CN117186061A - 4-羰基氨基异吲哚啉-1-酮衍生物、包括其的组合物及使用方法 - Google Patents
4-羰基氨基异吲哚啉-1-酮衍生物、包括其的组合物及使用方法 Download PDFInfo
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- CN117186061A CN117186061A CN202211670364.1A CN202211670364A CN117186061A CN 117186061 A CN117186061 A CN 117186061A CN 202211670364 A CN202211670364 A CN 202211670364A CN 117186061 A CN117186061 A CN 117186061A
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- alkylene
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- -1 4-carbonylaminoisoindolin-1-one derivatives Chemical class 0.000 title claims abstract description 49
- 239000000203 mixture Substances 0.000 title claims description 14
- 238000000034 method Methods 0.000 title description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 176
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 230000003287 optical effect Effects 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 22
- 230000000155 isotopic effect Effects 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims description 124
- 238000002360 preparation method Methods 0.000 claims description 122
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 33
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- 239000003814 drug Substances 0.000 claims description 27
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
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- 125000000217 alkyl group Chemical group 0.000 claims description 21
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- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 20
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- 239000000243 solution Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 16
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
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- 238000005406 washing Methods 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 9
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- 238000003786 synthesis reaction Methods 0.000 claims description 9
- 125000002723 alicyclic group Chemical group 0.000 claims description 8
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 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
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
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- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 201000005787 hematologic cancer Diseases 0.000 claims description 5
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-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
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-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
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 239000012317 TBTU Substances 0.000 claims description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical group 0.000 claims description 4
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000732 arylene group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
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- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
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- 239000005720 sucrose Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
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- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
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- 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
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
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- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 claims description 2
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
一种式(I)所示的4‑羰基氨基异吲哚啉‑1‑酮类化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物;及它们的药物组合物和用途。该化合物具有良好的抗多发性骨髓瘤活性,能够有效治疗和/或预防多发性骨髓瘤的生长繁殖。
Description
技术领域
本发明涉及一类4-羰基氨基异吲哚啉-1-酮化合物、其制备方法、包含其的药物组合物及用途。
背景技术
由于人口结构、生态环境及生活方式的持续改变,癌症逐渐成为威胁人类健康的最主要疾病之一。手术、放疗、化疗是目前用于癌症治疗的最常见方法。对于身体某部位的实体肿瘤,外科手术是治疗癌症的一线治疗方法。在接受手术之后,结合高能量的粒子射线摧残剩余的癌细胞-放疗,防止癌症复发,也是目前常规的治疗方法。在肿瘤体积较小,或针对不能使用手术疗法的癌症如血液瘤,可直接进行放疗或化疗。化疗药物通常通过结合细胞DNA来阻止分裂增殖、杀死正在分裂的细胞来起作用,目前已经有超过100种不同类型的化疗药物。但由于放疗和化疗都缺乏选择性,往往会带来严重的副作用。此外,化疗药物的耐药性也是癌症治疗的主要障碍之一。靶向治疗和免疫治疗是近年来提出的治疗癌症的新方法,给肿瘤耐药及肿瘤晚期患者带来了希望。分子靶向药物和免疫治疗药物已升级成为血液恶性肿瘤患者主要治疗手段,彻底改变了整个血液病的治疗模式。因此,开发更多、更精准的靶向治疗和免疫治疗方法,是预防、治疗和管理癌症及其他疾病必要途径。
血液系统病,尤其是恶性血液病(malignant hematopathy,MH),已严重威胁到人类的生命健康,临床上常见包括急性白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征等。其中,多发性骨髓瘤(multiple myeloma,MM)是一种克隆性浆细胞异常增殖的恶性疾病。由于单克隆浆细胞恶性增生、广泛浸润并分泌大量单克隆免疫球蛋白,从而导致广泛的骨质破坏、反复感染、贫血、高钙血症及肾功能不全等一系列临床症状。目前该疾病多发于中老年群体,是第二大血液系统恶性肿瘤。然而MM仍无法治愈,几乎所有的患者在整个病程中都要经历复发、耐药等问题,因此如何诊治和提高复发MM患者的疗效和预后是备受关注的问题。
新确诊的MM通常对很多细胞毒性药物敏感,治疗以诱导化疗后序贯自体造血干细胞移植(ASCT)为主,疗效通常可以持续,但绝大多数难逃复发、进展的命运。然而,沙利度胺、硼替佐米、来那度胺等新药的产生更改了多发性骨髓瘤的治疗方案。其中,主要治疗方案硼替佐米/来那度胺/地塞米松(VRD)、硼替佐米/环磷酰胺/地塞米松(VCD)、硼替佐米/沙利度胺/地塞米松(VTD)等。
骨髓增生异常综合征(myelodysplastic syndromes,MDS)是一组起源于造血干细胞的异质性髓系克隆性疾病,其特点是髓系细胞发育异常,表现为无效造血、难治性血细胞减少,高风险向急性髓系白血病(AML)转化,因此被称为白血病前期的恶性肿瘤。MDS的风险随年龄增长而升高。新近统计MDS年发病率为4/10万,在80岁以上人群达50/10万。多数MDS患者需要长期反复输血,统计发现超过90%MDS患者患病期间需要输血,其中30%-45%患者会有输血依赖,患者长期输血会导致铁过载的出现,若不进行适当的治疗,将导致严重的器官功能异常或死亡。尽管通过地西他滨、阿扎胞苷(AZA)、沙利度胺、来那度胺、造血干细胞移植(HSCT)等方法治疗MDS已经改善了患者的生命质量,但仍无法消灭MDS的恶性克隆作用。
其中,免疫调节剂沙利度胺、来那度胺均为谷氨酸衍生物,其主要通过直接的抗肿瘤作用、免疫调节作用及抗血管生成等机制实现对肿瘤的靶向治疗。(参考文献:N.Ferrara,R.S.Kerbel,Angiogenesis as a therapeutic target,Nature,438(2005)967-974.)。沙利度胺由于其引发婴儿产生严重的先天畸形于20世纪60年代曾被FDA召回,但目前,沙利度胺仍被用于治疗多发性骨髓瘤和其他血液癌症,当然药物安全性和严重的副作用仍是其无法回避的事实。来那度胺作为沙利度胺衍生物,自2005年由美国Celegene公司开发上市后,分别被批准用于治疗骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、滤泡性淋巴瘤或边缘区淋巴瘤等疾病。但FDA对来那度胺加了黑框警告,黑框警告内容包括胚胎胎儿毒性,血液学毒性(包括显著的中性粒细胞减少和血小板减少症)和静脉和动脉血栓栓塞。
此外,在多发性骨髓瘤中,由于癌细胞对氨基酸等营养物质的需求特别高,因此L型氨基酸转运体1(LAT1/SLC7A5)表达量异常升高。LAT1是L型氨基酸的摄入细胞内必须借助的跨膜转运体,在多种恶性肿瘤中异常高表达(参考文献:The L-Type Amino AcidTransporter LAT1-An Emerging Target in Cancer,International Journal ofMolecular Science (2019).),因此LAT1被认为是癌症治疗的重要药物靶标。
除此之外,来那度胺在水中溶解度差、生物利用度低,毒副作用高也是一直困扰该药物的主要问题。因此,开发降低毒副作用、提高溶解度、提高生物利用度、提高药物靶向性、增加肿瘤细胞中的药物浓度等是新一代免疫调节抑制剂的研究目标。
发明内容
本发明提供一种4-羰基氨基异吲哚啉-1-酮类化合物,如下式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物。具有良好的抗多发性骨髓瘤活性,能够有效治疗和/或预防多发性骨髓瘤的生长繁殖。还提供了包含所述化合物的制备方法、药物组合物和用途。
一种式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,
其中:
A选自-O-,-S-,-NH-,或者A不存在;
Q选自任选取代的亚烷基,或亚烷基亚芳基;
R1选自-H、烷基、-C(O)R4、-C(S)R4、-C(O)OR4、-C(O)NHR4、-C(O)NR4R4’;
R2选自-H、任选取代的烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基、芳基亚烷基、杂芳基、杂芳基亚烷基;
R3选自-H、羟基、烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基、芳基亚烷基、杂芳基、杂芳基亚烷基、亚烷基-OC(O)R4、亚烷基-OC(O)OR4、亚烷基-OC(O)NHR4、亚烷基-OC(O)NR4R4’,或-OR4;
各个R4和R4’相同或者不同,各自独立地选自氢、烷基、烯基、烯基烷基、炔基、炔基烷基、任选取代的芳基、任选取代的杂芳基、任选取代的脂环基、任选取代的脂杂环基、任选取代的芳基亚烷基或任选取代的杂芳基亚烷基;或者R4和R4’形成任选取代的3-7元环;
所述“任选取代的”是指未取代或被一个或多个取代基取代,其中所述“任选取代的亚烷基”、“任选取代的脂环基”、“任选取代的脂杂环基”、“任选取代的芳基”、“任选取代的杂芳基”、“任选取代的芳基亚烷基”和“任选取代的杂芳基亚烷基”的取代基各自独立地选自羟基、氨基、羧基、卤素、硝基、氰基、烷基、烷氧基、芳基、杂芳基、芳基亚烷基、杂芳基亚烷基、芳基氧基、杂芳基氧基、环烷基、脂杂环基、环烷基氧基、杂环烷基氧基、芳基烷氧基、杂芳基烷氧基、烷酰氧基甲基、烷酰氧基、烷氧酰氧基或烷氧酰基。
可选地,所述“烷基”,以及“烷氧基”、“芳基烷氧基”、“杂芳基烷氧基”、“烷酰氧基甲基”、“烷氧酰氧基”、“烷酰氧基”、“烷氧酰基”中的烷基部分各自独立地为C1-20直链或支链烷基,可选地,为C1-17直链或支链烷基,可选地,为C1-10直链或支链烷基,可选地,为C1-7直链或支链烷基,可选地,为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基,异戊基、新戊基、叔戊基、正己基、异己基、庚基、正辛基、正壬基、正癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、或十六烷基;
可选地,所述“亚烷基”、“烯基亚烷基”、“炔基亚烷基”、“芳基亚烷基”、“杂芳基亚烷基”、“亚烷基-OC(O)R4”、“亚烷基-OC(O)OR4”、“亚烷基-OC(O)NHR4”、或“亚烷基-OC(O)NR4R4’”或“亚烷基亚芳基”中的亚烷基部分各自独立地为为C1-20直链或支链亚烷基,可选地,为C1-17直链或支链亚烷基,可选地,为C1-10直链或支链亚烷基,可选地,为C1-8直链或支链亚烷基,可选地,为C1-6直链或支链亚烷基,可选地,为C1-3直链或支链亚烷基,可选地,为亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基,亚异戊基、亚新戊基、亚叔戊基、亚正己基、亚异己基、亚庚基、亚正辛基、亚正壬基、亚正癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、或亚十六烷基;
可选地,所述“环烷基氧基”、“环烷基”中的环烷基部分为C3-8环烷基,可选地,为环丙基、环丁基、环戊基或环己基;
所述“烯基”、“烯基亚烷基”中的烯基部分各自独立地为C2-C20直链或支链烯基,可选地,为C2-C15直链或支链烯基,可选地,为C2-C10直链或支链烯基,可选地,为C2-C8直链或支链烯基,可选地,为C2-C6直链或支链烯基,可选地,为C2-C4直链或支链烯基;
所述“炔基”、“炔基亚烷基”中的炔基部分各自独立地为为C2-C20直链或支链烯基,可选地,为C2-C15直链或支链炔基,可选地,为C2-C10直链或支链炔基,可选地,为C2-C8直链或支链炔基,可选地,为C2-C6直链或支链炔基,可选地,为C2-C4直链或支链炔基;
可选地,所述“脂杂环基”、“杂环烷基氧基”中的杂环基为环上含有选自O、N、S、SO或SO2的1-3个杂原子的C3-8(优选为C4-6)脂杂环基,可选地,为环氧乙烷基、硫杂环丙烷基、氮杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡咯基、吗啉基、哌啶基、或哌嗪基;
可选地,所述“芳基”、“芳基亚烷基”、“芳基烷氧基”、“芳基氧基”中的芳基为6-10元单环或双环稠合芳香环基团;可选地为苯基或萘基;
可选地,所述“亚烷基亚芳基”中的亚芳基为6-10元单环或双环稠合亚芳香环基团;可选地为亚苯基或亚萘基;
可选地,所述“杂芳基”、“杂芳基亚烷基”、“杂芳基氧基”、“杂芳基烷氧基”中的杂芳基各自独立地为含有选自O、N、S、SO或SO2的1-3个杂原子的5-10元单环或双环稠合杂芳香环基团,可选地,为吡咯基、吡唑基、吡啶基、呋喃基、咪唑基、噻唑基、噁唑基、氧杂卓基、硫杂卓基,1H-氮杂卓基、喹啉基、异喹啉基、吲哚基、嘧啶基或吡嗪基、或三唑基。
可选地,R1选自-H,或-(C=O)CH3,-(C=O)OC(CH3)3;
可选地,R2选自-H,甲基、乙基、叔丁基、烯丙基、炔丙基或苄基;
可选地,R3选自-H,-OH,
可选地,式(I)化合物的氨基酸部分为D构型或L构型。
可选地,所述式(I)化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,选自以下化合物:
可选地,本发明一种药物组合物,其包括上述式(I)化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,和药学上可接受的辅料。
可选地,所述的药学上可接受辅料选自:填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料或其它赋形剂。
可选地,所述的药学上可接受的辅料,其填充剂包括乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙、微晶纤维素的一种或几种的组合物;所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇、水的一种或几种的组合物;所述的崩解剂包括淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基纤维素钠、泡腾崩解剂的一种或几种的组合物。
可选地,所述药物组合物的给药方式包括:经口给药(例如,口腔)、舌下给药、肠胃外给药(例如,肌肉内、静脉内或者皮下)、直肠给药(例如,由栓剂或洗剂)、透皮给药(例如,皮肤电穿孔)或者通过吸入给药(例如,气雾剂),并且以固体、液体或气态剂量的形式,包括片剂和混悬剂给药等。可以在连续治疗下,以单一单位剂量形式,或以随意的单一剂量治疗,进行给药。治疗组合物还可以为油乳剂或分散剂的形式,其结合有亲脂性盐如双羟萘酸,或者为可生物降解的持续释放组合物的形式,其用于皮下或者肌肉内给药。
可选地,所述药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。所述固体及液体口服制剂包括:片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂、糖浆剂和溶液剂。所述的注射剂包括:小针、大输液、冻干粉针等。
又一方面,本发明提供一种上述式(I)的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,或上述药物组合物在制备用于预防和/或治疗血液系统疾病的药物中的用途;优选地,所述的疾病选自血癌和骨髓癌、淋巴瘤、卡波西肉瘤或骨髓增生异常综合征。本发明所提供的化合物可用于治疗、预防或管理原发或转移性肿瘤。
又一方面,本发明还提供一种如上述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物的制备方法;
包括将式(A)化合物和式(B)化合物通过步骤A得到式(C)化合物:
步骤A:将式(A)和式(B)通过取代反应制得式(C);
可选地,将式(A)和式(B)在碱(例如碳酸钾,碳酸铯,氢化钠,双三甲基硅基胺基锂等)催化下,在适合的溶剂中(例如N,N-二甲基甲酰胺,N,N-二甲基甲酰胺,二甲亚砜,N-甲基吡咯烷酮等),于0℃至25℃温度条件下,通过取代反应制得式(C)。
其中,
式(B)和式(C)中R3如式(I)中所述,但不为H,OR4;
式(B)中,B选自Cl,Br,I,OTs,OMs;
可选地,式(B)可以采用如下方法1-8中的一种,但并不限于以下方法:
方法1:
1)将羧基与二氯亚砜在回流条件下反应得到酰氯;2)将酰氯和多聚甲醛在氯化锌催化剂条件下制得式(B)化合物;
或方法2:
在室温下,向剧烈搅拌的酸的二氯甲烷溶液中加入饱和碳酸氢钠溶液和催化量四丁基硫酸氢铵,然后加入氯磺酸氯甲酯,反应完成后,分层,收集有机相,无水硫酸钠干燥,减压旋干,柱层析纯化后得式(B)化合物。
或方法3:
0℃下,向氯甲酸氯甲酯的二氯甲烷溶液中加入相应的仲胺,反应完成后,过滤,有机相用1N盐酸洗,无水硫酸钠干燥,减压除去溶剂,得式(B)化合物。
或方法4:
0℃下,向氯甲酸氯甲酯的二氯甲烷溶液中加入吡啶,然后加入相应的醇,反应完成后,过滤,有机相用1N盐酸洗,无水硫酸钠干燥,减压除去溶剂,得式(B)化合物。
或方法5:
将氯甲基试剂和溴化钠(或溴化钾)在乙腈(或丙酮)中回流,反应完成后,减压除去溶剂,加入有机溶剂和水,分层,收集有机相,无水硫酸钠干燥,减压除去溶剂,得相应的溴代式(B)化合物。
或方法6:
将氯甲基试剂和碘化钠(或碘化钾)在乙腈(或丙酮)中回流,反应完成后,减压除去溶剂,加入有机溶剂和水,分层,收集有机相,无水硫酸钠干燥,减压除去溶剂,得相应的碘代式(B)化合物。
或方法7:
将氯甲基试剂和甲磺酸银在乙腈中回流,反应完成后,减压除去溶剂,加入有机溶剂和水,分层,收集有机相,无水硫酸钠干燥,减压除去溶剂,得相应的甲磺基氧基取代的式(B)化合物。
或方法8:
将氯甲基试剂和对甲苯磺酸银在乙腈中回流,反应完成后,减压除去溶剂,加入有机溶剂和水,分层,收集有机相,无水硫酸钠干燥,减压除去溶剂,得相应的对苯磺基氧基取代的式(B)化合物。
各个Y选自-R4、-OR4、-NHR4、NR4R4’,其中R4、R4’如式(I)中所述。
或者,通过以下步骤A’的反应得到式(C):
步骤A’:将S1和S2通过缩合条件得到S3,再将S3经过脱保护得到S4,然后S4和S5在碱催化下通过取代和氨解甲酯得到LN-S5经铁粉还原得到式(C)。
还包括将式(C)和式(D)通过步骤B,
步骤B:将式(C)和式(D)通过酰化反应得式(E)。
优选地,将式(C)和对硝基苯基氯甲酸酯溶于(如四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮等)中,在回流条件下反应,得到式(E);
可选地,所述回流反应结束后,减压浓缩,加入乙酸乙酯、或二氯甲烷或石油醚搅拌均匀得到混悬液,减压过滤并洗涤或直接旋干,得到式(E)。
其中,式(C)和式(E)中,R3定义同上式(I)中所述;
或者,还包括将式(C)和式(F)通过步骤C得到式(G):
步骤C:将式(C)和式(F)通过酰化反应制得式(G);
可选地,式(G)的合成方法:低温下(优选0℃)将式(C)缓慢滴加至三光气的二氯甲烷或乙腈溶液中,缓慢升温至30℃-60℃(优选为45℃),待反应结束,减压浓缩,得式(G)。
其中,式(C)和式(G)中,R3定义同式(I)中所述;
或者,还包括将式(C)和式(H)通过步骤D得到式(J):
步骤D:将式(C)和式(H)通过缩合反应得式(J);
可选地,将式(C)和N,N′-羰基二咪唑分散在四氢呋喃中,在回流条件下反应,待反应结束,减压浓缩,加入乙酸乙酯搅拌均匀得到混悬液,减压过滤并洗涤或直接旋干,得式(J)。
其中,式(C)和式(J)中,R3定义同式(I)中所述;
当式(I)中A选自-O-,-S-,-NH-时,将式(E)或式(G)或式(J)与式(L)在碱催化下经亲核取代反应和任选的脱保护反应得到式(I),如以下合成步骤E:
步骤E:
式(L)中,W选自-OH,-SH,-NH2中的任意一个基团;
R5为Cl,或
式(E,或G或J)中,R3如式(I)所示;
可选地,当R1为Boc,R2为H,-CH3,-CH2CH3,-CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH3,-CH(CH3)2,-CH2CH2OH,或-CH2CHOHCH2OH,任选地采用以下方法脱保护:
将式(M)分散在适合的溶剂中(例如乙酸乙酯或二氧六环),然后通入氯化氢气体(或加入其他酸)脱保护,室温或40℃反应,析出固体,无固体加入乙醚后析出固体,过滤,得式(N)为盐的形式。
当R1为Cbz,R2为H,-CH3,-CH2CH3,-CH2CH2CH2CH3,-CH2CH2CH2CH2CH2CH3,-CH(CH3)2,-CH2CH2OH,或-CH2CHOHCH2OH,任选地采用以下方法脱保护。
将式(O)分散在合适溶剂中(例如甲醇或乙醇),经钯碳氢气还原得式(N)为游离态。游离态化合物也可将式(N)的盐形式分散在合适溶剂中(例如甲醇或乙醇),加等当量碱游离得到。
上述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物的制备方法,还包括将式(C)化合物和式(Q)化合物通过合成方法二得到式(R)化合物:
当式(I)中A不存在时,采用合成步骤F制备:将式(A)或式(C)与式(P)经适合的缩合剂(例如HATU或TBTU)缩合和任选的脱保护反应得式(R)
步骤F:
式(P)中,Q定义如上式(I)中所述。
本发明另一方面,提供所述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物或、或其消旋体、或其同位素标记物、或其氮氧化物或它们的药物组合物与其他一种或多种活性药物(“第二活性化合物”)联合用药,在制备用于预防和/或治疗血液系统疾病的药物中的用途;优选地,所述的疾病选自血癌和骨髓癌、淋巴瘤、卡波西肉瘤或骨髓增生异常综合征;优选地,所述其他活性药物为地塞米松和/或朋替佐米。
优选地,所述的疾病选自血癌和骨髓癌,如急性、慢性白血病以及多发性骨髓瘤,例如成淋巴细胞性白血病、慢性粒细胞白血病、骨髓性白血病、淋巴细胞性白血病、髓细胞性白血病、成人T细胞白血病、卡波西肉瘤、核型急性髓细胞白血病,慢性淋巴细胞白血病(CLL)、霍奇金淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、皮肤B细胞淋巴瘤、弥漫性大B细胞瘤、低级滤泡性淋巴瘤。本发明所提供的化合物可用于治疗、预防或管理原发、转移性、难治性或对化疗、放疗具有耐受性的肿瘤。
其中,“多发性骨髓瘤”是指以恶性浆细胞为特征的血液学病患,包括以下病症:意义未明的单克隆丙种球蛋白病(MGUS);低危、中危和高危多发性骨髓瘤;新诊断的多发性骨髓瘤(包括低危、中危和高危的新诊断的多发性骨髓瘤);适合移植和不适合移植的多发性骨髓瘤;郁积型(惰性)多发性骨髓瘤(包括低危、中危和高危的郁积型多发性骨髓瘤);复发的多发性骨髓瘤;难治性和抗性多发性骨髓瘤;活动性多发性骨髓瘤;孤立性浆细胞瘤;髓外浆细胞瘤;浆细胞白血病;中枢神经系统多发性骨髓瘤;轻链骨髓瘤;非分泌性骨髓瘤;免疫球蛋白D骨髓瘤;免疫球蛋白E骨髓瘤;以及诸如以下的遗传异常为特征的多发性骨髓瘤:细胞周期蛋白D易位(例如,t(11;14)(q13;q32);t(6;14)(q21;q32);t(12;14)(p13;q32)或t(6;20););MMSET易位(例如,t(4;14)(p16;q32));MAF易位(例如,t(14;16)(q32;q32);t(20;22);t(16;22)(q11;q13)或t(14;20)(q32;q11));或其它染色体因子(例如,17p13或13号染色体的缺失;del(17/17p)、非超二倍性和增加(1q))。
如本文中所用,除非另有说明,否则术语“治疗”是指减轻或减少与所治疗的疾病或病患例如多发性骨髓瘤相关的症状的严重性。术语“预防”包括抑制特定疾病或病症例如多发性骨髓瘤的症状。术语“复发”是指治疗后多发性骨髓瘤已缓解的患者在骨髓瘤中有骨髓瘤细胞返回和/或正常细胞减少的情况。术语“难治性和抗性”是指即使经过强化治疗,患者骨髓中仍残留骨髓瘤细胞和/或正常细胞减少的情况。
本发明所述第二活性成分实例可包括以下物质中的一种或多种:美法仑、长春新碱、环磷酰胺、依托泊苷、多柔比星、苯达莫司汀、澳比妥珠单抗、蛋白酶体抑制剂(例如,硼替佐米、卡非佐米、艾莎佐米、奥泊佐米或玛瑞佐米)、组蛋白脱乙酰基酶抑制剂(例如,帕比司他、ACY241)、BET抑制剂(例如GSK778)。
本发明的化合物可以以同位素示踪或富集形式存在,含有一个或多个原子,这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。原子例如氢、碳、磷、硫、氟、氯和碘的同位素包括但不局限于:2H,3H,13C,14C,15N,18O,32P,35S,18F,36Cl和125I。含有这些和/或其它原子的其它同位素的化合物在本发明范围之内。
本文使用的术语“光学异构体”指的是分子结构完全相同,物理化学性质相近,但旋光性不同的物质。包括任意比例光学异构混合物。式(I)化合物可以含有一个或多个不对称碳原子,并且其存在形式可以是旋光纯对映异构体,例如外消旋物的对映异构体混合物、旋光纯非对映异构体、非对映异构体混合物、非对映异构体的外消旋物或非对映异构体的外消旋物的混合物。可以通过例如外消旋物的拆分,通过不对称合成或不对称色谱法(使用手性吸附剂或洗脱剂的色谱法),获得旋光活性形式。本发明包括所有这些形式。
本文使用的术语“药学上可接受的盐”是指药学上可接受的无毒酸所制备的盐,包括无机酸盐和有机酸盐。例如但不限于盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、碳酸、硝酸、硫酸氢酸、甲磺酸、羟基乙磺酸、酒石酸、甲酸、乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、三氟乙酸、丙酮酸、肉桂酸、月桂酸、水杨酸、柠檬酸、琥珀酸、富马酸、苯甲酸、邻氨基苯甲酸、2-(4-羟基苯甲酰基)苯甲酸、苯磺酸、乙磺酸、对氨基苯磺酸、对甲苯磺酸、苯乙酸、抗坏血酸、褐藻酸、糠酸、硬脂酸、粘液酸、扁桃酸、苹果酸、扑酸、泛酸、樟脑磺酸、葡萄糖酸、谷氨酸、葡萄糖醛酸、半乳糖醛酸、缩水甘油酸、乳酸、苹果酸、马来酸、天冬氨酸、硫氰酸、葡庚酸、甘油磷酸、磺基水杨酸、半硫酸、草酸、丙二酸、苦味酸等。
本文所使用的术语“溶剂化物”是指进一步通过非共价分子间力结合的化学量或非化学量的溶剂的化合物。例如当溶剂为水时,该溶剂化物为水合物。
缩略语
DCM:二氯甲烷
DCE:二氯乙烷
THF:四氢呋喃
TFA:三氟乙酸
2-MeTHF:2-甲基四氢呋喃
DMSO:二甲亚砜
DMF:N,N-二甲基甲酰胺
DIPEA:N,N-二异丙基乙胺
HATU:2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯
TBTU:O-苯并三氮唑-N,N,N′,N′-四甲基脲四氟硼酸
NMP:N-甲基吡咯烷酮
DMAC:N,N-二甲基乙酰胺
LiHMDS:双三甲基硅基胺基锂TBS:叔丁基二甲基硅基
LAT1:L型氨基酸转体1
RPMI-8226:人多发性骨髓瘤细胞
NCI-H929:人骨髓瘤细胞
附图说明
图1为不同细胞中LAT1的表达情况。
图2为RPMI-8226模型中小鼠肿瘤体积变化趋势(n=7)。
图3为NCI-H929模型中小鼠肿瘤体积变化趋势(n=7)。
具体实施方式
除非另有定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同的含义。如果本文的术语有多个定义,除非另有说明,否则以本部分为主。
本发明的实施例详细说明如下,但所提供的实施例不以任何方式限制本发明。
实施例
通用合成方法1:
采用步骤F合成。
将式(A)(1.0当量)、式(P)(1.0当量)、三乙胺(1.0当量)和TBTU(1.0当量)溶于DMF当中,在室温条件下搅拌12h。
加入乙酸乙酯,再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相,收集有机相无水硫酸钠干燥,减压蒸干,用硅胶柱层析进行纯化后,加入TFA和DCM,室温搅拌1h,将反应液减压蒸干得白色固体。
上述产物溶解在甲醇中,加入Pd/C,在氢气环境下室温搅拌1h。过滤并收集滤液,减压蒸干,得终产物。
实施例1:化合物43的制备
采用通用合成方法1制备,得白色固体产物,收率83%。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),11.03(s,1H),8.10-7.52(m,4H),7.50(d,J=4.3Hz,2H),5.15(dd,J=13.4,5.1Hz,1H),4.39(m,2H),3.69(s,1H),3.08-2.89(m,2H),2.73-2.60(m,2H),2.36-2.28(m,1H),2.06-2.03(m,1H).
通用合成方法2:
采用步骤B和步骤E合成。
将式(C)(1.0当量)与式(D)(1.5当量)溶于THF中,在回流条件下搅拌2h。减压浓缩,加入乙酸乙酯搅拌均匀得到混悬液,减压过滤并乙酸乙酯洗涤或直接旋干,得式(E)。
将式(E)和式(L)(1.1当量)溶于DMF中,在常温搅拌下滴加DIPEA(1.5当量),继续室温搅拌至原料消失,加入酸水调节pH至3-4,加入乙酸乙酯,再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相,收集有机相无水硫酸钠干燥,过滤得滤液减压蒸干,用硅胶柱层析纯化后,脱保护或不脱保护得式(I)。
其中,式(L)的合成方法:将Boc保护的氨基酸(1.0当量)、碳酸铯(0.5当量)和碘乙烷、或1-碘丁烷、或1-碘己烷、或异丙基碘、或TBS保护的羟乙基碘、或4-(碘甲基)-2,2-二甲基-1,3-二氧环戊烷(1.1当量)分散在DMF中,室温搅拌过夜,萃取、柱层析得产物式(L)。
实施例2:化合物44的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率86.36%。
1H NMR(600MHz,DMSO-d6)δ11.02(s,1H),9.70(s,1H),8.59(s,2H),7.82-7.70(m,1H),7.50(dd,J=6.3,2.5Hz,2H),5.14(dt,J=13.3,4.7Hz,1H),4.63(ddd,J=12.1,8.7,3.5Hz,1H),4.51-4.33(m,3H),4.30(s,1H),2.99-2.88(m,1H),2.67-2.59(m,1H),2.37-2.27(m,1H),2.08-2.01(m,1H).
实施例3:化合物45的制备
采用通用合成方法1制备,得白色固体产物,收率86%。
1H NMR(400MHz,DMSO-d6)δ10.68(d,J=14.6Hz,1H),7.95-7.93(m,1H),7.49-7.45(m,2H),5.13(dd,J=13.1,4.9Hz,1H),4.49-4.33(m,2H),3.46-3.42(m,1H),3.17(s,1H),2.94-2.88(m,1H),2.61-2.55(m,3H),2.37-2.31(m,1H),2.03-1.96(m,3H).
实施例4:化合物46的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率33.72%。
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.21(s,1H),8.76(s,3H),7.79(dt,J=8.0,4.0Hz,1H),7.59-7.50(m,2H),7.31(d,J=8.6Hz,2H),7.22(d,J=8.6Hz,2H),5.15(dd,J=13.3,5.1Hz,1H),4.53(d,J=17.6Hz,1H),4.43(d,J=17.6Hz,1H),4.29(t,J=6.4Hz,1H),3.70(s,3H),3.18(ddd,J=21.2,14.2,6.5Hz,2H),2.98-2.86(m,1H),2.62(d,J=16.8Hz,1H),2.38(dd,J=13.1,4.5Hz,1H),2.11-2.00(m,1H).
实施例5:化合物47的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率55.55%。
1H NMR(600MHz,DMSO-d6)δ11.02(s,1H),9.54(d,J=15.4Hz,1H),8.49(s,2H),7.84-7.69(m,1H),7.60-7.32(m,2H),5.23-5.10(m,2H),4.45(dd,J=17.4,13.1Hz,1H),4.34(dd,J=17.4,8.6Hz,1H),4.09(s,1H),3.00-2.86(m,1H),2.65-2.59(m,1H),2.31(qd,J=13.0,5.4Hz,1H),2.08-2.00(m,1H),1.41(d,J=6.6Hz,3H).
实施例6:化合物49的制备
采用通用合成方法2制备,得白色固体,收率82.91%。
1H NMR(600MHz,DMSO-d6)δ12.88(s,1H),10.99(s,1H),10.32(s,1H),8.27(d,J=8.1Hz,1H),7.75-7.70(m,1H),7.56-7.49(m,2H),5.13(dd,J=12.9,4.6Hz,1H),4.46-4.30(m,3H),3.40(ddd,J=13.6,7.1,5.1Hz,1H),3.09(dt,J=13.7,8.2Hz,1H),2.96-2.87(m,1H),2.60(d,J=16.8Hz,1H),2.37(td,J=13.3,8.9Hz,1H),2.06-1.99(m,1H),1.85(d,J=1.9Hz,3H).
实施例7:化合物50的制备
采用通用合成方法2制备,得白色固体。收率86.36%。
1H NMR(DMSO-d6,600MHz):δ8.12(s,1H),7.62(s,1H),7.37(s,1H),7.21-7.26(m,2H),4.75-4.76(m,1H),4.39-4.57(m,3H),3.50(s,2H),3.01(s,2H),2.67-2.77(m,1H),2.04-2.33(m,4H),1.41-1.72(m,3H).
实施例8:化合物72的制备
采用通用合成方法2制备,用甲磺酸进行脱保护,,得甲磺酸盐为白色固体,收率27.31%。
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.17(s,1H),8.44(s,3H),7.82-7.76(m,1H),7.57-7.51(m,2H),7.26(dd,J=23.2,8.6Hz,4H),5.16(dd,J=13.3,5.1Hz,1H),4.51(d,J=17.6Hz,1H),4.39(dd,J=20.0,11.5Hz,2H),3.72(s,3H),3.12(d,J=5.1Hz,2H),2.99-2.87(m,1H),2.62(d,J=16.5Hz,1H),2.40-2.30(m,4H),2.09-1.99(m,1H).
实施例9:化合物73的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率58.84%。
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.20(s,1H),8.47(s,3H),7.78(dd,J=8.9,4.0Hz,1H),7.57-7.49(m,2H),7.34(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),5.15(dd,J=13.3,5.1Hz,1H),4.52(d,J=17.7Hz,1H),4.42(d,J=17.7Hz,1H),4.18(t,J=6.2Hz,1H),3.16(d,J=6.1Hz,2H),3.02-2.86(m,1H),2.62(d,J=16.8Hz,1H),2.37(dd,J=13.1,4.4Hz,1H),2.10-2.00(m,1H).
实施例10:化合物74的制备
采用通用合成方法2制备,用浓硫酸进行脱保护,得硫酸盐为白色固体,收率54.82%。
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.16(s,1H),8.42(s,3H),7.82-7.76(m,1H),7.54(d,J=3.6Hz,2H),7.26(dd,J=21.2,8.4Hz,4H),5.16(dd,J=13.2,4.9Hz,1H),4.53-4.35(m,3H),3.72(s,3H),3.11(d,J=6.6Hz,2H),2.98-2.89(m,1H),2.64-2.59(m,1H),2.38-2.34(m,1H),2.08-2.01(m,1H).
通用合成方法3:
采用步骤A、步骤C(或步骤D)和步骤E合成。
第一步:氯甲基试剂的制备
(1)在室温下,向剧烈搅拌的苯甲酸、或取代的苯甲酸、或正癸酸、或正十二酸、或正十四酸(1.0当量)的DCM溶液中加入饱和碳酸氢钠和四丁基硫酸氢铵(0.1当量)、氯磺酸氯甲酯(1.2当量),反应完成后,分层,收集有机相,无水硫酸钠干燥,减压旋干,柱层析纯化后得式(B)。
(2)将吗啉、或二甲胺、或二乙胺(1.0当量),DIPEA和DMAP溶于DCM中,降温至0℃,缓慢滴加氯甲酸氯甲酯(1.1当量)的DCM中,室温反应1.5h,加入DCM、用1N盐酸、饱和食盐水萃取,无水硫酸钠干燥,减压蒸馏得式(B)。
第二步:
将式(A)(1.0当量)、式(B)(1.2当量)(购买或自制)和碳酸铯(1.2当量)加入到DMF中,0℃至25℃搅拌3h。加入乙酸乙酯,再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相,收集有机相无水硫酸钠干燥,过滤得到滤液减压蒸干,用硅胶柱层析进行纯化得式(C)。
将式(C)(1.0当量)、式(F)(0.43当量)或式(H)(1.0当量)分散在乙腈中,在40℃搅拌1h,减压蒸干得式(G)或式(J)。
第三步:
将式(L)溶解在DCM中,降温至0℃,加入DIPEA和式(G)或式(J)的DCM溶液。低温反应30分钟后用稀酸水淬灭后,有机相用无水硫酸钠干燥后,减压蒸馏、柱层析纯化后得式(M)或式(O)后,脱保护得式(I)。
实施例11:化合物75的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率92.31%。
1H NMR(600MHz,DMSO-d6)δ10.18(s,1H),8.55(s,3H),7.94(d,J=7.3Hz,2H),7.81(d,J=6.6Hz,1H),7.68(t,J=7.4Hz,1H),7.57-7.43(m,4H),7.25(dd,J=44.2,8.4Hz,4H),5.94(d,J=9.6Hz,1H),5.87(d,J=9.6Hz,1H),5.38(dd,J=13.4,5.0Hz,1H),4.56(d,J=17.6Hz,1H),4.45(d,J=17.5Hz,1H),4.33(s,1H),3.71(s,3H),3.20-3.07(m,3H),2.89(d,J=16.3Hz,1H),2.19-2.07(m,1H).
实施例12:化合物77的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率78.42%。
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.49(s,1H),9.09(s,1H),8.63-7.92(m,4H),7.44(td,J=16.7,7.3Hz,4H),7.18(d,J=8.5Hz,2H),5.16(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.2Hz,1H),4.33(d,J=17.2Hz,1H),4.13(t,J=6.1Hz,1H),3.12-2.99(m,2H),3.00-2.86(m,1H),2.63(d,J=16.9Hz,1H),2.32(qd,J=13.1,4.3Hz,1H),2.11-2.01(m,1H).
实施例13:化合物78的制备
采用通用合成方法3制备,,得盐酸盐为白色固体,收率85.62%。
1H NMR(400MHz,DMSO-d6)δ13.92(s,1H),10.20(s,1H),8.38(s,3H),8.02-7.90(m,2H),7.81(dd,J=6.1,2.8Hz,1H),7.68(dt,J=8.7,1.3Hz,1H),7.62-7.41(m,4H),7.32(d,J=8.6Hz,2H),7.22(d,J=8.6Hz,2H),5.94(d,J=9.7Hz,1H),5.87(d,J=9.6Hz,1H),5.39(dd,J=13.4,5.0Hz,1H),4.56(d,J=17.7Hz,1H),4.44(d,J=17.6Hz,1H),4.21(s,1H),3.23-3.08(m,3H),2.95-2.82(m,1H),2.44(dd,J=13.3,8.9Hz,1H),2.18-2.08(m,1H).
实施例14:化合物82的制备
采用通用合成方法2制备,,得盐酸盐为白色固体,收率78.31%。
1H NMR(600MHz,DMSO-d6)δ11.02(s,1H),9.68(s,1H),8.70(s,3H),7.71(dd,J=10.9,4.7Hz,1H),7.58-7.40(m,2H),5.15(dd,J=13.3,5.0Hz,1H),4.66-4.56(m,1H),4.50-4.40(m,3H),4.35(dd,J=17.5,4.7Hz,1H),3.79(d,J=3.6Hz,3H),2.99-2.85(m,1H),2.66-2.60(m,1H),2.31(qd,J=13.2,4.4Hz,1H),2.09-2.01(m,1H).
实施例15:化合物83的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率90.57%。
1H NMR(600MHz,DMSO-d6)δ11.03(d,J=4.3Hz,1H),9.64(d,J=3.5Hz,1H),8.72(s,3H),7.72(dd,J=8.9,4.4Hz,1H),7.52(t,J=6.3Hz,2H),5.27-5.06(m,2H),4.44(dd,J=17.5,3.6Hz,1H),4.33(dd,J=17.5,4.4Hz,2H),3.77(d,J=5.0Hz,3H),2.99-2.87(m,1H),2.63(d,J=18.1Hz,1H),2.36-2.26(m,1H),2.11-2.02(m,1H),1.41(d,J=6.6Hz,3H).
实施例16:化合物84的制备
采用通用合成方法2制备,,得盐酸盐为白色固体,收率56.93%。
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),11.58(s,1H),8.62(s,3H),7.74-7.70(m,1H),7.58-7.52(m,2H),5.15(dd,J=13.3,5.1Hz,1H),4.45-4.32(m,3H),3.75(d,J=1.76Hz,3H),3.47-3.40(m,2H),2.98-2.86(m,1H),2.62(d,J=16.8Hz,1H),2.38(dd,J=13.1,4.5Hz,1H),2.11-2.00(m,1H).
实施例17:化合物85的制备
采用通用合成方法2制备,,得盐酸盐为白色固体,收率54.28%。
1H NMR(600MHz,DMSO-d6)δ11.02(s,1H),8.38(s,2H),7.73(dd,J=12.9,7.8Hz,1H),7.57-7.51(m,2H),5.15(dd,J=13.3,3.4Hz,1H),4.47-4.31(m,2H),4.13(s,1H),3.47(dd,J=14.6,5.0Hz,1H),3.36(dd,J=14.8,6.3Hz,1H),2.97-2.86(m,1H),2.64-2.59(m,1H),2.37-2.29(m,1H),2.04(dd,J=9.0,3.7Hz,1H).
实施例18:化合物86的制备
采用通用合成方法3制备,,得盐酸盐为白色固体,收率82.87%。
1H NMR(600MHz,DMSO-d6)δ9.70(s,1H),8.75(s,3H),7.99-7.91(m,2H),7.75(d,J=4.8Hz,1H),7.69(t,J=7.4Hz,1H),7.57-7.49(m,4H),5.93(d,J=9.7Hz,1H),5.88(d,J=9.6Hz,1H),5.37(dd,J=13.4,4.9Hz,1H),4.65-4.55(m,1H),4.55-4.30(m,4H),3.78(d,J=3.5Hz,3H),3.22-3.09(m,1H),2.89(dd,J=13.6,2.5Hz,1H),2.44-2.38(m,1H),2.19-2.10(m,1H).
实施例19:化合物87的制备
采用通用合成方法3制备,,得盐酸盐为白色固体,收率84.25%。
1H NMR(600MHz,DMSO-d6)δ10.65(d,J=7.8Hz,1H),8.75(s,3H),8.00-7.88(m,2H),7.76(ddd,J=12.9,7.9,0.8Hz,1H),7.69(t,J=7.4Hz,1H),7.64-7.45(m,4H),5.93(d,J=9.6Hz,1H),5.88(d,J=9.6Hz,1H),5.38(dd,J=13.5,5.0Hz,1H),4.50(dd,J=17.5,14.3Hz,1H),4.42-4.26(m,2H),3.74(d,J=3.0Hz,3H),3.51-3.40(m,2H),3.21-3.07(m,1H),2.91-2.84(m,1H),2.48-2.41(m,1H),2.17-2.08(m,1H).
实施例20:化合物88的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率56.85%。
1H NMR(600MHz,DMSO-d6)δ9.68(s,1H),8.78(s,3H),7.96-7.89(m,2H),7.80-7.74(m,1H),7.69(td,J=7.4,1.3Hz,1H),7.58-7.49(m,4H),5.94(dd,J=9.6,4.2Hz,1H),5.88(dd,J=9.6,1.9Hz,1H),5.37(ddd,J=13.5,10.9,5.0Hz,1H),5.23-5.16(m,1H),4.51(dd,J=17.4,7.4Hz,1H),4.42-4.30(m,2H),3.75(d,J=10.2Hz,3H),3.21-3.11(m,1H),2.93-2.86(m,1H),2.44-2.35(m,1H),2.19-2.09(m,1H),1.41(d,J=6.6Hz,3H).
实施例21:化合物89的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率71.08%。
1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),8.61(s,2H),7.96-7.91(m,2H),7.85-7.77(m,1H),7.68(td,J=7.5,1.3Hz,1H),7.60-7.47(m,4H),5.94(dd,J=9.7,1.8Hz,1H),5.87(d,J=9.6Hz,1H),5.36(dt,J=11.4,5.6Hz,1H),5.26-5.13(m,1H),4.53(d,J=17.5Hz,1H),4.39(dd,J=17.4,5.6Hz,1H),4.13(d,J=4.0Hz,1H),3.20-3.10(m,1H),2.90(dd,J=13.7,2.6Hz,1H),2.46-2.36(m,1H),2.18-2.10(m,1H),1.43-1.39(m,3H).
实施例22:化合物90的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率76.65%。
1H NMR(600MHz,DMSO-d6)δ7.96-7.90(m,2H),7.76(dd,J=12.6,7.9Hz,1H),7.69(t,J=7.4Hz,1H),7.61-7.50(m,4H),5.93(d,J=9.6Hz,1H),5.88(d,J=9.7Hz,1H),5.38(ddd,J=13.5,4.8,3.3Hz,1H),4.49(dd,J=17.5,12.5Hz,1H),4.38(dd,J=17.5,11.2Hz,1H),4.17-4.07(m,1H),3.50-3.43(m,1H),3.41-3.36(m,1H),3.20-3.12(m,1H),2.88(d,J=17.6Hz,1H),2.48-2.39(m,1H),2.16-2.06(m,1H).
实施例23:化合物91的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率72.36%。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.58(s,3H),8.02-7.82(m,2H),7.84-7.72(m,1H),7.74-7.64(m,1H),7.62-7.40(m,4H),5.99-5.79(dd,J=25.1,9.6Hz,2H),5.44-5.30(m,1H),4.67-4.57(m,1H),4.56-4.35(m,3H),4.28(t,J=4.2Hz,1H),3.22-3.07(m,1H),2.95-2.83(m,1H),2.43-2.35(m,1H),2.20-2.06(m,1H).
实施例24:化合物93的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率90.57%。
1H NMR(600MHz,DMSO-d6)δ10.16(s,1H),8.55(s,3H),7.83-7.78(m,1H),7.58-7.52(m,2H),7.29(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),5.69(d,J=9.4Hz,1H),5.61(d,J=9.4Hz,1H),5.33(dd,J=13.5,5.0Hz,1H),4.77(m,J=6.3Hz,1H),4.48(dd,J=67.0,17.6Hz,2H),4.32(t,J=6.6Hz,1H),3.71(s,3H),3.19-3.07(m,3H),2.86(dd,J=17.1,14.3Hz,1H),2.41(dd,J=13.2,4.4Hz,1H),2.15-2.04(m,1H),1.22(d,J=6.2Hz,6H).
实施例25:化合物94的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率90.57%。
1H NMR(600MHz,DMSO-d6)δ10.57(s,1H),8.59(s,3H),7.75(dd,J=15.8,8.0Hz,1H),7.56(m,J=15.4,7.7Hz,2H),5.65(dd,J=54.0,9.4Hz,2H),5.34(dd,J=13.5,5.0Hz,1H),4.77(m,J=12.5,6.2Hz,1H),4.38(m,J=26.0,22.9,13.9Hz,3H),3.75(d,J=2.5Hz,3H),3.50-3.38(m,2H),3.16-3.06(m,1H),2.85(d,J=16.1Hz,1H),2.44-2.39(m,1H),2.13-2.07(m,1H),1.22(d,J=6.2,1.8Hz,6H).
实施例26:化合物95的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率59.68%。
1H NMR(600MHz,DMSO-d6)δ10.57(s,1H),8.45(s,3H),7.80-7.72(m,1H),7.56(m,J=15.4,7.6Hz,2H),5.70(d,J=9.4Hz,1H),5.61(d,J=9.4Hz,1H),5.33(m,J=13.5,5.0,2.9Hz,1H),4.77(m,J=6.2Hz,1H),4.46(dd,J=17.5,13.1Hz,1H),4.35(dd,J=17.5,11.1Hz,1H),4.18(d,J=4.9Hz,1H),3.50-3.40(m,2H),3.16-3.07(m,1H),2.85(d,J=17.4Hz,1H),2.42(d,J=4.4Hz,1H),2.13-2.06(m,1H),1.22(d,J=6.2,1.8Hz,6H).
实施例27:化合物96的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率65.42%。
1H NMR(600MHz,DMSO-d6)δ13.85(s,1H),10.16(s,1H),8.37(s,3H),7.80(dd,J=6.3,2.4Hz,1H),7.58-7.52(m,2H),7.33(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),5.65(dd,J=47.4,9.4Hz,2H),5.33(dd,J=13.4,5.0Hz,1H),4.77(dt,J=12.5,6.2Hz,1H),4.48(dd,J=66.4,17.5Hz,2H),4.20(s,1H),3.18-3.06(m,3H),2.91-2.80(m,2H),2.14-2.06(m,1H),1.22(d,J=6.2Hz,6H).
实施例28:化合物97的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率67.24%。
1H NMR(400MHz,DMSO-d6)δ9.72(d,J=5.3Hz,1H),8.77(s,3H),7.79-7.70(m,1H),7.56-7.49(m,2H),5.65(dd,J=36.3,9.4Hz,2H),5.33(dd,J=13.5,5.0Hz,1H),4.84-4.71(m,1H),4.62(td,J=11.7,3.3Hz,1H),4.45(dt,J=15.3,6.1Hz,3H),4.35(dd,J=17.5,4.1Hz,1H),3.79(d,J=2.6Hz,3H),3.18-3.04(m,1H),2.89-2.8l(m,1H),2.43-2.34(m,1H),2.15-2.06(m,1H),1.22(d,J=6.2Hz,6H).
实施例29:化合物98的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率37.95%。
1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.62(s,3H),7.75(t,J=8.1Hz,1H),7.63-7.51(m,2H),5.63(dd,J=27.7,9.4Hz,2H),5.32(dd,J=13.4,4.9Hz,1H),4.5l-4.30(m,3H),3.75(s,3H),3.54(s,4H),3.44(d,J=5.0Hz,2H),3.32(d,J=4.6Hz,4H),3.16-3.06(m,1H),2.84(d,J=17.1Hz,1H),2.42-2.32(m,1H),2.10(d,J=5.5Hz,1H).
实施例30:化合物99的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率26.70%。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.54(s,3H),7.80(dd,J=5.9,3.1Hz,1H),7.59-7.53(m,2H),7.26(m,J=30.4,8.6Hz,4H),5.63(dd,J=34.2,9.3Hz,2H),5.3l(dd,J=13.4,5.0Hz,1H),4.47(dd,J=52.7,17.5Hz,2H),4.33(s,1H),3.71(s,3H),3.52(s,4H),3.32-3.26(m,4H),3.11(m,J=13.3,6.6Hz,3H),2.84(d,J=16.6Hz,1H),2.40(dd,J=13.0,4.4Hz,1H),2.15-2.06(m,1H).
实施例3l:化合物100的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率61.23%。
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.67(s,3H),7.74(d,J=4.3Hz,1H),7.56-7.51(m,2H),5.62(dd,J=29.7,9.3Hz,2H),5.31(dd,J=13.4,5.0Hz,1H),4.66-4.58(m,1H),4.53-4.30(m,4H),3.79(s,3H),3.54(s,4H),3.31(m,J=4.7Hz,4H),3.14-3.04(m,1H),2.84(d,J=16.0Hz,1H),2.39-2.31(m,1H),2.11(d,J=5.4Hz,1H).
实施例32:化合物101的制备
采用通用合成方法3制备,氯甲基试剂是购买所得,得盐酸盐为白色固体,收率69.55%。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.43(s,3H),7.84-7.72(m,1H),7.50(m,J=6.3Hz,2H),5.69(dd,J=9.4,1.7Hz,1H),5.61(d,J=9.4Hz,1H),5.39-5.25(m,1H),4.83-4.71(m,1H),4.65-4.55(m,1H),4.53-4.32(m,3H),4.13(s,1H),3.18-3.04(m,2H),2.85(d,J=16.9Hz,1H),2.41-2.30(m,1H),2.14-2.05(m,1H),1.22(d,J=6.2Hz,6H).
实施例33:化合物102的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率52.86%。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.84-7.77(m,1H),7.57-7.51(m,2H),7.33(d,J=8.2Hz,2H),7.19(d,J=8.3Hz,2H),5.63(dd,J=34.7,9.3Hz,2H),5.31(dd,J=13.5,5.0Hz,1H),4.48(dd,J=53.3,17.6Hz,2H),3.90(s,1H),3.81-3.75(m,1H),3.50(s,4H),3.31-3.29(m,4H),3.09(dd,J=19.3,14.5Hz,3H),2.84(d,J=16.6Hz,1H),2.40(d,J=9.1Hz,1H),2.11(d,J=5.9Hz,1H).
实施例34:化合物103制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率37.44%。
1H NMR(400MHz,DMSO-d6)δ10.56(d,J=4.3Hz,1H),8.43(s,3H),7.75(t,J=7.9Hz,1H),7.56(dt,J=15.1,7.5Hz,2H),5.63(dd,J=28.7,9.4Hz,2H),5.31(dd,J=13.4,3.1Hz,1H),4.46(dd,J=17.6,8.4Hz,1H),4.34(dd,J=17.5,6.9Hz,1H),4.23(s,1H),3.54(s,4H),3.47(d,J=9.5Hz,2H),3.34-3.29(m,4H),3.12-3.04(m,1H),2.84(d,J=16.8Hz,1H),2.39(dd,J=13.2,4.4Hz,1H),2.10(d,J=5.3Hz,1H).
实施例35:化合物104的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率42.45%。
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.62(s,3H),7.80(dd,J=5.9,2.9Hz,1H),7.57-7.50(m,2H),7.30(d,J=8.6Hz,2H),7.21(d,J=8.6Hz,2H),5.63(dd,J=20.3,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.47(dd,J=59.4,17.6Hz,2H),4.31(t,1H),3.70(s,3H),3.23-3.08(m,3H),2.90-2.81(m,1H),2.42-2.31(m,1H),2.19-2.05(m,1H),1.11(s,9H).
实施例36:化合物105的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率48.97%。
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.52(s,3H),7.82-7.73(m,1H),7.52(d,J=4.3Hz,2H),5.62(dd,J=31.8,9.3Hz,2H),5.30(d,J=8.4Hz,1H),4.63(d,J=8.5Hz,1H),4.54-4.24(m,4H),3.54(s,4H),3.31-3.28(m,4H),3.09(d,J=12.3Hz,1H),2.84(d,J=17.1Hz,1H),2.39(s,1H),2.10(dd,J=9.8,4.3Hz,1H).
实施例37:化合物106的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率68.45%。
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.70(s,3H),7.78-7.71(m,1H),7.56(m,J=15.2,7.5Hz,2H),5.63(dd,J=21.5,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.47(dd,J=17.6,9.2Hz,1H),4.37-4.29(m,2H),3.74(s,3H),3.44(t,J=5.4Hz,2H),3.13(m,J=18.1,13.5,4.8Hz,1H),2.90-2.80(m,1H),2.38(dd,J=13.2,4.4Hz,1H),2.15-2.06(m,1H),1.11(s,9H).
实施例38:化合物107的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率57.36%。
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.59(s,3H),7.80(dd,J=5.8,2.9Hz,1H),7.54(dd,J=8.2,5.3Hz,2H),7.30(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.59(dd,J=25.2,9.3Hz,2H),5.32(dd,J=13.3,5.0Hz,1H),4.47(dd,J=59.1,17.6Hz,2H),4.32(s,1H),3.70(s,3H),3.24-3.07(m,6H),2.84(d,J=16.5Hz,1H),2.38(dd,J=13.2,4.1Hz,1H),2.15-2.06(m,1H),1.01(s,6H).
实施例39:化合物108的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率58.41%。
1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.70(s,3H),7.74(s,1H),7.53(s,2H),5.63(dd,J=20.0,9.3Hz,2H),5.33(d,J=9.4Hz,1H),4.68-4.27(m,5H),3.79(s,3H),3.1l(d,J=12.1Hz,1H),2.86(d,J=23.9Hz,1H),2.36(d,J=12.8Hz,1H),2.12(s,1H),1.11(s,9H).
实施例40:109的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率51.78%。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.17(s,2H),7.80(dd,J=5.9,3.0Hz,1H),7.54(dd,J=8.3,5.2Hz,2H),7.31(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.63(dd,J=20.5,9.6Hz,2H),5.34(dd,J=13.3,5.0Hz,1H),4.46(dd,J=58.1,17.6Hz,2H),4.07(s,1H),3.12(ddd,J=18.1,13.4,7.0Hz,3H),2.85(d,J=16.4Hz,1H),2.45-2.31(m,2H),2.15-2.05(m,1H),1.11(s,9H).
实施例41:化合物110的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率28.51%。
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.45(s,2H),7.75(m,1H),7.56(m,2H),5.63(dd,J=21.1,9.6Hz,2H),5.34(dd,J=12.6,4.1Hz,1H),4.40(m,2H),4.20(d,J=2.8Hz,1H),3.48(dd,J=14.7,5.1Hz,2H),3.40(d,J=6.1Hz,2H),3.13(m,2H),2.84(d,J=17.4Hz,1H),2.39(dd,J=13.1,4.3Hz,1H),1.11(s,9H).
实施例42:化合物111的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率23.09%。
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.32(s,3H),7.81-7.71(m,1H),7.55-7.48(m,2H),5.63(dd,J=19.7,9.6Hz,2H),5.38-5.28(m,1H),4.60(d,J=12.0Hz,1H),4.48(dd,J=17.5,6.0Hz,1H),4.34(dd,J=17.4,4.1Hz,2H),4.13(s,1H),3.12(dd,J=23.4,10.2Hz,2H),2.85(d,J=16.8Hz,1H),2.37(s,1H),2.14-2.06(m,1H),1.12(d,J=9.2Hz,9H).
实施例43:化合物112的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率61.94%。
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.33(s,2H),7.90(dd,J=7.8,1.5Hz,1H),7.80(dd,J=6.3,2.6Hz,1H),7.73-7.66(m,1H),7.60-7.52(m,2H),7.41(t,J=7.7Hz,1H),7.33(d,J=8.5Hz,2H),7.23(dd,J=16.2,8.0Hz,3H),5.84(dd,J=24.0,9.7Hz,2H),5.76(s,1H),5.36(dd,J=13.3,5.0Hz,1H),4.50(dd,J=51.1,17.6Hz,2H),4.13(s,1H),3.21-3.04(m,4H),2.89(d,J=17.0Hz,1H),2.44(dd,J=13.2,4.4Hz,1H),2.25(s,3H),2.18-2.08(m,1H).
实施例44:化合物113的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率49.26%。
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.34(s,2H),7.76(t,J=6.7Hz,1H),7.56(dt,J=15.1,7.4Hz,2H),5.63(dd,J=30.2,9.6Hz,2H),5.32(d,J=8.2Hz,1H),4.40(m,2H),4.21(s,1H),3.47(dd,J=14.7,4.8Hz,2H),3.17-3.04(m,1H),2.84(d,J=17.1Hz,1H),2.40(d,J=13.0Hz,1H),2.28(t,J=7.3Hz,2H),2.10(s,1H),1.49(s,2H),1.23(s,10H),0.84(t,J=6.7Hz,3H).
实施例45:化合物114的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率65.29%。
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.32(s,3H),7.90(dd,J=7.8,1.6Hz,1H),7.79-7.68(m,2H),7.56(dt,J=15.2,7.5Hz,2H),7.42(td,J=7.6,1.1Hz,1H),7.25(dd,J=8.1,1.0Hz,1H),5.84(dd,J=22.4,10.0Hz,2H),5.37(d,J=13.5Hz,1H),4.42(m,3H),4.20(s,1H),3.47(m,2H),3.21-3.11(m,2H),2.89(d,J=17.3Hz,1H),2.42(s,1H),2.26(s,3H),2.16-2.09(m,1H).
实施例46:化合物115的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率56.50%。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.47(s,3H),7.90(dd,J=7.8,1.6Hz,1H),7.73(m,2H),7.52(dd,J=8.2,5.3Hz,2H),7.42(t,J=7.6Hz,1H),7.25(d,J=8.1Hz,1H),5.84(dd,J=20.3,9.7Hz,2H),5.41-5.31(m,1H),4.64(m,1H),4.50(dd,J=17.5,6.6Hz,1H),4.43-4.33(m,2H),4.29(s,1H),3.22-3.09(m,2H),2.89(d,J=16.8Hz,1H),2.44-2.37(m,1H),2.26(s,3H),2.18-2.09(m,1H).
实施例47:化合物116的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率37.55%。
1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.55(s,2H),7.90(dd,J=7.8,1.5Hz,1H),7.72(m,2H),7.56(dt,J=15.2,7.6Hz,2H),7.45-7.40(m,1H),7.25(d,J=8.1Hz,1H),5.84(dd,J=20.1,9.8Hz,2H),5.37(dd,J=13.2,5.2Hz,1H),4.46(m,1H),4.40-4.32(m,2H),3.75(s,3H),3.48-3.40(m,2H),3.20-3.12(m,1H),2.89(d,J=17.2Hz,1H),2.26(s,3H),2.14(d,J=5.4Hz,1H).
实施例48:化合物117的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率45.95%。
1H NMR(600MHz,DMSO-d6)δ9.75(s,1H),8.84(s,3H),7.91(d,J=7.7Hz,1H),7.82-7.66(m,2H),7.52(dd,J=8.1,5.3Hz,2H),7.43(t,J=7.6Hz,1H),7.25(d,J=8.0Hz,1H),5.91-5.76(m,2H),5.36(dd,J=13.4,4.9Hz,1H),4.62(td,J=12.0,3.4Hz,1H),4.55-4.30(m,4H),4.03(q,J=7.1Hz,1H),3.41(s,2H),3.16(ddd,J=18.2,11.9,5.4Hz,1H),2.90(dd,J=14.0,2.6Hz,1H),2.48-2.34(m,1H),2.13(dd,J=18.8,13.7Hz,1H),1.99(s,1H),1.17(t,J=7.1Hz,1H).
实施例49:化合物118的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率50.98%。
1H NMR(400MHz,DMSO-d6)δ10.71(d,J=4.2Hz,1H),8.82(s,3H),7.83-7.68(m,1H),7.55(dt,J=15.1,7.4Hz,2H),5.63(dd,J=30.1,9.6Hz,2H),5.53-5.28(m,1H),4.49(dd,J=17.6,9.3Hz,1H),4.41-4.26(m,2H),3.75(d,J=11.8Hz,3H),3.54-3.40(m,2H),3.22-3.03(m,1H),2.85(d,J=16.7Hz,1H),2.40(qd,J=13.2,4.1Hz,1H),2.28(t,J=7.3Hz,2H),2.15-2.05(m,1H),1.60-1.42(m,2H),1.33-1.14(m,8H),0.84(t,J=6.8Hz,3H).
实施例50:化合物119的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率31.28%。
1H NMR(600MHz,DMSO-d6)δ10.59(s,1H),8.49(s,3H),7.75(dd,J=13.0,7.9Hz,1H),7.56(dt,J=15.3,7.5Hz,2H),5.58(tt,J=19.2,5.6Hz,2H),5.32(ddd,J=13.4,4.8,2.8Hz,1H),4.47(dd,J=17.5,13.0Hz,1H),4.35(dd,J=17.5,10.8Hz,1H),4.21(d,J=4.2Hz,1H),3.52-3.44(m,1H),3.43-3.29(m,4H),3.18-3.07(m,1H),2.80(d,J=2.7Hz,6H),2.45-2.34(m,1H),2.16-2.07(m,1H).
实施例51:化合物120的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率43.77%。
1H NMR(600MHz,DMSO-d6)δ9.71(s,1H),8.60(s,3H),7.90-7.64(m,1H),7.64-7.40(m,2H),5.68-5.50(m,2H),5.31(dt,J=13.4,4.3Hz,1H),4.63(ddd,J=12.0,8.6,3.5Hz,1H),4.57-4.28(m,4H),3.43(dt,J=21.3,10.7Hz,1H),3.18-3.05(m,1H),2.80(d,J=3.7Hz,6H),2.36(qd,J=13.2,4.3Hz,1H),2.16-2.04(m,1H).
实施例52:化合物121的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率60.30%。
1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.82(s,1H),7.75(dd,J=9.8,5.0Hz,1H),7.55-7.49(m,1H),5.63(dd,J=28.7,9.6Hz,1H),5.32(dd,J=13.5,5.0Hz,1H),4.62(ddd,J=10.3,7.0,3.3Hz,1H),4.53-4.40(m,1H),3.78(d,J=1.0Hz,1H),3.17-3.06(m,1H),2.89-2.81(m,1H),2.37(dd,J=13.1,4.4Hz,1H),2.28(t,J=7.3Hz,1H),2.14-2.07(m,1H),1.53-1.44(m,1H),1.21(d,J=15.0Hz,4H),0.84(t,J=6.7Hz,2H).
实施例53:化合物122的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率57.39%。
1H NMR(600MHz,DMSO-d6)δ10.19(s,1H),7.81(dd,J=5.5,3.2Hz,1H),7.56-7.48(m,2H),7.34(d,J=8.4Hz,2H),7.20(d,J=8.5Hz,2H),5.72-5.52(m,2H),5.35-5.24(m,1H),4.55(d,J=17.5Hz,1H),4.41(d,J=17.5Hz,1H),4.03(s,1H),3.17(s,2H),2.88-2.81(m,1H),2.46-2.35(m,1H),2.27(t,J=7.3Hz,2H),2.14-2.07(m,1H),1.54-1.45(m,2H),1.24(d,J=9.0Hz,8H),0.84(dt,J=14.0,6.9Hz,3H).
实施例54:123的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率23.59%。
1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.62(s,3H),7.77(dd,J=9.6,4.9Hz,1H),7.57-7.48(m,2H),5.63(dd,J=27.9,9.6Hz,2H),5.40-5.24(m,1H),4.64(dt,J=11.9,3.3Hz,1H),4.56-4.29(m,4H),3.21-3.01(m,1H),2.91-2.77(m,1H),2.42-2.31(m,1H),2.28(t,J=7.3Hz,2H),2.16-2.06(m,1H),1.48(dd,J=13.8,6.9Hz,2H),0.84(t,J=6.8Hz,3H).
实施例55:化合物124的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率62.13%。
1H NMR(600MHz,DMSO-d6)δ9.71(s,1H),8.58(s,2H),7.86-7.71(m,1H),7.64-7.49(m,4H),7.15(d,J=8.4Hz,1H),7.02(t,J=7.5Hz,1H),5.81(dt,J=27.2,13.6Hz,2H),5.35(dt,J=13.4,4.4Hz,1H),4.62(tt,J=39.6,19.8Hz,1H),4.51(dd,J=17.4,7.6Hz,1H),4.48-4.32(m,2H),4.32(d,J=36.4Hz,1H),4.11(s,1H),3.80(d,J=7.8Hz,3H),3.41-3.25(m,1H),2.88(d,J=17.5Hz,1H),2.40(qd,J=13.1,4.0Hz,1H),2.21-2.02(m,1H).
实施例56:化合物125的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率33.38%。
1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.80(s,3H),7.88(d,J=8.9Hz,2H),7.75(dd,J=10.3,6.1Hz,1H),7.52(dd,J=7.1,5.8Hz,2H),7.06(d,J=8.9Hz,2H),5.86(dd,J=23.3,9.6Hz,2H),5.37(dd,J=13.4,4.9Hz,1H),4.72-4.32(m,5H),3.84(s,3H),3.78(d,J=2.8Hz,3H),3.24-3.07(m,1H),3.01-2.84(m,1H),2.47-2.36(m,1H),2.22-2.06(m,1H),1.99(s,1H),1.25-1.12(m,1H).
实施例57:化合物126的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率48.86%。
1H NMR(400MHz,DMSO-d6)δ14.09(s,1H),10.58(d,J=3.9Hz,1H),8.46(s,3H),7.76(t,J=8.2Hz,1H),7.59-7.39(m,4H),7.27(d,J=7.9Hz,1H),5.89(dd,J=28.4,9.6Hz,2H),5.38(d,J=10.4Hz,1H),4.49(dd,J=17.5,8.5Hz,1H),4.38(dd,J=17.6,6.9Hz,1H),4.23(s,1H),4.03(dd,J=14.3,7.2Hz,1H),3.82(s,3H),3.55-3.40(m,3H),3.25-3.08(m,1H),2.87(d,J=13.7Hz,1H),2.47-2.32(m,1H),2.19-2.06(m,1H),1.99(s,1H),1.19(dd,J=20.9,13.8Hz,1H).
实施例58:化合物127的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率41.67%。
1H NMR(600MHz,DMSO-d6)δ9.71(s,1H),8.61(s,3H),7.77(d,J=10.5Hz,1H),7.57-7.38(m,5H),7.26(d,J=8.1Hz,1H),5.89(dd,J=40.7,9.6Hz,2H),5.36(dd,J=13.3,4.5Hz,1H),4.63(dd,J=15.0,6.0Hz,1H),4.51(dd,J=17.4,7.5Hz,1H),4.46-4.36(m,2H),4.34(s,1H),3.26-3.09(m,1H),2.97-2.81(m,1H),2.43(qd,J=13.2,4.2Hz,1H),2.18-2.08(m,1H).
实施例59:化合物128的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率35.98%。
1H NMR(400MHz,DMSO-d6)δ13.90(s,1H),10.20(s,1H),8.44(s,2H),7.81(dd,J=5.5,3.5Hz,1H),7.58-7.53(m,2H),7.51(d,J=7.6Hz,1H),7.48-7.40(m,2H),7.33(d,J=8.5Hz,2H),7.28-7.24(m,1H),7.22(d,J=8.5Hz,2H),5.90(dd,J=31.9,9.6Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.51(dd,J=48.7,17.6Hz,2H),4.20(s,1H),3.81(s,3H),3.38(s,3H),2.89(d,J=16.7Hz,1H),2.21-2.06(m,1H).
实施例60:化合物129的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率55.52%。
1H NMR(600MHz,DMSO-d6)δ10.61(d,J=9.0Hz,1H),8.51(s,3H),7.89(d,J=8.9Hz,2H),7.76(dd,J=12.3,7.7Hz,1H),7.56(dt,J=15.3,7.6Hz,2H),7.06(d,J=8.9Hz,2H),5.86(dd,J=35.7,9.8Hz,2H),5.37(ddd,J=13.5,4.8,2.8Hz,1H),4.50(dd,J=17.5,l 1.3Hz,1H),4.43-4.29(m,1H),4.21(s,1H),3.84(s,3H),3.40(ddd,J=14.6,5.9,2.6Hz,3H),3.23-3.09(m,1H),2.88(d,J=10.5Hz,1H),2.48-2.39(m,1H),2.17-2.08(m,1H).
实施例6l:化合物130的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率48.59%。
1H NMR(600MHz,DMSO-d6)δ9.73(s,1H),8.65(s,3H),7.89(d,J=8.8Hz,2H),7.83-7.7l(m,1H),7.62-7.40(m,2H),7.06(d,J=8.8Hz,2H),5.86(dd,J=36.6,9.6Hz,2H),5.43-5.32(m,1H),4.64(ddd,J=12.2,9.0,3.5Hz,1H),4.52(dd,J=17.5,6.0Hz,1H),4.48-4.29(m,4H),3.84(s,3H),3.20-3.11(m,1H),2.93-2.85(m,1H),2.12(dd,J=17.3,10.5Hz,1H),1.9l(s,1H).
实施例62:化合物13l的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率47.64%。
1H NMR(400MHz,DMSO-d6)δ13.89(s,1H),10.22(s,1H),8.50(s,3H),7.96-7.84(m,2H),7.81(dt,J=7.4,3.7Hz,1H),7.61-7.53(m,2H),7.33(t,J=11.3Hz,2H),7.22(d,J=8.5Hz,2H),7.05(d,J=8.9Hz,2H),5.87(dd,J=27.6,9.6Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.51(dd,J=50.1,17.6Hz,2H),4.19(s,1H),3.83(s,3H),3.17(t,J=8.5Hz,2H),2.89(dd,J=10.2,6.5Hz,1H),2.50-2.36(m,2H),2.14(dd,J=8.7,3.4Hz,1H).
实施例63:化合物132的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率48.95%。
1H NMR(400MHz,DMSO-d6)δ10.58(d,J=67.0Hz,1H),8.75(d,J=148.3Hz,3H),7.76(dt,J=7.6,5.1Hz,1H),7.56(dt,J=15.2,7.4Hz,2H),5.59(dd,J=24.0,9.5Hz,2H),5.33(dd,J=13.3,3.9Hz,1H),4.49(dd,J=17.6,7.0Hz,1H),4.34(dd,J=17.6,5.4Hz,1H),4.17(dd,J=8.2,5.5Hz,1H),3.45(ddd,J=20.6,14.6,5.6Hz,3H),3.24-3.05(m,5H),2.87(dd,J=22.4,11.9Hz,1H),2.39(qd,J=13.2,4.2Hz,1H),2.15-2.04(m,1H),1.0l(s,6H).
实施例64:化合物133的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率53.83%。
1H NMR(600MHz,DMSO-d6)δ9.72(s,1H),8.62(s,3H),7.82-7.67(m,1H),7.58-7.44(m,2H),5.58(dt,J=21.6,10.8Hz,2H),5.32(ddd,J=13.4,11.0,4.4Hz,1H),4.63(ddd,J=1 1.8,6.3,3.6Hz,1H),4.50(dd,J=17.4,6.7Hz,1H),4.46-4.30(m,3H),3.26-3.05(m,5H),2.90-2.77(m,1H),2.35(qd,J=13.2,4.3Hz,1H),2.16-2.06(m,1H),1.11-0.83(m,6H).
实施例65:化合物134制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率49.29%。
1H NMR(600MHz,DMSO-d6)δ13.87(s,1H),10.21(s,1H),8.46(s,3H),7.80(dd,J=6.4,2.2Hz,1H),7.63-7.50(m,2H),7.34(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),5.58(dt,J=20.8,10.4Hz,2H),5.37-5.25(m,1H),4.55(d,J=17.5Hz,1H),4.42(t,J=17.9Hz,1H),4.16(d,J=38.4Hz,1H),3.42(d,J=30.7Hz,4H),3.16(dd,J=13.2,8.0Hz,4H),2.87(dt,J=17.0,11.6Hz,1H),2.38(qd,J=13.2,4.3Hz,1H),2.16-2.06(m,1H),1.09-0.93(m,6H).
实施例66:化合物135的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率48.46%。
1H NMR(600MHz,DMSO-d6)δ10.24(d,J=54.4Hz,1H),8.63(s,3H),7.90(dd,J=7.8,1.6Hz,1H),7.80(d,J=6.9Hz,1H),7.70(td,J=7.9,1.7Hz,1H),7.59-7.5l(m,2H),7.40(dd,J=11.8,4.3Hz,1H),7.30(d,J=8.5Hz,2H),7.23(dd,J=21.0,8.3Hz,3H),5.85(dd,J=34.3,9.7Hz,2H),5.36(dd,J=13.4,5.0Hz,1H),4.56(d,J=17.6Hz,1H),4.44(d,J=17.3Hz,1H),4.32(t,J=6.4Hz,1H),3.70(s,3H),3.22-3.09(m,3H),2.95-2.84(m,1H),2.48-2.38(m,1H),2.25(s,3H),2.13(dd,J=17.9,12.7Hz,1H).
实施例67:化合物136的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率34.39%。
1H NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.50(s,3H),7.88-7.74(m,1H),7.62-7.48(m,2H),7.34(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),5.58(dt,J=16.2,8.1Hz,2H),5.37-5.23(m,1H),4.53(t,J=17.0Hz,1H),4.42(d,J=17.5Hz,1H),4.18(t,J=6.1Hz,1H),3.21-3.05(m,3H),2.90-2.74(m,7H),2.40(qd,J=13.2,4.2Hz,1H),2.16-2.04(m,1H).
实施例68:化合物137的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率17.41%。
1H NMR(600MHz,DMSO-d6)δ10.63(s,1H),8.71(s,3H),7.75(dd,J=13.1,7.8Hz,1H),7.68-7.51(m,2H),5.58(dt,J=21.3,10.6Hz,2H),5.41一5.18(m,1H),4.46(t,J=16.3Hz,1H),4.34(dd,J=17.5,10.0Hz,2H),3.76(d,J=16.9Hz,3H),3.47(s,1H),3.19-3.02(m,1H),2.88-2.82(m,1H),2.80(d,J=4.1Hz,6H),2.38(qd,J=13.3,4.4Hz,1H),2.16-2.01(m,1H).
实施例69:化合物138的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率69.45%。
1H NMR(600MHz,DMSO-d6)δ9.74(s,11H),8.82(s,3H),7.76(d,J=4.9Hz,1H),7.60-7.43(m,2H),5.65-5.52(m,2H),5.33(ddd,J=18.7,13.5,5.0Hz,1H),4.62(td,J=11.4,3.4Hz,1H),4.54-4.41(m,3H),4.36(dd,J=17.4,6.7Hz,1H),3.78(s,3H),3.15-3.06(m,1H),2.82(dd,J=29.6,10.5Hz,6H),2.41-2.31(m,1H),2.15-2.07(m,1H).
实施例70:化合物139的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率24.88%。
1H NMR(600MHz,DMSO-d6)δ9.77(s,11H),8.91(s,3H),7.76(d,J=3.4Hz,1H),7.58-7.48(m,2H),5.67(d,J=9.6Hz,1H),5.60(d,J=9.6Hz,1H),5.31(dd,J=13.5,5.0Hz,1H),4.67-4.57(m,1H),4.56-4.43(m,3H),4.36(dd,J=17.4,1.6Hz,1H),3.78(s,3H),3.21-3.04(m,1H),2.85(d,J=17.4Hz,1H),2.38(qd,J=13.0,3.7Hz,1H),2.28(t,J=7.3Hz,2H),2.16-2.07(m,1H),1.55-1.44(m,2H),1.26(dd,J=20.7,6.6Hz,9H),1.18(t,J=7.1Hz,3H).
实施例71:化合物140的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率52.74%。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.52(s,3H),7.81(s,1H),7.55(s,2H),7.26(d,J=21.7Hz,3H),5.64(d,J=16.9Hz,2H),5.33(s,2H),4.65-4.27(m,4H),3.71(s,3H),3.13(s,3H),2.73(s,2H),2.21(d,J=54.3Hz,3H),1.49(s,2H),1.23(s,6H),0.84(s,3H).
实施例72:化合物141的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率74.75%。
1H NMR(400MHz,DMSO-d6)δ10.63(d,J=6.4Hz,1H),8.69(s,3H),7.84-7.70(m,1H),7.56(dt,J=15.4,7.8Hz,4H),7.15(d,J=8.4Hz,1H),7.02(t,J=7.5Hz,1H),5.81(dt,J=17.3,8.6Hz,2H),5.37(dd,J=13.4,5.0Hz,1H),4.48(dd,J=17.6,10.9Hz,1H),4.35(dd,J=17.3,6.6Hz,2H),3.81(s,3H),3.75(t,J=8.0Hz,3H),3.56(t,J=27.0Hz,2H),3.22-3.09(m,1H),2.88(t,J=8.2Hz,1H),2.49-2.34(m,1H),2.18-2.05(m,1H).
实施例73:化合物142的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率62.59%。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.75(s,3H),7.83-7.68(m,1H),7.66-7.42(m,4H),7.15(d,J=8.3Hz,1H),7.02(td,J=7.6,0.9Hz,1H),5.81(dt,J=17.7,8.9Hz,2H),5.36(dd,J=13.4,4.8Hz,1H),4.62(td,J=11.7,3.5Hz,1H),4.55-4.33(m,4H),3.88-3.64(m,6H),3.22-3.08(m,1H),2.94-2.83(m,1H),2.46-2.31(m,1H),2.14(dd,J=9.1,3.7Hz,1H).
实施例74:化合物143的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率70.57%。
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.61(s,3H),7.80(dd,J=6.2,2.7Hz,1H),7.56(tdd,J=11.1,5.9,2.0Hz,4H),7.30(d,J=8.6Hz,2H),7.26-7.18(m,2H),7.14(d,J=8.2Hz,1H),7.00(td,J=7.6,0.9Hz,1H),5.83(dd,J=24.4,9.6Hz,2H),5.37(dd,J=13.4,5.0Hz,1H),4.47(dt,J=35.9,17.9Hz,2H),4.33(s,1H),3.80(s,3H),3.70(s,3H),3.23-3.08(m,3H),2.96-2.79(m,1H),2.48-2.35(m,1H),2.21-2.09(m,1H).
实施例75:化合物144的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率70.38%。
1H NMR(400MHz,DMSO-d6)δ10.61(d,J=5.3Hz,1H),8.66(s,3H),7.76(ddd,J=9.2,7.7,1.2Hz,1H),7.63-7.40(m,5H),7.27(ddd,J=8.1,2.7,1.2Hz,1H),5.89(dd,J=26.9,9.7Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.56-4.29(m,3H),3.82(s,3H),3.75(t,J=7.0Hz,3H),3.52-3.42(m,2H),3.24-3.09(m,1H),2.98-2.82(m,1H),2.48-2.38(m,1H),2.19-2.08(m,1H).
实施例76:化合物145的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率35.54%。
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.83(s,3H),7.76(dd,J=9.8,5.4Hz,1H),7.58-7.37(m,5H),7.32-7.16(m,1H),5.89(dd,J=27.0,9.7Hz,2H),5.37(dd,J=13.4,5.0Hz,1H),4.70-4.57(m,1H),4.55-4.33(m,4H),3.88-3.71(m,6H),3.15(ddd,J=18.1,12.8,5.4Hz,1H),2.97-2.77(m,1H),2.43(dt,J=13.0,9.1Hz,1H),2.19-2.05(m,1H).
实施例77:化合物146的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率49.34%。
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.63(s,3H),7.81(dt,J=7.5,3.7Hz,1H),7.62-7.40(m,5H),7.35-7.12(m,5H),5.90(dd,J=31.7,9.6Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.51(dd,J=48.5,17.6Hz,2H),4.32(s,1H),3.81(s,3H),3.70(s,3H),3.22-3.04(m,3H),2.95-2.84(m,1H),2.48-2.39(m,1H),2.20-2.07(m,1H).
实施例78:化合物147的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率67.67%。
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.65(s,3H),7.92-7.85(m,2H),7.75(ddd,J=16.5,8.8,5.0Hz,1H),7.56(dt,J=15.2,7.5Hz,2H),7.11-7.00(m,2H),5.86(dd,J=23.1,9.6Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.56-4.32(m,3H),3.83(d,J=6.1Hz,3H),3.75(t,J=7.4Hz,3H),3.43(dd,J=8.8,3.2Hz,1H),3.15(ddd,J=18.1,13.1,5.3Hz,1H),2.89(s,1H),2.73(s,1H),2.47-2.34(m,1H),2.18-2.06(m,1H).
实施例79:化合物的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率72.46%。
1H NMR(600MHz,DMSO-d6)δ9.73(s,1H),8.80(s,3H),7.88(d,J=8.8Hz,2H),7.76(d,J=5.0Hz,1H),7.52(dd,J=7.5,5.6Hz,2H),7.06(d,J=8.9Hz,2H),5.86(dd,J=33.1,9.6Hz,2H),5.37(dd,J=13.4,4.9Hz,1H),4.61(tt,J=37.9,19.1Hz,1H),4.55-4.35(m,4H),3.84(s,3H),3.78(d,J=4.0Hz,3H),3.21-3.07(m,1H),2.94-2.82(m,1H),2.42(qd,J=12.7,3.8Hz,1H),2.13(dd,J=17.2,12.0Hz,1H).
实施例80:化合物149的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率57.13%。
1H NMR(600MHz,DMSO-d6)δ10.20(s,1H),8.67(s,3H),7.88(d,J=8.8Hz,3H),7.56-7.53(m,2H),7.30(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),7.05(dd,J=8.9,2.2Hz,3H),5.89(t,J=4.8Hz,1H),5.83(dd,J=9.6,3.2Hz,1H),5.37(dd,J=13.3,5.0Hz,1H),4.57(d,J=17.3Hz,1H),4.46(t,J=11.5Hz,1H),4.31(s,1H),4.13(t,J=6.3Hz,1H),3.83(s,3H),3.69(d,J=6.5Hz,3H),3.18-3.15(m,1H),2.92-2.88(m,1H),2.13(dd,J=10.9,5.8Hz,1H).
实施例81:化合物150的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率63.59%。
1H NMR(600MHz,DMSO-d6)δ10.20(s,1H),8.67(s,3H),7.88(d,J=8.8Hz,3H),7.56-7.53(m,2H),7.30(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),7.05(dd,J=8.9,2.2Hz,3H),5.89(t,J=4.8Hz,1H),5.83(dd,J=9.6,3.2Hz,1H),5.37(dd,J=13.3,5.0Hz,1H),4.57(d,J=17.3Hz,1H),4.46(t,J=11.5Hz,1H),4.31(s,1H),4.13(t,J=6.3Hz,1H),3.83(s,3H),3.69(d,J=6.5Hz,3H),3.18-3.15(m,1H),2.92-2.88(m,1H),2.13(dd,J=10.9,5.8Hz,1H).
实施例82:化合物151的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率54.86%。
1H NMR(600MHz,DMSO-d6)δ9.77(s,1H),8.91(s,3H),7.76(d,J=3.3Hz,1H),7.61-7.39(m,2H),5.71-5.52(m,2H),5.32(td,J=13.5,6.8Hz,1H),4.62(dd,J=13.2,5.5Hz,1H),4.50-4.46(m,2H),4.35(dt,J=17.4,4.7Hz,1H),3.78(s,3H),3.49-3.39(m,1H),2.93-2.79(m,2H),2.42-2.32(m,1H),2.18-2.07(m,1H),1.91(s,1H),1.20(tt,J=14.3,4.9Hz,2H),1.07-0.96(m,6H).
实施例83:化合物152的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率59.83%。
1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.67(s,3H),7.81(s,1H),7.56(s,2H),7.26(dd,J=38.8,8.1Hz,4H),5.65(dd,J=32.6,9.3Hz,2H),5.34(dd,J=13.3,4.6Hz,1H),4.77(dt,J=12.2,6.0Hz,1H),4.48(dd,J=50.0,17.6Hz,2H),4.26(t,J=6.3Hz,1H),4.21-4.06(m,2H),3.35(s,2H),3.17(ddd,J=26.7,13.7,5.9Hz,3H),2.85(d,J=16.7Hz,1H),2.47-2.27(m,1H),2.11(d,J=5.5Hz,1H),1.20(t,J=9.8Hz,6H).
实施例84:化合物153的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率23.32%。
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.63(s,3H),7.81(dd,J=5.5,3.2Hz,1H),7.62-7.46(m,2H),7.30(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.68-5.46(m,2H),5.32(dd,J=13.4,5.0Hz,1H),4.48(dd,J=51.3,17.6Hz,2H),4.32(s,1H),3.70(s,3H),3.37(s,2H),3.21-3.11(m,2H),2.91-2.71(m,6H),2.40(ddd,J=17.9,13.5,4.8Hz,1H),2.16-2.04(m,1H).
实施例85:化合物154的制备
采用通用合成方法2制备,得盐酸盐为白色固体,得白色固体,收率70.84%。
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.60(d,J=7.5Hz,1H),8.63(s,2H),7.95(s,1H),7.72(ddd,J=11.6,7.6,1.2Hz,1H),7.63-7.47(m,2H),5.17(dd,J=13.3,5.1Hz,1H),4.38(qd,J=17.7,8.3Hz,3H),4.20(qd,J=7.0,2.6Hz,2H),3.50-3.38(m,2H),2.89(s,3H),2.73(s,2H),1.24(t,J=7.1Hz,3H).
实施例86化合物155的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率69.41%。
1H NMR(600MHz,DMSO-d6)δ10.65(s,1H),8.74(s,3H),7.94(d,J=7.8Hz,2H),7.76(dd,J=12.6,7.8Hz,1H),7.69(t,J=7.4Hz,1H),7.62-7.50(m,4H),5.91(dd,J=33.8,9.6Hz,2H),5.39(dd,J=13.4,5.0Hz,1H),4.50(dd,J=17.5,13.2Hz,1H),4.38(dd,J=17.5,8.0Hz,1H),4.31(t,J=5.0Hz,1H),4.19(q,J=7.0Hz,2H),3.52-3.43(m,2H),3.37(s,1H),2.95-2.84(m,1H),2.49-2.38(m,1H),2.19-2.10(m,1H),1.22(td,J=7.1,2.5Hz,3H).
实施例87:化合物156的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率68.37%。
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.72(s,1H),8.79(s,3H),7.81-7.58(m,1H),7.60-7.35(m,2H),5.16(dd,J=13.3,5.1Hz,1H),4.70-4.55(m,1H),4.55-4.17(m,5H),3.01-2.88(m,1H),2.62(d,J=16.9Hz,1H),2.31(qd,J=13.2,4.3Hz,1H),2.10-2.01(m,1H),1.21(dt,J=28.6,7.1Hz,3H).
实施例88:化合物157的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率54.59%。
1H NMR(600MHz,DMSO-d6)δ9.74(s,1H),8.83(s,3H),7.94(d,J=7.5Hz,2H),7.76(s,1H),7.69(t,J=7.4Hz,1H),7.58-7.41(m,4H),5.91(dd,J=35.1,9.6Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.67-4.57(m,1H),4.56-4.34(m,4H),4.22(q,J=6.9Hz,2H),3.21-3.09(m,1H),2.90(d,J=17.1Hz,1H),2.42(tt,J=24.3,12.1Hz,1H),2.20-2.09(m,1H),1.29-1.20(m,3H).
实施例89:化合物158的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率43.68%。
1H NMR(600MHz,DMSO-d6)δ10.21(s,1H),8.71(s,3H),7.94(d,J=7.4Hz,2H),7.81(d,J=6.2Hz,1H),7.68(t,J=7.4Hz,1H),7.54(dd,J=14.0,6.4Hz,4H),7.32(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),5.9l(dd,J=39.5,9.6Hz,2H),5.38(dd,J=13.4,5.0Hz,1H),4.58(d,J=17.6Hz,1H),4.46(d,J=17.4Hz,1H),4.25(t,J=6.7Hz,1H),4.12(qq,J=10.9,7.1Hz,2H),3.24(dd,J=14.0,5.7Hz,1H),3.20-3.05(m,2H),2.95-2.86(m,1H),2.49-2.39(m,1H),2.20-2.11(m,1H),1.11(t,J=7.1Hz,3H).
实施例90:化合物159的制备
采用通用合成方法2制备,得盐酸盐为白色固体,收率57.53%。
1H NMR(600MHz,DMSO-d6)δ11.03(s,1H),10.18(s,1H),8.66(s,3H),7.86-7.75(m,1H),7.53(dd,J=7.1,5.8Hz,2H),7.31(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),5.15(dd,J=13.3,5.1Hz,1H),4.47(dd,J=58.0,17.6Hz,2H),4.27(s,1H),4.19-4.05(m,2H),3.21(dd,J=14.1,5.9Hz,1H),3.09(dd,J=12.6,6.2Hz,1H),2.98-2.89(m,1H),2.62(d,J=17.0Hz,1H),2.37(qd,J=13.2,4.3Hz,1H),2.05(dd,J=21.8,16.3Hz,1H),1.12(t,J=7.1Hz,3H).
实施例9l:化合物163的制备
采用通用合成方法3制备,得白色固体产物,收率49.26%。
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),7.80(dt,J=7.7,3.8Hz,1H),7.55(dd,J=6.4,2.9Hz,1H),7.31(d,J=8.5Hz,1H),7.15(d,J=8.5Hz,1H),5.63(dd,J=20.8,9.6Hz,1H),5.33(dd,J=13.4,5.0Hz,1H),4.47(dd,J=59.3,17.6Hz,1H),3.42(dd,J=7.7,4.7Hz,1H),3.16-3.07(m,1H),2.93-2.81(m,1H),2.42-2.33(m,1H),2.12(dd,J=14.2,8.9Hz,1H),1.10(s,4H).
实施例92:化合物164的制备
采用通用合成方法3制备,得游离态产物为白色固体,收率42.11%。
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.88(s,1H),8.16-8.01(m,1H),8.02-7.84(m,2H),7.81-7.63(m,2H),7.63-7.44(m,3H),7.46-7.30(m,1H),6.02-5.81(m,2H),5.36(dt,J=16.8,8.3Hz,1H),4.59-4.27(m,2H),3.57-3.23(m,4H),3.25-3.04(m,2H),2.98-2.82(m,1H),2.4l(dd,J=29.9,20.1Hz,1H),2.22-2.05(m,1H).
实施例93:化合物165的制备
采用通用合成方法2制备,得到游离态产物为白色固体,收率67.68%。
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.21(s,1H),7.79(dd,J=8.5,4.1Hz,2H),7.67-7.42(m,3H),7.40-7.23(m,2H),7.23-6.99(m,2H),5.15(dd,J=13.3,5.1Hz,1H),4.47(dd,J=41.5,17.7Hz,2H),3.46(dd,J=7.5,4.8Hz,2H),3.13(dt,J=34.8,17.5Hz,1H),3.05-2.85(m,2H),2.74-2.60(m,1H),2.49-2.30(m,1H),2.15-2.00(m,1H).
实施例94:化合物166的制备
采用通用合成方法2制备,得游离态产物为白色固体,收率49.71%。
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.61(s,1H),7.73(s,1H),7.55-7.44(m,2H),5.13(dd,J=13.2,5.1Hz,1H),4.52-4.29(m,2H),4.27-4.14(m,2H),3.70-3.62(m,3H),3.00-2.85(m,1H),2.60(dd,J=35.8,18.4Hz,2H),2.35(qd,J=13.4,4.5Hz,1H),2.10-1.90(m,3H).
实施例95:化合物167的制备
具体合成过程如下:
将Boc-L-谷氨酸(5g)、EDCI(15.51g)、HOBt(10.93g)、TEA(14.05mL)分散在干燥二氯甲烷(100mL)中,室温搅拌下滴加苄氧胺(2.59mL,22.24mmol)的二氯甲烷溶液,室温搅拌3天,加入二氯甲烷,依次用1MHCl洗,饱和碳酸氢钠洗,饱和食盐水洗,合并有机相,无水Na2SO4干燥,减压旋蒸至剩余少量溶剂,室温析晶,过滤。得到3.27g白色固体产物。
将上述产物(4.76g)溶于二氯甲烷(145mL)中,低温下加入三氟乙酸(29mL),室温搅拌4h,减压旋蒸除去溶剂,得到淡粉色固体产物,直接用于一步。
将上述产物(3.98g)和2-溴甲基-3-硝基苯甲酸甲酯(5g)分散在乙腈(75ml)中,低温下加入三乙胺(6ml),室温搅拌过夜,析出固体,过滤,干燥,得4.9g产物。
将上述产物(500mg)置于10mL甲苯,10mL水的混合溶液中,加入铁粉(284mg),醋酸铵(390mg),100℃反应3h,加入乙酸乙酯,依次用水洗,饱和食盐水洗,无水硫酸钠干燥,减压除去溶剂,残留物经硅胶柱层析得产物128mg。
将上述产物(120mg)、对硝基苯基氯甲酸酯(100mg)溶于四氢呋喃中,在回流条件下搅拌2h。减压浓缩,加入乙酸乙酯搅拌均匀得到混悬液,减压过滤并乙酸乙酯洗涤或直接旋干,得到残留物直接用于下一步。
将上述残留物和化合物Boc-L-半胱氨酸(73mg)溶于DMF中,在常温搅拌下滴加DIPEA(85mg),继续室温搅拌至原料消失,加入酸水调节PH至3-4,加入乙酸乙酯,再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相,收集有机相无水硫酸钠干燥,过滤得到滤液减压蒸干,用硅胶柱层析(石油醚∶乙酸乙酯=1∶2)进行纯化,得130mg泡沫状固体。
将上述产物分散在乙酸乙酯中,然后通入氯化氢气体,室温反应,析出固体,待反应完成后,过滤,用乙酸乙酯,正庚烷洗,50℃烘干,得到盐酸盐为白色固体,收率75.32%。
1H NMR(600MHz,DMSO-d6)δ7.96-7.90(m,2H),7.76(dd,J=12.6,7.9Hz,1H),7.69(t,J=7.4Hz,1H),7.61-7.50(m,4H),5.53(d,J=9.6Hz,1H),5.48(d,J=9.7Hz,1H),5.38(ddd,J=13.5,4.8,3.3Hz,1H),4.49(dd,J=17.5,12.5Hz,1H),4.38(dd,J=17.5,11.2Hz,1H),4.17-4.07(m,1H),3.50-3.43(m,1H),3.41-3.36(m,1H),3.20-3.12(m,1H),2.88(d,J=17.6Hz,1H),2.48-2.39(m,1H),2.16-2.06(m,1H).
实施例96:化合物168的制备
将实施例95产物分散在甲醇中,然后加入钯碳,在氢气环境下室温反应,,待反应完成后,过滤掉钯碳,将反应液滴加到叔丁基甲基醚中,析出固体,得到盐酸盐产物为白色固体,收率55.31%。
1H NMR(600MHz,DMSO-d6)δ10.12(s,1H),8.38(s,2H),7.73(dd,J=12.9,7.8Hz,1H),7.57-7.51(m,2H),5.15(dd,J=13.3,3.4Hz,1H),4.47-4.31(m,2H),4.13(s,1H),3.47(dd,J=14.6,5.0Hz,1H),3.36(dd,J=14.8,6.3Hz,1H),2.97-2.86(m,1H),2.64-2.59(m,1H),2.37-2.29(m,1H),2.04(dd,J=9.0,3.7Hz,1H).
实施例97:化合物169的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率45.71%。
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.40(s,2H),7.86-7.74(m,1H),7.54(dd,J=7.4,5.6Hz,2H),7.33(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.63(dd,J=26.0,9.6Hz,2H),5.32(dd,J=13.4,4.9Hz,1H),4.48(dd,J=53.5,17.6Hz,2H),4.14(dd,J=28.3,22.2Hz,1H),3.21-3.05(m,3H),2.84(d,J=17.2Hz,1H),2.46-2.33(m,1H),2.27(t,J=7.3Hz,2H),2.17-2.05(m,1H),1.47(d,J=6.6Hz,2H),1.32-1.12(m,20H),0.85(t,J=6.8Hz,3H).
实施例98:化合物170的制备
采用通用合成方法3制备,用浓硫酸条件脱保护,得到硫酸盐为白色固体,收率40.38%。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.17(s,1H),7.80(dd,J=5.9,3.0Hz,1H),7.54(dd,J=8.3,5.2Hz,1H),7.31(d,J=8.5Hz,1H),7.2l(d,J=8.5Hz,1H),5.63(dd,J=20.5,9.6Hz,1H),5.34(dd,J=13.3,5.0Hz,1H),4.46(dd,J=58.1,17.6Hz,1H),4.07(s,1H),3.16-3.02(m,2H),2.85(d,J=16.4Hz,1H),2.45-2.31(m,1H),2.18-2.05(m,1H),1.11(s,9H).
实施例99:化合物171的制备
采用通用合成方法3制备,用浓硝酸条件脱保护,得到硝酸盐为白色固体,收率57.74%。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.17(s,1H),7.80(dd,J=5.9,3.0Hz,1H),7.54(dd,J=8.3,5.2Hz,1H),7.31(d,J=8.5Hz,1H),7.21(d,J=8.5Hz,1H),5.63(dd,J=20.5,9.6Hz,1H),5.34(dd,J=13.3,5.0Hz,1H),4.46(dd,J=58.1,17.6Hz,1H),4.07(s,1H),3.16-3.02(m,2H),2.85(d,J=16.4Hz,1H),2.45-2.31(m,1H),2.18-2.05(m,1H),1.11(s,9H).
实施例100:化合物172的制备
采用通用合成方法3制备,用浓硫酸条件脱保护,得到硫酸盐为白色固体,收率53.69%。
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.34(s,1H),7.98-7.90(m,1H),7.80-7.66(m,1H),7.64-7.49(m,2H),5.91(dd,J=24.2,9.8Hz,1H),5.44-5.36(m,1H),4.42(ddd,J=25.9,17.6,9.2Hz,1H),4.26(s,1H),3.51-3.33(m,2H),3.16-3.11(m,1H),2.88(d,J=17.1Hz,1H),2.48-2.40(m,1H),2.17-2.09(m,1H).
实施例101:化合物173的制备
采用通用合成方法3制备,用浓硝酸条件脱保护,得到硝酸盐为白色固体,收率47.46%。
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.33(s,1H),7.97-7.91(m,1H),7.82-7.73(m,1H),7.69(t,J=7.4Hz,1H),7.56(dt,J=13.9,7.5Hz,2H),5.91(dd,J=24.3,9.7Hz,1H),5.45-5.35(m,1H),4.42(ddd,J=25.8,17.6,9.0Hz,1H),4.22(s,1H),3.50-3.37(m,1H),3.21-3.11(m,1H),2.88(d,J=17.5Hz,1H),2.47-2.39(m,1H),2.18-2.09(m,1H).
实施例102:化合物174的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率60.36%。
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.44(s,3H),7.87-7.70(m,1H),7.65-7.43(m,2H),5.63(dd,J=29.7,9.6Hz,2H),5.32(dd,J=13.2,3.8Hz,1H),4.40(ddd,J=22.9,17.6,6.4Hz,2H),4.19(s,1H),3.47(dd,J=14.6,5.1Hz,1H),3.42-3.37(m,2H),3.20-3.06(m,1H),2.84(d,J=17.0Hz,1H),2.46-2.35(m,1H),2.27(t,J=7.3Hz,2H),2.14-2.03(m,1H),1.47(d,J=6.9Hz,2H),1.22(s,20H),0.85(t,J=6.8Hz,3H).
实施例103:化合物175的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率62.47%。
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.54(s,3H),7.76(dd,J=9.9,5.1Hz,1H),7.58-7.47(m,2H),5.63(dd,J=27.4,9.6Hz,2H),5.31(dd,J=13.4,2.9Hz,1H),4.63(dt,J=11.9,3.4Hz,1H),4.55-4.26(m,4H),3.20-3.05(m,1H),2.84(d,J=16.8Hz,1H),2.43-2.30(m,1H),2.27(t,J=7.3Hz,2H),2.16-2.05(m,1H),1.47(d,J=6.6Hz,2H),1.33-1.11(m,20H),0.85(t,J=6.8Hz,3H).
实施例104:化合物176的制备
采用通用合成方法3制备,得盐酸盐为白色固体,收率64.32%。
1H NMR(400MHz,DMSO-d6)δ13.88(s,1H),10.21(s,1H),8.47(s,3H),7.80(dt,J=7.4,3.7Hz,1H),7.63-7.51(m,2H),7.34(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.63(dd,J=20.5,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.47(dd,J=60.4,17.6Hz,2H),4.20(s,1H),3.20-3.07(m,3H),2.93-2.79(m,1H),2.39(m,1H),2.19-2.06(m,1H),1.11(s,9H).
实施例105:化合物177的制备
采用通用合成方法3制备,得白色固体,收率67.21%。
1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),10.16(s,1H),8.24(d,J=8.1Hz,1H),7.78(dt,J=7.5,3.8Hz,1H),7.58-7.52(m,2H),7.28(d,J=8.5Hz,2H),7.15(d,J=8.5Hz,2H),5.63(dd,J=20.3,9.6Hz,2H),5.33(dd,J=13.4,5.0Hz,1H),4.58-4.34(m,3H),3.17-3.02(m,2H),2.90-2.81(m,2H),2.45-2.33(m,1H),2.11(dd,J=14.6,9.4Hz,1H),1.79(d,J=7.2Hz,3H),1.10(s,9H).
实施例106:化合物184的制备
采用通用合成方法3制备,得白色固体,收率67.3%。
1H NMR(400MHz,DMSO)δ10.20(s,1H),8.48(s,3H),7.81(dd,J=5.8,3.0Hz,1H),7.61-7.50(m,2H),7.33(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.63(dd,J=20.3,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.93(t,J=5.6Hz,1H),4.54(d,J=17.6Hz,1H),4.37(dd,J=21.4,12.0Hz,2H),4.14(t,J=4.9Hz,2H),3.61-3.52(m,2H),3.19-3.12(m,2H),2.85(d,J=16.5Hz,1H),2.39(dd,J=13.2,4.4Hz,1H),2.16-2.07(m,1H),1.20-1.02(m,9H),0.85(dt,J=9.3,5.8Hz,1H).
实施例107:化合物185的制备
采用通用合成方法3制备,得白色固体,收率62.4%。
1H NMR(400MHz,DMSO)δ10.20(s,1H),8.49(s,3H),7.81(s,1H),7.55(dd,J=8.3,5.2Hz,2H),7.33(d,J=7.0Hz,2H),7.21(d,J=8.4Hz,2H),5.63(dd,J=20.4,9.5Hz,2H),5.34(dd,J=13.3,5.2Hz,1H),5.05(s,1H),4.73(s,1H),4.54(d,J=17.5Hz,1H),4.39(d,J=17.6Hz,2H),4.24-4.13(m,1H),4.04(dt,J=14.0,6.6Hz,1H),3.67(s,1H),3.16(d,J=6.5Hz,2H),2.85(d,J=17.4Hz,1H),2.39(d,J=12.7Hz,1H),2.12(s,1H),1.32-0.97(m,9H),0.84(dd,J=9.3,7.0Hz,1H).
实施例108:化合物186的制备
采用通用合成方法3制备,得白色固体,收率64.5%。
1H NMR(400MHz,DMSO)δ10.21(s,1H),8.66(d,J=3.6Hz,3H),7.81(dd,J=5.4,3.4Hz,1H),7.60-7.50(m,2H),7.31(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.63(dd,J=20.2,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.97-4.83(m,1H),4.55(d,J=17.6Hz,1H),4.39(d,J=17.6Hz,1H),4.22(s,1H),3.27-2.99(m,3H),2.85(d,J=16.9Hz,1H),2.44-2.30(m,1H),2.11(dd,J=10.0,5.1Hz,1H),1.16(d,J=6.2Hz,3H),1.11(s,9H),1.05(t,J=7.5Hz,3H).
实施例109:化合物187的制备
采用通用合成方法3制备,得白色固体,收率60.3%。
1H NMR(400MHz,DMSO)δ10.22(s,1H),8.73(d,J=3.6Hz,3H),7.81(dd,J=5.7,3.1Hz,1H),7.65-7.44(m,2H),7.31(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),5.63(dd,J=20.2,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.56(d,J=17.6Hz,1H),4.40(d,J=17.6Hz,1H),4.28(d,J=5.4Hz,1H),4.10-3.98(m,2H),3.16(dtd,J=22.1,14.2,6.9Hz,3H),2.91-2.78(m,1H),2.39(ddd,J=26.5,13.4,4.0Hz,1H),2.11(dd,J=9.9,4.8Hz,1H),1.52-1.42(m,2H),1.21(tt,J=14.2,6.2Hz,3H),1.09(d,J=13.1Hz,9H),0.86-0.81(m,3H).
实施例110:化合物188的制备
采用通用合成方法3制备,得白色固体,收率69.5%。
1H NMR(400MHz,DMSO)δ10.22(s,1H),8.74(d,J=3.5Hz,3H),7.81(dd,J=6.1,2.7Hz,1H),7.62-7.49(m,2H),7.31(d,J=8.5Hz,2H),7.20(d,J=8.5Hz,2H),5.63(dd,J=20.2,9.6Hz,2H),5.34(dd,J=13.4,5.0Hz,1H),4.56(d,J=17.6Hz,1H),4.40(d,J=17.6Hz,1H),4.27(d,J=5.7Hz,1H),3.16(dtd,J=21.8,13.9,6.7Hz,3H),2.90-2.78(m,1H),2.39(ddd,J=27.0,13.6,4.6Hz,1H),2.11(dd,J=10.1,5.0Hz,1H),1.56-1.43(m,2H),1.22(t,J=10.3Hz,6H),1.11(s,9H),0.87-0.84(m,3H).
试验例
试验1:溶解度试验
试验方法:用5mL的离心管取约0.5mL的蒸馏水,慢慢加入干燥的的化合物至不能溶解(25℃产生震荡,仍浑浊)。将溶液过滤至另一个5mL的干净已称重的EP管中,再称重,计算出溶液的重量。将滤液冻干,称重并计算出所剩固体的溶质质量,计算溶剂的质量,进而计算化合物在水中的溶解度。结果列于表1。
表1.本发明化合物的溶解度
结论:本发明化合物在水中的溶解度远远大于已经上市药物来那度胺,水溶性能够提高几十倍至几百倍。这种高水溶性特点在理论上能够增加和提高药物在肾脏的排泄,减轻来那度胺存在的肾毒副作用,同时这种高水溶性特性使这些化合物容易制剂化和在临床上的应用更方便。
试验2:体外抗多发性骨髓瘤活性实验
试验方法:收集对数期的MM.1S细胞,以2×104个/孔的密度接种于96孔板内,37℃,5%C02培养箱中孵育2h后,分别加入终浓度为0.0001至50μM的化合物,每个化合物4个复孔,于37℃,5%CO2培养箱中孵育72h。孵育结束后,向细胞孔内加入20μL 5mg/mL的MTT溶液,4h后,弃上清,加入150μL DMSO,检测570nm波长处的吸光度值A测定。无细胞的空白孔测得的吸光度值A空白,以未加药处理的细胞孔测得的吸光度值为A对照,并按以下公式计算各孔细胞存活率:
细胞存活率(%)=(A测定-A空白)/(A对照-A空白)×100%。
用GraphPad Prism软件对细胞存活率和药物浓度作图,计算出IC50值。
对本发明化合物进行了上述活性测定试验,结果表明,本发明化合物均对人源多发性骨髓瘤MM.1S细胞具有较强的细胞增殖抑制活性。结果见表2。其中,IC50值小于0.05μM为A;IC50值大于0.05μM且小于0.1μM为B;IC50值大于0.1μM且小于0.5μM为C;IC50值大于0.5μM且小于1μM为D。
表2.本发明化合物的体外抗多发性骨髓瘤效果
试验3:单独与地塞米松组合的抗耐药型多发性骨髓瘤细胞活性实验
试验方法:本试验评估了地塞米松作为单一剂与本发明化合物或来那度胺的组合物对来那度胺耐药型多发性骨髓瘤NCI-H929细胞的增殖抑制的影响。试验采用MTT比色法检测细胞存活率,方法如试验2。
结果显示,本发明化合物对来那度胺耐药型NCI-H929细胞具有较强的细胞增殖抑制活性,且与第二活性组分地塞米松联合使用时,能够达到协同抑制NCI-H929细胞增殖的效果。结果见表3。其中,IC50值小于0.01μM为A;IC50值大于0.01μM且小于0.05μM为B;IC50值大于0.05μM且小于0.1μM为C;IC50值大于0.1μM且小于0.5μM为D。
表3.作为单一剂或与地塞米松组合的本发明化合物在抗来那度胺耐药型NCI-H929细胞中的抗增殖活性比较
试验4:氨基酸转运体LAT1/SLC7A5的靶向转运研究
1、稳态细胞株的构建:
本试验自主构建了293T高表达LAT1的稳态细胞株,用于本发明化合物的靶向转运试验研究。
试验方法:将处于对数生长期的293T细胞(6×105)接种于6孔细胞培养板,置于细胞培养箱培养过夜。使用PEI试剂将已经构建好的融合表达protein C标签的LAT1-pQCXIP质粒转染到细胞中。置于细胞培养箱培养6小时,弃上清,加入2ml完全培养基继续培养;转染48小时后,荧光显微镜观察绿色荧光蛋白表达,并使用8μg/mL、5μg/mL浓度的嘌呤霉素进行筛选13天,得到稳定高表达LAT1的293T细胞。
稳态细胞株构建的结果,通过Western-Blotting试验,使用protein C抗体,检测LAT1的蛋白表达情况。检测结果如图1所示。可见,该细胞株构建成功。2、本发明化合物的靶向细胞吸收试验
试验方法:使用293T和LAT1-293T稳态细胞株进行本试验研究。将细胞均匀铺入6em培养皿,次日细胞长满后,使用胰蛋白酶消化收集293T和LAT1-293T细胞,用PBS重悬细胞,37℃预孵育2h。用生理盐水调节细胞浓度至1×107个/ml,分装至1.5ml离心管中,200μL/管。化合物DMSO溶解,用生理盐水稀释至20μM(DMSO终浓度0.5%),加入到相应的离心管中,每管200μL,每个化合物3个复管。离心管颠倒混匀,37℃孵育30min。孵育结束后,8000rpm离心2min,收集细胞沉淀,用预冷的生理盐水洗细胞2次,小心吸弃上清。每管加入50μL含2%甲酸的纯化水,涡旋2min,细胞裂解完全后,每管加入200μL乙腈甲醇混合液(乙腈:甲醇=7:3),等待质谱检测。
试验结果:如表3所示,本发明化合物在高表达LAT1的293T细胞裂解液中的含量明显高于普通293T细胞,表明本发明化合物具有显著的LAT1靶向性。
表3.本发明化合物在293T细胞和293T-LAT1细胞中的吸收情况
试验5:体内抗肿瘤药效试验I
试验方法
(1)模型制备
使用6-8周NOD/SCID雌鼠,实验动物购自北京维通利华实验动物技术有限公司。动物饲养于SPF级环境下IVC系统中。所有实验动物自由摄食、饮水,室温20~25℃,温度40~70%,昼夜明暗交替时间12h/12h。将人的多发性骨髓瘤RPMI-8226细胞培养在含10%胎牛血清的1640培养液中。收集指数生长期的RPMI-8226细胞,1640培养液重悬至1×108个/mL,加入等体积Matrigel胶,小鼠皮下接种0.2mL/只注入到鼠的腋部,建立荷瘤裸鼠模型。待肿瘤生长至150~300mm3时,根据小鼠肿瘤大小和体重随机分组给药。肿瘤体积计算公式为:长径×短径2/2。
(2)分组给药
本试验共分为9组,分别为生理盐水组、化合物73给药组、化合物82给药组、化合物90给药组、化合物109给药组、化合物169给药组、化合物174给药组、化合物176给药组、来那度胺给药组、每组7只。口服给药,每天1次,其中来那度胺的剂量为100毫克每千克体重,其他药物均按照与来那度胺相比的等摩尔浓度,给药体积为10mL/kg,连续给药14天后,停药观察5天,采用每周2次测量瘤径的方法,观察受试药物的抗肿瘤效果和动物的体重变化。
(3)试验结果
结果如表4和图2所示,本发明所化合物与临床对照药物来那度胺相比具有更优越的肿瘤抑制效果,充分显示了本发明化合物在肿瘤细胞及肿瘤组织内的选择性蓄积和靶向性。
表4.RPMI-8226模型中的给药剂量、小鼠体重变化率和相对抑瘤率
**p<0.01,***p<0.001,vs溶剂对照组;体重变化率(%)=(测量当天体重-实验初始体重)/实验初始体重×100%
试验6:体内抗肿瘤药效试验II
试验方法
(1)模型制备
将人的多发性骨髓瘤NCI-H929细胞培养在含10%胎牛血清的1640培养液中。收集指数生长期的NCI-H929细胞,1640培养液重悬至5×107个/mL,加入等体积Matrigel胶,小鼠皮下接种0.2mL/只注入到鼠的腋部,建立荷瘤裸鼠模型。待肿瘤生长至150~300mm3时,根据小鼠肿瘤大小和体重随机分组给药。肿瘤体积计算公式为:长径×短径2/2。
(4)分组给药
本试验共分为9组,分别为生理盐水组、化合物73给药组、化合物82给药组、化合物90给药组、化合物109给药组、化合物169给药组、化合物174给药组组、化合物176给药组、来那度胺组,每组7只。口服给药,每天1次,其中来那度胺的剂量为100毫克每千克体重,其他药物均按照与来那度胺相比的等摩尔浓度,给药体积为10mL/kg,连续给药14天后,停药观察1天,采用每周2次测量瘤径的方法,观察受试药物的抗肿瘤效果和动物的体重变化。
(5)试验结果
结果如表5和图3所示,本发明所提供的化合物与临床对照药物来那度胺相比具有更优越的肿瘤抑制效果,充分显示了本发明化合物在肿瘤细胞及肿瘤组织内的选择性蓄积和靶向性。
表5.NCI-H929模型中的给药剂量、小鼠体重变化率和相对抑瘤率
**p<0.01,***p<0.001,vs溶剂对照组;体重变化率(%)=(测量当天体重-实验初始体重)/实验初始体重×100%。
Claims (10)
1.一种式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物(可选地,所述溶剂化物为水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,
其中:
A选自-O-,-S-,-NH-,或者A不存在;
Q选自任选取代的亚烷基,或亚烷基亚芳基;
R1选自-H、烷基、-C(O)R4、-C(S)R4、-C(O)OR4、-C(O)NHR4、-C(O)NR4R4’;
R2选自-H、任意取代的烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基、芳基亚烷基、杂芳基、杂芳基亚烷基;
R3选自-H、羟基、烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基、芳基亚烷基、杂芳基、杂芳基亚烷基、亚烷基-OC(O)R4、亚烷基-OC(O)OR4、亚烷基-OC(O)NHR4、亚烷基-OC(O)NR4R4’,或-OR4;
各个R4和R4’相同或者不同,各自独立地选自氢、烷基、烯基、烯基烷基、炔基、炔基烷基、任选取代的芳基、任选取代的杂芳基、任选取代的脂环基、任选取代的脂杂环基、任选取代的芳基亚烷基或任选取代的杂芳基亚烷基;或者R4和R4’形成任选取代的3-7元环;
所述“任选取代的亚烷基”、“任选取代的脂环基”、“任选取代的脂杂环基”、“任选取代的芳基”、“任选取代的杂芳基”、“任选取代的芳基亚烷基”和“任选取代的杂芳基亚烷基”的取代基各自独立地选自羟基、氨基、羧基、卤素、硝基、氰基、烷基、烷氧基、芳基、杂芳基、芳基亚烷基、杂芳基亚烷基、芳基氧基、杂芳基氧基、环烷基、脂杂环基、环烷基氧基、杂环烷基氧基、芳基烷氧基、杂芳基烷氧基、烷酰氧基甲基、烷酰氧基、烷氧酰氧基或烷氧酰基。
2.根据权利要求1所述的式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,其特征在于,
所述“烷基”,以及“烷氧基”、“芳基烷氧基”、“杂芳基烷氧基”、“烷酰氧基甲基”、“烷氧酰氧基”、“烷酰氧基”、“烷氧酰基”中的烷基部分各自独立地为C1-20直链或支链烷基,可选地,为C1-17直链或支链烷基,可选地,为C1-10直链或支链烷基,可选地,为C1-7直链或支链烷基,可选地,为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基,异戊基、新戊基、叔戊基、正己基、异己基、庚基、正辛基、正壬基、正癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、或十六烷基;
可选地,所述“亚烷基”、“烯基亚烷基”、“炔基亚烷基”、“芳基亚烷基”、“杂芳基亚烷基”、“亚烷基-OC(O)R4”、“亚烷基-OC(O)OR4”、“亚烷基-OC(O)NHR4”、或“亚烷基-OC(O)NR4R4’”或“亚烷基亚芳基”中的亚烷基部分各自独立地为为C1-20直链或支链亚烷基,可选地,为C1-17直链或支链亚烷基,可选地,为C1-10直链或支链亚烷基,可选地,为C1-8直链或支链亚烷基,可选地,为C1-6直链或支链亚烷基,可选地,为C1-3直链或支链亚烷基,可选地,为亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基,亚异戊基、亚新戊基、亚叔戊基、亚正己基、亚异己基、亚庚基、亚正辛基、亚正壬基、亚正癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、或亚十六烷基;
可选地,所述“环烷基氧基”、“环烷基”中的环烷基部分为C3-8环烷基,可选地,为环丙基、环丁基、环戊基或环己基;
可选地,所述“烯基”、“烯基亚烷基”中的烯基部分各自独立地为C2-C20直链或支链烯基,可选地,为C2-C1s直链或支链烯基,可选地,为C2-C10直链或支链烯基,可选地,为C2-C8直链或支链烯基,可选地,为C2-C6直链或支链烯基,可选地,为C2-C4直链或支链烯基;
可选地,所述“炔基”、“炔基亚烷基”中的炔基部分各自独立地为为C2-C20直链或支链烯基,可选地,为C2-C15直链或支链炔基,可选地,为C2-C10直链或支链炔基,可选地,为C2-C8直链或支链炔基,可选地,为C2-C6直链或支链炔基,可选地,为C2-C4直链或支链炔基;
可选地,所述“脂杂环基”、“杂环烷基氧基”中的杂环基为环上含有选自O、N、S、SO或SO2的1-3个杂原子的C3-8(优选为C4-6)脂杂环基,可选地,为环氧乙烷基、硫杂环丙烷基、氮杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡咯基、吗啉基、哌啶基、或哌嗪基;
可选地,所述“芳基”、“芳基亚烷基”、“芳基烷氧基”、“芳基氧基”中的芳基为6-10元单环或双环稠合芳香环基团;可选地为苯基或萘基;
可选地,所述“亚烷基亚芳基”中的亚芳基为6-10元单环或双环稠合亚芳香环基团;可选地为亚苯基或亚萘基;
可选地,所述“杂芳基”、“杂芳基亚烷基”、“杂芳基氧基”、“杂芳基烷氧基”中的杂芳基各自独立地为含有选自O、N、S、SO或SO2的1-3个杂原子的5-10元单环或双环稠合杂芳香环基团,可选地,为吡咯基、吡唑基、吡啶基、呋喃基、咪唑基、噻唑基、噁唑基、氧杂卓基、硫杂卓基,1H-氮杂卓基、喹啉基、异喹啉基、吲哚基、嘧啶基或吡嗪基、或三唑基。
3.根据权利要求1或2所述的式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,其特征在于,
R1选自-H,或-(C=O)CH3,-(C=O)OC(CH3)3;
可选地,R2选自-H,甲基、乙基、叔丁基、烯丙基、炔丙基或苄基;
可选地,R3选自-H,-OH,
4.根据权利要求1-3任一项所述的式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,其特征在于,所述式(I)化合物的氨基酸部分为D构型或L构型。
5.根据权利要求1-4任一项所述的式(I)化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,其特征在于,
所述药学上可接受的盐为无机酸盐或有机酸盐,优选地,选自盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、碳酸、硝酸、硫酸氢酸、甲磺酸、羟基乙磺酸、酒石酸、甲酸、乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、三氟乙酸、丙酮酸、肉桂酸、月桂酸、水杨酸、柠檬酸、琥珀酸、富马酸、苯甲酸、邻氨基苯甲酸、2-(4-羟基苯甲酰基)苯甲酸、苯磺酸、乙磺酸、对氨基苯磺酸、对甲苯磺酸、苯乙酸、抗坏血酸、褐藻酸、糠酸、硬脂酸、粘液酸、扁桃酸、苹果酸、扑酸、泛酸、樟脑磺酸、葡萄糖酸、谷氨酸、葡萄糖醛酸、半乳糖醛酸、缩水甘油酸、乳酸、苹果酸、马来酸、天冬氨酸、硫氰酸、葡庚酸、甘油磷酸、磺基水杨酸、半硫酸、草酸、丙二酸、或苦味酸。
6.根据权利要求1-5任一项所述的式(I)所示的化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,其特征在于,选自以下化合物:
7.权利要求1-6任一项所述的式(I)化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,其中式(I)化合物的制备方法:
包括将式(A)化合物和式(B)化合物通过步骤A得到式(C):
步骤A:将式(A)和式(B)通过取代反应制得式(C);
可选地,将式(A)和式(B)在碱(例如碳酸钾,碳酸铯,氢化钠,双三甲基硅基胺基锂等)催化下,在适合的溶剂中(例如N,N-二甲基甲酰胺,N,N-二甲基甲酰胺,二甲亚砜,N-甲基吡咯烷酮等),于0℃至25℃温度条件下,通过取代反应制得式(C);
其中,
式(B)和式(C)中,R3定义同式(I)中所述,但不为H,OR4;
式(B)中,B选自Cl,Br,I,OTs,OMs;
或者,通过以下步骤A’的反应得到式(C):
步骤A’:将S1和S2通过缩合条件得到S3,再将S3经过脱保护得到S4,然后S4和S5在碱催化下通过取代和氨解甲酯得到LN-S5,经还原得式(C);
还包括将式(C)和式(D)通过步骤B得式(E),
步骤B:将式(C)和式(D)通过酰化反应得式(E)
优选地,将式(C)和对硝基苯基氯甲酸酯溶于溶剂(如四氢呋喃或N,N-二甲基甲酰胺或N-甲基吡咯烷酮)中,在回流条件下反应,得到式(E);
可选地,所述回流反应反应结束后,减压浓缩,加入乙酸乙酯或二氯甲烷或石油醚等搅拌均匀得到混悬液,减压过滤并乙酸乙酯洗涤或直接旋干,得到式(E):
其中,式(E)中,R3定义同式(I)中所述;
或者,还包括将式(C)和式(F)通过步骤C得到式(G):
步骤C:将式(C)和式(F)通过酰化反应得到式(G);
优选地,低温下(优选0℃)将式(C)缓慢滴加至三光气的二氯甲烷或乙腈溶液中,缓慢升温至30℃-60℃(优选为45℃),待反应结束,减压浓缩,得式(G);
其中,式(G)中,R3定义同式(I)中所述;
或者,还包括将式(C)和式(H)通过步骤D得到式(J):
步骤D:将式(C)和式(D)通过缩合反应得式(J);
可选地,将式(C)和式(H)分散在适当溶剂中,在加热条件下反应,待反应结束,减压浓缩、过滤并用乙酸乙酯洗涤或直接旋干,得式(J);可选地,溶剂为DCM、或CAN、或THF、或DCE等;可选地,温度为45℃-90℃。
其中,式(J)中,R3定义同式(I)中所述;
当式(I)中A选自-O-,-S-,-NH-时,将式(E)或式(G)或式(J)与式(L)在碱催化下经亲核取代反应和任选的脱保护得到式(I),如以下合成步骤E:
步骤E:
式(L)中,C选自-OH,-SH,-NH2中的任意一个基团;
R5为Cl,或
当式(I)中A不存在时,采用合成步骤F制备:
步骤F:将式(A)或式(C)与式(P)采用缩合剂(例如HATU或TBTU等)缩合和任选的脱保护反应步骤得式(R),
其中,式(P)中,Q定义同式(I)中所述。
8.一种药物组合物,其包括权利要求1-6任一项所述的式(I)化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,和药学上可接受的辅料;
可选地,所述的药学上可接受辅料选自:填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料或其它赋形剂。
可选地,所述填充剂包括乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙、微晶纤维素的一种或几种;
可选地,所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇、水的一种或几种;
可选地,所述的崩解剂包括淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基纤维素钠、泡腾崩解剂的一种或几种;
可选地,所述药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型;所述固体及液体口服制剂包括:片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂、糖浆剂和溶液剂;所述的注射剂包括:小针、大输液、冻干粉针等。
9.权利要求1-6任一项所述的式(I)化合物,或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物,或者权利要求8所述的药物组合物在制备用于预防和/或治疗血液系统疾病的药物中的用途;优选地,所述的疾病选自血癌和骨髓癌、淋巴瘤、卡波西肉瘤或骨髓增生异常综合征。
10.权利要求1-6任一项所述的式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物或、或其消旋体、或其同位素标记物、或其氮氧化物,或者权利要求8所述的药物组合物与其它一种或多种活性药物联合用药,在制备用于预防和/或治疗血液系统疾病的药物中的用途;优选地,所述的疾病选自血癌和骨髓癌、淋巴瘤、卡波西肉瘤、骨髓增生异常综合征;优选地,所述其他活性药物为地塞米松和/或朋替佐米。
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