CN110546140B - 选择性hdac6抑制剂 - Google Patents
选择性hdac6抑制剂 Download PDFInfo
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- CN110546140B CN110546140B CN201880024895.9A CN201880024895A CN110546140B CN 110546140 B CN110546140 B CN 110546140B CN 201880024895 A CN201880024895 A CN 201880024895A CN 110546140 B CN110546140 B CN 110546140B
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- compound
- methyl
- benzohydroxamic acid
- difluoro
- triazol
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- 102100022537 Histone deacetylase 6 Human genes 0.000 title claims abstract description 39
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 title claims description 38
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 title claims description 36
- 239000003112 inhibitor Substances 0.000 title description 26
- VDEUYMSGMPQMIK-UHFFFAOYSA-N benzhydroxamic acid Chemical class ONC(=O)C1=CC=CC=C1 VDEUYMSGMPQMIK-UHFFFAOYSA-N 0.000 claims abstract description 213
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 359
- -1 2- (morpholin-4-yl) ethyl Chemical group 0.000 claims description 185
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 70
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 claims description 10
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 210000004698 lymphocyte Anatomy 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 claims description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 6
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
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- 230000001404 mediated effect Effects 0.000 claims description 5
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- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 4
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 4
- 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 claims description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 3
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 claims description 3
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 claims description 3
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 3
- 201000002481 Myositis Diseases 0.000 claims description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 claims description 3
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
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- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
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- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 2
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- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 claims description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
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Abstract
本发明涉及式(I)及(II)的新颖苯基羟肟酸化合物及其药学上可接受的盐、异构体及前药,其显示对组蛋白去乙酰酶6(HDAC6)酶的高选择性抑制活性。
Description
技术领域
本发明涉及组蛋白去乙酰酶6(histone deacetylase 6,HDAC6)酶的新选择性苯基羟肟酸(benzohydroxamic)抑制剂及其药物组合物。
因此,这些化合物可用于治疗与HDAC6活性有关的疾病,如移植物排斥、GVHD、肌炎、与淋巴细胞功能异常有关的疾病、多发性骨髓瘤、非霍奇金氏淋巴瘤(non-Hodgkinlymphoma)、周围神经病变、自身免疫疾病、炎性疾病、癌症及神经退化性病理(neurodegenerative pathology)。
背景技术
真核细胞的遗传物质被组织在染色质(chromatin)中,其为由DNA与蛋白质所组成的复杂且动态的结构。染色质的主要蛋白质组分为组蛋白,其为与形成核小体的DNA相互作用的碱性蛋白质,所述核小体为染色质的基本结构单元,为细胞核内的第一级染色体压缩(chromosomal compaction)。在决定核小体压缩以及调节复制及转录的分子复合物的相关DNA易接近性上,碱性组蛋白残基与DNA酸性残基之间的相互作用是决定性的。此相互作用主要受组蛋白乙酰化程度的影响。组蛋白N端赖氨酸残基的去乙酰化使带有正电荷的胺基质子化,与DNA中所含的负电荷相互作用。此种相互作用发生于染色质更紧密的状态,涉及基因表达沉默。相反地,相同残基的乙酰化防止离子键形成,导致染色质较不紧密的形式,其允许更大的DNA暴露及与活化基因转录的大分子复合物的相互作用。
组蛋白乙酰化之程度通过两类酶的活性平衡来调节:组蛋白乙酰基转移酶(histone acetyl-transferases HAT)及组蛋白去乙酰酶(histone deacetylases HDAC)。此种巧妙平衡的改变可导致细胞稳态(cellular homeostasis)的丧失,常见于各种人类疾病,包括癌症、神经障碍(neurological disorder)、炎症及自身免疫疾病。
组蛋白去乙酰酶是因其可逆地催化组蛋白N端赖氨酸残基的胺基之去乙酰化而被如此分类。随后,发现有大量这种酶的基质,因此其活性也归因于非组蛋白蛋白质(其为含有N-乙酰基-赖氨酸的HAT酶的基质),如转录因子、DNA修复酶及其它细胞核和细胞质的蛋白质。
人类HDAC种类由18种酶所组成,分成两组:锌依赖性HDAC、及NAD-依赖性HDAC,其也被称为静默信息调节蛋白(sirtuins)(第III类)。锌依赖性HDACs被进一步分为四类:1)第I类,包括HDAC1、2、3及8,是主要位于细胞核中的到处存在的同功酶;2)第IIa类,包括HDAC4、5、7及9,是位于细胞核及细胞质的同功酶;3)第IIb类,包括HDAC6及HDAC10,主要位于细胞质;及4)第IV类,仅包括HDAC11。不像第I类HDAC,第IIa及IIb类具有组织特异性表现。
通过调节基因表达及作用于组蛋白和转录因子,显然这些酶参与了众多的细胞功能。此外,通过作用于许多其它蛋白质基质,这些酶以及磷酸酶参与许多其它过程,如信号转导及细胞骨架重排。
近几十年来,HDAC已成为一种广被研究的治疗目标。已经合成数种HDAC抑制剂,其中一些目前处于进阶临床试验,其中四种已被批准用于不同类型的癌症:伏立诺他(Vorinostat)及罗米地辛(Romidepsin)用于皮肤T细胞淋巴瘤(CTLC),贝利司他(Belinostat)用于细胞周围T细胞淋巴瘤(PTLC),及帕比司他(Panobinostat)用于多发性骨髓瘤。这些最新的抑制剂可与不同的HDAC同功型(isoform)不同程度上地交互作用。
不论它们的临床效果,对于特定的同功型为非选择性的泛抑制剂(pan-inhibitors)的用途受到在临床前模型以及最重要地,临床试验中所观察到的其毒性和副作用的限制。因此,需要发展具有更好的药理学特性(pharmacological profile)及治疗窗(therapeutic window)(功效/毒性比)的HDAC抑制剂。
因此,科学界的注意力集中在对个别HDAC同功型的选择性抑制剂的合成及研究上,目标在于发展具有更佳药理能力的分子。
因此,HDAC抑制剂的用途可以是由基因表达引起的病理的重要治疗或诊断工具,如炎性疾病、糖尿病、糖尿病并发症、纯合子性地中海贫血(homozygous thalassemia)、纤维化、硬化、急性前髓细胞白血病(acute promyelocytic leukaemia,APL)、器官移植排斥、自身免疫病理、原虫感染、癌症等。HDAC家族或特定同功型(尤其是HDAC6)的选择性抑制剂可以特别用于治疗与增生性病症及蛋白质积累有关的病理、免疫***病症以及神经及神经退化性疾病,如中风、亨廷顿症(Huntington's disease)、ALS及阿兹海默症(Alzheimer'sdisease)。
特别是对于HDAC6同功型,已鉴定不同的基质,如α-微管蛋白、Hsp90(热休克蛋白90)、皮层蛋白(cortactin)、β-连环蛋白(β-catenin)。这些蛋白质乙酰化通过HDAC6的调控已与几个重要的过程相关,如免疫反应(Wang et al.,Nat.Rev.Drug Disc.(2009),8(12),969-981;J.Med.Chem.(2012),55,639-651;Mol.Cell.Biol.(2011),31(10),2066-2078)、包括细胞迁移及细胞-细胞交互作用的微管动态的调节(Aldana-Masangkay等人,J.Biomed.Biotechnol.(2011),2011,875824)、及变性蛋白质的降解。
此外,HDAC6参与了通过被称为聚集体(aggresome)的复合物的降解蛋白质的分解代谢过程:HDAC6能够结合多泛素化蛋白(polyubiquitinated proteins)及动力蛋白(dynein),从而活化一种将变性蛋白质沿着微管至聚集体的递送(Kawaguchi等人,Cell(2003)115(6),727-738)。
这种HDAC6细胞保护活性的改变已与各种神经退化性病理相关,如帕金森氏症(Parkinson's disease)(Outerio等人,Science(2007),317(5837),516-519)及亨廷顿症(Dompierre等人,J.Neurosci.(2007),27(13),3571-3583),其中降解蛋白质的积累为常见的病理学特征。
此外,HDAC6参与调节许多致癌性蛋白质,特别是在血液肿瘤中,如各种类型的白血病(Fiskus等人,Blood(2008),112(7),2896-2905;Rodriguez-Gonzales,Blood(2008),112(11),abstract 1923)及多发性骨髓瘤(Hideshima等人,Proc.Natl.Acad.Sci.USA(2005),102(24),8567-8572)。α-微管蛋白乙酰化通过HDAC6的调节可能涉及转移发生,其中细胞移动扮演重要的角色(Sakamoto等人,J.Biomed.Biotechnol.(2011),2011,875824)。
国际专利申请WO 2011/021209公开具有HDAC抑制活性的1,2,3-***化合物。
国际专利申请WO 2012/178208公开具有取代杂环的化合物,如苯并咪唑、苯并咪唑酮及苯并***,其具有选择性HDAC6抑制活性。
国际专利申请WO 2015/102426公开具有HDAC抑制活性的新吲哚衍生物。
国际专利申请WO 2015/087151公开具有HDAC抑制活性的新氮吲哚衍生物。
国际专利申请WO 2012/106343公开HDAC抑制剂及含有其的组合物。其还公开了治疗疾病及病况的方法,其中HDAC的抑制提供益处,所述疾病及病况如癌症、神经退化性病症、周围神经病变、神经疾病、创伤性脑损伤、中风、高血压、疟疾、自身免疫疾病、自闭症、泛自闭症障碍(autism spectrum disorders)及炎症。
文献“Valente等人,Journal of Medicinal Chemistry(2014),57(14),6259-6265”描述含有1,3,4-氧杂二唑(2)及2-氨基酰苯胺(2-aminoanilides)(3)作为组蛋白去乙酰酶抑制剂的羟肟酸酯。在其中,化合物2t、2x和3i被描述为最有效力及对HDAC1有选择性。
发明内容
定义
除非另外定义,否则本文使用的所有术语、符号及其它科学术语均意图具有本公开所属领域技术人员通常理解的含义。在一些情形中,为了清楚及/或为了便于参考而在本文中定义具有通常理解的意义的术语;因此,本文所包括的这种定义不应被解释为表示与本领域中一般所理解的实质差异。
术语“卤素”在本文中是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“C1-C4烷基”在本文中是指含1至4个碳原子的支链或直链烃。C1-C4烷基的示例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基。
术语“芳基”在本文中是指单-及多-碳环芳香族环***(i),其中在多碳环***中的各别碳环可稠合或彼此通过单键相连。适合的芳基包括但不限于:苯基、萘基及联苯基。
术语“芳氧基”在本文中是指O-芳基,其中“芳基”如上定义。
术语“烷氧基”在本文中是指O-烷基,其中“烷基”如上定义。
术语“环烷基”在本文中是指饱和或不饱和烃环,优选具有4至10个碳原子。环烷基的示例包括环丙基、环丁基、环戊基、环己基、环庚基及环辛基。
术语“芳烷基”在本文中是指如上定义的芳基连接于如上定义的烷基。芳烷基的示例为苄基。
术语“杂环”在本文中是指4-、5-、6-、7-或8-员单环型环,其为饱和的或不饱和的,且由碳原子及一或多个杂原子所组成,该杂原子选自N、O及S,且其中氮及硫杂原子可任选地被氧化且氮杂原子可任选地被四级铵化(quaternized)。杂环可连接到任何杂原子或碳原子上,条件是连接导致产生稳定的结构。此术语还包括任何双环***,其中上述杂环的任一个稠合至芳基或另一个杂环。当杂环为芳香族杂环时,其可被定义为“杂芳香族环”。
术语“不饱和环”在本文中是指部分或完全不饱和环。例如,不饱和C6单环是指环己烯、环己二烯及苯。
术语“经取代”在本文中是指通过定义(或未定义)的取代基的单-或多-取代,其条件为此单或多取代是化学上可允许的。
术语“生理学上可接受的赋形剂”在本文中是指其本身无任何药理学作用且当被施用至哺乳动物,优选人类时,不产生不良反应的物质。生理学上可接受的赋形剂在本领域中是广为人知的,且被公开于例如2009年第六版的Handbook of PharmaceuticalExcipients中,通过引用并入本文。
术语“其药学上可接受的盐或衍生物”在本文中是指具有盐化或衍生的化合物的生物学效力及性质且当施用至哺乳动物(优选人类)时不产生不利反应的盐或衍生物。药学上可接受的盐可为无机或有机盐,药学上可接受的盐的示例包括但不限于:碳酸盐、盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、马来酸盐、富马酸盐、三氟乙酸盐、2-萘磺酸盐及对甲苯磺酸盐。关于药学上可接受的盐的进一步信息可见于Handbook ofpharmaceutical salts,P.Stahl,C.Wermuth,WILEY-VCH,127-133,2008,通过引用并入本文。药学上可接受的衍生物包括酯、醚及N-氧化物。
术语“包含”、“具有”、“包括”及“含有”应被了解为开放式用语(意指“包括但不限于”)且也应被视为对如“基本上由......组成(essentially consist of)”,“基本上由...组成(essentially consisting of)”、“由...组成(consist of)”或“由...组成(consisting of)”的术语的支持。
术语“基本上由...组成(essentially consist of)”、“基本上由...组成(essentially consisting of)”应被理解为半封闭式用语,意指包括不影响本发明的新颖特征的其它成分(因此可包括任选的赋形剂)。
术语“由...组成(consist of)”、“由...组成(consisting of)”、应被理解为封闭式用语。
术语“异构体”是指立体异构体(或空间异构体),即,非对映异构体及对映异构体。
术语“前药”是指药理学上无活性的衍生物,其可在活体内历经代谢转化而提供本发明的通式所包括的活性化合物。本领域中已知有许多不同的前药(Prodrug approach:aneffective solution to overcome side-effects,Patil S.J.,Shirote P.J.,International Journal of Medical and Pharmaceutical Sciences,2011,1-13;Carbamate Prodrug Concept for Hydroxamate HDAC Inhibitors,Jung,Manfred等人,ChemMedChem,2011,1193-1198)。
术语“病理”包括一种或多种下列自身免疫疾病或病症:糖尿病、关节炎(包括类风湿性关节炎(rheumatoid arthritis)、青少年期的类风湿性关节炎(juvenile rheumatoidarthritis)、骨关节炎、牛皮癣性关节炎)、多发性硬化症、重症肌无力、全身性红斑狼疮、自身免疫甲状腺炎、皮肤炎(包括异位性皮肤炎及湿疹性皮肤炎)、牛皮癣、休格伦氏症候群(Sjogren's syndrome)(包括继发于休格伦氏症候群的干性角膜结膜炎)、斑秃、由节肢动物叮咬所造成的过敏反应、克隆氏症(Chron's disease)、胃溃疡、虹膜炎、结膜炎、角膜结膜炎、溃疡性结肠炎、哮喘、过敏性哮喘、皮肤的红斑性狼疮、硬皮病、***炎、直肠炎、对药物的反应、麻风病、红斑性狼疮、自身免疫眼色素层炎、过敏性脑脊髓炎、急性坏死性出血性脑病变、进行性双侧特发性听力丧失、再生不良性贫血、贫血、特发性血小板减少症、多发性软骨炎、华格纳氏肉芽病(Wegener's granulomatosis)、慢性活动性肝炎、史蒂芬-强森症候群(Stevens-Jonhson syndrome)、特发性口炎性腹泻(idiopathic sprues)、扁平苔藓(lichen planus)、葛瑞夫兹氏眼病变(Graves's ophthalmopathy)、类肉瘤病、原发性胆汁性肝硬化、后眼色素层炎、间质性肺纤维化。
术语“病理”是指一种或多种下列神经或神经退化性疾病:威尔逊氏病(Wilson'sdisease)、脊髓小脑性失调症、朊病毒疾病(prion disease)、帕金森氏症、亨廷顿症、肌肉萎缩性脊髓侧索硬化症(ALS)、淀粉样变性病、阿兹海默症、亚历山大氏病(Alexander'sdisease)、酒精性肝病、囊性纤维化、匹克氏病(Pick's disease)、脊髓性肌萎缩及路易体失智症(Lewy body dementia)。
术语“病理”进一步包括一种或多种下列疾病:类风湿性脊椎炎、缺血后再灌注损伤(post-ischemic reperfusion injury)、肠炎、慢性炎性肺病、湿疹、哮喘、急性呼吸窘迫症候群、感染性关节炎、慢性进行性关节炎、变形性关节炎、创伤后关节病、痛风性关节炎、莱特氏症候群(Reiter syndrome)、急性滑膜炎、急性脊椎炎、肾小球性肾炎、溶血性贫血、再生不良性贫血、嗜中性白血球减少症、移植物抗宿主病(GVHD)、移植排斥、慢性甲状腺炎、葛瑞夫兹氏病(Grave's disease)、胆汁性原发性肝硬化、接触性皮肤炎、晒伤、慢性肾衰竭、格巴二氏症候群(Guillain-Barre syndrome)、眼色素层炎、中耳炎、牙周病、肺间质纤维化、支气管炎、鼻窦炎、肺尘埃沉着病、肺衰竭症候群、肺气肿、肺纤维化、硅肺病或肺部慢性炎性疾病。
术语“病理”进一步包括一种或多种下列疾病:癌症、肿瘤生长、结肠癌、乳癌、骨癌、脑癌和其它癌症(例如骨肉瘤、神经母细胞瘤、结肠腺癌)、慢性骨髓性白血病(chronicmyeloid leukaemia,CML)、急性骨髓性白血病(acute myeloid leukaemia,AML)、急性前髓细胞白血病(APL)、贲门癌(肉瘤、黏液瘤、横纹肌瘤、纤维瘤、脂肪瘤及畸胎瘤)、肺癌(例如支气管癌、肺泡癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤性错构瘤(chondromatoushamartoma)、间皮瘤)、胃肠癌(例如食道癌、胃癌、胰脏癌、小肠癌、大肠癌)、生殖泌尿道癌(例如肾癌、膀胱癌及尿道癌、***癌、睪丸癌)、肝癌(例如肝细胞癌、胆管癌、肝母细胞瘤(hepatoblastoma)、血管肉瘤、肝细胞腺瘤、血管瘤)、骨癌(例如骨原性肉瘤、纤维肉瘤、恶性纤维性组织细胞瘤、软骨肉瘤、尤文氏肉瘤(Ewing's Sarcoma)、恶性淋巴瘤、多发性骨髓瘤、恶性巨细胞瘤、脊索瘤、软骨骨瘤(chondrosteoma)、良性脊索瘤、软骨母细胞瘤、软骨黏液纤维瘤(condromixofibroma)、骨样性骨瘤(osteoid osteoma))、神经***肿瘤(例如颅骨瘤、脑膜瘤、脑瘤、脊髓瘤)、妇科肿瘤(例如子宫瘤、子宫颈瘤、卵巢瘤、阴门及***瘤)、血液学癌症(例如血瘤、霍奇金氏病、非霍奇金氏病)、皮肤癌(例如恶性黑色素瘤、基底细胞癌、恶性鳞状细胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)、发育异常性母斑(dysplasticnaevus)、脂肪瘤、血管瘤、皮纤维瘤、蟹足肿、牛皮癣)及肾上腺肿瘤(例如神经母细胞瘤)。
附图说明
图1:在iDC(GMCSF-IL-4刺激的单核细胞)中PD-L1表达的抑制。人类单核细胞以HDAC6抑制剂处理,并以GMCSF-IL-4刺激5日。培育后,收集细胞并以抗PD-L1抗体标记。然后洗涤细胞,并使用流式细胞仪(BD FACSVerse)获取荧光数据。图上的数值表示于3个不同的供体(n=3)上进行的3次实验的平均值。PD-L1的表达通过荧光的几何平均值来表示。*=P<0.05,通过Student's t检验确定。
图2:化合物8及10减少活体内肿瘤生长,且具有与抗PD-1抗体相当的功效。箭头指出治疗开始日。
图3:HDAC6抑制剂减少活体内CT-26肿瘤生长,且其活性可通过与抗PD-1抗体合并治疗得到改善。统计在第30日通过Student's t检验进行评估。*,P<0.05;**,P<0.01;***,P<0.001。更详细内容参见内文。
图4:利用选择性HDAC6抑制剂的活体内治疗诱导特异性T细胞反应。将以化合物8及10处理、以及与抗PD-1抗体(anti PD-1Ab)组合处理的动物的脾细胞用由CT-26衍生的肿瘤肽刺激,并通过ELISPOT定量由CD4 T细胞产生的IFN-γ和TNF-α。
图5:利用选择性HDAC6抑制剂的活体内治疗诱导特异性T细胞反应。将以化合物8及10处理、以及与抗PD-1抗体组合处理的动物的脾细胞用由CT-26衍生的肿瘤肽刺激,并且通过ELISPOT定量CD8 T细胞产生的IFN-γ和TNF-α。
具体实施方式
发明人已根据实验而发现:以五员杂环中心核为特征的苯基羟肟酸化合物展现出高的且选择性的HDAC6酶抑制活性。
这些化合物还证实有低的细胞毒性,因此允许其长期使用。
依据第一方面,本发明涉及式(I)及(II)化合物及其药学上可接受的盐、异构体及前药:
其中
在式(I)中,A=N、O、S,而在式(II)中,A=N;
B=C、N;
在式(I)中,C=N、O,而在式(II)中,C=N;
X=CH2、S、NH、O、CD2;
n=0、1;
当n=1时,碳原子可被R12及R13取代,该R12及R13独立地选自H、D、-Me、-苯基、-F及-OH,或R12及R13可一起形成饱和环状部分(moiety),优选环丙烷、环丁烷、环戊烷或环己烷;
当n=1时,R6可不存在;
R4=R5=H、F;
R1为不存在,或其选自-H、-NH2、C1-C4烷基、苯基、一或多个卤素取代的苯基、芳烷基、环烷基、甲基呋喃、环丁基甲基、四氢呋喃-2-基-甲基、3-(二乙基氨基)丙基、2-甲氧基乙基、乙烯基、2-(甲基氢硫基)乙基、1-环丙基乙基、吡啶-2-基、(吡啶-3-基)甲基、2-(吡啶-2-基)乙基、2-(噻吩-2-基)乙基、3,4-二甲氧基苯基、4-甲氧基苯基、甲基苯基、2-氯-5-(吗啉-4-磺酰基)苯基、4-[(二氟甲基)氢硫基]苯基、4-(吗啉-4-磺酰基)苯基、5-(二甲基胺磺酰基)-2-甲基苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、2-(吗啉-4-基)乙基、3-(吗啉-4-基)丙基、1-萘基、2,3-二氢-1,4-苯并二恶英-6-基(2,3-dihydro-1,4-benzodioxin-6-yl)、二苯甲基、5-二氢茚基、噻吩及甲基噻吩;
R2为不存在,或其选自H、烷基、环烷基、环烷基-甲基、杂芳基、苯基、一或多个卤素取代的苯基、一或多个烷氧基取代的苯基、一或多个硝基取代的苯基、苄基、烷基取代的苄基、(2,2-二氟环戊基)甲基、2-溴-3-氟苯基、(2,2-二甲基环丙基)甲基、4-羟基苯基、2-(苄氧基)乙基、2-溴-4-甲氧基苯基、2-甲基-喹啉、3-甲基吡啶-4-基、4-甲磺酰基-2-甲基苯基、2-氯-4,6-二硝基苯基、1,3-苯并间二氧杂环戊烯-5-基甲基(1,3-benzodioxol-5-ylmethyl)或2-苄氧基苯基;
R3为不存在,或其选自H、烷氧基芳基、苯基、CF3取代的苯基、苄基、吡啶基、烷基、环烷基、环烷基-甲基、杂芳基、一或多个卤素取代的苯基、一或多个烷氧基取代的苯基、一或多个硝基取代的苯基、苄基、烷基取代的苄基、(2,2-二氟环戊基)甲基、2-溴-3-氟苯基、(2,2-二甲基环丙基)甲基、4-羟基苯基、2-(苄氧基)乙基、2-溴-4-甲氧基苯基、甲基-2-喹啉、3-甲基吡啶-4-基、4-甲磺酰基-2-甲基苯基、2-氯-4,6-二硝基苯基、1,3-苯并间二氧杂环戊烯-5-基甲基或2-苄氧基苯基;
R6为经取代或未经取代的单或多环残基,任选地为部分或全部不饱和,包含碳原子且任选地包含选自N、S或O的一或多个杂原子;
或R6可选自:
条件是在式(I)化合物中,当五员杂环核为1,3,4-氧杂二唑时,R6不为萘基。
另一类优选的化合物包含式(I)及(II)化合物及其药学上可接受的盐、异构体及药学上可接受的酯,其中五员杂环核选自四唑、1,2,4-***、1,3,4-氧杂二唑、1,2,4-氧杂二唑、1,3,4-噻二唑。
另一类优选的化合物包含式(I)及(II)化合物及其药学上可接受的盐、异构体及药学上可接受的盐,其中:
在式(I)中,A=N、O、S,而在式(II)中,A=N;
B=C、N;
在式(I)中C=N、O,而在式(II)中C=N;
X=CH2、S;
n=0、1;
当n=1时,碳原子可被R12及R13取代,该R12及R13独立选自H、-Me、-苯基、-F及-OH,或R12及R13可一起形成饱和环状部分,优选环丙烷、环丁烷、环戊烷或环己烷;
当n=1时,R6可不存在;
R4=R5=H、F;
R1为不存在,或其选自-H、-NH2、-CH3、-CH2CH3、苯基、对氟苯基、间氯苯基、对氯苯基、苄基、甲基呋喃、环丙基、异丁基、甲基苯基、三氟苯基、噻吩及2-(吗啉-4-基)乙基;
R2为不存在,或其选自H、苯基或对二氯苯基;
R3为不存在,或其选自H、邻甲氧基苯基、对三氟甲基苯基、苄基或吡啶基;
R6选自:
其中:
R7及R8独立选自H、D、-Cl、-F、-Br、-CF3、-Me、-Et、-OMe、-O苄基、-SF5、-OCH2F、-CH2NH2、-NH2、-CH2NMe2、-NMe2、-N(CH2CH2OCH3)2、-COOH、-COOMe、-OH、-NHNH2、-NO2、-OEt、-OCHF2、-OiPr、-CHF2、-NEt2、
或R7及R8可一起形成杂五员环状部分(-OCH2O-);
R9=R10=-H、-Me、-Et;
R11选自-H、-Cl、-CH3、-NO2及-Br。
下列式(I)及(II)化合物是特别优选的:
–(S)-N-(1-(3-(4-(羟基胺甲酰基)苄基)-1,2,4-氧杂二唑-5-基)-2-(噻唑-4-基)乙基)-3,4-二甲氧基苯甲酰胺(化合物1);
–3,5-二氟-N-羟基-4-((4-甲基-5-(萘-1-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物2);
–4-((5-(3-(N,N-二甲基胺磺酰基)苯基)-1,3,4-氧杂二唑-2-基)甲基)-N-羟基苯甲酰胺(化合物3);
–3,5-二氟-N-羟基-4-((4-甲基-5-(2-苯基丙-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物4);
–4-((5-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-1H-四唑-1-基)甲基)-3,5-二氟-N-羟基苯甲酰胺(化合物5);
–3,5-二氟-N-羟基-4-((5-(吡啶-2-基)-2H-四唑-2-基)甲基)苯甲酰胺(化合物6);
–二氟-N-羟基-4-((5-(嘧啶-2-基)-2H-四唑-2-基)甲基)苯甲酰胺(化合物7);
–N-羟基-4-((5-(噻吩-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物8);
–3,5-二氟-N-羟基-4-((4-甲基-5-(4-甲基-2-吗啉基噻唑-5-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物9);
–N-羟基-4-((4-甲基-5-(噻吩-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物10);
–4-((5-(呋喃-2-基)-2H-四唑-2-基)甲基)-N-羟基苯甲酰胺(化合物12);
–3,5-二氟-N-羟基-4-((5-(吡啶-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物13);
–3,5-二氟-N-羟基-4-((4-甲基-5-(吡啶-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物14);
–3,5-二氟-N-羟基-4-((5-(噻吩-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物15);
–3,5-二氟-N-羟基-4-((4-甲基-5-(4-(哌啶-1-基甲基)苯基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物16);
–3,5-二氟-N-羟基-4-((4-甲基-5-(噻吩-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物17);
–3,5-二氟-4-((5-(呋喃-2-基)-2H-四唑-2-基)甲基)-N-羟基苯甲酰胺(化合物19);
–N-羟基-4-((5-(吡啶-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物20);
–3-(3,4-二甲氧基苯基)-N-[(1S)-1-[3-[[4-(羟基胺甲酰基)苯基]甲基]-1,2,4-氧杂二唑-5-基]-2-噻唑-4-基-乙基]丙酰胺(化合物21);
–4-[[5-[4-(三氟甲基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物23);
–4-[(4,5-二苯基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物24);
–4-[[4-(2-呋喃基甲基)-5-(1H-吲哚-3-基)-1,2,4-***-3-基]氢硫基]苯羟肟酸;2,2,2-三氟乙酸(化合物25);
–4-[5-[(3,4-二甲氧基苯基)甲基]-1,3,4-氧杂二唑-2-基]苯羟肟酸(化合物26);
–4-[[5-苄基-4-(4-氟苯基)-1,2,4-***-3-基]氢硫基]苯羟肟酸;2,2,2-三氟乙酸(化合物27);
–4-[[4-氨基-5-[4-(二氟甲氧基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物28);
–4-[[5-(4-氟苯基)-4H-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物29);
–4-[[4-乙基-5-(4-氟苯基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物30);
–4-[[5-(4-氯苯基)四唑-2-基]甲基]苯羟肟酸(化合物31);
–4-[[5-(5-氯-2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物32);
–4-[[5-(2-氟苯基)四唑-2-基]甲基]苯羟肟酸(化合物33);
–4-[[5-(4-氟苯基)四唑-2-基]甲基]苯羟肟酸(化合物34);
–4-[[5-(4-甲氧基苯基)四唑-2-基]甲基]苯羟肟酸(化合物35);
–4-[(5-苄基四唑-2-基)甲基]苯羟肟酸(化合物36);
–4-[(5-苄基四唑-1-基)甲基]苯羟肟酸(化合物37);
–4-[[5-(2,4-二氯苯基)四唑-2-基]甲基]苯羟肟酸(化合物38);
–4-[[5-(3-甲基-2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物39);
–4-[[5-(5-甲基-2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物41);
–4-[[5-(苯并噻吩-3-基)四唑-2-基]甲基]苯羟肟酸(化合物42);
–4-[[5-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)四唑-2-基]甲基]苯羟肟酸(化合物43);
–4-[[5-[(3,4-二甲氧基苯基)甲基]-2-[4-(三氟甲基)苯基]-1,2,4-***-3-基]甲基]苯羟肟酸(化合物44);
–4-[[5-[(3,4-二甲氧基苯基)甲基]-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物45);
–4-[[5-(2-氟苯基)四唑-2-基]甲基]苯羟肟酸(化合物46);
–4-[[5-[(1S)-1-氨基-2-噻唑-4-基-乙基]-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物48);
–4-[[5-(3,4-二甲氧基苯基)-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物49);
–4-[[5-(2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物50);
–4-[[2-苄基-5-(4-氯苯基)-1,2,4-***-3-基]甲基]苯羟肟酸(化合物51);
–4-[[2-(2-吡啶基)-5-(2-噻吩基)-1,2,4-***-3-基]甲基]苯羟肟酸(化合物52);
–4-[[2-(2-甲氧基苯基)-5-(2-噻吩基)-1,2,4-***-3-基]甲基]苯羟肟酸(化合物53);
–4-[[5-(6,6-二甲基-3-甲基氢硫基-4-氧代-5,7-二氢-2-苯并噻吩-1-基)四唑-2-基]甲基]苯羟肟酸(化合物54);
–4-[[5-(苯并噻吩-2-基)四唑-2-基]甲基]苯羟肟酸(化合物55);
–4-[[5-(3,4-二甲氧基苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物57);
–4-[[5-(2,4-二氟苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物58);
–4-[[5-[3-(二甲基胺磺酰基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物59);
–4-[(5-苯基-1,3,4-氧杂二唑-2-基)氨基]苯羟肟酸(化合物60);
–4-[[4-氨基-5-[3-(二乙基胺磺酰基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物61);
–4-[[1-(2,4-二氯苯基)-5-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物62);
–4-[[5-(3-吡咯啶-1-基磺酰基苯基)-1,3,4-氧杂二唑-2-基]氨基]苯羟肟酸(化合物63);
–4-[[5-(3-吗啉基磺酰基苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物64);
–3,5-二氟-4-[[5-(2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物65);
–4-[[5-[3-(二乙基胺磺酰基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物66);
–4-[[4-甲基-5-[2-(对甲苯基)-4-喹啉基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物67);
–4-[(5-苯基-1,3,4-氧杂二唑-2-基)甲基]苯羟肟酸(化合物68);
–4-[[5-(4-吡咯啶-1-基磺酰基苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物69);
–4-[[5-(3-苄氧基-4-甲氧基-苯基)四唑-2-基]甲基]苯羟肟酸(化合物70);
–4-[[5-(3-苄氧基-4-甲氧基-苯基)四唑-1-基]甲基]苯羟肟酸(化合物71);
–4-[(5-环丙基-1-苯基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物72);
–4-[[5-[4-(二甲基氨基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物73);
–4-[[5-(4-甲基-2-吗啉基-噻唑-5-基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物75);
–4-[[5-[3-(二甲基氨基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物77);
–4-[[5-(3-甲氧基苯基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物78);
–4-[[5-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)四唑-2-基]甲基]-3,5-二氟-苯羟肟酸(化合物79);
–4-[[5-[3-(二甲基胺基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物80);
–4-[5-[4-(羟基胺甲酰基)苯基]氢硫基-4-甲基-1,2,4-***-3-基]哌啶-1-甲酸叔丁酯(化合物82);
–4-[[5-(2,3-二氢-1,4-苯并二恶英-3-基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物83);
–4-[[5-(1,3-苯并间二氧杂环戊烯-5-基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物84);
–4-[[5-(1,5-二甲基吡唑-3-基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物85);
–4-[[5-(2-呋喃基)四唑-1-基]甲基]苯羟肟酸(化合物86);
–4-[[5-(1-异喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物87);
–4-[[5-(1-异喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物88);
–4-[[5-(2-吡啶基)四唑-2-基]甲基]苯羟肟酸(化合物89);
–4-[[5-(2-喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物90);
–4-[[5-(2-喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物91);
–3,5-二氟-4-[[5-(2-呋喃基)四唑-1-基]甲基]苯羟肟酸(化合物92);
–3,5-二氟-4-[[5-(1-异喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物93);
–3,5-二氟-4-[[5-(1-异喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物94);
–3,5-二氟-4-[[5-(2-喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物95);
–3,5-二氟-4-[[5-(2-喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物96);
–3,5-二氟-4-[[5-(2-噻吩基)-4H-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物97);
–4-[(5-二苯甲基-4-甲基-1,2,4-***-3-基)氢硫基]-3,5-二氟-苯羟肟酸(化合物98);
–4-[[5-(3-氨基噻吩并[2,3-b]吡啶-2-基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物99);
–4-[[5-(1,5-二甲基吡唑-3-基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物100);
–3,5-二氟-4-[[4-甲基-5-(1-苯基环丁基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物101);
–3,5-二氟-4-[[5-[1-(3-氟苯基)环戊基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物102);
–3,5-二氟-4-[[5-[1-(4-甲氧基苯基)环己基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物103);
–3,5-二氟-4-[[5-[1-(4-甲氧基苯基)环丙基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物104);
–4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物106);
–4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物107);
–3,5-二氟-4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物108);
–3,5-二氟-4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物109);
–4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物110);
–4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物111);
–3,5-二氟-4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物112);
–3,5-二氟-4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物113);
–3,5-二氟-4-[[4-甲基-5-[3-(4-甲基-4-氧负离子基-哌嗪-4-鎓-1-基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(3,5-difluoro-4-[[4-methyl-5-[3-(4-methyl-4-oxido-piperazin-4-ium-1-yl)phenyl]-1,2,4-triazol-3-yl]sulfanyl]benzenecarbohydroxamic acid)(化合物114);
–3,5-二氟-4-[[4-(4-氟苯基)-5-(1-哌啶基甲基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物115);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-吡咯啶-1-基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物116);
–4-[(4-苄基-5-吗啉基-1,2,4-***-3-基)氢硫基]-3,5-二氟-苯羟肟酸(化合物117);
–4-[[5-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物118);
–3,5-二氟-4-[[5-(1-异喹啉基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物121);
–3,5-二氟-4-[[4-甲基-5-(2-喹啉基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物122);
–4-[(5-嘧啶-2-基四唑-2-基)甲基]苯羟肟酸(化合物123);
–4-[(5-嘧啶-2-基四唑-1-基)甲基]苯羟肟酸(化合物124);
–3,5-二氟-4-[(5-嘧啶-2-基四唑-1-基)甲基]苯羟肟酸(化合物125);
–4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-2-基]甲基]苯羟肟酸(化合物126);
–4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-1-基]甲基]苯羟肟酸(化合物127);
–3,5-二氟-4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-2-基]甲基]苯羟肟酸(化合物128);
–3,5-二氟-4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-1-基]甲基]苯羟肟酸(化合物129);
–4-[[5-[3-吗啉基-5-(三氟甲基)-2-吡啶基]四唑-2-基]甲基]苯羟肟酸(化合物130);
–4-[[5-[3-吗啉基-5-(三氟甲基)-2-吡啶基]四唑-1-基]甲基]苯羟肟酸(化合物131);
–4-[[5-(2-吡啶基甲基)四唑-2-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物132);
–4-[[5-(2-吡啶基甲基)四唑-1-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物133);
–3,5-二氟-4-[[5-(2-吡啶基甲基)四唑-2-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物134);
–3,5-二氟-4-[[5-(2-吡啶基甲基)四唑-1-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物135);
–3,5-二氟-4-[[4-甲基-5-[1-苯基-5-(2-噻吩基)吡唑-3-基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物136);
–3,5-二氟-4-[[5-(6-氟-2-甲基-3-喹啉基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物137);
–3,5-二氟-4-[[5-(4-氟苯基)-4-(2-吗啉基乙基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物138);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-吡嗪-2-基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物139);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(2-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物140);
–4-[[4-苄基-5-(吡咯啶-1-基-甲基)-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物141);
–4-[[4-苄基-5-(2-呋喃基)-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物142);
–4-[[4-苄基-5-(2-噻吩基)-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物143);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(2-噻吩基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物144);
–3,5-二氟-4-[[5-(2-氟苯基)-4-(2-呋喃基甲基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物145);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(4-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物146);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(3-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物147);
–3,5-二氟-4-[[5-(3-异喹啉基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物148);
–3,5-二氟-4-[(5-咪唑并[1,2-a]吡啶-3-基-4-甲基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物149);
–4-[[5-(1-苄基-4-苯基-4-哌啶基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物150);
–3,5-二氟-4-[[4-甲基-5-[3-(4-甲基哌嗪-1-基)磺酰基苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物151);
–4-[[5-[3-(4-苄基哌嗪-1-基)磺酰基苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物152);
–3,5-二氟-4-[[4-甲基-5-(3-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物153);
–4-[[2-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸甲酯(化合物154);
–4-[[1-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸甲酯(化合物155);
–6-[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]吡啶-3-甲酸甲酯(化合物156);
–6-[1-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]吡啶-3-甲酸甲酯(化合物157);
–4-[[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物158);
–4-[[1-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物159);
–4-[[2-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物160);
–4-[[1-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物161);
–6-[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]吡啶-3-甲酸(化合物162);
–3-[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]苯甲酸(化合物163);
–3,5-二氟-4-[[4-甲基-5-(8-喹啉基甲基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物164);
–4-[[5-(2,6-二氟苯基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物165);
–3,5-二氟-4-[[4-甲基-5-[3-(4-甲基哌嗪-1-基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物166);
–4-[[5-[3-(氮杂环庚烷-1-基甲基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物167);
–4-[[5-[4-(氮杂环庚烷-1-基甲基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物168);
–4-[[5-(4-氨基苯基)四唑-2-基]甲基]苯羟肟酸(化合物169);
–4-[[5-(4-氨基苯基)四唑-1-基]甲基]苯羟肟酸(化合物170);
–4-[[5-(4-氨基苯基)四唑-2-基]甲基]-3,5-二氟-苯羟肟酸(化合物171);
–4-[[5-(4-氨基苯基)四唑-1-基]甲基]-3,5-二氟-苯羟肟酸(化合物172);
–4-[[5-[4-(氨基甲基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物173);
–4-[[5-[4-(氨基甲基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物174);
–4-[[5-[4-(氨基甲基)苯基]四唑-2-基]甲基]-3,5-二氟-苯羟肟酸(化合物175);
–4-[[5-[4-(氨基甲基)苯基]四唑-1-基]甲基]-3,5-二氟-苯羟肟酸(化合物176);
–3,5-二氟-4-[[4-甲基-5-[1-(2-吡啶基)环丙基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物177);
–3,5-二氟-4-[[4-甲基-5-[1-(3-吡啶基)环丙基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物178);
–3,5-二氟-4-[(4-甲基-5-哒嗪-3-基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物179);
–3,5-二氟-4-[[5-(3-氟-2-吡啶基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物180);
–3,5-二氟-4-[[4-甲基-5-[3-(1-哌啶基甲基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物181);
–3,5-二氟-4-[[4-甲基-5-[3-(吗啉基甲基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物182);
–4-((3-((1H-吲哚-3-基)甲基)-5-(噻吩-2-基)-4H-1,2,4-***-4-基)甲基)-N-羟基苯甲酰胺(化合物183);
–4-[[5-[3-[[苄基(甲基)氨基]甲基]苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物184);
–4-[[3-[(3,4-二甲氧基苯基)甲基]-5-(2-噻吩基)-1,2,4-***-4-基]甲基]苯羟肟酸(化合物185);
–3,5-二氟-4-[[4-甲基-5-[1-甲基-1-(3-吡啶基)乙基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物186);
–3,5-二氟-4-[[5-[4-[甲基(甲基磺酰基)氨基]苯基]-1,3,4-噻二唑-2-基]氢硫基]苯羟肟酸(化合物187);
–4-[(5-苯基-1,3,4-氧杂二唑-2-基)氢硫基]苯羟肟酸(化合物188);
–4-[(5-苯基-1,2,4-氧杂二唑-3-基)甲基]苯羟肟酸(化合物189);
–4-[(5-苯基-1,3,4-噻二唑-2-基)甲基]苯羟肟酸(化合物190);
–3,5-二氟-N-羟基-4-((5-(吡啶-3-基)-1,3,4-噻二唑-2-基)硫基)苯甲酰胺(化合物191);
–3,5-二氟-4-[(5-苯基-1,3,4-氧杂二唑-2-基)氢硫基]苯羟肟酸(化合物192);
–4-[[5-(2-吗啉基-4-吡啶基)-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物193);
–3,5-二氟-N-羟基-4-((5-苯基-1,2,4-氧杂二唑-3-基)甲基)苯甲酰胺(化合物194);
–3,5-二氟-4-[[5-(4-吡啶基)-1,3,4-噻二唑-2-基]甲基]苯羟肟酸(化合物195);
–4-[[5-(5-溴-3-吡啶基)-1,3,4-噻二唑-2-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物196);
–3,5-二氟-4-[[5-(5-吗啉基-3-吡啶基)-1,3,4-噻二唑-2-基]甲基]苯羟肟酸(化合物197);
–3,5-二氟-N-羟基-4-((5-苯基-1,3,4-噻二唑-2-基)甲基)苯甲酰胺(化合物198);
–3,5-二氟-4-[[5-(2-呋喃基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物199);
–4-[[5-[5-[双(2-甲氧基乙基)氨基]-3-吡啶基]-1,2,4-氧杂二唑-3-基]甲基]-3,5-二氟-苯羟肟酸(化合物200);
–3,5-二氟-4-[[5-[5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)-3-吡啶基]-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物201);
–3,5-二氟-4-[[5-[5-(吡咯啶-1-基甲基)-2-呋喃基]-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物202);
–3,5-二氟-4-[[4-甲基-5-[5-(吗啉基甲基)-3-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物203);
–3,5-二氟-4-[[4-甲基-5-[5-(吗啉基甲基)-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物204);
–3,5-二氟-4-[[4-甲基-5-[5-[(4-甲基哌嗪-1-基)甲基]-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物205);
–4-[[5-[5-[(二甲基氨基)甲基]-2-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物206);
–3,5-二氟-4-[[4-甲基-5-[5-(吡咯啶-1-基甲基)-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物207);
–4-[[5-[5-乙基-4-(吡咯啶-1-基甲基)-2-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物208);
–4-[[4-甲基-5-[5-[(4-甲基哌嗪-1-基)甲基]-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物209);
–3,5-二氟-4-[[4-甲基-5-[6-(2-吡咯啶-1-基乙基)-3-吡啶基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物210);
–4-[[5-[5-(二乙基氨基甲基)-2-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物211);
–3,5-二氟-4-[[4-甲基-5-[5-(1-哌啶基甲基)-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物212);
–4-[[5-[5-(二乙基氨基甲基)-2-甲基-3-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物213);
–4-[(5-苯基四唑-2-基)甲基]苯羟肟酸(化合物214);
–4-[(5-苯基四唑-1-基)甲基]苯羟肟酸(化合物215);
–4-[(5-苯基-4H-1,2,4-***-3-基)甲基]苯羟肟酸(化合物216);
–N-羟基-4-((4-甲基-5-苯基-4H-1,2,4-***-3-基)甲基)苯甲酰胺(化合物217)。
下列式(I)及(II)化合物是特别优选的:
本发明的化合物可含有一个或多个手性中心(不对称碳原子),因此它们能以对映异构体的形式及/或非对映异构体的形式存在。
所有可能的光学异构体,单独或与彼此的混合物的形式,均落入本发明的范围内。
根据本发明的化合物可单独使用或与其它药物组合使用,例如蛋白酶体抑制剂、免疫化学抑制剂、类固醇、布罗莫结构域抑制剂(bromodomain inhibitor)及其它表观遗传药物(epigenetic drug)、传统化疗剂、激酶抑制剂,例如但不限于JAK家族、CTLA4、PD1或PDL1检查点抑制剂(checkpoint inhibitor),如纳武单抗(nivolumab)、派姆单抗(pemprolizumab)、皮地利珠单抗(pidilizumab)或BMS-936559(抗PD1)、阿特珠单抗(atezolizumab)或阿维鲁单抗(avelumab)(抗PDL1)、易普利单抗(ipilimumab)或崔梅利单抗(tremelimumab)(抗CTLA4)。
单独或组合的本发明的化合物优选用于治疗HDAC6介导的疾病。
单独或组合的本发明的化合物优选用于治疗移植物排斥、GVHD、肌炎、与淋巴细胞功能异常有关的疾病、多发性骨髓瘤、非霍奇金氏淋巴瘤、周围神经病变、自身免疫疾病、炎性疾病、癌症及神经退化性疾病、眼部疾病(例如眼色素层炎)。
因此,本发明还提供药物组合物,其包含治疗有效量的式(I)或(II)化合物、或其药学上可接受的盐、异构体及药理学上可接受的前药以及至少一种药学上可接受的赋形剂。
这种组合物可为液体,适用于肠内或肠胃外施用,或者为固体,例如以胶囊、锭剂、丸剂、粉剂或颗粒剂的形式用于口服施用,或者为适于皮肤施用的形式,如霜剂或软膏剂,或者用于吸入递送。
本发明的药物组合物可通过使用已知的方法来制备。
一般合成途径
本发明中描述的化合物可通过使用本领域技术人员已知的方法来制备。
在合成所述化合物中使用的所有起始材料、试剂、酸、碱、溶剂及催化剂均为商业上可取得的。
通过HPLC、UPLC或HPLC-MS分析来监测反应进程。
通过在DMF中在碳酸钾的存在下加热过夜,使1,2,4-***硫醇任选地与4-碘苯甲酸甲酯或3,4,5-三氟苯甲酸甲酯取代反应而获得***硫醇核化合物。以碘化铜及L-脯氨酸催化与4-碘-苯甲酸甲酯的反应(方案1),并于120℃加热(Liang-Feng等人,Tetrahedron(2011),67,2878-2881)。另一方面,与3,4,5-三氟苯甲酸甲酯的反应则在温和条件(55℃)下且无催化剂下进行(方案2)(Dudutiene等人,Bioorg.Med.Chem.(2013),21(7),2093-2106;WO03/062225)。
使用相同条件合成1,3,4-噻二唑-2-硫醇及1,3,4-氧杂二唑-2-硫醇核化合物。
通过在甲醇中在碱性介质(NaOH)以大量过量的羟基胺水溶液处理来实现酯衍生物转化成对应的羟肟酸。也可通过以NaOH将甲基酯水解并随后以HATU或其它偶合剂活化后与羟基胺缩合来合成羟肟酸。
方案1–具有***、噻二唑及氧杂二唑核的苯基羟肟酸衍生物的合成
方案2–具有***、噻二唑及氧杂二唑核的3,5-二氟苯基羟肟酸衍生物的合成
许多起始1,2,4-***-硫醇是商业上可取得的。在一些情况下,根据方案3所示的两种途径合成它们。由羧酸通过以T3P活化并在DMF中在DIPEA的存在下与N-取代的胺硫脲(hydrazine carbothioamide)缩合而制备开环中间体(open intermediate)(US 2007/0232808)。由酰肼起始,在回流的乙醇中以N-取代的异硫氰酸酯处理而获得相同的中间体(Lei等人,ChemMedChem(2016),11,822-826;Nadjet等人,Molecules(2015),20,16048-16067)。通过向反应混合物中加入NaOH水溶液而实现开环中间体的环化。
方案3–1,2,4-***-硫醇的合成
通过在低温下(0-5℃)以KOH及CS2处理对应的酰肼持续1小时并在第二步骤以H2SO4处理来合成非商业上可取得的1,3,4-噻二唑-2-硫醇,如方案4所述。
方案4–1,3,4-噻二唑-硫醇的合成
具有***核的化合物如方案5a所述制备,起始自2-(4-(甲氧基羰基)苯基)乙酸,通过与甲脒(carboxyimidamide)在HATU及DIPEA的存在下在DMF中反应。当起始产物完全转化成中间体后,将取代的肼及过量的乙酸加入反应混合物中。通过加热混合物过夜而实现***环的形成(Castanedo等人,J.Org.Chem.(2011),76(4),1177-1179)。
还通过开环中间体的环化而获得具有1,3,4-噻二唑及1,3,4-氧杂二唑架构的化合物,该开环中间体通过使用通常HATU、DIPEA活化的2-(4-(甲氧基羰基)苯基)乙酸或2-(2,6-二氟-4-(甲氧基羰基)苯基)乙酸与适当的酰肼的缩合而制备。酰肼为商业上可取得的,或者可容易地由对应的羧酸制备(方案5c)。使用劳森试剂(Lawesson’s Reagent)作为1,3,4-噻二唑衍生物的环化剂,而相同的中间体在回流甲苯或THF中以过量的伯吉斯试剂(Burgess’Reagent)处理时环化以提供1,3,4-氧杂二唑(方案5b)。由于2-(2,6-二氟-4-(甲氧基羰基)苯基)乙酸并非商业上可取得的,其通过在无水DMF中在氢化钠的存在下使3,4,5-三氟苯甲酸甲酯与丙二酸二叔丁酯反应而合成。所得的2-(2,6-二氟-4-(甲氧基羰基)苯基)丙二酸二叔丁酯通过在回流下以TFA处理而脱羧基化(方案5c)。
由于2-(2,6-二氟-4-(甲氧基羰基)苯基)乙酸的较低反应性,有必要以亚硫酰氯将其活化以实现缩合(方案5c)。通过如上述情况所述的羟基氨解(hydroxylaminolysis)而实现酯衍生物转化为对应的羟肟酸。
方案5–具有***、噻二唑及氧杂二唑核的苯基羟肟酸衍生物的合成
使用1,3,4-氧杂二唑衍生物作为起始材料用于合成带有***核的化合物。通过在THF中在MeNH2存在下加热氧杂二唑而实现转化,如方案6所述。
方案6–1,2,3-***衍生物的合成
在三甲胺的存在下,由对氨基甲基苯甲酸甲酯盐酸盐及对应的酰氯起始制备带有3,4,5-三取代的1,2,4-***作为骨架的化合物。将由此获得的酰胺在亚硫酰氯中进行回流以形成中间体亚胺酰氯(imidoyl chloride),其在与对应的酰肼反应,并随后于回流的甲苯中环化后得到所期望的产物(方案7)。(WO2011106650(A2)―2011-09-01;Begum等人Med.Chem.Commun.2015,6,80-89;Aster等人.Bioorg.Med.Chem.Lett.2008,18,2799-2804)。
方案7–具有3,4,5-三取代的1,2,4-***核的苯基羟肟酸衍生物的合成
通过在加热下,在乙腈中在碳酸钾的存在下,使N-H-四唑与4-(氯甲基)苯甲酸甲酯或4-(氯甲基)-3,5-二氟苯甲酸甲酯反应而获得含有四唑部分的化合物(方案8)(WO2012/106995)。
方案8–具有四唑核的苯基羟肟酸及3,5-二氟苯基羟肟酸衍生物的合成
位置选择性取决于四唑基质,通常为2,5-二取代的产物,其比1,5-二取代产物有利2-10倍。通过二氧化硅层析分离的位置异构体(regioisomer)分别用过量的羟基胺及氢氧化钠水溶液处理,以获得各自的羟肟酸产物。
一些起始N-H-四唑为商业上可取得的,而其它通过在加热下,以叠氮化钠及氯化铵在DMF中处理各自的腈而合成(方案9)。
方案9–NH-四唑的合成
通过在THF中在室温下(rt)将酰基酰肼与4-异氰酸基苯甲酸甲酯结合,并于过量伯吉斯试剂存在下将刚形成的中间体进行回流而获得含有2-氨基-1,3,4-氧杂二唑部分的化合物(方案10)(Dolman等人,J.Org.Chem.(2006),71(25),9548)。
方案10–具有2-氨基-1,3,4-氧杂二唑核的苯基羟肟酸衍生物的合成
如上列情形所述,通过羟基氨解而实现酯化合物至羟肟酸的转化。
通过在回流乙醇中在过量氢氧化钾或碳酸氢钠的存在下以羟基胺盐酸盐处理,由4-(氰基甲基)苯甲酸或对应的甲基酯合成1,2,4-氧杂二唑核化合物(方案11)。然后将如此获得的(Z)-4-(2-氨基-2-(羟基亚胺基)乙基)苯甲酸与事先经HATU及DIPEA或其它活化剂活化的适当的羧酸反应,以得到开环中间体,其通过在分子筛或环化剂如羰基二咪唑的存在下于100℃加热而进行环化。
方案11–具有1,2,4-氧杂二唑核的苯基羟肟酸衍生物的合成
羧酸转化为羟肟酸能以本领域已知的任何方法完成。一般通过以HATU、DCC或酰氯活化,并使活化的化合物与羟基胺水溶液反应而获得。在一些情形中,必须将羧酸与O-(四氢-2H-吡喃-2-基)羟基胺缩合,以便获得可通过以TFA处理而释放的羟肟酸保护形式(方案12)。
方案12–羧酸通过其保护的形式而转化成羟肟酸
为了合成具有1,3,4-氧杂二唑核的化合物(方案13),通过使经酰氯活化的对应酸与Boc-肼反应并随后以TFA处理来脱保护,而制备适当的酰肼。然后,将酰肼与预先以HATU及DIPEA活化的2-(4-(甲氧基羰基)苯基)乙酸缩合。通过在甲苯或THF中在回流下以过量的伯吉斯试剂处理,来实现开环中间体的环化。
方案13–具有1,3,4-氧杂二唑核的羟肟酸衍生物的合成
如先前所述,可通过在大量过量的氢氧化钠存在下使甲基酯与羟基胺反应进行羟基氨解,来获得最终的羟肟酸衍生物。
以下实施例旨在进一步说明本发明而非限制本发明。
实施例1–(S)-N-(1-(3-(4-(羟基胺甲酰基)苄基)-1,2,4-氧杂二唑-5-基)-2-(噻唑-4基)乙基-3,4-二甲氧基苯甲酰胺(化合物1)的合成
步骤A
在4-(氰基甲基)苯甲酸(3.04g,1当量)在EtOH(250ml)的溶液中,添加KOH(3.17g,3当量)及羟基胺盐酸盐(2.62g,2当量)。将反应混合物回流20小时。然后将溶液冷却,以水(300ml)稀释并以浓HCl酸化成pH 6。过滤沉淀的白色固体,并于50℃真空下干燥过夜。获得2.6g的产物,其不经任何进一步纯化而用于下一步骤。
步骤B
通过在室温下于DMA中以HATU(2.5g,1.3当量)及DIPEA(1.4ml)处理1小时,来活化(S)-2-(N-Fmoc-氨基)-3-(噻唑-4-基)丙酸(2g,1当量)。然后,添加另外的DIPEA(1.4mL)及(Z)-4-(2-氨基-2-(羟基亚胺基)乙基)苯甲酸(985mg,1当量)至反应混合物。当起始产物完全溶解后,添加分子筛以便移除形成的水,并帮助开环中间体的环化。两小时后,通过过滤去除分子筛,在减压下蒸发溶剂。将残余物溶解于甲醇中。通过过滤移除析出的白色固体。将溶剂部分蒸发。观察到另外的白色固体的沉淀,将其过滤。将溶液蒸发至干燥,残余物通过H2O/ACN/TFA梯度的逆相快速层析(reverse phase flash chromatography)(C18)纯化。
步骤C
通过在DMF中于室温下以HATU(73mg,1.3当量)及DIPEA(41μ,1.3当量)处理,来活化步骤B获得的酸(82mg,1当量)。添加O-(四氢-2H-哌喃-2-基)羟基胺(17mg,1当量)至反应混合物。在室温搅拌2小时后,于真空离心机中蒸发溶剂。残余物不经任何进一步纯化而用于下一步骤。
步骤D
将步骤C获得的产物稀释于1ml的THF中,并以DEA(70μl,4.5当量)处理。在40℃搅拌4小时后,在减压下通过蒸发而移除溶剂及过量的DEA。将残余物溶解于1ml的DMF中,并添加事先于DMF(1ml)中以HATU(74mg,1.3当量)及DIPEA(41μ,1.3当量)活化的3,4-二甲氧基苯甲酸(27mg,1当量)至此溶液。在室温下搅拌反应混合物4小时。最后,添加0.4ml的TFA以对羟肟酸官能团脱保护。4小时后,通过蒸发而移除溶剂及过量的TFA,并将残余物经由半制备LC-MS纯化(m/z 509.84[MH+])。
使用相同的程序合成下列化合物:
实施例2–(S)-4-((5-(1-氨基-2-(噻唑-4-基)乙基)-1,2,4-氧杂二唑-3-基)甲基)-N-羟基苯甲酰胺2,2,2-三氟乙酸盐(化合物48)的合成
在室温下于DMF(1ml)中以DEA(159μl,4.5当量)处理(9H-茀-9-基)甲基((1S)-1-(3-(4-(((四氢-2H-哌喃-2-基)氧基)胺甲酰基)苄基)-1,2,4-氧杂二唑-5-基)-2-(噻唑-4-基)乙基)胺甲酸酯(在化合物1的合成的步骤C中获得)(222mg,1当量)过夜。然后添加0.520ml的TFA(20当量)至反应混合物。通过蒸发而移除溶剂,并将残余物用半制备LC-MS纯化(m/z 346.04[MH+])。
实施例3–4-[[5-(3,4-二甲氧基苯基)-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物49)的合成
步骤A
在回流下将4-(氰基甲基)苯甲酸(3g,1当量)、羟基胺盐酸盐(2.6g,2当量)及氢氧化钾(3.2g,3当量)在乙醇(250ml)中的混合物加热过夜。冷却至室温后,添加300ml的水及15ml的1N HCl(pH≈5)至反应混合物。将作为沉淀物而获得的所期望产物滤出于烧结隔膜上,并于真空下干燥过夜。回收320mg的纯净产物。
步骤B
将步骤A获得的(Z)-4-(2-氨基-2-(羟基亚胺基)乙基)苯甲酸(319mg,1.1当量)溶解于甲苯(6ml)中,并添加吡啶(3ml)。将事先通过使3,4-二甲氧基苯甲酸与过量的亚硫酰氯反应而制备的3,4-二甲氧基苯甲酰氯(300mg,1当量)加至反应混合物中。将反应混合物回流4小时。在减压下蒸发溶剂,并将产物通过半制备LC-MS纯化。
步骤C
通过在室温下于DMF(1mL)中以HATU(103mg,1.3当量)及DIPEA(47μl,1.3当量)处理30分钟,来活化在步骤B中获得的4-((5-(3,4-二甲氧基苯基)-1,2,4-氧杂二唑-3-基)甲基)苯甲酸(71mg,1当量)。然后添加羟基胺盐酸盐(14mg,1当量)及另外的DIPEA(47μl,1.3当量)至反应混合物中。在室温搅拌过夜后,在减压下蒸发移除溶剂,并将残余物通过半制备LC-MS纯化。回收33mg的纯净产物(m/z 356.08[MH+])。
实施例4.4-((5-(2,4-二氟苯基)-1,3,4-氧杂二唑-2-基)甲基)-N-羟基苯甲酰胺(化合物58)的合成
步骤A
将Boc-肼(150mg,1当量)在ACN(2ml)中的溶液及95mg的NaHCO3(1当量)添加至2,4-二氟苯甲酰氯(200mg,1当量)在ACN(3ml)中的溶液。在室温下3小时后,在空气流中蒸发溶剂。残余物以TFA处理3小时。在空气流中移除酸,并将残余物溶解于EtOAc中,并以2.5%NaHCO3溶液洗涤。合并的有机相以Na2SO4干燥,过滤并蒸发至干燥。获得159mg的产物,其不经任何进一步纯化而用于下一步骤。
步骤B
添加HATU(439mg,1.3当量)及DIPEA(0.4mL,2.6当量)至2-(4-(甲氧基羰基)苯基)乙酸(224mg,1.3当量)在5ml的THF中的溶液。在室温搅拌反应混合物1小时直到试剂完全溶解。然后,添加2,4-二氟苯甲酰肼(2,4-difluorobenzohydrazide)(153mg,1当量)在THF(2ml)中的溶液至混合物。在室温下4小时后,观察到起始试剂完全转化为所期望的产物。通过在空气流中蒸发而移除溶剂。将残余物溶解于H2O,并将形成的沉淀物过滤于烧结隔膜上。产物(149mg)不经任何进一步纯化而使用于随后的步骤。
步骤C
在加热回流下,将175mg的伯吉斯试剂(1.72当量)加入至步骤B获得的化合物(149mg,1当量)在5ml干甲苯中的悬浮液中。1小时后,观察到起始化合物完全转化为环产物。在真空下蒸发移除溶剂。将残余物溶解于DCM,并以1N HCl及H2O洗涤。有机相用Na2SO4干燥,过滤并蒸发至干燥。回收132.3mg的产物,其不经任何进一步纯化而用于随后步骤。
步骤D
将0.707ml的羟基胺水溶液(60当量)加入至步骤C获得的化合物(132mg,1当量)在4ml的MeOH/THF中的溶液中。逐滴缓缓添加1.998ml的1N NaOH(5当量)。约1小时后,***通过添加1N HCl(2ml)而中和。在真空下蒸发溶剂,并将残余物以2.5%NaHCO3溶液稀释,过滤并以H2O洗涤。将固体悬浮于Et2O中并过滤。获得53mg的纯产物(m/z 332.01[MH+])。
下列化合物使用相同程序合成:
实施例5.4-[(5-苯基-1,3,4-氧杂二唑-2-基)氨基]苯羟肟酸(化合物60)的合成
步骤A
在室温下将68mg的苯甲酰肼(1当量)及4-异氰基苯甲酸甲酯(88.5mg,1当量)混合于THF(5mL)中。搅拌生成的溶液3小时。通过HPLC及LC-MS证实中间体的形成。在减压下通过蒸发而移除溶剂。将残余物溶解于甲苯。将混合物回流,并将伯吉斯试剂(298mg,2.5当量)以小部分的方式添加直到中间体完全转化成环产物。冷却至室温后,实施利用水的洗涤。将有机相干燥,过滤并蒸发至干燥。通过由DCM结晶来纯化产物。获得172mg的纯净产物(Dolman等人,J.Org.Chem.(2006),71(25),9548)。
步骤B
将步骤A获得的酯(172mg,1当量)悬浮于4ml的甲醇中,以冰浴于0℃冷却反应混合物并进行磁力搅拌。添加羟基胺(50%,水溶液,1.365ml,40当量)后,逐滴缓缓添加1M氢氧化钠(6ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后,通过HPLC确认起始产物转化成羟肟酸。将甲醇的部分于减压下蒸发移除,随后通过加入6ml 1M HCl水溶液及6ml的乙酸乙酯来淬灭反应。将相进行分离,并以额外的乙酸乙酯(3x)再次萃取水层。合并有机相,并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收26mg的纯产物(m/z 297.09[MH+])。
使用相同的程序合成下列化合物:
实施例6.3,5-二氟-N-羟基-4-((4-甲基-5-(吡啶-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物14)的合成
步骤A
将2-吡啶基甲酸(123mg,1当量)及4-甲基-3-硫氨基脲(116mg,1.1当量)悬浮于2ml的DMF中,并以冰浴将混合物冷却至0℃。在搅拌下缓缓添加T3P(50%DMF溶液,893μL,1.5当量)及二异丙基乙基胺(310μL,1.78当量)至反应混合物。移除冰浴,并使混合物于室温反应16小时。通过HPLC确认起始材料的完全转化。添加2ml的乙酸乙酯、2ml的水及2ml的4M NaOH水溶液至反应混合物。将相进行分离,有机层以4M NaOH水溶液再萃取。将合并的水相于70℃搅拌16小时。通过LC-MS确认开环中间体转化成所期望的产物。通过在搅拌下逐滴添加浓盐酸而调整反应混合物pH至5。通过过滤收集沉淀物。
获得157mg的产物,其不经任何进一步纯化而用于随后步骤。
步骤B
在氩气环境下,将4-甲基-5-(吡啶-2-基)-4H-1,2,4-***-3-硫醇(157mg,1当量)、3,4,5-三氟苯甲酸甲酯(156mg,eq)及碳酸钾(261mg,2.3当量)悬浮于2ml的DMF中。将生成的混合物加温至40℃并搅拌过夜。
反应混合物以10ml的乙酸乙酯及10ml的水稀释。将相进行分离,并将水层以额外的乙酸乙酯(3x)再萃取。合并有机相并以盐水(2x)洗涤,以硫酸钠干燥,过滤并浓缩。
通过快速层析(Grace Reveleris X2,己烷:乙酸乙酯)纯化粗制反应。获得149mg的纯净产物(Dudutiene等人,Bioorg.Med.Chem.(2013),21(7),2093-2106;国际专利申请WO03/062225)。
步骤C
将步骤B获得的酯(149mg,1当量)悬浮于5ml的甲醇中,并以冰浴于0℃冷却反应混合物并进行磁力搅拌。添加羟基胺(50%,水溶液,0.97ml,40当量)后,逐滴添加1M氢氧化钠(4.1ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后,通过HPLC确认起始产物转化成羟肟酸。在减压下,通过蒸发移除甲醇的部分,随后通过添加4.1ml的1M盐酸水溶液及6ml的乙酸乙酯来淬灭反应。将相进行分离,且以额外的乙酸乙酯(3x)再萃取水层。合并有机相并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收113mg的纯产物(m/z 363.94[MH+])。
使用此程序合成下列化合物:
使用此程序,由2-巯基-1,3,4-氧杂二唑起始来替代2-巯基-1,3,4-***而合成下列化合物:
实施例7.4-[[5-[3-(二乙基胺磺酰基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物66)的合成
步骤A
在氩气环境下在碘化铜(10mg,0.05当量)、L-脯氨酸(11mg,0.1当量)及碳酸钾(152mg,1.1当量)在1mL的DMF溶液中,依次添加4-碘苯甲酸甲酯(288mg,1.1当量)及N,N-二乙基-3-(5-巯基-4-甲基-4H-1,3,4-***-3-基)苯磺酰胺(326mg,1当量)。在120℃加热反应混合物,并搅拌过夜。通过HPLC观察杂芳香族硫醇的消耗。
反应混合物以10ml的乙酸乙酯及10ml的水稀释。将相进行分离,并以额外乙酸乙酯(3x)再萃取水层。合并有机相并以盐水(2x)洗涤,以硫酸钠干燥,过滤并浓缩。
通过快速层析(Grace Reveleris X2,己烷:乙酸乙酯)纯化粗产物。获得236mg的产物。
步骤B
将步骤A获得的酯(236mg,1当量)悬浮于15ml的甲醇,并将反应混合物以冰浴于0℃冷却并进行磁力搅拌。添加羟基胺(50%,水溶液,1.2ml,40当量)后,逐滴添加1M氢氧化钠(4.1ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后,通过HPLC确认起始产物转化成羟肟酸。在减压下通过蒸发而移除甲醇的部分,且反应随后通过添加4.1ml的1M盐酸水溶液及6ml的乙酸乙酯而淬灭。将相进行分离,且水层以额外的乙酸乙酯(3x)再萃取。合并有机相,并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收207mg的纯产物(m/z 432.00[MH+])。
使用此程序合成下列化合物:
使用此程序,由2-巯基-1,3,4-氧杂二唑起始来替代2-巯基-1,3,4-***而合成下列化合物:
实施例8.4-[[1-(2,4-二氯苯基)-5-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物62)的合成
步骤A
在硫氰酸钾(194mg,1当量)在干乙腈(6ml)的溶液中缓缓添加乙酰氯(143μL,1当量)。将混合物回流1小时,然后通过过滤移除形成的氯化钾。添加(2,4-二氯苯基)肼(427mg,1当量)至此溶液,并于回流下加热反应混合物。1.5小时后,LC-MS分析显示肼完全消耗。以冷水(50mL)充分稀释反应混合物,通过过滤而回收沉淀的固体。产物通过由n-Hex/EtOAc 75:25结晶而纯化。回收60mg产物。
步骤B
在碘化铜(2mg,0.05当量)、L-脯胺酸(3mg,0.1当量)及碳酸钾(35mg,1.1当量)在2ml的DMF溶液中,于氩气环境下,添加4-碘苯甲酸甲酯(66.5mg,1.1当量)及1-(2,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-硫醇(60mg,eq)。于120℃加热反应混合物并搅拌过夜。通过HPLC观察杂芳香族硫醇的消耗。
反应混合物以6ml的乙酸乙酯及6ml的水稀释。将相进行分离,且水层以额外的乙酸乙酯(3x)再萃取。合并有机相并以盐水洗涤(2x),以硫酸钠干燥,过滤并浓缩。获得的残余物不经任何进一步纯化而用于下列步骤。
步骤C
将步骤B获得的酯(40mg,1当量)悬浮于6ml的甲醇中,并以冰浴于0℃冷却反应混合物并进行磁力搅拌。添加羟基胺(50%,水溶液,236μl,40当量)后,逐滴添加1M氢氧化钠(1ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后,通过HPLC而确认起始产物转化为羟肟酸。于减压下通过蒸发而移除甲醇的部分,反应随后通过添加1ml的1M盐酸水溶液及1ml的乙酸乙酯而淬灭。将相进行分离,且水层以额外的乙酸乙酯(3x)再萃取。合并有机相,并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收30mg纯产物(m/z 396.89[MH+])。
实施例9.4-[[5-[(3,4-二甲氧基苯基)甲基]-2-[4-(三氟甲基)苯基]-1,2,4-***-3-基]甲基]苯羟肟酸(化合物44)的合成
步骤A
将2-(4-(甲氧基羰基)苯基)乙酸(97mg,0.5mmol)、1-氨基-2-(3,4-二甲氧基苯基)乙-1-亚胺基盐酸盐(1-amino-2-(3,4-dimethoxyphenyl)ethan-1-iminohydrochloride)(200mg,1.73当量)及HATU(209mg,1.1当量)装入具有螺帽的小瓶中。在氩气环境下依次加入2ml DMF及DIPEA(248μL,3当量)。在室温下搅拌反应混合物,并通过HPLC检查羧酸消耗及酰基脒(acylamidine)中间体形成。在2-3小时内观察到完全转化为中间体。
然后添加(4-(三氟甲基)苯基)肼盐酸盐(187mg,1.76当量)及乙酸(286μL,10当量)至反应混合物。密封小瓶,且加热混合物至80℃并搅拌过夜。
通过HPLC观察酰基脒中间体的消耗。
使混合物到达室温后,将其以乙酸乙酯稀释,并随后以饱和碳酸氢钠水溶液及盐水洗涤。有机层以硫酸钠干燥,过滤并浓缩至干燥。
产物通过快速层析(己烷:乙酸乙酯)而纯化(Castanedo等人,J.Org.Chem.(2011),76(4),1177-1179)。
步骤B
将步骤A获得的酯(82mg,1当量)悬浮于5ml的甲醇中,以冰浴于0℃冷却生成的反应混合物并进行磁力搅拌。添加羟基胺(50%,水溶液,189μl,20当量)后,逐滴添加1M氢氧化钠(1.6ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后通过HPLC确认起始产物转化成羟肟酸。在减压下通过蒸发移除甲醇的部分,反应随后通过添加1.6ml的1M盐酸水溶液及3ml的乙酸乙酯而淬灭。将相进行分离,且水层以额外的乙酸乙酯(3x)再萃取。合并有机相,并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收27mg纯产物(m/z 513.18[MH+])。
使用此程序合成下列化合物:
实施例10.4-((5-(呋喃-2-基)-2H-四唑-2-基)甲基)-N-羟基苯甲酰胺(化合物12)的合成
步骤A
将呋喃-2-甲腈(500mg,1当量)溶解于10ml的DMF中。在磁力搅拌下在室温下,添加叠氮化钠(770mg,2.2当量)及氯化铵(631mg,2.2当量)至反应混合物中。在120℃加热悬浮液,并搅拌过夜。通过LC-MS来观察起始材料的完全转化。
以冰浴将混合物冷却至0℃,以10ml的水稀释并以1M盐酸水溶液酸化。通过过滤而收集形成的沉淀物,并在于真空下干燥前以水洗涤二次。获得720mg的产物(国际专利申请WO2006/003096)。
步骤B
将碳酸钾(742mg,1当量)及5ml乙腈装入反应容器。在室温下在磁力搅拌下,将步骤A获得的四唑(364mg,1当量)作为固体添加,同时将4-氯甲基苯甲酸甲酯(1.1当量)作为在5ml乙腈中的溶液添加。将混合物于100℃加热,并搅拌过夜。通过LC-MS检查起始材料完全转化为两种位置异构的产物。通过过滤而去除不溶物质,于减压下蒸发滤液。两种位置异构体通过硅胶柱层析(甲苯:乙酸乙酯)而分离。回收384mg的2,5-二取代异构体及234mg的1,5-二取代异构体(国际专利申请WO2012/106995)。
步骤C
将步骤B获得的酯(100mg,1当量)悬浮于10ml的甲醇中,并于0℃以冰浴冷却生成的反应混合物并进行磁力搅拌。添加羟基胺(50%,水溶液,700μl,30当量)后,逐滴添加1M氢氧化钠(3.52ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后,通过HPLC确认起始产物转化成羟肟酸。在减压下通过蒸发而移除甲醇的部分,反应随后通过添加3.52ml的1M盐酸水溶液及6ml的乙酸乙酯而淬灭。将相进行分离,且水层以额外的乙酸乙酯(3x)再萃取。合并有机相,并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收93.5mg纯净产物(m/z 286.02[MH+])。
使用此程序合成下列化合物:
实施例11.4-((5-(2,3-二氢噻吩并[3,4-b][1,4]二恶英-5-基)-1H-四唑-1-基)甲基)-3,5-二氟-N-羟基苯甲酰胺(化合物5)的合成
步骤A
将碳酸钾(85mg,1当量)及2ml乙腈装入反应容器中。在室温下在磁力搅拌下,加入作为固体的四唑(105mg,1当量),同时将3,5-二氟-4-氯甲基苯甲酸甲酯(122.3mg,1.1当量)作为在2ml乙腈中的溶液添加。将混合物于100℃加热并搅拌过夜。通过LC-MS检查起始材料完全转化为两种位置异构的产物。通过过滤去除不溶物质,在减压下蒸发滤液。两种位置异构体通过硅胶柱层析(甲苯:乙酸乙酯)而分离。回收23mg的2,5-二取代异构体及52mg的1,5-二取代异构体(国际专利申请WO2012/106995)。
步骤B
将步骤A获得的酯(52mg,1当量)悬浮于2ml的甲醇中,并以冰浴于0℃冷却生成的反应混合物并进行磁力搅拌。添加羟基胺(50%,水溶液,311μl,40当量)后,逐滴添加1M氢氧化钠(1.3ml,10当量)水溶液。移除冰浴,使溶液到达室温。1小时后通过HPLC确认起始产物转化成羟肟酸。在减压下通过蒸发而移除甲醇的部分,反应随后通过添加1.3ml的1M盐酸水溶液及2ml的乙酸乙酯而淬灭。将相进行分离,且水层以额外的乙酸乙酯(3x)再萃取。合并有机相,并以碳酸氢钠饱和溶液(2x)、盐水(2x)洗涤,以硫酸钠干燥,过滤,并浓缩至干燥。回收32mg纯净产物(m/z 395.91[MH+])。
使用此程序合成下列化合物:
实施例12–3,5-二氟-N-羟基-4-((5-(吡啶-3-基)-1,3,4-噻二唑-2-基)硫基)苯甲酰胺(化合物191)的合成
步骤A
将KOH(1.48g,26.47mmol,1.1当量)溶解于45mL的无水乙醇中。添加酰肼(3.30g,24.06mmol,1当量),并冷却反应混合物至0-5℃。逐滴添加CS2(1.66mL,27.67mmol,1.15当量),并于0-5℃搅拌反应混合物1小时。收集生成的沉淀物,以冰丙酮冲洗并干燥而提供5.50g黄色固体。将所获得的中间体以小部分的方式加入冷却至0-5℃的25mL硫酸中。在0-5℃下1小时后,将反应混合物倒入冰水中,收集生成的沉淀物,以水冲洗并干燥。
步骤B
将步骤A获得的5-(吡啶-3-基)-1,3,4-噻二唑-2-硫醇(0.8g,4.1mmol,1当量)、4-碘苯甲酸(1.22g,4.92mmol,1.2当量)、L-脯氨酸(0.047g,0.4mmol,0.1当量)及K2CO3(2.26g,16.4mmol,4当量)在20mL的无水DMF中的混合物进行脱气,并添加CuI(0.039g,0.2mmol,0.05当量)。密封反应容器,并于120℃搅拌反应混合物48小时。通过LC-MS监测起始硫醇的完全转化。将反应混合物倒入150mL的水中,并通过硅藻土(Celite)垫过滤。以HCl酸化滤液。过滤形成的沉淀物,并连续以水、乙腈及二乙基醚冲洗。
步骤C
将HATU(0.181mg,0.476mmol,1.5当量)加入至步骤B获得的羧酸(0.1g,0.317mmol,1当量)及DIPEA(0.333mL,1.902mmol,6当量)在2mL的无水DMF的溶液中。在室温下搅拌反应混合物,并通过LC-MS监测酸全部转化成HATU-中间体:1小时后转化完成。添加NH2OH-HCl(0.066g,0.951mmol,3当量),并搅拌反应混合物2小时以上。通过LC-MS监测该反应。反应混合物以水稀释成50mL的总体积,并以EtOAc(225mL)萃取。蒸发后,获得101mg非常黏稠的橙色油。用乙腈研磨(~15min超声波处理)以形成沉淀物,通过过滤而收集沉淀物,用乙腈及二乙基醚冲洗并干燥。获得40mg纯产物(m/z 366.99[MH+])。LCMS:94.5%。NMR:OK。
使用此程序合成下列化合物:
实施例13–3,5-二氟-N-羟基-4-((5-苯基-1,3,4-噻二唑-2-基)甲基)苯甲酰胺(化合物198)的合成
步骤A
逐滴添加丙二酸叔丁酯(11.4g,52.73mmol,2当量)至NaH(1.5当量)于70mL的无水DMF的悬浮液中。在室温下搅拌5分钟后,添加3,4,5-三氟苯甲酸甲酯(5g,26.3mmol,1当量)。在室温下搅拌反应混合物3小时(观察到白色沉淀物形成),以水稀释并以EtOAc萃取。浓缩后,残余物通过柱层析而纯化。获得产物及丙二酸叔丁酯以1:3比例的不可分的混合物11.0g(通过NMR)。此混合物不经进一步纯化而用于下一步骤。
步骤B
将步骤A获得的混合物(8.6g,22mmol,1当量)及TFA(17mL,10当量)溶解于10mL的无水DCE中,并回流过夜。冷却后,蒸发溶剂,且将残余物以己烷处理,并收集形成的沉淀物。沉淀物及滤液的NMR分析显示,获得产物及丙二酸的混合物(约相同的2:1比例,产物更多)。合并收成物,并用于下一步骤。
步骤C
将步骤B中获得的混合物(0.5g,2.17mmol,1当量)溶解于5mL SOCl2中,回流1小时并浓缩。将获得的粗氯代酸酐(chloroanhydride)与在10mL无水DMF中的苯甲酰肼(0.643g,4.72mmol,2当量)混合,随后加入DIPEA(1.99mL,11.45mmol,5当量)。搅拌过夜后,将反应混合物以水淬灭,以EtOAc萃取并浓缩。将残余物以DCM处理并过滤。
步骤D
在120℃下,将步骤C获得的化合物(0.277g,0.88mmol,1当量)及劳森试剂(0.35g,0.86mmol,0.98当量)在5mL的甲苯中的混合物在密封小瓶中搅拌15分钟。通过UPLC检测起始材料的全部转化。蒸发溶剂,并通过柱层析纯化残余物,柱层析首先使用EtOAc在己烷中(梯度20%至100%),然后使用5%MeOH在DCM中。
步骤E
添加KOH(0.021g,0.37mmol,2当量)至步骤D获得的环化合物(0.06g,0.18mmol,1当量)在14mL的THF/水=4/1混合物的溶液中。在室温搅拌反应混合物过夜,并以1M HCl酸化。收集获得的沉淀物,并于真空中干燥。然后,将此固体溶解于THF与DIPEA(0.333mL,1.902mmol,6当量)中。添加HATU(0.181mg,0.476mmol,1.5当量),并在室温搅拌反应混合物,通过LC-MS监测酸至HATU-中间体的完全转化。添加NH2OH-HCl(0.066g,0.951mmol,3当量),并搅拌反应混合物2小时以上。以水稀释反应混合物至50mL的总体积,并以EtOAc(225mL)萃取。蒸发后获得101mg极黏稠的油。用乙腈研磨(~15分钟超声波处理)以形成沉淀物,通过过滤收集沉淀物,用乙腈及***冲洗并干燥。得到33mg纯产物(m/z 348.09[MH+])。
使用此程序合成下列化合物:
实施例14–3,5-二氟-N-羟基-4-((5-苯基-1,2,4-氧杂二唑-3-基)甲基)苯甲酰胺(化合物194)的合成
步骤A
逐滴添加氰基乙酸叔丁酯(11.4g,52.73mmol,2当量)至NaH(1.5当量)在70mL的无水DMF中的悬浮液中。在室温搅拌5分钟后,添加3,4,5-三氟苯甲酸甲酯(5g,26.3mmol,1当量)。在室温搅拌反应混合物3小时,以水稀释并以EtOAc萃取。在浓缩后,以柱层析纯化残余物,然后稀释于20mL的无水DCE中,并在回流下用TFA(8.6mL,10当量)处理过夜。蒸发溶剂,将残余物溶解于DCM,以NaHCO3饱和溶液洗涤,以Na2SO4干燥并浓缩。通过柱层析纯化粗产物。
步骤B
将步骤A获得的腈衍生物(2g,11mmol,1当量)、NH2OH盐酸盐(1.5g,22mmol,2当量)及NaHCO3(1.81,22mmol,2当量)在40mL甲醇中的混合物回流过夜。过滤及浓缩后,将获得的粗产物通过柱层析纯化(10%的EtOAc在DCM中)。
步骤C
将苯甲酰氯(0.243g,1.73mmol,1.2当量)加入至步骤B获得的(Z)-4-(2-氨基-2-(羟基亚胺基)乙基)-3,5-二氟苯甲酸甲酯(0.3g,1.44mmol,1当量)及DIPEA(0.75mL,4.32mmol,3当量)在2mL的无水DMF的溶液中。搅拌过夜后,反应混合物以水淬灭并以EtOAc萃取。柱层析纯化(净DCM)提供41mg产物。
步骤D
将KOH(0.014g,0.24mmol,2当量)加入至步骤C获得的甲基酯(0.04g,0.12mmol,1当量)在14mL的THF/水=4/1混合物的溶液中。在室温搅拌反应混合物过夜,并以1M HCl酸化。收集获得的沉淀物,并于真空中干燥。将获得的羧酸溶解于2mL的无水THF中。添加DIPEA(0.72mmol,6当量)及HATU(0.18mmol,1.5当量)。在室温搅拌反应混合物,并通过LC-MS监测酸全部转化成HATU-中间体。添加NH2OH盐酸盐(0.025g,0.36mmol,3当量),并搅拌反应混合物2小时以上,然后以水稀释成50mL的总体积,并以EtOAc(225mL)萃取。蒸发后获得101mg极黏稠的油。用乙腈研磨(~15分钟超声波处理)以形成沉淀物,通过过滤收集沉淀物,以乙腈及***冲洗并干燥。获得20mg纯产物(m/z 332.13[MH+])。
使用此程序合成下列化合物:
实施例15–N-羟基-4-((4-甲基-5-苯基-4H-1,2,4-***-3-基)甲基)苯甲酰胺(化合物217)的合成
步骤A
将乙酸(0.3mL)逐滴加入至粗4-((5-苯基-1,3,4-氧杂二唑-2-基)甲基)苯甲酸甲酯(0.38g,1.29mmol,1当量)在MeNH2在THF(15mL)的2M溶液的溶液中。密封反应小瓶,并使反应混合物于150℃搅拌过夜。冷却后,蒸发溶剂;残余物以水处理并以EtOAc萃取。将有机相干燥并蒸发,产生258mg橘色油,其不经进一步纯化而用于下一步骤。
步骤B
将步骤A获得的甲基酯(0.041g,0.139mmol,1当量)悬浮于8mL的甲醇中,并将生成的溶液以冰浴冷却。添加NH2OH在水中的50%溶液(0.34mL,40当量),随后缓慢添加1M NaOH溶液(1.4mL,10当量)。搅拌反应混合物使其到达室温(约1小时),并以1M HCl酸化。通过过滤收集白色沉淀物。制备HPLC纯化提供24mg纯产物(m/z 309.12[MH+])。
实施例16–4-((3-((1H-吲哚-3-基)甲基)-5-(噻吩-2-基)-4H-1,2,4-***-4-基)甲基)-N-羟基苯甲酰胺(化合物183)的合成
步骤A
将4-(氨基甲基)苯甲酸甲酯盐酸盐(402mg,2mmol,1当量)在三甲基氨(616uL,4.4mmol,2.2当量)的存在下溶解于二氯甲烷(8ml)中。然后添加2-噻吩羰基氯(236uL,2.2mmol,1.1当量),并于室温搅拌混合物过夜。
完成后,将反应混合物以二氯甲烷稀释并以水洗涤。有机层以Na2SO4干燥,过滤并浓缩,而提供粗产物,其不经任何进一步纯化即用于后续步骤。
步骤B
在氩气下,将4-((噻吩-2-甲酰胺基)甲基)苯甲酸甲酯(methyl 4-((thiophene-2-carboxamido)methyl)benzoate)(1mmol,1当量)悬浮于亚硫酰氯(4ml,5.5当量)中,并于回流温度下搅拌过夜。在减压下浓缩混合物,以移除过量的SOCl2。将如此获得的粗亚胺酰氯悬浮于干甲苯中,添加呈固体的吲哚-3-乙酸酰肼(189mg,1mmol,1当量)。将生成的混合物加热至120℃,并搅拌过周末。通过旋转蒸发而浓缩混合物。产物用EtOAc/MeOH 1%沉淀,并通过过滤收集。获得113mg产物。
步骤C
将步骤B获得的甲基酯(0.041g,0.139mmol,1当量)悬浮于8mL甲醇中,并以冰浴冷却生成的溶液。添加NH2OH在水中的50%溶液(0.34mL,40当量),随后缓慢添加1M NaOH溶液(1.4mL,10当量)。搅拌反应混合物,使其达到室温(约1小时),并以1M HCl酸化。通过过滤收集白色沉淀物。制备HPLC纯化提供纯产物(m/z 430.3[MH+])。
使用此程序合成下列化合物。
实施例17–酶筛选
对于每种合成的化合物,评估在重组人类HDAC6及HDAC3中的酶活性(表2)。为了获得完整的特性,被定义为HDAC6与另一种同功型之间的IC50比例的log值小于-2的显示良好HDAC6选择性的化合物也对所有其它同功型进行筛选(表3)。
对于每种测试化合物,制备五种不同浓度(通常在3-30000nM的范围内)在反应缓冲液(25mM Tris-HCl,pH 8,130mM NaCl,0.05%Tween-20,10%甘油)中的5X浓缩溶液,加DMSO标准化至更浓缩的抑制剂溶液中所存在的量,通常为相当于板中最终0.15%的0.75%。将10μL用于每个测试化合物浓度的一式三份的溶液置于96孔板上,并添加15μL的3.33X浓缩的酶在反应缓冲液中的溶液(25mM Tris-HCl,pH 8,130mM NaCl 0.05%Tween-20 10%甘油,1mg/ml BSA或2mg/ml的HDAC4、HDAC5及HDAC9,注意:对于HDAC7,使用50mMTRIS-HCl,pH8,137mM NaCl,2.7mM KCl及1mM MgCl2)至每一孔。在30℃培育一段时间后(培育时间依不同的同功型而变化并示于表1),加入25μL含有基质的溶液。作为基质,使用FLUOR DE脱乙酰酶基质(Enzo Life Sciences,cat#BML-KI104,FdL)、FLUOR DE-Green基质(Enzo Life Sciences,cat#BML-KI572FdL_G)及三氟乙酰基-L-赖氨酸(Tfal)-在25mM Tris-HCl,pH 8,130mM NaCl,0.05%Tween-20,10%甘油中的2X浓缩溶液)。在30℃的反应期间后(反应时间依不同的同功型而变化并报告于表1)中,加入50μL的由浓缩FLUOR DE显色剂I(Enzo Life Sciences,cat#BML-KI105)所组成的显色溶液,其在HAB加2μM TSA中稀释200倍,并于室温下黑暗中25分钟后,使用Victor 1420Multilabel Counter Perkin Elmer Wallac仪器进行荧光读数。
表1–各独立同功型的酶测试的操作细节
合成的化合物的HDAC6及HDAC3酶抑制的数据显示于表2。所选择的化合物的所有同功型的完全抑制特性显示于表3。分子显示良好的HDAC6活性及对其它同功型的显著选择性。
表2–对HDAC6的酶抑制活性测定(IC50nM)及相对于HDAC3的选择性(两种酶的IC50之间的比例的对数)
本发明的优选化合物显示HDAC6 IC50值低于20nM,且相对于HDAC3的选择性指数低于-1.6。
表3–根据本发明的一些优选化合物对所有HDAC的完全抑制特性(IC50nM)
实施例18–细胞毒性
在B 697前髓细胞系中评估所有合成的化合物的细胞毒性活性,并在末梢血液单核细胞(PBMC)中评估显示良好效力/选择性特性的化合物的细胞毒性活性。
将细胞接种于板(对于697为每孔2x104个细胞,对于PBMCs为每孔5x105个细胞)中。24小时后添加试验化合物(对于PBMCs为浓度1.5nM至10000nM,对于697为浓度1nM至10000nM),并培育72小时。使用CellTiterAqueous One Solution Cell ProliferationAssay(Promega)评估分子细胞毒性活性,其按照制造商的说明测量线粒体功能。
IC50值示于表4。大部分分子显示低的毒性。
表4–在697细胞系及PBMC中的细胞毒性(IC50nM)
n.a=无法取得
本发明的优选化合物对于697细胞系显示超过1000nM的IC50值,且对于PBMC显示超过5000nM的IC50值。
实施例19–在大鼠及人类S9肝脏组分(human S9 liver fraction)中对于第一阶段代谢(Phase I metabolism)的稳定性
在37℃下将试验化合物在大鼠及人类肝脏S9组分中培育至多90分钟,以便评估其通过肝脏酶的第一阶段代谢的稳定性。
将每种试验化合物以μM浓度(当样品通过UV/HPLC分析时为50μM,当样品通过LC-MS/MS分析时为1或2μM)与S9组分(蛋白质含量2mg/mL)在100mM磷酸盐缓冲液(pH 7.4)、3.3mM MgCl2及1.3mM NADPH中在37℃下在恒温振荡浴中培育0、10、30、60及90分钟。通过将样品置于冰浴中并添加酸化的乙腈而停止反应。在离心后(于14000rpm 10分钟),将等分(aliquot)的上清液以水稀释,以0.45μm再生纤维素针筒式过滤器过滤,并注入HPLC-UV或LC-MS/MS中。计算在不同培育时间下的残留量相对于初始量的百分比。还计算固有清除率(intrinsic clearance)。
实施例20–在大鼠及人类血浆中的稳定性
为了评估对循环酶的稳定性,在37℃下于恒温振荡浴中在人类及大鼠血浆中培育试验化合物。将每种试验化合物以μM(当通过UV/HPLC分析样品时为50μM,当通过LC-MS/MS分析样品时为1或2μM)的浓度培育0、15、30分钟及1、2及4个小时。通过将管置于冰浴上并加入酸化的乙腈而停止反应。在14000rpm离心10分钟后,以水稀释等分的上清液,以0.45μm注射过滤器过滤,并注入HPLC-UV或LC-MS/MS中。计算在不同培育时间下的残留量相对于初始量的百分比。还计算在血浆中的半衰期。
体外代谢稳定性数据总结于表5和5'中。大多数分子显示出良好的稳定性。
表5–优选的化合物的体外酶稳定性测定(90分钟后在S9中及4小时后在血浆中的残留百分比)。
n.a.=无法取得
本发明的优选化合物显示残余百分比在大鼠S9组分中高于25%,在人类S9组分中高于85%,在大鼠血浆中高于75%,且在人类血浆中高于90%。
表5'–体外酶稳定性测定(90分钟后在S9中及4小时后在血浆中的残留百分比)
n.a.=无法取得
本发明的优选化合物显示残余百分比在大鼠S9组分中高于25%,且在大鼠血浆中高于75%。
实施例21–在697细胞系中体外α-微管蛋白及H3组蛋白乙酰化
在B 697前髓细胞系上评估体外α-微管蛋白及H3组蛋白乙酰化测定。
将试验分子由DMSO中的20mM储备溶液以RPMI 10%FCS+0.01%DMSO培养基稀释成与终浓度相比为20X浓度,加入细胞中(15×106个细胞,总体积为30ml,在RPMI培养基10%FCS+0.01%DMSO中)以获得1000、333、111及37nM的终浓度,并于37℃、5%CO2下培育16小时。
在培育期结束时,自每个样品中取5x106个细胞,于1100rpm离心5分钟,并于4℃以0.9%NaCl洗涤。通过在4℃下将生成的团块(pellet)以150μl的含蛋白酶抑制剂及磷酸酶(Complete Easy Pack蛋白酶抑制剂鸡尾酒片,cat:04693116001;Phostop easypack磷酸酶抑制剂鸡尾酒,cat:01906837001-Roche)的Complete Lysis-M(Roche,cat-04719956051)处理30分钟来进行细胞溶解(lysis),然后在14,000rpm(20817x g)离心10分钟。将0.150μg的上清液(总蛋白质萃取物)稀释于100μl的1x PBS中,并使其在室温下固定于Maxisorp F96 NUN-IMMUNO板(Nunc cat#5442404)过夜。将板以洗涤缓冲液(PBS 1X+0.005%吐温20)洗涤两次,并以300μL的含10FCS的1x PBS在室温饱和1小时。在用缓冲液(含0.005%吐温的1x PBS)洗涤后,将板在抗乙酰化-α-微管蛋白抗体(单克隆抗乙酰化-微管蛋白克隆6-11B-1,小鼠腹水液,cat#T6793 Sigma,100μl,以1:1000稀释于含10%FCS的1x PBS中)或总抗α-微管蛋白抗体(在小鼠中产生的单克隆抗α-微管蛋白;cat#T6074Sigma)的存在下在室温培育两小时。在洗涤后,添加每孔100μl的TMB基质套组,在室温黑暗中10分钟。通过添加50μl的2N H2SO4停止反应。用Multiskan光谱分光亮度计于450nm波长下读板。
通过将乙酰化α-微管蛋白获得的吸亮度除以总α-微管蛋白的吸光度而计算乙酰化程度。
通过酸萃取组蛋白(Kazuhiro等人,PNAS(2002),99(13)8921-8926)而处理残余的细胞(10x106)。将细胞于4℃下以1100rpm离心5分钟,并于0.9%NaCl中洗涤一次。在4℃下,将生成的团块以细胞溶解缓冲液(10mM Tris·HCl,pH 6.5/50mM亚硫酸氢钠,1%TritonX-100/10mM MgCl2/8.6%蔗糖,含有蛋白酶抑制剂混合物(Roche))进行细胞溶解持续20分钟。以缓冲液重复洗涤生成的核团块,直到上清液澄清(在每次洗涤后以7,500xg离心5分钟),并最后在核缓冲液(10mM Tris·HCl/13mm EDTA,pH7,4)中洗涤,并再悬浮于250μl的0.2M HCl/H2SO4中。通过在4℃温和震荡下培育过夜来在酸性环境中萃取组蛋白。在4℃以14,000rpm离心10分钟后,将1250μl冰丙酮添加至上清液中,并于-20℃下培育过夜,以生成组蛋白的沉淀。将以14,000rpm在4℃离心10分钟后获得的团块用冰丙酮洗涤,蒸发至干燥,并重新悬浮于50μl蒸馏水中。通过使用BCA蛋白质测定试剂盒(Pierce cat:23227)的比色测定来进行总蛋白及组蛋白萃取物的蛋白质含量测定。
根据供货商报告的方法通过商品化的ELISA测定PathScan乙酰化组蛋白H3三明治式ELISA试剂盒,cat#7232C及PathScan总组蛋白H3三明治式ELISA试剂盒,cat#7253C CellSignaling),并通过使用Multiskan Spectrum测量450nm波长下的吸亮度,来定量H3组蛋白乙酰化及总H3量。通过分析每个样品的0.250μg及0.500μg组蛋白萃取物而进行ELISA试验。通过将H3组蛋白吸光度除以组蛋白总吸光度而计算乙酰化程度。
微管蛋白及H3组蛋白乙酰化的试验结果总结于表6及6’中,其分别表示为每种样品相对于对照样品(未处理)的乙酰化α-微管蛋白/总α-微管蛋白及H3Ac/H3Tot比例的倍数增加。分子显示良好的微管蛋白乙酰化,及不良的H3组蛋白乙酰化。
吉维诺司他(Givinostat)是一种泛-HDAC抑制剂,已被用作参考化合物。如预期,参考化合物显示出微管蛋白及H3组蛋白的良好乙酰化。WO2012/106343的实施例43为一种HDAC抑制剂,其已被用作比较化合物,以显示本发明化合物相对于具有下式的现有技术化合物的无法预期的效果:
实施例43
表6–在697细胞系中的微管蛋白乙酰化(乙酰化微管蛋白及总微管蛋白相对于对照的比例的倍数增加)
相对于实施例43,本发明的分子显示较高的微管蛋白的乙酰化。
表6':–在697细胞系中H3组蛋白的乙酰化(乙酰化H3及总H3相对于对照之间的报告的倍数增加)
n.a.=无法取得
除了吉维诺司他,所有分子均显示不良的H3组蛋白的乙酰化。
实施例22–药物动力学
在单次静脉内及口服施用至小鼠后,评价试验化合物的血浆水平及主要药物动力学参数。
经由静脉内途径的施用剂量为1.3-2.6mg/kg,通过经口胃管灌食的施用剂量为2.6-5.2mg/kg。在DMSO/PEG400/H2O的混合物中制备制剂。在以下采样时间收集血液:施用后5分钟、10分钟、15分钟、30分钟、1小时、2小时、4小时及6小时。通过添加在ACN中的1%甲酸而将血浆样品(100μL)去蛋白化,然后涡旋混合并离心。对于每个样品,收集等分的上清液,并以水稀释,以0.45μm再生纤维素过滤器过滤,并通过LC-MS/MS分析。以在0.5-200ng/mL范围内制备的校准曲线来计算试验化合物的血浆水平。
通过以非分室法(non-compartmental method)使用软件Kinetica TM v.5.1的平均血浆浓度曲线来计算药物动力学参数。
主要参数总结于表7。试验的三个分子显示出良好的口服生物利用度(bioavailability)。
表7–三种优选的化合物在小鼠中的药物动力学参数
实施例23–最大耐受剂量(MTD)的评估
在C57BL/6小鼠中长期腹膜内施用后,通过临床(体重及行为)和血液(白血球及血小板)参数评估来评估化合物的MTD。将化合物溶解于含有5%DMSO(对于化合物17,使用20%DMSO)的比例为1:1w/w的H2O/PEG400混合物中,然后进行施用。
在治疗前一天(第0天)称重所有动物,并测定平均体重。
将动物(每组8只动物)自第1日开始,每日一次,每周连续5日以下列进行处理:
a)10、30、50mg/kg的剂量的化合物,腹膜内,
b)100mg/kg的吉维诺司他(内部对照);及
c)用于溶解物质的载体溶液。
施用的溶液的体积为10mL/Kg。治疗重复2周,总共10次治疗/组。
以每日为基础,报告指示化合物可能有毒性的任何临床征兆(皮肤外观、活动性及动物反应性、呼吸等)。在第2、4、9及11日评价动物体重。
在第1、3、5、8、10及12日,自动物尾部取血液样品(约50μL),以评估物质对血液参数的作用。隔日对每组4只动物进行停药(withdrawal)。
将样品收集在含有EDTA的试管中,在生理溶液中适当稀释,并用细胞计数器分析。
在研究结束时(第12日),在最后一次处理后60分钟牺牲动物。为了检测任何内脏器官异常,进行大体尸体剖检评估。表8总结了根据本发明的一些化合物在MTD测定实验中获得的数据。吉维诺司他为一种HDAC泛抑制剂,其被用作参考。试验分子耐受性良好。
表8–四种根据本发明的优选化合物在小鼠的MTD实验中所监测的第12日的参数值
实施例24–通过小鼠调节性T细胞介导的T CD4淋巴细胞增生抑制测定
为了评估本专利中的分子增加调节性T细胞(Treg,CD4+CD25+)抑制活性的能力,使用T细胞(反应者T细胞(responder T cell),Teff)增殖抑制测定法。在增殖刺激的存在下,用Teff细胞(CD4+CD25-)培养不同浓度的Treg细胞。T细胞需要两种刺激来增殖:第一种是通过T细胞受体(TCR)识别与MHC相关的抗原而提供,第二种是衍生自共刺激分子如CD28。在无特异性抗原的情况下,能以识别构成次单元(CD3ε)之一的抗体进行TCR活化。在此测定中,使用抗CD3ε单克隆抗体及排除CD4 T细胞的脾细胞(CD4 T cell depleted splenocyte)作为活化剂刺激。因此,在HDAC6抑制剂的存在或不存在下,评估通过Treg减少Teff细胞增殖的能力。
通过初始负向选择及最终正向选择方法,使用基于磁珠分离技术的Treg分离试剂盒(Miltenyi Biotec)而分离Treg及Teff细胞。
使用70μm滤筛,从C57BL/6小鼠的脾脏获得单细胞悬浮液。
用ACK缓冲液处理细胞悬浮液以将红血球进行细胞溶解,然后以300x g离心5分钟。在离心后,将细胞再悬浮于PBS(磷酸盐缓冲生理盐水,Gibco)中,并计数。随后,将脾细胞再悬浮于由PBS、0.5%BSA及2mM EDTA组成的缓冲液中。
为了进行Treg分离的第一步骤,将CD4阴性细胞间接以抗CD8a、CD11b、CD45R、CD49b、Ter-119的生物素复合抗体(biotin-conjugated antibody)的混合物来磁性标记,通过负向选择而获得作为磁性MACS柱的流通液(flow-through)的抗生物素微珠CD4+细胞。
与微珠结合的细胞被洗脱,并保存用作增殖试验中的抗原呈现细胞(APC)。
在Treg纯化的第二步骤中,将预先富集的CD4+细胞以优先结合至Treg细胞的R-藻红素(PE)复合抗CD25抗体(R-phycoerythrin(PE)-conjugated anti-CD25 antibody)及与抗PE抗体偶合的磁珠来标记。然后将细胞悬浮液装载于管柱中。Teff细胞不结合而通过管柱(负向选择),而与珠结合的Treg细胞通过磁珠而黏附(正向选择)。然后,使用柱塞通过缓冲液流而从管柱中洗脱Treg细胞。Treg及Teff细胞纯化总结于以下流程图中:
所获得的细胞如下用于Treg抑制试验:
·来自首次正向选择的CD4-细胞作为APC
·Treg CD4+CD25+作为抑制细胞
·Teff CD4+CD25-作为反应/增殖细胞
在37℃下,以丝裂霉素C(50μg/ml,Sigma)处理CD4-细胞30分钟以防止其增殖。然后,将其以4.0×105/50μl的浓度再悬浮于完全培养基(RPMI,FBS 10%,青霉素/链霉素1X,50μMβ巯基乙醇)中。在37℃下将Teff以在PBS中的浓度为2μM的羧基荧光素琥珀酰亚胺基酯(carboxy fluorescein succinimidyl ester(CFSE))标记,培育10分钟后,以10%FBS PBS溶液阻断反应。CFSE标记使得能够共价修饰Teff细胞以通过荧光稀释来分析其增殖。然后,将经标记的Teff离心,并以5.0×104/50μl的终浓度再悬浮于完全培养基中。最后,通过纯化获得的Tregs在完全培养基中稀释至终浓度5.0×104/50μl。
然后,制备Teff(5.0×104)、T CD4-(4.0×105)的共培养物,并以不同比例(Teff比Treg细胞1:1、1:2、1:4、1:8的比例)将Treg细胞加入其中。将不同浓度的试验化合物或DMSO载体添加至细胞悬浮液中。最后,以1μg/ml的浓度添加抗CD3ε单克隆抗体(MiltenyiBiotec)。将细胞接种于平底96孔板中,并将每种条件设置技术性的一式二份。为了判定不同物质如何直接影响细胞增殖,评估在没有Treg细胞的情况下,在通过抗CD3ε单克隆抗体提供的刺激的存在下,化合物对经标记的Teff及CD4-细胞共培养物的作用。细胞增殖阴性对照仅在经标记的Teff上测定,其在无T CD4-存在及无抗CD3ε单克隆抗体存在下不应增殖。
在培育72小时后,将共培养的细胞在室温(RT)下用经PE/Cy5标记的抗CD4抗体(1:200稀释,Biolegend)标记15分钟。在标记后,洗涤细胞,并再悬浮于200μl PBS中。
通过观察T CD4+细胞群体中来自CFSE的信号的稀释,以流式细胞测量术来检测增殖的Teff的百分比。CFSE标记在通过细胞活化所诱导的有丝***后由子代细胞继承。CSFE荧光信号分析使得能够获得相对于非增殖群体而言具有较低荧光的群体所代表的增殖细胞的百分比。
在此试验中,必须排除所试验的物质的直接抗增殖活性。因此,已建立了一个阈值,如果在没有Treg的Teff细胞中观察到增殖减少>10%,则增殖抑制无法全部归因于单独的Treg的抑制活性的诱导。
为了比较化合物对Treg抑制能力的作用,通过将最小-最大标准化(min-maxstandardization)应用于每个样品与对照相比的增殖速率,来计算标准化的增殖速率。所获得的值被转换成标准化抑制百分比:
标准化抑制=100-(标准化增殖%)
然后,计算标准抑制百分比值图的曲线下面积(AUC)。通过公式提供相对抑制:(AUC药物/AUC对照),该相对抑制为使得能够比较化合物活性的值。通过使用GraphPadPrism 7软件的数据处理来进行上述程序。
整个程序的进一步细节可于Akimova等人,Methods Mol Biol(2016),1371:43-78中发现。
表9及表10中报告了Treg细胞抑制测定的结果。RS大于1.5的化合物在Treg细胞中诱导良好的抑制活性。高于2.5的RS值指出在此测定中的高活性。许多试验分子显示高活性。
表9–一些本发明的优选化合物的相对T-reg抑制
表10–根据本发明的其它化合物的相对T-reg抑制
化合物 | 浓度,μM | 实验批次# | RS |
22 | 0.25 | 5 | 4.2 |
23 | 0.25 | 3 | 4.2 |
28 | 0.25 | 1 | 2.9 |
33 | 0.10 | 2 | 4.6 |
50 | 0.25 | 5 | 4.2 |
58 | 0.25 | 1 | 3.4 |
59 | 0.5 | 1 | 4.8 |
61 | 1 | 3 | 1.1 |
65 | 1 | 3 | 4.4 |
66 | 1 | 3 | 2.6 |
对照 | 1.5 | 23 | 1.8 |
实施例25–与人类PBMCs的混合淋巴细胞反应(MLR)
为了研究HDAC6抑制剂抑制同种异体T CD4+细胞活化的能力,进行了混合淋巴细胞反应(MLR或混合淋巴细胞培养,CLM)测定。此为一种涉及在同种异体淋巴细胞存在下体外培养的淋巴细胞的母细胞转形(blast transformation)的反应。有所谓的“双向”反应,其中两个淋巴细胞群体相互刺激以增殖;以及所谓的“单向”反应,其中两个群体之一的增殖受到丝裂霉素C或辐射的抑制,这些细胞为所谓的“反应(responder)”细胞提供增殖刺激(刺激物)。
用于MLR的人类末梢血液单核细胞(PBMC)通过Ficoll梯度分离,由健康供体的肤色血球层(Buffy Coat)获得。
我们使用双向MLR。将来自两个供体的细胞以1:1的比例(同种异体刺激)每孔2x105的终浓度接种于U形底96孔板中的含10%FBS及抗生素的RPMI 1640培养基中。作为对照,我们分别接种来自每个供体的细胞(同基因刺激)。对于每种抑制剂的实验设置为同种异体刺激一式十份,及同基因刺激一式五份。细胞于37℃的培养箱中培养6日。
6日后,通过测量被认为是此测定的特征的前炎性细胞因子(pro-inflammatorycytokine)的产生来评估试验化合物的作用。为了此目的,收集培养上清液,并用于IFN-γ、TNF-α及IL-6炎性细胞因子测定。
MLR试验的结果总结于表11及12中。在试验中使用JAK抑制剂鲁索利替尼(ruxolitinib)作为活性参考化合物。
表11–根据本发明的一些优选化合物的MLR试验
表中的数值表示抑制百分比。负值表示诱导。
表12–根据本发明的其它化合物的MLR试验
化合物 | 浓度,μM | MLR exp# | IFN-γ | TNF-α | IL-6 |
58 | 0.25 | n.a | n.a | n.a | n.a |
59 | 0.5 | n.a | n.a | n.a | n.a |
61 | 1 | 1 | 16 | n.a | -21 |
65 | 1 | 2 | 45.0 | 67.3 | 5.4 |
66 | 1 | 3 | 53.0 | 42.8 | 12.9 |
对照 | 1.5 | 17 | 20.6 | 32.0 | 13.8 |
鲁索利替尼 | 0.05 | 15 | 87.9 | 61.2 | 73.3 |
实施例26–在体外衍生的树状细胞中的PD-L1表达的抑制
目前的文献描述了选择性HDAC6抑制剂作为用于癌症免疫疗法的免疫调节剂具有很大的潜力(Tavares MT等人ACS Med Chem Lett.2017;8(10):1031-1036)。
已知实体肿瘤具有强的类骨髓组分,其有助于肿瘤的发展、进展及散播。
树状细胞(DC)为专门的抗原呈现细胞(APC),其在适应性免疫反应的调节中扮演关键角色。它们可在MHC I类及II类的背景下有效呈现新肿瘤抗原,以刺激针对肿瘤的T细胞反应。然而,在肿瘤微环境中,癌细胞可经由DC而以各种方式抑制T细胞的活化。通过DC表面上的免疫检查点抑制剂(immune checkpoint inhibitor)PD-L1的表达的诱导来例示说明此活性。PD-L1可与T细胞上表达的PD-1相互作用,并抑制其活化。因此,减少DC上的PD-L1表达可代表对抗此过程的手段。
我们假设选择性HDAC6抑制可减少DC上PD-L1的表达,从而增加其T细胞刺激活性。
为了获得体外衍生的DC,在本发明所描述的两种选择性HDAC6抑制剂(化合物10及19)及WO2012/106343的实施例43的HDAC抑制剂的存在下,将由PBMC纯化的人类单核球以GMCSF(50ng/ml)及IL-4(10ng/ml)处理5日。对照细胞以抑制剂的载体处理。此过程诱导表达PD-L1的未成熟树状细胞(iDC)的形成(Brown JA等人J Immunol.2003;170:1257-66)。5日后,分析iDC的抑制性标记物PD-L1的表达。
如图1所示,本发明的化合物10及19以统计学上显著的方式降低PD-L1表达。相反地,WO2012/106343的实施例43不能减少PD-L1的表达,表明与化合物10及19观察到的相比,此分子具有不同的生物活性。
实施例27–活体内鼠肿瘤模型
使用四种不同的癌症免疫肿瘤小鼠模型来评估本发明的化合物8及10的活体内功效。在此实验中,我们比较了抗PD-1抗体的功效与HDAC6抑制剂所显示的功效。抗PD-1靶向免疫检查点PD-1/PD-L1轴(immune checkpoint PD-1/PD-L1 axis),且是一种在越来越多的恶性肿瘤中建立的免疫疗法(Pardoll D.M.,Nature Reviews Cancer,2012,12:252-264)。
使用下列细胞系在免疫活性小鼠中诱导肿瘤:
·EMT6(鼠乳癌)
·CT26(鼠大肠癌)
·4T1(三阴性鼠乳癌)
根据文献,将这些鼠肿瘤对抗PD-1治疗的敏感性总结于下表:
细胞系 | 预期的活体内抗PD-1的敏感性 |
EMT6 | ++++ |
CT26 | +++ |
4T1 | ++ |
·当肿瘤结节的直径达到约3mm时开始治疗性处理。
·每日一次,一周5日,通过经口胃管灌食以50mg/kg施用化合物8及10。
·每周三次,通过腹膜内注射以10mg/kg施用抗PD-1抗体。
实验结果示于图2。化合物8、10及抗PD1抗体在降低肿瘤生长方面具有相当的功效。结果也与抗PD-1抗体的预期功效一致。本发明的选择性HDAC6抑制剂具有降低的直接抗肿瘤活性,例如体外缺乏细胞毒性活性。因此,在这些免疫肿瘤模型中的活体内结果暗示用选择性HDAC6抑制剂的治疗导致抗肿瘤免疫反应的可能的活化。
为了证实化合物8及10的活体内抗肿瘤活性是通过免疫***的活化来介导,我们使用CT-26鼠模型进行进一步的实验。
成年BALB/c小鼠被皮下注射1×106个CT26肿瘤细胞(以磷酸盐缓冲生理盐水稀释至100μl)。一周后,每日以50mg/Kg口服向小鼠施用化合物8及10和/或以10mg/Kg注射抗PD1抗体。牺牲时,取脾脏以离体分析肿瘤免疫反应。以在MHC I及MHC II的背景下被识别的CT-26肿瘤特异性肽的混合物来刺激脾细胞。因此,使用此离体刺激,可检测通过CD4及CD8 T细胞介导的特异性肿瘤反应。
图3中显示的结果证实了之前本发明的分子作为单一药剂在减少肿瘤生长中的功效的数据。此减少再次与以抗PD-1抗体所获得的减少相当。此外,抗PD-1抗体及HDAC6抑制剂的组合治疗导致进一步的改善,特别是与化合物10。
为了证明针对肿瘤的免疫***的特异性活化,分离动物的脾脏,并在CD4及CD8 T细胞均识别的特异性CT-26肽的存在下培养脾脏细胞(Kreiter S.等人Nature,2015,520:692-696)。
结果显示于图4及图5中,其中指出每个治疗组中产生IFN-γ及TNF-α的CD4及CD8T细胞的百分比。
作为总结,图3-图5中显示的结果表明:
·选择性HDAC6抑制剂8及10可显著降低CT-26肿瘤进展。
·两种化合物的功效与抗PD-1抗体相当。
·化合物10与抗PD-1抗体的组合进一步改善肿瘤生长抑制。
·利用CT-26特异性肽的离体刺激表明,单独以HDAC6抑制剂治疗以及将HDAC6抑制剂与抗PD-1抗体组合的治疗诱发特异性抗肿瘤T细胞介导的免疫反应。
·离体测定的结果表明,与用抗PD-1抗体相比,用化合物8及10达到了更大的新抗原免疫反应。
Claims (12)
1.一种式(I)及(II)化合物或其药学上可接受的盐或立体异构体,
其中
在式(I)中,A=N、O、S,而在式(II)中,A=N;
B=C、N;
在式(I)中,C=N、O,而在式(II)中,C=N;
X=CH2、S;
n=0、1;
当n=1时,碳原子可被R12及R13取代,R12及R13独立选自H、-Me、-苯基,或R12及R13可一起形成饱和环状部分;
当n=1时,R6存在;
R4=R5=H、F;
R1不存在,或其选自-H、-NH2、-CH3、-CH2CH3、苯基、对氟苯基、间氯苯基、对氯苯基、甲基呋喃、异丁基、甲基苯基、三氟苯基、噻吩及2-(吗啉-4-基)乙基;
R2不存在,或其选自苯基;
R3不存在,或其选自邻甲氧基苯基、对三氟甲基苯基、苄基、或吡啶基;
R6选自:
其中:
R7及R8独立选自H、-Cl、-F、-Br、-CF3、-Me、-Et、-OMe、-O苄基、-SF5、-OCH2F、-CH2NH2、-CH2NMe2、-NH2、-NMe2、-N(CH2CH2OCH3)2、-COOH、-COOMe、
或R7及R8可一起形成杂五员环状部分(-OCH2O-);
R9=R10=-Me、-Et;
R11选自-H、-Cl和-CH3;
条件是在式(I)化合物中,当五员杂环核为1,3,4-氧杂二唑时,R6不为萘基。
2.根据权利要求1所述的化合物,其中饱和环状部分为环丙烷、环丁烷、环戊烷或环己烷。
3.根据权利要求1或2所述的化合物,其选自:
–(S)-N-(1-(3-(4-(羟基胺甲酰基)苄基)-1,2,4-氧杂二唑-5-基)-2-(噻唑-4-基)乙基)-3,4-二甲氧基苯甲酰胺(化合物1);
–3,5-二氟-N-羟基-4-((4-甲基-5-(萘-1-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物2);
–4-((5-(3-(N,N-二甲基胺磺酰基)苯基)-1,3,4-氧杂二唑-2-基)甲基)-N-羟基苯甲酰胺(化合物3);
–3,5-二氟-N-羟基-4-((4-甲基-5-(2-苯基丙-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物4);
–4-((5-(2,3-二氢噻吩并[3,4-b][1,4]二噁英-5-基)-1H-四唑-1-基)甲基)-3,5-二氟-N-羟基苯甲酰胺(化合物5);
–3,5-二氟-N-羟基-4-((5-(吡啶-2-基)-2H-四唑-2-基)甲基)苯甲酰胺(化合物6);
–二氟-N-羟基-4-((5-(嘧啶-2-基)-2H-四唑-2-基)甲基)苯甲酰胺(化合物7);
–N-羟基-4-((5-(噻吩-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物8);
–3,5-二氟-N-羟基-4-((4-甲基-5-(4-甲基-2-吗啉基噻唑-5-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物9);
–N-羟基-4-((4-甲基-5-(噻吩-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物10);
–4-((5-(呋喃-2-基)-2H-四唑-2-基)甲基)-N-羟基苯甲酰胺(化合物12);
–3,5-二氟-N-羟基-4-((5-(吡啶-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物13);
–3,5-二氟-N-羟基-4-((4-甲基-5-(吡啶-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物14);
–3,5-二氟-N-羟基-4-((5-(噻吩-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物15);
–3,5-二氟-N-羟基-4-((4-甲基-5-(4-(哌啶-1-基甲基)苯基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物16);
–3,5-二氟-N-羟基-4-((4-甲基-5-(噻吩-2-基)-4H-1,2,4-***-3-基)硫基)苯甲酰胺(化合物17);
–3,5-二氟-4-((5-(呋喃-2-基)-2H-四唑-2-基)甲基)-N-羟基苯甲酰胺(化合物19);
–N-羟基-4-((5-(吡啶-2-基)-1H-四唑-1-基)甲基)苯甲酰胺(化合物20);
–3-(3,4-二甲氧基苯基)-N-[(1S)-1-[3-[[4-(羟基胺甲酰基)苯基]甲基]-1,2,4-氧杂二唑-5-基]-2-噻唑-4-基-乙基]丙酰胺(化合物21);
–4-[[5-[4-(三氟甲基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物23);
–4-[(4,5-二苯基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物24);
–4-[[4-(2-呋喃基甲基)-5-(1H-吲哚-3-基)-1,2,4-***-3-基]氢硫基]苯羟肟酸;2,2,2-三氟乙酸(化合物25);
–4-[5-[(3,4-二甲氧基苯基)甲基]-1,3,4-氧杂二唑-2-基]苯羟肟酸(化合物26);
–4-[[5-苄基-4-(4-氟苯基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物27);
–4-[[4-氨基-5-[4-(二氟甲氧基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物28);
–4-[[5-(4-氟苯基)-4H-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物29);
–4-[[4-乙基-5-(4-氟苯基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物30);
–4-[[5-(4-氯苯基)四唑-2-基]甲基]苯羟肟酸(化合物31);
–4-[[5-(5-氯-2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物32);
–4-[[5-(2-氟苯基)四唑-2-基]甲基]苯羟肟酸(化合物33);
–4-[[5-(4-氟苯基)四唑-2-基]甲基]苯羟肟酸(化合物34);
–4-[[5-(4-甲氧基苯基)四唑-2-基]甲基]苯羟肟酸(化合物35);
–4-[(5-苄基四唑-2-基)甲基]苯羟肟酸(化合物36);
–4-[(5-苄基四唑-1-基)甲基]苯羟肟酸(化合物37);
–4-[[5-(2,4-二氯苯基)四唑-2-基]甲基]苯羟肟酸(化合物38);
–4-[[5-(3-甲基-2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物39);
–4-[[5-(5-甲基-2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物41);
–4-[[5-(苯并噻吩-3-基)四唑-2-基]甲基]苯羟肟酸(化合物42);
–4-[[5-(2,3-二氢噻吩并[3,4-b][1,4]二噁英-5-基)四唑-2-基]甲基]苯羟肟酸(化合物43);
–4-[[5-[(3,4-二甲氧基苯基)甲基]-2-[4-(三氟甲基)苯基]-1,2,4-***-3-基]甲基]苯羟肟酸(化合物44);
–4-[[5-[(3,4-二甲氧基苯基)甲基]-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物45);
–4-[[5-(2-氟苯基)四唑-2-基]甲基]苯羟肟酸(化合物46);
–4-[[5-[(1S)-1-氨基-2-噻唑-4-基-乙基]-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物48);
–4-[[5-(3,4-二甲氧基苯基)-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物49);
–4-[[5-(2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物50);
–4-[[2-苄基-5-(4-氯苯基)-1,2,4-***-3-基]甲基]苯羟肟酸(化合物51);
–4-[[2-(2-吡啶基)-5-(2-噻吩基)-1,2,4-***-3-基]甲基]苯羟肟酸(化合物52);
–4-[[2-(2-甲氧基苯基)-5-(2-噻吩基)-1,2,4-***-3-基]甲基]苯羟肟酸(化合物53);
–4-[[5-(6,6-二甲基-3-甲基氢硫基-4-氧代-5,7-二氢-2-苯并噻吩-1-基)四唑-2-基]甲基]苯羟肟酸(化合物54);
–4-[[5-(苯并噻吩-2-基)四唑-2-基]甲基]苯羟肟酸(化合物55);
–4-[[5-(3,4-二甲氧基苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物57);
–4-[[5-(2,4-二氟苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物58);
–4-[[5-[3-(二甲基胺磺酰基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物59);
–4-[[4-氨基-5-[3-(二乙基胺磺酰基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物61);
–4-[[5-(3-吗啉基磺酰基苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物64);
–3,5-二氟-4-[[5-(2-噻吩基)四唑-2-基]甲基]苯羟肟酸(化合物65);
–4-[[5-[3-(二乙基胺磺酰基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物66);
–4-[[4-甲基-5-[2-(对甲苯基)-4-喹啉基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物67);
–4-[(5-苯基-1,3,4-氧杂二唑-2-基)甲基]苯羟肟酸(化合物68);
–4-[[5-(4-吡咯啶-1-基磺酰基苯基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物69);
–4-[[5-(3-苄氧基-4-甲氧基-苯基)四唑-2-基]甲基]苯羟肟酸(化合物70);
–4-[[5-(3-苄氧基-4-甲氧基-苯基)四唑-1-基]甲基]苯羟肟酸(化合物71);
–4-[(5-环丙基-1-苯基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物72);
–4-[[5-[4-(二甲基氨基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物73);
–4-[[5-(6,6-二甲基-3-甲基磺酰基-4-氧代-5,7-二氢-2-苯并噻吩-1-基)四唑-2-基]甲基]苯羟肟酸(化合物74);
–4-[[5-(4-甲基-2-吗啉基-噻唑-5-基)-1,3,4-氧杂二唑-2-基]甲基]苯羟肟酸(化合物75);
–4-[[5-[5-(二甲基氨磺酰基)-2-氟-苯基]-4-甲基-1,2,4-***-3-基]硫烷基]苯羟肟酸(化合物76);
–4-[[5-[3-(二甲基氨基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物77);
–4-[[5-(3-甲氧基苯基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物78);
–4-[[5-(2,3-二氢噻吩并[3,4-b][1,4]二噁英-5-基)四唑-2-基]甲基]-3,5-二氟-苯羟肟酸(化合物79);
–4-[[5-[3-(二甲基氨基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物80);
–4-[5-[4-(羟基胺甲酰基)苯基]氢硫基-4-甲基-1,2,4-***-3-基]哌啶-1-甲酸叔丁酯(化合物82);
–4-[[5-(2,3-二氢-1,4-苯并二噁英-3-基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物83);
–4-[[5-(1,3-苯并间二氧杂环戊烯-5-基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物84);
–4-[[5-(1,5-二甲基吡唑-3-基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物85);
–4-[[5-(2-呋喃基)四唑-1-基]甲基]苯羟肟酸(化合物86);
–4-[[5-(1-异喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物87);
–4-[[5-(1-异喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物88);
–4-[[5-(2-吡啶基)四唑-2-基]甲基]苯羟肟酸(化合物89);
–4-[[5-(2-喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物90);
–4-[[5-(2-喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物91);
–3,5-二氟-4-[[5-(2-呋喃基)四唑-1-基]甲基]苯羟肟酸(化合物92);
–3,5-二氟-4-[[5-(1-异喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物93);
–3,5-二氟-4-[[5-(1-异喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物94);
–3,5-二氟-4-[[5-(2-喹啉基)四唑-2-基]甲基]苯羟肟酸(化合物95);
–3,5-二氟-4-[[5-(2-喹啉基)四唑-1-基]甲基]苯羟肟酸(化合物96);
–3,5-二氟-4-[[5-(2-噻吩基)-4H-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物97);
–4-[(5-二苯甲基-4-甲基-1,2,4-***-3-基)氢硫基]-3,5-二氟-苯羟肟酸(化合物98);
–4-[[5-(3-氨基噻吩并[2,3-b]吡啶-2-基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物99);
–4-[[5-(1,5-二甲基吡唑-3-基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物100);
–3,5-二氟-4-[[4-甲基-5-(1-苯基环丁基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物101);
–3,5-二氟-4-[[5-[1-(3-氟苯基)环戊基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物102);
–3,5-二氟-4-[[5-[1-(4-甲氧基苯基)环己基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物103);
–3,5-二氟-4-[[5-[1-(4-甲氧基苯基)环丙基]-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物104);
–4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物106);
–4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物107);
–3,5-二氟-4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物108);
–3,5-二氟-4-[[5-[3-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物109);
–4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物110);
–4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物111);
–3,5-二氟-4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物112);
–3,5-二氟-4-[[5-[4-(五氟-λ6-氢硫基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物113);
–3,5-二氟-4-[[4-甲基-5-[3-(4-甲基-4-氧负离子基-哌嗪-4-鎓-1-基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物114);
–3,5-二氟-4-[[4-(4-氟苯基)-5-(1-哌啶基甲基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物115);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-吡咯啶-1-基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物116);
–4-[(4-苄基-5-吗啉基-1,2,4-***-3-基)氢硫基]-3,5-二氟-苯羟肟酸(化合物117);
–4-[[5-(2,3-二氢噻吩并[3,4-b][1,4]二噁英-5-基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物118);
–3,5-二氟-4-[[5-(1-异喹啉基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物121);
–3,5-二氟-4-[[4-甲基-5-(2-喹啉基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物122);
–4-[(5-嘧啶-2-基四唑-2-基)甲基]苯羟肟酸(化合物123);
–4-[(5-嘧啶-2-基四唑-1-基)甲基]苯羟肟酸(化合物124);
–3,5-二氟-4-[(5-嘧啶-2-基四唑-1-基)甲基]苯羟肟酸(化合物125);
–4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-2-基]甲基]苯羟肟酸(化合物126);
–4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-1-基]甲基]苯羟肟酸(化合物127);
–3,5-二氟-4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-2-基]甲基]苯羟肟酸(化合物128);
–3,5-二氟-4-[[5-[5-(三氟甲基)-2-吡啶基]四唑-1-基]甲基]苯羟肟酸(化合物129);
–4-[[5-[3-吗啉基-5-(三氟甲基)-2-吡啶基]四唑-2-基]甲基]苯羟肟酸(化合物130);
–4-[[5-[3-吗啉基-5-(三氟甲基)-2-吡啶基]四唑-1-基]甲基]苯羟肟酸(化合物131);
–4-[[5-(2-吡啶基甲基)四唑-2-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物132);
–4-[[5-(2-吡啶基甲基)四唑-1-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物133);
–3,5-二氟-4-[[5-(2-吡啶基甲基)四唑-2-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物134);
–3,5-二氟-4-[[5-(2-吡啶基甲基)四唑-1-基]甲基]苯羟肟酸;2,2,2-三氟乙酸(化合物135);
–3,5-二氟-4-[[4-甲基-5-[1-苯基-5-(2-噻吩基)吡唑-3-基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物136);
–3,5-二氟-4-[[5-(6-氟-2-甲基-3-喹啉基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物137);
–3,5-二氟-4-[[5-(4-氟苯基)-4-(2-吗啉基乙基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物138);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-吡嗪-2-基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物139);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(2-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物140);
–4-[[4-苄基-5-(吡咯啶-1-基甲基)-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物141);
–4-[[4-苄基-5-(2-呋喃基)-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物142);
–4-[[4-苄基-5-(2-噻吩基)-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物143);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(2-噻吩基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物144);
–3,5-二氟-4-[[5-(2-氟苯基)-4-(2-呋喃基甲基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物145);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(4-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物146);
–3,5-二氟-4-[[4-(2-呋喃基甲基)-5-(3-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物147);
–3,5-二氟-4-[[5-(3-异喹啉基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物148);
–3,5-二氟-4-[(5-咪唑并[1,2-a]吡啶-3-基-4-甲基-1,2,4-***-3-基)氢硫基]苯羟肟酸(化合物149);
–4-[[5-(1-苄基-4-苯基-4-哌啶基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物150);
–3,5-二氟-4-[[4-甲基-5-[3-(4-甲基哌嗪-1-基)磺酰基苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物151);
–4-[[5-[3-(4-苄基哌嗪-1-基)磺酰基苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物152);
–3,5-二氟-4-[[4-甲基-5-(3-吡啶基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物153);
–4-[[2-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸甲酯(化合物154);
–4-[[1-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸甲酯(化合物155);
–6-[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]吡啶-3-甲酸甲酯(化合物156);
–6-[1-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]吡啶-3-甲酸甲酯(化合物157);
–4-[[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物158);
–4-[[1-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物159);
–4-[[2-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物160);
–4-[[1-[[2,6-二氟-4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]甲基]苯甲酸(化合物161);
–6-[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]吡啶-3-甲酸(化合物162);
–3-[2-[[4-(羟基胺甲酰基)苯基]甲基]四唑-5-基]苯甲酸(化合物163);
–3,5-二氟-4-[[4-甲基-5-(8-喹啉基甲基)-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物164);
–4-[[5-(2,6-二氟苯基)-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物165);
–3,5-二氟-4-[[4-甲基-5-[3-(4-甲基哌嗪-1-基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物166);
–4-[[5-[3-(氮杂环庚烷-1-基甲基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物167);
–4-[[5-[4-(氮杂环庚烷-1-基甲基)苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物168);
–4-[[5-(4-氨基苯基)四唑-2-基]甲基]苯羟肟酸(化合物169);
–4-[[5-(4-氨基苯基)四唑-1-基]甲基]苯羟肟酸(化合物170);
–4-[[5-(4-氨基苯基)四唑-2-基]甲基]-3,5-二氟-苯羟肟酸(化合物171);
–4-[[5-(4-氨基苯基)四唑-1-基]甲基]-3,5-二氟-苯羟肟酸(化合物172);
–4-[[5-[4-(氨基甲基)苯基]四唑-2-基]甲基]苯羟肟酸(化合物173);
–4-[[5-[4-(氨基甲基)苯基]四唑-1-基]甲基]苯羟肟酸(化合物174);
–4-[[5-[4-(氨基甲基)苯基]四唑-2-基]甲基]-3,5-二氟-苯羟肟酸(化合物175);
–4-[[5-[4-(氨基甲基)苯基]四唑-1-基]甲基]-3,5-二氟-苯羟肟酸(化合物176);
–3,5-二氟-4-[[4-甲基-5-[1-(2-吡啶基)环丙基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物177);
–3,5-二氟-4-[[4-甲基-5-[1-(3-吡啶基)环丙基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物178);
–3,5-二氟-4-[[5-(3-氟-2-吡啶基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物180);
–3,5-二氟-4-[[4-甲基-5-[3-(1-哌啶基甲基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物181);
–3,5-二氟-4-[[4-甲基-5-[3-(吗啉基甲基)苯基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物182);
–4-((3-((1H-吲哚-3-基)甲基)-5-(噻吩-2-基)-4H-1,2,4-***-4-基)甲基)-N-羟基苯甲酰胺(化合物183);
–4-[[5-[3-[[苄基(甲基)氨基]甲基]苯基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物184);
–4-[[3-[(3,4-二甲氧基苯基)甲基]-5-(2-噻吩基)-1,2,4-***-4-基]甲基]苯羟肟酸(化合物185);
–3,5-二氟-4-[[4-甲基-5-[1-甲基-1-(3-吡啶基)乙基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物186);
–3,5-二氟-4-[[5-[4-[甲基(甲基磺酰基)氨基]苯基]-1,3,4-噻二唑-2-基]氢硫基]苯羟肟酸(化合物187);
–4-[(5-苯基-1,3,4-氧杂二唑-2-基)氢硫基]苯羟肟酸(化合物188);
–4-[(5-苯基-1,2,4-氧杂二唑-3-基)甲基]苯羟肟酸(化合物189);
–4-[(5-苯基-1,3,4-噻二唑-2-基)甲基]苯羟肟酸(化合物190);
–3,5-二氟-N-羟基-4-((5-(吡啶-3-基)-1,3,4-噻二唑-2-基)硫基)苯甲酰胺(化合物191);
–3,5-二氟-4-[(5-苯基-1,3,4-氧杂二唑-2-基)氢硫基]苯羟肟酸(化合物192);
–4-[[5-(2-吗啉基-4-吡啶基)-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物193);
–3,5-二氟-N-羟基-4-((5-苯基-1,2,4-氧杂二唑-3-基)甲基)苯甲酰胺(化合物194);
–3,5-二氟-4-[[5-(4-吡啶基)-1,3,4-噻二唑-2-基]甲基]苯羟肟酸(化合物195);
–4-[[5-(5-溴-3-吡啶基)-1,3,4-噻二唑-2-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物196);
–3,5-二氟-4-[[5-(5-吗啉基-3-吡啶基)-1,3,4-噻二唑-2-基]甲基]苯羟肟酸(化合物197);
–3,5-二氟-N-羟基-4-((5-苯基-1,3,4-噻二唑-2-基)甲基)苯甲酰胺(化合物198);
–3,5-二氟-4-[[5-(2-呋喃基)-4-甲基-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物199);
–4-[[5-[5-[双(2-甲氧基乙基)氨基]-3-吡啶基]-1,2,4-氧杂二唑-3-基]甲基]-3,5-二氟-苯羟肟酸(化合物200);
–3,5-二氟-4-[[5-[5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)-3-吡啶基]-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物201);
–3,5-二氟-4-[[5-[5-(吡咯啶-1-基甲基)-2-呋喃基]-1,2,4-氧杂二唑-3-基]甲基]苯羟肟酸(化合物202);
–3,5-二氟-4-[[4-甲基-5-[5-(吗啉基甲基)-3-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物203);
–3,5-二氟-4-[[4-甲基-5-[5-(吗啉基甲基)-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物204);
–3,5-二氟-4-[[4-甲基-5-[5-[(4-甲基哌嗪-1-基)甲基]-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物205);
–4-[[5-[5-[(二甲基氨基)甲基]-2-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物206);
–3,5-二氟-4-[[4-甲基-5-[5-(吡咯啶-1-基甲基)-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物207);
–4-[[5-[5-乙基-4-(吡咯啶-1-基甲基)-2-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物208);
–4-[[4-甲基-5-[5-[(4-甲基哌嗪-1-基)甲基]-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物209);
–3,5-二氟-4-[[4-甲基-5-[6-(2-吡咯啶-1-基乙基)-3-吡啶基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物210);
–4-[[5-[5-(二乙基氨基甲基)-2-呋喃基]-4-甲基-1,2,4-***-3-基]氢硫基]-3,5-二氟-苯羟肟酸(化合物211);
–3,5-二氟-4-[[4-甲基-5-[5-(1-哌啶基甲基)-2-呋喃基]-1,2,4-***-3-基]氢硫基]苯羟肟酸(化合物212);
–4-[(5-苯基四唑-2-基)甲基]苯羟肟酸(化合物214);
–4-[(5-苯基四唑-1-基)甲基]苯羟肟酸(化合物215);
–4-[(5-苯基-4H-1,2,4-***-3-基)甲基]苯羟肟酸(化合物216);
–N-羟基-4-((4-甲基-5-苯基-4H-1,2,4-***-3-基)甲基)苯甲酰胺(化合物217)。
5.根据权利要求1所述的化合物,其与药物组合,所述药物选自蛋白酶体抑制剂、免疫检查点抑制剂、类固醇、布罗莫结构域抑制剂、表观遗传药物、传统化疗、激酶抑制剂。
6.根据权利要求5所述的化合物,其中所述药物选自JAK家族及CTLA4、PD1或PDL1检查点抑制剂。
7.根据权利要求1至6中任一项所述的化合物在制备药物中的用途。
8.根据权利要求7所述的用途,其中所述药物用于治疗一种或多种HDAC6介导的疾病,所述疾病选自器官移植排斥、肌炎、与淋巴细胞功能异常有关的疾病、多发性骨髓瘤、非霍奇金氏淋巴瘤、周围神经病变、自身免疫疾病、炎性疾病、癌症及神经退化性疾病、眼部疾病、及GVHD。
9.一种药物组合物,其包含治疗上有效量的至少一种根据权利要求1至6中任一项所述的式(I)或(II)化合物或其药学上可接受的盐、立体异构体,以及至少一种药学上可接受的赋形剂。
10.根据权利要求9所述的药物组合物,其适合通过肠内途径、肠胃外途径、口服途径、局部途径、或吸入途径而施用。
11.根据权利要求9或10所述的药物组合物,其为液体或固体的形式。
12.根据权利要求11所述的药物组合物,其为胶囊、片剂、包衣片剂、粉剂、颗粒剂、霜剂或软膏剂的形式。
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WO2021013163A1 (en) * | 2019-07-23 | 2021-01-28 | Taipei Medical University | Histone deacetylase 6 inhibitors and method for treating neuropathic pain |
BR112023002209A2 (pt) * | 2020-08-07 | 2023-04-25 | Italfarmaco Spa | Derivados de 2-(4-((benzo[b]tiofen-3-il)-1h-tetrazol-1-il)metil)fenil)-5-(difluorometil)-1,3,4-oxadiazol e compostos similares como inibidores seletivos de histona desacetilase 6 (hdac6) para uso no tratamento, por exemplo, de neuropatia periférica |
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IT202100009926A1 (it) | 2021-04-20 | 2022-10-20 | Italfarmaco Spa | Una combinazione comprendente un inibitore di hdac6 specifico e almeno un inibitore del checkpoint ctla4 |
TW202340480A (zh) | 2021-11-23 | 2023-10-16 | 義大利商義大利藥品股份有限公司 | 檢測rna生物標記之方法 |
WO2023219456A1 (ko) * | 2022-05-12 | 2023-11-16 | 숙명여자대학교 산학협력단 | 퀴놀린 계열 히스톤디아세틸화 효소 저해활성물질, 이의 제조방법 및 이를 유효성분으로 포함하는 약학적 조성물 |
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