,4(1H,3H)-二酮(5.0g,收率47.5%)。
步骤3:2,4-二氯-6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪
氮气保护下,将6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪-2,4(1H,3H)-二酮(15.0g,58.1mmol)和三氯氧磷(200mL)的混合液于100℃反应2小时后冷却到室温。将反应液真空减压浓缩,所得残留物倒入饱和碳酸氢钠水溶液中,用乙酸乙酯萃取(2×100mL),有机相用无水硫酸钠干燥。过滤,滤液真空浓缩得2,4-二氯-6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪(10.0g,收率58.3%)。
步骤4:4-氯-6-(6-三氟甲基吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
向2,4-二氯-6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪(5.0g,16.9mmol)的四氢呋喃(100mL)溶液中加入4-氨基-2-三氟甲基吡啶(3.3g,20.3mmol)和碳酸氢钠(2.14g,25.3mmol)。将该混合物在70℃反应8小时后冷却到室温。将反应液真空减压浓缩,所得残留物用硅胶色谱柱纯化得4-氯-6-(6-三氟甲基吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺(6.5g,收率91.2%)。
步骤4:4-(乙氧基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
向4-氯-6-(6-三氟甲基吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺(50.0mg,mmol)的四氢呋喃(20mL)溶液中加入乙氧基胺盐酸盐(12.0mg,0.18mmol)和碳酸氢钠(40.0mg,0.48mmol)。将该混合物在70℃反应8小时后冷却到室温。将反应液真空减压浓缩,所得残留物用硅胶色谱柱纯化得4-(乙氧基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺(40.0mg,收率80.0%)。1H-NMR(400MHz,CDCl3):δ=8.66-8.58(m,2H),8.49(s,1H),8.32(s,1H),8.10(t,J=7.9Hz,1H),7.94(s,1H),7.88(d,J=7.8Hz,1H),7.62(d,J=3.7Hz,1H),4.19(q,J=7.0Hz,2H),1.41(t,J=7.1Hz,3H)。
实施例2:4-(异丙基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-(异丙基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=11.35(s,1H),10.85(s,1H),8.66(s,1H),8.56(d,J=5.6Hz,2H),8.32(t,J=7.9Hz,1H),8.11(d,J=7.6Hz,1H),8.03(s,1H),4.28-4.06(m,1H),1.23(d,J=14.5Hz,6H)。
实施例3:4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=11.00(s,1H),10.84(s,1H),8.74(s,1H),8.57(t,J=6.5Hz,2H),8.31(t,J=7.9Hz,1H),8.11(d,J=7.7Hz,1H),7.99(s,1H),1.28(s,9H)。
实施例4:4-((环丙基甲氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-((环丙基甲氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-
(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=11.4(s,1H),10.9(s,1H),8.61(s,1H),8.57(d,J=5.6Hz,2H),8.32(t,J=7.9Hz,1H),8.17-8.09(m,2H),3.77(d,J=7.1Hz,2H),3.15(d,J=5.2Hz,1H),0.87-0.76(m,2H),0.57-0.47(m,2H)。
实施例5:N,N'-(6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2,4-二基)双(O-乙氧氨基)
参照实施例1的合成方法,制得N,N'-(6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2,4-二基)双(O-乙氧氨基)。1H-NMR(400MHz,DMSO-d6):δ=10.96(s,2H),8.48(d,J=7.8Hz,1H),8.24(t,J=7.9Hz,1H),8.04(d,J=7.7Hz,1H),3.90(q,J=7.0Hz,4H),1.30-1.06(m,6H)。
实施例6:2-甲基-1-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-2-醇
参照实施例1的合成方法,制得2-甲基-1-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-2-醇。1H-NMR(400MHz,CDCl3):δ=8.59(dd,J=10.7,6.7Hz,2H),8.29(s,1H),8.09(t,J=7.8Hz,1H),7.87(d,J=7.8Hz,1H),7.73(s,1H),4.00(s,2H),1.62(s,1H),1.32(s,6H)。
实施例7:2-甲基-2-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-1-醇
参照实施例1的合成方法,制得2-甲基-2-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-1-醇。1H-NMR(400MHz,DMSO-d6):δ=10.80(s,1H),8.54(d,J=5.8Hz,1H),8.29(t,J=7.9Hz,3H),8.08(m,2H),5.38(s,1H),4.56(s,1H),3.54-3.39(m,2H),1.27-1.10(m,6H)。
实施例8:4-((苄氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-((苄氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=11.52(s,1H),10.91(s,1H),8.60(s,2H),8.56(d,J=5.4Hz,1H),8.36(t,J=7.9Hz,1H),8.15(d,J=7.7Hz,2H),7.52(s,2H),7.47-7.35(m,3H),5.04(s,2H)。
实施例9:4-(2-甲基肼基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-(2-甲基肼基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=10.76(s,1H),8.67(s,1H),8.56(d,J=5.5Hz,1H),8.30(t,J=7.9Hz,1H),8.11(d,J=7.7Hz,2H),7.93(s,1H),5.39(s,1H),5.21(s,1H),3.40(s,,3H)。
实施例10:4-(叔丁氧氨基)-6-苯基-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-(叔丁氧氨基)-6-苯基-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=10.59(d,2H),8.59(m,1H),8.55(m,1H),8.32(m,2H),8.00(m,1H),7.56(m,3H),1.41-0.95(m,9H)。
实施例11:1-((4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-基)氨基)-2-甲基丙-2醇
参照实施例1的合成方法,制得1-((4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-基)氨基)-2-甲基丙-2醇。1H-NMR(400MHz,DMSO-d6):δ=10.29(d,2H),8.53(d,J=7.9Hz,1H),8.28(t,J=7.9Hz,1H),8.13-8.03(m,1H),4.86(s,1H),3.39(m,2H),1.27(m,9H),1.07(m,6H)。
实施例12:4-(叔丁氧氨基)-N-苯基-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-(叔丁氧氨基)-N-苯基-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=10.62(s,1H),10.12(s,1H),8.57(d,J=7.9Hz,1H),8.31(t,J=7.8Hz,1H),8.10(d,J=7.2Hz,1H),7.99(m,2H),7.32(t,J=7.9Hz,2H),7.03(t,J=7.4Hz,1H),1.29(s,9H)。
实施例13:N-苄基-4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得N-苄基-4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=10.26(s,2H),8.50(dd,J=13.2,5.0Hz,2H),8.33-8.18(m,1H),8.05(d,J=7.8Hz,1H),7.37(d,J=7.0Hz,1H),7.31(dd,J=10.1,4.8Hz,2H),7.22(t,J=7.2Hz,1H),4.55(d,J=6.2Hz,2H),1.18(s,9H)。
实施例14:4-(叔丁氧氨基)-N-异丙基-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺
参照实施例1的合成方法,制得4-(叔丁氧氨基)-N-异丙基-6-(6-(三氟甲基)吡啶-2-基)-
1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ=10.16(s,2H),8.49(d,J=8.1Hz,1H),8.04(d,J=7.4Hz,1H),7.83(d,J=7.9Hz,1H),4.16(m,1H),1.24(m,9H),1.18(m,6H)。
实验例1:IDH2抑制活性的测定
本申请采用以下方法来测定本申请的化合物对IDH2(R172K,40-end)的抑制活性,该抑制活性采用IC50这一指标来表示,IC50即IDH2的活性被抑制50%时的化合物的浓度。材料和方法:
通过辅助因子NADPH的消减来测定化合物对IDH2(R172K,40-end)的抑制活性。将化合物与酶和NADPH进行预孵育,然后通过添加a-KG启动反应,线性条件下反应120分钟。之后通过添加Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)终止反应。硫辛酰胺脱氢酶通过消减可供使用的辅助因子NADPH而终止IDH2m反应,它将NADPH氧化成NADP,并且将刃天青还原成高荧光的试卤灵,通过易于检测的荧光基团来量化在特定反应时间之后剩余的辅助因子NADPH的量。
具体地说,将2.5μl 3×梯度稀释的化合物加到384孔板中,接着添加5μl含有80nMIDH2(R172K,40-end)和40μM NADPH的反应缓冲液(20mM Tris-HCl,PH7.5;150mM NaCl;10mM MgCl2;10mM MnCl2;0.4mg/ml BSA和2mM DTT)。然后将上述测试混合物在23℃孵育120分钟,之后添加2.5μl含有4mM a-KG的反应缓冲液启动反应。室温孵育120分钟后,加入5μl用反应缓冲液配制的终止混合物(0.4U/ml Diaphorase和40μM Resazurin),使刃天青转化成试卤灵来测量剩余的NADPH。23℃孵育10分钟后,通过Flexstation 3在Ex535/Em595下进行荧光值测定。
实施例化合物的IDH2抑制活性如表1所示:
表1
实施例编号 | IC<sub>50</sub>(nM) |
1 | 22.40 |
2 | 28.79 |
3 | 31.69 |
4 | 38.19 |
6 | 46.85 |
7 | 153.6 |
8 | 239.3 |
10 | 51.42 |
实验例2:药代动力学参数的测定
本申请采用以下方法来测定本申请的化合物的药代动力学参数:
研究使用7-9周龄健康雄性成年大鼠,每组动物(3只雄性大鼠)单次灌胃给药,剂量为5mg/kg,灌胃给药组的动物在实验前禁食过夜,禁食时间从给药前10小时至给药后4小时。
在给药后0.25、0.5、1、2、4、6、8和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛取0.3mL全血,放于肝素抗凝管中,样品于4℃、4000rpm离心5min,血浆转移至离心管中,并放于-80℃保存直到分析。
血浆样品分析使用已确证的液相色谱-串联质谱联用方法(LC-MS/MS),个体动物的血浆浓度-时间数据用WinNonlin(专业版,版本6.3;Pharsight公司)软件进行分析,非房室模型被用于浓度分析,计算化合物的药代动力学参数,如表2所示:实施例3化合物具有较好的体内代谢水平和较长的半衰期,并在同等剂量下,其血药浓度高于IDH2抑制剂AG-221。
表2
实施例 | 3 | AG-221 |
剂量(mg/kg) | 5 | 5 |
T<sub>1/2</sub>(hr) | 12.0 | 3.73 |
T<sub>max</sub>(hr) | 5.0 | 4.00 |
C<sub>max</sub>(ng/mL) | 589 | 479 |
AUC<sub>0-inf</sub>(hr*ng/mL) | 10838 | 5385 |
Claims (16)
1.通式Ⅱ的化合物或其药学上可接受的盐
其中,
X1选自NH或O;
X2选自N;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1,2或3。
2.通式Ⅱ的化合物或其药学上可接受的盐
其中,
X1选自NH或O;
X2选自CH;
R1选自C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1,2或3。
3.权利要求1所述的化合物或其药学上可接受的盐,其中
X1选自O;
X2选自N;
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1或2。
4.权利要求2所述的化合物或其药学上可接受的盐,其中
X1选自O;
X2选自CH;
R1选自C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基,其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代;
R2选自苯基、吡啶基、苄基、C1-6烷基或C3-6环烷基,并可任选地被一个或多个R7取代;
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基,并且所述苯基或杂芳基可任选地被一个或多个R8取代;
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基;以及
n为0,1或2。
5.权利要求1-4中任一项所述的化合物或其药学上可接受的盐,其中X1为O;R1选自C1-6烷基并可任选地被一个或多个R6取代;以及每个R6选自羟基、苯基或C3-6环烷基;优选地,R1选自甲基、乙基、丙基或丁基并可任选地被1-2个R6取代;以及每个R6独立地选自羟基、苯基或环丙烷基。
6.权利要求1、3和5中任一项所述的化合物或其药学上可接受的盐,其中X1为O;X2为N;R2选自苯基、吡啶基、苄基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基,并可任选地被1个或2个R7取代;以及每个R7独立地选自羟基、卤代C1-3烷基或C1-6烷基;优选地,R2选自苯基、吡啶基、苄基、丙基、丁基、乙氧基,并可任选地被一个或多个R7取代;以及每个R7独立地选自羟基或三氟甲基。
7.权利要求2、4和5中任一项所述的化合物或其药学上可接受的盐,其中X1为O;X2为CH;R2选自苯基、吡啶基、苄基、甲基、乙基、丙基或丁基,并可任选地被1个或2个R7取代;以及每个R7独立地选自羟基、卤代C1-3烷基或C1-6烷基;优选地,R2选自苯基、吡啶基、苄基、丙基或丁基,并可任选地被一个或多个R7取代;以及每个R7独立地选自羟基或三氟甲基。
8.权利要求1-7中任一项所述的化合物或其药学上可接受的盐,其中X1为O;n为0或1;以及R3为卤代C1-3烷基;优选地,n为0或1,以及R3选自三氟甲基。
10.药物组合物,其包含权利要求1-9中任一项所述的化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
11.权利要求1-9中任一项所述的化合物或其药学上可接受的盐或权利要求10所述的药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
12.权利要求11所述的用途,其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
13.权利要求11或12所述的用途,其中所述由IDH2突变诱发的癌症选自:成胶质细胞瘤、骨髓增生异常综合征、骨髓组织增殖性赘生物、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤。
14.用于治疗由IDH2突变诱发的癌症的如权利要求1-9中任一项所述的化合物或其药学上可接受的盐或权利要求10所述的药物组合物。
15.权利要求14所述的化合物或其药学上可接受的盐或药物组合物,其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
16.权利要求15或16所述的化合物或其药学上可接受的盐或药物组合物,其中所述由IDH2突变诱发的癌症选自:成胶质细胞瘤、骨髓增生异常综合征、骨髓组织增殖性赘生物、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤。
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CN109890806B (zh) * | 2016-07-21 | 2022-04-26 | 南京圣和药业股份有限公司 | 作为异柠檬酸脱氢酶抑制剂的化合物及其应用 |
CN110139860B (zh) * | 2017-01-22 | 2021-08-10 | 正大天晴药业集团股份有限公司 | 1,3,5-三嗪衍生物的盐及其晶体、它们的制备方法、药物组合物和用途 |
CN109265444B (zh) * | 2017-07-17 | 2022-03-11 | 南京圣和药业股份有限公司 | 取代的三嗪类idh抑制剂的光学异构体及其应用 |
CN109467538A (zh) | 2017-09-07 | 2019-03-15 | 和记黄埔医药(上海)有限公司 | 环烯烃取代的杂芳环类化合物及其用途 |
CN110054615B (zh) * | 2018-01-19 | 2021-06-15 | 南京圣和药业股份有限公司 | 三嗪类idh抑制剂甲磺酸盐的晶型 |
CN110054616B (zh) * | 2018-01-19 | 2021-11-23 | 南京圣和药业股份有限公司 | 三嗪类idh抑制剂的制备方法 |
CN110054614B (zh) * | 2018-01-19 | 2021-12-28 | 南京圣和药业股份有限公司 | 三嗪类idh抑制剂的可药用盐及其制备方法 |
US20210275534A1 (en) | 2018-09-03 | 2021-09-09 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Solid pharmaceutical composition containing 1,3,5-triazine derivative or salt thereof |
KR20210124569A (ko) * | 2020-04-03 | 2021-10-15 | 주식회사 하임바이오 | 암 치료를 위한 신규 화합물 및 이를 포함하는 조성물 |
WO2022095756A1 (zh) * | 2020-11-09 | 2022-05-12 | 贝达药业股份有限公司 | 突变型idh1和idh2抑制剂及其应用 |
WO2023134686A1 (zh) * | 2022-01-11 | 2023-07-20 | 正大天晴药业集团股份有限公司 | 一种1,3,5-三嗪衍生物的制备方法 |
WO2023174235A1 (zh) * | 2022-03-15 | 2023-09-21 | 贝达药业股份有限公司 | 突变型idh1和idh2抑制剂及其应用 |
WO2024008138A1 (zh) * | 2022-07-07 | 2024-01-11 | 正大天晴药业集团股份有限公司 | 1,3,5-三嗪衍生物的药物组合 |
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GB1001665A (en) * | 1961-06-05 | 1965-08-18 | American Cyanamid Co | Triazine derivatives and process for their preparation |
JP3051896B2 (ja) * | 1991-03-20 | 2000-06-12 | 富士写真フイルム株式会社 | ハロゲン化銀写真感光材料 |
WO2006053109A1 (en) | 2004-11-10 | 2006-05-18 | Synta Pharmaceuticals Corp. | Heteroaryl compounds |
US20060235098A1 (en) | 2005-04-19 | 2006-10-19 | Burdeniuc Juan J | Polyurethane foams made with blowing catalyst compositions containing primary hydroxyl groups and high ethylenediamine backbones |
KR20130091729A (ko) | 2010-07-20 | 2013-08-19 | 베스타론 코포레이션 | 살충제 트라이아진 및 피리미딘 |
CN108912066B (zh) * | 2012-01-06 | 2022-06-24 | 安吉奥斯医药品有限公司 | 治疗活性化合物及其使用方法 |
WO2015003360A2 (en) | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
CN110386922A (zh) * | 2013-08-02 | 2019-10-29 | 安吉奥斯医药品有限公司 | 治疗活性化合物及其使用方法 |
US9975878B2 (en) | 2013-11-21 | 2018-05-22 | Ptc Therapeutics, Inc. | Substituted triazine BMI-1 inhibitors |
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AU2016299092B2 (en) | 2020-08-20 |
CN107922358B (zh) | 2021-05-07 |
DK3330258T3 (da) | 2021-08-16 |
RU2018105614A3 (zh) | 2019-11-20 |
EP3330258A1 (en) | 2018-06-06 |
BR112018001780A2 (zh) | 2018-09-11 |
CA2993687A1 (en) | 2017-02-02 |
CN107922358A (zh) | 2018-04-17 |
EP3330258B1 (en) | 2021-07-14 |
KR102303011B1 (ko) | 2021-09-16 |
CA2993687C (en) | 2023-09-26 |
RU2018105614A (ru) | 2019-08-29 |
AU2016299092A1 (en) | 2018-02-22 |
US20190062308A1 (en) | 2019-02-28 |
ZA201801301B (en) | 2020-07-29 |
KR20180031036A (ko) | 2018-03-27 |
US10745383B2 (en) | 2020-08-18 |
HK1246292A1 (zh) | 2018-09-07 |
JP2018521104A (ja) | 2018-08-02 |
HUE056537T2 (hu) | 2022-02-28 |
RU2724333C2 (ru) | 2020-06-23 |
ES2881695T3 (es) | 2021-11-30 |
TW201704224A (zh) | 2017-02-01 |
TWI722004B (zh) | 2021-03-21 |
WO2017016513A1 (zh) | 2017-02-02 |
PT3330258T (pt) | 2021-08-19 |
EP3330258A4 (en) | 2019-01-02 |
JP6786086B2 (ja) | 2020-11-18 |
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