CN116375688A - 哒嗪酮类化合物及其制备方法、药物组合物和应用 - Google Patents
哒嗪酮类化合物及其制备方法、药物组合物和应用 Download PDFInfo
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- CN116375688A CN116375688A CN202111589174.2A CN202111589174A CN116375688A CN 116375688 A CN116375688 A CN 116375688A CN 202111589174 A CN202111589174 A CN 202111589174A CN 116375688 A CN116375688 A CN 116375688A
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- Prior art keywords
- trifluoromethyl
- amino
- acid
- carbonyl
- azetidin
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- -1 Pyridazinone compound Chemical class 0.000 title claims abstract description 140
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 101000735473 Homo sapiens Protein mono-ADP-ribosyltransferase TIPARP Proteins 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 102100034905 Protein mono-ADP-ribosyltransferase TIPARP Human genes 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 101
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- TWSIYGATPWEKBK-UHFFFAOYSA-N 4h-1,3-benzodioxine Chemical class C1=CC=C2OCOCC2=C1 TWSIYGATPWEKBK-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229940114124 ferulic acid Drugs 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 2
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 2
- 235000001785 ferulic acid Nutrition 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 229960000448 lactic acid Drugs 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098895 maleic acid Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- VALZSZJVEFACEZ-UHFFFAOYSA-N azetidine-3-carboxamide Chemical compound NC(=O)C1CNC1 VALZSZJVEFACEZ-UHFFFAOYSA-N 0.000 claims 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000001727 in vivo Methods 0.000 abstract description 11
- 230000005764 inhibitory process Effects 0.000 abstract description 6
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- 230000000857 drug effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
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- 238000006243 chemical reaction Methods 0.000 description 43
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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Abstract
Description
技术领域
本发明涉及一类哒嗪酮类化合物及其制备方法、药物组合物和应用,尤其涉及一类 具有抗肿瘤活性的哒嗪酮酮类化合物及其制备方法、药物组合物和应用。
背景技术
研究表明人体大多数的PARP家族成员展现的是monoADP核糖转移酶活性。MonoPARP蛋白家族与癌症、炎症和神经退行性疾病的发展密切相关。PARP7是 monoPARP蛋白家族的成员之一,它是一种新的细胞中核酸感应器的负调控因子,其在 肿瘤中过度表达。由于癌细胞可以借助PARP-7来抑制干扰素信号,而使其“躲藏”在免 疫系统之外,因此,许多癌细胞都依赖PARP-7而存活。研究发现,抑制PARP7可恢复 细胞内的干扰素信号传导,恢复机体的先天和适应性免疫,进而抑制癌细胞的生长。在 肺癌、结直肠癌等癌症模型中,PARP7抑制剂表现出持久的肿瘤生长抑制作用。
目前尚未有PARP-7抑制剂被批准上市,Ribon公司开发的RBN-2397是首个对PARP-7具有较强抑制活性和选择性的化合物,在NCI-H1373细胞(人肺癌腺癌细胞) 的异种移植瘤模型中,RBN-2397每天口服一次在≥30mg/kg的剂量下具有显著的抗肿 瘤作用,并且呈剂量依赖性,目前已进入临床I期研究(NCT04053673)。但是,RBN-2397 在体内具有很高的清除率,导致在体内的暴露量和口服生物利用度都有极大的缺陷,且 其在动物体内药效表明,单一给以RBN-2397很难起到抗肿瘤作用,其必须与CYP450 抑制剂联用来降低其清除速度才能发挥作用。
发明内容
发明目的:针对现有化合物存在的药代动力学差、单药难以发挥作用等不足,本发明旨在提供一类抗肿瘤活性、药代动力学性质均优异的哒嗪酮类化合物及其制备方法、 药物组合物和应用。
技术方案:作为本发明涉及的第一方面,本发明的哒嗪酮类化合物具有式(I)的结构,所述哒嗪酮类化合物包含其异构体、药学上可接受的盐或它们的混合物:
其中:
m选自0、1、2或3;
R1选自氢、卤素、氰基、三氟甲基、C1~C6的烷基、C1~C6的烷氧基、甲硫基、甲 磺酰基、氨甲酰基;
R2或R3分别独立地选自氢、C1~C6烷基、取代的C3~C6环烷基或杂环烷基、氰基、 三氟甲基,或者R2和R3与所连碳原子一起形成C3~C6环烷基;所述C3~C6环烷基的取 代基选自氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、 二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基,所述取代基为一 个或多个;
R4选自取代的芳基、取代的杂芳基或取代的1,3-苯并二噁烷基,所述杂芳基或1,3- 苯并二噁烷基的取代基选自氢、卤素、氰基、三氟甲基、2,2,-二氟乙基、C1~C6的烷基、C1~C6的烷氧基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲氧羰 基或硝基,所述取代基为一个或多个;
A1选自-NH-、-O-、-S-或-N(CH3)-;
R5选自氢、卤素、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨 基、二乙氨基或乙酰氨基,R5为一个或多个;
优选,所述哒嗪酮类化合物结构中:
m选自0或1;
R1选自卤素、氰基或三氟甲基;
R2或R3分别独立地选自氢、甲基或三氟甲基;当R2和R3不同时,与R2和R3相连 的碳原子为消旋构型、R构型或S构型;
A1选自-NH-;
进一步优选,所述哒嗪酮类化合物结构中:
m为0。
进一步优选,所述哒嗪酮类化合物结构中:
R1为三氟甲基,R2为氢,R3为甲基,与R3相连的碳原子为S构型。
进一步优选,所述哒嗪酮类化合物结构中:
进一步优选,所述哒嗪酮类化合物结构中:
更具体地,所述哒嗪酮类化合物为以下任一化合物:
上述哒嗪酮类化合物的药学上可接受的盐为所述哒嗪酮类化合物与酸形成的盐,所 述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠 檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、 杏仁酸或阿魏酸。
作为本发明涉及的第二方面,所述哒嗪酮类化合物的制备方法为以下任一方法:
(1)当R1选自三氟甲基、氰基或卤素,R2为氢,R3选自甲基或氢,与R3相连 甲基为S构型,或R2和R3形成环丙基,R4为A1代表-NH-,A2为/> n1或n2各自独立地代表0或1,A3为/>A4为/>目标化合物I-A的制备 方法如下:
由化合物Ⅱ制备化合物Ⅳ,是将Ⅱ和Ⅲ共同溶于溶剂中,加入缚酸剂进行取代反应 得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、 乙二醇二甲醚或乙腈,优选乙腈;缚酸剂为碳酸钠、碳酸钾、三乙胺或N,N-二异丙基乙 胺(DIPEA),优选DIPEA。
由化合物Ⅳ制备化合物Ⅴ,是将Ⅳ溶于溶剂中,加入酸进行反应得到。反应溶剂为二氯甲烷、四氢呋喃或1,4-二氧六环,优选二氯甲烷;所用酸为氯化氢饱和的乙酸乙酯 溶液、氯化氢饱和的1,4-二氧六环溶液或三氟乙酸,优选三氟乙酸。
由化合物Ⅴ制备化合物Ⅶ,是将Ⅴ和Ⅵ溶于溶剂,加入缚酸剂进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇 二甲醚或乙腈,优选1,4-二氧六环;缚酸剂为碳酸钠、碳酸钾、三乙胺或DIPEA,优选 DIPEA。
由化合物Ⅶ制备化合物Ⅷ,是将Ⅶ溶于溶剂中,加入催化剂进行催化氢化反应得到。 反应溶剂为四氢呋喃、甲醇、乙醇或任意两者的混合溶剂,优选甲醇;催化剂为氢氧化钯或钯碳,优选钯碳。
由化合物Ⅷ制备化合物Ⅹ,是将Ⅷ溶于溶剂中,加入缩合剂,再加入碱和化合物Ⅸ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环、 乙二醇二甲醚或乙腈,优选N,N’-二甲基甲酰胺;缩合剂选自N,N'-羰基二咪唑(CDI)、 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、 N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)或六氟磷酸苯并三唑-1- 基-氧基三吡咯烷基(PyBop),优选EDCI;碱为三乙胺、碳酸氢钠、碳酸钠、碳酸钾或 DIPEA,优选DIPEA。
由化合物Ⅹ制备目标化合物Ⅰ-A,是将Ⅹ溶于溶剂,加入酸反应得到。溶剂为四氢呋喃、乙腈或二氯甲烷,优选二氯甲烷;酸为盐酸或三氟乙酸或三氟甲磺酸,优选三氟 乙酸或三氟甲磺酸。
(2)当R1选自三氟甲基、氰基或卤素,R2为氢,R3选自甲基或氢,与R3相连甲 基为S构型,或R2和R3形成环丙基,R4为A1为-NH-,A2为/> n1或n2各自独立地选自0或1,A3为/>A4为/>目标化合物I-B的制备 方法如下:
由化合物Ⅷ制备化合物Ⅻ,是将Ⅷ溶于溶剂中,加入缩合剂,再加入碱和化合物Ⅺ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环或 乙腈,优选N,N’-二甲基甲酰胺;缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙 基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳 二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三 氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)或六氟磷酸苯并三唑-1-基-氧基三吡咯烷 基(PyBop),优选EDCI;碱为三乙胺、碳酸氢钠、碳酸钠、碳酸钾或DIPEA,优选 DIPEA。
由化合物Ⅻ制备目标化合物Ⅰ-B,是将ⅩII溶于溶剂,加入酸进行反应得到。溶剂为四氢呋喃、乙腈或二氯甲烷,优选二氯甲烷;酸为盐酸或三氟乙酸或三氟甲磺酸,优 选三氟乙酸或三氟甲磺酸。
(3)当R1代表三氟甲基、氰基或卤素,R2为氢,R3选自甲基或氢,与R3相连甲 基为S构型,或R2和R3形成环丙基,R4为A1为-NH-,A2为/> A3为/>A4为目标化合物I-C的制备方法如下:/>
由化合物ⅩⅢ制备化合物ⅩⅣ,是将ⅩⅢ溶于溶剂,加入碱,再加入化合物Ⅲ进行反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六 环、乙二醇二甲醚或乙腈,优选N,N-二甲基甲酰胺;碱为氢化钠、碳酸钠、碳酸钾、三 乙胺或DIPEA,优选氢化钠。
由化合物ⅩⅣ制备化合物ⅩⅤ,是将ⅩⅣ溶于溶剂,加入碱的水溶液进行水解得到。 反应溶剂为四氢呋喃、甲醇、乙腈或任意两者的混合溶剂,优选四氢呋喃与甲醇混合溶剂;碱为氢氧化钠、氢氧化锂或氢氧化钾,优选氢氧化钠。
由化合物ⅩⅤ制备化合物ⅩⅥ,是将ⅩⅤ溶于溶剂,加入缩合剂,再加入碱和化合物Ⅸ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六 环、乙二醇二甲醚或乙腈,优选N,N-二甲基甲酰胺;缩合剂选自N,N'-羰基二咪唑(CDI)、 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、 N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 (HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、六氟磷酸苯并三唑-1- 基-氧基三吡咯烷基(PyBop),优选EDCI;碱为三乙胺、碳酸钠、碳酸钾或DIPEA, 优选DIPEA。
由化合物ⅩⅥ制备化合物ⅩⅦ,是将ⅩⅥ溶于溶剂中,加入酸进行反应得到。溶剂为二氯甲烷、四氢呋喃或1,4-二氧六环,优选二氯甲烷;酸为盐酸、三氟乙酸或硫酸, 优选三氟乙酸。
由化合物ⅩⅦ制备化合物ⅩⅧ,是将ⅩⅦ和化合物Ⅵ溶于溶剂,加入碱进行取代反 应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈,优选1,4-二氧六环;碱为碳酸钠、碳酸钾、三乙胺或DIPEA,优 选DIPEA。
由化合物ⅩⅧ制备化合物Ⅰ-C,是将ⅩⅧ溶于溶剂,加入酸进行反应得到。溶剂为四氢呋喃、乙腈或二氯甲烷,优选二氯甲烷;酸为盐酸或三氟乙酸或三氟甲磺酸,优选 三氟乙酸或三氟甲磺酸。
由化合物ⅩⅨ制备化合物ⅩⅩⅠ,是将ⅩⅨ溶于溶剂,加入缩合剂,再加入碱和化合物ⅩⅩ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二 氧六环、乙二醇二甲醚或乙腈,优选N,N-二甲基甲酰胺;缩合剂选自N,N'-羰基二咪唑 (CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺 (DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六 氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、六氟磷酸苯 并三唑-1-基-氧基三吡咯烷基(PyBop),优选EDCI;碱为三乙胺、碳酸钠、碳酸钾或 DIPEA,优选DIPEA。
由化合物ⅩⅩⅠ制备化合物ⅩⅩⅡ,是将ⅩⅩⅠ溶于溶剂,加入碱的水溶液进行水解得到。反应溶剂为四氢呋喃、甲醇、乙腈或任意两者的混合溶剂,优选四氢呋喃与甲 醇混合溶剂;碱为氢氧化钠、氢氧化锂或氢氧化钾,优选氢氧化钠。
由化合物ⅩⅩⅡ制备化合物ⅩⅩⅢ,是将ⅩⅩⅡ溶于溶剂,加入缩合剂,再加入N,O-二甲基羟胺盐酸盐进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲 酰胺、1,4-二氧六环、乙二醇二甲醚或乙腈,优选N,N-二甲基甲酰胺;缩合剂选自N,N'- 羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己 基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'- 四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU) 或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBop),优选CDI。
由化合物ⅩⅩⅢ制备化合物ⅩⅩⅣ,是将ⅩⅩⅢ溶于溶剂,在低温下加入甲基溴化 镁反应得到。反应溶剂为无水四氢呋喃、无水乙醚、无水二氯甲烷或无水二氧六环,优选无水四氢呋喃。
由化合物XXIV制备化合物XXV,是将XXIV溶于溶剂,加入氨源和催化剂反应 得到。溶剂为甲醇、乙醇、四氢呋喃或任意两者的混合溶剂,优选甲醇,氨源为甲酸铵 或乙酸铵,优选甲酸铵,催化剂优选二氯(五甲基环戊二烯基)合铑(III)二聚体。
由化合物ⅩXV制备化合物XXVI,是将XXV和化合物Ⅵ溶于溶剂,加入碱进行取 代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧 六环、乙二醇二甲醚或乙腈,优选1,4-二氧六环;碱为碳酸钠、碳酸钾、三乙胺或DIPEA, 优选DIPEA。
由化合物XXVI制备目标化合物Ⅰ-D,是将XXVI溶于溶剂,加入酸进行反应得到。 溶剂为四氢呋喃、乙腈、二氯甲烷或任意两者的混合溶剂,优选二氯甲烷;酸为盐酸或 三氟乙酸或三氟甲磺酸,优选三氟乙酸或三氟甲磺酸。
其中,m、Y1、Y2、R7、R8、R9、R10的定义如前所述;Boc为叔丁氧羰基;P为(三 甲基硅)乙氧基甲基(SEM)或对甲氧基苄基(PMB);
将相应的酸与以上方法制备的化合物(I)成盐,即得所述哒嗪酮类化合物的药学上可接受的盐。
作为本发明涉及的第三方面,所述药物组合物包含上述任一哒嗪酮类化合物以及药 学上可接受的载体。可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂或注射剂,制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药 用辅料。
作为本发明涉及的第四方面,所述哒嗪酮类化合物及其药物组合物可制备为PARP7 抑制剂药物,用于治疗肿瘤,具体治疗肺鳞腺癌、结肠癌、乳腺癌等癌症。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类哒嗪酮类化合物具有优异的体内药代动力学性质,半衰期、体内暴露量及生物利用度均得到显著提升,具有显著的成药优势;
(2)该类哒嗪酮类化合物具有优异的体内药效学性质,给予更低的剂量即可实现更优的肿瘤抑制活性;并且还可以促进免疫因子释放,无需联合用药,单独用药即可实 现显著的疗效;
(3)该类哒嗪酮类化合物可有效抑制PARP7酶活性,酶抑制IC50值最优小于0.1 μM,达到纳摩尔浓度级别;并且对多种肿瘤细胞均有抑制作用,肿瘤细胞抑制IC50值 最优小于0.05μM,达到纳摩尔浓度级别;
(4)该类哒嗪酮类化合物及其药物组合物应用广泛,可制备为抗肿瘤药物;所述药物在分子水平、细胞水平均可以发挥药效,尤其是具有更优异的体内药代动力学和药 效学性质;
(5)化合物制备方法简便易行。
附图说明
图1为化合物对干扰素释放的促进作用;
图2为化合物的体内抗肿瘤作用。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1:(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷 -1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-1)的合成
(S)-1-(2-((叔丁氧羰基)氨基)丙基)氮杂环丁烷-3-甲酸苄酯(IV-1)的合成
将氮杂环丁烷-3-甲酸苄酯(II-1)(16.0g,83.7mmol)溶于70mL乙腈中,加入(S)-(1- 溴丙-2-基)氨基甲酸叔丁酯(III-1)(21.9g,92.0mmol)和DIPEA(32.4g,251.1mmol),升温至80℃反应2小时。薄层色谱(V石油醚:V乙酸乙酯=1:1)监测反应完全, 加入200mL水,乙酸乙酯(100mL×3)萃取,合并有机相,用饱和食盐水洗涤,无水 硫酸钠干燥,抽滤,滤液浓缩。粗品通过硅胶柱层析(V石油醚:V乙酸乙酯=3:1) 纯化得25.4g无色油状物(IV-1),收率87.0%。ESI-MS[M+H]+349.2;1H NMR(300MHz, DMSO-d6)δ7.40-7.30(m,5H),5.14(s,2H),3.65-3.50(m,3H),3.40-3.30(m,3H),2.45(dd, J1=6Hz,J2=1.8Hz,2H),1.44(s,9H),1.08(d,J=6.6Hz,3H)。
(S)-1-(2-氨基丙基)氮杂环丁烷-3-甲酸苄酯(V-1)的合成
将化合物IV-1(6.9g,20.0m mol)溶于30mL二氯甲烷,加入20mL三氟乙酸,室 温搅拌0.5小时,薄层色谱(V二氯甲烷:V甲醇=15:1)监测反应完全,减压蒸除溶 剂,加入饱和碳酸氢钠水溶液调pH至7~8。用二氯甲烷(50mL×7)萃取,合并有机相, 用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,滤液浓缩得浅黄色油状物(V-1)4.40g, 收率88.7%。ESI-MS[M+H]+249.2。
(S)-1-(2-((6-氧代-5-三氟甲基-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨 基)丙基)氮杂环丁烷-3-甲酸苄酯(VII-1)的合成
将化合物V-1(2.2g,9.0mmol)溶于10mL 1,4-二氧六环中,加入5-氯-4-三氟甲基-2-((2-(三甲基硅基)乙氧基)甲基)哒嗪-3(2H)-酮(VI-1)(3.3g,10.0mmol)和DIPEA(3.5g,27.0mmol),升温至90℃反应2小时,薄层色谱(V石油醚:V乙酸乙酯=1:1)监 测反应完全。加入40mL水,乙酸乙酯(20mL×3)萃取,合并有机相,依次用饱和食 盐水洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗品通过硅胶柱层析(V石油醚:V乙 酸乙酯=3:1)纯化得4.1g无色油状物(VII-1),收率83.7%。ESI-MS[M+H]+541.2;1H NMR(300MHz,DMSO-d6)δ7.61(s,1H),7.38-7.32(m,5H),6.15(m,1H),5.37(dd,J1= 14.1Hz,J2=9.9Hz,2H),5.14(s,2H),3.74-3.55(m,5H),3.45-3.35(m,3H),2.72-2.54(m, 2H),1.23(d,J=6.6Hz,3H),0.99-0.91(m,2H),-0.01(s,9H)。
(S)-1-(2-((6-氧代-5-三氟甲基-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨 基)丙基)氮杂环丁-3-甲酸(VIII-1)的合成
将化合物VII-1(4.0g,7.4mmol)溶于20mL无水甲醇中,加入500mg钯碳,反 应体系用氢气置换后,在室温下反应30分钟,薄层色谱(V二氯甲烷:V甲醇=15:1) 监测反应完全,抽滤,滤饼用10mL甲醇洗涤,干燥后得白色固体(VIII-1)3.2g,收 率96.1%。ESI-MS[M+H]+451.2;1H NMR(300MHz,DMSO-d6)δ11.4(s,1H,-COOH), 7.62(s,1H,Ar-H),6.45-6.35(m,1H,-NH-),5.37(dd,J1=14.1Hz,J2=9.9Hz,2H, -Ar-CH2-O-),3.74-3.55(m,5H,-CH2-CH2-,-CH-),3.45-3.35(m,3H,-CH2-,-CH-), 2.72-2.54(m,2H,-CH2-),1.23(d,J=6.6Hz,3H,-CH3),0.99-0.91(m,2H,-Si-CH2-),-0.01 (s,9H,-(CH3)3)。
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙 -2-氨基)-2-((2-(三甲基硅基)乙氧基)甲基)哒嗪-3(2H)-酮(X-1)的合成
将化合物VIII-1(480.0mg,1.1mmol)溶于5mL二氯甲烷中,分别加入1-羟基苯 并三唑(HOBt,180.0mg,1.3mmol)和EDCI(210.0mg,1.3mmol),在室温下反应0.5 小时后,再依次加入2-(哌嗪-1-基)-5-三氟甲基嘧啶(IX-1)(280.0mg,1.2mmol)和 DIPEA(430.0mg,3.3mmol),继续在室温下反应1小时,薄层色谱(V二氯甲烷:V 甲醇=15:1)监测反应完全。加入10mL水,二氯甲烷(5mL×3)萃取,合并有机相, 用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗品通过硅胶柱层析(V 石油醚:V乙酸乙酯=1:2)纯化得白色固体(X-1)560.0mg,收率76.6%。ESI-MS [M+H]+665.2;1H NMR(300MHz,DMSO-d6)δ8.73(s,2H),8.00(s,1H),6.65-6.55(m,1H), 5.21(s,2H),4.20-4.00(m,1H),3.83-3.74(m,4H),3.66-3.45(m,8H),3.28-3.13(m,5H), 1.24(t,J=7.2Hz,1H),1.18(d,J=6.3Hz,3H),0.84(t,J=8.1Hz,2H),-0.04(s,9H)。
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙 -2-基)氨基)哒嗪-3(2H)-酮(I-A-1)的合成
将化合物X-1(531,2mg,0.8mmol)溶于3mL二氯甲烷,加入3mL三氟乙酸,在 室温下反应3小时。薄层色谱(V二氯甲烷:V甲醇=15:1)监测反应完全,减压蒸 除溶剂,加入饱和碳酸氢钠水溶液调pH至7~8,加入10mL水,二氯甲烷(10mL×3) 萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗 品通过硅胶柱层析(V二氯甲烷:V甲醇=40:1)纯化得白色固体(I-A-1)332.4mg, 收率77.8%。ESI-MS[M+H]+535.2;1H NMR(300MHz,DMSO-d6)δ12.50(s,1H),8.73(s, 2H),7.90(s,1H),6.49-6.35(m,1H),4.10-3.90(m,1H),3.92-3.72(m,4H),3.62-3.42(m, 11H),1.16(d,J=6.3Hz,3H)。
参照实施例1的制备方法,制备得到以下化合物:
实施例18:4-三氟甲基-5-((((S)-1-((S)-3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)吡咯 烷-1-基))丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-18)的合成
1-((S)-2-((叔丁氧羰基)氨基)丙基)吡咯烷-3-甲酸苄酯(IV-2)的合成
将吡咯烷-3-羧酸苄酯(II-2)(17.2g,83.7mmol)溶于70mL乙腈中,加入化合物III-1(21.9g,92.0mmol)和DIPEA(32.4g,251.1mmol),升温至80℃反应2小时。薄 层色谱(V石油醚:V乙酸乙酯=1:1)监测反应完全,加入200mL水,乙酸乙酯(100 mL×3)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液 浓缩。粗品通过硅胶柱层析(V石油醚:V乙酸乙酯=3:1)纯化得25.4g无色油状物 (IV-2),收率83.8%。ESI-MS[M+H]+363.2。
1-((S)-2-氨基丙基)吡咯烷-3-甲酸苄酯(V-2)的合成
将化合物IV-2(7.2g,19.9mmol)溶于30mL二氯甲烷,加入20mL三氟乙酸,室 温搅拌0.5小时,薄层色谱(V二氯甲烷:V甲醇=15:1)监测反应完全,减压蒸除溶 剂,加入饱和碳酸氢钠水溶液调pH至7~8。加二氯甲烷(50mL×5)萃取,合并有机 相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩得浅黄色油状物(V-2) 4.4g,收率84.6%。ESI-MS[M+H]+263.2。
1-((S)-2-((6-氧代-5-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢哒嗪-4-基) 氨基)丙基)吡咯烷-3-甲酸苄酯(VII-3)的合成 将化合物V-2(2.4g,9.0mmol)溶于10mL 1,4-二氧六环中,加入化合物VI-1(3.3g,10.0 mmol)和DIPEA(3.5g,27.0mmol),升温至90℃反应2小时,薄层色谱(V石油醚: V乙酸乙酯=1:1)监测反应完全。加入40mL水,乙酸乙酯(20mL×3)萃取,合并 有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗品通过硅胶 柱层析(V石油醚:V乙酸乙酯=3:1)纯化得4.2g无色油状物(VII-3),收率84.4%。 ESI-MS[M+H]+555.3。
1-((S)-2-((6-氧代-5-三氟甲基-1-((2-三甲基硅基乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨 基)丙基)吡咯烷-3-甲酸(VIII-3)的合成
将化合物VII-3(4.1g,7.4mmol)溶于20mL无水甲醇中,加入500mg钯碳,反 应体系用氢气置换后,室温下反应30分钟,薄层色谱(V二氯甲烷:V甲醇=15:1) 监测反应完全,抽滤,滤饼用10mL甲醇洗涤,干燥后得白色固体(VIII-3)3.2g,收 率93.3%。ESI-MS[M+H]+465.2。
4-三氟甲基-5-((2S)-1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)吡咯烷-1-基)丙-2-基) 氨基)-2-((2-三甲基硅基乙氧基)甲基)哒嗪-3(2H)-酮(X-18)的合成
以化合物VIII-3(139.2mg,0.3mmol)与化合物IX-1(70.0mg,0.3mmol)为原料, 制备过程参考化合物X-1,得到白色固体(X-18)129.0mg,,收率63.5%。ESI-MS: [M+H]+679.3。
4-三氟甲基-5-((((S)-1-((S)-3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)吡咯烷-1-基))丙 -2-基)氨基)哒嗪-3(2H)-酮(I-A-18)的合成
以化合物X-18(88.0mg,0.13mmol)为原料,制备过程参考化合物I-A-1,得到50.0mg白色固体(I-A-18),收率70.4%。ESI-MS[M+H]+549.2;1H NMR(300MHz,DMSO-d6) δ12.32(s,1H),8.71(s,2H),7.53(s,1H),6.19(t,J=1.8Hz,1H),4.50-4.40(m,1H), 4.10-4.05(m,2H),3.81-3.70(m,4H),3.67-3.60(m,4H),1.92-1.22(m,11H),1.22(d,J=6.3 Hz,3H)。
参照实施例18的制备方法,制备得到以下化合物:
实施例25:(S)-5-((1-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-羰基)氮杂环丁 烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-B-1)的合成
以化合物X-25(113.0mg,0.17mmol)为原料,制备过程参考化合物I-A-1,得到80.0mg白色固体(I-B-1),收率86.5%。ESI-MS[M+H]+545.2;1H NMR(400MHz, DMSO-d6)δ12.46(s,1H),7.89(s,1H),7.22(d,J=8.8Hz,1H),7.09(d,J=2.4Hz,1H), 6.70(dd,J1=8.8Hz,J2=2.4Hz,1H),6.45-6.35(m,1H),4.00-3.90(m,1H),3.65-3.45(m, 4H),3.45-3.35(m,3H),3.26-3.18(m,2H),3.10-3.00(m,4H),2.65-2.54(m,2H),1.12(d,J =6.3Hz,3H)。
实施例26:(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯 -1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-C-1)的合成
(S)-1-(2-(叔丁氧羰基氨基)丙基)-1H-吡咯-3-甲酸甲酯(XIV-1)的合成
将1H-吡咯-3-甲酸甲酯(XIII-1)(1.3g,10.3mmol)溶于5mL无水DMF,冰浴下 加入氢化钠(0.8g,20.0mmol),加毕,升至室温搅拌1小时,随后在冰浴下加入化合 物III-1(3.6g,15.0mmol),加毕,升温至50℃反应6小时。薄层色谱(V石油醚:V 丙酮=8:1)监测反应完全。加入10mL冰水淬灭反应,乙酸乙酯(20mL×3)萃取, 合并有机相,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗品用柱层 析(V石油醚:V丙酮=11:1)纯化得2.4g白色固体(XIV-1),收率82.8%。ESI-MS [M+H]+283.1;1H NMR(300MHz,CDCl3)δ7.23(t,J=2.1Hz,1H),6.55(d,J=2.1Hz, 2H),4.49(d,J=6.9Hz,1H),3.92(m,2H),3.77(s,3H),1.41(s,9H),1.07(d,J=6.9Hz, 3H)。
(S)-1-(2-(叔丁氧羰基氨基)丙基)-1H-吡咯-3-甲酸(XV-1)的合成
将化合物XIV-1(2.4g,8.5mmol)溶于20mL四氢呋喃和甲醇的混合溶剂(V四氢 呋喃:V甲醇=1:1),再将一水合氢氧化锂(1.8g,42.5mmol)溶于4mL水中所得的 溶液加到上述反应液中,升温至60℃反应12小时。薄层色谱(V石油醚:V乙酸乙酯= 4:1)监测反应完全,加入20mL水,乙酸乙酯(20mL×2)萃取,收集水相,用2mol/L 稀盐酸调pH至5~6,乙酸乙酯(20mL×3)萃取,合并有机相,用饱和氯化钠水溶液 洗涤,无水硫酸钠干燥,抽滤,滤液浓缩得白色固体(XV-1)1.9g,收率83.4%。ESI-MS [M+H]+269.1;1H NMR(300MHz,DMSO-d6)δ11.65(s,1H),7.30(t,J=2.1Hz,1H),6.86 (d,J=10.8Hz,1H),6.71(t,J=2.4Hz,1H),6.32(t,J=2.1Hz,1H),3.96-3.66(m,3H),1.33 (s,9H),0.98(d,J=6.6Hz,3H)。
(S)-(1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基甲酸叔 丁酯(XVI-1)的合成
将化合物XV-1(1.0g,3.9mmol)溶于6mL二氯甲烷中,加入HATU(1.6g,4.3 mmol),室温搅拌15分钟,随后依次加入化合物IX-1(1.0g,4.3mmol)和DIPEA(1.0 g,7.80mmol),室温反应30分钟。薄层色谱(V石油醚:V乙酸乙酯=1:1)监测反应 完全,加入20mL水,用乙酸乙酯(10mL×3)萃取,合并有机相,饱和氯化钠水溶液 洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。用柱层析(V石油醚:V乙酸乙酯=3:1) 纯化得1.4g白色固体(XVI-1),收率74.5%。ESI-MS[M+H]+483.2;1H NMR(300MHz, DMSO-d6)δ8.71(s,2H),7.14(t,J=2.1Hz,1H),6.90(d,J=10.8Hz,1H),6.73(t,J=2.4 Hz,1H),6.25(t,J=2.1Hz,1H),3.94-3.66(m,11H),1.33(s,9H),0.98(d,J=6.6Hz,3H)。
(S)-(1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基 (XVII-1)的合成
将化合物XVI-1(1.4g,2.9mmol)溶于5mL二氯甲烷中,加入3mL三氟乙酸, 室温反应15分钟,薄层色谱(V二氯甲烷:V甲醇=5:1)监测反应完全,减压蒸除 溶剂,加入饱和碳酸氢钠溶液使体系的pH至7~8,二氯甲烷(20mL×5)萃取,合并 有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩得浅黄色固体 (XVII-1)0.9g,收率90.9%。ESI-MS[M+H]+383.2;1H NMR(300MHz,DMSO-d6)δ8.74 (s,2H),7.21(t,J=2.1Hz,1H),6.81(t,J=2.4Hz,1H),6.27(t,J=2.1Hz,1H),3.94-3.66 (m,11H),0.98(d,J=6.6Hz,3H)。
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基)嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2- 基)氨基)-2-((2-三甲基硅基乙氧基)甲基)哒嗪-3(2H)-酮(XVIII-1)的合成
将化合物VI-1(1.0g,3.2mmol)溶于6mL1,4-二氧六环中,加入化合物XVII-1(1.1g,2.9mmol)和DIPEA(1.1g,8.6mmol),升温至90℃反应2小时,薄层色谱(V石油 醚:V乙酸乙酯=1:1)监测反应完全,加入20mL水,乙酸乙酯(10mL×3)萃取, 合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗品用柱 层析(V石油醚:V乙酸乙酯=3:1)纯化得到1.5g白色固体(XVIII-1),收率69.4%。 ESI-MS[M+H]+675.2;1H NMR(300MHz,DMSO-d6)δ8.74(s,2H),7.63(s,1H),7.14(t, J=2.1Hz,1H),6.75(t,J=2.7Hz,1H),6.73-6.66(m,1H),6.21-6.17(m,1H),5.18-5.10(m, 2H),4.50-4.40(m,1H),4.10-4.05(m,2H),3.88-3.80(m,4H),3.67-3.60(m,4H),3.53(t,J= 8.1Hz,2H),1.24(d,J=6.3Hz,3H),1.18(t,J=7.2Hz,1H),0.81(t,J=8.1Hz,2H),-0.06 (s,9H)。
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2- 基)氨基)哒嗪-3(2H)-酮(I-C-1)
将化合物XVIII-1(674.0mg,1.0mmol)溶于5mL二氯甲烷中,加入三氟乙酸4mL, 室温反应3小时,薄层色谱监测(V石油醚:V乙酸乙酯=1:4)反应完全,减压蒸除 溶剂,加入饱和碳酸氢钠溶液使其pH至7~8,加入10mL水,二氯甲烷(10mL×3) 萃取,合并有机相,无水硫酸钠干燥,抽滤,滤液浓缩。粗品用柱层析(V石油醚:V 乙酸乙酯=1:1)分离纯化得白色固体(I-C-1)350.0mg,收率64.3%。ESI-MS[M+H]+ 544.2;1H NMR(300MHz,DMSO-d6)δ12.37(s,1H),8.73(s,2H),7.90(s,1H),7.14(t,J= 1.5Hz,1H),6.74(t,J=2.4Hz,1H),6.54-6.45(m,1H),6.19(t,J=1.8Hz,1H),4.50-4.40 (m,1H),4.10-4.05(m,2H),3.88-3.80(m,4H),3.67-3.60(m,4H),1.22(d,J=6.3Hz,3H)。
实施例27:4-三氟甲基-5-((1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁-3- 基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-D-1)的合成
2-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)乙酸甲酯(XXI-1)的 合成
将1-(5-三氟甲基嘧啶-2-基)哌啶-4-甲酸(XIX-1)(1.1g,4.0mmol)溶于5mL二氯甲烷中,加入HATU(1.7g,4.4mmol),室温搅拌15分钟,加入2-(氮杂环丁烯-3-基) 乙酸甲酯(XX-1)(0.5g,4.0mmol)和DIPEA(1.0g,8.0mmol),加毕,在室温下反应 30分钟,薄层色谱监测(V石油醚:V乙酸乙酯=3:1)反应完全,加10mL水,二氯 甲烷(5mL×3)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽 滤,滤液浓缩。粗品用柱层析(V石油醚:V乙酸乙酯=1:1)纯化得白色固体(XXI-1) 1.5g,收率97.1%。ESI-MS[M+H]+387.2;1HNMR(300MHz,CDCl3)δ8.45(s,2H),4.82 (dt,J1=13.5Hz,J2=3.9Hz,2H),4.38(t,J=8.4Hz,1H),4.16(t,J=9.6Hz,1H),3.95-3.87 (m,1H),3.69(s,3H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m, 4H)。
2-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)乙酸(XXII-1)的合成
将化合物XXI-1(1.5g,3.8mmol)溶于5mL四氢呋喃中,加入甲醇5mL,再加入 5mol/L氢氧化钠水溶液2mL,加毕,室温反应1小时,薄层色谱监测(V石油醚:V 乙酸乙酯=1:1)反应完全。加水20mL,乙酸乙酯(10mL×2)萃取,水层用稀盐 酸调pH至4,析出白色固体,抽滤,滤饼用5mL水洗涤,收集滤饼,真空干燥得白色 固体(XXII-1)1.2g,收率83.5%。ESI-MS[M+H]+373.2;1HNMR(300MHz,CDCl3)δ8.45 (s,2H),4.82(dt,J1=13.5Hz,J2=3.9Hz,2H),4.38(t,J=8.4Hz,1H),4.16(t,J=9.6Hz, 1H),3.95-3.87(m,1H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70 (m,4H)。
N-甲氧基-N-甲基-2-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)乙酰 胺(XXIII-1)的合成
将化合物XXII-1(1.5g,4.0mmol)溶于6mL二氯甲烷中,依次加入CDI(1.0g,6.0mmol)和二甲羟胺盐酸盐(1.2g,12.0mmol),加毕,室温反应1小时,薄层色谱监测 (V二氯甲烷:V甲醇=15:1)反应完全,加入10mL水,二氯甲烷(8mL×3)萃取, 合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。粗品用柱 层析(V石油醚:V乙酸乙酯=1:1)纯化得白色固体(XXIII-1)1.2g,收率69.9%。 ESI-MS[M+H]+416.2;1HNMR(300MHz,CDCl3)δ8.45(s,2H),4.82(dt,J1=13.5Hz,J2= 3.9Hz,2H),4.38(t,J=8.4Hz,1H),4.16(t,J=9.6Hz,1H),3.95-3.87(m,1H),3.69(s,3H), 3.06-2.95(m,3H),2.72(s,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H)。
1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)丙-2-酮(XXIV-1)的合 成
将化合物XXIII-1(0.8g,2.0mmol)溶于5mL无水四氢呋喃中,在-15℃下加入甲 基溴化镁(1mol/L,4.0mL),加毕,保温反应4小时,薄层色谱监测(V二氯甲烷:V 甲醇=15:1)反应完全。加入10mL水淬灭反应,室温搅拌15分钟,乙酸乙酯(8mL ×3)萃取,合并有机相,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓缩。 粗品用柱层析(V石油醚:V乙酸乙酯=1:1)纯化得白色固体(XXIV-1)450.0mg, 收率60.8%。ESI-MS[M+H]+371.2;1HNMR(300MHz,CDCl3)δ8.45(s,2H),4.82(dt,J1= 13.5Hz,J2=3.9Hz,2H),4.38(t,J=8.4Hz,1H),4.16(t,J=9.6Hz,1H),3.95-3.87(m,1H), 3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),2.20(s,3H),1.80-1.70(m,4H)。
(3-(2-氨基丙基)氮杂环丁烷-1-基)(1-(5-三氟甲基嘧啶-2-基)哌啶-4-基)甲酮(XXV-1) 的合成
将化合物XXIV-1(0.5g,1.4mmol)溶于5mL甲醇中,依次加入甲酸铵(0.4g,7.0mmol)和二氯(五甲基环戊二烯基)合铑(III)二聚体(43.0mg,0.07mmol),加毕,升温至 70℃下反应3小时,薄层色谱监测(V二氯甲烷:V甲醇=10:1)反应完全,冷却至 室温,减压蒸除溶剂,加入2mol/L盐酸调pH至1~2,室温搅拌10分钟。乙酸乙酯(5 mL×2)萃取,水层用5mol/L氢氧化钠水溶液调pH至8~9,再次用乙酸乙酯(10mL ×5)萃取,合并有机层,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓 缩。粗品用柱层析(V二氯甲烷:V甲醇=10:1)纯化得白色固体(XXV-1)370.0mg, 收率71.3%。ESI-MS[M+H]+372.2;1HNMR(300MHz,DMSO-d6)δ8.70(s,2H),4.72(dt, J1=13.5Hz,J2=3.9Hz,2H),4.34(t,J=8.4Hz,1H),4.01-3.91(m,5H),3.55-3.45(m,1H), 3.15-2.95(m,3H),2.78-2.68(m,1H),1.80-1.65(m,3H),1.51-1.36(m,2H),1.11(d,J=6.3 Hz,3H)。
4-三氟甲基-5-((1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)丙-2-氨 基)-2-((2-三甲基硅基乙氧基)甲基)哒嗪-3(2H)-酮(XXVI-1)的合成
将化合物XXV-1(372.0mg,1.0mmol)溶于4mL 1,4-二氧六环中,加入化合物VI-1(350.0mg,1.1mmol),再加入DIPEA(388.0mg,3.0mmol),加毕,升温至90℃反应 3小时,薄层色谱监测(V二氯甲烷:V甲醇=15:1)反应完全。冷却至室温,加水 10mL,乙酸乙酯(8mL×3)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸 钠干燥,抽滤,滤液浓缩。粗品用柱层析(V二氯甲烷:V甲醇=70:1)纯化得白色 固体(XXVI-1)370.0mg,收率56.7%。ESI-MS[M+H]+654.3;1H NMR(300MHz, DMSO-d6)δ8.73(s,2H),8.00(s,1H),6.59(s,1H),5.21(s,2H),4.00(m,1H),3.83-3.74(m, 4H),3.66-3.45(m,9H),3.28-3.13(m,5H),1.24(t,J=7.2Hz,1H),1.18(d,J=6.3Hz,3H), 0.81(t,J=8.1Hz,2H),-0.06(s,9H)。
4-三氟甲基-5-((1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)丙-2-基) 氨基)哒嗪-3(2H)-酮(I-D-1)的合成
将化合物XXVI-1(327.0mg,0.5mmol)溶于3mL二氯甲烷中,加入三氟乙酸2mL, 在室温下反应3小时,薄层色谱监测(V二氯甲烷:V甲醇=15:1)反应完全,减压 蒸除溶剂,加入饱和碳酸氢钠水溶液调pH至7~8,再加入10mL水,二氯甲烷(10mL ×3)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,滤液浓 缩。粗品用柱层析(V石油醚:V乙酸乙酯=1:1)纯化得白色固体(I-D-1)230.0mg, 收率86.1%。ESI-MS[M+H]+534.2;1HNMR(400MHz,DMSO-d6)δ12.48(s,1H),8.67(s, 2H),7.92(s,1H),6.43-6.35(m,1H),4.70-4.60(m,2H),4.30-4.20(m,1H),4.05-3.95(m, 1H),3.90-3.82(m,1H),3.55-3.46(m,1H),3.10-3.00(m,2H),2.66-2.53(m,2H),2.03-1.95 (m,1H),1.82-1.65(m,3H),1.50-1.35(m,2H),1.17(d,J=6.3Hz,3H)。
实施例28:化合物对PARP7的酶抑制活性
实验材料:PARP7 Chemiluminescent Assay Kit,BPS Bioscience;DMSO,国药,Nivo, PerkinElmer。
实验方法:
(1)溶液与缓冲液的配置:
10X PBS配制:分别称取720mg KH2PO4,45g NaCl和5.311g Na2HPO4·12H2O溶解 在500mL去离子水中,将体系的pH调为7.4,在121℃下灭菌30分钟,冷却后放置 于4℃备用。
1X PBS配制:将10X PBS用去离子水稀释10倍,即1份10X PBS加入9份去离 子水稀释。
Wash buffer配制:1X PBS含有0.05%Tween-20。
1X PARP buffer配制:(现用现配)使用去离子水将10X PARP buffer进行10倍稀释, 放置在冰上备用。
(2)化合物工作液浓度的配制:
根据检测要求,将待测化合物用100%DMSO稀释至所需浓度,然后用1X PARPbuffer进行10倍稀释,配制成10X的化合物工作液。
(3)实验步骤:
a.实验前一天,冰上解冻5X histone mixture;
b.1X histone mixture配制,使用1X PBS将5X histone mixture配制成1Xhistone mixture;每孔取25μL 1X histone mixture到测试板中,在4℃下孵育过夜;
c.每孔取100μL Blocking buffer加入到测试板中,在25℃下孵育90分钟;
d.结束孵育后,甩干测试板中液体,重复洗板3次;
e.每孔取2.5μL的化合物工作液,按照实验排布图加入到测试板中;阳性对照孔中(Positive control)加入相应体积含有10%DMSO的1X PARP buffer,空白对照(Blank) 中加入相应体积的1X PARP buffer;
f.酶完全溶解后,用1X PARP buffer将酶原液稀释到6ng/μL;
g.取10μL每孔酶溶液加入到测试孔板中,空白对照孔加入对应体积的1X PARPbuffer,此时酶量为60ng每孔。注意:此步骤需要在冰上操作;
h.向测试板的各个孔中加入12.5μL master mixture(12.5μL master mixture包括1.25 μL 10X PARP buffer,1.25μL Opti-PARP 10X Assay mixture和10μL水);将测试板封膜置 于25℃下孵育60分钟;
i.孵育结束后,甩干测试板中的液体,重复洗板3次;
j.将试剂盒中的Streptavidin-HRP用Blocking buffer溶液稀释50倍,每孔各25μL 加入到测试板中,在25℃下孵育30分钟;
k.孵育结束后,甩干测试板中的液体,重复洗板3次;
l.按照1:1混合试剂盒中的ELISA ECL Substrate A和ELISA ECL Substrate B,向测 试板中加入每孔50μL混合液,并且马上使用Nivo进行Luminescence检测,读取发光值(RLU);
m.酶率计算:%Enzyme Activity=(RLU(Sample)-RLU(Blank))/ (RLU(Pos.Ctrl)-RLU(Blank))×100%;酶抑制率=1-%Enzyme Activity,具体结果如下 表1所示。
表1.受试化合物对PARP7的酶抑制活性数据
注:“+++”为IC50<0.1μM;“++”为IC50≥0.1μM且<0.5μM;“+”为IC50≥0.5μM。
如表1所示,本发明所有测试化合物均表现出对PARP7具有良好的酶抑制活性, 酶抑制IC50值均达到纳摩尔浓度级别。其中,实施例1、3~7、9~10、13、15~17、20 和25~27的酶抑制IC50值均小于0.1μM。
实施例29:化合物对肿瘤细胞的抗增殖活性
实验过程:
a.将培养至对数生长期的一组癌细胞系以含胎牛血清的培养基中的预先指定密度 涂铺至96孔板中;
b.细胞在24小时后用化合物或媒介(DMSO),处理,并且收集第0天板用于分析;
c.施药后将96孔板放在37℃、4.5%CO2恒温培养箱中培养,6天后各孔加入20μL1.0%的MTT噻唑蓝溶液;
d.继续放置于恒温培养箱中,4小时后用吸走上清培养液,每孔加入150μL DMSO,放在脱色摇床上混匀至结晶物溶解;
e.用多功能酶标仪测570nm处吸光度,按照改良寇式法计算IC50值: lgIC50=Xm-I[P-(3-Pm-Pn)/4],具体结果如下表2所示。
表2.受试化合物对肿瘤细胞的抗增殖活性数据
细胞系 | 实施例1(IC50) | 实施例26(IC50) |
NCI-H1373 | +++ | +++ |
HCC-827 | ++ | ++ |
SW-1990 | + | ++ |
SH-SY5Y | ++ | + |
CFPAC-1 | ++ | +++ |
注:“+++”为IC50<0.05μM;“++”为IC50≥0.05μM且<0.5μM;“+”为IC50≥0.5μM)。
以上数据表明本发明实施例1(I-A-1)和实施例26(I-C-1)对多种肿瘤细胞的增殖均有较好的抑制作用。
实施例30:化合物对干扰素释放的促进作用
在STING激动剂DMXAA存在的条件下,对RAW264.7通过PARP7抑制剂诱导干 扰素-β水平。将生长至对数生长期的RAW264.7细胞涂铺于96孔板中,37℃,5%CO2培养箱中孵育过夜至贴壁。细胞用剂量滴定的PARP7抑制剂和50μg/mL DMXAA共处 理24小时并收集上清液,通过ELISA(R&D,Mouse IFN--beta DuoSet Elisa)根据试剂盒 说明书进行处理,结果参见图1。
由图1可见,本发明化合物能明显促进干扰素β释放,因而可以用于肿瘤的免疫治疗,并且释放量优于阳性药RBN-2397。
实施例31:化合物的大鼠体内药代动力学研究
实验过程:选取雄性SD大鼠6只,3只口服给药(10mg/kg),3只静脉注射(1mg/kg),分别采集0分钟、2分钟、5分钟、10分钟、20分钟、30分钟、60分钟、2小时、4小 时、6小时、8小时血样,离心(3000转/5分钟),采集上清液使用LC-MS-MS进行分 析,结果使用winnonlin软件进行分析,具体结果如下表3所示。
表3.受试化合物在SD大鼠体内的药代动力学数据
IV:表示静脉注射,PO:表示灌胃给药
实验结果表明,本发明实施例1(I-A-1)的化合物在SD大鼠上具有良好的药代动力学性质。相较于阳性药RBN-2397,本发明化合物具有更长的半衰期,更大的体内暴 露量,更好的口服生物利用度。
实施例32:化合物的小鼠体内药效研究
对BALB/c小鼠在右侧腹皮下接种CT26细胞以发展肿瘤。在肿瘤接种后四天,选 择肿瘤尺寸在55-75mm3(平均肿瘤尺寸63mm3)范围内的24只小鼠并且基于其肿瘤 体积,随机划分为4组,每组6只小鼠。在随机分组后的第二天(将随机分组当天定义 为第0天)开始给药,分别用媒介物(0.5%甲基纤维素+0.2%吐温80)、化合物RBN-2397 (500mg/kg,每天1次,连续14天灌胃给药)、化合物I-A-1(100mg/kg,每天1次, 连续14天灌胃给药)、化合物I-A-1(50mg/kg,每天2次,连续14天灌胃给药)进行 给药,在给药期间每周测量肿瘤尺寸三次。整个研究在第14天终止,其药效结果参见 图2。
由图2可见,本发明化合物I-A-1在小鼠体内有着明显的抗肿瘤活性,相较于阳性药RBN-2397,本发明化合物I-A-1在更低剂量就能发挥更好的抗肿瘤作用。
Claims (12)
1.一种哒嗪酮类化合物,其特征在于,具有式(I)的结构,所述哒嗪酮类化合物包含其异构体、药学上可接受的盐或它们的混合物:
其中:
m选自0、1、2或3;
R1选自氢、卤素、氰基、三氟甲基、C1~C6的烷基、C1~C6的烷氧基、甲硫基、甲磺酰基、氨甲酰基;
R2或R3分别独立地选自氢、C1~C6烷基、取代的C3~C6环烷基或杂环烷基、氰基、三氟甲基,或者R2和R3与所连碳原子一起形成C3~C6环烷基;所述C3~C6环烷基的取代基选自氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基,所述取代基为一个或多个;
R4选自取代的芳基、取代的杂芳基或取代的1,3-苯并二噁烷基,所述杂芳基或1,3-苯并二噁烷基的取代基选自氢、卤素、氰基、三氟甲基、2,2,-二氟乙基、C1~C6的烷基、C1~C6的烷氧基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲氧羰基或硝基,所述取代基为一个或多个;
A1选自-NH-、-O-、-S-或-N(CH3)-;
R5选自氢、卤素、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、二乙氨基或乙酰氨基,R5为一个或多个;
3.根据权利要求1或2所述的哒嗪酮类化合物,其特征在于,所述结构中:
m为0。
4.根据权利要求1或2所述的哒嗪酮类化合物,其特征在于,所述结构中:
R1为三氟甲基,R2为氢,R3为甲基,与R3相连的碳原子为S构型。
7.根据权利要求1或2所述的哒嗪酮类化合物,其特征在于,所述哒嗪酮类化合物为以下任一化合物:
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-1),
(S)-4-三氟甲基-5-((1-(3-(4-(5-(4-三氟甲基)苯基))嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)-丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-2),
(S)-2-(4-(1-(2-((6-氧代-5-三氟甲基-1,6-二氢哒嗪-4-基)氨基)丙基)氮杂环丁烷-3-羰基)哌嗪-1-基)嘧啶-5-腈(I-A-3),
(S)-5-((1-(3-(4-(5-甲磺酰基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-4),
(S)-5-((1-(3-(4-(5-氯嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-5),
(S)-5-((1-(3-(4-(5-甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-6),
(S)-5-((1-(3-(4-(5-溴嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-7),
(S)-5-((1-(3-(4-(5-氟嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-8),
(S)-5-((1-(3-(4-(5-甲氧基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-9),
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基吡啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-10),
(S)-4-三氟甲基-5-((1-(3-(4-(4-三氟甲基苯基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-11),
(S)-5-((1-(3-(4-(二苯并[b,d]呋喃-4-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-12),
(S)-4-三氟甲基-5-((1-(3-(4-(4-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-13),
(S)-5-((1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙基-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-14),
(S)-1-(2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)-N-(1-(5-三氟甲基嘧啶-2-基)氮杂环丁烷-3-基)氮杂环丁烷-3-甲酰胺(I-A-15),
(S)-N-甲基-1-(2-((6-氧代-5-三氟甲基-1,6-二氢哒嗪-4-基)氨基)丙基)-N-(1-(5-三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氮杂环丁烷-3-甲酰胺(I-A-16),
5-(((2S)-1-(3-(2,6-二甲基-4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-A-17),
4-三氟甲基-5-((((S)-1-((S)-3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基]吡咯烷-1-基))丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-18),
(S)-4-三氟甲基-5-((1-(4-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)哌啶-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-19),
4-三氟甲基-5-((2-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)乙基)氨基)哒嗪-3(2H)-酮(I-A-20),
(S)-4-三氟甲基-5-((4-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丁基-2-基)氨基)哒嗪-3(2H)-酮(I-A-21),
(S)-4-氯-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-22),
(S)-4-溴-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-23),
4-三氟甲基-5-((1-((3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)甲基)环丙基)氨基)哒嗪-3(2H)-酮(I-A-24),
(S)-5-((1-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-三氟甲基哒嗪-3(2H)-酮(I-B-1),
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-C-1),
4-三氟甲基-5-((1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁-3-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-D-1)。
8.根据权利要求1或2所述的哒嗪酮类化合物,其特征在于,所述药学上可接受的盐为所述哒嗪酮类化合物与酸形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
9.一种权利要求1~8任一所述的哒嗪酮类化合物的制备方法,其特征在于,所述制备方法为以下任一方法:
(1)当R1选自三氟甲基、氰基或卤素,R2为氢,R3选自甲基或氢,与R3相连甲基为S构型,或R2和R3形成环丙基,R4为A1代表-NH-,A2为/>n1或n2各自独立地代表0或1,A3为/>A4为/>目标化合物I-A的制备方法如下:
(2)当R1选自三氟甲基、氰基或卤素,R2为氢,R3选自甲基或氢,与R3相连甲基为S构型,或R2和R3形成环丙基,R4为A1为-NH-,A2为/>n1或n2各自独立地选自0或1,A3为/>A4为/>目标化合物I-B的制备方法如下:
其中,m、Y1、Y2、R7、R8、R9、R10的定义如权利要求1~7任一所述;Boc为叔丁氧羰基;P为(三甲基硅)乙氧基甲基(SEM)或对甲氧基苄基(PMB);
将相应的酸与以上方法制备的化合物(I)成盐,即得所述哒嗪酮类化合物的药学上可接受的盐。
10.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~8任一所述哒嗪酮类化合物以及药学上可接受的载体。
11.一种权利要求1~8任一所述的哒嗪酮类化合物或权利要求10所述的药物组合物在制备PARP7抑制剂药物中的应用。
12.根据权利要求11所述的应用,其特征在于,所述药物为抗肿瘤药物。
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