CN113038948A - 杂环化合物 - Google Patents
杂环化合物 Download PDFInfo
- Publication number
- CN113038948A CN113038948A CN201980078144.XA CN201980078144A CN113038948A CN 113038948 A CN113038948 A CN 113038948A CN 201980078144 A CN201980078144 A CN 201980078144A CN 113038948 A CN113038948 A CN 113038948A
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- Prior art keywords
- substituted
- chloro
- pyridin
- urea
- compound
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 342
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 201000011510 cancer Diseases 0.000 claims abstract description 24
- 239000013078 crystal Substances 0.000 claims abstract description 20
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 8
- 239000012453 solvate Substances 0.000 claims abstract description 7
- -1 Pyrazolyl Chemical group 0.000 claims description 345
- 125000005843 halogen group Chemical group 0.000 claims description 133
- 239000003814 drug Substances 0.000 claims description 68
- 125000001424 substituent group Chemical group 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical group 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000001425 triazolyl group Chemical group 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- MKYDKGUTYKFCHS-JTQLQIEISA-N 1-[6-chloro-4-[(1S)-1-methoxyethyl]-1,5-naphthyridin-3-yl]-3-[6-(triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]urea Chemical compound ClC=1N=C2C(=C(C=NC2=CC1)NC(=O)NC=1C=NC(=C(C1)C(F)(F)F)N1N=CC=N1)[C@H](C)OC MKYDKGUTYKFCHS-JTQLQIEISA-N 0.000 claims description 10
- YASXOENRCPGYQB-VIFPVBQESA-N 1-[5-chloro-6-(difluoromethoxy)pyridin-3-yl]-3-[8-[(1S)-1-methoxyethyl]-2-methylimidazo[1,2-b]pyridazin-7-yl]urea Chemical compound ClC=1C=C(C=NC1OC(F)F)NC(=O)NC1=C(C=2N(N=C1)C=C(N2)C)[C@H](C)OC YASXOENRCPGYQB-VIFPVBQESA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical class 0.000 claims description 8
- XIZGLLSADFNPPE-LBPRGKRZSA-N 1-[4-[(1S)-1-methoxyethyl]-6-methyl-1,5-naphthyridin-3-yl]-3-[6-(triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]urea Chemical compound CO[C@@H](C)C1=C(C=NC2=CC=C(N=C12)C)NC(=O)NC=1C=NC(=C(C1)C(F)(F)F)N1N=CC=N1 XIZGLLSADFNPPE-LBPRGKRZSA-N 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- QDTOTZUBNNQTIG-UHFFFAOYSA-N 1-[5-chloro-6-(triazol-2-yl)pyridin-3-yl]-3-(2-methyl-8-propan-2-ylimidazo[1,2-b]pyridazin-7-yl)urea Chemical compound ClC=1C=C(C=NC1N1N=CC=N1)NC(=O)NC1=C(C=2N(N=C1)C=C(N2)C)C(C)C QDTOTZUBNNQTIG-UHFFFAOYSA-N 0.000 claims description 5
- VDXYKDPULPAMFX-NSHDSACASA-N 1-[8-[(1S)-1-methoxyethyl]-2-methylimidazo[1,2-b]pyridazin-7-yl]-3-[6-(triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]urea Chemical compound CO[C@@H](C)C=1C=2N(N=CC1NC(=O)NC=1C=NC(=C(C1)C(F)(F)F)N1N=CC=N1)C=C(N2)C VDXYKDPULPAMFX-NSHDSACASA-N 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 5
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical class 0.000 claims description 5
- ZRTRVWVBBGGJKA-NSHDSACASA-N 1-[5-chloro-6-(triazol-2-yl)pyridin-3-yl]-3-[8-[(1S)-1-methoxyethyl]-2-methylimidazo[1,2-b]pyridazin-7-yl]urea Chemical compound ClC=1C=C(C=NC1N1N=CC=N1)NC(=O)NC1=C(C=2N(N=C1)C=C(N2)C)[C@H](C)OC ZRTRVWVBBGGJKA-NSHDSACASA-N 0.000 claims description 4
- AGXMSTXRPJQSNW-JTQLQIEISA-N 1-[5-cyano-6-(difluoromethoxy)pyridin-3-yl]-3-[8-[(1S)-1-methoxyethyl]-2-methylimidazo[1,2-b]pyridazin-7-yl]urea Chemical compound C(#N)C=1C=C(C=NC1OC(F)F)NC(=O)NC1=C(C=2N(N=C1)C=C(N2)C)[C@H](C)OC AGXMSTXRPJQSNW-JTQLQIEISA-N 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- TWJGQZBSEMDPQP-UHFFFAOYSA-N 2-chloro-n-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1,2,4-triazol-1-yl]phenyl]acetamide Chemical compound C=1C=C(NC(=O)CCl)C=CC=1N1N=C(OCCOC)N=C1C1=CC=C(Cl)C(Cl)=C1 TWJGQZBSEMDPQP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 229940122339 MALT1 inhibitor Drugs 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical class 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 22
- 102000057613 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Human genes 0.000 abstract description 6
- 108700026676 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Proteins 0.000 abstract description 6
- 229940043274 prophylactic drug Drugs 0.000 abstract description 6
- 229940126585 therapeutic drug Drugs 0.000 abstract description 6
- 101150113681 MALT1 gene Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 312
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 198
- 235000013877 carbamide Nutrition 0.000 description 169
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 103
- 239000004202 carbamide Substances 0.000 description 99
- 239000011541 reaction mixture Substances 0.000 description 92
- 230000002829 reductive effect Effects 0.000 description 83
- 150000003672 ureas Chemical class 0.000 description 70
- 239000000203 mixture Substances 0.000 description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 238000000034 method Methods 0.000 description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 62
- 229940079593 drug Drugs 0.000 description 56
- 239000003112 inhibitor Substances 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 46
- 239000002904 solvent Substances 0.000 description 46
- 125000001153 fluoro group Chemical group F* 0.000 description 45
- 238000010898 silica gel chromatography Methods 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 41
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 125000001309 chloro group Chemical group Cl* 0.000 description 40
- 239000012044 organic layer Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 229910052731 fluorine Inorganic materials 0.000 description 39
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 39
- 229910052801 chlorine Inorganic materials 0.000 description 37
- 238000003756 stirring Methods 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- 239000002585 base Substances 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 125000006239 protecting group Chemical group 0.000 description 33
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 32
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 239000003153 chemical reaction reagent Substances 0.000 description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 25
- 229920006395 saturated elastomer Polymers 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 239000011737 fluorine Substances 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 17
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- 239000000126 substance Substances 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
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- 125000003277 amino group Chemical group 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 12
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 12
- RWISYPZSGXHJNJ-UHFFFAOYSA-N 6-(triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine Chemical compound NC1=CC(=C(N=C1)N1N=CC=N1)C(F)(F)F RWISYPZSGXHJNJ-UHFFFAOYSA-N 0.000 description 11
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 9
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- 238000004128 high performance liquid chromatography Methods 0.000 description 9
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
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- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
提供了一种化合物,其可具有抑制MALT1的作用并有望用作癌症等的预防或治疗药物。式(I)表示的化合物[其中各符号如说明书中所定义]、其盐或它们的共晶体、水合物或溶剂化物。
Description
技术领域
本发明涉及一种杂环化合物,其可具有抑制MALT1(粘膜相关淋巴组织蛋白1)的作用,并有望用作癌症等的预防或治疗药物。
背景技术
在负责细胞介导的免疫的主要T细胞和B细胞中,T细胞受体信号和B细胞受体信号在其功能中起重要作用。这些信号的转导异常引起各种疾病,例如癌症和炎性疾病。实际上,在癌症的情况下,据报道,对T细胞源性白血病淋巴瘤例如ATL(成人T细胞白血病淋巴瘤)(其为难治性淋巴瘤之一)患者进行的遗传分析揭示了T细胞受体信号/NF-κB途径中的遗传异常,并且在其他B细胞淋巴瘤(例如ABC型DLBCL(弥漫性大B细胞淋巴瘤)和MCL(套细胞淋巴瘤))中也持续激活B细胞受体信号传导途径/NF-κB途径。
这些T细胞和B细胞受体信号在其中合并的CBM蛋白复合物由支架蛋白CARD11、衔接蛋白BCL10和具有类半胱天冬酶(paracaspase)活性的MALT1组成。T细胞受体信号和B细胞受体信号促进CBM蛋白复合物的形成,从而导致MALT1的类半胱天冬酶活性增强并激活转录因子NF-κB。
因此,预期抑制MALT1活性的抑制剂能够纠正由T细胞受体信号和B细胞受体信号异常引起的MALT1活性的增强,并且被认为可用作由MALT1的活性引起的癌症、炎性疾病等的预防或治疗药物。
预期本发明的化合物可用于预防或治疗可能受MALT1影响的疾病(在说明书中有时缩写为“MALT1相关疾病”)。预期其可用于预防或治疗疾病,包括但不限于,癌症[例如,结肠直肠癌(例如,结肠癌、直肠癌、肛门癌、家族性结肠直肠癌、遗传性非息肉病性结肠直肠癌和胃肠道间质瘤)、肺癌(例如非小细胞肺癌、小细胞肺癌和恶性间皮瘤)、间皮瘤、胰腺癌(例如胰腺导管癌和胰腺内分泌肿瘤)、咽癌、喉癌、食道癌、胃癌(例如乳头状腺癌、黏液性腺癌和腺鳞癌)、十二指肠癌、小肠癌、乳腺癌(例如浸润性导管癌、原位导管癌和炎性乳腺癌)、卵巢癌(例如上皮性卵巢癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤和低度卵巢肿瘤)、睾丸癌、前列腺癌(例如激素依赖性前列腺癌、激素非依赖性前列腺癌和去势抵抗性前列腺癌)、肝癌(例如肝细胞癌、原发性肝癌和肝外胆管癌)、甲状腺癌(例如甲状腺髓样癌)、肾癌(例如肾细胞癌(例如,透明细胞肾细胞癌)、肾盂和输尿管的移行细胞癌)、子宫癌(例如宫颈癌、子宫内膜癌和子宫肉瘤)、妊娠性绒毛膜癌、脑瘤(例如髓母细胞瘤、神经胶质瘤、松果体星形细胞瘤、毛细胞星形细胞瘤、弥漫性星形细胞瘤、间变性星形细胞瘤和垂体腺瘤)、视网膜母细胞瘤、皮肤癌(例如基底细胞癌和恶性黑色素瘤(例如黑素瘤))、肉瘤(例如横纹肌肉瘤、平滑肌肉瘤、软组织肉瘤、梭形细胞肉瘤和骨肉瘤)、恶性骨肿瘤、膀胱癌、血液癌(例如多发性骨髓瘤、白血病(例如急性髓细胞性白血病和急性淋巴细胞性白血病))、恶性淋巴瘤(例如弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、成人T细胞白血病/淋巴瘤和慢性骨髓增生性疾病)、霍奇金病和原发性未知癌症],抑制癌症生长、抑制转移、促进细胞凋亡或预防或治疗癌前病变(例如骨髓异型性综合征)。另外,预期本发明的化合物可用于预防或治疗自身免疫和/或炎性疾病(例如脑脊髓炎、结肠炎、特应性疾病、类风湿性关节炎、多发性硬化症和系统性红斑狼疮)、骨病、代谢疾病、神经系统疾病和神经退行性疾病、癌症、心血管疾病、过敏和哮喘、阿尔茨海默氏病、激素相关疾病、炎性疾病、病毒感染(例如人免疫缺陷病毒感染)和细菌感染(例如败血症)。
专利文献1公开了以下化合物,该化合物具有抑制MALT1的作用并且可用于治疗自身免疫性病症和炎性疾病,例如类风湿性关节炎、多发性硬化症、系统性红斑狼疮和血管炎病况,源自造血系统的癌症,包括慢性骨髓性白血病、骨髓性白血病、非霍奇金淋巴瘤和其他B细胞淋巴瘤或实体瘤等。
[其中每个符号如文献中所定义]。
专利文献2公开了以下化合物,该化合物具有抑制MALT1的作用并且可用于治疗自身免疫性病症和炎性疾病,例如类风湿性关节炎、多发性硬化症、牛皮癣、干燥综合征、系统性红斑狼疮和血管炎病况,源自造血系统的癌症,包括慢性骨髓性白血病、骨髓性白血病、非霍奇金淋巴瘤和其他B细胞淋巴瘤或实体瘤等。
[其中每个符号如文献中所定义]。
专利文献3公开了以下化合物,该化合物具有抑制MALT1的作用并且可用于治疗自身免疫病症、炎性疾病、癌症等。
[其中每个符号如文献中所定义]。
专利文献4公开了以下化合物,该化合物具有通过补充E3泛素连接酶而抑制MALT1和促进MALT1蛋白降解的作用,并且可用于治疗癌症,例如血液癌、淋巴细胞性恶性疾病、白血病、淋巴瘤和多发性骨髓瘤等。
[其中每个符号如文献中所定义]。
引用列表
专利文献
专利文献1:WO 2015/181747
专利文献2:WO 2017/081641
专利文献3:WO 2018/020474
专利文献4:WO 2018/085247。
发明内容
技术问题
本发明的目的是提供一种新型化合物,其具有抑制MALT1的作用,并有望用作癌症等的预防或治疗药物,以及提供含有该化合物的药物。
解决问题的方案
由于努力研究以解决上述问题,本发明人已经发现,由下式(I)表示的化合物可具有优异的抑制MALT1的作用,从而完成了本发明。
即,本发明如下。
[1]由式(I)表示的化合物,或其盐,或其共晶体、水合物或溶剂化物(在说明书中有时缩写为“化合物(I)”):
(其中
A表示
R1表示1)氢原子,2)卤素原子,3)氰基,4)可被1-3个卤素原子取代的C1-3烷基,5)C1-3烷氧基,6)C3-6环烷基,或7)苯基;
R2表示1)氢原子或2)卤素原子;
R3表示1)可被1-3个选自C1-3烷氧基、羟基和卤素原子的取代基取代的C1-6烷基,2)可被1-3个选自C1-3烷基和卤素原子的取代基取代的吡唑基,3)C3-6环烷基,4)被C1-3烷基二取代的氨基,或5)可被1-3个卤素原子取代的苯基;
R4和R6表示1)氢原子,2)卤素原子,3)可被1-3个选自a)羟基、b)可被4-甲氧基苯基取代的C1-3烷氧基和c)卤素原子的取代基取代的C1-3烷基,或4)可被1-3个卤素原子取代的C1-3烷氧基;
R5、R7和R9表示1)可被1-3个C1-3烷氧基取代的C1-6烷基或2)可被1-3个卤素原子取代的苯基;
R8表示C1-3烷基;和
B表示
1)可被1-3个取代基取代的苯基,所述取代基选自a)卤素原子,b)氰基,c)可被1-3个卤素原子取代的C1-3烷氧基,和d)三唑基;
2)可被1-3个取代基取代的C3-6环烷基,所述取代基选自a)可被1-3个卤素原子取代的C1-3烷基和b)卤素原子,
3)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子,b)氰基,c)可被1-3个卤素原子取代的C1-3烷基,d)可被1-3个选自卤素原子和C1-3烷氧基的取代基取代的C1-3烷氧基,e)可被1-3个C1-3烷基取代的吡唑基,f)可被1-3个C1-3烷基取代的咪唑基,g)可被1-3个C1-3烷基取代的三唑基,所述C1-3烷基可被1-3个选自C1-3烷氧基和卤素原子的取代基取代,h)氮杂环丁烷基,i)吡咯烷酮基,j)可被1-3个C1-3烷基取代的四唑基,k)嘧啶基,和l)噁唑基,
4)可被1-3个取代基取代的吡唑基,所述取代基选自a)可被1-3个卤素原子取代的C1-3烷基,b)可被1-3个卤素原子取代的C1-3烷氧基,c)氰基,和d)卤素原子,或
5)可被1-3个卤素原子取代的咪唑并吡啶基。
[2]根据[1]的化合物,其中A是
[3]根据[1]的化合物,其中A是
[4]根据[1]的化合物,其中A是
R1是1)卤素原子或2)C1-3烷基;
R2是氢原子;
R3是可被1-3个C1-3烷氧基取代的C1-6烷基;
R4是1)卤素原子或2)C1-3烷基;
R5是可被1-3个C1-3烷氧基取代的C1-6烷基;和
B是可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子,b)氰基,c)可被1-3个卤素原子取代的C1-3烷基,d)可被1-3个卤素原子取代的C1-3烷氧基,和e)三唑基。
[5]根据[1]的化合物,其为(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
(S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
(S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(5-氰基-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲,或
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲。
[6]根据[1]的化合物,其为(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲。
[7]根据[1]的化合物,其为(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲。
[8]一种药物,其含有根据[1]的化合物或其盐或其共晶体、水合物或溶剂化物。
[9]根据[8]的药物,其为MALT1抑制剂。
[10]根据[8]的药物,其是用于癌症的预防或治疗药物。
本发明的有利效果
本发明的化合物可具有抑制MALT1的作用,并且可用作药物,例如用于癌症等的预防或治疗药物。
具体实施方式
在下文中,对说明书中使用的每个取代基的定义进行详细描述。除非另有说明,否则每个取代基具有以下定义。
在说明书中,“卤素原子”的实例包括氟、氯、溴和碘。
在说明书中,“C1-6烷基”的实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基和2-乙基丁基。
在说明书中,“C3-6环烷基”的实例包括环丙基、环丁基、环戊基和环己基。
在说明书中,“C1-3烷氧基”的实例包括甲氧基、乙氧基、丙氧基和异丙氧基。
在说明书中,“被C1-3烷基二取代的氨基”的实例包括二甲基氨基、乙基甲基氨基、二乙基氨基、乙基丙基氨基和二丙基氨基。
在说明书中,“C1-3烷基”包括上述具有1至3个碳原子的“C1-6烷基”。
在下文中,对式(I)中每个符号的定义进行详细描述。
A表示
A优选是
在本发明的一个优选实施方案中,A是
在本发明的另一个优选实施方案中,A是
R1表示1)氢原子,2)卤素原子(例如氯原子、溴原子),3)氰基,4)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),5)C1-3烷氧基(例如甲氧基),6)C3-6环烷基(例如环丙基),或7)苯基。
R1更优选是1)卤素原子(例如氯原子)或2)C1-3烷基(例如甲基)。
R2表示1)氢原子或2)卤素原子(例如氟原子、氯原子)。
R2优选是氢原子。
R3表示1)可被1-3个选自C1-3烷氧基(例如甲氧基)、羟基和卤素原子(例如氟原子)的取代基取代的C1-6烷基(例如乙基、异丙基、仲丁基),2)可被1-3个选自C1-3烷基(例如甲基)和卤素原子(例如氯原子)的取代基取代的吡唑基(例如4-吡唑基),3)C3-6环烷基(例如环丙基),4)被C1-3烷基(例如甲基)二取代的氨基,或5)可被1-3个卤素原子(例如氯原子)取代的苯基。
R3优选是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基、异丙基)。
R4和R6表示1)氢原子,2)卤素原子(例如氯原子),3)可被1-3个取代基取代的C1-3烷基(例如甲基、乙基),所述取代基选自a)羟基,b)可被4-甲氧基苯基取代的C1-3烷氧基(例如甲氧基)和c)卤素原子(例如氟原子),或4)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基、乙氧基)。
R4优选是1)卤素原子(例如氯原子)或2)C1-3烷基(例如甲基)。
R6优选是1)氢原子,2)卤素原子(例如氯原子),3)C1-3烷基(例如甲基)或4)C1-3烷氧基(例如甲氧基)。
R5、R7和R9表示1)可被1-3个C1-3烷氧基(例如甲氧基、乙氧基)取代的C1-6烷基(例如乙基、异丙基)或2)可被1-3个卤素原子(例如氯原子)取代的苯基。
R5优选是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基)。
R7优选是1)可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基、异丙基)或2)可被1-3个卤素原子(例如氯原子)取代的苯基。
R9优选是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-3烷基(例如乙基)。
R8表示C1-3烷基(例如甲基)。
B表示
1)可被1-3个取代基取代的苯基,所述取代基选自a)卤素原子(例如氟原子、氯原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),和d)三唑基,
2)可被1-3个取代基取代的C3-6环烷基(例如环己基),所述取代基选自a)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基)和b)卤素原子(例如氟原子),
3)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氟原子、氯原子、溴原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个选自卤素原子(例如氟原子)和C1-3烷氧基(例如甲氧基)的取代基取代的C1-3烷氧基(例如甲氧基、乙氧基),e)可被1-3个C1-3烷基(例如甲基)取代的吡唑基,f)可被1-3个C1-3烷基(例如甲基)取代的咪唑基,g)可被1-3个C1-3烷基(例如甲基)取代的三唑基,所述C1-3烷基可被1-3个选自C1-3烷氧基(例如甲氧基)和卤素原子(例如氟原子)的取代基取代,h)氮杂环丁烷基,i)吡咯烷酮基,j)可被1-3个C1-3烷基(例如甲基)取代的四唑基,k)嘧啶基,和l)噁唑基,
4)可被1-3个取代基取代的吡唑基,所述取代基选自a)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基、乙基、异丙基),b)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),c)氰基,和d)卤素原子(例如氯原子),或
5)可被1-3个卤素原子(例如氯原子)取代的咪唑并吡啶基。
B优选是可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氯原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个卤素原子(例如氟原子)取代的C 1-3烷氧基(例如甲氧基),和e)三唑基。
化合物(I)的合适实例包括以下化合物。
[化合物I-1]
化合物(I),其中A是
R1是1)氢原子,2)卤素原子(例如氯原子、溴原子),3)氰基,4)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),5)C1-3烷氧基(例如甲氧基),6)C3-6环烷基(例如环丙基),或7)苯基;
R2是1)氢原子或2)卤素原子(例如氟原子、氯原子);
R3是1)可被1-3个选自C1-3烷氧基(例如甲氧基)、羟基和卤素原子(例如氟原子)的取代基取代的C1-6烷基(例如乙基、异丙基、仲丁基),2)可被1-3个选自C1-3烷基(例如甲基)和卤素原子(例如氯原子)的取代基取代的吡唑基(例如4-吡唑基),3)C3-6环烷基(例如环丙基),4)被C1-3烷基(例如甲基)二取代的氨基,或5)可被1-3个卤素原子(例如氯原子)取代的苯基;
R4是1)氢原子,2)卤素原子(例如氯原子),3)可被1-3个取代基取代的C1-3烷基(例如甲基、乙基),所述取代基选自a)羟基,b)可被4-甲氧基苯基取代的C1-3烷氧基(例如甲氧基)和c)卤素原子(例如氟原子),或4)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基、乙氧基);
R5是1)可被1-3个C1-3烷氧基(例如甲氧基、乙氧基)取代的C1-6烷基(例如乙基、异丙基)或2)可被1-3个卤素原子(例如氯原子)取代的苯基;
R6是1)氢原子,2)卤素原子(例如氯原子),3)C1-3烷基(例如甲基)或4)C1-3烷氧基(例如乙氧基);
R7是1)可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(乙基、异丙基)或2)可被1-3个卤素原子(例如氯原子)取代的苯基;
R8是C1-3烷基(例如甲基);
R9是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-3烷基(例如乙基);和
B是
1)可被1-3个取代基取代的苯基,所述取代基选自a)卤素原子(例如氟原子、氯原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),和d)三唑基,
2)可被1-3个取代基取代的C3-6环烷基(例如环己基),所述取代基选自a)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基)和b)卤素原子(例如氟原子),
3)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氟原子、氯原子、溴原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个选自卤素原子(例如氟原子)和C1-3烷氧基(例如甲氧基)的取代基取代的C1-3烷氧基(例如甲氧基、乙氧基),e)可被1-3个C1-3烷基(例如甲基)取代的吡唑基,f)可被1-3个C1-3烷基(例如甲基)取代的咪唑基,g)可被1-3个C1-3烷基(例如甲基)取代的三唑基,所述C1-3烷基可被1-3个选自C1-3烷氧基(例如甲氧基)和卤素原子(例如氟原子)的取代基取代,h)氮杂环丁烷基,i)吡咯烷酮基,j)可被1-3个C1-3烷基(例如甲基)取代的四唑基,k)嘧啶基,和l)噁唑基,
4)可被1-3个取代基取代的吡唑基,所述取代基选自a)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基、乙基、异丙基),b)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),c)氰基,和d)卤素原子(例如氯原子),或
5)可被1-3个卤素原子(例如氯原子)取代的咪唑并吡啶基。
[化合物I-2]
化合物(I),其中A是
R1是1)卤素原子(例如氯原子)或2)C1-3烷基(例如甲基);
R2是氢原子;
R3是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基、异丙基);
R4是1)卤素原子(例如氯原子)或2)C1-3烷基(例如甲基);
R5是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基);和
B是可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氯原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),和e)三唑基。
[化合物I-3]
化合物(I),其中A是
R1是C1-3烷基(例如甲基);
R2是氢原子;
R3是被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基、异丙基);
R4是1)卤素原子(例如氯原子)或2)C1-3烷基(例如甲基);
R5是可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(例如乙基);和
B是可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氯原子),b)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),和d)三唑基。
[化合物I-4]
化合物(I),其中A是
R1是1)氢原子,2)卤素原子(例如氯原子、溴原子),3)氰基,4)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),5)C1-3烷氧基(例如甲氧基),6)C3-6环烷基(例如环丙基),或7)苯基;
R2是1)氢原子或2)卤素原子(例如氟原子、氯原子);
R3是1)可被1-3个选自C1-3烷氧基(例如甲氧基)、羟基和卤素原子(例如氟原子)的取代基取代的C1-6烷基(例如乙基、异丙基、仲丁基),2)可被1-3个选自C1-3烷基(例如甲基)和卤素原子(例如氯原子)的取代基取代的吡唑基(例如4-吡唑基),3)C3-6环烷基(例如环丙基),4)被C1-3烷基(例如甲基)二取代的氨基,或5)可被1-3个卤素原子(例如氯原子)取代的苯基;和
B是
1)可被1-3个取代基取代的苯基,所述取代基选自a)卤素原子(例如氟原子、氯原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),和d)三唑基,
2)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氯原子、溴原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),e)可被1-3个C1-3烷基(例如甲基)取代的吡唑基,f)可被1-3个C1-3烷基(例如甲基)取代的咪唑基,g)可被1-3个C1-3烷基(例如甲基)取代的三唑基,所述C1-3烷基可被1-3个选自C1-3烷氧基(例如甲氧基)和卤素原子(例如氟原子)的取代基取代,和h)噁唑基,
3)可被1-3个取代基取代的吡唑基,所述取代基选自a)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),b)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),c)氰基,和d)卤素原子(例如氯原子),或
5)可被1-3个卤素原子(例如氯原子)取代的咪唑并吡啶基。
[化合物I-5]
化合物(I),其中A是
R4是1)氢原子,2)卤素原子(例如氯原子),3)可被1-3个取代基取代的C1-3烷基(例如甲基、乙基),所述取代基选自a)羟基,b)可被4-甲氧基苯基取代的C1-3烷氧基(例如甲氧基)和c)卤素原子(例如氟原子),或4)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基、乙氧基);
R5是1)可被1-3个C1-3烷氧基(例如甲氧基、乙氧基)取代的C1-6烷基(例如乙基、异丙基)或2)可被1-3个卤素原子(例如氯原子)取代的苯基;和
B是
1)可被1-3个卤素原子(例如氟原子)取代的苯基,
2)可被1-3个取代基取代的C3-6环烷基(例如环己基),所述取代基选自a)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基)和b)卤素原子(例如氟原子),
3)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氟原子、氯原子、溴原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个选自卤素原子(例如氟原子)和C1-3烷氧基(例如甲氧基)的取代基取代的C1-3烷氧基(例如甲氧基、乙氧基),e)可被1-3个C1-3烷基(例如甲基)取代的三唑基,所述C1-3烷基可被1-3个选自C1-3烷氧基(例如甲氧基)和卤素原子(例如氟原子)的取代基取代,f)氮杂环丁烷基,g)吡咯烷酮基,h)可被1-3个选自C1-3烷基(例如甲基)的取代基取代的四唑基,i)嘧啶基,和j)噁唑基,或
4)可被1-3个C1-3烷基(例如甲基、乙基、异丙基)取代的吡唑基,所述C1-3烷基可被1-3个卤素原子(例如氟原子)取代。
[化合物I-6]
化合物(I),其中A是
R6是1)氢原子,2)卤素原子(例如氯原子),3)C1-3烷基(例如甲基)或4)C1-3烷氧基(例如乙氧基);
R7是1)可被1-3个C1-3烷氧基(例如甲氧基)取代的C1-6烷基(乙基,异丙基)或2)可被1-3个卤素原子(例如氯原子)取代的苯基;和
B是
1)可被1-3个卤素原子(例如氟原子)取代的苯基,或
2)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氯原子),b)氰基,c)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),d)可被1-3个卤素原子(例如氟原子)取代的C1-3烷氧基(例如甲氧基),和e)三唑基。
[化合物I-7]
化合物(I),其中A是
R8是C1-3烷基(例如甲基);
R9是可被1-3个C 1-3烷氧基(例如甲氧基)取代的C1-3烷基(例如乙基);和
B是可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子(例如氯原子),b)可被1-3个卤素原子(例如氟原子)取代的C1-3烷基(例如甲基),c)C1-3烷氧基(例如甲氧基)和d)三唑基。
[化合物I-8]
(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
(S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
(S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(5-氰基-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲,或
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲。
[化合物I-9]
(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,或
(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲。
由式(I)表示的化合物的盐优选是药理学上可接受的盐。这种盐的实例包括与无机碱的盐、与有机碱的盐、与无机酸的盐、与有机酸的盐以及与碱性或酸性氨基酸的盐。
与无机碱的盐的合适实例包括碱金属盐,例如钠盐和钾盐;碱土金属盐,例如钙盐和镁盐;铝盐;和铵盐。
与有机碱的盐的合适实例包括与三甲胺、三乙胺、吡啶、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、三甲胺[三(羟甲基)甲胺]、叔丁胺、环己胺、苄基胺、二环己基胺和N,N-二苄基乙二胺的盐。
与无机酸的盐的合适实例包括与盐酸、氢溴酸、硝酸、硫酸和磷酸的盐。
与有机酸的盐的合适实例包括与甲酸、乙酸、三氟乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸和对甲苯磺酸的盐。
与碱性氨基酸的盐的合适实例包括与精氨酸、赖氨酸和鸟氨酸的盐。
与酸性氨基酸的盐的合适实例包括与天冬氨酸和谷氨酸的盐。
在下文中,对本发明化合物的制备方法进行描述。
以下制备方法的每个步骤中使用的原料和试剂,以及所获得的化合物可各自形成盐。这种盐的实例包括与本发明化合物的上述盐相似的那些盐。
当在每个步骤中获得的化合物是游离化合物时,可以通过本身已知的方法将其转化为所需的盐。相反,当在每个步骤中获得的化合物是盐时,可以通过本身已知的方法将其转化成游离形式或另一种所需的盐。
在每个步骤中作为反应溶液或粗产物获得的化合物可以用于下一反应。或者,可以根据常规方法通过分离手段,例如浓缩、结晶、重结晶、蒸馏、溶剂萃取、分馏或色谱法,从反应混合物中分离和/或纯化在每个步骤中获得的化合物。
当用于每个步骤的原料或试剂化合物是可商购的时,可以原样使用可商购的产品。
在每个步骤的反应中,反应时间可以根据所使用的试剂或溶剂而变化,但是除非另有说明,否则其通常为1分钟至48小时,优选为10分钟至24小时。
在每个步骤的反应中,反应温度可以根据所使用的试剂或溶剂而变化,但是除非另有说明,否则其通常为-78℃至300℃,优选为-78℃至150℃。
在每个步骤的反应中,压力可以根据所使用的试剂或溶剂而变化,但是除非另有说明,否则其通常为1atm至20atm,优选为1atm至3atm。
在每个步骤的反应中,例如,可以使用微波合成仪,例如由Biotage制造的Initiator。反应温度可以根据所使用的试剂或溶剂而变化,但是除非另有说明,否则其通常为室温至300℃,优选为50℃至250℃。反应时间可以根据所使用的试剂或溶剂而变化,但是除非另有说明,否则其通常为1分钟至48小时,优选为1分钟至8小时。
除非另有说明,在每个步骤的反应中,相对于底物,试剂的用量为0.5当量至20当量,优选0.8当量至5当量。当试剂用作催化剂时,相对于底物,试剂的用量为0.001当量至1当量,优选0.01当量至0.2当量。当试剂还用作反应溶剂时,试剂的用量为溶剂的量。
除非每个步骤的反应中另有说明,否则反应在没有溶剂的情况下进行或通过溶解或悬浮在合适的溶剂中进行。溶剂的具体实例包括实施例或以下中所述的溶剂。
醇类:甲醇、乙醇、叔丁醇、2-甲氧基乙醇等;
醚类:乙醚、二苯醚、四氢呋喃、1,2-二甲氧基乙烷等;
芳烃类:氯苯、甲苯、二甲苯等;
饱和烃类:环己烷、己烷等;
酰胺类:N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;
卤代烃类:二氯甲烷、四氯化碳等;
腈类:乙腈等;
亚砜类:二甲亚砜等;
芳香族有机碱类:吡啶等;
酸酐类:乙酸酐等;
有机酸类:甲酸、乙酸、三氟乙酸等;
无机酸类:盐酸、硫酸等;
酯类:乙酸乙酯等;
酮类:丙酮、甲乙酮等;
水。
作为溶剂,可以以适当的比例混合使用两种或更多种。
当在每个步骤的反应中使用碱时,例如,使用以下所示的碱或实施例中所述的碱。
无机碱:氢氧化钠、氢氧化镁、碳酸钠、碳酸钙、碳酸氢钠等;
有机碱:三乙胺、二乙胺、吡啶、4-二甲基氨基吡啶、N,N-二甲基苯胺、1,4-二氮杂双环[2.2.2]辛烷、1,8-二氮杂双环[5.4.0]-7-十一碳烯、咪唑、哌啶等;
金属醇盐:乙醇钠、叔丁醇钾等;
碱金属氢化物:氢化钠等;
金属氨基化物(metal amides):氨基化钠、二异丙基氨基锂、六甲基二硅基氨基锂等;
有机锂:正丁基锂等。
当在每个步骤的反应中使用酸或酸性催化剂时,例如,使用以下所示的酸或酸性催化剂,或实施例中所述的酸或酸性催化剂。
无机酸:盐酸、硫酸、硝酸、氢溴酸、磷酸等;
有机酸:乙酸、三氟乙酸、柠檬酸、对甲苯磺酸、10-樟脑磺酸等;
路易斯酸:三氟化硼乙醚络合物、碘化锌、无水氯化铝、无水氯化锌、无水氯化铁等。
除非另有说明,否则每个步骤的反应根据本身已知的方法进行,所述方法例如描述于:The fifth series of experimental chemistry, 第13至19卷 (Chemical Societyof Japan编辑); New experimental chemistry, 第14至15卷 (Chemical Society ofJapan编辑); Precise Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th.Eicher, Nankodo Co., Ltd.); Revised Organic Name Reactions; The ReactionMechanism and Essence (Hideo Togo, Kodansha, Ltd.编写); ORGANIC SYNTHESESCollective Volume I to VII (John Wiley & Sons Inc); Modern Organic Synthesisin the Laboratory A Collection of Standard Experimental Procedures (Jie JackLi编写, OXFORD UNIVERSITY出版); Comprehensive Heterocyclic Chemistry III, 第1至第14 卷(Elsevier Japan); Strategic applications of named reactions inorganic synthesis (Kiyoshi Tomioka监督翻译, Kagaku-Dojin Publishing Company,Inc.出版); 1989年出版的Comprehensive Organic Transformations (VCH PublishersInc.)等,或每个步骤的反应根据实施例中所述的方法进行。
在每个步骤中,官能团的保护或脱保护反应根据本身已知的方法进行,所述方法例如描述于:"Protective Groups in Organic Synthesis, 第4版" (Theodora W.Greene, Peter G. M. Wuts编写), Wiley-Interscience于2007年出版; "ProtectingGroups 3rd Ed." (P.J. Kocienski编写), Thieme于2004年出版等,或官能团的保护或脱保护反应根据实施例中所述的方法进行。
醇的羟基和酚羟基等的保护基的实例包括醚型保护基,例如甲氧基甲基醚、苄基醚、叔丁基二甲基甲硅烷基醚、四氢吡喃基醚;羧酸酯型保护基,例如乙酸酯;磺酸酯型保护基,例如甲磺酸酯;和碳酸酯型保护基,例如碳酸叔丁酯。
醛的羰基的保护基的实例包括缩醛型保护基,例如二甲基缩醛;和环状缩醛型保护基,例如1,3-二噁烷。
酮的羰基的保护基的实例包括缩酮型保护基,例如二甲基缩酮;环状缩酮型保护基,例如1,3-二噁烷;肟型保护基,例如O-甲基肟;和腙型保护基,例如N,N-二甲基腙。
羧基的保护基的实例包括酯型保护基,例如甲酯;和酰胺型保护基,例如N,N-二甲基酰胺。
用于硫羟基(thiol)的保护基的实例包括醚型保护基,例如苄基硫醚;和酯型保护基,例如硫羟乙酸酯(thioacetic acid ester)、硫羟碳酸酯(thiocarbonate)和硫羟氨基甲酸酯(thiocarbamate)。
氨基和芳族杂环如咪唑、吡咯或吲哚的保护基的实例包括氨基甲酸酯型保护基,例如氨基甲酸苄酯;酰胺型保护基,例如乙酰胺;烷基胺型保护基,例如N-三苯基甲胺,和磺酰胺型保护基,例如甲磺酰胺。
可以通过使用本身已知的方法,例如使用酸、碱、紫外线、肼、苯肼、N-甲基二硫代氨基甲酸钠、四丁基氟化铵、乙酸钯或卤化三烷基硅烷(例如,碘化三甲基硅烷、溴化三甲基硅烷)的方法,或还原方法来进行保护基的去除。
在每个步骤中,进行还原反应时,所用的还原剂包括金属氢化物,例如氢化铝锂、三乙酰氧基硼氢化钠、氰基硼氢化钠、二异丁基氢化铝(DIBAL-H)、硼氢化钠和四甲基三乙酰氧基硼氢化铵;硼烷,例如硼烷四氢呋喃络合物;雷尼镍;雷尼钴;氢;甲酸;和三乙基甲硅烷。当还原碳-碳双键或三键时,使用其中使用催化剂例如钯-碳或Lindlar催化剂的方法。
在每个步骤中,当进行氧化反应时,所使用的氧化剂包括过酸,例如间氯过氧苯甲酸(mCPBA)、过氧化氢和叔丁基过氧化氢;高氯酸盐,例如高氯酸四丁基铵;氯酸盐,例如氯酸钠;亚氯酸盐,例如亚氯酸钠;高碘酸,例如高碘酸钠;高价碘试剂,例如亚碘酰苯;具有锰的试剂,例如二氧化锰和高锰酸钾;铅,例如四乙酸铅;具有铬的试剂,例如氯铬酸吡啶鎓(PCC)、重铬酸吡啶鎓(PDC)和Jones试剂;卤素化合物,例如N-溴代琥珀酰亚胺(NBS);氧;臭氧;三氧化硫-吡啶络合物;四氧化锇;二氧化硒;和2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)。
在每个步骤中,当进行自由基环化反应时,所使用的自由基引发剂包括偶氮化合物,例如偶氮二异丁腈(AIBN);水溶性自由基引发剂,例如4-4'-偶氮双-4-氰基戊酸(ACPA);在空气或氧存在下的三乙基硼;和过氧化苯甲酰。另外,所使用的自由基反应试剂包括三丁基锡烷、三(三甲基甲硅烷基)硅烷、1,1,2,2-四苯基乙硅烷、二苯基硅烷和碘化钐。
在每个步骤中,当进行维蒂希反应时,所用的维蒂希试剂包括烷叉磷烷(alkylidene phosphoranes)。烷叉磷烷可以通过本身已知的方法来制备,例如通过使鏻盐与强碱反应来制备。
在每个步骤中,当进行Horner-Emmons反应时,所用的试剂包括膦酰基乙酸酯,例如二甲基膦酰基乙酸甲酯和二乙基膦酰基乙酸乙酯;和碱,例如碱金属氢化物和有机锂。
在每个步骤中,当进行Friedel-Crafts反应时,使用的试剂包括路易斯酸和酰氯的组合,或路易斯酸和烷基化剂的组合(例如卤代烷、醇、烯烃等)。或者,可以使用有机酸或无机酸代替路易斯酸,并且可以使用酸酐如乙酸酐代替酰氯。
在每个步骤中,当进行芳族亲核取代反应时,将亲核试剂(例如,胺、咪唑等)和碱(例如,有机碱等)用作试剂。
在每个步骤中,当与碳负离子进行亲核加成反应、与碳负离子进行亲核1,4-加成反应(迈克尔加成反应)或与碳负离子进行亲核取代反应时,用于生成碳负离子的碱包括有机锂、金属醇盐、无机碱和有机碱。
在每个步骤中,当进行格氏反应时,格氏试剂包括芳基卤化镁,例如苯基溴化镁;和烷基卤化镁,例如甲基溴化镁。格氏试剂可以通过本身已知的方法来制备,例如,通过使用醚或四氢呋喃作为溶剂使烷基卤或芳基卤与金属镁反应。
在每个步骤中,当进行Knoevenagel缩合反应时,位于两个吸电子基团之间的活性亚甲基化合物(例如丙二酸、丙二酸二乙酯、丙二腈等)和碱(例如有机碱、金属醇盐、无机碱)用作试剂。
在每个步骤中,当进行Vilsmeier-Haack反应时,将磷酰氯和酰胺衍生物(例如,N,N-二甲基甲酰胺等)用作试剂。
在每个步骤中,当进行醇、烷基卤和磺酸酯的叠氮化物反应时,所使用的叠氮化剂包括二苯基磷酰基叠氮化物(DPPA)、三甲基甲硅烷基叠氮化物和叠氮化钠。例如,在将醇叠氮化时,使用以下方法:使用二苯基磷酰基叠氮化物(DPPA)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)的方法、使用三甲基甲硅烷基叠氮化物和路易斯酸的方法等。
在每个步骤中,当进行还原胺化反应时,所用的还原剂包括三乙酰氧基硼氢化钠、氰基硼氢化钠、氢和甲酸。当底物是胺化合物时,所用的羰基化合物包括醛例如多聚甲醛和乙醛,以及酮例如环己酮。当底物是羰基化合物时,所用的胺包括氨;伯胺,例如甲胺;和仲胺,例如二甲胺。
在每个步骤中,当进行Mitsunobu反应时,偶氮二甲酸酯(例如,偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD))和三苯基膦用作试剂。
在每个步骤中,当进行酯化反应、酰胺化反应或脲形成反应时,所用的试剂包括酰基卤,例如酰氯和酰溴;以及活化的羧酸,例如酸酐、活性酯和硫酸酯。羧酸的活化剂包括基于碳二亚胺的缩合剂,例如1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(WSCD);基于三嗪的缩合剂,例如4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉鎓-n-水合物(DMT-MM);基于碳酸酯的缩合剂,例如1,1-羰基二咪唑(CDI);二苯基磷酰基叠氮化物(DPPA);苯并三唑-1-基氧基-三二甲基氨基鏻盐(BOP试剂);碘化2-氯-1-甲基吡啶鎓(Mukaiyama试剂);亚硫酰氯;卤代甲酸低级烷基酯,例如氯甲酸乙酯;O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HATU);硫酸;或其组合。当使用基于碳二亚胺的缩合剂时,可以将例如1-羟基苯并三唑(HOBt)、N-羟基琥珀酰亚胺(HOSu)或4-二甲基氨基吡啶(DMAP)的添加剂进一步添加到反应中。
在每个步骤中,当进行偶联反应时,使用的金属催化剂包括钯化合物,例如乙酸钯(II)、四(三苯基膦)钯(0)、二氯双(三苯基膦)钯(II)、二氯双(三乙基膦)钯(II)、三(二亚苄基丙酮)二钯(0)和1,1'-双(二苯基膦基)二茂铁氯化钯(II);镍化合物,例如四(三苯基膦)镍(0);铑化合物,例如三(三苯基膦)氯化铑(III);钴化合物;铜化合物,例如氧化铜和碘化亚铜(I);和铂化合物。此外,可以将碱添加到反应中,并且这种碱包括无机碱。
在每个步骤中,当进行硫羰基化反应时,通常使用五硫化二磷作为硫羰基化剂。除五硫化二磷外,还可以使用具有1,3,2,4-二硫二磷杂环丁烷-2,4-二硫化物结构的试剂,例如2,4-双(4-甲氧基苯基)-1,3,2,4-二硫二磷杂环丁烷-2,4-二硫化物(Lawesson试剂)。
在每个步骤中,当进行Wohl-Ziegler反应时,使用的卤化剂包括N-碘代琥珀酰亚胺、N-溴代琥珀酰亚胺(NBS)、N-氯代琥珀酰亚胺(NCS)、溴和硫酰氯。此外,可以通过向反应中加入自由基引发剂如热、光、过氧化苯甲酰或偶氮二异丁腈来加速反应。
在每个步骤中,当进行羟基的卤化反应时,所使用的卤化剂包括氢卤酸和无机酸的酰卤,特别是用于氯化的盐酸、亚硫酰氯和氯氧化磷,以及用于溴化的48%氢溴酸。另外,可以使用通过三苯基膦与四氯化碳、四溴化碳等的作用由醇制备烷基卤的方法。或者,可以使用通过两步反应合成烷基卤的方法,该反应包括将醇转化为磺酸酯,然后与溴化锂、氯化锂或碘化钠反应。
在每个步骤中,当进行Arbuzov反应时,所用的试剂包括烷基卤,例如溴乙酸乙酯;和亚磷酸酯,例如亚磷酸三乙酯和亚磷酸三(异丙基)酯。
在每个步骤中,当进行磺酸酯酯化反应时,所使用的磺酰化剂包括甲磺酰氯、对甲苯磺酰氯、甲磺酸酐和对甲苯磺酸酐。
在每个步骤中,当进行水解反应时,使用酸或碱作为试剂。另外,当进行叔丁酯的酸水解反应时,可以添加甲酸、三乙基甲硅烷等以还原性地捕集副产物叔丁基阳离子。
在每个步骤中,当进行脱水反应时,所使用的脱水剂包括硫酸、五氧化二磷、氧氯化磷、N,N'-二环己基碳二亚胺、氧化铝和多磷酸。
当在每个步骤中获得的化合物具有氨基、咪唑、吡咯、芳族杂环例如吲哚、羧基、羟基等作为取代基时,这些基团可以被保护基例如上文列出的那些保护。在这种情况下,可以通过在所需阶段去除保护基而获得目标化合物。这些保护基的引入或去除以与上述相同的方式进行。
此外,在每个步骤中,可以任选地并入上述反应等。
在下文中,对化合物(I)的制备方法进行描述。
除非另有说明,以下反应式中的每个符号具有与上述相同的含义。原料化合物可以容易地在市场上获得,或者可以通过本身已知的方法或类似方法来制备,除非描述了特定的制备方法。
化合物(I)可以通过以下方法由化合物(II)制备。
化合物(II)可以是商购的产品,或者可以通过使用本身已知的方法来制备。
化合物(IV)可以通过化合物(III)与羟胺衍生物在碱或酸的存在下的胺化反应来制备。羟胺衍生物包括O-(4-硝基苯甲酰基)羟胺、羟胺-O-磺酸和O-二苯基氧膦基羟胺。
化合物(V)可以通过使化合物(IV)与丙烯酸酯在氧气气氛下,在钯催化剂和无机盐例如溴化锂的存在下反应来制备。钯催化剂包括乙酸钯(II),丙烯酸酯包括丙烯酸甲酯和丙烯酸乙酯。或者,化合物(V)也可以通过在酸存在下使化合物(IV)与3,3-二甲氧基丙酸甲酯反应、然后在碱存在下进行分子内环化来制备。
化合物(VIII)可以是本身可商购的产品,或者可以通过使用本身已知的方法或类似方法来制备。
化合物(I)可以通过使化合物(VIII)与化合物(VII)反应来制备,化合物(VII)通过使用Curtius重排使化合物(VI)在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下反应而获得。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(IX)可以通过使用Curtius重排在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下使化合物(VI)反应来制备。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(I)可以在化合物(IX)、化合物(VIII)、活化剂和任选地碱的共存下通过脲形成而制备。活化剂包括氯甲酸酯衍生物,例如氯甲酸2,2,2-三氯乙酯、氯甲酸苯酯或氯甲酸对硝基苯酯、三光气、光气、N,N'-羰基二咪唑或N,N'-二琥珀酰亚胺基碳酸酯。其中,优选三光气和氯甲酸2,2,2-三氯乙酯。
在上述步骤中,取代基R1和R2可以通过亲电取代反应、偶联反应或本身已知的方法在所需阶段转化为其他类型的取代基。例如,可以通过对其中R1为氢原子的化合物(IV)进行亲电取代反应来制备其中R1为卤素原子的化合物(IV)。用于该反应的亲电子试剂包括N-碘代琥珀酰亚胺、N-溴代琥珀酰亚胺(NBS)、N-氯代琥珀酰亚胺(NCS)、溴和硫酰氯。另外,其中R1为C1-3烷基(例如甲基)的化合物(V)可以通过使其中R1为离去基团(例如卤素原子)的化合物(V)与有机硼酸或有机硼酸酯试剂(例如2,4,6-三甲基环三硼氧烷)反应来制备。该反应可以在碱或无机盐(例如磷酸三钾)、上述金属络合物例如钯的存在下或在膦配体的存在下进行。膦配体的实例包括2-二环己基膦基-2',6'-二甲氧基联苯(SPhos)。
化合物(V)也可以通过以下方法制备。
化合物(X)可以是可商购的产品或通过使用本身已知的方法来制备。
化合物(XI)可以通过化合物(X)的胺化反应来制备。胺化方法包括与由化合物(III)制备化合物(IV)的方法相同的方法。
化合物(XIII)可以通过在N,N-二甲基甲酰胺缩二甲醇的存在下使化合物(XII)反应来制备。
化合物(XIV)的X1表示卤素原子。在制备化合物(XIV)的卤化反应中使用的卤化剂除上述以外还包括氧溴化磷。
化合物(V)可以通过引入偶联反应、取代反应或本身已知的方法由化合物(XIV)制备。
在上述步骤中,取代基R1和R2可以通过亲电取代反应或本身已知的方法在所需阶段转化为其他类型的取代基。
化合物(I)也可以通过以下方法制备。
化合物(XV)可以是可商购的产品或通过使用本身已知的方法来制备。X1表示卤素原子。
化合物(XVII)可以通过在酸存在下使化合物(XVI)和硝基烯胺(nitroenamine)衍生物进行亲核取代反应来制备。硝基烯胺衍生物包括(E)-4-(2-硝基乙烯基)吗啉。
化合物(XVIII)可以通过化合物(XVII)的分子内环化反应来制备。该反应可以任选地在碱的存在下进行。
化合物(XIX)可以通过还原化合物(XVIII)来制备。除上述之外,还原剂包括铁、氯化锡(II)和氯化锡(II)二水合物。
化合物(I)可以在化合物(XIX)、化合物(VIII)、活化剂和任选地碱的共存下通过脲形成而制备。活化剂包括氯甲酸酯衍生物,例如氯甲酸2,2,2-三氯乙酯、氯甲酸苯酯或氯甲酸对硝基苯酯、三光气、光气、N,N'-羰基二咪唑或N,N'-二琥珀酰亚胺基碳酸酯。其中,优选三光气和氯甲酸2,2,2-三氯乙酯。
在上述步骤中,取代基R4和R5可以通过在所需阶段引入偶联反应、取代反应或本身已知的方法来转化。
化合物(I)也可以通过以下方法制备。
化合物(XX)可以是可商购的产品或通过使用本身已知的方法来制备。
化合物(XXI)可以通过在酸存在下使化合物(XX)和硝基烯胺衍生物进行亲核取代反应来制备。硝基烯胺衍生物包括(E)-4-(2-硝基乙烯基)吗啉。
化合物(XXII)可以通过化合物(XXI)的分子内环化反应来制备。该反应可以任选地在碱的存在下进行。
化合物(XXIII)的X1表示卤素原子。在制备化合物(XXIII)的卤化反应中使用的卤化剂除上述以外还包括三溴化磷。
可以通过引入偶联反应、取代反应或本身已知的多步法由化合物(XXIII)制备化合物(XVIII)。在制备化合物(XVIII)的偶联反应中使用的催化剂除上述以外还包括PdCl2(Amphos)2。
化合物(XIX)可以通过还原化合物(XVIII)来制备。除上述之外,还原剂包括铁、氯化锡(II)和氯化锡(II)二水合物。
化合物(I)可以在化合物(XIX)、化合物(VIII)、活化剂和任选地碱的共存下通过脲形成而制备。活化剂包括氯甲酸酯衍生物,例如氯甲酸2,2,2-三氯乙酯、氯甲酸苯酯或氯甲酸对硝基苯酯、三光气、光气、N,N'-羰基二咪唑或N,N'-二琥珀酰亚胺基碳酸酯。其中,优选三光气和氯甲酸2,2,2-三氯乙酯。
在上述步骤中,取代基R4和R5可以通过在所需阶段引入偶联反应、亲核取代反应或本身已知的方法来转化。
化合物(I)也可以通过以下方法制备。
化合物(XXIV)可以是可商购的产品或通过使用本身已知的方法来制备。
化合物(XXVI)可以通过在酸存在下使化合物(XXV)和3-氧代丙酸衍生物进行亲核取代反应来制备。3-氧代丙酸衍生物包括3,3-二甲氧基丙酸甲酯。
化合物(XXVII)可以通过化合物(XXVI)的分子内环化反应来制备。该反应可以任选地在碱的存在下进行。
化合物(I)可以通过使化合物(VIII)与化合物(XXIX)反应来制备,化合物(XXIX)通过使用Curtius重排使化合物(XXVIII)在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下反应而获得。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(XXX)可以通过使用Curtius重排在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下使化合物(XXVIII)反应来制备。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(I)可以在化合物(XXX)、化合物(VIII)、活化剂和任选地碱的共存下通过脲形成而制备。活化剂包括氯甲酸酯衍生物,例如氯甲酸2,2,2-三氯乙酯、氯甲酸苯酯或氯甲酸对硝基苯酯、三光气、光气、N,N'-羰基二咪唑或N,N'-二琥珀酰亚胺基碳酸酯。其中,优选三光气和氯甲酸2,2,2-三氯乙酯。
在上述步骤中,取代基R6和R7可以通过在所需阶段引入偶联反应、取代反应或本身已知的方法来转化。
化合物(I)也可以通过以下方法制备。
化合物(XXXI)可以是可商购的产品,或者可以通过使用本身已知的方法来制备。
化合物(XXXII)可以通过在酸的存在下使化合物(XXXI)和烷氧基亚甲基丙二酸衍生物进行亲核取代反应来制备。烷氧基亚甲基丙二酸衍生物包括乙氧基亚甲基丙二酸二乙酯。
化合物(XXXIII)可以通过化合物(XXXII)的分子内环化反应来制备。
化合物(XXXIV)可以通过使化合物(XXXIII)与氯(氯甲基)二甲基甲硅烷在碱的存在下反应来制备。
化合物(XXXV)可以通过使化合物(XXXIV)与氟化铯反应来制备。
化合物(XXXVI)的X1表示卤素原子。在制备化合物(XXXVI)的卤化反应中使用的卤化剂除上述以外还包括三溴化磷。
化合物(I)可以通过使化合物(VIII)与化合物(XXXIX)反应来制备,化合物(XXXIX)通过使用Curtius重排使化合物(XXXVIII)在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下反应而获得。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(XXXX)可以通过使用Curtius重排在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下使化合物(XXXVIII)反应来制备。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(I)可以在化合物(XXXX)、化合物(VIII)、活化剂和任选地碱的共存下通过脲形成而制备。活化剂包括氯甲酸酯衍生物,例如氯甲酸2,2,2-三氯乙酯、氯甲酸苯酯或氯甲酸对硝基苯酯、三光气、光气、N,N'-羰基二咪唑或N,N'-二琥珀酰亚胺基碳酸酯。其中,优选三光气和氯甲酸2,2,2-三氯乙酯。
在上述步骤中,取代基R9可以通过在所需阶段引入偶联反应、取代反应或本身已知的方法来转化。
化合物(I)也可以通过以下方法制备。
化合物(XXXXI)可以是可商购的产品,或通过使用本身已知的方法或与对于化合物(XXVII)的方法相同的方法制备。
化合物(XXXXIII)可以通过在碱的存在下将化合物(XXXXII)烷基化来制备。除了上述以外,碱还包括氢氧化锂。
化合物(I)可以通过使化合物(VIII)与化合物(XXXXV)反应来制备,化合物(XXXXV)通过使用Curtius重排使化合物(XXXXIV)在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下反应而获得。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(XXXXVI)可以通过使用Curtius重排在二苯基磷酰基叠氮化物(DPPA)、任选地碱的共存下使化合物(XXXXIV)反应来制备。除上述以外,所使用的溶剂还包括2-甲基四氢呋喃。
化合物(I)可以在化合物(XXXXVI)、化合物(VIII)、活化剂和任选地碱的共存下通过脲形成而制备。活化剂包括氯甲酸酯衍生物,例如氯甲酸2,2,2-三氯乙酯、氯甲酸苯酯或氯甲酸对硝基苯酯、三光气、光气、N,N'-羰基二咪唑或N,N'-二琥珀酰亚胺基碳酸酯。其中,优选三光气和氯甲酸2,2,2-三氯乙酯。
在上述步骤中,取代基R8和R9可以通过在所需阶段引入偶联反应、取代反应或本身已知的方法来转化。
通过应用本身已知的方法转化所获得的化合物(I)的取代基(即,引入取代基或官能团转化)也可以制备化合物(I)中包含的另一种化合物或其盐。
作为引入取代基或官能团转化的方法,使用已知的通用方法。它们的实例包括将卤素原子(例如氟、氯、溴、碘)或可被卤化的C1-6烷基磺酰氧基[例如甲磺酰氧基、乙磺酰氧基、三氯甲烷磺酰氧基、三氟甲烷磺酰氧基(三氟甲磺酸酯)]转化为甲基、环丙基、乙烯基、氰基、甲酰基、羰基、羧基、羟基、氨基或硼基,通过Seyferth-Gilbert增碳反应(Seyferth-Gilbert homologation)将甲酰基转化为乙炔基,通过水解将酯转化为羧基,通过酰胺化将羧基转化为氨基甲酰基,通过还原将羧基转化为羟甲基,通过还原或烷基化将羰基转化为醇,羰基的还原胺化,羰基的肟形成,氨基的酰化,氨基的脲形成,氨基的磺酰化,氨基的烷基化,活性卤素与胺的取代或胺化,羟基的烷基化以及羟基的取代或胺化。
在进行引入取代基或官能团转化时,在存在发生与预期反应不同的反应的反应位点的情况下,本发明范围内包括的化合物也可以通过以下方法制备:通过本身已知的方法预先将保护基引入反应位点,并且根据需要在完成所需的反应之后通过本身已知的方法除去保护基。
例如,当原料化合物或中间体具有氨基、羧基或羟基作为取代基时,这些基团可以用肽化学等中常用的保护基保护。在这种情况下,可以根据需要在反应后通过除去保护基而获得目标化合物。
通过上述制备方法获得的化合物(I)可以通过已知的方法分离和纯化,例如溶剂萃取、溶液的pH变化、转移溶解、结晶、重结晶和色谱法。
当化合物(I)包含光学异构体、空间异构体、位置异构体和旋转异构体时,这些异构体也作为化合物(I)包括在内,并且可以通过本身已知的合成技术和分离技术各自作为单一产物获得。例如,当化合物(I)具有光学异构体时,从化合物中分离出的光学异构体也包括在化合物(I)中。
在此,光学异构体可以通过本身已知的方法制备。
化合物(I)可以是结晶的。
化合物(I)的晶体(下文有时简称为“本发明的晶体”)可以通过对化合物(I)应用本身已知的结晶方法而使其结晶来制备。
预期本发明的晶体具有优异的理化性质(例如熔点、溶解性、稳定性)和生物学性质(例如体内动力学(吸收、分布、代谢、排泄)、药物功效),并可用作药物。
化合物(I)可以是药学上可接受的共晶体或共晶体盐。在此,共晶体或共晶体盐是指在室温下由两种或更多种独特固体组成的结晶物质,这些固体的物理性质(例如,结构、熔点、熔化热、吸湿性、溶解性和稳定性)彼此不同。共晶体或共晶体盐可以根据本身已知的共结晶方法来制备。
化合物(I)可以是水合物、非水合物、非溶剂化物或溶剂化物。
此外,化合物(I)中还包括其中1H已被转化为2H(D)的经氘转化的化合物。
化合物(I)可以用同位素(例如3H、13C、14C、18F、35S、125I)等标记。同位素标记或取代的化合物(I)可以用作例如PET中使用的示踪剂(PET(正电子发射断层扫描)示踪剂),并有望可用于例如医学诊断等领域。
化合物(I)可以用作前药。
化合物(I)的前药是通过在生物体内的生理条件下与酶、胃酸等反应而转化为化合物(I)的化合物,即,经历氧化、还原、水解等以酶促变为化合物(I)的化合物,或者由于胃酸等而经历水解等以变为化合物(I)的化合物。
化合物(I)的前药包括化合物(I)的氨基被酰化、烷基化或磷酸化的化合物(例如,化合物(I)的氨基被二十烷酰化、丙氨酰化、戊氨基羰基化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基羰基化、四氢呋喃化(tetrahydrofuranylated)、吡咯烷基甲基化、新戊酰氧基甲基化或叔丁基化的化合物);化合物(I)的羟基被酰化、烷基化、磷酸化或硼酸化的化合物(例如,化合物(I)的羟基被乙酰化、棕榈酰化、丙酰化、新戊酰化、琥珀酰化、富马酰化、丙氨酰化或二甲基氨基甲基羰基化的化合物);化合物(I)的羧基被酯化或酰胺化的化合物(例如,化合物(I)的羧基被乙基酯化、苯基酯化、羧甲基酯化、二甲基氨基甲基酯化、新戊酰氧基甲基酯化、乙氧基羰基氧基乙基酯化、2-苯并[c]呋喃酮基(phthalidyl)酯化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯化、环己基氧基羰基乙基酯化或甲基酰胺化的化合物)。这些化合物可以通过本身已知的方法由化合物(I)制备。
另外,化合物(I)的前药可以是在生理条件下变为化合物(I)的化合物,如Hirokawa Shoten,1990年第7卷,Molecular Design中第163至198页“Pharmaceuticalresearch and development” 中所述。
在说明书中,前药可以形成盐。这样的盐包括作为由上式(I)表示的化合物的盐示例的那些。
化合物(I)或其前药(下文有时简称为“本发明的化合物”)可以具有MALT1抑制活性,并且可以用作癌症的预防或治疗药物、癌症生长的抑制剂和癌症转移的抑制剂。
本发明的化合物可用作药物,因为本发明的化合物显示出对MALT1的选择性抑制活性,并且在药物效力、药代动力学(例如吸收性、分布、代谢、排泄)、溶解性(例如水溶性)、与其他药品的相互作用(例如抑制药物代谢酶的作用)、安全性(例如急性毒性、慢性毒性、遗传毒性、生殖毒性、心脏毒性、致癌性、中枢毒性)和稳定性(例如化学稳定性、对酶的稳定性)方面也是优异的。
因此,本发明的化合物可用于抑制哺乳动物(例如小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴、人)中的过度(异常)MALT1作用。
本发明的化合物可以原样或与药理学上可接受的载体组合来作为药物口服或胃肠外给药于哺乳动物(优选人)。
在下文中,对含有本发明化合物的药物(有时简称为“本发明的药物”)进行详细描述。本发明的药物的剂型的实例包括口服制剂,例如片剂(例如糖衣片剂、薄膜衣片剂、舌下片剂、口含片剂、口服速崩片剂)、丸剂、颗粒剂、粉剂、胶囊(例如软胶囊、微胶囊)、糖浆剂、乳剂、混悬剂和薄膜制剂(例如口腔崩解膜、口腔粘膜粘附膜)。另外,本发明的药物的剂型的实例包括肠胃外制剂,例如注射剂、输注剂、透皮剂(例如离子电渗透皮剂)、栓剂、软膏、鼻腔剂、经肺剂和滴眼剂。此外,本发明的药物可以是控释制剂,例如速释制剂和持续释放制剂(例如持续释放微胶囊)。
本发明的药物可以通过制药领域中通常使用的公知的制备方法(例如日本药典中记载的方法)来制备。另外,如果需要,本发明的药物可以以适当的量包含在制药领域中通常使用的添加剂,例如赋形剂、粘合剂、崩解剂、润滑剂、甜味剂、表面活性剂、助悬剂、乳化剂、着色剂、防腐剂、芳香物质、调味剂、稳定剂或增稠剂。
上述的药理学可接受的载体包括这些添加剂。
例如,可以使用赋形剂、粘合剂、崩解剂、润滑剂等来制备片剂,并且可以使用赋形剂、粘合剂、崩解剂等来制备丸剂和颗粒剂。另外,可以使用赋形剂等来制备粉剂和胶囊,可以使用甜味剂等来制备糖浆剂,并且可以使用助悬剂、表面活性剂、乳化剂等来制备乳剂或混悬剂。
赋形剂的实例包括乳糖、蔗糖、葡萄糖、淀粉、蔗糖、微晶纤维素、甘草粉、甘露糖醇、碳酸氢钠、磷酸钙和硫酸钙。
粘合剂的实例包括5至10重量%的淀粉糊、10至20重量%的阿拉伯胶溶液或明胶溶液、1至5重量%的黄蓍胶溶液、羧甲基纤维素溶液、藻酸钠溶液或甘油。
崩解剂的实例包括淀粉和碳酸钙。
润滑剂的实例包括硬脂酸镁、硬脂酸、硬脂酸钙和纯化的滑石。
甜味剂的实例包括葡萄糖、果糖、转化糖、山梨糖醇、木糖醇、甘油和单糖浆。
表面活性剂的实例包括月桂基硫酸钠、聚山梨酯80、失水山梨糖醇单脂肪酸酯和聚氧乙烯40硬脂酸酯(Polyoxyl 40 stearate)。
助悬剂的实例包括阿拉伯胶、藻酸钠、羧甲基纤维素钠、甲基纤维素和膨润土。
乳化剂的实例包括阿拉伯胶、黄蓍胶、明胶和聚山梨酯80。
例如,在本发明的药物是片剂的情况下,可以通过向本发明的化合物中添加例如赋形剂(例如乳糖、蔗糖、淀粉)、崩解剂(例如淀粉、碳酸钙)、粘合剂(例如淀粉、阿拉伯胶、羧甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素)或润滑剂(例如滑石、硬脂酸镁、聚乙二醇6000),然后根据本身已知的方法模压成型,然后任选地以本身已知的方式进行掩味、肠溶或持久包衣,来制备片剂。作为用于包衣的包衣剂,可以使用包括羟丙基甲基纤维素,例如乙基纤维素、羟甲基纤维素、羟丙基纤维素、聚乙二醇(polyoxyethylene glycol)、吐温80、Pluronic F68、邻苯二甲酸醋酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸羟甲基纤维素琥珀酸酯、Eudragit(由德国的ROHM生产,甲基丙烯酸/丙烯酸共聚物)和染料(例如红色氧化铁、二氧化钛)。
注射剂包括静脉注射剂、皮下注射剂、皮内注射剂、肌内注射剂、腹膜内注射剂和滴注注射剂。
通过本身已知的方法,即通过将本发明的化合物溶解、悬浮或乳化在无菌水性或油性液体中来制备此类注射剂。水性液体包括盐水和含有葡萄糖或其他助剂(例如D-山梨糖醇、D-甘露糖醇、氯化钠)的等渗溶液。水性液体可包含合适的增溶剂,例如醇(例如乙醇)、多元醇(例如丙二醇、聚乙二醇)或非离子表面活性剂(例如聚山梨酯80、HCO-50)。油性液体包括芝麻油和大豆油。油性液体可包含合适的增溶剂。增溶剂包括苯甲酸苄酯和苯甲醇。另外,在注射剂中,可掺入缓冲剂(例如磷酸盐缓冲剂、乙酸钠缓冲剂)、舒缓剂(soothing agent)(例如苯扎氯铵、盐酸普鲁卡因)、稳定剂(例如人血清白蛋白、聚乙二醇)、防腐剂(例如苯甲醇、苯酚)等。制备的注射溶液通常可以填充在安瓿瓶中。
本发明化合物在本发明的药物中的含量根据制剂的形式而变化,但相对于整个制剂,通常为约0.01至约100重量%,优选约2至约85重量%,更优选约5至约70重量%。
添加剂在本发明的药物中的含量根据制剂的形式而变化,但相对于整个制剂,通常为约1至约99.9重量%,优选约10至约90重量%。
本发明的化合物稳定,毒性低,可以安全使用。本发明化合物的日剂量根据患者的病况和体重、化合物的类型、给药途径等而变化。例如,当为了治疗癌症而口服给药于患者时,成年人(体重约60kg)的日剂量为约1至约1000 mg,优选约3至约300 mg,更优选约10至约200 mg的本发明化合物。日剂量可以以单剂量或以2至3次分剂量给药。
当本发明的化合物经肠胃外给药时,其通常以液体制剂的形式(例如注射剂)给药。本发明化合物的单剂量根据给药靶标、靶器官、症状、给药方法等而变化。例如,通常优选通过静脉内注射给药每千克体重约0.01至约100 mg,优选约0.01至约50 mg,更优选约0.01至约20 mg的本发明的化合物。
本发明的化合物可以与其他药物组合使用。具体地,本发明的化合物可以与药物例如激素治疗剂、化学治疗剂、免疫治疗剂或抑制细胞生长因子及其受体的作用的药物组合使用。下文将可以与本发明的化合物组合使用的药物简称为“伴随药物”。
作为“激素治疗剂”,例如,可以使用磷雌酚、己二烯雌酚、氯烯雌醚、乙酸甲羟孕酮、乙酸甲地孕酮、乙酸氯地孕酮、乙酸环丙孕酮、达那唑、烯丙雌醇、孕三烯酮、美帕曲星、雷洛昔芬、奥美昔芬、左美洛昔芬、抗雌激素(例如柠檬酸他莫昔芬、柠檬酸托瑞米芬)、丸剂、美雄烷、1,2-二氢睾内酯(testololactone)、氨鲁米特、LH-RH激动剂(例如醋酸戈舍瑞林、布舍瑞林、醋酸亮丙瑞林)、屈洛昔芬、环硫雄醇、乙炔雌二醇磺酸盐、芳香化酶抑制剂(例如盐酸法倔唑、阿那曲唑、来曲唑、依西美坦、伏氯唑、福美司坦)、抗雄激素(例如氟他米特、比卡鲁胺、尼鲁米特、恩杂鲁胺)、5α-还原酶抑制剂(例如非那雄胺、依立雄胺、度他雄胺)、肾上腺皮质激素药物(例如地塞米松、泼尼松龙、倍他米松、去炎松)、雄激素合成抑制剂(例如阿比特龙)、类维生素A和减慢类维生素A代谢的药物(例如利阿唑)、甲状腺激素及它们的药物递送系统(DDS)制剂。
作为“化学治疗剂”,例如,可以使用烷基化剂、抗代谢物、抗癌抗生素和植物来源的抗癌剂。
作为“烷基化剂”,例如,可以使用氮芥、氮芥N-氧化物盐酸盐、苯丁酸氮芥、环磷酰胺、异环磷酰胺、噻替派、carbocon、甲苯磺酸英丙舒凡、白消安、尼莫斯汀盐酸盐、二溴甘露醇、美法仑、达卡巴嗪、雷莫司汀、雌莫司汀磷酸钠、曲他胺(triethylene melamine)、卡莫斯汀、洛莫斯汀、链脲菌素、哌泊溴烷、依托格鲁、卡铂、顺铂、米铂、奈达铂、奥沙利铂、六甲蜜胺、氨莫司汀、二溴螺氯铵(dibrospidium hydrochloride)、福莫司汀、泼尼莫司汀、嘌嘧替派、盐酸苯达莫司汀、替莫唑胺、曲奥舒凡、氯乙环磷酰胺、净司他丁斯酯(zinostatinstimalamer)、阿多来新、半胱胺亚硝脲、比折来新以及它们的DDS制剂。
作为“抗代谢物”,例如,可以使用巯基嘌呤、6-巯基嘌呤核苷、硫代肌苷、甲氨蝶呤、培美曲塞、依诺他滨、阿糖胞苷、阿糖胞苷烷磷酯、盐酸环胞苷、5-FU药物(例如氟尿嘧啶、替加氟、UFT、去氧氟尿苷、卡莫氟、加洛他滨、乙嘧替氟、卡培他滨)、氨蝶呤、奈拉滨、甲酰四氢叶酸钙(leucovorin calcium)、tabloid、甘氨硫嘌呤(butocin)、亚叶酸钙、左亚叶酸钙、克拉屈滨、乙嘧替氟、氟达拉滨、吉西他滨、羟基尿素、喷司他丁、吡曲克辛、碘苷、米托胍腙、噻唑羧胺核苷、氨莫司汀、苯达莫司汀以及它们的DDS制剂。
作为“抗癌抗生素”,例如,可以使用放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、盐酸博来霉素、硫酸博来霉素、硫酸培洛霉素、盐酸柔红霉素、盐酸阿霉素、盐酸阿克拉霉素、盐酸吡柔比星、盐酸表柔比星、新致癌菌素、光神霉素、抗癌霉素、嗜癌素(carzinophilin)、米托坦、盐酸佐柔比星、盐酸米托蒽醌、盐酸伊达比星以及它们的DDS制剂(例如,包裹阿霉素的PEG核糖体)。
作为“植物来源的抗癌剂”,例如,可以使用依托泊苷、磷酸依托泊苷、硫酸长春碱、硫酸长春新碱、硫酸长春地辛、替尼泊苷、紫杉醇、多西他赛、卡巴他赛、长春瑞滨以及它们的DDS制剂。
作为“免疫治疗剂”,例如,可以使用溶链菌制剂、云芝孢内多糖、裂褶菌多糖、香菇多糖、乌苯美司、干扰素、白介素、巨噬细胞集落刺激因子、粒细胞集落刺激因子、促红细胞生成素、淋巴毒素、BCG疫苗、短小棒状杆菌、左旋咪唑、多糖K、丙考达唑、抗CTLA4抗体(例如伊匹单抗、替西木单抗)、抗PD-1抗体(例如纳武单抗、派姆单抗)和抗PD-L1抗体。
“抑制细胞生长因子及其受体的作用的药物”中的“细胞生长因子”可以是任何促进细胞生长的物质,并且通常包括作为分子量为20,000或更小的肽的因子并通过与受体结合而以低浓度发挥它们的作用。具体而言,可以使用(1)EGF(表皮生长因子)或具有基本相同活性的物质[例如TGFα],(2)胰岛素或具有基本相同活性的物质[例如胰岛素、IGF(胰岛素样生长因子)-1,IGF-2],(3)FGF(成纤维细胞生长因子)或具有基本相同活性的物质(例如酸性FGF、碱性FGF、KGF(角质形成细胞生长因子)、FGF-10],和(4)其他细胞生长因子[例如CSF(集落刺激因子)、EPO(促红细胞生成素)、IL-2(白介素-2)、NGF(神经生长因子)、PDGF(血小板源性生长因子)、TGFβ(转化生长因子β)、HGF(肝细胞生长因子)、VEGF(血管内皮生长因子)、调蛋白和血管生成素]。
“细胞生长因子受体”可以是具有结合上述细胞生长因子能力的任何受体。具体而言,可以使用EGF受体、调蛋白受体(例如HER3)、胰岛素受体、IGF受体-1、IGF受体2、FGF受体-1或FGF受体-2、VEGF受体、血管生成素受体(例如Tie2)、PDGF受体等。
作为“抑制细胞生长因子及其受体的作用的药物”,可以使用EGF抑制剂、TGFα抑制剂、调蛋白抑制剂、胰岛素抑制剂、IGF抑制剂、FGF抑制剂、KGF抑制剂、CSF抑制剂、EPO抑制剂、IL-2抑制剂、NGF抑制剂、PDGF抑制剂、TGFβ抑制剂、HGF抑制剂、VEGF抑制剂、血管生成素抑制剂、EGF受体抑制剂、HER2抑制剂、HER4抑制剂、胰岛素受体抑制剂、IGF-1受体抑制剂、IGF-2受体抑制剂、FGF受体-1抑制剂、FGF受体-2抑制剂、FGF受体-3抑制剂、FGF受体-4抑制剂、VEGF受体抑制剂、Tie-2抑制剂、PDGF受体抑制剂、TLR受体抑制剂、Abl抑制剂、Raf抑制剂、FLT3抑制剂、c-Kit抑制剂、Src抑制剂、PLC抑制剂、PKC抑制剂、Smo抑制剂、ALK抑制剂、ROR1抑制剂、Trk抑制剂、Ret抑制剂、mTOR抑制剂、Aurora抑制剂、PLK抑制剂、MEK(MEK1/2)抑制剂、MET抑制剂、CDK抑制剂、Akt抑制剂、ERK抑制剂、PI3K抑制剂、IKK抑制剂、BTK抑制剂、IRAK抑制剂、HDAC抑制剂、TAK1抑制剂、TBK1抑制剂、ZAP抑制剂、SYK抑制剂、LCK抑制剂、TYK2抑制剂、SYK抑制剂、JAK抑制剂、FAK抑制剂、LYN抑制剂等。更具体地,可以使用抗VEGF抗体(例如贝伐单抗、雷莫芦单抗(ramucurumab))、抗HER2抗体(例如曲妥珠单抗、帕妥珠单抗)、抗EGFR抗体(例如西妥昔单抗、帕尼单抗、马妥珠单抗、尼妥珠单抗)、抗HGF抗体、伊马替尼、厄洛替尼、吉非替尼、索拉非尼、舒尼替尼、达沙替尼、拉帕替尼、瓦他拉尼、依鲁替尼、伯舒替尼、卡博替尼、克唑替尼、阿来替尼、维莫德吉、阿昔替尼、莫特塞尼、尼洛替尼、6-[4-(4-乙基哌嗪-1-基甲基)苯基]-N-[1(R)-苯基乙基]-7H-吡咯并[2,3-d]嘧啶-4-胺(AEE-788)、凡德他尼、西罗莫司脂化物、依维莫司、enzastaurin、陶扎色替、2-[N-[3-[4-[5-[N-(3-氟苯基)氨基甲酰基甲基]-1H-吡唑-3-基氨基]喹唑啉-7-基氧基]丙基]-N-乙基氨基]乙基磷酸酯(AZD-1152)、4-[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂䓬-2-基氨基]苯甲酸、N-[2-甲氧基-5-[(E)-2-(2,4,6-三甲氧基苯基)乙烯基磺酰基甲基]苯基]甘氨酸钠盐(ON-1910Na)、伏拉塞替(volasertib)、司美替尼、曲美替尼、N-[2(R),3-二羟基丙氧基]-3,4-二氟-2-(2-氟-4-碘苯基氨基)苯甲酰胺(PD-0325901)、伯舒替尼、瑞戈非尼、阿法替尼、艾代拉里斯(idelalisib)、色瑞替尼、达拉非尼等。
除上述药物外,还可以使用天冬酰胺酶、乙酰葡醛酯、盐酸丙卡巴肼、原卟啉-钴络合物盐、汞血卟啉-钠、拓扑异构酶I抑制剂(例如伊立替康、拓扑替康、indotecan、indimitecan)、拓扑异构酶II抑制剂(例如索布佐生)、分化诱导剂(例如类维生素A、维生素D)、其他血管生成抑制剂(例如烟曲霉素、鲨鱼提取物、COX-2抑制剂)、α受体阻滞剂(例如坦洛新盐酸盐)、双膦酸(例如帕米膦酸盐、唑来膦酸盐)、沙利度胺、来那度胺、泊马度胺、5阿扎胞苷、地西他滨、蛋白酶体抑制剂(例如硼替佐米、卡非佐米、伊沙佐米)、NEDD8抑制剂(例如pevonedistat)、UAE抑制剂、PARP抑制剂(例如奥拉帕尼、尼拉帕尼、维利帕尼)、BCL2抑制剂(例如维奈托克、obatoclax、奥利默森(oblimersen))、抗肿瘤抗体例如抗CD20抗体(例如利妥昔单抗、奥比妥珠单抗(obinutuzumab))和抗CCR4抗体(例如莫格利珠单抗(mogamulizumab))、抗体-药物缀和物(例如曲妥珠单抗-美坦新缀合物、维布妥昔单抗)、使用嵌合抗原受体(CARs)的基因修饰T细胞疗法(CAR-T疗法)(例如tisagenlecleucel、axicabtagene ciloleucel)等作为伴随药物。
本发明的化合物与伴随药物的组合可以提供优异的效果。例如,(1)与其中单独给药本发明的化合物或伴随药物的情况相比,可以降低剂量,(2)可以与本发明的化合物组合使用的药物可以根据患者的症状(轻度、重度等)进行选择,(3)可以将治疗持续时间设置的更长,(4)可以维持治疗效果,和(5)通过与伴随药物组合使用本发明化合物,可以实现协同作用。
在下文中,将其中与伴随药物组合使用本发明化合物的情况称为“本发明的伴随药物”。
当使用本发明的伴随药物时,本发明的化合物和伴随药物的给药时机不受限制,但本发明的化合物和伴随药物可以同时或以一定时间间隔(time lag)给药于要给药的对象。当以一定时间间隔给药时,时间间隔将根据所给药的活性成分、剂型和给药方法而变化。例如,当首先给药伴随药物时,本发明的化合物可以在给药伴随药物后的1分钟至3天内,优选10分钟至1天内,更优选15分钟至1小时内给药。当首先给药本发明的化合物时,伴随药物可以在给药本发明的化合物后的1分钟至1天内,优选10分钟至6小时内,更优选15分钟至1小时内给药。伴随药物的剂量可以基于临床上使用的剂量,并且可以根据要给药的对象、给药途径、疾病、组合等适当地选择。
本发明的化合物和伴随药物组合使用时的给药形式的实例包括(1)给药通过同时配制本发明的化合物和伴随药物而获得的单一制剂,(2)通过相同的给药途径同时给药通过分别配制本发明的化合物和伴随药物而获得的两种制剂,(3)通过相同的给药途径以一定时间间隔给药通过分别配制本发明的化合物和伴随药物而获得的两种制剂,(4)通过不同的给药途径同时给药通过分别配制本发明的化合物和伴随药物而获得的两种制剂,和(5)通过不同的给药途径以一定时间间隔给药通过分别配制本发明的化合物和伴随药物而获得的两种制剂(例如,以本发明的化合物和伴随药物的顺序给药,或以相反的顺序给药)。
伴随药物的剂量可基于临床上使用的剂量适当地选择。另外,本发明的化合物和伴随药物的掺合比可以根据要给药的对象、给药途径、目标疾病、症状、组合等适当地选择。例如,当要给药的对象是人时,相对于1重量份的本发明的化合物,可以使用0.01至100重量份的伴随药物。
此外,本发明的化合物或本发明的伴随药物可以与非药物疗法组合使用。具体地,本发明的化合物或本发明的伴随药物可以与以下非药物疗法组合,例如,(1)外科手术,(2)使用血管紧张素II等的诱发高血压化疗,(3)基因疗法,(4)热疗法,(5)冷冻疗法,(6)激光消融,和(7)放射疗法。
例如,通过在外科手术等之前或之后,或在这两种或三种的组合治疗之前或之后使用本发明的化合物或本发明的伴随药物,可以实现例如抑制耐药性的产生、延长无病生存期、抑制癌症转移或复发以及延长生命的效果。
另外,可以组合使用本发明的化合物或本发明的伴随药物的治疗以及支持疗法[(i)给药针对各种感染性疾病的并发症的抗生素(例如β-内酰胺类如盐酸头孢替安(pansporin),大环内酯类如克拉霉素);(ii)给药用于改善营养障碍的高热量输液、氨基酸制剂和多种维生素,(iii)给药用于缓解疼痛的吗啡,(iv)给药改善副作用例如恶心、呕吐、食欲不振、腹泻、白细胞减少症、血小板减少症、血红蛋白浓度降低、脱发、肝损伤、肾损伤、DIC和发烧的药物,以及(v)给药用于抑制癌症多药耐药性的药物等]。
实施例
参考以下实施例、制备例和测试例进一步详细描述本发明,但是本发明不限于此。在不脱离本发明的范围的情况下,可以对本发明进行修改。
以下实施例中的“室温”通常表示约10℃至约35℃。除非另有说明,混合溶剂中表示的比率表示体积比。除非另有说明,百分比(%)表示重量%。
在硅胶柱色谱法中,当描述为NH时,使用氨基丙基甲硅烷键合的硅胶,当描述为Diol时,使用3-(2,3-二羟基丙氧基)丙基甲硅烷键合的硅胶,并且当描述为DiNH时,使用N-(2-氨基乙基)-3-氨基丙基甲硅烷键合的硅胶。当在HPLC(高效液相色谱法)中描述为C18时,使用十八烷基键合的硅胶。除非另有说明,洗脱溶剂的比率表示体积比。
在以下实施例中使用以下缩写。
Boc2O:二碳酸二叔丁酯
CDCl3:氘代氯仿
DMSO-d6:氘代二甲基亚砜
1H NMR:质子核磁共振
LC/MS:液相色谱质谱仪
ESI:电喷雾电离
APCI:大气压化学电离
DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯
DIEA:二异丙基乙胺
DMAP:4-二甲基氨基吡啶
DMF:N,N-二甲基甲酰胺
mp:熔点
DPPA:二苯基磷酰基叠氮化物
MS:质谱
[M+H]+,[MH]-:分子离子峰
M:摩尔浓度
N:当量浓度
Pd(OAc)2:乙酸钯(II)
SPhos:2-二环己基膦基-2',6'-二甲氧基联苯
TEA:三乙胺
TFA:三氟乙酸
THF:四氢呋喃。
1H NMR通过傅里叶变换NMR测量。分析使用ACD/SpecManager(商品名)等。没有描述非常松散的质子(例如羟基和氨基的质子)的峰。
MS通过LC/MS测量。作为电离法,使用ESI法或APCI法。所描述的数据是测得(实测)值。通常,观察到分子离子峰([M+H]+,[M-H]-等),但是在具有叔丁氧基羰基的化合物的情况下,作为碎片离子,可以观察到消除的叔丁氧基羰基或叔丁基的峰。另外,在具有羟基的化合物的情况下,作为碎片离子,可以观察到脱离的H2O的峰。在盐的情况下,通常观察到游离分子离子峰或碎片离子峰。
参考例1
5-氯-6-(二氟甲氧基)吡啶-3-胺
A)3-氯-2-(二氟甲氧基)-5-硝基吡啶
在室温下向3-氯-5-硝基吡啶-2-醇(10 g)和乙腈(300 mL)的混合物中加入2,2-二氟-2-(氟磺酰基)乙酸(11.86 mL)和硫酸钠(3.26 g),然后在相同温度下搅拌过夜。在室温下向所得反应混合物中进一步添加2,2-二氟-2-(氟磺酰基)乙酸(11.86 mL)和硫酸钠(3.26 g),然后在相同温度下搅拌3天。向反应混合物中加入饱和碳酸氢钠水溶液以使其呈碱性,然后减压浓缩。用乙酸乙酯萃取水层,用水和饱和盐水洗涤有机层,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,得到标题化合物(4.31 g)。
B)5-氯-6-(二氟甲氧基)吡啶-3-胺
将3-氯-2-(二氟甲氧基)-5-硝基吡啶(2.57 g)、氯化锡(II)二水合物(12.91 g)和乙醇(100 mL)的混合物在70℃下搅拌过夜。将所得反应混合物用乙酸乙酯和饱和碳酸氢钠水溶液稀释,然后滤出不溶物。滤液的水层用乙酸乙酯萃取,有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(2.17 g)。
参考例2
6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺
A)5-硝基-2-(2H-1,2,3-三唑-2-基)-3-(三氟甲基)吡啶
在室温下向2-氯-5-硝基-3-(三氟甲基)吡啶(3.0 g)和THF(15 mL)的混合物中加入2H-1,2,3-三唑(0.921 mL)。将所得反应混合物在相同温度下搅拌2小时。反应混合物用水稀释,然后水层用乙酸乙酯萃取。有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(2.75 g)。
B)6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺
在室温下向5-硝基-2-(2H-1,2,3-三唑-2-基)-3-(三氟甲基)吡啶(3.54 g)、10%盐酸/甲醇溶液(101 mL)和甲醇(100 mL)的混合物中加入氯化锡(II)(12.95 g),并将所得反应混合物在相同温度下搅拌2小时。在减压下蒸馏出溶剂,将乙酸乙酯加入到残余物中,并向混合物中加入2N氢氧化钠水溶液以进行中和。滤出沉淀物,然后将滤液的水层用乙酸乙酯萃取。有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(2.95 g)。
参考例3
5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺
A)3-氯-5-硝基-2-(2H-1,2,3-三唑-2-基)吡啶
将2,3-二氯-5-硝基吡啶(5.0 g)、2H-1,2,3-三唑(1.7 mL)、碳酸钾(4.3 g)和DMF(25 mL)的混合物在室温下搅拌3小时。将所得反应混合物倒入冰水中,然后用乙酸乙酯萃取两次。有机层用水和饱和盐水洗涤两次,然后经硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(3.5 g)。
B)5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺
将3-氯-5-硝基-2-(2H-1,2,3-三唑-2-基)吡啶(3.3 g)、氯化锡(II)二水合物(16.3 g)和乙醇(100 mL)的混合物在70℃下搅拌过夜。反应混合物用乙酸乙酯稀释,加入饱和碳酸氢钠水溶液,然后滤出不溶物。分离有机层,用水和饱和盐水洗涤,经硫酸钠干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(2.4g)。
参考例4
5-氨基-2-(二氟甲氧基)烟腈
将5-氯-6-(二氟甲氧基)吡啶-3-胺(319 mg)、三(二亚苄基丙酮)二钯(0)(300mg)、Sphos (269 mg)、氰化锌(1.54 g)和DMF (10 mL)的混合物在微波辐射下在120℃下搅拌1小时。将所得反应混合物倒入10%氨水溶液中,然后用乙酸乙酯萃取。有机层用10%氨水溶液、水洗涤,然后用饱和盐水洗涤,经硫酸镁干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(205 mg)。
实施例1
(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲
A)2-甲氧基-1-(1-(三苯基甲基)-1H-咪唑-2-基)丙-1-酮
在-10℃下向1-(三苯基甲基)-1H-咪唑(50 g)和THF(600 mL)的混合物中滴加1.6M正丁基锂/己烷溶液(100 mL),然后将温度升至0℃。然后,将所得反应混合物在相同温度下搅拌30分钟。将反应混合物冷却至-78℃,然后滴加2-甲氧基丙酸甲酯(20.94 g)。将所得反应混合物在相同温度下搅拌1小时,然后将温度升至室温持续3小时。向反应混合物中加入饱和氯化铵水溶液(10 mL),然后用乙酸乙酯萃取水层。有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。将己烷加入到残余物中,并通过过滤收集沉淀物,得到标题化合物(50 g)。
B)1-(1H-咪唑-2-基)-2-甲氧基丙-1-酮
将2-甲氧基-1-(1-(三苯基甲基)-1H-咪唑-2-基)丙-1-酮(150 g)和5%乙酸/甲醇溶液(500 mL)的混合物加热至回流持续16小时。将所得反应混合物冷却至室温后,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(44g)。
C)1-(1-氨基-1H-咪唑-2-基)-2-甲氧基丙-1-酮
在室温下向1-(1H-咪唑-2-基)-2-甲氧基丙-1-酮(20 g)和DMF(100 mL)的混合物中加入1 M的叔丁醇钾在THF中的溶液(143 mL)。然后,将所得反应混合物在相同温度下搅拌30分钟。在室温下向反应混合物中加入O-(4-硝基苯甲酰基)羟胺(26 g),然后在相同温度下搅拌16小时。将冰冷的水(40 mL)加入到反应混合物中,并在减压下蒸馏出溶剂。向残余物中加入乙酸乙酯(200 mL),滤出不溶物,并将滤液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(17 g)。
D)(2-(2-甲氧基丙酰基)-1H-咪唑-1-基)氨基甲酸叔丁酯
在室温下向1-(1-氨基-1H-咪唑-2-基)-2-甲氧基丙-1-酮(17 g)和DMF(50 mL)的混合物中加入DMAP(6.1 g),然后在相同温度下加入Boc2O(22.3 mL)。将所得反应混合物在80℃下搅拌1小时,然后冷却至室温。减压蒸馏出溶剂,残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(13 g)。
E)(4-溴-2-(2-甲氧基丙酰基)-1H-咪唑-1-基)氨基甲酸叔丁酯
在室温下向(2-(2-甲氧基丙酰基)-1H-咪唑-1-基)氨基甲酸叔丁酯(8.0 g)和DMF(40 mL)的混合物中滴加N-溴代琥珀酰亚胺(5.2 g)在DMF(10 mL)中的溶液。然后,将所得反应混合物在相同温度下搅拌16小时。反应混合物用水(80 mL)稀释,然后用乙酸乙酯萃取水层。有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(5.5 g)。
F)1-(1-氨基-4-溴-1H-咪唑-2-基)-2-甲氧基丙-1-酮
在0℃下向(4-溴-2-(2-甲氧基丙酰基)-1H-咪唑-1-基)氨基甲酸叔丁酯(10 g)和二氯甲烷(100 mL)的混合物中添加TFA(20 mL)。然后,将所得反应混合物在室温下搅拌1小时。将反应混合物在减压下浓缩,并将饱和碳酸氢钠水溶液(50 mL)加入到残余物中。用乙酸乙酯萃取水层,有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。将正戊烷加入到残余物中,并通过过滤收集沉淀物,得到标题化合物(7.0 g)。
G)2-溴-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯
在室温下向1-(1-氨基-4-溴-1H-咪唑-2-基)-2-甲氧基丙-1-酮(7.0 g)和THF(50mL)的混合物中加入丙烯酸甲酯(5.1 mL)和溴化锂(9.71 g)。将所得反应混合物用氧气脱气,然后在相同温度下将Pd(OAc)2(1.27 g)加入到反应混合物中,然后在氧气气氛下在50℃搅拌16小时。将反应混合物用冰冷的水(50 mL)稀释,然后用乙酸乙酯萃取水层。有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(5.0 g)。
H)8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸甲酯
将2-溴-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯(8.0 g)、甲苯(70mL)和水(10 mL)的混合物用氮气脱气后,在室温下加入磷酸三钾(17.6 g)和2,4,6-三甲基环硼氧烷(7.12 mL)。在将混合物用氮气进一步脱气之后,在室温下添加Pd(OAc)2(571 mg)和SPhos(1.57 g),然后在80℃下搅拌3小时。将所得反应混合物用饱和碳酸氢钠水溶液(50mL)稀释,然后用乙酸乙酯萃取水层。有机层用水和饱和盐水洗涤,然后经无水硫酸钠干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(4.0 g)。
I)(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸甲酯
通过HPLC(CHIRALCEL OD-H (VJ002),20 mm ID×250 mm L,流动相:己烷/2-丙醇= 950/50)对8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸甲酯(4.36 g)进行分级。在减压下浓缩保留时间较短的含有目标产物的级分,得到标题化合物(2034 mg)。
光学纯度:99.9%ee,保留时间:6.845分钟(CHIRALCEL OD-H (VK069),4.6 mm ID×250 mm L,流动相:己烷/2-丙醇=950/50)。
使用单晶X射线衍射仪确定绝对构型。
J)(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸三氟乙酸盐
在室温下向(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸甲酯(1.71 g)和乙酸(17 mL)的混合物中加入6 N盐酸溶液(17.15 mL),然后在100℃搅拌过夜。将得到的反应混合物在减压下浓缩,残余物通过HPLC(C18,流动相:水/乙腈(含有0.1%TFA))分级。将获得的级分在减压下浓缩,然后在减压下干燥,得到标题化合物(2.6 g)。
K)(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-胺
在室温下向(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸三氟乙酸盐(2.6 g)、TEA(5.3 mL)和甲苯(150 mL)的混合物中加入DPPA(4.9 mL),然后在相同温度下搅拌2小时。向所得反应混合物中加入乙酸(50 mL)和水(50 mL),然后在80℃下搅拌过夜。减压浓缩反应混合物后,残余物用饱和碳酸氢钠水溶液稀释,然后用乙酸乙酯萃取水层。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,得到标题化合物(1.38 g)。
L)(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲
在0℃下向(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-胺(1180 mg)、DIEA(3.49 mL)和THF(10 mL)的混合物中加入三光气(679.1 mg),然后在室温下搅拌1小时。在室温下向所得反应混合物中加入参考例1中获得的5-氯-6-(二氟甲氧基)吡啶-3-胺(1.17 g),然后在60℃下搅拌2小时。向反应混合物中加入饱和碳酸氢钠水溶液,水层用乙酸乙酯萃取,有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,然后通过硅胶柱色谱法(甲醇/乙酸乙酯)纯化,得到标题化合物(1.83 g)。
使用单晶X射线衍射仪确定绝对构型。
实施例2:
(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
A)(6-氯-2-(2-甲氧基丙酰基)吡啶-3-基)氨基甲酸叔丁酯
在-78℃下向(2-溴-6-氯吡啶-3-基)氨基甲酸叔丁酯(20.0 g)和THF(160 mL)的混合物中加入1.08 M甲基锂/乙醚溶液(72.3 mL),然后在相同温度下搅拌15分钟。在-78℃下将1.6 M正丁基锂/己烷溶液(52.8 mL)加入到所得反应混合物中,然后在相同温度下搅拌15分钟。在-78℃下向反应混合物中加入2-甲氧基-1-吗啉代丙-1-酮(16.9 g)在THF(60mL)中的溶液,然后在升温至室温的同时搅拌2小时。在室温下将乙酸(15 mL)在水(150 mL)中的溶液加入到反应混合物中,然后用乙酸乙酯萃取水层。有机层用饱和碳酸氢钠水溶液和饱和盐水洗涤,然后经无水硫酸镁干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(15.81 g)。
B)1-(6-氯-3-((2-硝基乙烯基)氨基)吡啶-2-基)-2-甲氧基丙-1-酮
在室温下向(6-氯-2-(2-甲氧基丙酰基)吡啶-3-基)氨基甲酸叔丁酯(15.7 g)和乙酸乙酯(100 mL)的混合物中加入4N氯化氢在环戊基甲基醚中的溶液(200 mL),随后在相同温度下搅拌2小时。在室温下向所得反应混合物中进一步加入4N氯化氢在环戊基甲基醚中的溶液(100 mL),然后在相同温度下搅拌过夜,并在减压下蒸馏出溶剂。将获得的残余物、(E)-4-(2-硝基乙烯基)吗啉(9.47 g)、6N盐酸溶液(36 mL)和丙酮(120 mL)的混合物在室温下搅拌3小时。反应混合物用水(240 mL)稀释,然后在0℃下搅拌1小时。通过过滤收集沉淀物,用水洗涤,并将得到的固体在减压下干燥,得到标题化合物(12.55 g)。
C)2-氯-8-(1-甲氧基乙基)-7-硝基-1,5-萘啶
在室温下向DBU(6.62 mL)和THF(120 mL)的混合物中加入1-(6-氯-3-((2-硝基乙烯基)氨基)吡啶-2-基)-2-甲氧基丙-1-酮(12.55 g)在THF(280 mL)中的溶液,然后在相同温度下搅拌1小时。通过向所得反应混合物中加入2N盐酸溶液将pH调节至弱酸性后,将混合物用水稀释,然后用乙酸乙酯萃取水层。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(9.82 g)。
D)6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺
将2-氯-8-(1-甲氧基乙基)-7-硝基-1,5-萘啶(5.00 g)、氯化锡(II)二水合物(21.1 g)和乙酸乙酯(150 mL)的混合物在60℃下搅拌2小时,然后在室温下搅拌过夜。将得到的反应混合物用乙酸乙酯稀释,并将混合物用2M碳酸钾水溶液中和。滤出沉淀物,然后将滤液的水层用乙酸乙酯萃取。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,得到标题化合物(3.91 g)。
E)(S)-6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺
通过HPLC(CHIRALPAK IG (VJ003),20 mm ID×250 mm L,流动相:己烷/乙醇=900/100)将6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺(3.84 g)分级。在减压下浓缩保留时间较长的含有目标产物的级分,得到标题化合物(1865 mg)。
光学纯度:99.9%ee,保留时间:7.359分钟(CHIRALPAK AD-H (VJ019),4.6 mm ID×250 mm L,流动相:己烷/2-丙醇=850/150)。
使用单晶X射线衍射仪确定绝对构型。
F)(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
反应按以下4个分步进行。
反应混合物1:在0℃下向三光气(62 mg)和THF(5 mL)的混合物中加入(S)-6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺(100 mg)和DIEA(0.220 mL)在THF(2 mL)中的溶液,然后在相同温度下搅拌1小时。在0℃下向得到的反应混合物中加入参考例2中获得的6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(106 mg),然后在60℃下搅拌过夜。
反应混合物2:在0℃下向三光气(187 mg)和THF(12 mL)的混合物中加入(S)-6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺(300 mg)和DIEA(0.660 mL)在THF(6 mL)中的溶液,然后在相同温度下搅拌1小时。在0℃下向所得反应混合物中添加参考例2中获得的6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(318 mg),然后在60℃下搅拌2小时。在相同温度下向反应混合物中加入6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(29 mg),然后搅拌过夜。
反应混合物3:在0℃下向三光气(375 mg)和THF(24 mL)的混合物中加入(S)-6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺(600 mg)和DIEA(1.32 mL)在THF(12 mL)中的溶液,然后在相同温度下搅拌1小时。在0℃下向得到的反应混合物中添加参考例2中得到的6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(636 mg),然后在60℃下搅拌2小时。在相同温度下向反应混合物中加入6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(116mg),然后搅拌过夜。
反应混合物4:在0℃下向三光气(531 mg)和THF(34 mL)的混合物中加入(S)-6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-胺(850 mg)和DIEA(1.87 mL)在THF(17 mL)中的溶液,然后在相同温度下搅拌1小时。在0℃下向得到的反应混合物中添加参考例2中得到的6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(901 mg),然后在60℃下搅拌2小时。在相同温度下向反应混合物中加入6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(164mg),然后搅拌过夜。
合并反应混合物1至4,并用饱和碳酸氢钠水溶液稀释合并的混合物,然后用乙酸乙酯萃取水层。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。将THF和乙酸乙酯加入到残余物中,滤出不溶物,并将滤液减压浓缩。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,得到粗晶体(3.46 g)。将获得的粗晶体在80℃下溶解于乙酸乙酯(20 mL)中,并且在相同温度下将正庚烷(180 mL)滴加至混合溶液中。将混合溶液在相同温度下搅拌1小时,然后冷却至室温,然后在相同温度下搅拌过夜。通过过滤收集沉淀物,用乙酸乙酯和正庚烷的混合溶液洗涤,然后减压干燥,得到标题化合物(3.35 g)。
使用单晶X射线衍射仪确定绝对构型。
实施例3:
(S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
A)8-(1-甲氧基乙基)-2-甲基-7-硝基-1,5-亚萘基(naphthylene)
将2-氯-8-(1-甲氧基乙基)-7-硝基-1,5-萘啶(500 mg)、2,4,6-三甲基环硼氧烷(0.39 mL)、Pd(dppf)Cl2/CH2Cl2(153 mg)、磷酸三钾(793 mg)和1,2-二甲氧基乙烷(20 mL)的混合物在微波辐射下在100℃加热1.5小时。所得反应混合物用乙酸乙酯稀释。通过硅藻土滤出不溶物,并用乙酸乙酯洗涤。将滤液在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(439 mg)。
B)4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-胺
将8-(1-甲氧基乙基)-2-甲基-7-硝基-1,5-萘啶(470 mg)、氯化锡(II)二水合物(2.57 g)、THF(3 mL)和乙醇(12 mL)的混合物于室温搅拌过夜,在60℃下持续7小时。所得反应混合物用乙酸乙酯稀释,并用饱和碳酸氢钠水溶液中和。滤出不溶物,并用乙酸乙酯洗涤。滤液用乙酸乙酯萃取两次。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,然后通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,得到标题化合物(306 mg)。
C)N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
在0℃下向4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-胺(80 mg)、参考例2中得到的6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(101 mg)和吡啶(0.089 mL)在THF(5mL)中的溶液中添加三光气(54.6 mg)在THF(1 mL)中的溶液。将所得反应混合物在0℃下搅拌30分钟,并在室温下搅拌30分钟。在0℃下加入吡啶(0.089 mL),然后加入三光气(54.6mg)在THF(1 mL)中的溶液。将所得反应混合物在0℃下搅拌30分钟,并在室温下搅拌4小时。将混合物倒入饱和碳酸氢钠水溶液中,然后用乙酸乙酯萃取两次。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,得到标题化合物(127 mg)。
D)(S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲(119.8 mg)通过HPLC(CHIRALPAK AD-H (VA001),20mm ID×250mm L,流动相:己烷/乙醇=700/300)分级。在减压下浓缩保留时间较短的含有目标产物的级分,得到标题化合物(55.6 mg)。
实施例4:
(S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲
在室温下向(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸甲酯(743mg)在THF(30 mL)中的溶液中添加8 M氢氧化钠水溶液(4 mL)。将所得反应混合物搅拌2天。将反应混合物在减压下浓缩,然后残余物用乙酸乙酯萃取。用6N盐酸溶液将水层调节至pH4,并减压浓缩。将残余物悬浮在乙醇中,滤出不溶物,并将滤液减压浓缩。在室温下向残余物(848 mg)和三乙胺(1.51 mL)在甲苯(50 mL)中的溶液中加入DPPA(1.16 mL)。将混合物在室温搅拌40分钟后,加入参考例3中获得的5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺(705 mg)。将得到的反应混合物在100℃下搅拌2小时,然后倒入饱和碳酸氢钠水溶液中,然后用乙酸乙酯萃取。分离有机层并用饱和盐水洗涤,然后经无水硫酸镁干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,甲醇/乙酸乙酯)和硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(488 mg)。
实施例5
(S)-N-(5-氰基-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲
在室温下向(S)-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸三氟乙酸盐(80 mg)、TEA(0.17 mL)和甲苯(5 mL)的混合物中加入DPPA(0.12 mL),然后在相同温度下搅拌所得反应混合物30分钟。此外,在室温下添加DPPA(0.12 mL),然后在相同温度下搅拌反应混合物30分钟。加入参考例4中获得的5-氨基-2-(二氟甲氧基)烟腈(57.9 mg),然后将反应混合物在110℃搅拌3小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和盐水洗涤,然后经无水硫酸镁干燥,在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,乙酸乙酯/己烷)纯化,并悬浮在乙酸乙酯/己烷中和用乙酸乙酯/己烷洗涤,得到标题化合物(65 mg)。
实施例6
(S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
A)8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸
在室温下向8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸甲酯(262 mg)在甲醇中的溶液中添加8 M氢氧化钠水溶液(0.53 mL),然后在相同温度下搅拌5小时。将所得反应混合物用2N盐酸溶液中和,并在减压下浓缩。将残余物悬浮在乙酸乙酯中,并滤出不溶物。减压浓缩滤液,得到标题化合物(256 mg)。
B)N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
在室温下向8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-甲酸(166 mg)和三乙胺(0.30 mL)在甲苯(10 mL)中的溶液中加入DPPA(0.18 mL)。将混合物在室温搅拌40分钟后,加入参考例2中获得的6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-胺(162 mg)。将得到的反应混合物在100℃下搅拌2小时,然后倒入饱和碳酸氢钠水溶液中,然后用乙酸乙酯萃取。分离有机层并用饱和盐水洗涤,然后经无水硫酸镁干燥,并在减压下蒸馏出溶剂。残余物通过硅胶柱色谱法(NH,甲醇/乙酸乙酯)纯化,并悬浮在乙酸乙酯/己烷中和用乙酸乙酯/己烷洗涤,得到标题化合物(183 mg)。
C)(S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲
N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲(183 mg)通过HPLC(CHIRALPAK IC (VB004),20mmID×250mm L,流动相:己烷/2-丙醇=300/700)分级。在减压下浓缩保留时间较短的含有目标产物的级分。将浓缩物用乙酸乙酯/己烷洗涤,得到标题化合物(62 mg)。
实施例7
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲
A)1-(三苯基甲基)-1H-咪唑
在0℃下向咪唑(25 g)在二氯甲烷(300 mL)中的溶液中加入TEA(77 mL)。将混合物搅拌5分钟后,在相同温度下一点一点地加入三苯基甲基氯(102 g)。将所得反应混合物在室温搅拌12小时。将反应混合物用水稀释,然后用二氯甲烷萃取两次。有机层用水洗涤,然后用饱和盐水洗涤,经硫酸钠干燥,然后在减压下浓缩。残余物用己烷洗涤,得到标题化合物(110 g)。
B)2-甲氧基-2-甲基-1-(1-(三苯基甲基)-1H-咪唑-2-基)丙-1-酮
在-10℃下向1-(三苯基甲基)-1H-咪唑(1.0 g)在THF(15 mL)中的溶液中滴加1.4M正丁基锂/己烷溶液(2.3 mL),然后在0℃下搅拌30分钟。将得到的反应混合物冷却至-78℃后,滴加2-甲氧基-2-甲基丙酸甲酯(0.5 g),然后在相同温度下搅拌1小时,然后在室温下搅拌3小时。向反应混合物中加入饱和氯化铵水溶液,然后用乙酸乙酯萃取两次。有机层用水洗涤,然后用饱和盐水洗涤,经硫酸镁干燥,然后在减压下浓缩。将残余物悬浮在己烷中并用己烷洗涤,得到标题化合物(650 mg)。
C)1-(1H-咪唑-2-基)-2-甲氧基-2-甲基丙-1-酮
将2-甲氧基-2-甲基-1-(1-(三苯基甲基)-1H-咪唑-2-基)丙-1-酮(4.2 g)和5%乙酸-甲醇溶液(50 mL)的混合物回流16小时。将得到的反应混合物冷却至室温,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(1.2 g)。
D)1-(1-氨基-1H-咪唑-2-基)-2-甲氧基-2-甲基丙-1-酮
向1-(1H-咪唑-2-基)-2-甲氧基-2-甲基丙-1-酮(1.4 g)在DMF(15 mL)中的溶液中加入1 M的叔丁醇钾在THF中的溶液(9.2 mL),然后在相同温度下搅拌30分钟。在室温下向所得混合物中加入O-(4-硝基苯甲酰基)羟胺(1.7 g),然后在相同温度下搅拌16小时。向反应混合物中加入冷水,然后在减压下浓缩。用乙酸乙酯稀释残余物,并滤出不溶物。减压浓缩滤液,残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(1.0 g)。
E)N-(2-(2-(2-甲氧基-2-甲基丙酰基)-1H-咪唑-1-基)(叔丁氧基)甲酰胺
在室温下向1-(1-氨基-1H-咪唑-2-基)-2-甲氧基-2-甲基丙-1-酮(1.0 g)在DMF(10 mL)中的溶液中加入DMAP(0.34 g),然后加入Boc2O(1.2 mL)。将所得反应混合物在80℃下搅拌1小时,然后冷却至室温,并在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(1.1 g)。
F)N-(4-溴-2-(2-(2-甲氧基-2-甲基丙酰基)-1H-咪唑-1-基)(叔丁氧基)甲酰胺
向N-(2-(2-(2-甲氧基-2-甲基丙酰基)-1H-咪唑-1-基)(叔丁氧基)甲酰胺(1.0g)在DMF(10 mL)中的溶液中滴加N-溴代琥珀酰亚胺(0.82 g)在DMF(5 mL)中的溶液,然后在室温下搅拌16小时。向反应混合物中加入饱和碳酸钠水溶液,然后减压浓缩。残余物用乙酸乙酯萃取两次,有机层用水洗涤,然后用饱和盐水洗涤,经硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(700 mg)。
G)1-(1-氨基-4-溴-1H-咪唑-2-基)-2-甲氧基-2-甲基丙-1-酮
在0℃下向N-(4-溴-2-(2-(2-甲氧基-2-甲基丙酰基)-1H-咪唑-1-基)(叔丁氧基)甲酰胺(700 mg)在二氯甲烷(10 mL)中的溶液中加入三氟乙酸(3 mL),然后在室温下搅拌1小时。将得到的反应混合物在减压下浓缩,残余物用饱和碳酸氢钠水溶液中和。将混合物用乙酸乙酯萃取两次。用水洗涤有机层,然后用饱和盐水洗涤,用硫酸钠洗涤,然后在减压下浓缩。残余物用戊烷洗涤,得到标题化合物(450 mg)。
H)2-溴-8-(2-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯
在室温下向1-(1-氨基-4-溴-1H-咪唑-2-基)-2-甲氧基-2-甲基丙-1-酮(400 mg)在THF(5 mL)中的溶液中添加丙烯酸甲酯(0.3 mL)和溴化锂(531 mg)。将混合物置于氧气气氛中,添加Pd(OAc)2(69 mg),并将混合物在氧气气氛下于50℃搅拌16小时。将所得反应混合物倒入水中,然后用乙酸乙酯萃取两次。有机层用水洗涤,然后用饱和盐水洗涤。有机层经硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(250 mg)。
I)2-甲基-8-(2-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯
向2-溴-8-(2-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯(200 mg)在甲苯(6 mL)和水(0.4 mL)中的溶液中加入2,4,6-三甲基环硼氧烷(0.15 mL)和磷酸三钾(390mg)。然后,将混合物置于氮气气氛中。加入Pd(OAc)2(28 mg)和SPhos(101 mg),并将混合物在80℃下搅拌3小时。将所得反应混合物倒入碳酸氢钠水溶液中,然后用乙酸乙酯萃取两次。有机层用水和饱和盐水洗涤,经硫酸钠干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(120 mg)。
J)甲基2-甲基-8-(2-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸
向2-甲基-8-(2-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯(300 mg)在乙醇(10 mL)中的溶液中加入8 M氢氧化钠水溶液(0.72 mL),然后将得到的反应混合物在60℃搅拌过夜。加入8 M氢钠水溶液(1.44 mL),然后在80℃下搅拌过夜。向反应混合物中加入6 M盐酸,使其在pH 4下呈酸性,然后减压浓缩。将残余物悬浮在乙醇中,将不溶物滤出并用乙醇洗涤。减压浓缩滤液,同时与甲苯共沸沸腾,得到标题化合物(406 mg)。
K)N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲
向甲基2-甲基-8-(2-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸(50 mg)和三乙胺(0.04 mL)在DMF(5 mL)中的混合物中加入DPPA(0.05 mL),然后在室温下搅拌2小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和盐水洗涤,经硫酸镁干燥,然后在减压下浓缩。向残余物中加入甲苯(5 mL)、三乙胺(0.04 mL)和参考例3中获得的5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺(27.5 mg),然后在110℃下搅拌3小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和盐水洗涤,经硫酸镁干燥,然后在减压下浓缩。残余物通过HPLC纯化,得到标题化合物(2 mg)。
实施例8
N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲
A)1-氨基-1H-咪唑-2-甲酸乙酯
在氮气气氛下,在-10℃下,将1M的六甲基二硅基氨基锂在THF中的溶液(171 mL)滴加到咪唑-2-甲酸乙酯(20 g)在无水DMF(400 mL)中的溶液中,然后在相同温度下搅拌30分钟。在0℃下加入O-二苯基氧膦基羟胺(39.9 g)在无水DMF(1000 mL)中的溶液。将所得反应混合物在室温搅拌16小时,然后在减压下浓缩。向残余物中加入水,然后用二氯甲烷萃取4次。萃取物用饱和盐水洗涤两次,然后经无水硫酸钠干燥,并减压浓缩,得到标题化合物(23.0 g)。
B)1-((叔丁氧基羰基)氨基)-1H-咪唑-2-甲酸乙酯
向1-氨基-1H-咪唑-2-甲酸乙酯(23.0 g)和DMAP(8.72 g)在无水DMF(250 mL)中的溶液中滴加Boc2O(28.0 g)。将混合物在氮气气氛下在80至85℃下搅拌4小时,然后在减压下浓缩。残余物用二氯甲烷稀释,并用饱和柠檬酸水溶液洗涤,然后用饱和盐水洗涤。经无水硫酸钠进行干燥,然后减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/二氯甲烷)纯化,得到标题化合物(26.6 g)。
C)1-((叔丁氧基羰基)氨基)-4-氯-1H-咪唑-2-甲酸乙酯
向1-((叔丁氧基羰基)氨基)-1H-咪唑-2-甲酸乙酯(80.0 g)在无水DMF(800 mL)中的溶液中一点一点地加入N-氯代琥珀酰亚胺(50.2 g),然后在氮气气氛下于室温下搅拌16小时。用水稀释所得反应混合物,并用乙酸乙酯萃取3次。有机层用水洗涤两次,并用饱和盐水洗涤两次,经无水硫酸钠干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚)纯化,得到标题化合物(16.8 g)。
D)3-(1-((叔丁氧基羰基)氨基)-4-氯-1H-咪唑-2-基)-3-氧代丙酸乙酯
在氮气气氛下,在-10℃下,向1-((叔丁氧基羰基)氨基)-4-氯-1H-咪唑-2-甲酸乙酯(22.0 g)和乙酸乙酯(33.5 g)在无水THF(250 mL)中的溶液中滴加1 M的六甲基二硅基氨基锂在THF中的溶液(266 mL)。将所得反应混合物在相同温度下搅拌30分钟,然后在室温下搅拌4.5小时。将反应混合物冷却至0℃后,添加乙酸以将pH调节至5,然后用饱和碳酸氢钠水溶液将pH调节至8。用乙酸乙酯萃取3次后,有机层用饱和盐水洗涤两次,经硫酸钠干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/二氯甲烷)纯化,得到标题化合物(19.7 g)。
E)2-氯-8-羟基咪唑并[1,2-b]哒嗪-7-甲酸乙酯
向3-(1-((叔丁氧基羰基)氨基)-4-氯-1H-咪唑-2-基)-3-氧代丙酸乙酯(31.0 g)在无水二氯甲烷(400 mL)中的溶液中加入N,N-二甲基甲酰胺缩二甲醇(13.4 g)。将所得反应混合物在室温搅拌16小时,然后在减压下浓缩。残余物通过硅胶柱色谱法(甲醇/二氯甲烷)纯化,得到标题化合物(16.0 g)。
F)8-溴-2-氯咪唑并[1,2-b]哒嗪-7-甲酸乙酯
向2-氯-8-羟基咪唑并[1,2-b]哒嗪-7-甲酸乙酯(16.0 g)在乙腈(150 mL)中的溶液中加入氧溴化磷(30.4 g),然后将所得反应混合物在氮气气氛下在80至90℃下搅拌2小时。将混合物冷却至室温后,加入冰水,然后用饱和碳酸氢钠水溶液中和。将混合物用乙酸乙酯萃取3次。有机层用水洗涤两次,并用饱和盐水洗涤两次,经硫酸钠干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚)纯化,得到标题化合物(8.24 g)。
G)2-氯-8-(丙烯-2-基)咪唑并[1,2-b]哒嗪-7-甲酸乙酯
将8-溴-2-氯咪唑并[1,2-b]哒嗪-7-甲酸乙酯(1.0 g)、异丙烯基三氟硼酸钾(534mg)、磷酸三钾(2.09 g)、1,1'-双(二苯基膦基)二茂铁氯化钯(II)(240 mg)、无水DMF(5mL)和无水1,4-二噁烷(15 mL)的混合物在氮气气氛下于80至85℃搅拌16小时。将所得反应混合物冷却至室温,然后用乙酸乙酯稀释。有机层用水和饱和盐水洗涤两次,经硫酸钠干燥,然后减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚)纯化,得到标题化合物(715 mg)。
H)2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸乙酯
将2-氯-8-(丙烯-2-基)咪唑并[1,2-b]哒嗪-7-甲酸乙酯(1.20 g)和三(三苯基膦)氯化铑(I)(418 mg)在无水乙醇(30 mL)中的混合物在氢气气氛下在10至15℃下搅拌40小时。将混合物在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚)纯化,得到标题化合物(955 mg)。
I)2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸
向2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸乙酯(955 mg)在甲醇(10 mL)、THF(10 mL)和水(10 mL)中的溶液中加入氢氧化钠(571 mg),然后在氮气气氛下于10℃将混合物搅拌1小时。向所得反应混合物中加入2N盐酸溶液以调节pH至5后,混合物用乙酸乙酯萃取3次。有机层用饱和盐水洗涤两次,经硫酸钠干燥,然后在减压下浓缩。残余物用乙酸乙酯/石油醚洗涤,得到标题化合物(800 mg)。
J)N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲
在10℃下向2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸(60 mg)和三乙胺(51mg)在二噁烷(3 mL)中的混合物中加入DPPA(130 mg)。将混合物在相同温度下搅拌30分钟后,加入参考例1中获得的5-氯-6-(二氟甲氧基)吡啶-3-胺(58 mg),然后在氮气气氛下在100℃下搅拌1小时。将得到的反应混合物在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚)纯化,然后通过HPLC纯化,得到标题化合物(31 mg)。
实施例9
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲
A)2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯
在室温下向2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸(462 mg)在甲醇中的溶液中加入0.6 M的三甲基甲硅烷基重氮甲烷在己烷中的溶液(9.6 mL)。将反应混合物在室温下搅拌1小时,然后减压浓缩,得到标题化合物(475 mg)。
B)2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯
在氩气气氛下向2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯(475 mg)、2,4,6-三甲基环硼氧烷(0.52 mL)、磷酸三钾(1.92 g)、SPhos(307 mg)、甲苯(3 mL)和水(0.3mL)的混合物中加入Pd(OAc)2(84 mg)。将得到的反应混合物在130℃加热1小时,然后倒入饱和碳酸氢钠水溶液中,然后用乙酸乙酯萃取。有机层用饱和盐水洗涤,经硫酸镁干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,得到标题化合物(356mg)。
C)2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸
向2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸甲酯(356 mg)在甲醇(15 mL)中的溶液中加入2M氢氧化钠水溶液(1.5 mL),然后将混合物在室温下搅拌2小时。向混合物中加入8M氢氧化钠水溶液(0.76 mL),然后在室温下搅拌4小时。在0℃下向所得反应混合物中加入1N盐酸溶液进行中和后,用乙酸乙酯萃取混合物。有机层用水洗涤,然后用饱和盐水洗涤,经硫酸镁干燥,然后减压浓缩,得到标题化合物(254 mg)。
D)N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲
向2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-甲酸(80 mg)和三乙胺(0.15 mL)在甲苯(10 mL)中的溶液中加入二苯基磷酰基叠氮化物(0.09 mL)。在相同温度下搅拌混合物40分钟后,加入参考例3中获得的5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺(71 mg),然后在100℃搅拌2小时。将所得反应混合物倒入饱和碳酸氢钠水溶液中,然后用乙酸乙酯萃取。有机层用饱和盐水洗涤,经硫酸镁干燥,然后在减压下浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/己烷)纯化,并悬浮在乙酸乙酯/己烷中和用乙酸乙酯/己烷洗涤,得到标题化合物(83 mg)。
以相同方式合成以下实施例10至270的化合物。
[表1-1]
实施例编号 | 盐 | MS | |
1 | (S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 427.0 | |
2 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 491.1 | |
3 | (S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 473.0 | |
4 | (S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 428.1 | |
5 | (S)-N-(5-氰基-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 418.1 | |
6 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 461.9 | |
7 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 442.1 | |
8 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 429.0 | |
9 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 412.0 | |
10 | (R)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | HCI | 427.1 |
11 | (R)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | H<sub>2</sub>SO<sub>4</sub> | 427.1 |
12 | (S)-N-(6-氯-4(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | HCI | 493.1 |
13 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 0.5H<sub>2</sub>SO<sub>4</sub> | 493.1 |
14 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 427.1 |
[表1-2]
15 | (R)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 427.0 | |
16 | N-(5-氰基吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 350.1 | |
17 | N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 462.0 | |
18 | (R)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 461.9 | |
19 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 428.0 | |
20 | (R)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 428.2 | |
21 | (S)-N-(5-氯-6-(3-甲基-1H-1,2,4-三唑-1-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 442.2 | |
22 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 475.9 | |
23 | (S)-N-(5-氯-2-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 442.2 | |
24 | (S)-N-(5-氯-6-(1,3-噁唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 428.1 | |
25 | (S)-N-(5-氯-6-(1-甲基-1H-咪唑-4-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 441.1 | |
26 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(1,3-噁唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 462.2 | |
27 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(5-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 408.1 | |
28 | (S)-N-(6-(二氟甲氧基)-5-甲基吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 407.1 |
[表1-3]
29 | (S)-N-(5-氯-6-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 442.1 | |
30 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(4-甲基-2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 476.2 | |
31 | (S)-N-(5-(二氟甲基)-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 444.2 | |
32 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-[6-(4-(甲氧基甲基)-2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基]脲 | 506.3 | |
33 | (S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(3-甲基-1H-1,2,4-三唑-1-基)-5-(三氟甲基)吡啶-3-基)脲 | 476.2 | |
34 | (S)-N-[6-(4-(二氟甲基)-2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基]-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 512.2 | |
35 | (S)-N-(5-溴-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 471.1 | |
36 | (S)-N-[5-氯-6-(4-(甲氧基甲基)-2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 472.2 | |
37 | (S)-N-(5-氯-6-(4-甲基-2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 442.1 | |
38 | (S)-N-(6-(二氟甲氧基)-5-(二氟甲基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 443.1 | |
39 | (S)-N-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 418.9 | |
40 | (S)-N-(5-氯-6-(二氟甲氧基)-2-甲基吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 441.1 | |
41 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氰基吡啶-3-基)脲 | 381.0 | |
42 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 491.0 |
[表1-4]
43 | (R)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 491.1 | |
44 | (R)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | HCI | 493.1 |
45 | (R)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 0.5H<sub>2</sub>SO<sub>4</sub> | 493.1 |
46 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 427.1 | |
47 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 459.1 | |
48 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 459.1 | |
49 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 459.1 | |
50 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 448.1 | |
51 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-甲氧基吡啶-3-基)脲 | 421.9 | |
52 | N-(5-氯-6-(2-甲氧基乙氧基)吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 465.9 | |
53 | N-(6-(氮杂环丁烷-1-基)-5-氯吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 447.0 | |
54 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(2-氧代吡咯烷-1-基)吡啶-3-基)脲 | 474.9 | |
55 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(1-乙基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 443.0 | |
56 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(3-(二氟甲基)-1-甲基-1H-吡唑-5-基)脲 | 411.0 |
[表1-5]
57 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氟-6-甲氧基吡啶-3-基)脲 | 406.0 | |
58 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(2-氰基-5-甲基吡啶-4-基)脲 | 397.2 | |
59 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 456.0 | |
60 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 458.1 | |
61 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 458.1 | |
62 | N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 507.1 | |
63 | (R)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 507.1 | |
64 | (R)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-2-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 473.1 | |
65 | (R)-N-(5-氯-6-(二氟甲氧基)-2-甲基吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 472.0 | |
66 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 507.2 | |
67 | (S)-N-(5-氯-6-(二氟甲氧基)-2-甲基吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 472.1 | |
68 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-2-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 473.2 | |
69 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(1,3-噁唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 493.1 | |
70 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 439.1 |
[表1-6]
71 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(3-甲基-1H-1,2,4-三唑-1-基)吡啶-3-基)脲 | 473.1 | |
72 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(1,3-噁唑-2-基)吡啶-3-基)脲 | 459.1 | |
73 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氯-6-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-基)脲 | 473.1 | |
74 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(二氟甲氧基)-5-甲基吡啶-3-基)脲 | 438.1 | |
75 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-氰基-6-(二氟甲氧基)吡啶-3-基)脲 | 449.1 | |
76 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(4-甲基-2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 507.2 | |
77 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-{6-(4-(甲氧基甲基)-2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基}脲 | 537.2 | |
78 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(3-甲基-1H-1,2,4-三唑-1-基)-5-(三氟甲基)吡啶-3-基)脲 | 507.2 | |
79 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(5-(二氟甲基)-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 475.1 | |
80 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(4-(二氟甲基)-2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 543.2 | |
81 | (S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(二氟甲氧基)-5-(二氟甲基)吡啶-3-基)脲 | 474.1 | |
82 | (S)-N-(5-溴-6-(二氟甲氧基)吡啶-3-基)-N'-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 502.1 | |
83 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 439.1 | |
84 | N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 473.1 |
[表1-7]
85 | (R)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 472.9 | |
86 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 438.1 | |
87 | N-(2-氰基-5-甲基吡啶-4-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 377.2 | |
88 | (R)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 487.2 | |
89 | (R)-N-(5-氯-6-(二氟甲氧基)-2-甲基吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 452.1 | |
90 | (R)-N-(5-氯-2-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 453.2 | |
91 | (R)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 439.2 | |
92 | (R)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | HCI | 439.2 |
93 | (S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 487.2 | |
94 | (S)-N-(5-氯-6-(二氟甲氧基)-2-甲基吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 452.2 | |
95 | (S)-N-(5-氯-2-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 453.2 | |
96 | (S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | 439.2 | |
97 | (S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)脲 | HCI | 439.2 |
98 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 353.9 |
[表1-8]
99 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | HCOOH | 464.1 |
100 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | HCOOH | 430.0 |
101 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | HCOOH | 421.1 |
102 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3-氰基-1-甲基-1H-吡唑-5-基)脲 | HCOOH | 357.0 |
103 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | HCOOH | 400.0 |
104 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3,4-二氰基苯基)脲 | 378.1 | |
105 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-甲氧基吡啶-3-基)脲 | 384.0 | |
106 | N-(5-氯-6-甲氧基吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 395.1 | |
107 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3-(二氟甲氧基)-1-甲基-1H-吡唑-5-基)脲 | 398.0 | |
108 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(1-(二氟甲基)-1H-吡唑-4-基)脲 | 368.0 | |
109 | N-(5-氯-6-氰基吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 388.0 | |
110 | N-(8-氯咪唑并[1,2-a]吡啶-6-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 404.0 | |
111 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-氰基-5-(三氟甲基)吡啶-3-基)脲 | 422.0 | |
112 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-氰基-5-(三氟甲基)吡啶-3-基)脲 | 422.0 |
[表1-9]
113 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3-(二氟甲基)-1-甲基-1H-吡唑-5-基)脲 | 382.0 | |
114 | N-(3-氯-1-甲基-1H-吡唑-5-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 366.0 | |
115 | N-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(1-(二氟甲基)-3-甲基-1H-吡唑-4-基)脲 | 384.0 | |
116 | N-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 446.0 | |
117 | N-(6-氯-5-(三氟甲基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 413.1 | |
118 | N-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)吡啶-3-基)脲 | 459.1 | |
119 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 410.9 | |
120 | N-(6-氰基-5-(三氟甲基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 404.2 | |
121 | N-(3-氯-4-甲氧基苯基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 374.1 | |
122 | N-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(2-(三氟甲基)吡啶-4-基)脲 | 379.2 | |
123 | N-(3-氯-4-(三氟甲氧基)苯基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 427.9 | |
124 | N-(3-氯-4-(二氟甲氧基)苯基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 409.9 | |
125 | N-(5-氯-6-(1-甲基-1H-吡唑-3-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 425.0 | |
126 | N-(3-氯-4-(1H-1,2,4-三唑-1-基)苯基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 411.0 |
[表1-10]
127 | N-(5-氰基-6-(二氟甲氧基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 402.0 | |
128 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3,4-二氰基苯基)脲 | 394.0 | |
129 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 370.0 | |
130 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-甲氧基吡啶-3-基)脲 | 400.0 | |
131 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 437.1 | |
132 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 415.9 | |
133 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 447.9 | |
134 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 479.9 | |
135 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 479.9 | |
136 | N-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 479.9 | |
137 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 444.9 | |
138 | N-(2-溴-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 414.0 | |
139 | N-(5-氰基吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-苯基咪唑并[1,2-b]哒嗪-7-基)脲 | 414.1 | |
140 | N-(5-氰基吡啶-3-基)-N'-(2-环丙基-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 378.1 |
[表1-11]
141 | N-(5-氰基吡啶-3-基)-N'-(2-甲氧基-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 366.0 | |
142 | N-(2-氰基-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 361.1 | |
143 | N-(5-氯-6-甲氧基吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-(三氟甲基)咪唑并[1,2-b]哒嗪-7-基)脲 | 445.1 | |
144 | N-(5-氯-6-甲氧基吡啶-3-基)-N'-(2-(二氟甲基)-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 427.2 | |
145 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-(二氟甲基)-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 464.1 | |
146 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-(二氟甲基)-8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 464.1 | |
147 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(3-氟-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 445.1 | |
148 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(3-氟-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 445.1 | |
149 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(3-氟-8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 445.1 | |
150 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲 | 441.1 | |
151 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)脲 | 413.9 | |
152 | N-(8-(1-甲氧基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 447.9 | |
153 | N-(8-(2-氯苯基)咪唑并[1,2-b]哒嗪-7-基)-N'-(2,4-二氟苯基)脲 | 400.1 | |
154 | N-(8-(2-氯苯基)咪唑并[1,2-b]哒嗪-7-基)-N'-(2,4-二氟苯基)脲 | HCI | 400.1 |
[表1-12]
155 | N-(3-氯-8-(2-氯苯基)咪唑并[1,2-b]哒嗪-7-基)-N'-(2,4-二氟苯基)脲 | 434.0 | |
156 | N-(2-氯-8-(二甲基氨基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 355.0 | |
157 | N-(2-氯-8-环丙基咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 351.9 | |
158 | N-(2-氯-8-乙基咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 339.9 | |
159 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 367.9 | |
160 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氯-6-(1H-1,2,3-三唑-1-基)吡啶-3-基)脲 | 444.0 | |
161 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 444.0 | |
162 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 478.1 | |
163 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)吡啶-3-基)脲 | 478.1 | |
164 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 414.0 | |
165 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(3-氰基-1-甲基-1H-吡唑-5-基)脲 | 373.1 | |
166 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 435.0 | |
167 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 435.1 | |
168 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 435.1 |
[表1-13]
169 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(3-(二氟甲氧基)-1-甲基-1H-吡唑-5-基)脲 | 412.1 | |
170 | N-(8-(丁-2-基)-2-氯咪唑并[1,2-b]哒嗪-7-基)-N'-(3-氯-1-甲基-1H-吡唑-5-基)脲 | 380.1 | |
171 | N-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | 408.0 | |
172 | N-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3-氰基-1-甲基-1H-吡唑-5-基)脲 | 411.1 | |
173 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 483.0 | |
174 | N-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 518.1 | |
175 | N-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 475.1 | |
176 | N-(5-氯-6-甲氧基吡啶-3-基)-N'-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 447.0 | |
177 | N-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 454.0 | |
178 | N-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(3-(二氟甲氧基)-1-甲基-1H-吡唑-5-基)脲 | 452.0 | |
179 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 484.0 | |
180 | N-(3-氯-1-甲基-1H-吡唑-5-基)-N'-(2-氯-8-(1,1,1-三氟丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 419.9 | |
181 | N-(2-氯-8-(1-羟基乙基)咪唑并[1,2-b]哒嗪-7-基)-N'-(2,4-二氟苯基)脲 | 368.0 | |
182 | N-(2-氯-8-(1-甲氧基丙-2-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | HCOOH | 384.0 |
[表1-14]
183 | N-(2-氯-8-(3-氯-1-甲基-1H-吡唑-4-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基吡啶-3-基)脲 | HCOOH | 428.1 |
184 | N-(2-氯-8-(3-氯-1-甲基-1H-吡唑-4-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氰基-6-甲氧基吡啶-3-基)脲 | 458.0 | |
185 | N-(2-氯-8-(3-氯-1-甲基-1H-吡唑-4-基)咪唑并[1,2-b]哒嗪-7-基)-N'-(5-氯-6-甲氧基吡啶-3-基)脲 | 466.9 | |
186 | N-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)-N'-(8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲 | 366.0 | |
187 | N-(6-甲氧基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 425.1 | |
188 | N-(6-甲氧基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 489.1 | |
189 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(6-甲氧基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 455.1 | |
190 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(6-甲氧基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 454.0 | |
191 | N-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(6-甲氧基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 446.2 | |
192 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)脲 | 490.1 | |
193 | N-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 525.1 | |
194 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)脲 | 491.1 | |
195 | N-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)-N'-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)脲 | 461.1 | |
196 | N-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)脲 | 482.1 |
[表1-15]
197 | N-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)脲 | 484.1 | |
198 | N-(5-氰基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-(三氟甲基)-1,5-萘啶-3-基)脲 | 484.1 | |
199 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 424.1 | |
200 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-1,5-萘啶-3-基)脲 | 425.1 | |
201 | N-(4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 459.2 | |
202 | N-(6-氯-4-(1-乙氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 506.8 | |
203 | N-(6-(二氟甲基)-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 509.2 | |
204 | N-(6-乙基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 487.2 | |
205 | N-(6-乙基-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 487.2 | |
206 | N-(6-氯-4-(2-甲氧基丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 507.2 | |
207 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 476.9 | |
208 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(3-(1,1-二氟乙基)-1-甲基-1H-吡唑-5-基)脲 | 409.2 | |
209 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(3-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-5-基)脲 | 427.1 | |
210 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-(二氟甲基)-6-甲氧基吡啶-3-基)脲 | 422.1 |
[表1-16]
211 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(1-(丙-2-基)-3-(三氟甲基)-1H-吡唑-5-基)脲 | 441.1 | |
212 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(3,3-二氟环己基)脲 | 383.2 | |
213 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(3-(三氟甲基)环己基)脲 | 415.1 | |
214 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 443.1 | |
215 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-(三氟甲基)吡啶-4-基)脲 | 409.9 | |
216 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-氰基吡啶-4-基)脲 | 366.9 | |
217 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 441.9 | |
218 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-(三氟甲基)吡啶-3-基)脲 | 409.9 | |
219 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-甲氧基-5-(三氟甲基)吡啶-3-基)脲 | 439.9 | |
220 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-氰基吡啶-3-基)脲 | 366.9 | |
221 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-氯-6-(2,2,2-三氟乙氧基)吡啶-3-基)脲 | 473.8 | |
222 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-(二氟甲基)吡啶-4-基)脲 | 390.1 | |
223 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-(二氟甲氧基)吡啶-4-基)脲 | 408.1 | |
224 | N-(5-氯-6-(二氟甲基)吡啶-3-基)-N'-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 426.1 |
[表1-17]
225 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-氰基-5-甲基吡啶-4-基)脲 | 380.9 | |
226 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-氰基-6-甲基吡啶-4-基)脲 | 380.9 | |
227 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-氰基-3-甲基吡啶-4-基)脲 | 380.9 | |
228 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-甲基-2-(三氟甲基)吡啶-4-基)脲 | 424.1 | |
229 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-甲基-5-(三氟甲基)吡啶-3-基)脲 | 424.0 | |
230 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(1H-四唑-5-基)-5-(三氟甲基)吡啶-3-基)脲 | 477.9 | |
231 | N-(5-溴-2-(三氟甲基)吡啶-4-基)-N'-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 487.7 | |
232 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-氟-2-(三氟甲基)吡啶-4-基)脲 | 427.9 | |
233 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-氯-2-(三氟甲基)吡啶-4-基)脲 | 443.9 | |
234 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-甲基-6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 490.9 | |
235 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(5-氯-6-(嘧啶-2-基)吡啶-3-基)脲 | 453.9 | |
236 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(1-甲基-1H-四唑-5-基)-5-(三氟甲基)吡啶-3-基)脲 | 491.9 | |
237 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'(6-(2-甲基-2H-四唑-5-基)-5-(三氟甲基)吡啶-3-基)脲 | 491.9 | |
238 | N-(5-氯-6-(二氟甲氧基)-2-甲基吡啶-3-基)-N'-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 454.1 |
[表1-18]
239 | N-(5-氯-2-甲基-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 457.1 | |
240 | N-(6-氯-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(2-甲氧基-5-(三氟甲基)吡啶-3-基)脲 | 438.1 | |
241 | N-(4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 443.2 | |
242 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(丙-2-基)-1,5-萘啶-3-基)脲 | 409.1 | |
243 | N-(6-甲基-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 456.9 | |
244 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(6-甲基-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 422.9 | |
245 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(6-甲基-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 422.0 | |
246 | N-(2-氰基-5-甲基吡啶-4-基)-N'-(6-甲基-4-(丙-2-基)-1,5-萘啶-3-基)脲 | 361.1 | |
247 | N-(6-(2,2-二氟乙氧基)-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 522.9 | |
248 | N-(6-(二氟甲氧基)-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 508.9 | |
249 | N-(6-(甲氧基甲基)-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 487.1 | |
250 | N-(6-{((4-甲氧基苯基)甲氧基)甲基}-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 593.2 | |
251 | N-(6-(羟基甲基)-4-(丙-2-基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 473.2 | |
252 | N-(4-(2-氯苯基)-1,5-萘啶-3-基)-N'-(2,4-二氟苯基)脲 | 411.1 |
[表1-19]
253 | N-(2-氯-8-(2-氯苯基)咪唑并[1,2-b]哒嗪-7-基)-N'-(2,4-二氟苯基)脲 | 434.0 | |
254 | N-(4-(2-氯苯基)-1,6-萘啶-3-基)-N'-(2,4-二氟苯基)脲 | 411.1 | |
255 | N-(5-甲氧基-4-(1-甲氧基乙基)-1,6-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 487.1 | |
256 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(5-甲氧基-4-(1-甲氧基乙基)-1,6-萘啶-3-基)脲 | 453.1 | |
257 | N-(5-氰基吡啶-3-基)-N'-(5-甲氧基-4-(1-甲氧基乙基)-1,6-萘啶-3-基)脲 | 377.1 | |
258 | N-(5-氯-4-(1-甲氧基乙基)-1,6-萘啶-3-基)-N'-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)脲 | 457.0 | |
259 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(5-甲基-4-(丙-2-基)-1,6-萘啶-3-基)脲 | 422.2 | |
260 | N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)脲 | 438.1 | |
261 | N-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 473.2 | |
262 | N-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 473.2 | |
263 | N-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 473.2 | |
264 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)脲 | 439.1 | |
265 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)脲 | 439.1 | |
266 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-5-甲基-1,6-萘啶-3-基)脲 | 439.1 |
[表1-20]
267 | N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(4-(1-甲氧基乙基)-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)脲 | 455.2 | |
268 | N-(4-(1-甲氧基乙基)-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 489.2 | |
269 | N-(4-(1-甲氧基乙基)-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲 | 489.2 | |
270 | N-(5-氯-6-甲氧基吡啶-3-基)-N'-(4-(1-甲氧基乙基)-6-甲基-5-氧代-5,6-二氢-1,6-萘啶-3-基)脲 | 418.0 |
制备例1(胶囊的制备)
1)实施例1的化合物 30 mg
2)纤维素细粉 10 mg
3)乳糖 19 mg
4)硬脂酸镁 1 mg
总计 60 mg
将1)、2)、3)和4)混合并装入明胶胶囊中。
制备例2(片剂的制备)
1)实施例1的化合物 30 g
2)乳糖 50 g
3)玉米淀粉 15 g
4)羧甲基纤维素钙 44 g
5)硬脂酸镁 1 g
1000片片剂总计 140 g
将1)、2)和3)的全部量以及30 g的4)用水揉捏并真空干燥,然后制粒。将14 g的4)和1 g的5)与该粒状粉末混合,然后用压片机压片。以此方式,获得1000片片剂,每片包含30mg实施例1的化合物。
测试例1
重组人MALT1蛋白的制备
使用GC-030-D09 (pENTR221/MALT1,GeneCopoeia)作为模板以及具有在N端的BamH I限制酶和在C端的Not I限制酶的引物,在人MALT1基因上进行PCR,以形成人MALT1(340-789aa)二聚体。使用酵母DNA作为模板以及具有在N端的Nde I限制酶、接头序列(GGAAGTGGCTCAGGTAGC (SEQ ID NO:1))和在C端的BamH I限制酶的引物,在酵母GCN4的亮氨酸拉链基因上进行PCR,以产生酵母GCN4(251-281aa)。将获得的两个片段都用限制酶处理,并插入pET28a (Novagen)载体的Nde I和Not I之间,以产生重组人MALT1蛋白表达载体pET28a/His-LZ-hMALT1v1(340-789)-His。
通过用ECOS感受态大肠杆菌BL21(DE3)(Nippon Gene Co.,Ltd.)转化如上制备的表达质粒来制备重组人MALT1蛋白。将通过转化获得的大肠杆菌接种到300 mL的LB培养基(1%胰蛋白胨、0.5%酵母提取物、0.5%氯化钠、0.01%氨苄青霉素)中,并在30℃下培养16小时。将获得的培养液移植到装有6 L主要发酵培养基(0.3%磷酸二氢钾、0.6%磷酸氢二钠、0.1%氯化铵、0.05%氯化钠、0.024%硫酸镁、0.01%消泡剂PE-L、1.5%山梨糖醇、1.5%酪蛋白氨基酸、0.5%酵母提取物和0.01%氨苄青霉素)的罐式培养罐中,在37℃、5L/min的通气速率和400 rpm的搅拌转速下开始培养。当培养液的浊度达到约500 Klett单位时,将培养温度降低至16℃,然后添加异丙基-β-D-硫代吡喃半乳糖苷(IPTG)至终浓度为0.1 mM。此外,进行培养16小时以诱导人MALT1蛋白的表达。培养结束后,将培养液以5,000rpm离心10分钟。将获得的表达人MALT1蛋白的大肠杆菌悬浮在含有50 mM Tris-HCl pH8.0、300 mM NaCl、5 mM DTT、5 U/ml核酸酶(benzonase)、20 mM咪唑、10%甘油和0.1%NP-40的缓冲溶液中后,使用Sonifier (Branson)进行超声处理。将该压碎的液体离心(15,300×G,30分钟,TOMY MX-301),并将获得的上清液通过并吸附到预先用50 mM Tris-HCl pH8.0、300 mM NaCl、5 mM DTT和10%甘油平衡的Ni-NTA Superflow (QIAGEN)柱上,然后在含有50 mM Tris-HCl pH 8.0、300 mM NaCl、5 mM DTT、10%甘油和250 mM咪唑的缓冲液中洗脱。此外,在预先用含有50 mM Tris-HCl pH 8.0、150 mM NaCl、5 mM DTT和10%甘油的缓冲溶液平衡的Superdex 200 pg柱上进行凝胶过滤,以收集目标级分,并加入等量的50mM Tris-HCl pH 8.0、150 mM NaCl、5 mM DTT和90%甘油以得到纯化的人MALT1蛋白。将制备的蛋白储存在-30℃下,并使用BSA作为标准品,使用BCA蛋白检测试剂盒(PIERCE)测定蛋白浓度。
MALT1酶抑制活性的测定
向384孔黑板(Greiner)中加入2μL用检测缓冲液((20 mM HEPES (DojinLaboratories)、10 mM KCl (Wako Pure Chemical Industries,Ltd.)、1.5 mM MgCl2 (Sigma-Aldrich)、1 mM EDTA (pH 8.0)(Nippon Gene Co.,Ltd.)、0.01%Triton X-100(Sigma-Aldrich)和1 mM DTT (Wako Pure Chemical Industries,Ltd.))稀释的化合物溶液。随后,加入2μL纯化的重组人MALT1酶溶液,然后在室温下孵育60分钟。向混合物中加入2μL底物溶液(75μM Ac-LRSR-AFC (SM Biochemicals)、20 mM HEPES (DojinLaboratories)、10 mM KCl (Wako Pure Chemical Industries,Ltd.)、1.5 mM MgCl2 (Sigma-Aldrich)、1 mM EDTA (pH 8.0)(Nippon Gene Co.,Ltd.)、0.01%Triton X-100(Sigma-Aldrich)和1 mM DTT (Wako Pure Chemical Industries,Ltd.),随后在室温下孵育60分钟。用酶标仪Envision (PerkinElmer)测定刚加入底物后和酶促反应后的400nm激发和485nm发射的荧光值,将通过酶促反应增加的荧光值用于计算抑制率(%)。相对于不添加酶的值为100%和不添加化合物的值为0%,计算抑制率(%)。
MALT1酶抑制活性的测定结果如下所示。
[表2]
实施例编号 | 3 μM化合物时的MALT1酶抑制率(%) |
1 | 104 |
2 | 99 |
3 | 101 |
4 | 111 |
5 | 99 |
6 | 108 |
7 | 98 |
8 | 94 |
9 | 99 |
22 | 104 |
31 | 103 |
35 | 105 |
36 | 101 |
59 | 95 |
66 | 99 |
133 | 99 |
173 | 99 |
255 | 97 |
261 | 98 |
269 | 99 |
270 | 94 |
由这些结果表明,本发明的化合物具有MALT1酶抑制活性。
测试例2
使用OCI-Ly3细胞测定生长抑制活性
将OCI-Ly3细胞接种到含有20%FCS(胎牛血清,Thermo Fisher Scientific)和一硫代甘油(Fujifilm Wako Pure Chemical Corporation)的细胞培养基IMDM(FujifilmWako Pure Chemical Corporation)中以在96孔板上达到1.25×103个细胞/孔。将CellTiter-Glo溶液(Promega)添加至未添加受试化合物的细胞中,然后在室温下搅拌15分钟。随后,在接种当天用Envision (PerkinElmer)测定发光值。使已经添加了溶解于二甲基亚砜(Fujifilm Wako Pure Chemical Corporation)中的受试化合物的细胞在CO2孵育箱(37℃)中放置6天。随后,以相同方式测定发光值。通过以下公式计算受试化合物对OCI-Ly3细胞生长的抑制率(%)。
细胞生长抑制率(%)= (1-(受试化合物处理第6天的发光值-受试化合物处理前的发光值)/(不添加化合物的第6天的发光值-化合物处理前的发光值))×100
细胞生长抑制率的测定结果如下所示。
[表3]
实施例编号 | 3 μM化合物时的细胞生长抑制率(%) |
1 | 96 |
2 | 97 |
3 | 99 |
4 | 97 |
5 | 93 |
6 | 99 |
7 | 95 |
9 | 99 |
22 | 102 |
31 | 96 |
35 | 95 |
36 | 96 |
59 | 98 |
66 | 100 |
133 | 98 |
173 | 85 |
255 | 99 |
261 | 88 |
269 | 95 |
270 | 40 |
由这些结果表明,本发明的化合物抑制细胞生长。
测试例3
对带有OCI-Ly3细胞的癌症模型的抗肿瘤作用
将人弥漫性大细胞B细胞淋巴瘤细胞OCI-Ly3 (DSMZ,German Collection ofMicroorganisms and Cell Cultures)悬浮在Matrigel (BD Biosciences):HBSS (ThermoFisher Scientific)=1:1溶液中,将1×107个细胞皮下移植到NOG雌性小鼠(CLEA Japan,Inc.)的腹部。测量植入的肿瘤的肿瘤直径,并通过以下公式计算肿瘤体积。
肿瘤体积=长轴×短轴×短轴×(1/2)
选择具有肿瘤体积约为120 mm3的被植入的肿瘤的个体,并且在实验中每组使用6只动物。每天两次以10 mg/kg (10 mL/kg)的剂量口服给药受试化合物在0.5%甲基纤维素溶液 (Fujifilm Wako Pure Chemical Corporation)中的悬浮液,持续3周。在开始给药的前一天和随时间推移每3-4天测量肿瘤体积,并在21天给药结束后的第二天最后测量肿瘤直径以计算肿瘤体积。通过以下公式将受试化合物给药组与对照给药组相比的肿瘤生长计算为平均肿瘤体积增加比率T/C。
T/C = ((受试化合物给药组给药结束后的肿瘤体积-受试化合物给药组给药开始前一天的肿瘤体积)/(对照给药组给药结束后的肿瘤体积-对照给药组给药开始前一天的肿瘤体积))×100
受试化合物的T/C如下所示。
[表4]
实施例编号 | 剂量 (mg/kg) | T/C (%) |
1 | 10 | 13.4 |
2 | 10 | 2.0 |
3 | 10 | 38.7 |
4 | 10 | 43.3 |
由这些结果表明,本发明的化合物在人弥散性大细胞B细胞淋巴瘤细胞OCI-Ly3皮下移植模型中具有抗肿瘤作用。
工业适用性
本发明的化合物可具有抑制MALT1的作用,并有望用作癌症等的预防或治疗药物。
本申请基于在日本提交的日本专利申请No.2018-222530,其全部内容通过引用并入本文。
序列表
<110> Takeda Pharmaceutical Company Limited
<120> 杂环化合物
<130> 092968
<150> JP2018-222530
<151> 2018-11-28
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 接头序列
<400> 1
ggaagtggct caggtagc 18
Claims (10)
1.由式(I)表示的化合物,或其盐,或其共晶体、水合物或溶剂化物,
(其中
A表示
R1表示1)氢原子,2)卤素原子,3)氰基,4)可被1-3个卤素原子取代的C1-3烷基,5)C1-3烷氧基,6)C3-6环烷基,或7)苯基;
R2表示1)氢原子或2)卤素原子;
R3表示1)可被1-3个选自C1-3烷氧基、羟基和卤素原子的取代基取代的C1-6烷基,2)可被1-3个选自C1-3烷基和卤素原子的取代基取代的吡唑基,3)C3-6环烷基,4)被C1-3烷基二取代的氨基,或5)可被1-3个卤素原子取代的苯基;
R4和R6表示1)氢原子,2)卤素原子,3)可被1-3个选自a)羟基、b)可被4-甲氧基苯基取代的C1-3烷氧基和c)卤素原子的取代基取代的C1-3烷基,或4)可被1-3个卤素原子取代的C1-3烷氧基;
R5、R7和R9表示1)可被1-3个C1-3烷氧基取代的C1-6烷基或2)可被1-3个卤素原子取代的苯基;
R8表示C1-3烷基;和
B表示
1)可被1-3个取代基取代的苯基,所述取代基选自a)卤素原子,b)氰基,c)可被1-3个卤素原子取代的C1-3烷氧基,和d)三唑基;
2)可被1-3个取代基取代的C3-6环烷基,所述取代基选自a)可被1-3个卤素原子取代的C1-3烷基和b)卤素原子,
3)可被1-3个取代基取代的吡啶基,所述取代基选自a)卤素原子,b)氰基,c)可被1-3个卤素原子取代的C1-3烷基,d)可被1-3个选自卤素原子和C1-3烷氧基的取代基取代的C1-3烷氧基,e)可被1-3个C1-3烷基取代的吡唑基,f)可被1-3个C1-3烷基取代的咪唑基,g)可被1-3个C1-3烷基取代的三唑基,所述C1-3烷基可被1-3个选自C1-3烷氧基和卤素原子的取代基取代,h)氮杂环丁烷基,i)吡咯烷酮基,j)可被1-3个C1-3烷基取代的四唑基,k)嘧啶基,和l)噁唑基,
4)可被1-3个取代基取代的吡唑基,所述取代基选自a)可被1-3个卤素原子取代的C1-3烷基,b)可被1-3个卤素原子取代的C1-3烷氧基,c)氰基,和d)卤素原子,或
5)可被1-3个卤素原子取代的咪唑并吡啶基。
5.根据权利要求1所述的化合物,其为(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
(S)-N-(4-(1-甲氧基乙基)-6-甲基-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
(S)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(5-氰基-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
(S)-N-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲,
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(8-(2-甲氧基丙-2-基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲,
N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(2-氯-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲,或
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-N'-(2-甲基-8-(丙-2-基)咪唑并[1,2-b]哒嗪-7-基)脲。
6.根据权利要求1所述的化合物,其为(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N'-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]哒嗪-7-基)脲。
7.根据权利要求1所述的化合物,其为(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-萘啶-3-基)-N'-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)脲。
8.一种药物,其包含根据权利要求1所述的化合物或其盐或其共晶体、水合物或溶剂化物。
9.根据权利要求8所述的药物,其为MALT1抑制剂。
10.根据权利要求8所述的药物,其是用于癌症的预防或治疗药物。
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WO2018020474A1 (en) * | 2016-07-29 | 2018-02-01 | Lupin Limited | Substituted thiazolo-pyridine compounds as malt1 inhibitors |
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WO2018165385A1 (en) * | 2017-03-08 | 2018-09-13 | Cornell University | Inhibitors of malt1 and uses thereof |
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AU2019390863A1 (en) | 2021-06-24 |
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TW202039484A (zh) | 2020-11-01 |
TW202306956A (zh) | 2023-02-16 |
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TWI784213B (zh) | 2022-11-21 |
WO2020111087A1 (ja) | 2020-06-04 |
PH12021551251A1 (en) | 2021-12-06 |
BR112021009994A2 (pt) | 2021-08-17 |
EP3888652A4 (en) | 2022-10-19 |
KR20210092301A (ko) | 2021-07-23 |
JP2022017461A (ja) | 2022-01-25 |
JP6972384B2 (ja) | 2021-11-24 |
KR20220019848A (ko) | 2022-02-17 |
US11230545B2 (en) | 2022-01-25 |
AU2019390863A2 (en) | 2021-07-01 |
IL303962A (en) | 2023-08-01 |
CA3120774A1 (en) | 2020-06-04 |
IL283368A (en) | 2021-07-29 |
ZA202104402B (en) | 2023-01-25 |
WO2020111087A9 (ja) | 2021-01-21 |
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