CN117430570A - 罗丹宁乙酸类化合物及其药物组合物和用途 - Google Patents
罗丹宁乙酸类化合物及其药物组合物和用途 Download PDFInfo
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- CN117430570A CN117430570A CN202210831602.6A CN202210831602A CN117430570A CN 117430570 A CN117430570 A CN 117430570A CN 202210831602 A CN202210831602 A CN 202210831602A CN 117430570 A CN117430570 A CN 117430570A
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- -1 Rhodamine acetic acid compound Chemical class 0.000 title claims abstract description 155
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 157
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 9
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- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 claims abstract description 4
- 229940126731 protein tyrosine phosphatase inhibitor Drugs 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 129
- 238000000034 method Methods 0.000 claims description 76
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical compound OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
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- GUJYFCBXDUPORN-UHFFFAOYSA-N [4-fluoro-3-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(F)C(C(F)(F)F)=C1 GUJYFCBXDUPORN-UHFFFAOYSA-N 0.000 description 9
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- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical group OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 8
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
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- 125000000753 cycloalkyl group Chemical group 0.000 description 5
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- LTIXGHREVBIYDW-UHFFFAOYSA-N 3-[4-fluoro-3-(trifluoromethyl)phenyl]benzaldehyde Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1C1=CC=CC(C=O)=C1 LTIXGHREVBIYDW-UHFFFAOYSA-N 0.000 description 4
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
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- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 3
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- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 3
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 3
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- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 3
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明属于医药技术领域,公开了罗丹宁乙酸类化合物、其在制备结核分枝杆菌蛋白酪氨酸磷酸酶抑制剂中的应用,以及在治疗和/或预防结核分枝杆菌引起的感染性疾病药物中的应用。具体地说,本发明涉及式(I)所示化合物或其药学可接受的盐以及包含本发明化合物的药物组合物,其中A、R1、R2、R3如说明书所述。
Description
技术领域
本发明属于医药技术领域。特别涉及通式(I)所示的罗丹宁乙酸类化合物,以该化合物为活性成分的药物组合物,它们在制备结核分枝杆菌蛋白酪氨酸磷酸酶抑制剂中的应用,以及它们在治疗和/或预防由结核分枝杆菌引起的感染性疾病中的应用。
背景技术
结核病(TB)是由结核分枝杆菌引起的传染性致死疾病。世界卫生组织报告(GLOBAL TUBERCULOSIS REPORT 2020)显示:2019年全球预计有新发结核病患者1000万,死亡患者140万,是目前致死率排名前十的疾病之一,其致死率高于艾滋病。在2019年的结核病患者中,约50万为一线药利福平耐药(RR-TB),这其中78%为多药耐药结核(MDR-TB)。因此,研发具有新结构和新机制,对MDR-TB有效的抗结核药物具有十分重要的意义。
结核分枝杆菌侵染人体后,被肺部巨噬细胞中的吞噬体吞噬,人体初始免疫反应启动,免疫反应细胞将受感染的巨噬细胞隔离,形成肉芽肿,肉芽肿含有大量血管以及免疫细胞,这提高了药物到达感染部位和宿主免疫系统抵抗结核分枝杆菌的能力。然而结核分枝杆菌会分泌蛋白酪氨酸磷酸酶B(MptpB)进入巨噬细胞,MptpB使宿主信号转导过程中的蛋白去磷酸化,调控宿主与病原体相互作用,阻止了巨噬细胞免疫系统的启动,结核分枝杆菌依靠这些方式逃避免疫系统的杀灭,因此抑制MptpB可恢复宿主正常免疫能力,从而来杀灭结核分枝杆菌。MptpB抑制剂不需要进入结核分枝杆菌内部即可发挥抗结核作用,具有克服耐药、缩短治疗周期等优点,这为耐药结核的治疗,特别是对免疫功能低下或障碍的结核病患者(如HIV感染者、器官移植患者),提供了新的治疗策略。
发明内容
本发明要解决的技术问题是提供一种结构新颖、MptpB抑制活性强的罗丹宁乙酸类化合物。
为此,本发明第一方面提供通式(I)所示的化合物或其药学上可接受的盐,
其中,
A环为苯环、萘环、含有一个选自N、S中的杂原子的5-6元芳杂环;
R1选自C1-C4烷基、MeSC1-C4烷基、C3-C6环烷基、苄基、苯基;
R2选自H、F、Cl、Br;
R3选自-OCH2R4、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的其中X和Y各自独立地选自C、N、O或S;
所述R3中的取代基独立地选自:F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基;
R4选自卤素取代C1-C3烷基、C3-C6环烷基、苯基、5-6元杂芳基,其中的苯基和杂芳基独立和任意地被F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基取代。
在一些方面,式(I)化合物选自式(II):
其中,
A环为苯环、萘环、含有一个选自N、O、S中的杂原子的5-6元芳杂环;
R1选自C1-C4烷基、MeSC1-C4烷基、C3-C6环烷基、苄基、苯基;
R2选自H、F、Cl、Br;
R3选自-OCH2R4、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的其中X和Y各自独立地选自C、N、O或S;
所述R3中的取代基独立地选自:F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基;
R4选自卤素取代C1-C3烷基、C3-C6环烷基、苯基、5-6元杂芳基,其中的苯基和杂芳基独立和任意地被F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基取代。
在一些方面,式(II)化合物选自式(III):
其中,A环为苯环、萘环;
R1为
R2为H、F、Cl、Br;
R4为
在一些方面,式(II)化合物或其药学上可接受的盐,
其中,A环为苯环、萘环、噻吩环、吡啶环;
R1为
R2为H、F、Cl、Br;
R3为
在一些方面,式(I)化合物选自式(IV):
其中,
A环为苯环、萘环、含有一个选自N、O、S中的杂原子的5-6元芳杂环;
R1选自C1-C4烷基、MeSC1-C4烷基、C3-C6环烷基、苄基、苯基;
R2选自H、F、Cl、Br;
R3选自-OCH2R4、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的其中X和Y各自独立地选自C、N、O或S;
所述R3中的取代基独立地选自:F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基;
R4选自卤素取代C1-C3烷基、C3-C6环烷基、苯基、5-6元杂芳基,其中的苯基和杂芳基独立和任意地被F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基取代。
在一些方面,式(I)化合物选自式(V):
其中,A环为苯环、萘环;
R1为
R2为H、F、Cl、Br;
R4为
在一些方面,式(IV)化合物或其药学上可接受的盐,
其中,A环为苯环、萘环、噻吩环、吡啶环;
R1为
R2为H、F、Cl、Br;
R3为
根据本发明第一方面任一项化合物,其为选自下列的化合物:
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本发明第二方面提供了一种药用组合物,其包括治疗和/或预防有效量的第一方面任一项所述的化合物或其药学上可接受的盐以及任选的一种或多种药学上可接受的辅料。
本发明第三方面提供了本发明第一方面任一项所述化合物及其药学可接受的盐,或者本发明第三方面任一项所述药物组合物在制备结核分枝杆菌蛋白酪氨酸磷酸酶抑制剂中的应用。
本发明第四方面提供了本发明第一方面任一项所述化合物及其药学可接受的盐,或者本发明第三方面任一项所述药物组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。
发明详述
下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。
术语“取代的”是指所给结构中特定原子上的任意一个或多个氢原子被具体取代基所取代,只要特定原子的价态是正常的并且取代后所得化合物是稳定的。除非其他方面表明,一个任选的取代基团可以在基团各个可取代的位置进行取代。当给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
各种含烃部分的碳原子含量通过指明了该部分中最小和最大碳原子数的前缀表示。Ci-Cj表示具有整数“i”(包含i)至整数“j”(包含j)个碳原子的部分。因此,例如C1-C4烷基指具有1至4个(包含1和4)碳原子的烷基,特别指甲基、乙基、C3烷基和C4烷基。
如本文所述的,术语“烷基”是指具有指定数目碳原子数的烷基,其为直链或支链的烷基,并且其可包括其子基团,例如提及“C1-C4烷基”时,其还可以包括C1-C3烷基、C1-C2烷基、C2-C4烷基、C3-C4烷基等表示的子范围的基团,以及具体基团例如甲基、乙基、正丙基、异丙基。术语“烷氧基”和“烷胺基”属于惯用表达,是指分别通过一个氧原子或胺基连接到分子的其余部分的烷基基团,其中的烷基如本发明所述。烷氧基基团包括,但并不限于,甲氧基、乙氧基、异丙氧基、正丙氧基、等等。烷胺基基团包括,但并不限于,甲胺基、乙胺基、异丙胺基、正丙胺基、等。
术语“卤素取代烷基”表示烷基基团被一个或多个卤素原子所取代,包含,但并不限于,三氟甲基、二氟甲基等。
如本文所述的,术语“卤”、“卤素”等表示氟(F)、氯(Cl)、溴(Br)或碘(I)。
如本文所述的,术语“环烷基”是指具有指定数目环碳原子数的环状烷基,并且其可包括其子基团,例如提及“3-6元环烷基”时,其还可以包括3-5元环烷基、4-6元环烷基等表示的子范围的基团,以及具体基团例如环丙基、环丁基、环戊基、环己基。
如本文所述的,术语“杂芳基”在本文中指具有1至3个杂原子作为环原子,其余的环原子为碳的芳香基团,其中杂原子包括氧、硫和氮。例如“5-6元杂芳基”包括5元杂芳基和6元杂芳基。其中5元杂芳基包括,但并不限于咪唑基、呋喃基、噻吩基、三氮唑基、四氮唑基、吡唑基(如2-吡唑基)、噻唑基、噁唑基、异恶唑基。6元杂芳基包括吡啶基、哒嗪基、嘧啶基、吡嗪基、1,3,5-三嗪基。在实施方案中,所述的杂芳基为噻吩基、呋喃基、吡啶基。
如本文所述的,术语“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。环上原子的数目通常被定义为环的元数,例如“3-6元环”是指环绕排列3-6个原子。
如本文所述的,术语“有效量”是指可在受试者中实现所期望的治疗本发明所述疾病或病症的药物用量。
如本文所述的,术语“药学可接受的”例如在描述“药学可接受的盐”时,表示该盐不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质,例如在为进行手性拆分时所形成的作为中间体的盐,虽然这种中间体的盐并不能直接给予受试者,但该盐可在为获得本发明终产物中起作用。
如本文所述的,术语“药物组合物”,其还可以是指“组合物”,其可用于在受试者特别是哺乳动物中实现治疗本发明所述疾病或病症。
疾病的“治疗”包括:
(1)预防该疾病,即,使暴露至或易感染该疾病但未经历或显示该疾病症状的哺乳动物不发生该疾病的临床症状,
(2)抑制该疾病,即,阻止或减少该疾病或其临床症状的进展,
(3)减轻该疾病,即,引起该疾病或其临床症状的复原。
如本文所述的,术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。例如,本发明所述疾病和/或病症指结核分枝杆菌感染性疾病。
本发明再一方面还涉及以本发明中的化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。
本发明中的化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
具体实施方式
通过下面的实施例可以对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。
对于以下全部实施例,可使用本领域技术人员已知的标准操作和纯化方法。除非另有说明,所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振氢谱(1H NMR)来确定的。核磁共振氢谱位移(δ)以百万分之一(ppm)的单位给出。耦合常数(J)以赫兹(Hz)为单位。核磁共振谱用Mercury-400或Brucker-500型核磁共振仪测定,氘代氯仿或氘代二甲基亚砜作溶剂,四甲基硅烷(TMS)为内标。
制备例1
(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸的制备
合成路线:
实验步骤:
于100mL反应瓶中加入(S)-2-氨基-2-苯乙酸(1.81g,12mmol)、二硫化碳(0.92g,12mmol)、氢氧化钾(1.37g,24mmol),注入水(50mL),室温反应过夜后,加入氯乙酸钠(1.40g,12mmol),反应4小时。用盐酸调pH至2-3,105℃加热2小时。冷却,乙酸乙酯萃取,有机层用饱和食盐水洗,用无水硫酸钠干燥,过滤,浓缩,硅胶(200-300目)柱色谱分离,含0.5%甲酸的二氯甲烷混合液为洗脱剂。得化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸,略带黄色的透明油状物1.87g,收率58.3%。
1H NMR(400MHz,CDCl3)δ:7.63–7.56(m,2H),7.37–7.34(m,3H),6.91(s,1H),3.99(d,J=18.4Hz,1H),3.89(d,J=18.0Hz,1H).
制备例2
(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸的制备
实验步骤:
将制备例1中的(S)-2-氨基-2-苯乙酸替换为(R)-2-氨基-2-苯乙酸进行反应,得化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸,略带黄色的透明油状物1.69g,收率51.6%。
1H NMR(400MHz,CDCl3)δ:9.18(s,1H),7.63–7.56(m,2H),7.38–7.33(m,3H),6.91(s,1H),3.98(d,J=18.4Hz,1H),3.89(d,J=18.0Hz,1H).
制备例3
(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸的制备
实验步骤:
将制备例1中的(S)-2-氨基-2-苯乙酸替换为(S)-2-氨基己酸(3.15g,24mmol)进行反应,得化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸,略带黄色的透明油状物3.69g,收率62.2%。
1H NMR(400MHz,CDCl3)δ:9.81(s,1H),5.61(t,J=7.6Hz,1H),3.99(s,2H),2.23–2.16(m,2H),1.39–1.14(m,4H),0.88(t,J=7.0Hz,3H).
制备例4
(R)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸的制备
实验步骤:
将制备例1中(S)-2-氨基-2-苯乙酸替换为(R)-2-氨基己酸(1.57g,12mmol)进行反应,得化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸,略带黄色的透明油状物1.82g,收率61.4%。
1H NMR(400MHz,CDCl3)δ:9.54(s,1H),5.61(t,J=7.6Hz,1H),3.99(s,2H),2.25–2.18(m,2H),1.38–1.15(m,4H),0.88(t,J=7.0Hz,3H).
制备例5
(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸的制备
实验步骤:
将制备例1中的(S)-2-氨基-2-苯乙酸替换为(S)-2-氨基-2-环己基乙酸(1.89g,12mmol)进行反应,可得化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸,略带黄色的透明油状物1.90g,收率57.8%。
1H NMR(400MHz,CDCl3)δ:10.48(s,1H),5.31(d,J=8.8Hz,1H),4.00(s,2H),2.51–2.31(m,2H),1.77–1.63(m,3H),1.34–1.08(m,5H),0.97–0.85(m,1H).
制备例6
(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸的制备
实验步骤:
将制备例1中的(S)-2-氨基-2-苯乙酸替换为(R)-2-氨基-2-环己基乙酸(2.83g,18mmol)进行反应,得化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸,略带黄色的透明油状物3.16g,收率64.2%。
1H NMR(400MHz,CDCl3)δ:8.34(s,1H),5.31(d,J=8.0Hz,1H),4.00(s,2H),2.55–2.26(m,2H),1.79–1.62(m,3H),1.35–1.08(m,5H),0.99–0.87(m,1H).
制备例7
(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环戊基乙酸的制备
实验步骤:
将制备例1中的(S)-2-氨基-2-苯乙酸替换为(S)-2-氨基-2-环戊基乙酸(2.15g,15mmol)进行反应,得化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环戊基乙酸,略带黄色的透明油状物2.35g,收率60.3%。
1H NMR(400MHz,CDCl3)δ:9.64(s,1H),5.41(s,1H),3.98(s,2H),3.17–2.85(m,1H),2.23–2.20(m,1H),1.78–1.39(m,6H),1.15–1.06(m,1H).
制备例8
(S)-2-(4-氧代-2-硫代噻唑啉-3-基)戊酸的制备
实验步骤:
将制备例1中的(S)-2-氨基-2-苯乙酸替换为(S)-2-氨基戊酸(1.76g,15mmol)进行反应,得化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)戊酸,略带黄色的透明油状物2.31g,收率65.9%。
1H NMR(400MHz,CDCl3)δ:9.79(s,1H),5.64(t,J=7.6Hz,1H),3.99(s,2H),2.25–2.15(m,2H),1.41–1.23(m,2H),0.94(t,J=7.2Hz,3H).
实施例1
(S,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(化合物1)的制备
合成路线:
实验步骤:
于12mL玻璃封管中加入(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(80mg,0.3mmol)、5-溴-2-((4-氯苄基)氧基)苯甲醛(98mg,0.3mmol),注入甲苯(6mL),加入N-甲基哌嗪(1滴),微波110W,125-140℃,反应40分钟。冷却,浓缩,硅胶(200-300目)柱色谱分离,石油醚-含0.5%甲酸的二氯甲烷(V:V=100:50-70)混合液为洗脱剂。得化合物1,黄色固体158mg,收率92.1%。
1H NMR(400MHz,DMSO-d6)δ:13.60(s,1H),7.87(s,1H),7.67(dd,J=8.8Hz,J=2.4Hz,1H),7.60(d,J=2.4Hz,1H),7.52–7.44(m,6H),7.39–7.31(m,3H),7.20(d,J=8.8Hz,1H),6.80(s,1H),5.30(s,2H).
实施例2
(R,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(化合物2)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(99mg,0.4mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(130mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物2,黄色固体209mg,收率96.6%。
1H NMR(400MHz,DMSO-d6)δ:13.65(s,1H),7.87(s,1H),7.64(dd,J=8.8Hz,J=2.4Hz,1H),7.58–7.43(m,7H),7.40–7.31(m,3H),7.16(d,J=8.8Hz,1H),6.81(s,1H),5.28(s,2H).
实施例3
(S,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-3-苯基丙酸(化合物3)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-3-苯丙酸(85mg,0.3mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(98mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物3,黄色固体145mg,收率81.9%。
1H NMR(400MHz,DMSO-d6)δ:13.47(s,1H),7.82(s,1H),7.67(dd,J=8.8Hz,J=2.4Hz,1H),7.53(d,J=2.4Hz,1H),7.51–7.44(m,4H),7.22–7.12(m,6H),5.85(s,1H),5.29(s,2H),3.54–3.44(m,2H).
实施例4
(R,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-3-苯基丙酸化合物4的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-3-苯丙酸(88mg,0.31mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(102mg,0.31mmol)为原料,采用实施例1中相似操作步骤,得到化合物4,黄色固体128mg,收率69.6%。
1H NMR(400MHz,DMSO-d6)δ:13.48(s,1H),7.82(s,1H),7.67(dd,J=8.8Hz,J=2.4Hz,1H),7.53(s,1H),7.50–7.45(m,4H),7.22–7.11(m,6H),5.85(s,1H),5.30(s,2H),3.55–3.44(m,2H).
实施例5
(S,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(化合物5)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(82mg,0.3mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(99mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物5,黄色固体126mg,收率84.6%。
1H NMR(400MHz,DMSO-d6)δ:13.24(s,1H),7.87(s,1H),7.68(dd,J=8.8Hz,J=2.4Hz,1H),7.61(d,J=2.4Hz,1H),7.54–7.43(m,4H),7.21(d,J=8.8Hz,1H),5.30(s,2H),5.20(s,1H),2.43–2.28(m,2H),1.72–1.56(m,3H),1.29–1.03(m,5H),0.89–0.80(m,1H).
实施例6
(S,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-4-甲基戊酸(化合物6)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-4-甲基戊酸(96mg,0.39mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(105mg,0.39mmol)为原料,采用实施例1中相似操作步骤,得到化合物6,黄色固体150mg,收率69.4%。
1H NMR(400MHz,DMSO-d6)δ:13.34(s,1H),7.86(s,1H),7.68(dd,J=8.8Hz,J=2.4Hz,1H),7.59(d,J=2.4Hz,1H),7.53–7.43(m,4H),7.21(d,J=8.8Hz,1H),5.57(s,1H),5.31(s,2H),2.19–2.12(m,1H),2.04–1.96(m,1H),1.53–1.42(m,1H),0.91(d,J=6.4Hz,3H),0.86(d,J=6.4Hz,3H).
实施例7
(S,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-4-(甲硫基)丁酸(化合物7)的制备
合成路线:
实验步骤:
以化合物(S)-4-(甲硫基)-2-(4-氧代-2-硫代噻唑啉-3-基)丁酸(80mg,0.3mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(98mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物7,黄色固体120mg,收率69.8%。
1H NMR(400MHz,CDCl3)δ:8.02(s,1H),7.51(d,J=2.4Hz,1H),7.45(dd,J=8.8Hz,J=2.4Hz,1H),7.39–7.31(m,4H),6.82(d,J=8.8Hz,1H),5.97(s,1H),5.14(s,2H),2.68–2.47(m,4H),2.09(s,3H).
实施例8
(S,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物8)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(74mg,0.3mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(98mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物8,黄色固体140mg,收率84.3%。
1H NMR(400MHz,DMSO-d6)δ:13.28(s,1H),7.86(s,1H),7.68(dd,J=8.8Hz,J=2.4Hz,1H),7.59(d,J=2.4Hz,1H),7.51–7.45(m,4H),7.21(d,J=8.8Hz,1H),5.53(t,J=7.6Hz,1H),5.31(s,2H),2.19–2.13(m,2H),1.31–1.13(m,4H),0.82(t,J=7.0Hz,3H).
实施例9
(R,Z)-2-(5-(5-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物9)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(74mg,0.3mmol)和5-溴-2-((4-氯苄基)氧基)苯甲醛(98mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物9,黄色固体111mg,收率66.9%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.85(s,1H),7.68(dd,J=8.8Hz,J=2.4Hz,1H),7.60(d,J=2.4Hz,1H),7.52–7.46(m,4H),7.21(d,J=8.8Hz,1H),5.53(t,J=7.6Hz,1H),5.31(s,2H),2.19–2.12(m,2H),1.30–1.15(m,4H),0.82(t,J=7.0Hz,3H).
实施例10
(S,Z)-2-(5-(2-溴-6-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物10)的制备
合成路线:
实验步骤:
第一步2-溴-6-((4-氯苄基)氧基)苯甲醛的制备
于100mL反应瓶中加入2-溴-6-羟基苯甲醛(603mg,3mmol)、4-氯苄氯(580mg,3.6mmol)、碳酸钾(830mg,6mmol),并用氩气保护,注入N,N-二甲基甲酰胺(15mL),120-125℃加热4小时。冷却,加入水(100mL),可析出固体,过滤,水洗,干燥得类白色固体902mg,收率92.3%。
1H NMR(400MHz,DMSO-d6)δ:10.33(s,1H),7.56–7.44(m,5H),7.32(t,J=7.2Hz,2H),5.27(s,2H).
第二步(S,Z)-2-(5-(2-溴-6-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和2-溴-6-((4-氯苄基)氧基)苯甲醛(132mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物10,黄色固体172mg,收率77.5%。
1H NMR(400MHz,DMSO-d6)δ:13.27(s,1H),7.80(s,1H),7.44–7.38(m,6H),7.25(dd,J=6.4Hz,J=2.8Hz,1H),5.52(s,1H),5.34(s,2H),2.24–2.05(m,2H),1.31–1.09(m,4H),0.83(t,J=7.0Hz,3H).
实施例11
(S,Z)-2-(5-(4-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物11)的制备
合成路线:
实验步骤:
第一步4-溴-2-((4-氯苄基)氧基)苯甲醛的制备
将实施例10第一步中的化合物2-溴-6-羟基苯甲醛替换为4-溴-2-羟基苯甲醛进行反应,得化合物4-溴-2-((4-氯苄基)氧基)苯甲醛,白色固体897mg,收率91.8%。
1H NMR(400MHz,DMSO-d6)δ:9.98(s,2H),7.89(d,J=6.0Hz,1H),7.65(d,J=2.0Hz,1H),7.57-7.45(m,5H),5.33(s,2H).
第二步(S,Z)-2-(5-(4-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和4-溴-2-((4-氯苄基)氧基)苯甲醛(130mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物11,黄色固体182mg,收率81.9%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),7.79(s,1H),7.53–7.46(m,4H),7.45–7.43(m,2H),7.22–7.21(m,1H),5.54(t,J=7.6Hz,1H),5.23(s,2H),2.21–2.14(m,2H),1.35–1.14(m,4H),0.83(t,J=7.0Hz,3H).
实施例12
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(S,Z)-2-(5-(3-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物12)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和3-溴-2-((4-氯苄基)氧基)苯甲醛(130mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物12,黄色固体173mg,收率78.4%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),7.87(d,J=8.0Hz,1H),7.71(s,1H),7.52(d,J=8.0Hz,1H),7.44–7.39(m,4H),7.31(t,J=8.0Hz,1H),5.53(s,1H),5.02(s,2H),2.21–2.13(m,2H),1.35–1.16(m,4H),0.85(t,J=7.0Hz,3H).
实施例13
(S,Z)-2-(5-((2-((4-氯苄基)氧基)萘-1-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物13)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和2-((4-氯苄基)氧基)-1-萘甲醛(120mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物13,黄色固体189mg,收率90.0%。
1H NMR(400MHz,DMSO-d6)δ:13.27(s,1H),8.26(s,1H),8.13(d,J=9.2Hz,1H),7.97(d,J=9.6Hz,1H),7.87(d,J=8.0Hz,1H),7.67–7.57(m,2H),7.51–7.39(m,5H),5.58(s,1H)5.46(s,2H),2.27–2.14(m,2H),1.33–1.17(m,4H),0.85(t,J=7.0Hz,3H).
实施例14
(S,Z)-2-(5-(3-溴-4-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物14)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和3-溴-4-((4-氯苄基)氧基)苯甲醛(130mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物14,黄色固体140mg,收率63.1%。
1H NMR(400MHz,DMSO-d6)δ:13.28(s,1H),7.98(d,J=2.4Hz,1H),7.81(s,1H),7.64(dd,J=8.8Hz,J=2.4Hz,1H),7.54-7.48(m,4H),7.39(d,J=8.8Hz,1H),5.55(t,J=7.6Hz,1H),5.33(s,2H),2.22–2.13(m,2H),1.33–1.14(m,4H),0.83(t,J=7.0Hz,3H).
实施例15
(S,Z)-2-(5-(3-溴-5-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物15)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和3-溴-5-((4-氯苄基)氧基)苯甲醛(131mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物15,黄色固体167mg,收率75.2%。
1H NMR(400MHz,DMSO-d6)δ:13.29(s,1H),7.88(s,1H),7.53–7.472(m,5H),7.42(d,J=8.4Hz,1H),7.35(dd,J=8.4Hz,J=2.0Hz,1H),5.53(t,J=7.6Hz,1H),5.32(s,2H),2.50–2.12(m,2H),1.32–1.11(m,4H),0.82(t,J=7.0Hz,3H).实施例16
(S,Z)-2-(5-(2-(苄氧基)-5-溴亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物16)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和2-(苄氧基)-5-溴苯甲醛(116mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物16,黄色固体156mg,收率75.0%。
1H NMR(400MHz,DMSO-d6)δ:13.25(s,1H),7.87(s,1H),7.68(dd,J=8.8,2.4Hz,1H),7.59(d,J=2.4Hz,1H),7.49–7.33(m,5H),7.23(d,J=8.8Hz,1H),5.53(t,J=7.6Hz,1H),5.31(s,2H),2.19–2.13(m,2H),1.32–1.13(m,4H),0.82(t,J=7.0Hz,3H).
实施例17
(S,Z)-2-(5-(5-溴-2-((3-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物17)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(74mg,0.3mmol)和5-溴-2-((3-氯苄基)氧基)苯甲醛(99mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物17,黄色固体112mg,收率67.5%。
1H NMR(400MHz,DMSO-d6)δ:7.87(s,1H),7.69(dd,J=8.8Hz,J=2.4Hz,1H),7.60(d,J=2.4Hz,1H),7.55(s,1H),7.47–7.39(m,3H),7.21(d,J=8.8Hz,1H),5.52(t,J=7.6Hz,1H),5.32(s,2H),2.19–2.13(m,2H),1.33–1.13(m,4H),0.82(t,J=7.0Hz,3H).
实施例18
(S,Z)-2-(5-(5-溴-2-((2-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物18)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和5-溴-2-((2-氯苄基)氧基)苯甲醛(130mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物18,黄色固体158mg,收率71.2%。
1H NMR(400MHz,DMSO-d6)δ:13.26(s,1H),7.85(s,1H),7.71(dd,J=8.8Hz,J=2.4Hz,1H),7.64–7.51(m,3H),7.47–7.35(m,2H),7.29(d,J=8.8Hz,1H),5.52(t,J=7.6Hz,1H),5.35(s,2H),2.18–2.12(m,2H),1.33–1.08(m,4H),0.82(t,J=7.0Hz,3H).
实施例19
(S,Z)-2-(5-(5-溴-2-((4-(三氟甲基)苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物19)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和5-溴-2-((4-(三氟甲基)苄基)氧基)苯甲醛(144mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物19,黄色固体164mg,收率69.8%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.89(s,1H),7.79(d,J=8.0Hz,2H),7.71–7.66(m,3H),7.61(d,J=2.4Hz,1H),7.20(d,J=8.8Hz,1H),5.53(t,J=7.6Hz,1H),5.43(s,2H),2.19–2.13(m,2H),1.33–1.12(m,4H),0.82(t,J=7.0Hz,3H).
实施例20
(S,Z)-2-(5-(5-溴-2-((4-(三氟甲氧基)苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物20)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和5-溴-2-((4-(三氟甲氧基)苄基)氧基)苯甲醛(150mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物20,黄色固体183mg,收率86.7%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.87(s,1H),7.69(dd,J=8.8Hz,J=2.4Hz,1H),7.62–7.59(m,3H),7.41(d,J=8.4Hz,2H),7.23(d,J=8.8Hz,1H),5.53(t,J=7.6Hz,1H),5.34(s,2H),2.19–2.13(m,2H),1.33–1.11(m,4H),0.82(t,J=7.0Hz,3H).
实施例21
(S,Z)-2-(5-(5-溴-2-((4-甲氧基苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物21)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和5-溴-2-((4-甲氧基苄基)氧基)苯甲醛(128mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物21,黄色固体154mg,收率70.0%。
1H NMR(400MHz,DMSO-d6)δ:13.26(s,1H),7.82(s,1H),7.68(dd,J=8.8,2.4Hz,1H),7.57(d,J=2.4Hz,1H),7.43–7.38(m,2H),7.25(d,J=8.8Hz,1H),6.99–6.93(m,2H),5.53(t,J=7.6Hz,1H),5.21(s,2H),3.76(s,3H),2.18–2.12(m,2H),1.32–1.12(m,4H),0.82(t,J=7.0Hz,3H).
实施例22
(S,Z)-2-(5-(5-溴-2-(环己基甲氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物22)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(99mg,0.4mmol)和5-溴-2-(环己基甲氧基)苯甲醛(119mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物22,黄色固体169mg,收率80.1%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.88(s,1H),7.67(dd,J=8.8,2.4Hz,1H),7.54(d,J=2.4Hz,1H),7.17(d,J=8.8Hz,1H),5.55(t,J=7.6Hz,1H),3.95(d,J=6.0Hz,2H),2.20–2.14(m,2H),1.84–1.63(m,6H),1.30–1.03(m,9H),0.83(t,J=7.0Hz,3H).
实施例23
(S,Z)-2-(5-(5-溴-2-(环丙基甲氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物23)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和5-溴-2-(环丙基甲氧基)苯甲醛(102mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物23,黄色固体122mg,收率62.9%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.87(s,1H),7.66(dd,J=8.8Hz,J=2.4Hz,1H),7.59(d,J=2.4Hz,1H),7.14(d,J=8.8Hz,1H),5.55(d,J=7.6Hz,1H),4.01(d,J=7.2Hz,2H),2.21–2.14(m,2H),1.34–1.15(m,4H),0.83(t,J=7.0Hz,3H),0.65–0.58(m,2H),0.42–0.35(m,2H).
实施例24
(S,Z)-2-(5-(5-溴-2-(2-溴乙氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物24)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和5-溴-2-(2-溴乙氧基)苯甲醛(123mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物24,黄色固体178mg,收率82.8%。
1H NMR(500MHz,DMSO-d6)δ:13.29(s,1H),7.93(d,J=13.0Hz,1H),7.69(dd,J=9.0Hz,J=2.5Hz,1H),7.57(d,J=2.5Hz,1H),7.21(d,J=9.0Hz,1H),5.55(s,1H),4.51–4.42(m,2H),4.03–3.86(m,2H),2.19–2.16(m,2H),1.33–1.15(m,4H),0.83(t,J=7.0Hz,3H).
实施例25
(S,Z)-2-(5-(5-溴-2-((2-溴噻吩-3-基)甲氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物25)的制备
合成路线:
实验步骤:
第一步5-溴-2-((2-溴噻吩-3-基)甲氧基)苯甲醛的制备
于50mL反应瓶中加入5-溴-2-羟基苯甲醛(603mg,3mmol)、2-溴-3-(溴甲基)噻吩(921mg,3.6mmol)、碳酸钾(830mg,6mmol),并用氩气保护,注入N,N-二甲基甲酰胺(15mL),120-125℃加热4小时。冷却,加入水(100mL),可少量析出固体,乙酸乙酯萃取,有机层用饱和食盐水洗,用无水硫酸钠干燥,过滤,浓缩,硅胶(200-300目)柱色谱分离,石油醚-乙酸乙酯(V:V=100:4)混合液为洗脱剂,得化合物5-溴-2-((2-溴噻吩-3-基)甲氧基)苯甲醛,白色固体995mg,收率88.2%。
1H NMR(400MHz,DMSO-d6)δ:10.27(s,1H),7.84(dd,J=8.8Hz,J=2.4Hz,1H),7.76(d,J=2.4Hz,1H),7.65(d,J=5.6Hz,1H),7.36(d,J=8.8Hz,1H),7.23(d,J=5.6Hz,1H),5.20(s,2H).
第二步(S,Z)-2-(5-(5-溴-2-((2-溴噻吩-3-基)甲氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和5-溴-2-((2-溴噻吩-3-基)甲氧基)苯甲醛(151mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物25,黄色固体257mg,收率84.8%。
1H NMR(400MHz,DMSO-d6)δ:13.28(s,1H),7.81(s,1H),7.71(dd,J=8.8Hz,J=2.4Hz,1H),7.65(d,J=6.0Hz,1H),7.60(d,J=2.4Hz,1H),7.30(d,J=8.8Hz,1H),7.15(d,J=6.0Hz,1H),5.52(t,J=7.6Hz,1H),5.18(s,2H),2.19–2.10(m,2H),1.34–1.10(m,4H),0.82(t,J=7.0Hz,3H).
实施例26
(S,Z)-2-(5-(5-溴-2-((2-氯吡啶-4-基)甲氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物26)的制备
合成路线:
实验步骤:
第一步5-溴-2-((2-氯吡啶-4-基)甲氧基)苯甲醛的制备
于50mL反应瓶中加入5-溴-2-羟基苯甲醛(603mg,3mmol)、2-氯-4-(氯甲基)吡啶(583mg,3.6mmol)、碳酸钾(830mg,6mmol),并用氩气保护,注入N,N-二甲基甲酰胺(15mL),120-125℃加热4小时。冷却,加入水(100mL),乙酸乙酯萃取。有机层用饱和食盐水洗,用无水硫酸钠干燥,过滤,浓缩,硅胶(200-300目)柱色谱分离,石油醚-乙酸乙酯(V:V=100:25)混合液为洗脱剂,得化合物5-溴-2-((2-氯吡啶-4-基)甲氧基)苯甲醛,白色固体320mg,收率32.7%。
第二步(S,Z)-2-(5-(5-溴-2-((2-氯吡啶-4-基)甲氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和5-溴-2-((2-氯吡啶-4-基)甲氧基)苯甲醛(130mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物26,黄色固体87mg,收率39.5%。
1H NMR(400MHz,DMSO-d6)δ:13.28(s,1H),8.44(d,J=5.2Hz,1H),7.93(s,1H),7.69(dd,J=8.8Hz,J=2.4Hz,1H),7.63(d,J=2.4Hz,1H),7.58(s,1H),7.45(dd,J=5.2Hz,J=1.6Hz,1H),7.14(d,J=8.8Hz,1H),5.55(t,J=7.6Hz,1H),5.41(s,2H),2.20–2.14(m,2H),1.34–1.13(m,4H),0.83(t,J=7.0Hz,3H).
实施例27
(S,Z)-2-(5-(3-溴-5-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(化合物27)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(160mg,0.8mmol)和3-溴-5-((4-氯苄基)氧基)苯甲醛(195mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物27,黄色固体424mg,收率92.2%。
1H NMR(400MHz,DMSO-d6)δ:13.65(s,1H),7.82(s,1H),7.52–7.45(m,6H),7.44–7.42(m,2H),7.39–7.33(m,3H),7.20(s,1H),6.81(s,1H),5.21(s,2H).
实施例28
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(S,Z)-2-(5-(3-溴-4-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-)-2-苯乙酸(化合物28)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(160mg,0.8mmol)和3-溴-4-((4-氯苄基)氧基)苯甲醛(195mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物28,黄色固体398mg,收率86.5%。
1H NMR(400MHz,DMSO-d6)δ:13.62(s,1H),7.97(d,J=2.0Hz,1H),7.84(s,1H),7.64(dd,J=8.8Hz,J=2.0Hz,1H),7.55–7.46(m,6H),7.41–7.34(m,4H),6.80(s,1H),5.33(s,2H).
实施例29
(S,Z)-2-(5-(4-溴-2-((4-氯苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-)-2-苯乙酸(化合物29)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(160mg,0.8mmol)和4-溴-2-((4-氯苄基)氧基)苯甲醛(195mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物29,黄色固体408mg,收率88.7%。
1H NMR(400MHz,DMSO-d6)δ:13.59(s,1H),7.90(s,1H),7.52–7.47(m,7H),7.42(d,J=8.4Hz,1H),7.38–7.31(m,4H),6.79(s,1H),5.31(s,2H).
实施例30
(S,Z)-2-(5-(5-溴-2-((4-甲氧基苄基)氧基)亚苄基)-4-氧代-2-硫代噻唑啉-3-)-2-苯乙酸(化合物30)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(160mg,0.8mmol)和5-溴-2-((4-甲氧基苄基)氧基)苯甲醛(193mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物30,黄色固体430mg,收率94.3%。
1H NMR(400MHz,DMSO-d6)δ:7.84(s,1H),7.66(dd,J=8.8Hz,J=2.4Hz,1H),7.57(d,J=2.4Hz,1H),7.53–7.46(m,2H),7.43–7.32(m,5H),7.23(d,J=9.2Hz,1H),6.95(d,J=8.8Hz,1H),6.79(s,1H),5.20(s,2H),3.75(s,3H).
实施例31
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物31)的制备
合成路线:
实验步骤:
第一步4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛的制备
于100mL反应瓶中加入4-溴苯甲醛(554mg,3mmol)、(4-氟-3-(三氟甲基)苯基)硼酸(749mg,3.6mmol)、四(三苯基膦)钯(104mg,0.09mmol)、碳酸钠(636mg,6mmol),并用氩气保护,注入1,4-二氧六环(15mL)和水(3mL),105℃加热6小时。冷却,加入水(15mL),用乙酸乙酯(15mL)萃取3次,合并有机层。有机层用饱和食盐水洗,用无水硫酸钠干燥,过滤,浓缩,硅胶(200-300目)柱色谱分离,石油醚-乙酸乙酯(V:V=100:4)混合液为洗脱剂。得化合物4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛,类白色固体702mg,收率87.2%。
1H NMR(400MHz,DMSO-d6)δ:10.08(s,1H),8.19–8.14(m,1H),8.11(dd,J=6.8Hz,J=2.4Hz,1H),8.06–7.96(m,4H),7.68(dd,J=10.4Hz,J=8.6Hz,1H).
第二步(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(74mg,0.3mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(80mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物31,黄色固体110mg,收率73.8%。
1H NMR(400MHz,DMSO-d6)δ:13.28(s,1H),8.18–8.09(m,1H),8.11(dd,J=6.8Hz,J=2.4Hz,1H),7.97(d,J=8.4Hz,2H),7.92(s,1H),7.79(d,J=8.4Hz,2H),7.71–7.63(m,1H),5.57(t,J=7.6Hz,1H),2.24–2.17(m,2H),1.33–1.21(m,4H),0.84(t,J=7.0Hz,3H).
实施例32
(R,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物32)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(74mg,0.3mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(80mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物32,黄色固体128mg,收率85.9%。
1H NMR(400MHz,DMSO-d6)δ:13.29(s,1H),8.19–8.14(m,1H)8.11(dd,J=6.8Hz,J=2.4Hz,1H),7.97(d,J=8.8Hz,2H),7.92(s,1H),7.79(d,J=8.8Hz,2H),7.67(dd,J=10.4Hz,J=8.8Hz,1H),5.57(t,J=7.6Hz,1H),2.24–2.16(m,2H),1.35–1.15(m,4H),0.84(t,J=7.0Hz,3H).
实施例33
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)-3-苯基丙酸(化合物33)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-3-苯丙酸(84mg,0.3mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(79mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物33,黄色固体117mg,收率73.6%。
1H NMR(400MHz,DMSO-d6)δ:13.46(s,1H),8.18–8.12(m,1H),8.09(dd,J=6.8Hz,J=2.4Hz,1H),7.95(d,J=8.4Hz,2H),7.88(s,1H),7.74(d,J=8.4Hz,2H),7.66(dd,J=10.4Hz,J=8.8Hz,1H),7.25–7.13(m,5H),5.90(s,1H),3.56–3.45(m,2H).
实施例34
(R,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)-3-苯基丙酸(化合物34)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-3-苯丙酸(84mg,0.3mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(82mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物34,黄色固体113mg,收率71.1%。
1H NMR(400MHz,DMSO-d6)δ:13.51(s,1H),8.18–8.12(m,1H),8.10(dd,J=6.8Hz,J=2.4Hz,1H),7.95(d,J=8.4Hz,2H),7.88(s,1H),7.74(d,J=8.4Hz,2H),7.66(dd,J=10.4Hz,J=8.8Hz,1H),7.25–7.14(m,5H),5.89(s,1H),3.55–3.44(m,2H).
实施例35
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)2-环己基乙酸(化合物35)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(94mg,0.34mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(92mg,0.34mmol)为原料,采用实施例1中相似操作步骤,得到化合物35,黄色固体173mg,收率96.1%。
1H NMR(400MHz,DMSO-d6)δ:13.28(s,1H),8.18–8.13(m,1H),8.11(dd,J=6.8Hz,J=2.4Hz,1H),7.97(d,J=8.4Hz,2H),7.94(s,1H),7.78(d,J=8.4Hz,2H),7.66(dd,J=10.4Hz,J=8.8Hz,1H),5.24(s,1H),2.47–2.31(m,2H),1.72–1.60(m,3H),1.34–1.03(m,5H),0.93–0.84(m,1H).
实施例36
(R,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)2-环己基乙酸(化合物36)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(91mg,0.33mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(89mg,0.33mmol)为原料,采用实施例1中相似操作步骤,得到化合物36,黄色固体141mg,收率89.8%。
1H NMR(400MHz,DMSO-d6)δ:8.19–8.13(m,1H),8.11(dd,J=6.8Hz,J=2.4Hz,1H),7.97(d,J=8.8Hz,2H),7.94(s,1H),7.79(d,J=8.8Hz,2H),7.67(dd,J=10.4Hz,J=8.8Hz,1H),5.24(s,1H),2.46–2.32(m,2H),1.73–1.56(m,3H),1.32–1.04(m,5H),0.90–0.84(m,1H).
实施例37
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)-4-甲基戊酸(化合物37)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-4-甲基戊酸(94mg,0.38mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(103mg,0.38mmol)为原料,采用实施例1中相似操作步骤,得到化合物37,黄色固体140mg,收率74.1%。
1H NMR(400MHz,DMSO-d6)δ:13.39(s,1H),8.19–8.13(m,1H),8.11(dd,J=6.8Hz,J=2.4Hz,1H),7.97(d,J=8.4Hz,2H),7.92(s,1H),7.78(d,J=8.4Hz,2H),7.66(dd,J=10.4Hz,J=8.8Hz,1H),5.60(s,1H),2.27–2.16(m,1H),2.07–1.99(m,1H),1.54–1.45(m,1H),0.93(d,J=6.8Hz,3H),0.88(d,J=6.8Hz,3H).
实施例38
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(化合物38)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-苯乙酸(81mg,0.3mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(88mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物38,黄色固体134mg,收率86.5%。
1H NMR(400MHz,DMSO-d6)δ:13.62(s,1H),8.18–8.12(m,1H),8.10(dd,J=6.8Hz,J=2.4Hz,1H),8.04–7.88(m,3H),7.78(d,J=8.4Hz,2H),7.66(dd,J=10.4Hz,J=8.8Hz,1H),7.56–7.49(m,2H),7.42–7.33(m,3H),6.83(s,1H).
实施例39
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)-4-甲硫基丁酸(化合物39)的制备
合成路线:
实验步骤:
以化合物(S)-4-(甲硫基)-2-(4-氧代-2-硫代噻唑啉-3-基)丁酸(84mg,0.32mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(86mg,0.32mmol)为原料,采用实施例1中相似操作步骤,得到化合物39,黄色固体136mg,收率83.4%。
1H NMR(400MHz,Acetone-d6)δ:8.17–8.08(m,2H),7.97(d,J=8.8Hz,2H),7.85–7.78(m,3H),7.61–7.53(m,1H),5.96(s,1H),2.70–2.54(m,4H),2.08(s,3H).
实施例40
(S,Z)-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)-3-苯基丙酸(化合物40)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-3-苯丙酸(90mg,0.32mmol)和3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(82mg,0.32mmol)为原料,采用实施例1中相似操作步骤,得到化合物40,黄色固体141mg,收率86.0%。
1H NMR(400MHz,DMSO-d6)δ:13.52(s,1H),8.12–8.06(m,2H),7.97(d,J=8.8Hz,2H),7.88(s,1H),7.82–7.71(m,4H),7.25–7.14(m,5H),5.90(s,1H),3.58–3.49(m,2H).
实施例41
(R,Z)-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)-3-苯基丙酸(化合物41)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-3-苯丙酸(84mg,0.3mmol)和3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(75mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物41,黄色固体103mg,收率66.9%。
1H NMR(400MHz,DMSO-d6)δ:13.52(s,1H),8.12–8.06(m,2H),7.96(d,J=8.4Hz,2H),7.88(s,1H),7.82–7.71(m,4H),7.27–7.12(m,5H),5.90(s,1H),3.58–3.49(m,2H).
实施例42
(S,Z)-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)-2-环戊基乙酸(化合物42)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环戊基乙酸(228mg,0.88mmol)和3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(200mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物42,黄色固体256mg,收率65.1%。
1H NMR(400MHz,DMSO-d6)δ:13.25(s,1H),8.07(d,J=8.4Hz,2H),7.99(d,J=8.4Hz,2H),7.94(s,1H),7.82–7.73(m,4H),5.36(s,1H),3.10–2.85(m,1H),2.16(m,1H),1.67–1.35(m,6H),1.13–1.06(m,1H).
实施例43
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(S,Z)-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)戊酸(化合物43)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)戊酸(205mg,0.88mmol)和3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(200mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物43,黄色固体311mg,收率83.6%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),8.11–8.08(m,2H),7.99(d,J=8.4Hz,2H),7.93(s,1H),7.80–7.73(m,4H),5.58(t,J=7.2Hz,1H),2.26–2.11(m,2H),1.33–1.21(m,2H),0.89(t,J=7.2Hz,3H).
实施例45
(S,Z)-2-(5-((4-(4-氟-3-(三氟甲基)苯基)萘-1-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物45)的制备
合成路线:
实验步骤:
第一步4-(4-氟-3-(三氟甲基)苯基)-1-萘醛的制备
将实施例31第一步中的化合物4-溴苯甲醛替换为4-溴-1-萘醛进行反应,得化合物4-(4-氟-3-(三氟甲基)苯基)-1-萘醛,白色固体552mg,收率86.8%。
1H NMR(400MHz,DMSO-d6)δ:10.47(s,1H),9.32–9.26(m,1H),8.28(d,J=7.2Hz,1H),7.94–7.90(m,2H),7.83–7.64(m,5H).
第二步(S,Z)-2-(5-((4-(4-氟-3-(三氟甲基)苯基)萘-1-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(130mg,0.53mmol)和4-(4-氟-3-(三氟甲基)苯基)-1-萘醛(167mg,0.53mmol)为原料,采用实施例1中相似操作步骤,得到化合物45,黄色固体234mg,收率81.3%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),8.54(s,1H),8.33(d,J=8.4Hz,1H),7.95–7.88(m,2H),7.85(d,J=7.6Hz,1H),7.81(dd,J=8.4Hz,J=1.2Hz,1H),7.78–7.65(m,4H),5.60(t,J=7.6Hz,1H),2.27–2.20(m,2H),1.37–1.22(m,4H),0.86(t,J=7.0Hz,3H).
实施例46
(R,Z)-2-(5-((4-(4-氟-3-(三氟甲基)苯基)萘-1-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物46)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(111mg,0.49mmol)和4-(4-氟-3-(三氟甲基)苯基)-1-萘醛(143mg,0.49mmol)为原料,采用实施例1中相似操作步骤,得到化合物46,黄色固体204mg,收率76.1%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),8.54(s,1H),8.33(d,J=8.0Hz,1H),7.95–7.89(m,2H),7.85(d,J=7.6Hz,1H),7.81(dd,J=8.4Hz,J=1.2Hz,1H),7.78–7.65(m,4H),5.60(t,J=7.6Hz,1H),2.27–2.19(m,2H),1.37–1.22(m,4H),0.86(t,J=7.0Hz,3H).
实施例47
(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物47)的制备
合成路线:
实验步骤:
第一步4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-甲醛的制备
将实施例31第一步中的化合物4-溴苯甲醛替换为3-溴苯甲醛进行反应,得化合物4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-甲醛,白色固体1.19g,收率88.7%。
1H NMR(400MHz,DMSO-d6)δ:10.11(s,1H),8.30(s,1H),8.20–8.08(m,3H),7.96(d,J=7.6Hz,1H),7.77–7.64(m,2H).
第二步(S,Z)-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-甲醛(108mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物47,黄色固体166mg,收率83.4%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),8.16–8.07(m,3H),7.97(s,1H),7.92(d,J=7.2Hz,1H),7.73–7.64(m,3H),5.57(t,J=7.6Hz,1H),2.23–2.18(m,2H),1.32–1.23(m,4H),0.84(t,J=7.0Hz,3H).
实施例48
(S,Z)-2-环己基-2-(5-((4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)乙酸(化合物48)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(120mg,0.44mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-3-甲醛(108mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物48,黄色固体166mg,收率83.4%。
1H NMR(400MHz,DMSO-d6)δ:13.27(s,1H),8.16–8.07(m,3H),7.99(s,1H),7.94–7.90(m,1H),7.73–7.64(m,3H),5.24(s,1H),2.47–2.29(m,2H),1.75–1.56(m,3H),1.34–1.01(m,5H),0.93–0.82(m,1H).
实施例49
(S,Z)-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)己酸(化合物49)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(70mg,0.28mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(71mg,0.28mmol)为原料,采用实施例1中相似操作步骤,得到化合物49,黄色固体115mg,收率84.6%。
1H NMR(400MHz,DMSO-d6)δ:13.34(s,1H),8.12–8.08(m,2H),7.99(d,J=8.4Hz,2H),7.93(s,1H),7.82–7.71(m,4H),5.57(t,J=7.6Hz,1H),2.24–2.17(m,2H),1.35–1.14(m,4H),0.84(t,J=7.0Hz,3H).
实施例50
(R,Z)-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)己酸(化合物50)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(77mg,0.31mmol)和4'-氟-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(78mg,0.31mmol)为原料,采用实施例1中相似操作步骤,得到化合物50,黄色固体106mg,收率71.1%。
1H NMR(400MHz,DMSO-d6)δ:13.29(s,1H),8.13–8.06(m,2H),7.99(d,J=8.8Hz,2H),7.93(s,1H),7.84–7.72(m,4H),5.57(t,J=7.6Hz,1H),2.27–2.14(m,2H),1.35–1.16(m,4H),0.84(t,J=7.0Hz,3H).
实施例51
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(S,Z)-2-环己基-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)乙酸(化合物51)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(82mg,0.3mmol)和3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(75mg,0.3mmol)为原料,采用实施例1中相似操作步骤,得到化合物51,黄色固体110mg,收率72.4%。
1H NMR(400MHz,DMSO-d6)δ:13.27(s,1H),8.09(d,J=8.4Hz,2H),7.98(d,J=8.4Hz,2H),7.94(s,1H),7.83–7.72(m,4H),5.25(s,1H),2.49–2.30(m,2H),1.76–1.55(m,3H),1.35–1.04(m,5H),0.94–0.85(m,1H).
实施例52
(R,Z)-2-环己基-2-(4-氧代-2-硫代-5-((3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)乙酸(化合物52)的制备
合成路线:
实验步骤:
以化合物(R)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(241mg,0.88mmol)和3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(200mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物52,黄色固体396mg,收率78.3%。
1H NMR(400MHz,DMSO-d6)δ:13.27(s,1H),8.10(s,2H),7.99(d,J=8.4Hz,2H),7.94(s,1H),7.81–7.73(m,4H),5.25(s,1H),2.47–2.32(m,2H),1.75–1.55(m,3H),1.34–1.05(m,5H),0.92–0.85(m,1H).
实施例53
(S,Z)-2-(4-氧代-2-硫代-5-((4'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)-2-环己基乙酸(化合物53)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(120mg,0.44mmol)和4'-(三氟甲基)-[1,1'-联苯]-4-甲醛(101mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物53,黄色固体181mg,收率89.6%。
1H NMR(400MHz,DMSO-d6)δ:13.27(s,1H),8.03–7.92(m,5H),7.86(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),5.25(s,1H),2.48–2.32(m,2H),1.73–1.58(m,3H),1.33–1.05(m,5H),0.94–0.83(m,1H).
实施例54
(S,Z)-2-(5-((3'-氯-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(化合物54)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(121mg,0.44mmol)和3'-氯-[1,1'-联苯]-4-甲醛(87mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物54,黄色固体164mg,收率86.8%。
1H NMR(500MHz,DMSO-d6)δ:13.24(s,1H),7.96–7.90(m,3H),7.84(s,1H),7.76(t,J=8.5Hz,3H),7.58–7.46(m,2H),5.24(s,1H),2.46–2.31(m,2H),1.72–1.60(m,3H),1.33–1.02(m,5H),0.95–0.81(m,1H).
实施例55
(S,Z)-2-(4-氧代-2-硫代-5-((4'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)己酸(化合物55)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和4'-(三氟甲基)-[1,1'-联苯]-4-甲醛(100mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物55,黄色固体152mg,收率79.2%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),7.99(d,J=8.0Hz,2H),7.96(d,J=8.0Hz,2H),7.93(s,1H),7.86(d,J=8.0Hz,2H),7.81(d,J=8.0Hz,2H),5.58(t,J=7.2Hz,1H),2.28–2.12(m,2H),1.37–1.14(m,4H),0.84(t,J=7.0Hz,3H).
实施例56
(S,Z)-2-(5-((4'-甲氧基-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物56)的制备
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(219mg,0.88mmol)和3'-甲氧基-[1,1'-联苯]-4-甲醛(146mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物56,黄色固体322mg,收率91.2%。
1H NMR(400MHz,DMSO-d6)δ:13.31(s,1H),7.96–7.82(m,3H),7.76–7.68(m,4H),7.10–7.03(m,2H),5.57(t,J=7.6Hz,1H),3.82(s,3H),2.24–2.14(m,2H),1.37–1.12(m,4H),0.84(t,J=7.0Hz,3H).
实施例57
(S,Z)-2-(5-([1,1'-联苯]-4-基亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物57)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和[1,1'-联苯]-4-甲醛(146mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物57,黄色固体266mg,收率80.9%。
1H NMR(400MHz,DMSO-d6)δ:13.32(s,1H),7.91–7.88(m,3H),7.81–7.73(m,4H),7.52(t,J=7.4Hz,2H),7.43(t,J=7.4Hz,1H),5.57(t,J=7.6Hz,1H)2.35–2.06(m,2H),1.37–1.13(m,4H),0.83(d,J=7.0Hz,3H).
实施例58
(S,Z)-2-(5-((3'-甲氧基-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物58)的制备
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和3'-甲氧基-[1,1'-联苯]-4-甲醛(170mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物58,黄色固体308mg,收率87.3%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.91–7.89(m,3H),7.75(t,J=8.8Hz,2H),7.42(t,J=8.0Hz,1H),7.34(ddd,J=7.6Hz,J=1.6Hz,J=1.2Hz,1H),7.30(dd,J=2.4Hz,J=1.6Hz,1H),7.01(ddd,J=8.4Hz,J=2.4Hz,J=0.8Hz,1H),5.57(t,J=7.6Hz,1H),3.84(s,3H),2.34–2.14(m,2H),1.39–1.10(m,4H),0.84(t,J=7.0Hz,3H).
实施例59
(S,Z)-2-(5-((3'-氯-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物59)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(109mg,0.44mmol)和3'-氯-[1,1'-联苯]-4-甲醛(87mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物59,黄色固体161mg,收率90.4%。
1H NMR(400MHz,DMSO-d6)δ:13.31(s,1H),7.98–7.88(m,3H),7.84(s,1H),7.81–7.70(m,3H),7.59–7.47(m,2H),5.57(t,J=7.6Hz,1H),2.29–2.09(m,2H),1.36–1.16(m,4H),0.84(t,J=7.0Hz,3H).
实施例60
(S,Z)-2-(5-((4'-氯-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物60)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和4'-氯-[1,1'-联苯]-4-甲醛(172mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物60,黄色固体299mg,收率83.8%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),7.93–7.86(m,3H),7.86–7.80(m,2H),7.76(d,J=8.8Hz,2H),7.39–7.30(m,2H),5.57(t,J=7.6Hz,1H),2.24–2.17(m,2H),1.36–1.12(m,4H),0.84(t,J=7.0Hz,3H).
实施例61
(S,Z)-2-(5-(4-(5-氯噻吩-2-基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物61)的制备
合成路线:
实验步骤:
第一步4-(5-氯噻吩-2-基)苯甲醛的制备
将实施例31第一步中的(4-氟-3-(三氟甲基)苯基)硼酸替换为(5-氯噻吩-2-基)硼酸进行反应,得化合物4-(5-氯噻吩-2-基)苯甲醛,白色固体654mg,收率73.4%。
1H NMR(400MHz,DMSO-d6)δ:10.00(s,1H),7.95(d,J=8.8Hz,2H),7.85(d,J=8.8Hz,2H),7.64(d,J=4.4Hz,1H),7.25(d,J=4.4Hz,1H).
第二步(S,Z)-2-(5-(4-(5-氯噻吩-2-基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和4-(5-氯噻吩-2-基)苯甲醛(178mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物61,黄色固体325mg,收率89.8%。
1H NMR(400MHz,DMSO-d6)δ:13.31(s,1H),7.86(s,1H),7.81(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),7.61(d,J=4.0Hz,1H),7.24(d,J=4.0Hz,1H),5.56(t,J=7.6Hz,1H),2.23–2.16(m,2H),1.33–1.15(m,4H),0.83(t,J=7.0Hz,3H).
实施例62
(S,Z)-2-(5-(4-(3-氯吡啶-4-基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物62)的制备
合成路线:
实验步骤:
第一步4-(3-氯吡啶-4-基)苯甲醛的制备
将实施例31第一步中的(4-氟-3-(三氟甲基)苯基)硼酸替换为(3-氯吡啶-4-基)硼酸进行反应,得化合物4-(3-氯吡啶-4-基)苯甲醛,白色固体167mg,收率50.3%。
1H NMR(400MHz,DMSO-d6)δ:10.11(s,1H),8.79(s,1H),8.64(d,J=4.8Hz,1H),8.06(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),7.55(d,J=4.8Hz,1H).
第二步(S,Z)-2-(5-(4-(3-氯吡啶-4-基)亚苄基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(190mg,0.77mmol)和4-(3-氯吡啶-4-基)苯甲醛(152mg,0.7mmol)为原料,采用实施例1中相似操作步骤,得到化合物62,黄色固体153mg,收率48.9%。
1H NMR(400MHz,DMSO-d6)δ:13.34(s,1H),8.78(s,1H),8.63(d,J=4.8Hz,1H),7.93(s,1H),7.82(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),7.56(d,J=4.8Hz,1H),5.57(t,J=7.2Hz,1H),2.24–2.17(m,2H),1.34–1.15(m,4H),0.84(t,J=7.0Hz,3H).
实施例63
(S,Z)-2-(4-氧代-2-硫代-5-((4-(3-(三氟甲基)苯基)萘-1-基)亚甲基)噻唑啉-3-基)己酸(化合物63)的制备
合成路线:
实验步骤:
第一步4-(3-(三氟甲基)苯基)-1-萘醛的制备
将实施例31第一步中的将4-溴苯甲醛替换为4-溴-1-萘醛,将(4-氟-3-(三氟甲基)苯基)硼酸替换为3-(三氟甲基)苯硼酸进行反应,得化合物4-(3-(三氟甲基)苯基)-1-萘醛,白色固体634mg,收率90.4%。
1H NMR(400MHz,DMSO-d6)δ:10.48(s,1H),9.34–9.25(m,1H),8.28(d,J=7.2Hz,1H),7.94–7.90(m,1H),7.87–7.78(m,5H),7.76(d,J=7.6Hz,1H),7.69–7.64(m,1H).
第二步(S,Z)-2-(4-氧代-2-硫代-5-((4-(3-(三氟甲基)苯基)萘-1-基)亚甲基)噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和4-(3-(三氟甲基)苯基)-1-萘醛(240mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物63,黄色固体356mg,收率84.0%。
1H NMR(400MHz,DMSO-d6)δ:13.34(s,1H),8.55(s,1H),8.36–8.30(m,1H),7.93–7.87(m,1H),7.87–7.77(m,5H),7.77–7.72(m,1H),7.71–7.62(m,2H),5.61(t,J=7.6Hz,1H),2.33–2.12(m,2H),1.38–1.17(m,4H),0.86(t,J=7.0Hz,3H).
实施例64
(S,Z)-2-(5-((2-氯-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物64)的制备
合成路线:
实验步骤:
第一步2-氯-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛的制备
将实施例31第一步中的将4-溴苯甲醛替换为4-溴-3-氯苯甲醛,将(4-氟-3-(三氟甲基)苯基)硼酸替换为3-(三氟甲基)苯硼酸进行反应,得化合物2-氯-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛,白色固体995mg,收率87.4%。
1H NMR(400MHz,DMSO-d6)δ:10.07(s,1H),8.13(d,J=1.6Hz,1H),7.98(dd,J=8.0Hz,J=1.6Hz,1H),7.88–7.80(m,3H),7.76–7.72(m,2H).
第二步(S,Z)-2-(5-((2-氯-3'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和2-氯-3'-(三氟甲基)-[1,1'-联苯]-4-甲醛(228mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物64,黄色固体318mg,收率77.4%。
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),7.96(s,1H),7.92(s,1H),7.87–7.80(m,3H),7.76(t,J=8.0Hz,1H),7.72–7.67(m,2H),5.57(t,J=7.6Hz,1H),2.26–2.14(m,2H),1.34–1.16(m,4H),0.84(t,J=7.0Hz,3H).
实施例65
(S,Z)-2-(5-((4-(3-氯苯基)萘-1-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物65)的制备
合成路线:
实验步骤:
第一步4-(3-氯苯基)-1-萘醛的制备
将实施例31第一步中的将4-溴苯甲醛替换为4-溴-1-萘醛,将(4-氟-3-(三氟甲基)苯基)硼酸替换为3-氯苯硼酸进行反应,得化合物4-(3-氯苯基)-1-萘醛,白色固体1.03g,收率96.1%。
1H NMR(400MHz,DMSO-d6)δ:10.46(s,1H),9.28(d,J=9.2Hz,1H),8.26(d,J=7.6Hz,1H),7.85(d,J=8.4Hz,1H),7.81–7.76(m,1H),7.71(d,J=7.6Hz,1H),7.68–7.63(m,1H),7.62–7.58(m,3H),7.51–7.47(m,1H).
第二步(S,Z)-2-(5-((4-(3-氯苯基)萘-1-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和4-(3-氯苯基)-1-萘醛(213mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物65,黄色固体358mg,收率84.8%。
1H NMR(400MHz,DMSO-d6)δ:13.36(s,1H),8.53(s,1H),8.31(d,J=8.8Hz,1H),7.89–7.80(m,2H),7.76–7.71(m,1H),7.68–7.58(m,5H),7.51–7.47(m,1H),5.60(t,J=7.6Hz,1H),2.26–2.20(m,2H),1.38–1.19(m,4H),0.86(t,J=7.0Hz,3H).
实施例66
(S,Z)-2-(5-((5-(3-氯苯基)吡啶-2-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物66)的制备
合成路线:
实验步骤:
第一步5-(3-氯苯基)吡啶甲醛的制备
将实施例31第一步中的将4-溴苯甲醛替换为5-溴吡啶甲醛,将(4-氟-3-(三氟甲基)苯基)硼酸替换为3-氯苯硼酸进行反应,得化合物5-(3-氯苯基)吡啶甲醛,白色固体356mg,收率81.8%。
1H NMR(400MHz,DMSO-d6)δ:10.05(s,1H),9.19(d,J=2.4Hz,1H),8.39(dd,J=8.4Hz,J=2.4Hz,1H),8.02(dd,J=8.4Hz,1H),7.97–9.55(m,1H),7.85–7.82(m,1H),7.63–7.53(m,2H).
第二步(S,Z)-2-(5-((5-(3-氯苯基)吡啶-2-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和5-(3-氯苯基)吡啶甲醛(175mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物66,黄色固体311mg,收率86.9%。
1H NMR(400MHz,DMSO-d6)δ:13.26(s,1H),9.21(d,J=2.4Hz,1H),8.35(dd,J=8.0Hz,J=2.4Hz,1H),8.05(d,J=8.4Hz,1H),7.98–7.91(m,2H),7.86–7.82(m,1H),7.60–7.50(m,2H),5.58(t,J=7.6Hz,1H),2.24–2.17(m,2H),1.37–1.13(m,4H),0.83(t,J=7.0Hz,3H).
实施例67
(S,Z)-2-(5-((5-(3-氯苯基)噻吩-2-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物67)的制备
合成路线:
实验步骤:
第一步5-(3-氯苯基)噻吩-2-甲醛的制备
将实施例31第一步中的将4-溴苯甲醛替换为5-溴噻吩-2-甲醛,将(4-氟-3-(三氟甲基)苯基)硼酸替换为3-氯苯硼酸进行反应,得化合物5-(3-氯苯基)噻吩-2-甲醛,白色固体820mg,收率92.0%。
1H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),8.06(d,J=4.0Hz,1H),7.92–7.90(m,1H),7.85(d,J=4.0Hz,1H),7.78–7.75(m,1H),7.54–7.48(m,2H).
第二步(S,Z)-2-(5-((5-(3-氯苯基)噻吩-2-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和5-(3-氯苯基)噻吩-2-甲醛(179mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物67,黄色固体305mg,收率84.3%。
1H NMR(400MHz,DMSO-d6)δ:13.29(s,1H),8.11(s,1H),7.93–7.91(m,1H),7.88(d,J=4.0Hz,1H),7.84–7.81(m,1H),7.79–7.76(m,1H),7.53–7.46(m,2H),5.54(t,J=6.8Hz,1H),2.23–2.13(m,2H),1.34–1.14(m,4H),0.83(t,J=7.0Hz,3H).
实施例68
(S,Z)-2-(5-((2,3'-二氯-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物68)的制备
合成路线:
实验步骤:
第一步2,3'-二氯-[1,1'-联苯]-4-甲醛的制备
将实施例31第一步中的将4-溴苯甲醛替换为4-溴-3-氯苯甲醛,将(4-氟-3-(三氟甲基)苯基)硼酸替换为3-氯苯硼酸进行反应,得化合物2,3'-二氯-[1,1'-联苯]-4-甲醛,白色固体904mg,收率90.0%。
1H NMR(400MHz,DMSO-d6)δ:10.06(s,1H),8.10(d,J=1.6Hz,1H),7.95(dd,J=8.0Hz,J=1.6Hz,1H),7.69(d,J=8.0Hz,1H),7.59–7.51(m,3H),7.50–7.44(m,1H).
第二步(S,Z)-2-(5-((2,3'-二氯-[1,1'-联苯]-4-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸的制备
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和2,3'-二氯-[1,1'-联苯]-4-甲醛(200mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物68,黄色固体326mg,收率84.9%。
1H NMR(400MHz,DMSO-d6)δ:13.34(s,1H),7.95–7.90(m,2H),7.71–7.61(m,2H),7.59–7.50(m,3H),7.48–7.45(m,1H),5.57(t,J=7.6Hz,1H),2.23–2.16(m,2H),1.38–1.11(m,4H),0.84(t,J=7.0Hz,3H).
实施例69
(S,Z)-2-(4-氧代-2-硫代-5-((2'-(三氟甲基)-[1,1'-联苯]-4-基)亚甲基)噻唑啉-3-基)-2-环己基乙酸(化合物69)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)-2-环己基乙酸(120mg,0.44mmol)和2'-(三氟甲基)-[1,1'-联苯]-4-甲醛(100mg,0.4mmol)为原料,采用实施例1中相似操作步骤,得到化合物69,黄色固体182mg,收率90.1%。
1H NMR(400MHz,DMSO-d6)δ:13.26(s,1H),7.95(s,1H),7.87(d,J=8.0Hz,1H),7.75(d,J=8.4Hz,3H),7.67(t,J=7.6Hz,1H),7.53(d,J=8.4Hz,2H),7.46(d,J=7.2Hz,1H),5.25(s,1H),2.48–2.32(m,2H),1.74–1.55(m,3H),1.33–1.04(m,5H),0.96–0.82(m,1H).
实施例70
(S,Z)-2-(5-(4-(2,3-二氢苯并呋喃-5-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物70)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和4-(2,3-二氢苯并呋喃-5-基)苯甲醛(179mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物70,黄色固体358mg,收率98.6%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.87(s,1H),7.82(d,J=8.4Hz,2H),7.70(d,J=8.4Hz,2H),7.67(d,J=2.0Hz,1H),7.53(dd,J=8.4Hz,J=2.0Hz,1H),6.88(d,J=8.4Hz,1H),5.57(t,J=7.6Hz,1H),4.60(t,J=8.8Hz,2H),3.26(t,J=8.8Hz,2H),3.24–2.16(m,2H),1.34–1.15(m,4H),0.84(t,J=7.0Hz,3H).
实施例71
(S,Z)-2-(5-(4-(苯并[d][1,3]二氧戊环-5-基)亚甲基)-4-氧代-2-硫代噻唑啉-3-基)己酸(化合物71)的制备
合成路线:
实验步骤:
以化合物(S)-2-(4-氧代-2-硫代噻唑啉-3-基)己酸(218mg,0.88mmol)和4-(苯并[d][1,3]二氧戊环-5-基)苯甲醛(181mg,0.8mmol)为原料,采用实施例1中相似操作步骤,得到化合物71,黄色固体352mg,收率96.7%。
1H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),7.88(s,1H),7.84(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),7.38(d,J=2.0Hz,1H),7.29(dd,J=8.0Hz,J=2.0Hz,1H),7.04(d,J=8.0Hz,1H),6.09(s,2H),5.57(t,J=7.6Hz,1H),2.23–2.16(m,2H),1.32–1.16(m,4H),0.84(t,J=7.0Hz,3H).
生物活性测试
以对硝基苯基磷酸酯(p-nitrophenyl phosphate,pNPP)为底物,在Tris-NaCl缓冲液(50mM Tris/100mM NaCl,pH为7.0)中,使用96孔板测定化合物对MptpB蛋白酶的抑制活性。活性测试在含有1.5μg MptpB和不同浓度待测试化合物的200μL反应体系中进行,先将反应液在室温下孵化10分钟,然后加入pNPP至其浓度为1.3mM(达到其Km值),在37℃温度下,使用Infinite 200PRO分光光度计(TECAN)在405nm处测试其反应5分钟时间的吸光度。其中,不含MptpB蛋白酶的反应液作为空白对照组也通过同样的方法测试其吸光度。在对应浓度下测试其对MptpB的抑制率,使用软件Origin 9拟合化合物浓度和抑制率,并计算IC50值。所有测试均进行三次独立平行试验。
表1.本发明部分化合物MptpB抑制活性
化合物 | IC50(μM) | 化合物 | IC50(μM) | 化合物 | IC50(μM) |
化合物1 | 0.51±0.03 | 化合物26 | 1.32±0.05 | 化合物55 | 0.86±0.09 |
化合物2 | 0.58±0.03 | 化合物28 | 1.34±0.06 | 化合物56 | 0.55±0.06 |
化合物3 | 4.21±0.72 | 化合物29 | 0.75±0.05 | 化合物57 | 0.62±0.04 |
化合物4 | 2.59±0.12 | 化合物30 | 0.84±0.04 | 化合物58 | 0.75±0.05 |
化合物5 | 2.05±0.46 | 化合物31 | 0.48±0.08 | 化合物59 | 0.38±0.06 |
化合物7 | 1.81±0.16 | 化合物35 | 0.49±0.06 | 化合物60 | 0.60±0.04 |
化合物9 | 0.70±0.04 | 化合物38 | 2.34±0.21 | 化合物61 | 0.43±0.04 |
化合物11 | 0.05±0.0019 | 化合物39 | 1.73±0.05 | 化合物62 | 0.80±0.07 |
化合物12 | 1.36±0.02 | 化合物42 | 0.59±0.10 | 化合物63 | 0.59±0.20 |
化合物14 | 0.05±0.0010 | 化合物43 | 1.20±0.04 | 化合物64 | 0.42±0.10 |
化合物15 | 0.06±0.0016 | 化合物45 | 0.67±0.05 | 化合物65 | 0.67±0.04 |
化合物16 | 0.65±0.02 | 化合物47 | 0.62±0.03 | 化合物66 | 0.53±0.05 |
化合物17 | 0.78±0.02 | 化合物48 | 2.96±0.04 | 化合物67 | 0.44±0.02 |
化合物18 | 0.59±0.10 | 化合物49 | 0.35±0.03 | 化合物68 | 0.33±0.04 |
化合物19 | 0.45±0.05 | 化合物50 | 1.48±0.02 | 化合物69 | 0.92±0.03 |
化合物20 | 1.45±0.13 | 化合物54 | 0.99±0.04 | ||
化合物21 | 0.06±0.0032 | 化合物51 | 0.64±0.04 | ||
化合物22 | 0.93±0.06 | 化合物52 | 0.40±0.01 | ||
化合物25 | 0.66±0.03 | 化合物53 | 3.13±0.17 |
由表1可知,本发明化合物具有强的MptpB抑制活性。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (11)
1.如式(I)所示的化合物或其药学上可接受的盐:
其中,
A环为苯环、萘环、含有一个选自N、S中的杂原子的5-6元芳杂环;
R1选自C1-C4烷基、MeSC1-C4烷基、C3-C6环烷基、苄基、苯基;
R2选自H、F、Cl、Br;
R3选自-OCH2R4、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的其中X和Y各自独立地选自C、N、O或S;
所述R3中的取代基独立地选自:F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基;
R4选自卤素取代C1-C3烷基、C3-C6环烷基、苯基、5-6元杂芳基,其中的苯基和杂芳基独立和任意地被F、Cl、Br、羟基、羧基、-COOCH3、硝基、氰基、三氟甲基、三氟甲氧基、C1-C4烷基、C3-C6环烷基、C1-C3烷氧基或C1-C3烷胺基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,所述的化合物由通式(II)所示:
其中,A环、R1、R2、R3如权利要求1所述。
3.根据权利要求2所述的化合物或其药学上可接受的盐,所述的化合物由通式(III)所示:
其中,A环为苯环、萘环;
R1为
R2为H、F、Cl、Br;
R4为
4.根据权利要求2所述的化合物或其药学上可接受的盐,
其中,A环为苯环、萘环、噻吩环、吡啶环;
R1为
R2为H、F、Cl、Br;
R3为
5.根据权利要求1所述的化合物或其药学上可接受的盐,所述的化合物由通式(IV)所示:
其中,A环、R1、R2、R3如权利要求1所述。
6.根据权利要求5所述的化合物或其药学上可接受的盐,所述的化合物由通式(V)所示:
其中,A环为苯环、萘环;
R1为
R2为H、F、Cl、Br;
R4为
7.根据权利要求5所述的化合物或其药学上可接受的盐,
其中,A环为苯环、萘环、噻吩环、吡啶环;
R1为
R2为H、F、Cl、Br;
R3为
8.根据权利要求1所述的化合物或其药学上可接受的盐,其为选自以下化合物
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9.一种药物组合物,其包括治疗和/或预防有效量的权利要求1至8任一项所述的化合物或其药学上可接受的盐以及任选的一种或多种药学上可接受的辅料。
10.权利要求1至8任一项所述化合物或其药学可接受的盐或者权利要求9所述组合物在制备结核分枝杆菌蛋白酪氨酸磷酸酶抑制剂中的应用。
11.权利要求1至8任一项所述化合物或其药学可接受的盐或者权利要求9所述组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。
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