CN1578663A - 组蛋白脱乙酰化酶抑制剂 - Google Patents
组蛋白脱乙酰化酶抑制剂 Download PDFInfo
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- CN1578663A CN1578663A CNA028226909A CN02822690A CN1578663A CN 1578663 A CN1578663 A CN 1578663A CN A028226909 A CNA028226909 A CN A028226909A CN 02822690 A CN02822690 A CN 02822690A CN 1578663 A CN1578663 A CN 1578663A
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- chemical compound
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- aryl
- phenyl
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- 102000003964 Histone deacetylase Human genes 0.000 title claims abstract description 122
- 108090000353 Histone deacetylase Proteins 0.000 title claims abstract description 122
- 239000003112 inhibitor Substances 0.000 title claims description 61
- 150000001875 compounds Chemical class 0.000 claims abstract description 562
- 239000000203 mixture Substances 0.000 claims abstract description 214
- 238000000034 method Methods 0.000 claims abstract description 171
- 230000005764 inhibitory process Effects 0.000 claims abstract description 23
- -1 3-amino-2-thienyl Chemical group 0.000 claims description 196
- 125000003118 aryl group Chemical group 0.000 claims description 159
- 125000001072 heteroaryl group Chemical group 0.000 claims description 122
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 94
- 229920006395 saturated elastomer Polymers 0.000 claims description 86
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 74
- 150000003839 salts Chemical class 0.000 claims description 74
- 229910052757 nitrogen Inorganic materials 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 62
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 43
- 229910052799 carbon Inorganic materials 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 25
- 150000001408 amides Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical group OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 claims description 14
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 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 11
- 125000001624 naphthyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 235000010292 orthophenyl phenol Nutrition 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 3
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 claims description 2
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 claims description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000005466 alkylenyl group Chemical group 0.000 claims 1
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 230000002255 enzymatic effect Effects 0.000 abstract description 12
- 201000010099 disease Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000002062 proliferating effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 227
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 209
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 168
- 238000006243 chemical reaction Methods 0.000 description 149
- 239000000243 solution Substances 0.000 description 146
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- 239000002585 base Substances 0.000 description 111
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 108
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 96
- 239000000376 reactant Substances 0.000 description 95
- 238000003756 stirring Methods 0.000 description 88
- 238000005160 1H NMR spectroscopy Methods 0.000 description 84
- 238000005481 NMR spectroscopy Methods 0.000 description 84
- 239000000460 chlorine Substances 0.000 description 83
- 238000005406 washing Methods 0.000 description 77
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 67
- 238000001035 drying Methods 0.000 description 67
- 239000012043 crude product Substances 0.000 description 66
- 210000004027 cell Anatomy 0.000 description 63
- 239000007787 solid Substances 0.000 description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
- 238000000746 purification Methods 0.000 description 61
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 56
- 239000012044 organic layer Substances 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 53
- 229910002027 silica gel Inorganic materials 0.000 description 53
- 229960001866 silicon dioxide Drugs 0.000 description 53
- 238000004364 calculation method Methods 0.000 description 49
- 239000000725 suspension Substances 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 42
- 239000007864 aqueous solution Substances 0.000 description 37
- 108091034117 Oligonucleotide Proteins 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 229960004365 benzoic acid Drugs 0.000 description 33
- 239000005711 Benzoic acid Substances 0.000 description 32
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 27
- 239000011734 sodium Substances 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 206010012812 Diffuse cutaneous mastocytosis Diseases 0.000 description 23
- 108010033040 Histones Proteins 0.000 description 23
- 206010028980 Neoplasm Diseases 0.000 description 23
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 23
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 23
- 229910052801 chlorine Inorganic materials 0.000 description 23
- 238000000926 separation method Methods 0.000 description 23
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- 238000011282 treatment Methods 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 18
- 239000000074 antisense oligonucleotide Substances 0.000 description 17
- 238000012230 antisense oligonucleotides Methods 0.000 description 17
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 17
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 17
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- 150000001721 carbon Chemical group 0.000 description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 16
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 description 15
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- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
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- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 12
- 235000010233 benzoic acid Nutrition 0.000 description 12
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 125000002652 ribonucleotide group Chemical group 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 108091028664 Ribonucleotide Proteins 0.000 description 11
- 238000013459 approach Methods 0.000 description 11
- 230000004663 cell proliferation Effects 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
- 239000002336 ribonucleotide Substances 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
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- AKRYBBWYDSDZHG-UHFFFAOYSA-N nitrosobis(2-oxopropyl)amine Chemical compound CC(=O)CN(N=O)CC(C)=O AKRYBBWYDSDZHG-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
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- 238000010992 reflux Methods 0.000 description 9
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- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 8
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- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 8
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- 238000001556 precipitation Methods 0.000 description 8
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 7
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- 125000003636 chemical group Chemical group 0.000 description 7
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- 238000001727 in vivo Methods 0.000 description 7
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 description 7
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Images
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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Abstract
本发明涉及抑制组蛋白脱乙酰化酶。本发明提供了涉及抑制组蛋白脱乙酰化酶活性的化合物和方法。本发明还提供了治疗细胞增殖性疾病和病症的组合物和方法。
Description
发明领域
本发明涉及抑制组蛋白脱乙酰化酶(deacetylase)。本发明更具体涉及抑制组蛋白脱乙酰化酶活性的化合物和方法。
相关技术概述
在真核细胞中,细胞核DNA与组蛋白结合以形成称为染色质的紧密复合物。组蛋白构成了在真核生物物种之间通常高度保守的碱性蛋白家族。称为H2A、H2B、H3和H4的核心组蛋白结合以形成蛋白核心。DNA沿着该蛋白核心缠绕,同时组蛋白的碱性氨基酸与DNA的带负电荷的磷酸根基团相互作用。约有146个DNA的碱基对沿着组蛋白核心缠绕,以构成核小体颗粒—染色质的重复结构基元。
Csordas,Biochem.J.,286:23-38(1990)提出,组蛋白发生N-末端赖氨酸残基的α,ε-氨基的翻译后乙酰化,这是被组蛋白乙酰转移酶(HAT1)催化的反应。乙酰化中和了赖氨酸侧链的正电荷,并且据信会影响染色质结构。Taunton等人,Science,272:408-411(1996)提出,转录因子到达染色质模板的路径被组蛋白高度乙酰化增强。Taunton等人还指出,在基因组的转录沉默区域中发现了富集的乙酰化组蛋白H4。
组蛋白乙酰化是可逆修饰,其中脱乙酰化是由称为组蛋白脱乙酰化酶(HDAC)的一族酶催化的。Grozinger等人,Proc.Natl.Acad.Sci.USA,96:4868-4873(1999)中提出HDAC分为两类,第一类由酵母Rpd3-样蛋白代表,第二类由酵母Hda1-样蛋白代表。Grozinger等人还提出,人HDAC1、HDAC2和HDAC3蛋白是第一类HDAC的成员,并且公开了称为HDAC4、HDAC5和HDAC6的新蛋白,它们是第二类HDAC的成员。Kao等人,Genes & Dev.,14:55-66(2000)公开了HDAC7二类HDAC的一个新成员。Van den Wyngaert,FEBS,478:77-83(2000)公开了HDAC8第一类HDAC的一个新成员。
Richon等人,Proc.Natl.Acad.Sci.USA,95:3003-3007(1998)公开了HDAC活性被曲古抑菌素A(TSA)—一种从吸水链霉菌(Streptomyces hygroscopicus)中分离的天然产物和合成化合物辛二酰苯胺异羟肟酸(SAHA)抑制。Yoshida和Beppu,Exper.Cell Res.,177:122-131(1988)指出,TSA在细胞周期的G1和G2期引起大鼠成纤维细胞的停滞,这意味着HDAC在细胞周期中具有调控作用。Finnin等人,Nature,401:188-193(1999)提出,TSA和SAHA抑制细胞生长,诱导末端分化,并防止在小鼠中形成肿瘤。Suzuki等人,U.S.专利6,174,905、EP 0847992、JP 258863/96和第10138957号日本专利申请公开了诱导细胞分化和抑制HDAC的苯甲酰胺衍生物。Delorme等人,WO01/38322和PCT IB01/00683公开了起HDAC抑制剂作用的另外一些化合物。
编码具有HDAC活性的蛋白的基因序列的分子克隆已确立了存在一组离散的HDAC酶同种型。Grozinger等人,Proc.Natl.Acad.Sci.USA,96:4868-4873(1999)中提出HDAC分为两类,第一类由酵母Rpd3-样蛋白代表,第二类由酵母Hda1-样蛋白代表。Grozinger等人还提出,人HDAC1、HDAC2和HDAC3蛋白是第一类HDAC的成员,并且公开了称为HDAC4、HDAC5和HDAC6的新蛋白,它们是第二类HDAC的成员。Kao等人,Gene & Development,14:55-66(2000)公开了称为HDAC-7的第二类的另一个成员。最近,Hu,E.等人.J.Bio.Chem.275:15254-13264(2000)公开了第一类组蛋白脱乙酰化酶的一个最新成员HDAC-8。尚不清楚这些HDAC酶起什么作用。
这些发现表明,抑制HDAC活性是干预细胞周期调控的一种新方法,并且HDAC抑制剂在细胞增殖性疾病或病症的治疗中有着很大的治疗潜力。迄今为止,本领域中已知的组蛋白脱乙酰化酶抑制剂很少。因此需要确定出另外的HDAC抑制剂和确定出有效HDAC抑制活性所需的结构特征。
发明概述
本发明提供了治疗细胞增殖性疾病的化合物和方法。本发明提供了组蛋白脱乙酰化酶活性的新抑制剂。
在第一个方面,本发明提供了可用作组蛋白脱乙酰化酶抑制剂的化合物。
在第二个方面,本发明提供了组合物,其中包含本发明组蛋白脱乙酰化酶抑制剂和可药用载体、赋形剂或稀释剂。
在第三个方面,本发明提供了抑制细胞中组蛋白脱乙酰化酶的方法,包括将需要抑制组蛋白脱乙酰化酶的细胞与本发明组蛋白脱乙酰化酶抑制剂接触。
上面仅仅总结了本发明的一些方面,其在性质上不是限制性的。下面更充分地描述这些方面和其它方面以及实施方案。
附图简单说明
图1是表明化合物106在HCT 116人结肠直肠肿瘤模型中的抗肿瘤活性的图。
图2-11显示了关于在测定实施例2中描述的体内试验中使用的其它化合物的另外数据。
优选实施方案的详细描述
本发明提供了抑制组蛋白脱乙酰化酶活性的化合物和方法。本发明还提供了用于治疗细胞增殖性疾病和病症的组合物和方法。本文中引用的专利和科学文献建立了本领域技术人员可以获得的知识。在本文中引用的公布的专利、申请和参考文献以同样的程度在此引入作为参考,即每个特定且单独在此引入作为参考。当不一致时,本申请公开内容将占优势。
对于本发明目的,使用下列定义(除非另有说明):
本文所用术语“组蛋白脱乙酰化酶”和“HDAC”是指能将乙酰基从在组蛋白的N-末端的赖氨酸残基的,-氨基上除去的酶家族的任一个成员。除非在上下文中另有说明,术语“组蛋白”是指得自任何物种的任何组蛋白,包括H1、H2A、H2B、H3、H4和H5。优选的组蛋白脱乙酰化酶包括I类和II类酶。组蛋白脱乙酰化酶优选为人HDAC,包括但不限于HDAC-1、HDAC-2、HDAC-3、HDAC-4、HDAC-5、HDAC-6、HDAC-7和HDAC-8。在某些其它优选的实施方案中,组蛋白脱乙酰化酶得自原生动物或真菌来源。
术语“组蛋白脱乙酰化酶抑制剂”和“组蛋白脱乙酰化酶的抑制剂”是指具有本文所定义结构的化合物,其能够与组蛋白脱乙酰化酶相互作用并且抑制组蛋白脱乙酰化酶的酶活性。“抑制组蛋白脱乙酰化酶活性”是指降低组蛋白脱乙酰化酶将乙酰基从组蛋白上除去的能力。在某些优选的实施方案中,组蛋白脱乙酰化酶活性被降低了至少约50%,更优选至少约75%,还更优选至少约90%。在其它优选的实施方案中,组蛋白脱乙酰化酶活性被降低了至少95%,更优选至少99%。
优选地,这样的抑制是特异性的,也就是说,组蛋白脱乙酰化酶抑制剂降低组蛋白脱乙酰化酶将乙酰基从组蛋白上除去的能力的浓度,低于产生另一不相关生物作用所需的抑制剂浓度。优选地,组蛋白脱乙酰化酶抑制活性所需的抑制剂浓度比产生不相关生物作用所需的浓度低至少2倍,更优选低至少5倍,甚至更优选低至少10倍,最优选低至少20倍。
简单起见,在本文中,化学基团部分主要定义为和称为单价化学基团部分(例如烷基、芳基等)。然而,在合适的结构情况下,还使用这样的术语来表示本领域技术人员清楚的相应的多价基团部分。例如,虽然“烷基”部分通常是指单价基团(例如CH3-CH2-),但是在一些情况下,二价连接基团部分可以是“烷基”,在这种情况下本领域技术人员知道烷基是二价基团(例如-CH2-CH2-),其等同于术语“亚烷基”(类似地,在其中需要二价基团并且其被表述为“芳基”的情况下,本领域技术人员知道术语“芳基”是指相应的二价基团部分,即亚芳基)。应当理解,所有原子都具有关于形成键的其标准价数(即,对于碳是4,对于N是3,对于O是2,对于S,根据硫的氧化态是2、4或6)。有时基团部分被定义为例如(A)a-B-,其中a是0或1。在这样的情况下,当a是0时,该基团部分是B-,当a是1时,该基团部分是A-B-。很多本文公开的基团部分以多个互变异构形式存在,所有它们都包括在任何给定的互变异构结构范围内。
术语“烃基”是指直链、支链或环状烷基、链烯基或炔基,所述基团分别如本文所定义。“C0”烃基是用于指共价键。因此,“C0-C3-烃基”包括共价键、甲基、乙基、丙基和环丙基。
本文所用术语“烷基”是指具有1-12个碳原子,优选1-8个碳原子,更优选1-6个碳原子的直链和支链脂族基团,所述基团可任选被1、2或3个取代基取代。优选的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和己基。“C0”烷基(例如在“C0-C3-烷基”中)是共价键(象“C0”烃基一样)。
本文所用术语“链烯基”是指具有一个或多个碳-碳双键,有2-12个碳原子,优选2-8个碳原子,更优选2-6个碳原子的不饱和直链或支链脂族基团,所述基团可任选被1、2或3个取代基取代。优选的链烯基包括但不限于乙烯基、丙烯基、丁烯基、戊烯基和己烯基。
本文所用术语“炔基”是指具有一个或多个碳-碳三键,有2-12个碳原子,优选2-8个碳原子,更优选2-6个碳原子的不饱和直链或支链脂族基团,所述基团可任选被1、2或3个取代基取代。优选的炔基包括但不限于乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
“亚烷基”、“亚链烯基”或“亚炔基”是如上所定义的烷基、链烯基或炔基,其位于两个其它化学基团之间并连接这两个化学基团。优选的亚烷基包括但不限于亚甲基、亚乙基、亚丙基和亚丁基。优选的亚链烯基包括但不限于亚乙烯基、亚丙烯基和亚丁烯基。优选的亚炔基包括但不限于亚乙炔基、亚丙炔基和亚丁炔基。
本文所用术语“环烷基”包括具有3-12个碳原子,优选3-8个碳原子,更优选3-6个碳原子的饱和及部分不饱和环状烃基,其中所述环烷基还可以任选被取代。优选的环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。
术语“杂烷基”是指如上所定义的烷基,其中链中有一个或多个碳原子被选自O、S和N的杂原子代替。
“芳基”是包含1-3个芳环的C6-C14芳族基团,所述基团可任选被取代。芳基优选为C6-C10芳基。优选的芳基包括但不限于苯基、萘基、蒽基和芴基。“芳烷基”或“芳基烷基”包括共价连接在烷基上的芳基,二者中任一个可独立地任选被取代或者未取代。芳烷基优选为(C1-C6)烷(C6-C10)芳基,包括但不限于苄基、苯乙基和萘基甲基。
“杂环基”或“杂环基团”是具有约3-约8个原子,其中一个或多个原子选自N、O和S的环结构。杂环基可任选在一个或多个位置上在碳上被取代。杂环基还独立地任选在氮上被烷基、芳基、芳烷基、烷基羰基、烷基磺酰基、芳基羰基、芳基磺酰基、烷氧基羰基、芳烷氧基羰基取代,或者在硫上被氧代基或低级烷基取代。优选的杂环基包括但不限于环氧基、氮杂环丙烯基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、噻唑烷基、恶唑烷基、恶唑烷酮基和吗啉代。在一些优选的实施方案中,杂环基与芳基、杂芳基或环烷基稠合。这样的稠合杂环的实例包括但不限于四氢喹啉和二氢苯并呋喃。从该术语范围内具体排除的是具有相邻环O和/或S原子的化合物。
本文所用术语“杂芳基”是指这样的基团,其具有5-14个环原子,优选具有5、6、9或10个环原子;具有6、10或14个在环排列中共享的π电子;并且除了碳原子以外,每个环具有1-3个选自N、O和S的杂原子。“杂芳烷基”或“杂芳基烷基”包括共价连接在烷基上的杂芳基,二者中任一个可独立地任选被取代或者未取代。优选的杂烷基包括C1-C6烷基和具有5、6、9或10个环原子的杂芳基。从该术语范围内具体排除的是具有相邻环O和/或S原子的化合物。优选的杂芳烷基的实例包括吡啶基甲基、吡啶基乙基、吡咯基甲基、吡咯基乙基、咪唑基甲基、咪唑基乙基、噻唑基甲基和噻唑基乙基。从该术语范围内具体排除的是具有相邻环O和/或S原子的化合物。
“亚芳基”、“亚杂芳基”或“亚杂环基”是如上所定义的芳基、杂芳基或杂环基,其位于两个其它化学基团之间并连接这两个化学基团。
优选的杂环基和杂芳基包括但不限于吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻吩基、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、假吲哚基、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1 ,3,4-噁二唑基、恶唑烷基、恶唑基、恶唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、phenoxathiinyl、吩恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和夹氧蒽基。
如本文所用的那样,当基团部分(例如环烷基、烃基、芳基、杂芳基、杂环、脲等)被表述为“任选取代的”时,这是指基团可任选具有1-4个,优选1-3个,更优选1或2个非氢取代基。合适的取代基包括但不限于卤素、羟基、氧代基(例如被氧代基取代的环-CH-是-C(O)-)、硝基、卤代烃基、烃基、芳基、芳烷基、烷氧基、芳氧基、氨基、酰基氨基、烷基氨基甲酰基、芳基氨基甲酰基、氨基烷基、酰基、羧基、羟基烷基、烷磺酰基、芳烃磺酰基、烷磺酰胺基、芳烃磺酰胺基、芳烷基磺酰胺基、烷基羰基、酰氧基、氰基和脲基。自身未被进一步取代(除非另有说明)的优选的取代基是:
(a)卤素、氰基、氧代基、羧基、甲酰基、硝基、氨基、脒基、胍基,
(b)C1-C5烷基或链烯基或芳基烷基亚氨基、氨基甲酰基、叠氮基、酰胺基、巯基、羟基,羟基烷基、烷基芳基、芳基烷基、C1-C8烷基、C1-C8链烯基、C1-C8烷氧基、C1-C8烷氧基羰基、芳氧基羰基、C2-C8酰基、C2-C8酰基氨基、C1-C8烷硫基、芳基烷硫基、芳硫基、C1-C8烷基亚磺酰基、芳基烷基亚磺酰基、芳基亚磺酰基、C1-C8烷基磺酰基、芳基烷基磺酰基、芳基磺酰基、C0-C6N-烷基氨基甲酰基、C2-C15 N,N-二烷基氨基甲酰基、C3-C7环烷基、芳酰基、芳氧基、芳基烷基醚、芳基、与环烷基或杂环或另一芳环稠合的芳基、C3-C7杂环,或与环烷基、杂环基或芳基稠合或螺稠合的任何这些环,其中每个上述基团可任选被一个或多个在上文(a)中列出的基团取代;和(c)-(CH2)s-NR30R31,其中s为0(在这种情况下,氮直接键合到被取代的基团部分上)至6,并且R30和R31分别独立地为氢、氰基、氧代基、酰胺基、脒基、C1-C8羟基烷基、C1-C3烷基芳基、芳基-C1-C3烷基、C1-C8烷基、C1-C8链烯基、C1-C8烷氧基、C1-C8烷氧基羰基、芳氧基羰基、芳基-C1-C3烷氧基羰基、C2-C8酰基、C1-C8烷基磺酰基、芳基烷基磺酰基、芳基磺酰基、芳酰基、芳基、环烷基、杂环基或杂芳基,其中每个上述基团可任选被一个或多个在上文(a)中列出的基团取代;或者
R30和R31与它们所连接的N一起形成,杂环基或杂芳基,每个所述基团可任选被1-3个在上文(a)中列出的取代基取代。
此外,在环状基团(即环烷基、杂环基、芳基、杂芳基)上的取代基包括5-6元单环基团和10-12元二环基团,它们与母环部分稠合以形成二环或三环稠合环系。例如,任选被取代的苯基包括下列基团:
“卤代烃基”是其中有一个至所有氢被一个或多个卤素取代的烃基。
本文所用术语“卤素原子”或“卤素”是指氯、溴、氟或碘。本文所用术语“酰基”是指烷基羰基或芳基羰基取代基。术语“酰基氨基”是指在氮原子上连接的酰胺基团(即R-CO-NH-)。术语“氨基甲酰基”是指在羰基碳原子上连接的酰胺基团(即NH2-CO-)。酰基氨基或氨基甲酰基的氮原子也可以被取代。术语“磺酰胺基”是指通过硫原子或氮原子连接的磺酰胺基团。术语“氨基”包括NH2、烷基氨基、芳基氨基和环状氨基。本文所用术语“脲基”是指取代或未取代的脲基团。
本文所用术语“基团”是指包含一个或多个未成对电子的化学基团。
被取代的基团部分是其中有一个或多个氢独立地被另一化学取代基取代的基团。作为非限制性实例,取代的苯基包括2-氟苯基、3,4-二氯苯基、3-氯-4-氟-苯基、2-氟-3-丙基苯基。作为另一非限制性实例,取代的正辛基包括2,4-二甲基-5-乙基-辛基和3-环戊基-辛基。包括在该定义内的是被氧取代以形成羰基(-CO-)的亚甲基(-CH2-)。
如上所定义的“未取代”(例如未取代的环烷基、未取代的杂芳基等)是指不具有该基团的定义(上文)所提供的任何任选取代基的如上所定义的基团。因此,例如,“芳基”包括苯基和被卤素取代的苯基,“未取代的芳基”不包括被卤素取代的苯基。
特定种类本发明化合物的优选实施方案包括优选实施方案的组合。例如,段落[0042]确定了优选的Ay1,段落[0046]确定了优选的Ar1(二者都是关于段落[0041]的化合物(1))。因此,另一优选的实施方案包括段落[0041]中的式(1)化合物,其中Ay1如段落[0042]中所定义,Ar1如段落[0046]中所定义。
化合物
[0041]在第一个方面,本发明提供了新的组蛋白脱乙酰化酶抑制剂。在第一个实施方案中,新的组蛋白脱乙酰化酶抑制剂是式(1)化合物
及其可药用盐,其中
R3和R4独立地选自氢、L1、Cy1和-L1-Cy1,其中
L1是C1-C6烷基、C2-C6杂烷基或C3-C6链烯基;且
Cy1是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;或者
R3和R4与相邻氮原子一起形成5-、6-或7-元环,其中所述环原子独立地选自C、O、S和N,并且其中所述环可任选被取代,和任选形成二环环系的一部分,或任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环和环系可任选被取代;
Y1选自-N(R1)(R2)、-CH2-C(O)-N(R1)(R2)、卤素和氢,其中
R1和R2独立地选自氢、L1、Cy1和-L1-Cy1,其中
L1是C1-C6烷基、C2-C6杂烷基或C3-C6链烯基;
Cy1是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;或者
R1和R2与相邻氮原子一起形成5-、6-或7-元环,其中所述环原子独立地选自C、O、S和N,并且其中所述环可任选被取代,和任选形成二环环系的一部分,或任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环和环系可任选被取代;
Y2是化学键或N(R0),其中R0选自氢、烷基、芳基、芳烷基和酰基;
Ak1是C1-C6亚烷基、C1-C6-亚杂烷基(优选其中一个-CH2-被-NH-替代的C1-C6-亚杂烷基,更优选-NH-CH2-)、C2-C6亚链烯基或C2-C6亚炔基;
Ar1是亚芳基或亚杂芳基,每一所述基团可任选被取代;且
Z1选自
其中Ay1是芳基或杂芳基,所述基团可任选被取代。
[0042]在依据段落[0041]的化合物中,优选的是,Ay1是苯基或噻吩基,每一所述基团被-OH或-NH2取代。
在依据段落[0041]的化合物中,更优选的是,Ay1是任选被氨基或羟基取代的苯基或噻吩基,其中所述氨基或羟基取代基优选在与Ay2连接的氮的邻位。
在依据段落[0041]的化合物中,更优选的是,Ay1是邻位苯胺、邻位苯酚、3-氨基-2-噻吩基,或3-羟基-2-噻吩基及其互变异构体。
在依据段落[0041]的化合物的某些优选实施方案中,Z1是
[0046]在依据段落[0041]的化合物的某些优选实施方案中,Ar1是亚苯基。在某些实施方案中,Ak1是亚烷基,优选亚甲基。在某些优选实施方案中,Y2是-NH-。在某些优选实施方案中,Y1是-N(R1)(R2)或-CH2-C(O)-N(R1)(R2)。
在依据段落[0041]的化合物的某些实施方案中,R1和R2分别独立地选自氢、L1、Cy1和-L1-Cy1。在其它实施方案中,R1和/或R2是氢。在其它实施方案中,R1和/或R2是烷基或链烯基,优选烯丙基。在其它实施方案中,R1和/或R2是芳基、杂芳基、芳烷基或杂芳烷基,每一所述基团的环可任选被取代,并任选与一个或多个芳基环稠合。某些优选的芳基、杂芳基、芳烷基和杂芳烷基包括苯基、吡啶基或吡咯基环。在其它实施方案中,R1和/或R2是环烷基,例如环丙基、环戊基或环己基,所述基团可任选被取代,并任选与一个或多个芳基环稠合。
在依据段落[0041]的化合物的某些实施方案中,R3和R4分别独立地选自氢、L1、Cy1和-L1-Cy1。在其它实施方案中,R3和/或R4是氢。在其它实施方案中,R3和/或R4是烷基或链烯基,优选烯丙基。在其它实施方案中,R3和/或R4是芳基、杂芳基、芳烷基或杂芳烷基,每一所述基团的环可任选被取代,并任选与一个或多个芳基环稠合。某些优选的芳基、杂芳基、芳烷基和杂芳烷基包括苯基、吡啶基或吡咯基环。在其它实施方案中,R3和/或R4是环烷基,例如环丙基、环戊基或环己基,所述基团可任选被取代,并任选与一个或多个芳基环稠合。
如上所述,L1是C1-C6烷基、C2-C6杂烷基或C3-C6链烯基。然而,本领域技术人员应当理解,当L1不是末端基团时,L1是C1-C6亚烷基、C2-C6亚杂烷基或C3-C6亚链烯基。在某些实施方案中,L1是亚烷基,优选亚甲基或亚乙基。在某些实施方案中,L1是链烯基,优选烯丙基。在某些实施方案中,Cy1是杂环基,包括但不限于哌啶、吡咯烷、哌嗪和吗啉,每一所述基团可任选被取代,并任选与一个或多个芳基环稠合。在其它实施方案中,Cy1是环烷基,例如环丙基、环戊基或环己基。在其它实施方案中,Cy1是芳基或杂芳基,例如苯基、吡啶基或吡咯基,每一所述基团可任选被取代,并任选与一个或多个芳基环稠合。在某些实施方案中,Cy1与一个或两个苯环稠合。在某些实施方案中,Cy1具有1-约5个选自C1-C4烷基、C1-C4烷氧基和卤素的取代基。优选的取代基的实例包括甲基、甲氧基和氟。
在依据段落[0041]的化合物的某些实施方案中,R1和R2和/或R3和R4与相邻氮原子一起形成5-或6-元环,其中所述环原子独立地选自C、O和N,并且其中所述环可任选被取代,并任选与一个或多个芳基环稠合。在某些优选实施方案中,R1和R2和/或R3和R4与相邻氮原子一起形成环例如吡咯烷、哌啶、哌嗪和吗啉,其中所述环可任选被取代,并且任选与芳基环稠合。在某些实施方案中,包含R1和R2或R3和R4的环与苯环稠合。在某些实施方案中,包含R1和R2或R3和R4的环具有包含芳基或环烷基环的取代基,其中任一个可任选被取代,并任选与环烷基环、芳基环、杂芳基环或杂环稠合。优选的取代基包括但不限于苯基、苯基甲基和苯基乙基,所述基团的苯基环可任选与环烷基环、芳基环或杂环稠合。
[0051]在优选的实施方案中,本发明HDAC抑制剂包括式1(a)化合物
及其可药用盐,其中
J是C1-C3-烃基、-N(R20)-、-N(R20)-CH2-、-O-或-O-CH2-;R20是-H或-Me;
X和Y独立地选自-NH2、环烷基、杂环基、芳基、杂芳基和A-(C1-C6-烷基)n-B-;
A是H、C1-C6-烷氧基、环烷基、杂环基、芳基或杂芳基;
B是-NH-、-O-或一个键;且
n是0(在这种情况下A直接键合到B上)或1。
在依据段落[0051]的化合物中,优选A是任选被一个或多个选自卤素(优选氯)和甲氧基的基团取代的苯基,且B是-NH-。在另一个实施方案中,A选自环丙基、吡啶基和茚满基。
在依据段落[0051]的化合物中,优选的是,J是-NH-CH2-、-O-CH2-、-N(CH3)-CH2-、-CH=CH-或-CH2-CH2-。
在依据段落[0051]的化合物中,R20优选为-H。
在依据段落[0051]的化合物中,X优选选自
且Y优选选自
在依据段落[0051]的化合物的更优选的实施方案中,本发明HDAC抑制剂包括下列式1a化合物:
[0057]在第二个方面,本发明新的组蛋白脱乙酰化酶抑制剂是式(2)化合物
及其可药用盐,其中
Cy2是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;
X1选自共价键、M1-L2-M1和L2-M2-L2,其中
L2在每次出现时独立地选自化学键、C1-C4亚烷基、C2-C4亚链烯基和C2-C4亚炔基,条件是:当X1是M1-L2-M1时,L2不是化学键;
M1在每次出现时独立地选自-O-、-N(R7)-、-S-、-S(O)-,S(O)2-、-S(O)2N(R7)-、-N(R7)-S(O)2-、-C(O)-、-C(O)-NH-,-NH-C(O)-、-NH-C(O)-O-和-O-C(O)-NH-,其中R7选自氢、烷基、芳基、芳烷基、酰基、杂环基和杂芳基;且
M2选自M1、亚杂芳基和亚杂环基,任一所述环可任选被取代;
Ar2是亚芳基或亚杂芳基,每一所述基团可任选被取代;
R5和R6独立地选自氢、烷基、芳基和芳烷基;
q是0或1;且
Ay2是5-6元环烷基、杂环基或杂芳基,所述基团被氨基或羟基取代(这些基团优选在与Ay2连接的酰胺氮的邻位),并且还任选被进一步取代;条件是:当Cy2是萘基,X1是-CH2-,Ar2是苯基,R5和R6是H,且q是0或1时,Ay2不是苯基或邻羟基苯基。
在依据段落[0057]的化合物的优选实施方案中,当Ay2是任选被卤素、硝基或甲基取代的邻苯酚,Ar2是任选取代的苯基,X1是-O-、-CH2-、-S-、-S-CH2-、-S(O)-、-S(O)2-、-C(O)-或-OCH2-时,Cy2不是任选取代的苯基或萘基。
在依据段落[0057]的化合物的另一优选实施方案中,当Ay2是任选被卤素、C1-C6-烷基、C1-C6-烷氧基或-NO2取代的邻苯胺基,q是0,Ar2是苯基,且X1是-CH2-时,Cy2不是取代的吡啶酮(吡啶酮的取代基不限于本文描述的取代基)。
在依据段落[0057]的化合物的另一优选实施方案中,当X1是-CH2-,Ar2是任选取代的苯基,q是1,且R6是H时,则Cy2不是任选取代的咪唑。
在依据段落[0057]的化合物的另一优选实施方案中,当Ar2是被氨基或羟基取代的苯基,X1是C0-C8-烷基-X1a-C0-C8-烷基,其中X1a是-CH2-、-O-、-S-、-NH-、-C(O)-时,Cy2不是任选取代的萘基或二氢萘或四氢萘。
在依据段落[0057]的化合物的另一优选实施方案中,当Ay2是邻苯酚,Ar2是取代的苯基,X1是-O-、-S-、-CH2-、-O-CH2-、-S-CH2-或-C(O)-,且R5和R6是H时,Cy2不是任选取代的萘基。
在依据段落[0057]的化合物的另一优选实施方案中,当Ay2是邻苯胺基,q是0,Ar2是未取代的苯基,X1是-CH2-时,Cy2不是取代的6-氢咪唑并[5,4-d]哒嗪-7-酮-1-基或取代的6-氢咪唑并[5,4-d]哒嗪-7-硫酮-1-基。
在依据段落[0057]的化合物中,优选地,Ay2是苯基或噻吩基,所述基团分别被-OH或-NH2取代。
在依据段落[0057]的化合物中,更优选地,Ay2是任选被氨基或羟基取代的苯基或噻吩基,其中所述氨基或羟基优选在与Ay2连接的氮的邻位。
在依据段落[0057]的化合物中,更优选地,Ay2是邻苯胺、邻苯酚、3-氨基-2-噻吩基或3-羟基-2-噻吩基及其互变异构体。
[0067]在另一个实施方案中,本发明新的组蛋白脱乙酰化酶抑制剂是依据段落[0057]的那些,其中
q是1;
M1在每次出现时选自-N(R7)-、-S-、-C(O)-NH-和-O-C(O)-NH-,其中
R7选自氢、烷基、芳基、芳烷基和酰基;且
Ay2是任选取代的苯胺基。
在依据段落[0067]的化合物的某些优选实施方案中,Ay2的-NH2在与Ay2连接的氮原子的邻位。在某些实施方案中,R5和R6独立地选自氢和C1-C4烷基。在某些优选实施方案中,R5和R6是氢。
[0069]在依据段落[0067]的化合物的某些实施方案中,Ar2具有下式或
在依据段落[0069]的化合物的某些优选实施方案中,Ar2选自亚苯基、亚吡啶基、亚嘧啶基和亚喹啉基。
在依据段落[0067]的化合物的某些实施方案中,X1是化学键。在某些实施方案中,X1是L2-M2-L2,且M2选自-NH-、-N(CH3)-、-S-、-C(O)-N(H)-和-O-C(O)-N(H)-。在某些实施方案中,X1是L2-M2-L2,其中至少一个出现的L2为化学键。在其它实施方案中,X1是L2-M2-L2,其中至少一个出现的L2为亚烷基,优选亚甲基。在其它实施方案中,X1是L2-M2-L2,其中至少一个出现的L2为亚链烯基。在某些实施方案中,X1是M1-L2-M1,且M1选自-NH-、-N(CH3)-、-S-和-C(O)-N(H)-。
每一所述基团可任选被取代,并任选与一个或多个芳基环稠合。在某些实施方案中,Cy2具有1-3个独立地选自下列的取代基:烷基、烷氧基、氨基、硝基、卤素、卤代烷基和卤代烷氧基。优选的取代基的实例包括甲基、甲氧基、氟、三氟甲基、三氟甲氧基、硝基、氨基、氨基甲基和羟基甲基。
[0073]在依据段落[0057]的化合物的优选实施方案中,本发明包括式(2a)化合物:
及其可药用盐,其中
Ara是苯基或噻吩基;
R6是H或C1-C6-烷基(优选-CH3);
Y和Z独立地为-CH=或-N=;
W是卤素、(V’-L4)t-V-L3-;
L3是一个键、-C1-C6-烃基、-(C1-C3-烃基)m1-X’-(C1-C3-烃基)m2、-NH-(C0-C3-烃基)、(C1-C3-烃基)-NH-或-NH-(C1-C3-烃基)-NH-;
m1和m2独立地为0或1;
X’是-N(R21)-、-C(O)N(R21)-、N(R21)C(O)-、-O-或-S-;
R21是-H、V”-(C1-C6-烃基)c;
L4是(C1-C6-烃基)a-M-(C1-C6-烃基)b;
a和b独立地为0或1;
M是-NH-、-NHC(O)-、-C(O)NH-、-C(O)-、-SO2-、-NHSO2-或-SO2NH-;
V、V’和V”独立地选自环烷基、杂环基、芳基和杂芳基;
t是0或1;
或者,W、其所键合的环C以及Y一起形成单环环烷基、杂环基、芳基或杂芳基;且
在依据段落[0073]的化合物的优选实施方案中:Y和Z是-CH=,且R6是H;
W是V-L3;
L3是-NH-CH-或-CH-NH-;
V是苯基,所述苯基可任选被1-3个独立地选自下列的基团取代:卤素、羟基、C1-C6-烃基、C1-C6-烃氧基或烃硫基(特别是甲氧基或甲硫基),其中每一所述烃基可任选被一个或多个选自卤素、亚硝基、氨基、磺酰胺基和氰基的基团取代;且
Ara是苯基,并且与其键合的氨基彼此呈邻位关系。
在依据段落[0073]的化合物的某些优选实施方案中,V是任选取代的选自下列的环基团:
在依据段落[0073]的化合物的另一优选实施方案中,W选自
在依据段落[0073]的化合物的另一优选实施方案中,
和Ara环没有被进一步取代。
在依据段落[0073]的化合物的特别优选的实施方案中,本发明化合物选自下列化合物,其中除非另有说明,Ara是苯基(并且优选地,键合在Ara上的酰胺氮与氨基氮彼此呈邻位关系):
[0079]在依据段落[0057]的化合物的优选实施方案中,本发明包括式(2b)化合物:
及其可药用盐,其中
Ay2是苯基或噻吩基,每一所述基团在邻位上被-NH2或-OH取代,并分别任选被1-3个独立地选自-NH2、-OH和卤素的取代基进一步取代;
q是0或1;
X1选自-CH2-、-NH-CH2-和-S-CH2-;
Cy2是单环或稠合二环芳基或杂芳基,所述基团任选被1-3个选自下列的取代基取代:CH3-、CH3O-、任选被1-3个CH3O-取代的苯基、吗啉基、吗啉基-C1-C3-烷氧基、氰基和CH3C(O)NH-;条件是:当Cy2是萘基,X1是-CH2-,且q是0或1时,Ay2不是邻羟基苯基。
在依据段落[0079]的化合物中,优选地,Cy2是苯基、吡啶基、嘧啶基、苯并咪唑基、苯并噻唑基、噻吩基、四氢喹唑啉基或1,3-二氢喹唑啉-2,4-二酮,每一所述基团可任选被1-3个CH3O-取代。更优选地,Cy2是被1-3个CH3O-取代的苯基。
[0082]在第三个实施方案中,新的组蛋白脱乙酰化酶抑制剂是式(3)化合物:
及其可药用盐,其中
Ar3是亚芳基或亚杂芳基,任一所述基团可任选被取代;
Cy3是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;
条件是当Cy3是在环中具有-C(O)-、-C(S)-、-S(O)-或-S(O)2-的环基团时,
Cy3不被包含芳基或杂芳基环的基团额外取代;且
X2选自化学键、L3、W1-L3、L3-W1、W1-L3-W1和L3-W1-L3,其中
W1在每次出现时为S、O或N(R9),其中R9选自氢、烷基、芳基和芳烷基;且
L3是C1-C4亚烷基、C2-C4亚链烯基或C2-C4亚炔基;
条件是X2不包含-C(O)-、-C(S)-、-S(O)-或-S(O)2-基团;
并且条件还是:当Cy3是吡啶时,X2是L3、W1-L3或L3-W1。
其中Q在每次出现时独立地为N或C,并且C可任选被取代。
优选地,在依据段落[0082]的化合物中,X2选自L3、W1-L3、L3-W1、W1-L3-W1和L3-W1-L3。
且Cy3不是取代或未取代的二氮杂卓(diazepine)或苯并呋喃基团。
在依据段落[0082]的化合物的某些实施方案中,Q在每次出现时为C(R8),其中R8选自氢、烷基、芳基、芳烷基、烷氧基、氨基、硝基、卤素、卤代烷基和卤代烷氧基。在某些其它实施方案中,1-约3个变量Q是氮。在某些优选实施方案中,Ar3选自亚苯基、亚吡啶基、亚噻唑基和亚喹啉基。
在依据段落[0082]的化合物的某些实施方案中,X2是化学键。在其它实施方案中,X2是非环烃基。在某些这样的实施方案中,X2是亚烷基,优选亚甲基或亚乙基。在其它这样的实施方案中,X2是亚链烯基或亚炔基。在其它这样的实施方案中,烃链中的一个碳被-NH-或-S-代替。在某些优选实施方案中,X2是W1-L3-W1,且W1是-NH-或-N(CH3)-。
[0088]在依据段落[0082]的化合物的某些实施方案中,Cy3是环烷基,优选环己基。在其它实施方案中,Cy3是芳基或杂芳基,例如苯基、吡啶基、嘧啶基、咪唑基、噻唑基、噁二唑基、喹啉基或芴基,每一所述基团可任选被取代,并任选与一个或多个芳基环稠合。在某些实施方案中,Cy3环基团与苯环稠合。在某些实施方案中,Cy3具有1-3个独立地选自下列的取代基:烷基、烷氧基、芳基、芳烷基、氨基、卤素、卤代烷基和羟基烷基。优选的取代基的实例包括甲基、甲氧基、氟、三氟甲基、氨基、硝基、氨基甲基、羟基甲基和苯基。某些其它优选的取代基具有式-K1-N(H)(R10),其中
K1是化学键或C1-C4亚烷基;
R10选自Z’和-Ak2-Z’,其中
Ak2是C1-C4亚烷基;且
Z’是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,
并且每一所述基团可任选与一个或多个芳基或杂芳基环或与一个或多个饱和或部分不饱和环烷基或杂环稠合。
优选地,在段落[0082]的化合物中,当Ar4是亚喹喔啉基时,X3不是-CH(OH)-。
在另一优选的实施方案中,Ar3是
其中X是-CH2-、-NH-、O或S。Ar3优选是
且X是S或O。
[0093]在优选的实施方案中,本发明新的组蛋白脱乙酰化酶抑制剂是依据段落[0057]的那些,其中
Ay2是邻苯胺基;
q是0;且
X1是M1-L2-M1或L2-M2-L2。
在依据段落[0093]的化合物的优选实施方案中,Ar2是芳基或杂芳基;且Cy2-X1-选自
a)A1-L1-B1-,其中A1是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L1是-(CH2)0-1NH(CH2)0-1-、-NHC(O)-或-NHCH2-;且其中B1是苯基或共价键;
b)A2-L2-B2-,其中A2是CH3(C=CH2)-、任选取代的环烷基、任选取代的烷基或任选取代的芳基;其中L2是-C≡C-;且其中B2是共价键;
c)A3-L3-B3-,其中A3是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L3是共价键;且其中B3是-CH2NH-;
d)A4-L4-B4-,其中A4是任选取代的芳基;其中L4是-NHCH2-;且其中B4是噻吩基;
e)A5-L5-B5-,其中A5是任选取代的杂芳基或任选取代的杂环基;其中L5是共价键;且其中B5是-SCH2-;
f)吗啉基-CH2-;
g)任选取代的芳基;
h)A6-L6-B6-,其中A6是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L6是共价键;且其中B6是-NHCH2-;
i)A7-L7-B7-,其中A7是任选取代的杂芳基或任选取代的杂环基;其中L7是共价键;且其中B7是-CH2-;
j)任选取代的杂芳基或任选取代的杂环基;
k)A8L8-B8-,其中A8是任选取代的苯基;其中L8是共价键;且其中B8是-O-;
l)A9-L9-B9-,其中A9是任选取代的芳基;其中L9是共价键;且其中B9是呋喃基;
m)A10-L10-B10-,其中A10是任选取代的杂芳基或任选取代的杂环基;其中L10是-CH(CH2CH3)-;且其中B10是-NHCH2-;
n)A11-L11-B11-,其中A11是任选取代的杂芳基或任选取代的杂环基;其中L11是共价键;且其中B11是-OCH2-;
o)A12-L12-B12-,其中A12是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L12是-NHC(O)-;且其中B12是-N(任选取代的芳基)CH2-;
p)A13-L13-B13-,其中A12是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L13是共价键;且其中B13是-NHC(O)-;
q)A14-L14-B14-,其中A14是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L14是-NHC(O)(任选取代的杂芳基);且其中B14是-S-S-;
r)F3CC(O)NH-;
s)A15-L15-B15-,其中A15是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L15是-(CH2)0-1NH(任选取代的杂芳基)-;且其中B15是-NHCH2-;
t)A16-L16-B16-,其中A16是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L16是共价键;且其中B16是-N(任选取代的烷基)CH2-;和
u)A16-L16-B16-,其中A16是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L16是共价键;且其中B16是-(任选取代的芳基-CH2)2-N-。
在依据段落[0093]的化合物的另一优选实施方案中,Cy2-X1-选自
a)D1-E1-F1-,其中D1是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E1是-CH2-或共价键;且其中B1是共价键;
b)D2-E2-F2-,其中D2是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E2是-NH(CH2)0-2-;且其中F2是共价键;
c)D3-E3-F3-,其中D3是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E3是-(CH2)0-2NH-;且其中F3是共价键;
d)D4-E4-F4-,其中D4是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E4是-S(CH2)0-2-;且其中F4是共价键;
e)D5-E5-F5-,其中D5是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E5是-(CH2)0-2S-;且其中F5是共价键;和
f)D6-E6-F6-,其中D6是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E6是-NH(CH2)0-2NH-;且其中F6是共价键。
[0096]在优选的实施方案中,本发明的HDAC抑制剂包括具有(3b)的段落[0057]化合物:
及其可药用盐,其中Y和Z独立地为N或CH,且W选自:
在依据段落[0096]的化合物的优选实施方案中,化合物包括其中Y、Z和W如下所定义的那些:
在依据段落[0096]的化合物的另一优选实施方案中,化合物包括其中Y、Z和W如下所定义的那些:
在另一优选的实施方案中,本发明新的组蛋白脱乙酰化酶抑制剂选自下列化合物及其可药用盐:
在另一优选的实施方案中,本发明化合物选自在表2a-b、3a-d、4a-c和5a-5f中列出的那些。
合成
其中Y1是-N(R1)(R2)的式(1)化合物可优选依据在反应方案1中描述的合成路线制得。因此,将三氯三嗪I与胺II在二异丙基乙基胺存在下反应,以生成二氯氨基三嗪III。将胺R1R2NH加到二氯氨基三嗪III中,以生成二氨基氯三嗪V。在四氢呋喃(THF)或1,4-二噁烷中用氨或R3R4NH处理V,以获得三氨基三嗪VI。
或者,可将二氯氨基三嗪III与氨气在1,4-二噁烷中反应,以生成二氨基氯三嗪IV。然后在密封的烧瓶中,在THF或1,4-二噁烷中用R1R2NH处理IV,以获得三氨基三嗪VI。
通过用氢氧化物碱例如氢氧化锂处理来将VI中的酯基团水解,以获得相应的酸VII。在BOP试剂、三乙胺和二甲基甲酰胺(DMF)存在下用1,2-苯二胺处理酸VII,以获得苯胺基酰胺VIII。
反应方案1
其中Y1是-CH2-C(O)-N(R1)(R2)的式(1)化合物可优选如反应方案2所示制得。因此,用乙酰氯和三乙胺处理哌嗪IX,以生成酰胺X。将X与二氯吗啉基三嗪和六甲基二硅氧烷锂反应,以获得化合物XI。如反应方案1所述,将XI氯化物转化成XII苯胺基酰胺:用胺和二异丙基乙基胺处理;然后用氢氧化锂处理;之后用BOP试剂、苯二胺、三乙胺和DMF处理。
反应方案2
其中Ar2是亚吡啶基且X1包含-N(R7)-的式(2)化合物,其中Ar3是亚吡啶基且X2包含-N(R9)-的式(3)化合物,和其中Ar4是亚吡啶基且X3包含-N(R11)-的式(4)化合物可优选依据反应方案3中描述的方法制得。用胺RNH2处理二溴吡啶XIII或XIV,以分别生成氨基溴吡啶XV或XVI。在一氧化碳下,用二乙酰氧基钯、二苯基膦基二茂铁、DMF、二异丙基乙基胺和苯二胺处理XV或XVI,以分别生成苯胺基酰胺XVII或XVIII。
在氮气氛下,在DMF中,用丙烯酸叔丁酯、二异丙基乙基胺、二苄基丙酮钯和三邻甲苯基膦(POT)处理XV或XVI,以分别获得化合物XIX和XX。通过在二氯甲烷中与三氟乙酸反应,将XIX或XX的酯基团水解,以分别生成在XXI或XXII中的相应酸基团。用苯二胺、BOP和三乙胺处理酸XXI或XXII,以分别获得苯胺基酰胺XXIII或XXIV。
反应方案3
其中X1包含-O-C(O)-NH-的式(2)化合物可优选依据反应方案4所示的合成路线制得。因此,将甲醇XXV与羰基二咪唑(CDI)、三乙胺和1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)加到在DMF内的溴苄基胺XXVI中,以生成化合物XXVII。苯胺基酰胺XXVIII制备中的其余合成步骤如上文反应方案3所述。
反应方案4
其中X1包含-N(R7)-的式(2)化合物可优选如反应方案5所示制得。在DMF中,在碳酸钾存在下,将胺XXIX与对溴苄基溴反应,以生成溴苄基胺XXX。在DMF中用N-丙烯酰硝基苯胺、二苄基丙酮钯、POT和二异丙基乙基胺处理XXX,以获得N-硝酰苯胺(nitroanilide)XXXI。通过在甲醇和水中用氯化亚锡处理将N-硝酰苯胺XXXI转化成相应的苯胺基酰胺XXXII。
用低聚甲醛处理在甲酸中的胺XXXI以获得甲基胺XXXIII。然后通过在甲醇和水中用氯化亚锡处理将XXXIII中的N-硝酰苯胺部分转化成XXXIV中的相应的苯胺基酰胺部分。
反应方案5
或者,其中X1包含-N(R7)-的式(2)化合物可依据反应方案6所示的合成路线制得。用盐酸处理在甲醇中的羧酸XXXV,以生成酯XXXVI。通过在DMF中于60℃用催化剂例如三乙胺、甲氧基苄基氯、碘化钠和碳酸钾处理,将XXXVI中的伯胺基团转化成XXXVI中的仲胺基团。如上文反应方案3所述,通过用氢氧化钠、THF和甲醇处理,然后用BOP、三乙胺和苯二胺在DMF中处理,将酯XXXVI转化成苯胺基酰胺XXXVII。
反应方案6
其中X1包含
或-C(O)-NH-的式(2)化合物可优选依据反应方案7中描述的方法制得。将胺68加到在DMF内的卤代芳基化合物XXXVIII或XXXIX和碳酸钾中,以分别获得芳基胺XL或XLI。然后使用类似于上文反应方案3-6中描述的方法制得苯胺基酰胺XLII或XLIII。
反应方案7
化合物例如XLVII和XLIX可优选如反应方案8所示制得。将二溴吡啶与二氨基乙烷合并,以生成胺XLIV。在甲醇和水中用衣托酸酐LV处理胺XLIV,然后在甲酸中回流,以获得化合物XLVI。用苄基氨基二乙酸与乙酸酐的反应产物处理胺XLIV,以获得化合物XLVIII。按照类似于上文反应方案3-7中描述的方法将溴吡啶基胺XLVI和XLVIII分别转化成相应的二烯苯胺基酰胺XLVII和XLIX。
反应方案8
化合物例如LIV可优选依据反应方案9所示的合成路线制得。用氨基茚满和二异丙基乙基胺处理三氯三嗪,以生成二氯氨基三嗪L。用溴苄基胺和二异丙基乙基胺处理,以获得二氨基氯三嗪LI。加入氨气和二噁烷,以获得三氨基三嗪LII。用保护的N-丙烯酰苯胺、三乙胺、POT和二苄基丙酮钯处理,以获得二烯苯胺基酰胺LIII,将其用三氟乙酸脱保护,以获得终产物LIV。
反应方案9
其中Ar2是亚喹啉基且X1包含-N(R7)-的式(2)化合物,其中Ar3是亚喹啉基且X2包含-N(R9)-的式(3)化合物,和其中Ar4是亚喹啉基且X3包含-N(R11)-的式(4)化合物可优选依据反应方案10中描述的方法制得。将在吡啶中的二羟基喹啉LV和二甲基氨基吡啶(DMAP)用三氟甲磺酸酐处理,以获得二(三氟甲烷磺酰氧基)-喹啉LVI。用对甲氧基苄基胺处理LVI,以获得氨基喹啉LVII。然后按照类似于上文反应方案1-9中描述的方法制得苯胺基酰胺LVIII和LIX。
反应方案10
a.Tf2O/Py/DMAP/0C
b.对甲氧基苄基胺/120C
c.1,2-苯二胺/CO(40psi)/Pd(OAc)2/dppf/DMF/DIPEA/70C
d.丙烯酸叔丁酯/Pd2(dba)3/POT/DMF/DIPEA/120C
e.TFA/DCM/Rt
f.1,2-苯二胺/BOP/DMF/TEA/rT
其中X2包含硫原子的式(3)化合物,和其中X3包含硫原子的式(4)化合物可优选如反应方案11所示制得。使用类似于上文反应方案6所述的方法将溴化物LX转化成二芳基酯LXI。然后使用类似于上文反应方案1所述的合成方法,将酯LXI转化成相应的酸LXIV。或者,可用氯乙基吗啉、碘化钠、碳酸钾、三乙胺和碘化四丁基铵(TBAI)在DMF中处理酯LXI,以生成酯LXIII,然后如反应方案1所示将其转化成酸LXIV。按照类似于上文反应方案1所述的方法将酸LXIV转化成苯胺基酰胺LXV。
反应方案11
或者,其中X2包含硫原子的式(3)化合物,和其中X3包含硫原子的式(4)化合物可依据反应方案12中描述的方法制得。硫烷基苯胺基酰胺LXVIII是用类似于上文反应方案3和5中描述的方法制得的。
反应方案12
其中X2包含-N(R9)-的式(3)化合物,和其中X3包含-N(R11)-的式(4)化合物可依据反应方案13描述的合成路线制得。氨基苯胺基酰胺LXXI是按照类似于上文反应方案1和6中描述的合成步骤制得的。
反应方案13
其中X2包含硫原子的式(3)化合物,和其中X3包含硫原子的式(4)化合物可如反应方案14所示制得。将苯二胺与二碳酸二叔丁酯反应,然后与碘苯甲酸、二甲基氨基丙基乙基碳二亚胺、羟基苯并三唑和三乙胺反应,以获得保护的苯胺基酰胺LXXII。使用类似于反应方案3中描述的方法,将LXXII的碘基团转化成LXXIII的甲酯基团。通过用还原剂例如二异丁基氢化铝(DIBAL-H)处理,将LXXIII的甲酯基团转化成LXXIV的羟基。加入杂环基巯基化合物Het-SH和三苯基膦以及偶氮二甲酸二乙酯,以将LXXIV的羟基转化成LXXV的硫烷基。用三氟乙酸将LXXV脱保护,以获得硫烷基苯胺基酰胺LXXVI。
反应方案14
其中X2是化学键的式(3)化合物可优选依据反应方案15中描述的合成路线制得。因此,用芳基硼酸、苯、乙醇、碳酸钠水溶液和三苯基膦钯处理氯芳基苯胺基酰胺LXXVII,以获得二芳基苯胺基酰胺LXXVIII。
反应方案15
化合物例如LXXXI可优选依据反应方案16中描述的方法获得。因此,用对氨基甲基苯甲酸处理在乙酸中的苯-1,2-甲醛LXXIX,以生成苯甲酸LXXX。通过用羟基苯并三唑、二氯乙烷和苯二胺处理,将酸LXXX转化成相应的苯胺基酰胺LXXXI。
反应方案16
a.对氨基甲基苯甲酸/AcOH/5min/回流
b.HOBT/EDC/l,2-二氨基苯
化合物例如LXXXVI和LXXXIX可优选依据反应方案18中描述的方法制得。将邻苯二甲酸酐LXXXV和对氨基甲基苯甲酸在乙酸中合并,以生成羧酸中间体,使用类似于上文反应方案15和16中描述的方法将其转化成苯胺基酰胺LXXXVI。
将4-(2-氨基乙基)苯酚加到在乙酸内的邻苯二甲酸酐LXXXV中,以获得羟基化合物LXXXVII。通过用氢化钠、THF、DMF和苯基氨基二-三氟甲磺酸酯处理,将LXXXVII的羟基转化成LXXXVIII的三氟甲磺酸酯基。依据类似于上文反应方案3中描述的方法处理LXXXVIII,以获得苯胺基酰胺LXXXIX。
反应方案18
a.对氨基甲基苯甲酸/AcOH/回流/3hrs
b.HOBT/EDC/l,2-二氨基苯
c.4-(2-氨基乙基)苯酚/AcOH/5hrs/回流
d.PhNTf2/NaH/THF-DMF/30min/0℃
e.1.CO/Pd(OAc)2/dppf/Et3N/MeOH-DMF/4天/75℃
2.AcOH/HCl/3hrs/回流
化合物例如XCI-XCVI可优选依据反应方案19中描述的合成路线制得。用在水中的对氨基甲基苯甲酸和三乙胺处理衣托酸酐(isatoicanhydride)XC,然后用甲酸处理,以获得中间体羧酸,使用类似于上文反应方案16中描述的方法将其转化成苯胺基酰胺XCI。
或者,用在水中的对氨基甲基苯甲酸和三乙胺处理衣托酸XC,然后用盐酸和亚硝酸钠处理,以获得中间体羧酸,使用类似于上文反应方案16中描述的方法将其转化成苯胺基酰胺XCII。
或者,用在水中的对氨基甲基苯甲酸和三乙胺处理衣托酸XC,以获得苯甲酸XCIII。用氢氧化钠、二噁烷、氯甲酸甲酯和甲醇处理XCIII,以获得喹唑啉二酮羧酸中间体,使用类似于上文反应方案16中描述的方法将该中间体的酸基团转化成XCIV的苯胺基酰胺基团。或者,用碳酸钾和甲基碘处理在DMF中的喹唑啉二酮羧酸中间体,以生成苯甲酸甲酯中间体,通过用氢氧化钠、甲醇和水处理将其转化成苯甲酸中间体。然后使用类似于上文反应方案16中描述的方法将该苯甲酸中间体转化成相应的苯胺基酰胺XCV。
或者,用乙酸酐处理XCIII,然后用乙酸处理,以生成羧酸中间体,使用类似于上文反应方案16中描述的方法将其转化成苯胺基酰胺XCVI。
反应方案19
化合物例如C可优选如反应方案20所示制得。用在二氯甲烷中的硫代羰基二咪唑处理烷基胺XCVII,然后用氢氧化铵处理,以获得硫脲XCVIII。用在二噁烷中的甲氧基丙烯酸甲酯和N-溴琥珀酰亚胺处理硫脲XCVIII,以生成噻唑酯IC。使用类似于上文反应方案1中描述的方法将酯IC转化成相应的苯胺基胺C。
反应方案20
其中X2是化学键,且Cy3具有氨基取代基的式(3)化合物可优选依据反应方案21中描述的合成路线制得。因此,依据类似于上文反应方案15中描述的方法处理保护的碘芳基苯胺基酰胺CI,以获得二芳基苯胺基酰胺CII。通过用伯胺和三乙酰氧基硼氢化钠处理,然后用冰醋酸处理,将CII中的醛基团转化成相应的仲胺基团。使用类似于上文反应方案3中描述的方法将所得化合物脱保护,以获得CIII。
反应方案21
其中X2包含亚炔基的式(3)化合物,和其中X3包含亚炔基的式(4)化合物可如反应方案22所示制得。用三苯基膦氯化钯、碘化亚铜和1-乙炔基环己基胺处理保护的碘芳基苯胺基酰胺CI,以获得炔基芳基苯胺基酰胺CIV。使用类似于上文反应方案21中描述的方法,将CIV中的伯胺基团转化成相应的仲胺基团,并将苯胺脱保护,以获得CV。
反应方案22
化合物例如CVIII可优选依据反应方案24中描述的合成路线制得。在二异丙基乙基胺存在下,用4-氨基苯甲酸甲酯处理二氯氨基三嗪CVI,以生成二氨基三嗪CVII。加入氨气和二噁烷,然后使用上文反应方案1中描述的相同方法进行皂化和肽偶联。
反应方案30
化合物例如CX可优选依据反应方案30中描述的合成路线制得。将三氯氨基三嗪与各种溴化烷基镁进行格式反应,然后在二异丙基乙基胺存在下,用4-氨基苯甲酸甲酯处理,以生成烷基氨基三嗪CIX。然后使用类似于上文反应方案1中描述的方法将酯CIX转化成相应的苯胺基酰胺CX。
反应方案32
使用反应方案1中描述的通常条件进行二氯三嗪的胺化,以获得CXI。使用乙烯基锡烷进行Stille偶联,以获得CXII。然后用保护的N-碘酰苯胺、三乙胺、POT和二苄基丙酮钯处理,以生成苯胺基酰胺,用三氟乙酸将其脱保护,以获得烯烃CXIII。将该烯烃氢化,以获得最终的化合物CXIV。
反应方案33
化合物例如CXVIII可优选依据反应方案33中描述的合成路线制得。用三溴化硼处理甲氧基氨基苯并噻唑,以获得相应的酸CXV。在偶氮二甲酸二乙酯和三苯基膦存在下,使用羟基乙基吗啉进行Mitsunobu反应,以获得胺CXVI。使用苯基硅烷和锡催化剂,用4-甲酰基苯甲酸甲酯进行还原胺化,以获得CXVII。然后按照类似于上文反应方案1中描述的方法进行皂化和常规肽偶联,以获得所需N-酰苯胺CXVIII。
反应方案42
用硫化氢处理4-甲基氰基苯甲酸,以获得CXIX,然后在1,3-二氯丙酮存在下进行环化,以获得CXX。用吗啉处理,然后使用标准条件进行肽偶联,以生成CXXI。
反应方案49
i:BrCH2C6H4COOMe/MeONa/THF;
ii:PhNHNH2;
iii:NaOH,then HCl
iv:HOBt/EDCxHCl然后1,2-二氨基苯;
v:BrCH2C6H4COOMe/MeONa/MeOH,然后HCl/AcOH;
vi:CH2(CN)2/S8/Et2NH;
vii:AcCl;
viii:2-N-Bocamino苯胺;
ix:TFA
化合物例如CXXIII和CXXVII可优选依据合成反应方案49制得。在NaOMe和苯基肼存在下,用溴甲基苯甲酸甲酯连续处理乙酰基丙酮,然后皂化,以获得酸中间体CXXII。使用标准方法将该中间体与1,2-二氨基苯偶联以获得CXXIII。
在NaOMe和1∶1混合物AcOH-HCl(浓)存在下,用溴甲基苯甲酸甲酯连续处理乙酰基丙酮,以获得酸中间体CXXIV。将该酮基酸与硫和丙二腈在碱存在下反应,以生成噻吩CXXV,使用标准方法将其转化成所要的CXXVII。
反应方案50
化合物例如CXXX可优选依据合成反应方案50制得。用羟基胺处理4-氰基甲基苯甲酸,以生成偕胺肟CXXVIII,通过用乙酸酐处理将其转化成恶二唑CXXIX。使用标准方法将后者与1,2-二氨基苯偶联,以获得CXXX。
反应方案57
化合物例如CXXXIII可依据反应方案57中描述的合成路线制得。用亚硫酰氯处理4-甲酰基苯甲酸,以获得酰氯,将其与保护的N-酰苯胺偶联,以生成CXXXI。使用苯基硅烷和锡催化剂,用二甲氧基苯胺还原胺化,以获得保护的N-酰苯胺CXXXII。用异氰酸酯处理,然后用三氟乙酸脱保护,以获得N-脲酰苯胺(ureidoanilide)CXXXIII。
药物组合物
在第二个方面,本发明提供了药物组合物,其中包含本发明组蛋白脱乙酰化酶抑制剂和可药用载体、赋形剂或稀释剂。可通过本领域众所周知的任何方法配制本发明化合物,并且可制成能通过任何途径给药的形式,所述途径包括但不限于非胃肠道、口服、舌下、透皮、局部、鼻内、气管内或直肠内给药途径。在一些优选的实施方案中,本发明化合物可在医院中静脉内给药。在一些其它优选的实施方案中,给药可优选通过口服途径进行。
载体的特征取决于给药途径。本文所用术语“可药用”是指这样的无毒材料,其与生物系统例如细胞、细胞培养物、组织或生物体相容,并且不干扰活性组分的生物活性的有效性。因此,除了本发明抑制剂以外,本发明组合物还包含稀释剂、填充剂、盐、缓冲剂、稳定剂、助溶剂和本领域众所周知的其它材料。可药用制剂的制备描述在例如Remington’s Pharmaceutical Sciences,18th Edition,ed.A.Gennaro,Mack Publishing Co.,Easton,PA,1990中。
本文所用术语可药用盐是指保持上述化合物希望的生物活性,并且表现出最小或没有任何不良毒性作用的盐。这样的盐的实例包括但不限于与下列酸形成的酸加成盐:无机酸(例如盐酸、氢溴酸、硫酸、磷酸、硝酸等),和有机酸例如乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、扑酸、藻酸、聚谷氨酸、萘磺酸、萘二磺酸和聚半乳糖醛酸。化合物还可以作为本领域技术人员已知的可药用季铵盐给药,这样的季铵盐具体包括式-NR+Z-的铵盐,其中R是氢、烷基或苄基,且Z是抗衡离子,包括氯离子、溴离子、碘离子、-O-烷基、甲苯磺酸基、甲磺酸基、磺酸基、磷酸根或羧酸基(例如苯甲酸基、琥珀酸基、乙酸基、羟乙酸基、马来酸基、苹果酸基、柠檬酸基、酒石酸基、抗坏血酸基、苯甲酸基、肉桂酸基、扁桃酸基、苯甲醇阴离子和二苯基乙酸基)。
活性化合物以足以给患者递送治疗有效量,同时在所治疗的患者中不引起严重毒性作用的量包含在可药用载体或稀释剂中。对于所有上述病症,活性化合物的优选剂量为约0.01-300mg/kg,优选为0.1-100mg/kg每天,更通常为0.5-约25mg/千克接受者的体重/天。典型的局部给药剂量为在适当载体中的0.01-3%wt/wt。本发明可药用衍生物的有效剂量可根据欲给药的母化合物的重量计算。如果衍生物自身表现出活性,则可以用衍生物的重量如上所述估计有效剂量或者通过本领域技术人员已知的其它方法估计有效剂量。
抑制组蛋白脱乙酰化酶
在第三个方面,本发明提供了抑制细胞中组蛋白脱乙酰化酶的方法,包括将希望抑制其组蛋白脱乙酰化酶的细胞与本发明组蛋白脱乙酰化酶抑制剂接触。因为本发明化合物能抑制组蛋白脱乙酰化酶,所以它们是用于在体外研究生物过程中组蛋白脱乙酰化酶的作用的有用研究工具。此外,本发明化合物可选择性地抑制HDAC的一些异构体。
可使用已知方法测定组蛋白脱乙酰化酶的酶活性。例如Yoshida等人,J.Biol.Chem.,265:17174-17179(1990)描述了通过检测曲古柳菌素(trichostatin A)处理的细胞中的乙酰化组蛋白来评价组蛋白脱乙酰化酶的酶活性。Taunton等人,Science,272:408-411(1996)类似地描述了通过使用内源性和重组HDAC-1来测定组蛋白脱乙酰化酶的酶活性的方法。
在某些优选实施方案中,组蛋白脱乙酰化酶抑制剂与细胞中的所有组蛋白脱乙酰化酶相互作用并降低它们的活性。在依据本发明该方面的某些其它优选实施方案中,组蛋白脱乙酰化酶抑制剂与细胞中少数组蛋白脱乙酰化酶而不是所有组蛋白脱乙酰化酶相互作用,并降低它们的活性。在一些优选的实施方案中,抑制剂与一种组蛋白脱乙酰化酶(例如HDAC-1)反应并降低其活性,而不与其它组蛋白脱乙酰化酶(例如HDAC-2、HDAC-3、HDAC-4、HDAC-5、HDAC-6、HDAC-7和HDAC-8)相互作用或降低它们的活性。如下所述,一些特别优选的组蛋白脱乙酰化酶抑制剂是与涉及肿瘤发生的组蛋白脱乙酰化酶相互作用并降低其酶活性的那些。一些其它优选的组蛋白脱乙酰化酶抑制剂与真菌组蛋白脱乙酰化酶相互作用并降低其酶活性。
优选地,依据本发明第三个方面的方法引起所接触的细胞的细胞增殖被抑制。短语“抑制细胞增殖”是用来指,与未接触的细胞相比,组蛋白脱乙酰化酶抑制剂延迟与抑制剂接触的细胞生长的能力。细胞增殖的评价可通过使用Coulter细胞计数器(Coulter,Miami,FL)或血细胞计数器计数接触和未接触的细胞来进行。当细胞在实体生长(例如实体瘤或器官)中时,这样的细胞增殖评价可通过用卡钳测定生长,并比较接触的细胞与未接触的细胞的生长尺寸来进行。
优选地,与未接触的细胞相比,与抑制剂接触的细胞的生长被延迟了至少50%。更优选地,细胞增殖被抑制了100%(即接触的细胞在数目上没有任何增加)。更优选地,短语“抑制细胞增殖”包括,与未接触的细胞相比,接触的细胞的数目减少或尺寸减小。因此,本发明抑制细胞增殖的组蛋白脱乙酰化酶抑制剂可诱导接触的细胞经受生长延迟、经受生长停滞、经受编程性细胞死亡(即细胞凋亡)或经受坏死性细胞生长。
本发明组蛋白脱乙酰化酶抑制剂的细胞增殖抑制能力使得不同步生长的细胞群体同步化。例如,本发明组蛋白脱乙酰化酶抑制剂可用于在体外抑制处于细胞周期的G1或G2期的非瘤形成细胞群体。这样的同步化使得能够例如鉴定在细胞周期的G1或G2期时段内表达的基因和/或基因产物。这样的培养细胞的同步化还可用于测试新转染方案的效力,其中转染效力随着欲转染的细胞的特定细胞周期时期而变并取决于特定细胞周期的时期。本发明组蛋白脱乙酰化酶抑制剂的应用使得细胞群体同步化,由此能够有助于检测提高的转染效力。
在某些优选实施方案中,接触的细胞是瘤形成细胞。术语“瘤形成细胞”是用来指表现出异常细胞生长的细胞。瘤形成细胞的异常细胞生长优选是增加的细胞生长。瘤形成细胞可以是增生细胞,在体外表现出缺乏生长接触抑制的细胞,在体内不能转移的良性肿瘤细胞,或在体内能够转移,并且在试图除去之后可复发的癌细胞。术语“肿瘤发生”是用来指导致肿瘤生长发展的细胞增殖诱导。在某些实施方案中,本发明组蛋白脱乙酰化酶抑制剂在接触的细胞中诱导细胞分化。因此,当与组蛋白脱乙酰化酶抑制剂接触时,瘤形成细胞可被诱导发生分化,导致产生在种系发生方面比接触的细胞更高级的非瘤形成子细胞。
在某些优选实施方案中,接触的细胞在动物中。因此,本发明提供了治疗动物中细胞增殖疾病或病症的方法,包括给需要这种治疗的动物施用治疗有效量的本发明组蛋白脱乙酰化酶抑制剂。动物优选为哺乳动物,更优选为驯养的哺乳动物。动物最优选为人。
术语“细胞增殖疾病或病症”是指特征是异常细胞生长,优选异常增加的细胞增殖的任何病症。这样的细胞增殖疾病或病症的实例包括但不限于癌症、再狭窄和牛皮癣。在特别优选的实施方案中,本发明提供了抑制动物中瘤形成细胞增殖的方法,包括给体内存在至少一种瘤形成细胞的动物施用治疗有效量的本发明组蛋白脱乙酰化酶抑制剂。
某些本发明化合物具有抗原生动物来源的组蛋白脱乙酰化酶的抑制活性。因此,本发明还提供了治疗或预防原生动物疾病或感染的方法,包括给需要这种治疗的动物施用治疗有效量的本发明组蛋白脱乙酰化酶抑制剂。动物优选为哺乳动物,更优选为人。优选地,依据本发明该实施方案使用的组蛋白脱乙酰化酶抑制剂抑制原生动物组蛋白脱乙酰化酶的程度大于其抑制哺乳动物组蛋白脱乙酰化酶,特别是人组蛋白脱乙酰化酶的程度。
本发明还提供了治疗真菌疾病或感染的方法,包括给需要这种治疗的动物施用治疗有效量的本发明组蛋白脱乙酰化酶抑制剂。动物优选为哺乳动物,更优选为人。优选地,依据本发明该实施方案使用的组蛋白脱乙酰化酶抑制剂抑制真菌组蛋白脱乙酰化酶的程度大于其抑制哺乳动物组蛋白脱乙酰化酶,特别是人组蛋白脱乙酰化酶的程度。
术语“治疗有效量”是指足以在个体的细胞中引起组蛋白脱乙酰化酶活性被抑制的剂量,或足以在个体中抑制细胞增殖或诱导细胞分化的剂量。给药可通过任何途径进行,包括但不限于非胃肠道、口服、舌下、透皮、局部、鼻内、气管内或直肠内给药途径。在一些特别优选的实施方案中,本发明化合物可在医院中静脉内给药。在一些其它优选的实施方案中,给药可优选通过口服途径进行。
当全身给药时,组蛋白脱乙酰化酶抑制剂优选以足以达到下列抑制剂血液水平的剂量给药:约0.01μM-约100μM,更优选约0.05μM-约50μM,还更优选约0.1μM-约25μM,仍更优选约0.5μM-约25μM。对于局部给药,比此低得多的浓度可能是有效的,并且可耐受高得多的浓度。本领域技术人员应当理解,产生疗效所需的组蛋白脱乙酰化酶抑制剂的剂量可根据欲治疗的组织、器官或特定动物或患者而显著改变。
在本发明第三个方面的一些优选实施方案中,方法包括将细胞与抑制组蛋白脱乙酰化酶表达的反义低聚核苷酸接触。核酸水平抑制剂(例如反义低聚核苷酸)与蛋白水平抑制剂(即组蛋白脱乙酰化酶的酶活性抑制剂)的联合使用带来了提高的抑制作用,由此降低了达到给定抑制作用所需的抑制剂的量—与单独使用任一种抑制剂所需的量相比。依据本发明该方面的反义低聚核苷酸与编码HDAC-1、HDAC-2、HDAC-3、HDAC-4、HDAC-5、HDAC-6、HDAC7和/或HDA C-8的RNA或双螺旋DNA区域互补(参见例如对于HDAC-1的GenBankAccession Number U50079,对于HDAC-2的GenBank AccessionNumber U31814,和对于HDAC-3的GenBank Accession NumberU75697)。
对于本发明目的,术语“低聚核苷酸”包括两个或多个脱氧核苷、核糖核苷或2’-取代的核糖核苷残基或其任何组合的聚合物。优选地,这样的低聚核苷酸具有约6-约100个核苷残基,更优选约8-约50个核苷残基,最优选约12-约30个核苷残基。核苷残基可通过任何多种已知的核苷间键彼此偶联。这样的核苷间键包括但不限于硫代磷酸酯、二硫代磷酸酯、烷基磷酸酯、烷基硫代膦酸酯、磷酸三酯、氨基磷酸酯、硅氧烷、碳酸酯、羧基甲基酯、乙酰胺酸酯、氨基甲酸酯、硫醚、桥连氨基磷酸酯、桥连膦酸亚甲基酯、桥连硫代磷酸酯和砜核苷间键。在一些优选的实施方案中,这些核苷间键可以是磷酸二酯、磷酸三酯、硫代磷酸酯或氨基磷酸酯键或其组合。术语低聚核苷酸还包括具有化学修饰的碱基或糖和/或具有另外的取代基,包括但不限于亲脂性基团、嵌入剂、二胺和金刚烷的聚合物。
对于本发明目的,术语“2’取代的核糖核苷”包括其中在戊糖部分的2’-位的羟基被取代以生成2’-O-取代的核糖核苷的核糖核苷。优选地,这样的取代是被下列基团取代:含有1-6个饱和或不饱和碳原子的低级烷基或具有2-6个碳原子的芳基或烯丙基,其中这样的烷基、芳基或烯丙基可以是未取代或取代的,例如被卤素、羟基、三氟甲基、氰基、硝基、酰基、酰氧基、烷氧基、羧基、烷氧羰基或氨基取代。术语“2’取代的核糖核苷”还包括其中2’-羟基被氨基或卤素,优选氟替代的核糖核苷。
在本发明该方面使用的特别优选的反义低聚核苷酸包括嵌合低聚核苷酸和杂合低聚核苷酸。
对于本发明目的,“嵌合低聚核苷酸”是指具有一种以上类型的核苷间键的低聚核苷酸。这样的嵌合低聚核苷酸的一个优选的实例是包含硫代磷酸酯、磷酸二酯或二硫代磷酸酯区域—优选包含约2-约12个核苷,和烷基磷酸酯或烷基硫代膦酸酯区域的嵌合低聚核苷酸(参见例如Pederson等人U.S.专利5,635,377和5,366,878)。优选地,这样的嵌合低聚核苷酸含有至少3个选自磷酸二酯和硫代磷酸酯键或其组合的连续的核苷间键。
对于本发明目的,“杂合低聚核苷酸”是指具有一种以上类型的核苷的低聚核苷酸。这样的杂合低聚核苷酸的一个优选实例包含核糖核苷酸或2’-取代的核糖核苷酸区域—优选包含约2-约12个2’-取代的核苷酸,和脱氧核糖核苷酸区域。优选地,这样的杂合低聚核苷酸包含至少3个连续的脱氧核糖核苷,并且还包含核糖核苷、2’-取代的核糖核苷,优选2’-O-取代的核糖核苷或其组合(参见例如Metelev和Agrawal,U.S.专利5,652,355)。
在本发明中使用的反义低聚核苷酸的精确核苷酸序列和化学结构可以变化,只要低聚核苷酸保持其抑制目标基因表达的能力即可。这可通过测试特定反义低聚核苷酸是否有活性来容易地确定。对于此目的,有用的测定包括定量测定编码基因产物的mRNA,基因产物的Western印迹分析测定,酶活性基因产物的活性测定,或软琼脂生长测定,或报道基因构建测定,或体内肿瘤生长测定,所有这些都详细描述在本说明书或Ramchandani等人(1997)Proc.Natl.Acad.Sci.USA 94:684-689中。
在本发明中使用的反义低聚核苷酸可在合适的固体载体上用众所周知的化学方法来常规合成,这些方法包括H-膦酸酯化学、氨基磷酸酯化学或H-膦酸酯化学与氨基磷酸酯化学的组合(即对于某些循环使用H-膦酸酯化学,对于其它循环使用氨基磷酸酯活性)。合适的固体载体包括用于固相低聚核苷酸合成的任何标准固体载体例如孔控玻璃(CPG)(参见例如Pon,R.T.(1993)Methods in Molec.Biol.20:46.5-496)。
特别优选的低聚核苷酸具有约13-约35个核苷酸的核苷酸序列,包括表1所示序列。还特别优选的低聚核苷酸具有表1所示的约15-约26个核苷酸的核苷酸序列。
表1
Oligo | 目标 | 登记号 | 核苷酸位置 | 序列 | 在基因内的位置 |
HDAC1 AS1HDAC1 AS2HDAC1 MM | 人HDAC1人HDAC1人HDAC1 | U50079U50079U50079 | 1585-16041565-15841585-1604 | 5’-GAAACGTGAGGGACTCAGCA-3’5’-GGAAGCCAGAGCTGGAGAGG-3’5’-GTTAGGTGAGGCACTGAGGA-3’ | 3’-UTR3’-UTR3’-UTR |
HDAC2 ASHDAC2 MM | 人HDAC2人HDAC2 | U31814U31814 | 1643-16221643-1622 | 5’-GCTGAGCTGTTCTGATTTGG-3’5’-CGTGAGCACTTCTCATTTCC-3’ | 3’-UTR3’-UTR |
HDAC3 ASHDAC3 MM | 人HDAC3人HDAC3 | AF039703AF039703 | 1276-12951276-1295 | 5’-CGCTTTCCTTGTCATTGACA-3’5’-GCCTTTCCTACTCATTGTGT-3’ | 3’-UTR3’-UTR |
HDAC4 AS1HDAC4 MM1HDAC4 AS2HDAC4 MM4 | 人HDAC4人HDAC4人HDAC4人HDAC4 | AB006626AB006626AB006626AB006626 | 514-33514-337710-297710-29 | 5-GCTGCCTGCCGTGCCCACCC-3’5’-CGTGCCTGCGCTGCCCACGG-3’5’-TACAGTCCATGCAACCTCCA-3’5’-ATCAGTCCAACCAACCTCGT-3’ | 5’-UTR5’-UTR3’-UTR3’-UTR |
HDAC5 AS | 人HDAC5 | AF039691 | 2663-2682 | 5’-CTTCGGTCTCACCTGCTTGG-3’ | 3’-UTR |
HDAC6 ASHDAC6 MM | 人HDAC6人HDAC6 | AJ011972AJ011972 | 3791-38103791-3810 | 5’-CAGGCTGGAATGAGCTACAG-3’5’-GACGCTGCAATCAGGTAGAC-3’ | 3’-UTR3’-UTR |
HDAC7 AS | 人HDAC7 | AF239243 | 2896-2915 | 5’-CTTCAGCCAGGATGCCCACA-3’ | 3’-UTR |
HDAC8 AS1HDAC8 AS2 | 人HDAC8人HDAC8 | AF230097AF230097 | 51-701328-1347 | 5’-CTCCGGCTCCTCCATCTTCC-3’5’-AGCCAGCTGCCACTTGATGC-3’ | 5’-UTR3’-UTR |
下列实施例是为了进一步举例说明本发明的一些优选实施方案,并不是为了限制本发明的范围。
实施例
实施例1
4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]-三嗪-2-基-氨基]-甲基}-N-(2-氨基-苯基)-苯甲酰胺(化合物8)
步骤1:4-[(4,6-二氯-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸甲酯(化合物3)
在-78℃、氮气氛下,向氰尿酰氯1(8.23g,44.63mmol)在无水THF(100mL)内的搅拌着的溶液中加入4-(氨基甲基)苯甲酸甲酯.HCl 2(10.00g,49.59mmol)在无水THF(50mL)中的悬浮液,然后加入i-Pr2NEt(19.00mL,109.10mmol)。30分钟后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:5/95),获得了本标题化合物3(12.12g,38.70mmol,87%产率),为浅黄色固体。1H NMR(300MHz,CDCl3)δ(ppm):AB系统(δA=8.04,δB=7.38,J=8.5Hz,4H),6.54(bt,1H),4.76(d,J=6.3Hz,2H),3.93(s,3H)。
途径A
步骤2:4-[(4-氨基-6-氯-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸甲酯(化合
物4)
在150mL密封烧瓶内,将3(6.00g,19.16mmol)在无水1,4-二噁烷(60mL)中的溶液于室温搅拌,用NH3气饱和5分钟,温热至70℃并保持6小时。让该反应混合物冷却至室温,将使用NH3气的饱和步骤在室温重复进行5分钟,将该反应混合物再次温热至70℃并保持18小时。然后让该反应混合物冷却至室温,倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:30/70),获得了本标题化合物4(5.16g,17.57mmol,91%产率),为白色固体。1H NMR(300MHz,CDCl3)δ(ppm):AB系统(δA=8.01,δB=7.35,J=8.1Hz,4H),5.79(bs,1H),5.40-5.20(m,2H),4.72-4.63(m,2H),3.91(s,3H)。
途径B
步骤2:4-[(4-氯-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸
甲酯(化合物5)
在室温、氮气氛下,向3(3.00g,9.58mmol)在无水THF(50mL)内的搅拌着的溶液中分别加入i-Pr2NEt(8.34mL,47.90mmol)和2-氨基茚满.HCl(1.95g,11.50mmol)或R1R2NH(1.2当量)。18小时后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩,获得了本标题化合物5(4.06g,9.91mmol,定量产率),为白色粉末。1H NMR(300MHz,CDCl3)δ(ppm):旋转异构体混合物,8.06-7.94(m,2H),7.43-7.28(m,2H),7.24-7.12(m,4H),6.41和6.05(2bt,1H),5.68-5.44(m,1H),4.92-4.54(m,3H),3.92(bs,3H),3.41-3.12(m,2H),2.90-2.70(m,2H)。
步骤3:4-[(4-氨基-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲
酸甲酯(化合物6)
用NH3气胺化的一般方法:
在150mL密封烧瓶内,将5(3.90g,9.51mmol)在无水1,4-二噁烷(80mL)中的溶液于室温搅拌,用NH3气饱和5分钟,温热至140℃并保持6小时。让该反应混合物冷却至室温,将使用NH3气的饱和步骤在室温重复进行5分钟,将该反应混合物再次温热至140℃并保持18。然后让该反应混合物冷却至室温,倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:3/97),获得了本标题化合物6(3.50g,8.96mmol,94%产率),为浅黄色粘性固体。1H NMR(300MHz,CDCl3)δ(ppm):7.99(bd,J=8.2Hz,2H),7.41-7.33(m,2H),7.24-7.13(m,4H),5.50-5.00(m,2H),4.90-4.55(m,5H),3.92(s,3H),3.40-3.10(m,2H),2.90-2.70(m,2H).13C NMR:(75 MHz,CDCl3)δ(ppm):166.88,167.35,166.07,144.77,141.07,129.82,128.93,127.01,126.61,124.70,52.06,51.80,44.25,40.16.HRMS(计算值):390.1804,(实测值):390.1800。
途径A和B,
步骤3,使用伯胺和/或仲胺的一般方法:
在50-75mL密封烧瓶内,将4(500mg,1.70mmol,1当量)、i-Pr2NEt(1.48mL,8.51mmol,5当量)和R1R2NH或R3R4NH(1.5-3当量)在无水THF或1,4-二噁烷(20-30mL)中的搅拌着的溶液温热至120-140℃,并保持15-24小时。然后让该反应混合物冷却至室温,倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物,获得了本标题化合物。
步骤4:4-[(4-氨基-6-(2-茚满基-氨基)-[1,3.5]三嗪-2-基-氨基)-甲基]-苯甲
酸(化合物7)
在室温,向6(2.07g,5.30mmol)在THF(50mL)内的搅拌着的溶液中加入LiOH.H2O(334mg,7.96mmol)在水(25mL)中的溶液。18小时后,将该反应混合物在水中稀释,用1N HCl酸化直至pH 5-6以获得白色沉淀。1小时后,将该悬浮液过滤,用水将滤饼充分洗涤,并干燥,获得了本标题化合物7(1.73g,4.60mmol,87%产率),为白色固体。1HNMR(300MHz,丙酮-d6)δ(ppm):8.05(bd,J=8.1Hz,2H),7.56-7.42(m,2H),7.30-7.10(m,4H),5.90-5.65(m,2H),4.85-4.60(m,4H),3.40-2.80(m,4H).HRMS(计算值):376.1648,(实测值):376.1651。
步骤5:4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]-三嗪-2-基-氨基]-甲
基}-N-(2-氨基-苯基)-苯甲酰胺(化合物8)
在室温、氮气氛下,向7(200mg,0.53mmol)在无水DMF(5mL)内的搅拌着的溶液中分别加入Et3N(74μl,0.53mmol)和BOP试剂(282mg,0.64mmol)。40分钟后,滴加1,2-苯二胺(64mg,0.58mmol)、Et3N(222μl,1.59mmol)在无水DMF(2mL)中的溶液。1.5小时后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:2/98→5/95),获得了本标题化合物8(155mg,0.33mmol,63%产率),为浅黄色泡沫状物。1H NMR(300MHz,丙酮-d6)δ(ppm):9.04(bs,1H),7.96(bd,J=8.0Hz,2H),7.50-7.40(m,2H),7.30(dd,J=8.0Hz,1.4Hz,1H),7.22-7.08(m,4H),6.99(ddd,J=8.0Hz,7.5Hz,1.5Hz,1H),6.86(dd,J=8.0Hz,1.4Hz,1H),6.67(dt,J=7.5Hz,1.4Hz,1H),6.60-.5.49(m,4H),4.80-4.50(m,4H),3.30-3.08(m,2H),2.96-2.74(m,2H)。
实施例2-28
实施例2-28描述了使用制备实施例1的化合物8所述的相同方法制备化合物9-35。特征数据列在表2a和2b中。
表2a
在实施例2-28中制得的化合物的特征
表2b
实施例29
N-(2-氨基-苯基)-4-({4-[2-(4-苯并[1,3]二氧杂环戊烯-5-基甲基-哌嗪-1-基)-2-氧代-乙基]-6-吗啉-4-基-[1,3,5]三嗪-2-基氨基}-甲基)-苯甲酰胺(化合物39)
步骤1:N-乙酰基-1-胡椒基哌嗪(化合物37)
在0℃,向1-胡椒基哌嗪36(5.00g,22.7mmol)在无水CH2Cl2(60mL)内的搅拌着的溶液中加入Et3N(6.33mL,45.4mmol),然后加入乙酰氯(1.94mL,27.2mmol)。将该反应混合物在0℃搅拌30分钟,然后在室温搅拌2小时。将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:4/96),获得了本标题化合物37(5.52g,21.11mmol,93%产率),为黄色固体。1H NMR:(300MHz,CDCl3)δ(ppm):6.83(s,1H),6.72(m,2H),5.92(s,2H),3.59(t,J=5.1Hz,2H),3.44-3.40(m,4H),2.42(dt,J=5.1Hz,5.1Hz,4H),2.06(s,3H)。
步骤2:2-氯-4-吗啉-4-基-6-[2-(4-苯并[1,3]二氧杂环戊烯-5-基甲基-哌嗪
-1-基)-2-氧代-乙基]-[1,3,5]三嗪(化合物38)
在-78℃,向37(3.00g,11.4mmol)在无水THF(25mL)内的搅拌着的溶液中缓慢地加入LiHMDS的溶液(11.4mL,11.4mmol,1M在THF中的溶液)。将该反应混合物在-78℃搅拌1小时,加入2,4-二氯-6-吗啉-4-基-[1,3,5]三嗪(2.69g,11.4mmol)在无水THF(25mL)中的溶液。将该反应混合物缓慢地温热至室温,16小时后,用饱和NH4Cl水溶液中止该反应。将THF蒸发,用AcOEt稀释残余物。将有机层依次用饱和氯化铵和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:1/99→3/97),获得了本标题化合物38(4.84g,10.49mmol,92%产率),为浅黄色固体。1H NMR(300MHz,CDCl3)δ(ppm):6.84(s,1H),6.77-6.69(m,2H),5.95(s,2H),3.75-3.43(m,16H),2.42(m,4H)。
步骤3:N-(2-氨基-苯基)-4-({4-[2-(4-苯并[1,3]二氧杂环戊烯-5-基甲基-
哌嗪-1-基)-2-氧代-乙基]-6-吗啉-4-基-[1,3,5]三嗪-2-基氨基}-甲基)-苯甲
酰胺(化合物39)
本标题化合物39是按照与实施例1步骤5相同的方法制得的。1HNMR(CDCl3)δ(ppm):7.96(bs,1H),7.87(d,J=8.2Hz,2H),7.39(d,J=8.2Hz,2H),7.33(d,J=8.5Hz,1H),7.10(dt,J=7.6Hz,1.2Hz,1H),6.87-6.81(m,3H),6.75-6.68(m,2H),5.93(s,2H),5.67(bs,1H),4.64(s,2H),3.90(bs,2H),3.75-3.35(m,16H),2.45-2.30(m,4H)。
实施例40
N-(2-氨基苯基)-6-(2-苯基氨基-乙基氨基)-烟酰胺(化合物44)
步骤1:N-(5-溴-吡啶-2-基)-N’-苯基-乙烷-1.2-二胺(化合物42)
将2,5-二溴吡啶40(2.08g,8.6mmol)和苯基-1,2-乙基二胺(1.98g,14.6mmol,1.7当量)的混合物在120℃于氮气氛下搅拌6小时。冷却至室温后,将该固体混合物在研钵中研磨,溶解在乙酸乙酯(200mL)中,用饱和NaHCO3(2×50mL)洗涤,干燥(MgSO4),过滤并浓缩。经由短色谱柱(硅胶,洗脱用50%乙醚在己烷中的混合物)纯化后,获得了浅黄色固体42(1.75g,6.01mmol,70%产率)。13C NMR(300MHz,丙酮-d6)δ(ppm):158.6,149.6,148.8,139.9,129.8,117.1,113.1,110.8,106.6,43.9,41.5.LMRS=294.0(M+1)。
步骤2:N-(2-氨基苯基)-6-(2-苯基氨基-乙基氨基)-烟酰胺(化合物44)
将5-溴-2-N-烷基-2-氨基吡啶42(352mg,1.2mmol)、1,2-苯二胺(3.95mmol,3.3当量)、Pd(OAc)2(0.31mmol,26%mol)和1,1’-二(二苯基膦基)二茂铁(124mg,0.22mmol)的混合物悬浮在脱气的DMF(3mL)中,用二异丙基乙基胺(0.9mL,5.2mmol)处理,用CO冲洗该系统。将该反应混合物温热至60℃,在该温度下于CO(气囊)下搅拌18小时。将DMF真空蒸发后,经由色谱柱纯化残余物(硅胶,洗脱用3%-6%甲醇在二氯甲烷中的混合物),获得了258mg(0.74mmol,62%产率)氨基N-酰苯胺(aminoanilide)44。1H-NMR(CD3OD-d4),δ(ppm):8.67(d,J=2.2Hz,1H),7.97(dd,J=8.9Hz,2.5Hz,1H),7.58(m,1H),7.51(m,1H),7.15(dd,J=7.7Hz,1.1Hz,1H),7.08(m,2H),6.89(dd,J=8.0Hz,1.4Hz,1H),6.76(dt,J=7.7Hz,4.4Hz,1H),6.67(t,J=7.7Hz,2H),6.60(m,2H),4.87(bs,4H),3.60(t,J=6.3Hz,2H),3.35(t,J=6.3Hz,2H)。
实施例41
N-(2-氨基-苯基)-6-(4-甲氧基-苄基氨基)-烟酰胺(化合物45)
步骤1:N-(5-溴-吡啶-2-基)-4-甲氧基苄基胺(化合物43)
2,6-二溴吡啶41(6.03mmol,2当量)和对甲氧基苄基胺(413mg,3.01mmol)的混合物在120℃于氮气氛下搅拌6小时。如上所述进行后处理,并经由硅胶垫纯化(洗脱用50%乙醚在己烷中的混合物),获得了浅黄色固体43(773mg,2.60mmol,87%产率)。13C NMR(300MHz,CDCl3)δ(ppm):159.1,139.7,132.1,130.5,128.9,127.2,116.2,114.3,104.8,55.4,46.0.LMRS=295.0(M+1)。
步骤2:N-(2-氨基-苯基)-6-(4-甲氧基-苄基氨基)-烟酰胺(化合物45)
按照实施例40步骤2中描述的方法,但是用43代替42,以61%的产率获得了本标题化合物45。
实施例42
N-(2-氨基苯基)-3-[6-(2-苯基氨基-乙基氨基)-吡啶-3-基]-丙烯酰胺(化合物50)
步骤2:3-[6-(2-苯基氨基-乙基氨基)-吡啶-3-基]-丙烯酸叔丁酯(化合物
46)
在50mL烧瓶内,将42(308mg,1.05mmol)、丙烯酸叔丁酯(0.8mL,5.5mmol)、二异丙基乙基胺(0.8mL,4.6mmol)、三邻甲苯基膦(POT,192mg,0.63mmol)、Pd2(dba)3(73mg,0.08mmol)在无水DMF(4mL)中的混合物在120℃(预热的油浴)于氮气氛下搅拌2小时。除去DMF后,通过色谱法纯化残余粗产物(硅胶柱,50%乙醚在己烷中的混合物),获得了316mg的46(88%产率)。13C NMR(300MHz,CDCl3)δ(ppm):166.6,159.3,149.6,147.8,140.7,134.9,129.1,119.8,117.3,115.9,112.6,107.8,80.0,43.5,40.9,28.1.LRMS=340.3(M+1)。
步骤3:3-[6-(2-苯基氨基-乙基氨基)-吡啶-3-基)-丙烯酸(化合物48)
将酯46(0.93mmol)溶解在40%TFA在二氯甲烷中的溶液(10mL)中,将该溶液在室温搅拌过夜。通过与乙腈(3×10mL)真空蒸馏来除去溶剂,在高度真空下贮存6小时。所得固体残余物48不用进一步纯化直接用于下一反应。LRMS=284.1(M+1)。
步骤4:N-(2-氨基苯基)-3-[6-(2-苯基氨基-乙基氨基)-吡啶-3-基]-丙烯酰
胺(化合物50)
将酸48(0.93mmol)、BOP(495mg,1.12mmol)和1,2-苯二胺(124mg,1.15mmol)的混合物溶解在无水乙腈(4mL)中,用三乙胺(0.8mL,5.7mmol)处理。将所得溶液在室温于氮气氛下搅拌16小时。真空浓缩后,粗产物经由色谱柱纯化(5%甲醇在二氯甲烷中的混合物),然后从氯仿中重结晶,获得了50(247mg,71%产率)。1H-NMR(DMSO-d6),δ(ppm):9.25(bs,1H),8.21(d,J=1.6Hz,1H),7.67(d,J=8.5Hz,1H),7.43(d,J=15.7Hz,1H),7.32(d,J=7.4Hz,1H),7.24(t,J=1.0Hz,1H),7.08(t,J=7.4Hz,2H),6.91(t,J=8.0Hz,1H),6.75(dt,J=8.0Hz,0.4Hz,1H),6.57(m,6H),5.20(bs,1H),3.48(t,J=6.3Hz,2H),3.33(bs,2H),3.21(t,J=6.3Hz,2H)。
实施例43
N-(2-氨基苯基)-3-[6-(4-甲氧基-苄基氨基)-吡啶-2-基]-丙烯酰胺(化合物51)
步骤2:N-(2-氨基苯基)-3-[6-(4-甲氧基-苄基氨基)-吡啶-2-基]-丙烯酰胺
(化合物51)
按照实施例42步骤2、3、4中描述的方法,但是用43代替42,以50%的产率(2步的产率)获得了本标题化合物51。1H-NMR(CDCl3),δ(ppm):7.60(bs,1H),7.55(bs,1H),7.43(t,J=7.7Hz,1H),7.29(d,J=8.3Hz,2H),7.1 7(d,J=15.1Hz,1H),7.06(t,J=7.7Hz,1H),6.88(d,J=8.3Hz,2H),6.80(m,2H),6.70(m,3H),6.41(d,J=8.5Hz,1H),4.50(d,J=5.5Hz,2H),3.80(s,3H),3.45(bs,2H)。
实施例44
4-[2-(2-氨基-苯基氨基甲酰基)-乙烯基]-苄基}-氨基甲酸吡啶-3-基甲基酯(化合物55)
步骤1:(4-溴-苄基)-氨基甲酸吡啶-3-基-甲基酯(化合物54)
在室温将4-溴苄基胺HCl(3.0g,13.4mmol)溶解在DMF(60mL)中,然后用10分钟滴加Et3N(4.13mL,29.7mmol),获得了浑浊溶液。向该溶液中加入DBU(2.42mL,16.2mmol)和1,1’-羰基二咪唑(2.41g,14.8mmol)。在室温搅拌1小时后,用10分钟滴加3-吡啶基甲醇(1.44mL,14.8mmol)。将所得反应混合物搅拌过夜,然后减压浓缩。将所得残余物用乙醚/EtOAc(9∶1)稀释,然后用H2O洗涤。用Na2SO4将有机层干燥,过滤,然后浓缩,获得了粗产物,将其从EtOAc中重结晶,获得了2.55g产物54(59%产率,LRMS=323(M+1)。
步骤2:4-[2-(2-氨基-苯基氨基甲酰基)-乙烯基]-苄基}-氨基甲酸吡啶-3-
基甲基酯(化合物55)
按照实施例42步骤2、3的方法,但是用54代替42,用丙烯酸代替丙烯酸叔丁酯,以20%的总产率获得了本标题化合物55。1H NMR:(DMSO-d6)δ(ppm):10.03(s,1H),9.32(s,1H),8.65(s,1H),8.55(d,J=3.3Hz,1H),7.85(d,J=7.69Hz,1H),7.40-7.60(m,6H),7.3 1(d,J=7.69Hz,1H),6.89(dd,J=7.14Hz,J=7Hz,1H),6.71-6.79(m,2H),6.55(dd,J=7.1Hz,J=7Hz,1H),5.20(s,2H),4.93(bs,2H)。
实施例45
N-(2-氨基苯基)-3-{4-[(3,4,5-三甲氧基-苄基氨基)-甲基]-苯基}-丙烯酰胺(化合物59)
步骤1:(4-溴-苄基)-(3,4,5-三甲氧基-苄基)-胺(化合物57)
向K2CO3(522mg,3.77mmol)在无水DMF内的搅拌着的悬浮液中加入3,4,5-三甲氧基苄基胺(1.10mL,6.44mmol,2.2当量),然后加入对溴苄基溴(0.73g,2.91mmol)在无水DMF(8mL)中的溶液。将该混合物在氮气氛、黑暗条件下于室温搅拌2天,用二氯甲烷(200mL)稀释,用盐水洗涤,干燥(MgSO4),过滤并浓缩。通过硅胶柱色谱纯化残余粗产物(洗脱用5%甲醇在二氯甲烷中的混合物),获得了2.59mmol(89%产率)二苄基胺57。13C NMR(300MHz,CDCl3)δ(ppm):152.5,138.8,136.1,135.4,130.6,129.2,119.8,104.2,59.9,55.3,52.6,51.7.LRMS=368.4(M+1)。
步骤2:N-(2-硝基-苯基)-3-{4-[(3,4,5-三甲氧基-苄基氨基)-甲基]-苯基}-
丙烯酰胺(化合物58)
制备硝基N-丙烯酰基苯胺
在0℃,向2-硝基苯胺(1.73g,12.5mmol)、DMAP(321mg,2.6mmol)和2,6-二-叔丁基-4-甲基苯酚(308mg)在无水二氯甲烷(50mL)内的混合物中加入三乙胺(10.6mL,76mmol),然后加入丙烯酰氯(3.2mL,38mmol,3.0当量),将该混合物在室温搅拌16小时。用二氯甲烷(250mL)稀释该溶液,冷却至0℃,用饱和NaHCO3处理过量试剂(搅拌1小时)。然后将有机层洗涤(5%KHSO4,然后是盐水),干燥(MgSO4),过滤并减压浓缩。通过硅胶柱色谱纯化(洗脱用50%乙醚在己烷中的混合物)后,获得了642mg(3.34mmol,27%产率)所需酰胺。13C NMR(300MHz,CDCl3)δ(ppm):163.6,136.0,135.6,134.5,131.3,128.6,125.4,123.1,121.8.LRMS=193.2(M+1)。
步骤3:N-(2-氨基苯基)-3-{4-[(3,4,5-三甲氧基-苄基氨基)-甲基]-苯基}-
丙烯酰胺(59)
将硝基化合物58(127mg,0.27mmol)、SnCl2(429mg,2.26mmol,8.4当量)和NH4OAc(445mg)的混合物悬浮在甲醇(9.5mL)和水(1.5mL)中,将该混合物在70℃加热45分钟。将该混合物用乙酸乙酯(100mL)稀释,依次用盐水和饱和NaHCO3洗涤,干燥(MgSO4),过滤,并浓缩。通过硅胶色谱柱纯化(洗脱用5-10%甲醇在二氯甲烷中的混合物),获得了52mg(43%产率)59。1H-NMR(CDCl3),δ(ppm):8.25(bs,1H),7.59(d,J=15.6Hz,1H),7.38(d,J=7.5Hz,2H),7.29(d,J=7.5Hz,2H),7.25(m 1H),7.02(t,J=6.8Hz,1H),6.75(m,2H),6.62(d,J=15.6Hz,1H),6.58(s,2H),3.97(bs,3H),3.80(s,9H),3.78(s,2H),3.72(s,2H)。
实施例46
N-(2-氨基苯基)-3-(4-{[(3,4,5-三甲氧基-苄基)-氨基]-甲基}-苯基)-丙烯酰胺(化合物61)
步骤1:3-{4-{[甲基-(3,4,5-三甲氧基-苄基)-氨基]-甲基}-苯基)-N-(2-硝
基-苯基)-丙烯酰胺(化合物60)
将胺58(180.2mg,0.38mmol)溶解在88%的HCO2H(6mL)中,用过量低聚甲醛(7.67mmol)处理,将该混合物在70℃搅拌2.5小时。缓慢地加入饱和NaHCO3溶液,用二氯甲烷(2×75mL)萃取,干燥(MgSO4),过滤并浓缩。通过硅胶色谱柱纯化(洗脱用3-5%甲醇在二氯甲烷中的混合物)后,获得了纯的N-甲基胺60(118mg,63%产率)。13C NMR(300MHz,CDCl3)δ(ppm):164.5,153.1,143.5,142.3,136.8,136.1,136.0,135.3,134.9,132.9,129.3,128.2,125.8,123.1,122.2,120.3,105.4,62.2,61.2,60.8,56.0,42.5.LRMS=492.5(M+1)。
步骤2:N-(2-氨基苯基)-3-(4-{[(3,4,5-三甲氧基-苄基)-氨基]-甲基}-苯
基)-丙烯酰胺(化合物61)
按照实施例45步骤3中描述的方法,但是用硝基化合物60代替58,以72%的产率获得了本标题化合物61。1H-NMR(DMSO-d6),δ(ppm):9.15(bs,1H),8.13(bs,1H),7.58(d,J=1.9Hz,1H),7.30 (m 4H),7.12(d,J=7.7Hz,1H),6.91(m 3H),6.75(d,J=7.8Hz,1H),6.57(m 2H),4.83(bs,2H),4.43(d,J=5.5Hz,2H),3.72(s,3H),3.33(s,3H)。
实施例47
N-(2-氨基苯基)-3-{4-(4-甲氧基-苄基氨基)-苯基}-丙烯酰胺(化合物65)
步骤1:3-(4-氨基-苯基)-丙烯酸甲酯盐酸盐(化合物63)
在室温将4-氨基-肉桂酸(10.41g,0.052mol)溶解在甲醇(100mL)中。然后加入HCl在二噁烷中的溶液(15.6mL,4 N)。将该反应混合物加热回流过夜。将澄清的溶液蒸发至一半体积,然后在室温静置。通置。通过真空过滤收集所获得的白色悬浮液。将母液再蒸发至四分之一体积,并冷却至室温。将悬浮液再次过滤。将两次过滤所收集的固体合并,真空干燥,获得了7.16g的63(64.3%产率)。LRMS:178(M+1)。
步骤2:3-{4-(4-甲氧基-苄基氨基)-苯基}-丙烯酸甲酯盐酸盐(化合物64)
向化合物63(3.57g,16.7mmol)在DMF(30mL)内的悬浮液中加入Et3N,10分钟后,依次加入4-甲氧基苄基氯(2.0g,12.8mmol)、NaI(0.38g,2.6mmol)和K2CO3(3.53g,25.5mmol)。将该混合物在60℃加热过夜,蒸发至干。将残余物在饱和NaHCO3溶液(50mL)与EtOAc(50mL×3)之间分配。将合并的有机层用盐水洗涤,然后蒸发至干。通过快速色谱法纯化残余物,然后从异丙醇中重结晶,获得了1.16g的64(产率30.6%,LRMS=298)和1.46g的63(49%回收产率)。
步骤3:N-(2-氨基苯基)-3-{4-(4-甲氧基-苄基氨基)-苯基}-丙烯酰胺(化
合物65)
按照实施例42步骤4中描述的方法,但是用64代替48,以32%的产率获得了本标题化合物65。1H NMR:(DMSO-d6)δ(ppm):9.15(s,1H),7.24-7.38(m,6H),6.84-6.90(m,3H),6.72(m,2H),6.49-6.60(m,4H),4.84(s,2H),4.22(d,J=5.77Hz,2H)。
实施例48
N-(2-氨基-苯基)-3-(4-苯乙烯基氨基-苯基)-丙烯酰胺(化合物71)
步骤1:N-(4-碘-苯基)-(3-苯基-烯丙基)-胺(化合物69)
按照实施例47步骤2中描述的方法,但是用68代替63,以70%的产率获得了本标题化合物69。LRMS=288(M+1)
步骤2:N-(2-氨基-苯基)-3-(4-苯乙烯基氨基-苯基)-丙烯酰胺(71)
按照实施例42步骤2、4中描述的方法,但是用69代替42,用丙烯酸代替丙烯酸叔丁酯,以60%的总产率获得了本标题化合物71。1HNMR:(DMSO-d6)δ(ppm):9.22(bs,1H),7.45 (d,J=6.9Hz,2H),7.39(d,J=9.0Hz,2H),7.34(d,J=7.4Hz,2H),7.26(dt,J=7.4Hz,6.8Hz,2H),6.93(dt,J=7.9Hz,7.1Hz,1H),6.78(d,J=7.9Hz,1H),6.69(d,J=8.5Hz,2H),6.63-6.55(m,4H),6.44-6.37(m,1H),4.95(bs,2H),3.95(bs,2H)。
实施例49
N-(2-氨基-苯基)-3-[4-(4-甲氧基-苯甲酰胺)]-丙烯酰胺(化合物72)
步骤1:N-(4-碘-苯基)-4-甲氧基-苯甲酰胺(化合物70)
按照实施例47步骤2中描述的方法,但是用68代替63,以90%的产率获得了本标题化合物70。LRMS=354.0(M+1)
步骤2:N-(2-氨基-苯基)-3-[4-(4-甲氧基-苯甲酰胺)]-丙烯酰胺(化合物
72)
按照实施例42步骤2、4中描述的方法,但是用70代替42,用丙烯酸代替丙烯酸叔丁酯,以90%的总产率获得了本标题化合物72。1HNMR:(DMSO-d6)δ(ppm):9.4(bs,1H),7.60(d,J=8.5Hz,1H),7.54-7.45(m,3H),7.87(d,J=7.7Hz,1H),7.10(d,J=8.8Hz,1H),6.95-6.77(m,3H),6.62(d,J=7.7Hz,2H),6.08-6.04(m,2H),4.98(bs,2H),3.72(s,3H)。
实施例50
N-(2-氨基苯基)-3-{6-[2-(4-氧代-4H-喹唑啉-3-基)-乙基氨基]-吡啶-3-基}-丙烯酰胺(化合物76)
步骤1:N-(5-溴-吡啶-2-基)-乙烷-1,2-二胺(化合物73)
按照实施例40步骤1中描述的方法,但是用1,2-二氨基乙烷代替烷基胺,以84%的产率获得了本标题化合物73。13C NMR(300MHz,CD3OD):159.1,148.7,140.7,111.7,107.2,44.3,41.7.LRMS=218.1(M+1)
步骤2:3-[2-(5-溴-吡啶-2-基氨基)-乙基]-3H-喹唑啉-4-酮(化合物75)
将伯胺73(1.17g,5.40mmol)和衣托酸酐74(880mg,5.40mmol)在甲醇(25mL)中的悬浮液于50℃搅拌3小时,然后浓缩。将所得油状残余物溶解在88%甲酸(20mL)中,回流过夜。除去甲酸后,经由硅胶柱色谱纯化固体残余物(5%甲醇在二氯甲烷中的混合物),获得了1.24g(3.6mmol,67%产率)75。13C NMR(300MHz,CDCl3):161.6 ,156.8,147.7,147.6,147.2,139.8,134.5,127.4,126.8,126.3,121.6,110.1,107.0,46.3,40.1.LRMS=347.1(M+1)。
步骤3:N-(2-氨基苯基)-3-{6-[2-(4-氧代-4H-喹唑啉-3-基)-乙基氨基]-吡
啶-3-基}-丙烯酰胺(化合物76)
按照实施例42步骤2-4中描述的方法,但是用75代替42,以68%的总产率获得了本标题化合物76。1H-NMR(DMSO-d6),δ(ppm):9.24(bs,1H),8.17(dd,J=8.0Hz,1.6Hz,1H),8.11(bs,1H),8.08(d,J=1.9Hz,1H),7.82(dt,J=8.5Hz,1.4Hz,1H),7.64(d,J=8.2Hz,2H),7.25(t,J=5.8Hz,1H),6.90(dt,J=15.7Hz,1H),6.74(dd,J=8.0Hz,1.4Hz,1H),6.58(m,3H),4.95(bs,2H),4.17(t,J=5.2Hz,2H),3.68(m,J=5.2Hz,2H)。
实施例51
N-(2-氨基苯基)-3-{6-[2-(4-苄基-2,6-二氧代-哌嗪-1-基)-乙基氨基]-吡啶-3-基}-丙烯酰胺(化合物78)
步骤2:4-苄基-1-[2-(5-溴-吡啶-2-基氨基)-乙基]-哌嗪-2,6-二酮(化合物
77)
将苄基亚氨基二乙酸(702mg,3.15mmol)和乙酸酐(15mL)的悬浮液在120℃搅拌45分钟。将该反应混合物用无水甲苯稀释,真空浓缩以除去挥发性物质。将残余物溶解在无水甲苯(15mL)中,经由套管转移到含有胺73(475mg,3.2mmol)的反应烧瓶中。将该混合物在90℃加热16小时,浓缩,通过硅胶柱色谱纯化(洗脱用5%甲醇在二氯甲烷中的混合物),获得了684mg(1.70mmol,54%产率)77。
步骤3:N-(2-氨基苯基)-3-{6-[2-(4-苄基-2,6-二氧代-哌嗪-1-基)-乙基氨
基]-吡啶-3-基}-丙烯酰胺(化合物78)
按照实施例42步骤2-4中描述的方法,但是用77代替42,以60%的总产率获得了本标题化合物78。1H-NMR(CD3OD-d4),δ(ppm):8.09(d,J=1.8Hz,1H),7.68(dd,J=8.7Hz,2.1Hz,1H),7.53(d,J=15.6Hz,1H),7.29(m,6H),7.20(dd,J=7.8Hz,1.2Hz,1H),7.02(dt,J=9.0Hz,1.2Hz,1H),6.86(dd,J=8.1Hz,1.2Hz,1H),6.73(dt,J=7.5Hz,1.5Hz,1H),6.61(d,J=15.6Hz,1H),6.50(d,J=8.7Hz,1H),4.85(bs,3H),3.97(t,J=7.5Hz,2H),3.60(s,2H),3.57(t,J=7.5Hz,2H),3.38(s,4H)。
实施例52
(E)-4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基-氨基]-甲基}-N-(2-氨基-苯基)-肉桂酰胺(化合物83)
步骤1:4,6-二氯-2-(2-茚满基-氨基)-[1,3,5]三嗪(化合物79)
在-78℃、氮气氛下,通过套管向氰尿酰氯(13.15g,71.33mmol)在无水THF(100mL)内的搅拌着的溶液中缓慢地加入2-氨基茚满(10.00g,75.08mmol)、i-Pr2NEt(14.39mL,82.59mmol)在无水THF(60mL)中的溶液。50分钟后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱(AcOEt/CH2Cl2:2/98→5/95)和共沉淀(AcOEt/己烷)纯化该残余粗产物,获得了本标题化合物79(18.51g,65.78mmol,92%产率),为米黄色粉末。1H NMR(300MHz,CDCl3)δ(ppm):7.29-7.18(m,4H),6.02(bd,J=6.3Hz,1H),4.94-4.84(m,1H),3.41(dd,J=16.2,6.9Hz,2H),2.89(dd,J=16.1,4.5Hz,2H)。
步骤2:2-(4-溴-苄基-氨基)-4-氯-6-(2-茚满基-氨基)-[1,3,5]三嗪(化合物
80)
在室温、氮气氛下,向79(2.68g,9.52mmol)在无水THF(50mL)内的搅拌着的溶液中分别加入i-Pr2NEt(4.79mL,27.53mmol)和4-溴苄基胺.HCl(2.45g,11.01mmol)。17小时后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:3/97→5/95),获得了本标题化合物80(4.00g,9.29mmol,97%产率),为白色粉末。1H NMR(300MHz,CDCl3)δ(ppm):旋转异构体混合物,7.52-7.42(m,2H),7.26-7.11(m,6H),6.51和6.12(2m,1H),5.72-5.46(m,1H),4.94-4.64(m,1H),4.62-4.46(m,2H),3.43-3.16(m,2H),2.92-2.74(m,2H)。
步骤3:4-氨基-2-(4-溴-苄基-氨基)-6-(2-茚满基-氨基)-[1,3,5]三嗪(化合
物81)
在75mL密封烧瓶内,将80(2.05g,4.76mmol)在无水1,4-二噁烷(60mL)中的溶液于室温搅拌,用NH3气饱和5分钟,温热至140℃并保持18小时。让该反应混合物冷却至室温,将使用NH3气的饱和步骤重复进行5分钟,将该反应混合物再次温热至140℃并保持24小时。然后让该反应混合物冷却至室温,倒入1N HCl内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:5/95),获得了本标题化合物81(1.96g,4.76mmol,定量产率),为无色泡沫状物。1H NMR(300MHz,CDCl3)δ(ppm):7.43(d,J=8.2Hz,2H),7.25-7.12(m,6H),5.70-5.10(m,2H),5.00-4.65(m,3H),4.52(bs,2H),3.40-3.10(m,2H),2.90-2.65(m,2H)。
步骤4:(E)-4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基-氨基]-甲
基}-N-[2-(N-叔丁氧基羰基)-氨基-苯基]-肉桂酰胺(化合物82)
制备N-[2-(N-叔丁氧基羰基)-氨基-苯基]-丙烯酰胺
按照实施例45步骤2中描述的方法,但是用硝基化合物2-(N-叔丁氧基羰基)-氨基-苯胺代替2-硝基苯胺,以77%的产率获得了本标题化合物。1H NMR(300MHz,CDCl3)δ(ppm):8.51(bs,1H),7.60-7.45(m,1H),7.38-7.28(m,1H),7.20-7.05(m,2H),6.98(bs,1H),6.41(dd,J=17.0Hz,1.1Hz,1H),6.25(dd,J=16.9Hz,10.0Hz,1H),5.76(dd,J=10.2Hz,1.4Hz,1H),1.52(s,9H)。
在50mL密封烧瓶内,将81(300mg,0.73mmol)、丙烯酰胺(230mg,0.88mmol)、Et3N(407μl,2.92mmol)、三邻甲苯基膦(POT,13mg,0.04mmol)、Pd2(dba)3(20mg,0.02mmol)在无水DMF(10mL)中的溶液于室温搅拌,用氮气饱和15分钟,温热至100℃并保持15小时。然后让该反应混合物冷却至室温,倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:2/98→5/95),获得了本标题化合物82(240mg,0.41mmol,56%产率),为米黄色固体。1H NMR(300MHz,CDCl3)δ(ppm):8.46(bs,1H),7.71(bd,J=15.7Hz,1H),7.62-7.05(m,13H),6.54(bd,J=15.9Hz,1H),5.95-4.90(m,4H),4.85-4.48(m,3H),3.40-3.14(m,2H),2.90-2.70(m,2H),1.52(s,9H)。
步骤5:(E)-4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基-氨基]-甲
基}-N-(2-氨基-苯基)-肉桂酰胺(化合物83)
在室温,向82(230mg,0.39mmol)在CH2Cl2(5mL)内的搅拌着的溶液中加入TFA(1mL,95%水溶液)。18小时后,将该反应混合物倒入饱和NaHCO3水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NaHCO3、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:5/95),获得了本标题化合物83(170mg,0.35mmol,89%产率),为黄色固体。1HNMR(300MHz,丙酮-d6)δ(ppm):8.87(bs,1H),7.69(d,J=15.7Hz,1H),7.59(bd,J=7.7Hz,2H),7.49-7.34(m,3H),7.28-7.11(m,4H),7.05-6.91(m,2H),6.88(dd,J=8.0,1.4Hz,1H),6.69(td,J=7.6,1.4Hz,1H),6.65-5.50(m,4H),4.83-4.53(m,5H),3.34-3.11(m,2H),2.98-2.80(m,2H)。
a.Tf2O/Py/DMAP/0C
b.对甲氧基苄基胺/120c
c.1,2-苯二胺/CO(40psi)/Pd(OAc)2/dppf/DMF/DIPEA/70C
d.丙烯酸叔丁酯/Pd2(dba)3/POT/DMF/DIPEA/120C
e.TFA/DCM/Rt
f.1,2-苯二胺/BOP/DMF/TEA/rT
实施例53
N-(2-氨基苯基)-2-(4-甲氧基-苄基氨基)-喹啉-6-基-酰胺(化合物87)
步骤1:2,6-二三氟甲磺酰氧基-喹啉(化合物85):
将2,6-二羟基喹啉84(1.254g,7.78mmol)和DMAP(几粒晶体)在无水吡啶(15mL)中的溶液用纯净的三氟甲磺酸酐(5.2g,18.4mmol,1.2当量)处理,在0℃搅拌5小时。然后将该溶液倒入盐水/饱和NaHCO3混合物内,用二氯甲烷(2×150mL)萃取,干燥(MgSO4),过滤并浓缩。通过硅胶柱色谱纯化(30%-50%乙醚在己烷中的混合物),获得了2.58g(6.1mmol,78%产率)85。13C NMR(300MHz,CDCl3):154.5,147.8,144.6,142.0,131.6,127.8,124.9,119.3,118.7,114.9.LRMS=426.0(M+1)。
步骤2:N-(2-氨基苯基)-2-(4-甲氧基-苄基氨基)-喹啉-6-基-酰胺(化合物
87)
按照实施例40步骤1、2中描述的方法,但是用85代替40,以92%的产率获得了本标题化合物87。1H-NMR(DMSO-d6),δ(ppm):9.66(bs,1H),8.32(s,1H),8.05(d,J=8.8Hz,1H),7.96(dd,J=9.1Hz,2.2Hz,1H),7.72(d,J=2.2Hz,1H),7.55(dd,J=8.5Hz,2.2Hz,1H),7.34(dd,J=8.5Hz,2.2Hz,1H),7.20(d,J=7.7Hz,1H),6.97(t,J=7.7Hz,1H),6.90(m 2H),6.80(d,J=7.9Hz,1H),6.61(t,J=6.3Hz,1H),4.90(bs 2H),4.58(d,J=3.3Hz,2H),3.73(s,3H),3.33(bs,1H)。
实施例54
N-(2-氨基苯基)-3-[2-(4-甲氧基-苄基氨基)-喹啉-6-基]-丙烯酰胺(化合物88)
步骤3:N-(2-氨基苯基)-3-[2-(4-甲氧基-苄基氨基)-喹啉-6-基]-丙烯酰胺
(化合物88)
按照实施例42步骤1-4中描述的方法,但是用85代替40,以71%的总产率获得了本标题化合物88。1H-NMR(DMSO-d6),δ(ppm):9.70(bs,1H),9.40(bs,1H),8.20(d,J=8.9Hz,1H),8.03(bs,2H),7.94(d,J=7.2Hz,1H),7.64(dd,J=15.7Hz,2.5Hz,1H),7.41(d,J=8.5Hz,2H),7.39(m,1H),7.14(d,J=8.9Hz,1H),7.05(d,J=15.7Hz,1H),6.97(m,1H),6.95(d,J=8.5Hz,2H),6.81(d,J=8.0Hz,1H),6.65(t,J=7.2Hz,1H),4.76(s,2H),3.75(s,3H)。
实施例55-84
实施例55-84描述了使用实施例40-54中描述的用于制备化合物44-88的相同方法来制备化合物89-118。特征数据列在表3a-d中。
表3a
在实施例42-84中制备的化合物的特征
表3b
实施例 | 化合物 | n | 名称 | 特征 | 方案反应 |
53 | 87 | 0 | 2-(4-甲氧基-苄基氨基)-喹啉-6-甲酸(2-氨基苯基)-酰胺 | 1H-NMR(DMSO-d6),δ(ppm):9.66(bs,1H),8.32(s,1H),8.05(d,J=8.8Hz,1H),7.96(dd,J=9.1Hz,2.2Hz,1H),7.72(d,J=2.2Hz,1H),7.55(dd,J=8.5Hz,2.2Hz,1H),7.34(dd,J=8.5Hz,2.2Hz,1H),7.20(d,J=7.7Hz,1H),6.97(t,J=7.7Hz,1H),6.90(m2H),6.80(d,J=7.9Hz,1H),6.61(t,J=6.3Hz,1H),4.90(bs 2H),4.58(d,J=3.3Hz,2H),3.73(s,3H),3.33(bs,1H). | 10 |
实施例 | 化合物 | n | 名称 | 特征 | 反应方案 |
54 | 88 | 1 | N-(2-氨基苯基)-3-[2-(4-甲氧基-苄基氨基)-喹啉-6-基]-丙烯酰胺 | 1H-NMR(DMSO-d6),δ(ppm):9.70(bs,1H),9.40(bs,1H),8.20(d,J=8.9Hz,1H),8.03(bs,2H),7.94(d,J=7.2Hz,1H),7.64(dd,J=15.7Hz,2.5Hz,1H),7.41(d,J=8.5Hz,2H),7.39(m,1H),7.14(d,J=8.9Hz,1H),7.05(d,J=15.7Hz,1H),6.97(m,1H),6.95(d,J=8.5Hz,2H),6.81(d,J=8.0Hz,1H),6.65(t,J=7.2Hz,1H),4.76(s,2H),3.75(s,3H). | 10 |
表3c
实施例 | 化合物 | 名称 | 特征 | 反应方案 |
43 | 51 | N-(2-氨基苯基)-3-[6-(4-甲氧基-苄基氨基)-吡啶-2-基]-丙烯酰胺 | 1H-NMR(CDCl3),δ(ppm):7.60(bs,1H),7.55(bs,1H),7.43(t,J=7.7Hz,1H),7.29(d,J=8.3Hz,2H),7.17(d,J=15.1Hz,1H),7.06(t,J=7.7Hz,1H),6.88(d,J=8.3Hz,2H),6.80(m,2H),6.70(m,3H),6.41(d,J=8.5Hz,1H),4.50(d,J=5.5Hz,2H),3.80(s,3H),3.45(bs,2H). | 3 |
表3d
实施例85
N-(2-氨基-苯基)-4-(1H-苯并咪唑-2-基硫基甲基)-苯甲酰胺(化合物126)
步骤1:4-(1H-苯并咪唑-2-基硫基甲基)-苯甲酸甲酯(化合物122)
按照实施例47步骤2中描述的方法,但是使用119,并用121代替63,以95%的产率获得了本标题化合物122。LRMS=299.1(M+1)。
步骤2:N-(2-氨基-苯基)-4-(1H-苯并咪唑-2-基硫基甲基)-苯甲酰胺(126)
按照实施例1步骤4和5中描述的方法,但是用122代替6,以62%的产率获得了本标题化合物126。1H NMR:(DMSO-d6)δ(ppm):9.57(s,1H),7.89(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.53(bs,2H),7.36(bs,2H),7.14-7.08(m,3H),6.94(t,J=8.2Hz,1H),6.74(d,J=6.9Hz,1H),6.56(t,J=8.0Hz,1H),4.87(bs,2H),4.62(s,2H)。
实施例87
N-(2-氨基-苯基)-4-[6-(2-吗啉-4-基-乙基氨基)-苯并噻唑-2-基硫基甲基]-苯甲酰胺(化合物128)
步骤1:4-(6-氨基-苯并噻唑-2-基硫基甲基)-苯甲酸甲酯(122)
按照实施例47步骤2中描述的方法,但是使用120,并用121代替63,以45%的产率获得了本标题化合物122。LRMS=331.0(M+1)。
步骤2:4-[6-(2-吗啉-4-基-乙基氨基)-苯并噻唑-2-基硫基甲基]-苯甲酸甲
酯(化合物124)
向4-(6-氨基-苯并噻唑-2-基硫基甲基)-苯甲酸甲酯122(800mg,2.42mmol)在DMF(24mL)内的溶液中依次加入固体4-(2-氯乙基)吗啉盐酸盐(296mg,2.66mmol)、K2CO3(611mg,5.08mmol)、NaI(363mg,2.42mmol)、Et3N(370μL,2.66mmol)和碘化四丁基铵(894mg,2.42mmol),将该混合物在120℃搅拌24小时,再加入4-(2-氯乙基)吗啉盐酸盐(296mg,2.66mmol)。将该混合物在120℃搅拌8小时,真空除去溶剂。将所得黑色浆液在H2O与EtOAc之间分配。将有机层依次用HCl 1N和饱和NaHCO3水溶液洗涤。用EtOAc将沉淀萃取2次,用MgSO4干燥,并浓缩。通过快速色谱法纯化(MeOH/CHCl3:5∶95to10∶90),获得了48mg(4%产率)124,为浅黄色油状物。LRMS=444.1(M+1)。
步骤3:N-(2-氨基-苯基)-4-[6-(2-吗啉-4-基-乙基氨基)-苯并噻唑-2-基硫
基甲基]-苯甲酰胺(化合物128)
按照实施例1步骤4和5中描述的方法,但是用124代替6,以76%的产率获得了本标题化合物128。1H NMR:(丙酮-d6)δ(ppm):9.06(bs,1H),7.98(d,J=8.2Hz,2H),7.63(d,J=8.5Hz,2H),7.62(d,J=8.8Hz,2H),7.29(d,J=8.0Hz,1H),7.06(d,J=2.2Hz,1H),7.02-6.97(m,1H),6.87-6.82(m,2H),6.66(dt,J=7.4Hz,1.4Hz,1H),4.63(s,2H),3.64-3.60(m,4H),3.25(t,J=6.3Hz,2H),2.63(t,J=6.3Hz,2H),2.54-2.42(m,4H)。
实施例88
N-(2-氨基-苯基)-4-(喹啉-2-基硫基甲基)-苯甲酰胺(化合物131)
步骤1:2-(4-溴-苄基硫基)-喹啉(化合物130)
按照实施例47步骤2中描述的方法,但是用129代替63,以89%的产率获得了标题化合物130。LRMS=332.0(M+1)。
步骤2:N-(2-氨基-苯基)-4-(喹啉-2-基硫基甲基)-苯甲酰胺(131)
按照实施例40步骤2中描述的方法,但是用129代替42,以70%的产率获得了本标题化合物131。1H NMR:(DMSO-d6)δ(ppm):9.62(bs,1H),8.21(d,J=8.8Hz,1H),8.00-7.89(m,4H),7.79(dd,J=6.8Hz,1.3Hz,1H),7.68(d,J=6.3Hz,2H),7.56(t,J=6.8Hz,1H),7.44(d,J=8.7Hz,1H),7.17(d,J=8.2Hz,1H),6.99(dt,J=7.9Hz,7.4Hz,1H),6.79(d,J=6.9Hz,1H),6.61(dt,J=7.7Hz,7.4Hz,1H),4.69(s,2H)。
实施例89
N-(2-氨基-苯基)-4-(嘧啶-2-基氨基甲基)-苯甲酰胺(化合物134)
步骤1:4-(嘧啶-2-基氨基甲基)-苯甲酸甲酯(化合物133)
按照实施例47步骤2中描述的方法,但是用132代替63,以76%的产率获得了本标题化合物133。LRMS=244.2(M+1)。
步骤2:N-(2-氨基-苯基)-4-(嘧啶-2-基氨基甲基)-苯甲酰胺(134)
按照实施例1步骤4和5中描述的方法,但是用129代替6,以91%的产率获得了本标题化合物134。1H NMR:(DMSO-d6)δ(ppm):9.6(bs,1H),8.32(d,J=4.9Hz,2H),7.97(dt,J=9.9Hz,7.9Hz,2H),7.85-7.83(m,1H),7.47,(d,J=8.2Hz,2H),7.20(d,J=7.9Hz,1H),7.01(dt,J=7.7Hz,7.4Hz,1H),6.82(d,J=7.9Hz,1H),6.66-6.62(m,1H),4.98(bs,2H),4.61(d,2H)。
实施例90
N-(2-氨基-苯基)-4-(1-甲基-1H-咪唑-2-基硫基甲基]-苯甲酰胺(化合物139)
步骤1:[2-(4-碘-苯甲酰基氨基)-苯基]-氨基甲酸叔丁酯(化合物135)
向二碳酸二叔丁酯(39g,181mmol)在THF(139mL)中的置于水浴内的溶液中加入1,2-苯二胺(15g,139mmol)和DMAP(1.7g,14mmol)。将该混合物在室温搅拌16小时,并真空除去溶剂。将粗产物在EtOAc与水之间分配。将有机层用HCl 1N洗涤,然后用饱和NaHCO3水溶液洗涤。将合并的有机层用盐水洗涤,用MgSO4干燥,并浓缩,获得了化合物(18.9g,65%产率),为浅米黄色粉末。LRMS=209.1(M+1)。
在室温向4-碘苯甲酸(8.0g,32.3mmol)在DMF(65mL)内的溶液中依次加入1-[3-(二甲基氨基)丙基]-3-乙基碳二酰亚胺盐酸盐(8.0g,41.9mmol)和1-羟基苯并三唑(5.2g,38.7mmol)。将该混合物搅拌1小时,经由套管向该混合物中加入(2-氨基-苯基)-氨基甲酸叔丁酯(6.3g,30.2mmol)在DMF(20mL)中的溶液,然后加入三乙胺(5.9mL,4.9mmol)。将该混合物搅拌16小时,并真空除去溶剂。将粗产物在氯仿与水之间分配。将有机层用饱和NaHCO3水溶液洗涤,用MgSO4干燥,浓缩,获得了浅棕色浆状物,将其在热的EtOAc或Et2O中结晶,获得了135(9.3g,70%产率),为白色固体。LRMS=461.0(M+Na+)。
步骤2:N-[2-叔丁氧基羰基氨基-苯基)-对氨基甲酰基苯甲酸甲酯(化合
物136)
按照实施例40步骤2中描述的方法,但是用135代替42,以95%的产率获得了本标题化合物136。LRMS=393.1(M+Na+)。
步骤3:[2(4-羟基甲基-苯甲酰基氨基)-苯基]-氨基甲酸叔丁酯(137)
在氮气氛下,向冷却至-20℃的136(7.5g,20.6mmol)在THF(40mL)内的溶液中加入1M DIBAL-H(122mL,122mmol)在甲苯中的溶液。在室温搅拌18小时后,将该混合物冷却至0℃,通过滴加H2O(10mL)和2N NaOH(5mL)来小心地处理。将铝盐倾析出来,取出上清液。将有机层用H2O、1N HCl(6次)、饱和NaHCO3水溶液、盐水洗涤,用MgSO4干燥,并浓缩(2.04g,43%)。通过快速色谱法纯化粗产物(EtOAc/己烷50∶50 to 70∶30),获得了137(1.14g,16%产率),为固体泡沫状物。LRMS=365.2(M+Na+)。
步骤4:{2-[4-(1-甲基-咪唑-2-基硫基甲基)-苯甲酰基氨基]-苯基}-氨基
甲酸叔丁酯(化合物138)
在室温、于氮气氛下,向N-甲基-2-巯基咪唑(28mg,0.25mmol)在THF(1mL)内的溶液中依次加入137(70mg,0.20mmol)、三苯基膦(70mg,0.27mmol),然后滴加偶氮二甲酸二乙酯(48μL,0.31mmol)。将该混合物搅拌2小时,并真空除去溶剂。通过快速色谱法纯化,使用MeOH/CHCl3(5∶95)洗脱,以91%的产率获得了本标题化合物138(81mg),发现其含有某些亚肼基二甲酸二乙酯残余物。该化合物不用进一步纯化直接使用。
步骤5:N-(2-氨基-苯基)-4-(1-甲基-1H-咪唑-2-基硫基甲基]-苯甲酰胺(化
合物139)
按照实施例42步骤3中描述的方法,但是用138代替46,以62%的产率获得了本标题化合物139。1H NMR:(丙酮-d6)δ(ppm):9.07(bs,1H),7.93(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),7.29(d,J=8.0Hz,1H),7.10(d,J=1.1Hz,1H),7.03-6.96(m,2H),6.86(dd,J=8.0Hz,1.4Hz,1H),6.67(dt,J=7.4Hz,1.1Hz,1H),4.63(bs,2H),4.29(s,2H),3.42(s,3H)。
实施例91
N-(2-氨基-苯基)-6-(3-甲氧基苯基)-烟酰胺(化合物141)
向3-甲氧基苯基硼酸(152mg,1.0mmol)和140(248g,1.0mmol)的混合物中加入苯(8mL)和乙醇(4mL),然后加入2M Na2CO3水溶液(3.2mL,6.4mmol)。将该反应混合物在氮气氛下搅拌30分钟,然后迅速加入Pd(PPh3)4(58mg,0.05mmol)。回流24小时后,将该混合物冷却至室温,经由硅藻土垫过滤,用乙酸乙酯(30mL)洗涤。将该有机溶液用盐水(5mL)洗涤,干燥(MgSO4),并浓缩。通过快速硅胶色谱纯化(己烷/乙酸乙酯:1/1),获得了141(302mg,95%产率)。1H NMR(CDCl3)δ(ppm):9.11(d,J=1.8Hz,1H),8.30(dd,J=8.4Hz,1.8Hz,1H),7.57(d,J=8.4Hz,1H),7.52-7.47(m,1H),7.36(m,1H),7.22(m,1H),7.09-6.78(m,4H),3.84(s,3H),3.39(brs,2H)。
a.对氨基甲基苯甲酸/AcOH/5min/回流
b.HOBT/EDC/1,2-二氨基苯
实施例92
N-(2-氨基-苯基)-4-(1-氧代-1,3-二氢-异吲哚-2-基甲基)-苯甲酰胺(化合物144)
步骤1:4-(1-氧代-1,3-二氢-异吲哚-2-基甲基)-苯甲酸(化合物143)
向苯-1,2-二甲醛142(1.0g,7.46mmol)在10mL乙酸内的溶液中加入4-氨基甲基苯甲酸(1.13g,7.46mmol)。将该反应混合物回流5分钟,并冷却至室温。形成了结晶沉淀,用CH2Cl2研制,获得了本标题化合物143(1.29g,49%)。
步骤2:N-(2-氨基-苯基)-4-(1-氧代-1,3-二氢-异吲哚-2-基甲基)-苯甲酰
胺(化合物144)
在室温,向上述羧酸(0.32g,0.89mmol)在DMF(8mL)内的溶液中加入HOBt(0.16g,1.15mmol)和EDC(0.25g,1.33mmol),将该溶液搅拌1.5小时。最后,加入苯二胺(0.12g,1.07mmol),将该混合物搅拌18-20小时。真空除去DMF,将粗产物在乙酸乙酯与H2O之间分配。用Na2SO4将有机层干燥,并浓缩。通过柱色谱法纯化(CH2Cl2-MeOH(19∶1)),以46%的产率获得了144。1H NMR:(DMSO-d6)δ9.71(s,1H),7.46(d,J=8.0Hz,2H),7.80(d,J=8.0Hz,2H),7.55-7.70(m,3H),7.46(d,J=8.2Hz,2H),7.20(d,J=7.7Hz,1H),7.02(t,J=7.7Hz,1H),6.83(d,J=8.0Hz,1H),6.65(t,J=7.4Hz,1H),4.93(bs,2H),4.87(s,2H),4.47(s,2H)。
a.对氨基甲基苯甲酸/AcOH/回流/3hrs
b.HOBT/EDC/1,2-二氨基苯
c.4-(2-氨基乙基)苯酚/AcOH/5hrs/回流
d.PhNTf2/NaH/THF-DMF/30min/0℃
e.1.CO/Pd(OAc)2/dppf/Et3N/MeOH-DMF/4天/75℃
2.AcOH/HCl/3hrs/回流
实施例94
N-(2-氨基-苯基)-4-(1,3-二氧代-1,3-二氢-异吲哚-2-基甲基)-苯甲酰胺(化合物149)
将邻苯二甲酸酐148(1.3g,8.9mmol)和4-氨基甲基苯甲酸在20mL乙酸中回流3小时,冷却至室温,蒸发,获得了固体残余物,用水研制,过滤并干燥,获得了羧酸中间体(1.7g,68%)。LMRS=282.0(M+1)。
按照类似于实施例92步骤2中描述的方法,但是用上述酸代替143,以17%的产率获得了本标题化合物149。1H NMR:(DMSOd6)δ9.59(s,1H),7.82-7.91(m,6H),7.40(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,1H),6.93(t,J=7.7Hz,1H),6.73(d,J=8.0Hz,1H),6.55(t,J=7.4Hz,1H),4.83(bs,4H)。
实施例95
N-(2-氨基-苯基)-4-[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙基]-苯甲酰胺(化合物152)
步骤1:2-[2-(4-羟基-苯基)-乙基]-异吲哚-1,3-二酮(化合物150)
按照类似于实施例94步骤1中描述的方法,但是用4-氨基甲基苯甲酸代替酪胺,以48%的产率获得了本标题化合物150。LMRS=268.0(M+1)。
步骤2:三氟甲磺酸4-[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)乙基)-苯基
酯(151)
在0℃,向氢化钠(90mg,25mmol)在无水THF(20mL)内的溶液中加入150(500mg,8.9mmol),然后加入无水DMF(2mL)。将该反应混合物在0℃搅拌20分钟,向其中滴加PhN(Tf)2,再搅拌2小时,蒸发,获得了固体残余物,通过硅胶柱色谱纯化(CH2Cl2-MeOH(19∶1)),获得了151(639mg,86%产率)。LMRS=400.0(M+1)。
步骤3:N-(2-氨基-苯基)-4-[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙基]-
苯甲酰胺(化合物152)
按照类似于实施例40步骤2中描述的方法,但是用151代替42,以15%的产率获得了本标题化合物152。1H NMR:(DMSO d6)δ 9.57(s,1H),7.78-7.87(m,6H),7.31(d,J=8.0Hz,2H),7.12(d,J=7.7Hz,1H),6.93(t,J=6.9Hz,1H),6.74(d,J=8.0Hz,1H),6.56(t,J=7.4Hz,1H),4.83(bs,2H),3.85(t,J=7.1Hz,2H),3.00(t,J=7.1Hz,2H)。
实施例96
N-(2-氨基-苯基)-4-(4-氧代-4H-喹唑啉-3-基甲基)-苯甲酰胺(化合物154)
将4-氨基甲基苯甲酸(1.00g,6.60mmol)在水(20mL)中的悬浮液用Et3N(0.86mL,6.60mmol)处理,然后加入衣托酸酐153(980mg,6.00mmol)。将该反应混合物在40℃加热3小时,蒸发,形成了油状残余物,将其在甲酸(20mL)中回流7小时。真空除去甲酸,获得了固体,用水研制,过滤,获得了羧酸(1.61g,96%).LMRS=281.0(M+1)。
按照类似于实施例92步骤2中描述的方法,但是用上述羧酸代替143,以43%的产率获得了本标题化合物154。1H NMR:(DMSO d6)δ9.71(s,1H),8.68(s,1H),8.23(d,J=8.0Hz,1H),8.01(d,J=8.0Hz,1H),7.92(t,J=8.0,2H),7.78(d,J=8.0Hz,1H),7.63(t,J=7.4,1H),7.55(d,J=7.7Hz,2H),7.22(d,J=7.4Hz,1H),7.04(t,J=7.1Hz,1H),6.85(d,J=8.0Hz,1H),6.67(t,J=7.4Hz,1H),5.35(s,2H)。
实施例97
N-(2-氨基-苯基)-4-(4-氧代-4H-苯并[d][1,2,3]三嗪-3-基甲基)-苯甲酰胺(化合物155)
将4-氨基甲基苯甲酸(1.00g,6.60mmol)在水(20mL)中的悬浮液用Et3N(0.86mL,6.60mmol)处理,然后加入衣托酸酐(980mg,6.00mmol)。将该反应混合物在40℃加热3小时,冷却至0℃。用浓HCl(5mL)将该冷的反应混合物酸化,用5分钟向其中滴加NaNO2溶液(520mg,7.5mmol 5mL水溶液),然后在室温静置过夜。收集所形成的沉淀,用水洗涤,并干燥,获得了羧酸(1.62g,96%).LMRS=282.0(M+1)。
按照类似于实施例92步骤2中描述的方法,但是用上述羧酸代替143,以27%的产率获得了本标题化合物155。1H NMR:(DMSO d6)δ9.62(s,1H),8.25(t,J=6.7Hz,2H),8.11(ddd,J=7.1Hz,1.4Hz,1H),7.93-7.98(m,3H),7.49(d,J=8.2Hz,2H),7.1 3(d,J=7.7Hz,1H),6.94(t,J=8.0Hz,1H),6.75(d,J=8.0Hz,1H),6.57(t,J=7.7Hz,1H),5.66(s,2H),4.87(bs,2H)。
实施例98
N-(2-氨基-苯基)-4-(2,4-二氧代-1,4-二氢-2H-喹唑啉-3-基甲基)-苯甲酰胺(化合物157)
步骤1:4-[(2-氨基-苯甲酰基氨基)-甲基]-苯甲酸(化合物156)
向4-氨基甲基苯甲酸(5.09g,33.7mmol)在H2O(50mL)内的悬浮液中加入Et3N(4.7mL,33.7mmol),然后加入衣托酸酐153(5.0g,30.6mmol)。将该棕色混合物在40℃加热2小时直至该混合物变均匀,然后真空除去Et3N。将所得水溶液酸化(10%HCl/H2O),将该混合物在H2O与乙酸乙酯之间分配。将合并的有机萃取液用Na2SO4干燥,过滤并蒸发,获得了156,为白色固体(6.0g,72%)。LMRS=271.0(M+1)。
步骤2:N-(2-氨基-苯基)-4-(2,4-二氧代-1,4-二氢-2H-喹唑啉-3-基甲
基)-苯甲酰胺(化合物157)
将上述羧酸156(1.72g,6.36mmol)悬浮在NaOH(2.55g,63.6mmol)在H2O(12mL)内的溶液中。向该溶液中加入二噁烷(10mL)直至该混合物变均匀。将该溶液在冰浴中冷却至0℃,用2小时滴加氯甲酸甲酯(1.25mL,16.1mmol)。反应完全后,将过量氯甲酸甲酯和二噁烷真空除去,用甲醇(80mL)和H2O(20mL)将该混合物稀释。将该溶液在50℃加热1小时直至环合完全。真空除去甲醇,然后用乙酸乙酯萃取水层。将水相酸化(10%HCl/H2O),用乙酸乙酯(2×300mL)萃取。将有机萃取液合并,用Na2SO4干燥,过滤并蒸发至干。用温热的甲醇研制所得粗产物,获得了羧酸,为白色固体(1.7g,90%)。LMRS=319.0(M+Na)。
按照类似于实施例92步骤2中描述的方法,但是用所得喹唑啉二酮羧酸代替143,获得了本标题化合物157。1H NMR:(DMSO-d6)δ11.56(brs,1H),9.59(brs,1H),7.96-7.88(m,3H),7.67(dt,J=8.4,1.4Hz,1H),7.30(d,J=7.8Hz,2H),7.21(t,J=7.5Hz,2H),7.13(d,J=6.9Hz,1H),6.92(dt,J=6.9,1.2Hz,1H),6.75(d,J=6.9Hz,1H),6.57(t,J=6.9Hz,1H),5.15(brs,2H),4.86(brs,2H)。
实施例99
N-(2-氨基-苯基)-4-(1-甲基-2,4-二氧代-1,4-二氢-2H-喹唑啉-3-基甲基)-苯甲酰胺(化合物158)
步骤2:4-(1-甲基-2,4-二氧代-1,4-二氢-2H-喹唑啉-3-基甲基)-苯甲酸甲
酯
向喹唑啉二酮羧酸(1.0g,3.38mmol)在DMF(7mL)内的溶液中加入K2CO3(1.4g,10.1mmol),然后将该混合物冷却至0℃。加入MeI(1.05mL,16.9mmol),将该混合物在冰浴中温热至室温并保持过夜。真空除去过量甲基碘和DMF,将粗产物在乙酸乙酯与H2O之间分配。将水相再次用乙酸乙酯洗涤,将合并的有机萃取液用Na2SO4干燥,然后真空浓缩,获得了所需产物,为灰白色固体(0.93g,85%)。LMRS=325.0(M+1)。
步骤3:4-(1-甲基-2,4-二氧代-1 4-二氢-2H-喹唑啉-3-基甲基)-苯甲酸
向上述甲酯(1.25g,3.85mmol)在甲醇(35mL)内悬浮液中加入1NNaOH(30mL,38.5mmol),将该混合物在45-50℃加热3小时直至其变均匀。真空除去甲醇,将粗产物在乙酸乙酯与H2O之间分配。将水相酸化(10%HCl/H2O),用乙酸乙酯(2×300mL)萃取。将这些有机萃取液用Na2SO4干燥,真空浓缩,获得了产物5,为白色固体(1.15g,96%)。LMRS=311.0(M+1)。
步骤4:N-(2-氨基-苯基)-4-(1-甲基-2,4-二氧代-1,4-二氢-2H-喹唑啉-3-
基甲基)-苯甲酰胺(化合物158)
按照类似于实施例92步骤2中描述的方法,但是用上述羧酸代替143,以10%的产率获得了本标题化合物158。1H NMR:(DMSO-d6)δ9.59(brs,1H),8.03(d,J=7.8Hz,1H),7.89(d,J=7.8Hz,2H)7.80(dt,J=6.9,1.5Hz,1H),7.49(d,J=8.7Hz,1H),7.42(d,J=8.1Hz,2H),7.32(t,J=7.7Hz,1H),7.13(d,J=7.8Hz,1H),6.95(t,J=7.6Hz,1H),6.75(d,J=7.8Hz,1H),6.57(t,J=7.5Hz,1H),5.21(brs,2H),4.86(brs,2H),3.54(s,3H)。
实施例100
N-(2-氨基-苯基)-4-(2-甲基-4-氧代-4H-喹唑啉-3-基甲基)-苯甲酰胺(化
合物159)
将156(903mg,3.34mmol)在乙酸酐(15mL)中的悬浮液于50℃加热1小时。将乙酸酐真空蒸发,钯固体残余物溶解在乙酸(30mL)中。将该溶液回流48小时,蒸发,形成了另一固体残余物,将其从AcOEt/CHCl3混合物中重结晶,获得了羧酸中间体(420mg,43%产率)。LMRS=385.0(M+1)。
按照类似于实施例92步骤2中描述的方法,但是用上述羧酸代替143,以49%的产率获得了本标题化合物159。1HNMR:(DMSO)δ(ppm):9.64(bs,1H),8.17(dd,J=8.0,1.6Hz,1H),7.95(d,J=8.2Hz,2H),7.95(dd,J=8.8,2.5Hz,1H),7.84(ddd,J=7.6,7.0,1.5Hz,1H),7.64(d,J=7.7Hz,1H),7.53(ddd,J=7.6,7.6,1.1Hz,1H),7.33(d,J=8.2Hz,2H),7.14(dd,J=7.7,1.1Hz,1H),6.96(ddd,J=7.6,7.6,1.5Hz,1H),6.77(dd,J=8.0,1.4Hz,1H),6.58(ddd,J=7.6,7.6,1.3Hz,1H),5.46(s,2H),4.89(bs,2H)2.5(s,3H,与DMSO信号重叠)。
实施例101
N-(2-氨基苯基)-2-(4-甲氧基-苄基氨基)-噻唑-5-基-酰胺(化合物163)
步骤1:4-甲氧基苄基-硫脲(化合物161)
在0℃,向硫代羰基二咪唑(1.23g,6.22mmol,1.5当量)在无水二氯甲烷(10mL)内的溶液中滴加纯净的烷基胺160(4.15mmol,1.0当量),将该溶液在0℃-15℃搅拌16小时。在0℃加入浓的氢氧化铵(3mL,45mmol,3.6当量)在1,4-二噁烷(6mL)中的溶液,在室温搅拌7小时。将该溶液用乙酸乙酯(250mL)稀释,用盐水(2×50mL)洗涤,干燥(MgSO4),过滤并浓缩。通过柱色谱法纯化(硅胶,洗脱用5%甲醇在二氯甲烷中的混合物)后,获得了161,为黄色固体(700.2mg,3.6mmol,86%产率)。1H NMR:(丙酮-d6)δ(ppm):7.53(bs,1H),7.28(d,J=8.8Hz,2H),6.87(d,J=8.8Hz,2H),6.67(bs,2H),4.67(s,2H),3.77 (s,3H).LMRS=197.1(M+1)。
步骤2:2-(4-甲氧基苄基氨基)噻唑-5-甲酸甲酯(化合物162)
将反式2-甲氧基丙烯酸甲酯(461mg,3.97 mmol,1当量)在50%1,4-二噁烷在水中的混合物(4mL)内的于-10℃搅拌着的溶液用N-溴琥珀酰亚胺(792mg,4.46mmol,1.12当量)处理,在同一温度下搅拌1小时,转移到含有硫脲161(700.2mg,3.6mmol)的烧瓶内,将该混合物在80℃搅拌2小时。冷却至室温后,加入浓的NH4OH(0.8mL),搅拌10分钟,将所得沉淀过滤,用水洗涤,获得了363mg(1.3mmol,36%产率)162,将滤液蒸发后,又另外获得了作为蒸发残余物的454mg(HPLC测定的纯度为91%)(总产率计算为77%)。1H NMR:(丙酮-d6)δ(ppm):7.97(bs,1H),7.72(bs,1H),7.33(d,J=8.1Hz,2H),6.90(d,J=8.1Hz,2H),4.52(s,2H),3.78(s,3H),3.75(s,3H).LMRS=279.1(M+1)。
步骤3:N-(2-氨基苯基)-2-(4-甲氧基-苄基氨基)-噻唑-5-基-酰胺(化合物
163)
按照实施例1步骤4和5中描述的方法,但是用162代替6,以50%的产率获得了本标题化合物163。1H-NMR(甲醇-d4),δ(ppm):7.86(s,1H),7.29(d,J=8.8Hz,2H),7.11(dd,J=8.0Hz,1.4Hz,1H),7.04(dt,J=8.0Hz,1.4Hz,1H),6.90(d,J=8.8Hz,2H),6.86(m,1H),6.74(dt,J=7.4Hz,1.4Hz,1H),4.85(bs,4H),4.45(s,2H),3.78(s,3H)。
实施例102-121
实施例102-121描述了使用实施例47-101中描述的制备化合物62-163的相同方法来制备化合物164-183。特征数据列在表4a和4b中。
表4a
在实施例102-121中制得的化合物的特征
表4b
表4c
其它化合物的特征
反应方案21
实施例122
步骤1:{2-[(3’-甲酰基-联苯-4-羰基)-氨基]-苯基}-氨基甲酸叔丁酯(185)
按照实施例15步骤1中描述的方法,但是用184代替140,以74%的产率获得了本标题化合物185。1H NMR(CDCl3):δ10.10(s,1H),9.41(s,1H),8.13(m,1H),8.07(d,J=8.4Hz,2H),7.89(m,2H),7.77(m,1H),7.70(d,J=8.4Hz,2H),7.64(m,1H),7.27-7.09(m,3H),7.03(s,1H),1.52(s,9H)。
步骤2:N-(2-氨基苯基)-4-[3-(茚满-2-基氨基甲基)苯基]]-苯甲酰胺(186)
向联苯甲醛(104mg,0.25mmol)和2-氨基茚满(33.3mg,0.25mmol)在二氯乙烷(1mL)内的搅拌着的溶液中加入三乙酰氧基硼氢化钠(80)mg,0.375mmol),然后加入冰醋酸(15ul,0.25mmol),将该混合物在室温搅拌3小时。除去挥发性物质后,将残余物在乙酸乙酯与10%碳酸氢钠水溶液之间分配。将合并的有机层用水洗涤,干燥并浓缩。通过快速色谱法纯化(10%甲醇在氯仿中的混合物),获得了所需的Boc-单保护的产物(112mg,84%产率),为白色固体。1H NMR(CDCl3):δ9.21(s,1H),8.03(d,J=8.7Hz,2H),7.83(m,1H),7.69(d,J=8.7Hz,2H),7.65(s,1H),7.54-7.38(m,3H),7.28(m,7H),6.82(s,1H),3.95(s,2H),3.74(m,1H),3.22(dd,J=15.6,6.9Hz,2H),2.89(dd,J=15.6,6.6Hz,2H),1.53(s,9H)。
按照实施例42步骤3中描述的方法,但是用上面的化合物代替46,以98%的产率获得了本标题化合物186。1H NMR(20%CD3OD在CDCl3中的混合物):δ7.95.(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.57(m,1H),7.54-6.79(m,11H),3.95(s,2H),3.66(m,1H),3.16(dd,J=15.6,6.9Hz,2H),2.81(dd,J=15.6,6.6Hz,2H)。
实施例123-126
实施例123-126(化合物187-190)是用在实施例122中描述的制备化合物186的方法(反应方案21)制得的。
反应方案22
实施例127
步骤1:{2-[4-(1-氨基-环己基乙炔基)-苯甲酰基氨基]-苯基}-氨基甲酸叔
丁酯(191)
将碘化物184(438mg,1.0mmol)、Pd(PPh3)2Cl2(35mg,0.05mmol)、三苯基膦(7.6mg,0.025mmol)和1-乙炔基环己基胺(185mg,1.5mmol)的混合物在含有三乙胺(0.56mL,4.0mmol)的THF(4mL)中于室温搅拌20分钟。向其中加入CuI(3.8mg,0.02mmol),继续搅拌2小时。然后将该反应混合物用乙酸乙酯(30mL)稀释,用水洗涤,将有机层干燥并浓缩。通过快速色谱法纯化(10%甲醇在氯仿中的混合物),获得了所需产物191(420mg,97%产率)。1H NMR(CDCl3):δ9.36(s,1H),7.94(d,J=8.4Hz,2H),7.77(d,J=7.5Hz,1H),7.47(d,J=8.4Hz,2H),7.25-6.85(m,3H),2.10-1.30(m.10H),1.51(s,9H)。
步骤2:N-(2-氨基苯基)-4-[1-(4-甲氧基-苄基氨基)-环己基乙炔基]-苯甲
酰胺(192)
按照实施例122步骤2中描述的方法,但是用对甲氧基苯甲醛代替2-氨基茚满,以74%的产率获得了本标题化合物192。1H NMR(CDCl3):δ8.44(s,1H),7.82(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),7.31(d,J=8.4Hz,2H),7.23(m,1H),7.05(m,1H),6.84(d,J=8.7Hz,2H),6.78(m,2H),3.97(s,2H),3.76(s,3H),2.10-1.30(m.10H)。
反应方案23
实施例133
步骤1:N-[2-(叔丁氧基羰基)-氨基-苯基]-4-(三甲基甲硅烷基乙炔基)苯
甲酰胺(197)
在0℃、氮气氛下,向184(5.00g,11.41mmol)在无水THF(100ml)内的搅拌着的溶液中分别加入Pd(PPh3)2Cl2(240mg,0.34mmol)、CuI(130mg,0.69mmol)和三甲基甲硅烷基乙炔(2.10ml,14.84mmol)。然后滴加无水Et3N(6.36ml,45.66mmol)。用4小时将温度缓慢地温热至室温。将该反应混合物倒入饱和NH4Cl水溶液内,用乙酸乙酯稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:20/80→50/50),获得了本标题化合物197(4.42g,10.83mmol,94%产率),为黄色粉末。1H NMR(300MHz,CDCl3)δ(ppm):9.26(bs,1H),AB系统(δA=7.91,δB=7.55,J=8.3Hz,4H),7.85(d,J=7.9Hz,1H),7.32-7.13(m,3H),6.70(bs,1H),1.53(s,9H),0.28(s,9H)。
步骤2:N-(2-氨基-苯基)-4-(三甲基甲硅烷基乙炔基)苯甲酰胺(198)
按照实施例42步骤3中描述的方法,但是用上面的化合物代替46,获得了本标题化合物198(70mg,0.23mmol),为白色固体,主要由198和199的混合物组成。1H NMR(300MHz,丙酮-d6)δ(ppm):9.20(bs,1H),AB系统(δA=8.07,δB=7.62,J=8.2Hz,4H),7.32(d,J=7.6Hz,1H),7.05(td,J=7.6,1.2Hz,1H),6.90(d,J=7.6Hz,1H),6.72(t,J=7.3Hz,1H),4.66(bs,2H),0.30(s,9H)。
步骤3:N-(2-氨基-苯基)-4-乙炔基苯甲酰胺(199)
在-20℃、氮气氛下,向198和199的混合物在无水THF(15ml)内的搅拌着的溶液中加入TBAF溶液(1ml,1.0M在THF中的溶液)。用2小时让该反应混合物温热至室温,在室温搅拌18小时。然后将该反应混合物倒入饱和NH4Cl水溶液内,用乙酸乙酯稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:30/70),获得了本标题化合物199(215mg,0.91mmol,2步骤的产率为46%),为浅黄色粉末。1H NMR(300MHz,丙酮-d6)δ(ppm):9.19(bs,1H),AB系统(δA=8.08,δB=7.66,J=8.5Hz,4H),7.33(d,J=7.6Hz,1H),7.05(t,J=7.3Hz,1H),6.91(d,J=7.6Hz,1H),6.72(t,J=7.6Hz,1H),4.67(bs,2H),3.88(s,1H)。
实施例134
步骤1:N-[2-(叔丁氧基羰基)-氨基-苯基]-4-乙炔基苯甲酰胺(200)
在-20℃、氮气氛下,向199的混合物(3.48g,8.53mmol)在无水THF(50ml)内的搅拌着的溶液中缓慢地加入TBAF溶液(9.4ml,9.38mmol,1.0M在THF中的溶液)。用2小时让该反应混合物温热至室温,在室温搅拌4小时。然后将该反应混合物浓缩,用乙酸乙酯稀释,依次用饱和NH4Cl水溶液、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:25/75→30/70),获得了本标题化合物200(2.53g,7.53mmol,88%产率),为浅黄色泡沫状物。1H NMR(300MHz,CDCl3)δ(ppm):9.31(bs,1H),AB系统(δA=7.94,δB=7.59,J=8.5Hz,4H),7.83(d,J=7.6Hz,1H),7.30-7.10(m,3H),6.75(bs,1H),3.23(s,1H),1.53(s,9H)。
步骤2:N-(2-氨基-苯基)-4-[3-(4-氯苯基)-3-吗啉-4-基-1-丙炔-1-基]-苯甲
酰胺(201)
在氮气氛下,向200(200mg,0.60mmol)在无水1,4-二噁烷(5ml)内的搅拌着的溶液中分别加入4-氯苯甲醛(100mg,0.71mmol)、吗啉(60μl,0.68mmol)和CuI(6mg,0.03mmol)。向该反应混合物中通入氮气5分钟,温热至105℃。18小时后,让该反应混合物冷却至室温,用乙酸乙酯稀释,依次用饱和NH4Cl水溶液、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:40/60),获得了所需化合物(193mg,0.35mmol,59%产率),为浅黄色泡沫状物。1H NMR(300MHz,CDCl3)δ(ppm):9.40(bs,1H),AB系统(δA=7.96,δB=7.36,J=8.5Hz,4H),7.79(d,J=7.9Hz,1H),7.59(d,J=8.4Hz,4H),7.25-7.10(m,3H),6.91(s,1H),4.80(s,1H),3.82-3.68(m,4H),2.69-2.5 8(m,4H),1.53(s,9H)。
按照实施例42步骤3中描述的方法,但是用上面的化合物代替46,以67%的产率获得了本标题化合物201。1H NMR(300MHz,DMSO-d6)δ(ppm):9.80(bs,1H),AB系统(δA=8.06,δB=7.71,J=8.1Hz,4H),AB系统(δA=7.65,δB=7.52,J=8.3Hz,4H),7.20(d,J=7.9Hz,1H),7.02(t,J=7.3Hz,1H),6.82(d,J=7.0Hz,1H),6.64(t,J=7.5Hz,1H),5.10(s,1H),4.97(bs,2H),3.72-3.58(m,4H),2.67-2.46(m,4H)。
反应方案24
实施例135
步骤1:4-(4-氯-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基-氨基)-苯甲酸甲酯
(203)
在室温、氮气氛下,向202(2.00g,7.11mmol)在无水THF(50ml)内的搅拌着的溶液中分别加入i-Pr2NEt(1.86ml,10.66mmol)和4-氨基苯甲酸甲酯(1.29g,8.53mmol)或ArNH2(1.2当量)。然后将该反应混合物回流24小时。冷却后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:2/98→5/95),获得了本标题化合物203(1.70g,4.30mmol,60%产率),为米黄色粉末。1H NMR(300MHz,CDCl3)δ(ppm):旋转异构体混合物,2 AB系统(δA=8.03,δA’=8.00,δB=7.70,δB’=7.61,JAB=JA’B’=8.8Hz,4H),7.43和7.31(2bs,1H),7.29-7.19(m,4H),5.84和5.78(2d,J=7.2和7.7Hz,1H),4.98-4.77(2m,1H),3.91和3.90(2s,3H),3.41(dd,J=16.1,7.0Hz,2H),2.94和2.89(2dd,J=15.9,4.9Hz,2H)。
步骤2:4-[4-氨基-6-(2-茚满基-氨基)-[1,3,5]-三嗪-2-基氨基]-N-(2-氨基-
苯基)-苯甲酰胺(204)
本标题化合物204是按照实施例1途径B步骤3-5中描述的相同方法,在3个步骤中由203制得的。1H NMR(300MHz,丙酮-d6)δ(ppm):旋转异构体混合物,8.98(m,1H),8.49和8.28(2m,1H),8.10-7.92(m,4H),7.35-7.14(m,5H),7.03(td,J=7.6,1.5Hz,1H),6.90(dd,J=6.6,1.3Hz,1H),6.71(td,J=7.6,1.3Hz,1H),6.57和6.42(2m,1H),6.04和5.86(2m,2H),4.92-4.76(m,1H),4.70-4.58(m,1H),3.44-3.26(m,2H),3.08-2.92(m,2H).HRMS(计算值):452.2073,(实测值):452.2062。
反应方案25
实施例136
步骤1:4-[(4-氯-6-(2-茚满基-氨基)-[1,3,5]三嗪-2-基氧基)-甲基]-苯甲酸
甲酯(206)
在0℃,氮气氛下,向205(2.00g,7.11mmol)在无水THF(50ml)内的搅拌着的溶液中加入i-Pr2NEt(1.86ml,10.66mmol)和4-(羟基甲基)苯甲酸甲酯(1.30g,7.82mmol)。几分钟后,分批加入NaH(95%,186mg,7.11mmol)。然后让该反应混合物温热至室温。24小时后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:2/98),获得了本标题化合物206(2.00g,4.88mmol,69%产率),为无色粘性泡沫状物。1H NMR(300MHz,CDCl3)δ(ppm):旋转异构体混合物,2 AB系统(δA=8.06,δA’=8.03,δB=7.52,δB’=7.46,JAB=JA’B’=8.5Hz,4H),7.26-7.17(m,4H),5.94和5.85(2 bd,J=7.8Hz,1H),5.48和5.39(2s,2H),4.92-4.76(2m,1H),3.94和3.92(2s,3H),3.39和3.33(2dd,J=16.0,7.0Hz,2H),2.89和2.84(2dd,J=16.0,4.9Hz,2H)。
步骤2:4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]-三嗪-2-基氧基]-甲
基}-N-(2-氨基-苯基)-苯甲酰胺(207)
本标题化合物207是按照实施例1途径B步骤3-5中描述的相同方法,在3个步骤中由206获得的。1H NMR(300MHz,丙酮-d6+εDMSO-d6)δ(ppm):9.49(m,1H),8.1 2-8.03(m,2H),7.60(t,J=7.7Hz,2H),7.35(d,J=7.1Hz,1H),7.28-7.13(m,4H),7.07-6.94(m,2H),6.90(dd,J=7.3,1.4Hz,1H),6.70(td,J=7.3,1.1Hz,1H),6.44(bs,1H),6.25(bs,1H),5.47和5.41(2s,2H),4.87-4.68(m,3H),3.35-3.20(m,2H),3.02-2.88(m,2H).HRMS(计算值):467.2070,(实测值):467.2063。
反应方案26
实施例210
4-[(4-氯-6-苯乙基-氨基-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸甲酯(208)
本标题化合物208是按照实施例1途径B步骤2中描述的相同方法,由2制得的(R1R2NH=苯乙基胺)。
步骤1:4-[(4-苯乙基氨基-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸甲酯
(209)
向208(300mg,0.75mmol)在MeOH(35mL)内的脱气溶液中加入10%Pd/C(24mg,0.023mmol)。将该反应混合物在1atm的H2压力下于室温搅拌20小时,然后用N2吹扫。通过经由硅藻土过滤除去钯,将该反应混合物浓缩。通过快速硅胶色谱法纯化残余粗产物(MeOH/CH2Cl2:4/96),获得了本标题化合物209(135mg,0.37mmol,50%产率)。1H NMR(300MHz,CDCl3)δ(ppm):8.08(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),7.50-7.15(m,6H),4.85-4.65(m,2H),3.98(s,3H),3.82-3.62(m,2H),3.05-2.85(m,2H)。
步骤2:N-(2-氨基-苯基)-4-[(4-苯乙基氨基-[1,3,5]三嗪-2-基-氨基)-甲
基]-苯甲酰胺(210)
本标题化合物210是按照实施例1步骤4和5中描述的相同方法,在2个步骤中由209制得的。1H NMR:(300MHz,丙酮-d6)δ(ppm):9.03(s,1H),8.17-7.87(m,3H),7.49(dd,J=19.2,8.2Hz,2H),7.32-7.03(m,6H),6.99(t,J=7.6Hz,1H),6.86(d,J=8.0Hz,1H),6.67(t,J=7.4Hz,1H),6.60-6.30(m,2H),4.72(t,J=6.3Hz,1H),4.65-4.56(m,1H),3.67-3.5 1(m,2H),2.95-2.80(m,2H)。
反应方案27
实施例138
步骤1:4-[(4,6-二甲氧基-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸甲酯(211)
在75ml密封烧瓶内,将2-氯-4,6-二甲氧基-1,3,5-三嗪(540mg,3.08mmol)、4-(氨基甲基)苯甲酸甲酯.HCl2(689mg,3.42mmol)、i-Pr2NEt(1.49ml,8.54mmol)在无水THF(30ml)内的搅拌着的悬浮液在80℃温热5小时。然后让该反应混合物冷却至室温,倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:10/90→30/70),获得了本标题化合物211(870mg,2.86mmol,93%产率),为白色固体。1H NMR(300MHz,CDCl3)δ(ppm):AB系统(δA=8.01,δB=7.39,JAB=8.5Hz,4H),6.08-6.00(m,1H),4.73(d,J=6.3Hz,2H),3.95(s,6H),3.92(s,3H)。
本标题化合物212是按照实施例1步骤4和5中描述的相同方法,在2个步骤中由211制得的。1H NMR(300MHz,丙酮-d6+∑DMSO-d6)δ(ppm):9.58(bs,1H),8.27(t,J=6.3Hz,1H),AB系统(δA=8.04,δB=7.53,JAB=8.4Hz,4H),7.31(d,J=6.9Hz,1H),),7.02(td,J=7.6,1.6Hz,1H),6.88(dd,J=7.9,1.4Hz,1H),6.68(td,J=7.6,1.4Hz,1H),4.86-4.78(m,2H),4.69(d,J=6.3Hz,2H),),3.90和3.89(2s,6H).HRMS(计算值):380.1597,(实测值):380.1601。
步骤2:N-(2-氨基-苯基)-4-[(4,6-二甲氧基-[1,3,5]-三嗪-2-基-氨基)-甲
基]-苯甲酰胺(212)
反应方案28
实施例139
步骤1:4-[(6-(2-茚满基-氨基)-4-甲氧基-[1,3,5]三嗪-2-基-氨基)-甲基]-苯
甲酸(213)
在室温下,向5(300mg,0.73mmol)在MeOH/THF(10ml/5ml)混合物内的搅拌着的溶液中加入KOH水溶液(10%,5ml)。3天后,用旋转蒸发仪将该反应混合物浓缩,在水中稀释,用1N HCl酸化直至pH5-6,获得了白色沉淀。15分钟后,将该悬浮液过滤,用水将滤饼充分洗涤,并干燥,获得了本标题化合物213(282mg,0.72mmol,98%产率),为白色固体。MS:m/z=392.1[MH].+。
步骤2:N-(2-氨基-苯基)-4-{[6-(2-茚满基-氨基)-4-甲氧基-[1,3,5]-三嗪-2-
基-氨基]-甲基}-苯甲酰胺(214)
本标题化合物214是按照实施例1步骤5中描述的相同方法,在一个步骤中由213制得的。1H NMR(300MHz,丙酮-d6+∑DMSO-d6)δ(ppm):旋转异构体混合物,9.69-9.53(m,1H),AB系统(δA=8.04,δB=7.52,JAB=7.8Hz,4H),7.80-7.60(m,1H),7.45-7.10(m,6H),7.01(t,J=7.6Hz,1H),6.88(d,J=8.2Hz,1H),6.68(t,J=7.6Hz,1H),4.92-4.60(m,5H),3.90-3.78(m,3H),3.3 5-3.22(m,2H),3.02-2.83(m,2H).HRMS(计算值):481.2226,(实测值):481.2231。
反应方案29
实施例29
步骤1:4-[(4,6-二氯-[1,3,5]三嗪-2-基-N-甲基-氨基)-甲基]-苯甲酸甲酯
(216)
在室温、氮气氛下,向NaH(95%,81mg,3.19mmol)在无水THF(10ml)内的搅拌着的悬浮液中依次加入3(500mg,1.60mmol)在无水THF(10ml)中的溶液和MeI(298μl,4.79mmol)。16小时后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:10/90→20/80),获得了本标题化合物215(200mg,0.61mmol,38%产率),为白色固体结晶。1H NMR(300MHz,CDCl3)δ(ppm):AB系统(δA=8.04,δB=7.31,JAB=8.2Hz,4H),4.93(s,2H),3.93(s,3H),3.18(s,3H)。
步骤2:4-{[4-氨基-6-(2-茚满基-氨基)-[1,3,5]-三嗪-2-基-N-甲基-氨基]-
甲基}-N-(2-氨基-苯基)-苯甲酰胺(216)
本标题化合物216是按照实施例1途径B步骤2-5中描述的相同方法,在4个步骤中由215制得的。1H NMR(300MHz,丙酮-d6)δ(ppm):9.11(bs,1H),8.03(d,J=8.0Hz,2H),7.43(bs,2H),7.33(d,J=7.7Hz,1H),),7.28-7.09(m,4H),7.04(td,J=7.6,1.5Hz,1H),6.90(dd,J=8.0,1.4Hz,1H),6.71(td,J=7.5,1.3Hz,1H),6.25-6.05(m,1H),5.82和5.64(2bs,2H),5.00-4.56(m,5H),3.42-2.76(m,7H).HRMS(计算值):480.2386,(实测值):480.2377。
反应方案30
实施例141
步骤1:4-[(4-氯-6-甲基-[1,3,5]三嗪-2-基-氨基)-甲基]-苯甲酸甲酯(217)
在-30℃、氮气氛下,向氰尿酰氯1(2.00g,10.85mmol)在无水THF(100ml)内的搅拌着的溶液中缓慢地加入MeMgBr溶液(17ml,23.86mmol,1.4M在无水THF/甲苯中的溶液)。1小时后,用3小时让该反应混合物温热至室温。然后分别加入4-(氨基甲基)苯甲酸甲酯HCl 2(2.08g,10.30mmol)和i-Pr2NEt(3.78ml,21.69mmol)。18小时后,将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/CH2Cl2:10/90→15/85),获得了本标题化合物217(780mg,2.67mmol,25%产率),为黄色粉末。1H NMR(300MHz,CDCl3)δ(ppm):旋转异构体混合物,2AB系统(δA=8.03,δA’=8.02,δB=7.39,δB’=7.38,J=8.5Hz,4H),6.28-6.08(2m,1H),4.76和4.74(2d,J=6.3Hz,2H),3.92(s,3H),2.46和2.42(2s,3H)。
步骤2:N-(2-氨基-苯基)-4-{[6-(2-茚满基-氨基)-4-甲基-[1,3,5]-三嗪-2-基
-氨基]-甲基}-苯甲酰胺(218)
本标题化合物218是按照实施例1步骤3-5中描述的相同方法,在3个步骤中由217制得的。1H NMR(300MHz,丙酮-d6+∑DMSO-d6)δ(ppm):旋转异构体混合物,9.62-9.50(m,1H),8.04(d,J=8.0Hz,2H),7.68-7.37(m,3H),7.33(d,J=7.7Hz,1H),7.28-7.07(m,5H),7.02(t,J=7.4Hz,1H),6.89(d,J=7.9Hz,1H),6.69(t,J=7.4Hz,1H),4.92-4.60(m,5H),3.35-3.10(m,2H),3.02-2.82(m,2H),2.25-2.12(m,3H)。
反应方案31
实施例142
步骤1:(2-{4-[2-(4,6-二氨基-[1,3,5]三嗪-2-基)-乙烯基]-苯甲酰基氨基}-
苯基)-氨基甲酸叔丁酯(219)
向184(40mg,0.091mmol)和2-乙烯基-4,6-二氨基-1,3,5-三嗪(11mg,0.083mmol)在无水DMF(1mL)内的脱气溶液中加入三邻甲苯基膦(POT)(1.5mg,0.005mmol),然后加入Et3N(46μL,0.33mmol)和三(二亚苄基丙酮)二钯(O)(2mg,0.0025mmol)。将该溶液在100C加热16小时。然后减压除去DMF。将该反应混合物在AcOEt与饱和NH4Cl之间分配。分离后,将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:5/95),获得了本标题化合物219(25mg,0.056mmol,67%产率)。1HNMR(300MHz,丙酮-d6)δ(ppm):8.27(s,1H),8.06(d,J=8.1Hz,2H),7.96(d,J=15.9Hz,1H),7.79(d,J=8.1Hz,2H),7.76-7.69(m,1H),7.62-7.55(m,1H),7.26-7.15(m,2H),6.90(d,J=15.9Hz),6.21(s,4H),1.50(s,9H)。
步骤2:N-(2-氨基-苯基)-4-[2-(4,6-二氨基-[1,3,5]三嗪-2-基)-乙烯基]-苯
甲酰胺(220)
在室温,向219(25mg,0.056mmol)在CH2Cl2(1.5mL)内的搅拌着的溶液中加入TFA(0.3mL,4.3mmol)。30分钟后,缓慢地加入饱和NaHCO3直至达到pH8,减压除去CH2Cl2,加入AcOEt,分离各相。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(MeOH/CH2Cl2:10/90),获得了本标题化合物220(19mg,0.054mmol,98%产率)。1H NMR:(300MHz,丙酮-d6)δ(ppm):8.33,8.13(2d,J=7.5Hz,1H),8.22(d,J=15.9Hz,1H),8.01(d,J=8.1Hz,2H),7.84(d,J=8.1Hz,2H),7.38-6.96(m,2H),7.03(d,J=15.9Hz,1H),6.94-6.62(m,2H)。
反应方案32
实施例143a
步骤1:2-氨基-4-氯-6-哌啶-1-基-[1,3,5]三嗪(221)
向2,4-二氯-6-哌啶-1-基-[1,3,5]三嗪(500mg,2.15mmol)在无水1,4-二噁烷(20mL)内的溶液中通过氨气5分钟。在密封的管中将该溶液在70℃加热16小时。让该反应混合物冷却至室温,在AcOEt与饱和NH4Cl溶液之间分配。分离后,将有机层用水和盐水洗涤,用无水Na2SO4干燥,过滤并浓缩,获得了本标题化合物221(453mg,2.12mmol,98%产率)。LRMS:[MH].+=214.1。
步骤2:2-氨基-4-哌啶-1-基-6-乙烯基-[1,3,5]三嗪(222)
向221(358mg,1.68mmol)在无水甲苯(7mL)内的溶液中加入三丁基(乙烯基)锡(514μL,1.76mmol),然后加入Pd(PPh3)4(97mg,0.084mmol),在密封的管中将该反应混合物在100℃加热16小时。然后让该反应混合物冷却至室温,浓缩,直接通过快速硅胶色谱纯化(AcOEt/己烷:10/90→30/70),获得了本标题化合物222(含有氯化三丁基锡)。
步骤3:N-(2-氨基-苯基)-4-[2-(4-氨基-6-哌啶-1-基-[1,3,5]三嗪-2-基)-乙
烯基]-苯甲酰胺(223)
本标题化合物223是按照反应方案31步骤1和2中的相同方法,在2个步骤中由222制得的。1H NMR:(300MHz,DMSO-d6)δ(ppm):9.69(s,1H),8.01(d,J=7.5Hz,2H),7.87(d,J=16.0Hz,1H),7.80(d,J=7.5Hz,2H),7.18(d,J=7.5Hz,1H),7.04-6.92(m,1H),6.91(d,J=16Hz,1H),6.85-6.68(m,3H),6.60(t,J=7.2Hz,1H),4.93(s,2H),3.77(s,4H),1.63(s,2H),1.52(s,4H)。
实施例143b
步骤4:N-(2-氨基-苯基)-4-[2-(4-氨基-6-哌啶-1-基-[1,3,5]三嗪-2-基)-乙
基]-苯甲酰胺(224)
向223(18mg,0.043mmol)在MeOH(5mL)内的溶液中加入10%Pd/C(10mg,0.021mmol)。使用氢化装置将该反应混合物在H2压力(40psi)下于室温摇动16小时。然后用氮气吹扫该反应混合物,经由硅藻土过滤,并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(MeOH/CH2Cl2:2/98→4/96),获得了本标题化合物224(10mg,0.024mmol,56%产率)。1H NMR(300MHz,CDCl3-CD3OD)δ(ppm):7.82(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,2H),7.08(t,J=7.0Hz,1H),6.89-6.79(m,2H),7.80-6.90(m,1H),3.76(s,4H),3.13(t,J=8.1Hz,2H),2.88(t,J=8.1Hz,2H),1.90-1.40(m,10H)。
反应方案33
实施例144
步骤1:2-氨基-苯并噻唑-6-醇(225):
将2-氨基-6-甲氧基苯并噻唑(5.00g,27.8mmol)在二氯甲烷(70mL)中的悬浮液于氮气氛下冷却至0℃,滴加三溴化硼(3.93mL,41.6mmol)。将该浅黄色混合物搅拌3小时,让其缓慢地从0℃温热至10℃。通过滴加甲醇来缓慢地中止该反应,在室温搅拌过夜后,通过过滤收集白色固体(6.04g,88%产率)。将该氢溴酸盐溶解在水中,用乙酸乙酯洗涤,用饱和NaHCO3水溶液中和。通过过滤收集所得晶体,并在烘箱中于135℃干燥1小时,获得了本标题化合物225,为无色晶体(3.63g,79%产率)。1H NMR:(CD3OD)δ(ppm):7.27(d,J=8.8Hz,1H),7.08(d,J=2.2Hz,1H),6.80(dd,J=8.4,2.2Hz,1H)。
步骤2:6-(2-吗啉-4-基-乙氧基)-苯并噻唑-2-基胺(226)
在室温、氮气氛下,向苯并噻唑225(3.62g,21.8mmol)在THF内的溶液中依次加入4-(2-羟基乙基)吗啉(3.17mL,26.1mmol)、三苯基膦(7.43g,28.3mmol),然后滴加偶氮二碳酸二乙酯(4.46mL,28.3mmol)。将该溶液搅拌3.5小时,在真空下部分除去THF。将该混合物在乙酸乙酯与H2O之间分配。将合并的有机层用1N HCl萃取。将合并的酸性萃取液用饱和NaHCO3水溶液中和,用乙酸乙酯溶解沉淀。将合并的有机层用盐水洗涤,用MgSO4干燥,并浓缩。将滤液浓缩,获得了本标题化合物226(5.83g,96%产率),为浅黄色油状物。1H NMR:(丙酮-d6)δ(ppm):7.37(d,J=8.8Hz,1H),7.34(d,J=2.6Hz,1H),6.94(dd,J=8.8,2.6Hz,1H),6.60(bs,2H),4.19(t,J=6.2Hz,2H),3.70-3.67(m,4H),2.90(s,2H),2.8 1(t,J=6.2Hz,2H),2.62-2.58(m,4H)。
步骤3:4-{[6-(2-吗啉-4-基-乙氧基)-苯并噻唑-2-基氨基]-甲基}-苯甲酸
甲酯(227):
向含有苯并噻唑226(5.80g,20.8mmol)的圆底烧瓶中加入4-甲酰基苯甲酸甲酯(5.11g,31.1mmol),然后加入THF(8mL)、氯化二丁基锡(315mg,1.04mmol),并滴加苯基甲硅烷(3.24mL,31.1mmol)。将所得混合物在室温于氮气氛下搅拌过夜。将该混合物在乙酸乙酯中稀释,并过滤。将滤液在乙酸乙酯与水之间分配,将合并的有机层用1N HCl洗涤。用饱和NaHCO3水溶液将合并的酸性层中和,用乙酸乙酯萃取沉淀。将合并的有机层用盐水洗涤,用MgSO4干燥,并浓缩。通过快速色谱法纯化所得粗产物,用MeOH/CHCl3(10∶90)洗脱,获得了227(3.69g,42%产率)。1H NMR:(丙酮-d6)δ(ppm):8.04(d,J=8.5Hz,2H),7.65(d,J=8.8Hz,2H),7.41(d,J=8.8Hz,1H),7.34(d,J=2.5Hz,1H),6.94(dd,J=8.5,2.7Hz,1H),4.50(t,J=5.5Hz,2H),3.86(s,3H)。
步骤4:N-(2-氨基-苯基)-4-{[6-(2-吗啉-4-基-乙氧基)-苯并噻唑-2-基氨
基]-甲基}-苯甲酰胺(228):
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,获得了本标题化合物228(958mg,46%),为无色固体。1H NMR:(CD3OD)δ(ppm):8.04(d,J=8.2Hz,2H),7.62(d,J=8.5Hz,2H),7.40(d,J=8.8Hz,1H),7.3 1(d,J=2.5Hz,1H),7.25(d,J=7.4Hz,1H),7.1 5(t,J=7.4Hz,1H),6.97(dd,J=8.8,2.5Hz,2H),6.84(t,J=7.4Hz,1H),4.78(s,2H),4.21(t,J=5.2Hz,2H),3.81-3.77(m,4H),2.87(t,J=5.5,2H),2.69-3.66(m,4H)。
反应方案34
实施例145
步骤1:4-[(5-溴-苯并噻唑-2-基氨基)-甲基]-苯甲酸甲酯(229):
按照实施例144步骤3中描述的方法,但是用2-氨基-6-溴苯并噻唑代替226,以56%的产率获得了本标题化合物229。1H NMR:(DMSO-d6)δ(ppm):8.78(t,J=5.9Hz,1H),8.01(d,J=8.2Hz,2H),7.99(s,1H),7.56(d,J=8.2Hz,2H),7.43-7.34(m,2H),4.74(d,J=5.9Hz,2H),3.90(s,3H)。
步骤2:4-{[5-(3,4,5-三甲氧基-苯基)-苯并噻唑-2-基氨基]-甲基}-苯甲酸
甲酯(230):
按照实施例15步骤1中描述的方法,但是用229代替140,以44%的产率获得了本标题化合物230,为无色晶体。1H NMR:(DMSO-d6)δ(ppm):8.73(t,J=5.7Hz,1H),8.11(d,J=1.8Hz,1H),8.02(d,J=8.4Hz,2H),7.63-7.57(m,3H),7.48(d,J=8.4Hz,1H),6.97(s,2H),4.77(d,J=5.7Hz,2H),3.92(m,6H),3.90(s,3H),3.74(s,3H)。
步骤3:N-(2-氨基-苯基)-4-{[5-(3,4,5-三甲氧基-苯基)-苯并噻唑-2-基氨
基]-甲基}-苯甲酰胺(231):
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,以69%的产率获得了本标题化合物231。1H NMR:(丙酮-d6)δ(ppm):8.31(d,J=7.9Hz,2H),8.20(d,J=7.5Hz,1H),8.13(s,1H),7.73-7.58(m,3H),7.63(d,J=7.5Hz,2H),7.48-7.43(m,2H),7.05(s,2H),4.98(s,2H),4.00(s,6H),3.84(s,3H)。
反应方案35
实施例146
步骤1:4-[(6-甲氧基-苯并噻唑-2-基氨基)-甲基]-苯甲酸甲酯(232):
向2-氨基-6-甲氧基苯并噻唑(2.00g,11.1mmol)在二氯乙烷(20mL)与THF(20mL)的混合物内的溶液中依次加入4-甲酰基苯甲酸甲酯(1.82g,11.1mmol)、三乙酰氧基硼氢化钠(3.53g,16.7mmol)和乙酸(1.27mL,22.2mmol)。将该混合物搅拌2天,通过加入饱和NaHCO3水溶液来中止反应。将该混合物倒入含有水的分液漏斗中,用二氯甲烷萃取。将合并有机萃取液用盐水洗涤,用MgSO4干燥并真空浓缩。通过快速色谱法纯化粗产物,用EtOAc/己烷(20∶80-30∶70)洗脱,获得了本标题化合物232(1.85g,51%产率)。1H NMR:(丙酮-d6)δ(ppm):8.04(d,J=8.5Hz,2H),7.65(d,J=8.8Hz,2H),7.41(d,J=8.8Hz,1H),7.34(d,J=2.5Hz,1H),6.94(dd,J=8.5,2.7Hz,1H),4.50(t,J=5.5Hz,2H),3.86(s,3H)。
步骤2:N-(2-氨基-苯基)-4-[(6-甲氧基-苯并噻唑-2-基氨基)-甲基]-苯甲
酰胺(233):
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,以19%的产率获得了本标题化合物233,为浅米黄色固体。1H NMR:(DMSO-d6)δ(ppm):9.68(s,1H),8.44(t,J=5.8Hz,1H),8.00(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.39(d,J=2.7Hz,1H),7.34(d,J=8.8Hz,1H),7.21(d,J=6.6Hz,1H),7.05(t,J=6.3Hz,1H),7.00(d,J=1.4Hz,1H),6.88(dd,J=8.8,2.7Hz,1H),6.86(dd,J=8.0,1.4Hz,1H),6.65(td,J=7.4,1.4Hz,1H),4.95(s,2H),4.70(d,J=5.8Hz,2H),3.79(s,3H)。
反应方案36
实施例147
步骤1:4-(6-甲氧基-1H-苯并咪唑-2-基硫基甲基)-苯甲酸甲酯氢溴酸
盐(234):
向4-(溴甲基)苯甲酸甲酯(2.51g,11.0mmol)在DMF(50mL)内的溶液中加入5-甲氧基-2-苯并咪唑硫醇(1.98g,11.0mmol)。将该混合物在室温搅拌24小时,将溶剂真空蒸发。将残余物悬浮在乙酸乙酯中,通过过滤收集氢溴酸盐,获得了本标题化合物234(4.10g,91%产率),为无色固体。1H NMR:(DMSO-d6)δ(ppm):7.90(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,1H),7.03(s,1H),6.94(d,J=8.2Hz,1H),4.65(s,2H),3.82(s,3H),3.79(s,3H)。
步骤2::4-[6-(2-吗啉-4-基-乙氧基)-1H-苯并咪唑-2-基硫基甲基]-苯甲
酸甲酯(235):
按照实施例144步骤1、2中描述的方法,但是用上面的化合物代替2-氨基-6-甲氧基苯并噻唑,以37%的产率获得了本标题化合物235。1H NMR:(CDCl3)δ(ppm):8.04-8.00(m,2H),7.77-7.72(m,1H),7.69-7.59(m,1H),7.56-7.49(m,2H),6.96-6.90(m,1H),4.68(s,2H),4.31-4.16(m,4H),3.97(s,3H),3.98-3.91(m,2H),3.82-3.72(m,2H),2.75-2.47(m,4H)。
步骤3:N-(2-氨基-苯基)-4-[6-(2-吗啉-4-基-乙氧基)-1H-苯并咪唑-2-基
硫基甲基]-苯甲酰胺(236):
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,以11%的产率获得了本标题化合物236。1H NMR:(CD3OD)δ(ppm):7.89(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.28(d,J=8.5Hz,1H),7.19-7.06(m,3H),6.93-6.79(m,3H),4.55(s,2H),4.1 8(t,J=6.3Hz,2H),3.65-3.62(m,4H),2.51(t,J=6.6Hz,2H),2.46-2.42(m,4H)。
反应方案37
实施例148
步骤1:4-吗啉-4-基-苯甲酸甲酯(237):
向火焰干燥的耐压容器中加入碳酸铯(912mg,2.80mmol)和甲苯(8mL),用氮气吹扫烧瓶。加入乙酸钯(9.0mg,0.004mmol)和外消旋-2,2′-二(二苯基膦基)-1,1′-联萘(37mg,0.06mmol)。将该混合物脱气,在100℃加热18小时。让该混合物冷却至室温,经由硅藻土过滤,用乙酸乙酯洗涤,在乙酸乙酯与水之间分配。将有机层用饱和NaHCO3水溶液、盐水洗涤,用MgSO4干燥。并真空浓缩,获得了本标题化合物237(443mg,100%产率)。1H NMR:(CDCl3)δ(ppm):8.02(d,J=9.2Hz,2H),6.95(d,J=8.8Hz,2H),3.95(s,4H),3.92(s,3H),3.38-3.35(m,4H)。
步骤2:N-(2-氨基-苯基)-4-吗啉-4-基-苯甲酰胺(238):
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,以33%的产率获得了本标题化合物238。1H NMR:(DMSO-d6)δ(ppm):7.20(d,J=7.9Hz,1H),7.07(d,J=8.8Hz,2H),7.01(t,J=7.0Hz,1H),6.83(d,J=7.9Hz,1H),6.65(t,J=7.5Hz,1H),4.90(s,2H),3.81-3.79(m,4H),3.32-3.28(m,4H)。
反应方案38
实施例149
步骤1:3-甲基硫基-3-(吡啶-4-基氨基)-丙烯腈(239)
在室温向吡啶-4-基胺(1.0g,11.0mmol)和3,3-二-甲基硫基-丙烯腈(2.05g,12.6mmol)在DMF内的溶液中加入4A分子筛粉末。将该混合物搅拌1小时。然后将该混合物冷却至0℃,用1小时分批加入60%NaH在油中的分散液(0.92g,23.0mmol),在0℃再搅拌2小时。移去冷却浴,将该混合物在室温搅拌20小时。真空除去DMF,通过柱色谱法纯化粗产物(EtOAc-25%MeOH/EtOAc的梯度),获得了所需产物,为灰白色固体(1.9g,89%)。
步骤2:N-(2-氨基-苯基)-4-{[2-氰基-1-(吡啶-4-基氨基)-乙烯基氨基]-甲
基}-苯甲酰胺(240)
向3-甲基硫基-3-(吡啶-4-基氨基)-丙烯腈(0.2g,1.0mmol)、4-氨基甲基-苯甲酸(0.173g,1.14mmol)、DMAP(1mg)和Et3N(0.14ml,1.0mmol)的混合物中加入无水吡啶(0.5ml)。将所得搅拌着的混合物在55℃加热4.5小时,再加入Et3N(0.14ml),用约30小时将该混合物从75℃加热至90℃。当反应完全时,在真空下部分除去吡啶,通过柱色谱法纯化粗产物(EtOAc-20%MeOH/EtOAc的梯度),获得了所需产物,为灰白色固体(130mg,44%)。
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,以33%的产率获得了本标题化合物240。1H NMR:1H NMR:(300MHz,DMSO-d6)δ(ppm):9.69(br,2H),8.48(br,3H),8.03(d,J=7.9Hz,2H),7.51(d,J=8.4Hz,2H),7.29(br,2H),7.23(d,J=7.9Hz,1H),7.03(t,J=7.0Hz,1H),6.84(d,J=7.9Hz,1H),6.65(t,J=7.3Hz,1H),4.96(br,2H),4.62(d,J=5.7Hz,2H)。
反应方案39
实施例150
步骤1:4-[(2-氯-9H-嘌呤-6-基氨基)-甲基]-苯甲酸甲酯(241)
将2,6-二氯-9H-嘌呤(1g,5.29mmol)、4-氨基甲基-苯甲酸甲酯盐酸盐(1.2当量,1.28g)和NaHCO3(2.1当量,935mg)在水中的悬浮液于100℃加热。将由此形成的均匀溶液回流30分钟。过滤出所得白色沉淀,用冷水洗涤,并真空干燥,获得了本标题化合物241(1g,3.14mmol,60%)。LRMS计算值:317.7,实测值:318.3(MH)+.
步骤2:4-{[2-氯-9-(2-甲氧基-乙基)-9H-嘌呤-6-基氨基]-甲基}-苯甲酸甲
酯(242)
按照实施例144步骤2中描述的方法,但是用上面的化合物代替2-氨基-6-甲氧基苯并噻唑,以41%的产率获得了本标题化合物242。
步骤3:N-(2-氨基-苯基)-4-{[2-氯-9-(2-甲氧基-乙基)-9H-嘌呤-6-基氨
基]-甲基}-苯甲酰胺(243):
按照实施例1步骤4、5中描述的方法,但是用上面的化合物代替6,以85%的产率获得了本标题化合物243。1H NMR(CDCl3)δ(ppm):9.64(s,1H),8.94(bs,1H),8.18(s,1H),7.96(d,J=7.8Hz,2H),7.52(d,J=7.8Hz,2H),7.21(d,J=7.7Hz,1H),7,01(dd,J=7.3,8.0Hz,1H),6.81(d,J=8.0Hz,1H),6.62(dd,J=7.3,7.7Hz,1H),4.91(bs,2H),4.78(bs,2H),4.18(m,2H),3.70(m,2H),3.26(s,3H)
反应方案40
实施例151
步骤1:4-{[3-(2-氯-6-氟-苯基)-5-甲基-异恶唑-4-羰基]-氨基-甲基}-苯甲
酸甲酯(244)
在0℃、氮气氛下,向4-(氨基甲基)苯甲酸甲酯.HCl2(809mg,4.01mmol)在无水CH2Cl2(25ml)内的搅拌着的溶液中依次加入i-Pr2NEt(1.91ml,10.95mmol)和3-(2-氯-6-氟苯基)-5-甲基异恶唑-4-羰基氯(1.00g,3.65mmol)。45分钟后,让该反应混合物温热至室温并保持3小时。然后将该反应混合物浓缩,用AcOEt稀释,依次用饱和NH4Cl、H2O、饱和NaHCO3、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩,获得了本标题化合物244(1.50g,定量产率),为无色粘性泡沫状物。1HNMR(300MHz,CDCl3)δ(ppm):7.93(d,J=7.9Hz,2H),7.46-7.35(m,1H),7.29(d,J=8.4Hz,1H),7.15-7.05(m,3H),5.49(bs,1H),4.46(d,J=5.7Hz,2H),3.92(s,3H),2.80(s,3H)。
步骤2:4-{[3-(2-氯-6-氟-苯基)-5-甲基-异恶唑-4-羰基]-氨基-甲基}-苯甲
酸(245)
在室温,向244(1.45g,3.60mmol)在THF(20ml)内的搅拌着的溶液中加入LiOH.H2O(453mg,10.80mmol)在水(20ml)中的溶液。20小时后,将该反应混合物浓缩,用水稀释,用1N HCl酸化直至pH6,获得了白色沉淀。10分钟后,将该悬浮液过滤,用水将滤饼充分洗涤,并干燥,获得了本标题化合物245(1.23g,3.15mmol,88%产率),为白色固体。1H NMR(300MHz,DMSO-d6)δ(ppm):8.69(t,J=5.9Hz,1H),7.91(d,J=7.9Hz,2H),7.70-7.58(m,1H),7.51(d,J=7.9Hz,1H),7.45-7.30(m,3H),4.44(d,J=5.7Hz,2H),2.72(s,3H)。
步骤3:4-(9-氯-3-甲基-4-氧代-4H-异恶唑并[4,3-c]喹啉-5-基甲基)-苯甲
酸(246)
在室温,向245(795mg,2.05mmol)在无水DMF(10ml)内的搅拌着的悬浮液中加入NaOH(409mg,10.22mmol)在无水MeOH(5.1ml)中的溶液。然后将该反应混合物温热至40℃。3天后,将该反应混合物浓缩,用水稀释,用1N HCl酸化直至pH5,获得了淡红色沉淀。30分钟后,将该悬浮液过滤,用水将滤饼充分洗涤,并干燥,获得了本标题化合物246(679mg,1.84mmol,90%产率),为浅红色固体。1H NMR(300MHz,DMSO-d6)δ(ppm):AB系统(δA=7.92,δB=7.40,J=8.4Hz,4H),7.56(t,J=8.1Hz,1H),7.47(d,J=7.5Hz,1H),7.31(d,J=8.3Hz,1H),5.59(bs,2H),2.95(s,3H)。
步骤4:N-(2-氨基-苯基)-4-(9-氯-3-甲基-4-氧代-4H-异恶唑并[4,3-c]喹啉
-5-基甲基)-苯甲酰胺(247)
本标题化合物247是按照实施例1步骤5中描述的相同方法在一步中由246制得的。1H NMR(300MHz,DMSO-d6)δ(ppm):9.65(s,1H),AB系统(δA=7.95,δB=7.42,J=8.1Hz,4H),7.58(t,J=8.1Hz,1H),7.48(d,J=7.5Hz,1H),7.35(d,J=8.3Hz,1H),7.17(d,J=7.5Hz,1H),7.00(t,J=7.3Hz,1H),6.80(d,J=7.5Hz,1H),6.62(t,J=7.3Hz,1H),5.61(bs,2H),4.91(s,2H),2.97(s,3H)。
反应方案41
实施例152
步骤1:4-(1H-咪唑-2-基)-苯甲酸(248)
向4-甲酰基苯甲酸(2.00g,12.3mmol)在氢氧化铵(9ml)内的搅拌着的溶液中加入乙二醛(2.86ml,20.0mmol)。将该反应混合物在室温搅拌16小时。向该反应混合物中加入1N HCl以将其酸化至pH5。将溶剂蒸发,把残余物在水(20ml)中研制30分钟,过滤,获得了本标题化合物248(2.08g,83%),为白色固体。LRMS:188.1(计算值);189.1(实测值)。
步骤2:N-(2-氨基-苯基)-4-(1H-咪唑-2-基)-苯甲酰胺(249)
本标题化合物249是按照实施例1步骤5中描述的相同方法制得的。1H NMR(CDCl3)δ(ppm):1H NMR:(DMSO)δ(ppm):9.72(bs,1H),8.07(s,4H),7.26(s,2H),7.18(d,J=7.9Hz,1H),6.98(dd,J=7.5,7.5Hz,1H),6.79(d,J=7.9Hz,1H),6.60(dd,J=7.5,7.5Hz,1H).MS:(计算值)278.1;(实测值)279.1(MH)+。
反应方案42
实施例153
步骤1:4-硫代氨基甲酰基甲基-苯甲酸(250)
向4-氰基甲基-苯甲酸(1.65g,10.24mmol)和Et3N(5ml)在吡啶内的搅拌着的悬浮液中通入H2S鼓泡3小时。将该反应混合物在室温搅拌16小时。然后将水加到该反应混合物中,搅拌1小时,用1M HCl将其酸化至pH6。将溶剂蒸发,把残余物在水(20ml)中研制30分钟,过滤,获得了本标题化合物250(2.08g,83%),为白色固体。1H NMR(DMSO)δ(ppm):12.85(bs,1H),9.53(bs,1H),9.43(bs,1H),7.88(d,J=8.1Hz,2H),7.44(d,J=8.1Hz,2H),3.88(s,2H)。
步骤2:4-(4-氯甲基-噻唑-2-基甲基)-苯甲酸(251)
将250(729mg,3.73mmol)和1,3-二氯丙酮(474mg,3.73mmol)在THF(30ml)中的溶液于40℃搅拌48小时。将溶剂蒸发,然后将残余物溶解在乙酸乙酯中,用盐水洗涤,用无水MgSO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(2-4%MeOH/CH2Cl2),获得了本标题化合物(827mg,83%产率),为白色固体。1H NMR(DMSO)δ(ppm):12.93(bs,1H),7.91(d,J=8.1Hz,2H),7.63(s,1H),7.46(d,J=8.1Hz,2H),4.78(s,2H),4.42(s,2H)。
步骤3:N-(2-氨基-苯基)-4-(4-吗啉-4-基甲基-噻唑-2-基甲基)-苯甲酰胺
(252)
将K2CO3(599mg,4.33mmol)加到251(527mg,1.97mmol)和吗啉(189μl,2.17mmol)在THF(15ml)内的溶液中,回流48小时。将溶剂蒸发。通过快速硅胶色谱纯化残余粗产物(3-50%MeOH/CH2Cl2),获得了本标题化合物252(238mg,38%产率),为浅黄色固体。LRMS:318.2(计算值)319.2(实测值)。
本标题化合物252是按照实施例1步骤5中描述的相同方法制得的。1H NMR(DMSO)δ(ppm):9.63(bs,1H),7.94(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,2H),7.33(s,1H),7.15(d,J=8.1Hz,1H),6.97(dd,J=7.7,7.7Hz,1H),6.77(d,J=7.3Hz,1H),6.59(dd,J=8.1,8.1Hz,1H),4.90(bs,2H),4.40(s,2H),3.59-3.56(m,6H),2.44-2.38(m,4H).LRMS:408.2(计算值)409.2(实测值)。
反应方案43
实施例154
步骤1:3-[3-(4-甲氧基羰基-苄基)-脲基]-噻吩-2-甲酸甲酯(253)
采用Nakao描述的方法(K.Nakao,R.Shimizu,H.Kubota,M.Yasuhara,Y.Hashimura,T.Suzuki,T.Fujita和H.Ohmizu;Bioorg.Med.Chem.1998,6,849-868.),获得了本标题化合物253(1.01g,91%),为黄色固体。1H NMR(CDCl3)δ(ppm):9.55(bs,1H),8.00-7.97(m,3H),7.42-7.37(m,3H),5.45(t,J=5.8Hz,1H),4.52(d,J=6.0Hz,2H),3.91(s,3H),3.82(s,3H)。
步骤2:4-(2,4-二氧代-1,4-二氢-2H-噻吩并[3,2-d]嘧啶-3-基甲基)-苯甲酸
(254)
向253(422mg,1.21mmol)在MeOH(15ml)内的悬浮液中加入NaOH(145mg,3.63mmol)。将该反应混合物在60℃加热16小时。然后加入水(1ml),将该反应混合物再搅拌1小时。将溶剂蒸发,把残余物溶解在水中,用HCl 1M将其酸化至pH5。过滤出沉淀,获得了所需化合物254(348mg,95%),为白色固体。LRMS:302.0(计算值);303.0(实测值)。
步骤3:N-(2-氨基-苯基)-4-(1-乙基-2,4-二氧代-1,4-二氢-2H-噻吩并
[3,2-d]嘧啶-3-基甲基)-苯甲酰胺(255)
先采用实施例99步骤2、3中描述的相同方法,然后采用实施例1步骤5中描述的相同方法,获得了本标题化合物255,为黄色固体(73%)。1H NMR:(DMSO)δ(ppm):9.61(bs,1H,NH),8.22(d,J=5.5Hz,1H,CH),7.91(d,J=8.2Hz,2H,CH),7.43-7.40(m,3H,CH),7.15(d,J=7.4Hz,1H,CH),6.96(dd,J=7.6,7.6Hz,1H,CH),6.77(d,J=7.1Hz,1H,CH),6.59(dd,J=7.4,7.4Hz,1H,CH),5.17(s,2H,NCH2),4.88(bs,2H,NH2)4.09(q,J=7.0,2H,CH2),1.22(t,J=7.0,3H,CH3).LRMS:420.1(计算值);421.0(实测值)。
反应方案44
实施例155
步骤1:3H-噻吩并[3,2-d]嘧啶-4-酮(256)
3-氨基-2-噻吩甲酸甲酯(510mg,3.24mmol)溶解在甲酰胺(20ml)中,在170℃加热16小时。将溶剂蒸发。然后通过快速硅胶色谱纯化该残余粗产物(2-4%MeOH/CH2Cl2),获得了本标题化合物256(157mg,32%产率)。LRMS:152.0(计算值);152.9(实测值)。
步骤2:N-(2-氨基苯基)-4-(4-氧代-4H-噻吩并[3,2-d]嘧啶-3-基甲基)-苯
甲酰胺(257)
采用实施例85步骤1中描述的方法,但是用上面的化合物代替119,然后采用实施例1步骤4、5中描述的方法,以41%的产率获得了本标题化合物257。1H NMR:(DMSO)δ(ppm):9.61(bs,1H),8.70(s,1H),8.22(dd,J=5.2,0.5Hz,1H),7.95(d,J=8.2Hz,2H),7.47(d,J=8.5Hz,2H),7.44(dd,J=5.2,0.6 Hz,1H),7.15(d,J=7.7Hz,1H),6.96(dd,J=6.9,6.9Hz,1H),6.77(d,J=7.1Hz,1H),6.58(dd,J=7.0,7.0Hz,1H),5.31(s,2H),4.87(bs,2H).MS:376.1(计算值);377.1(实测值)。
反应方案45
实施例156
步骤1:2-氨基-4,5-二甲基-噻吩-3-甲酸甲酯(258)
采用Hozien描述的方法(Z.A.Hozien,F.M.Atta,Kh.M.Hassan,A.A.Abdel-Wahab和S.A.Ahmed;Synht.Commun..1996,26(20),3733-3755.),获得了本标题化合物258(1.44g,17%),为黄色固体。LRMS:197.1(计算值);200.1(实测值)。
步骤2:N-(2-氨基-苯基)-4-(5,6-二甲基-4-氧代-4H-噻吩并[2,3-d]嘧啶-3-
基甲基)-苯甲酰胺(259)
按照实施例155步骤1、2中描述的方法,但是用258代替256,获得了本标题化合物259,为白色固体(55%)。1H NMR:(DMSO)δ(ppm):9.61(bs,1H),8.57(s,1H),7.94(d,J=8.0Hz,2H),7.45(d,J=7.7Hz,2H),7.16(d,J=7.7Hz,1H),6.96(dd,J=7.6,7.6Hz,1H),6.77(d,J=8.0Hz,1H),6.59(dd,J=7.4,7.4Hz,1H),5.25(s,2H),4.87(bs,2H),2.39(s,3H),2.37(s,3H).LRMS:404.1(计算值);405.0(实测值)。
反应方案46
实施例157
步骤1:4-(4-氧代-色满-3-亚基甲基)-苯甲酸甲酯(260)
将浓H2SO4(2ml)缓慢地加到4-色满酮(2.00g,13.50mmol)和4-甲酰基苯甲酸甲酯(2.11g,12.86mmol)在冰醋酸内的溶液中。将该反应混合物在室温搅拌16小时。将溶剂浓缩至一半体积,将所得沉淀过滤,并用乙酸乙酯洗涤,获得了本标题化合物260(3.11g,82%),为紫色固体。1H NMR:(DMSO)δ(ppm):8.05(d,J=8.2Hz,2H),7.90(d,J=7.6Hz,1H),7.79(s,1H),7.64-7.59(m,3H),7.15(dd,J=7.6,7.6Hz,1H),7.07(d,J=8.2Hz,1H),5.43(s,2H),3.89(s,3H)。
步骤2:4-(4-氧代-4H-色烯-3-基甲基)-苯甲酸甲酯(261)
将水(0.2ml)和RhCl3.H2O(7mg,0.034mmol)加到化合物260(200mg,0.680mmol)在EtOH(2ml)和CHCL3(2ml)内的悬浮液中。将该反应混合物在70℃搅拌16小时。将该反应混合物冷却,在乙酸乙酯中稀释,用盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(0.5-1%MeOH/CH2Cl2),获得了本标题化合物261(118mg,59%),为白色固体。1H NMR:(DMSO)δ(ppm):8.45(s,1H),8.03(dd,J=7.9,1.8Hz,1H),7.87(d,J=8.4Hz,2H),7.83-7.77(m,1H),7.65(d,J=8.3Hz,1H),7.50-7.43(m3,1H),3.82(s,3H),3.80(s,2H)。
步骤3:N-(2-氨基-苯基)-4-(4-氧代-4H-色烯-3-基甲基)-苯甲酰胺(262)
本标题化合物262是按照实施例1步骤4、5中描述的相同方法获得的。1H NMR:(DMSO)δ(ppm):9.56(bs,1H),8.45(s,1H),8.04(d,J=7.9Hz,1H),7.88(d,J=8.4Hz,2H),7.80(dd,J=7.5,7.5Hz,1H),7.65(d,J=8.4Hz,1H),7.51-7.42(m,3H),7.14(d,J=7.9Hz,1H),6.96(dd,J=7.3,7.3Hz,1H),6.76(d,J=7.9Hz,1H),6.58(dd,J=7.3,7.3Hz,1H),4.86(bs,2H),3.80(s,2H).LRMS:370.1(计算值);371.1(实测值)。
实施例158
步骤2:4-色满-3-基甲基-苯甲酸甲酯(263)
将Pd/C 10%加到260(200mg,0.68mmol)在MeOH(40ml)和DMA(10ml)内的预先在真空下净化的悬浮液中。将该反应混合物在室温搅拌4小时。将MeOH蒸发后,把水加到油状残余物中,将所获得的沉淀过滤。然后通过快速硅胶色谱纯化该残余粗产物(5-8%AcOEt/Hex),获得了本标题化合物263(114mg,59%),为白色固体。LRMS:282.1(计算值);283.0(实测值)。
步骤3:N-(2-氨基-苯基)-4-色满-3-基甲基-苯甲酰胺(265)
本标题化合物265是按照实施例1步骤4、5中描述的相同方法获得的。1H NMR:(丙酮)δ(ppm):9.06(bs,1H),8.01(d,J=7.9Hz,2H),7.42(d,J=8.4Hz,2H),7.31(d,J=7.9Hz,1H),7.08-6.98(m,3H),6.87(d,J=7.5Hz,1H),6.82-6.66(m,3H),4.62(s,2H),4.22-4.17(m,1H),4.88-3.81(m,1H),2.88-2.71(m,3H),2.61-2.53(m,1H),2.41-2.33(m,1H).LRMS:358.2(计算值);359.1(实测值)。
实施例159
步骤2:4-(4-氧代-色满-3-基甲基)-苯甲酸甲酯(264)
将260(400mg,1.36mmol)和苯磺酰基肼(702mg,4.08mmol)在DMF(7ml)中的悬浮液于100℃搅拌48小时。将溶剂蒸发,将残余物在AcOEt中稀释,用饱和NH4Cl和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(5%AcOEt/HEx),获得了本标题化合物264(170mg,42%),为白色固体。LRMS:296.1(计算值);297.0(实测值)。
步骤3:N-(2-氨基-苯基)-4-(4-氧代-色满-3-基甲基)-苯甲酰胺(266)
本标题化合物266是按照实施例1步骤4、5中描述的相同方法获得的。1H NMR:(丙酮)δ(ppm):9.62(bs,1H),7.93(d,J=7.9Hz,2H),7.79(d,J=7.9Hz,1H),7.58(dd,J=7.0,7.0Hz,1H),7.39(d,J=7.9Hz,2H),7.1 7-7.04(m,3H),6.97(dd,J=7.0,7.0Hz,1H),6.78(d,J=7.9Hz,1H),6.60(dd,J=7.5,7.5Hz,1H),4.88(s,2H),4.44-4.39(m,1H),4.28-4.21(m,1H),2.26-3.21(m,2H),2.83-2.74(m,1H).LRMS:372.1(计算值);372.1(实测值)。
反应方案47
实施例160
步骤1:4-(3-氧代-3,4-二氢-2H-苯并[1,4]恶嗪-2-基甲基)-苯甲酸甲酯
(266)
将Et3N(3.18ml,22.8mmol)加到2-H-1,4-苯并恶嗪-3-(4H)-酮(2.50g,16.8mmol)和4-甲酰基苯甲酸甲酯(4.59g,27.5mmol)在Ac2O(20ml)内的搅拌着的溶液中。将该反应混合物回流16小时。将该混合物冷却3天后,将固体过滤,并用乙酸乙酯洗涤,获得了本标题化合物266(657mg,13%),为黄色固体。LRMS:295.1(计算值);296.0(实测值)。
步骤2:4-(3-氧代-3,4-二氢-苯并[1,4]恶嗪-2-亚基甲基)-苯甲酸甲酯(267)
本标题化合物267是按照实施例158步骤2中描述的相同方法制得的。LRMS:297.1(计算值);298.1(实测值)。
步骤3:N-(2-氨基-苯基)-4-(4-乙基-3-氧代-3,4-二氢-2H-苯并[1,4]恶嗪-2-
基甲基)-苯甲酰胺(269)
本标题化合物269是采用实施例99步骤2、3中描述的相同方法,然后采用实施例1步骤4、5中描述的相同方法,由267制得的。1H NMR:(DMSO)δ(ppm):9.61(bs,1H),7.91(d,J=7.9Hz,2H),7.39(d,J=7.9Hz,2H),7.22(d,J=7.9Hz,1H),7.17(d,J=7.5Hz,1H),7.11-6.91(m,4H),6.77(d,J=7.0Hz,1H),6.60(dd,J=7.0,7.0Hz,1H),4.95-4.91(m,1H),4.89(bs,2H),3.95(q,J=7.0Hz,2H),3.28-3.22(m,1H),3.17-2.89(m,1H),1.16(t,J=7.0Hz,3H).LRMS:401.2(计算值);402.1(实测值)。
实施例161
步骤1:N-(2-氨基-苯基)-4-(3-氧代-3,4-二氢-2H-苯并[1,4]恶嗪-2-基甲 基)-苯甲酰胺
(270)
本标题化合物270是按照实施例1步骤4、5中描述的相同方法由267制得的。1H NMR:(DMSO)δ(ppm):10.74(bs,1H),9.61(bs,1H),7.91(d,J=8.4Hz,2H),7.41(d,J=7.9Hz,2H),7.17(d,J=7.5Hz,1H),6.99-6.85(m,5H),6.78(d,J=7.5Hz,1H),6.60(dd,J=7.0,7.0Hz,1H),4.92-4.89(m,3H),3.29-3.23(m,1H),3.15-3.07(m,1H).MS:(计算值)373.1;(实测值)374.1(MH)+。
反应方案48
实施例162
步骤1:4-(1-氧代-茚满-2-基甲基)-苯甲酸甲酯(271)
在-60℃将2M LDA在THF中的溶液(4.16ml,8.32mmol)加到茚满酮(1.00g,7.57mmol)在THF(10ml)内的溶液中。在15分钟时间内将溶液缓慢地温热至0℃,再搅拌15分钟。然后将该反应冷却至-78℃,缓慢地加入4-溴苯甲酸甲酯(1.73g,7.57mmol)。将该溶液缓慢地温热至-20℃,搅拌4小时。用HCL 1M处理该反应混合物,将溶剂蒸发。将残余物在乙酸乙酯中稀释,用盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(5-20%AcOEt/HEx),获得了本标题化合物271(245mg,17%),为白色固体。LRMS:280.1(计算值);281.1(实测值)。
步骤2:N-(2-氨基-苯基)-4-(1-氧代-茚满-2-基甲基)-苯甲酰胺(272)
本标题化合物272是按照实施例1、步骤4、5中描述的相同方法制得的。1H NMR:(DMSO)δ(ppm):9.59(bs,1H),7.91(d,J=7.6Hz,2H),7.69-7.64(m,2H),7.54(d,J=7.6Hz,1H),7.45-7.40(m,3H),7.16(d,[=8.2Hz,1H),6.96(dd,J=7.3,7.3Hz,1H),6.77(d,J=8.2Hz,1H),6.59(dd,J=7.3,7.3Hz,1H),4.87(bs,2H),3.23-3.14(m,3H),2.85-2.81(m,2H).LRMS:356.1(计算值);357.2(实测值)。
实施例163
步骤1:4-(1-氧代-茚满-2-亚基甲基)-苯甲酸(273)
在0℃,向茚满酮(2.00g,15.1mmol)和4-羧基苯甲醛(1.89g,12.6mmol)在EtOH(10ml)内的悬浮液中加入KOH(1.77g,31.5mmol)。将该反应混合物在0℃搅拌30分钟,然后在室温搅拌16小时。将溶剂蒸发,把残余物溶解在水中,用HCl 1M酸化至pH5。过滤出沉淀,用水洗涤,获得了本标题化合物273(2.27g,57%),为黄色固体。LRMS:264.1(计算值);265.0(实测值)。
步骤2:N-(2-氨基-苯基)-4-(1-氧代-茚满-2-亚基甲基)-苯甲酰胺(274)
本标题化合物274是按照实施例1步骤5中描述的相同方法制得的。LRMS:354.1(计算值);355.0(实测值)。
步骤3:N-(2-氨基-苯基)-4-(1-羟基-茚满-2-基甲基)-苯甲酰胺(275)
向274(300mg,0.85mmol)在MeOH(8ml)和水(1ml)内的悬浮液至加入NaBH4(75mg,1.95mmol)。将该反应混合物在50℃搅拌16小时,并冷却。将水加到该溶液中,过滤出沉淀,用冷水洗涤,获得了本标题化合物275(224mg,74%),为白色固体。1H NMR:(丙酮)δ(ppm):9.05(bs,1H),8.00(dd,J=8.2,2.7Hz,2H),7.47(d,J=8.5Hz,1H),7.43(d,J=8.2Hz,1H),7.38-7.30(m,2H),7.22-7.12(m,3H),7.01(ddd,J=7.6,7.6,1.5Hz,1H),6.87(dd,J=8.0,1.1Hz,1H),6.68(dd,J=7.6,7.6Hz,1H),4.98(t,J=5.8Hz,0.4H),4.89(t,J=6.7Hz,0.6H),4.63(bs,2H),4.45(d,J=6.9Hz,0.6H),4.06(d,J=6.0Hz,0.4H),3.30-3.19(m,1H),2.88-2.48(m,3H,CH2).LRMS:358.2(计算值);359.1(实测值)。
反应方案49
i:BrCH2C6H4COOMe/MeONa/THF; 实施例165
ii:PhNHNH2;
iii:NaOH,然后HCl
iv:HOBt/EDC.HCl然后1,2-二氨基苯;
v:BrCH2C6H4COOMe/MeONa/MeOH,然后HCl/AcOH;
vi:CH2(CN)2/S8/Et2NH(或Et3N);
vii:AcCl,PhCOCl或PhNCO;
viii:2-N-Bocamino苯胺;
ix:TFA
实施例164
步骤1:4-(3,5-二甲基-1-苯基-1H-吡唑-4-基甲基)-苯甲酸(276)
在0℃,向NaH溶液(60%在矿物油中的溶液,250mg,6.3mmol)中加入乙酰基丙酮(0.646ml,6.3mmol),然后加入4-溴甲基-苯甲酸甲酯2(1.2g,5.2mmol)。将该反应混合物在室温搅拌1小时,回流2小时。加入苯基肼(0.51ml,5.2mmol),将该反应混合物再回流1小时。真空除去THF,将油状残余物在水与乙酸乙酯之间分配。分离出有机层,干燥,蒸发,通过硅胶柱色谱纯化,用EtOAc-己烷(1∶1)洗脱,获得了油状物(800mg),在室温将其用NaOH(0.8g,20mmol)在20ml水中的溶液处理1小时。进行下列步骤-用HCl酸化(pH6),用乙酸乙酯萃取所得乳液,用硫酸钠干燥萃取液,蒸发,通过柱色谱法纯化(洗脱剂EtOAc-己烷,1∶1),获得了390mg 276(本标题化合物)与278的混合物(摩尔比1∶2)。[M-1]+ 307.0和191.1。将该混合物以自身的形式用于下一步骤。
步骤2.N-(2-氨基-苯基)-4-(3,5-二甲基-1-苯基-1H-吡唑-4-基甲基)-苯甲
酰胺(277)
按照类似于实施例92步骤2中描述的方法,但是用276代替143,以25%的产率获得了本标题化合物277(通过色谱法纯化,使用EtOAc-己烷,1∶1洗脱)。1H NMR:(300MHz,DMSO-d6,δ(ppm):9.64(s,1H);7.97(d,J=7.6Hz,2H),7.42-7.56(m,5H),7.37(d,J=8.2Hz,2H),7.22(d,J=7.6Hz,1H),7.03(t,J=7.6Hz,1H),6.84(d,J=8.2Hz,1H),6.66(t,J=7.6Hz,1H),4.93(s,2H),3.92(s,2H),2.34(s,3H),2.18(s,3H)。
实施例165
步骤1:4-(3-氧代-丁基)-苯甲酸(278)
在室温,向乙酰基丙酮(5.0ml,49mmol)溶液中加入NaOMe(25%wt,10.8ml,47.3mmol),然后加入4-溴甲基-苯甲酸甲酯2(9.0g,39.3mmol)。将该反应混合物回流3小时,冷却至室温,用HCl酸化(pH 1-2)。将所得溶液蒸发,获得了残余物,将其在冰醋酸(50ml)与浓HCl(25ml)的混合物中回流4小时。将酸真空除去,用水研制残余物以形成结晶,通过过滤收集所得结晶,并干燥,获得了278(6.72g,80%产率)。[M-1]191.1。
步骤2. 4-(5-氨基-4-氰基-3-甲基-噻吩-2-基甲基)-苯甲酸279
向4-(3-氧代-丁基)-苯甲酸278(700mg,3.65mmol)、丙二腈(241mg,3.65mmol)和硫(130mg,3.65mmol)在20ml EtOH内的回流的悬浮液中加入二乙胺(0.5ml,4.8mmol)。将该反应混合物回流1小时,冷却至室温,用浓HCl酸化(pH 4-5),蒸发,获得了固体残余物。将该残余物在水与乙酸乙酯之间分配,分离出有机层,干燥,蒸发,通过硅胶柱色谱纯化,用EtOAc-己烷,1∶1洗脱,获得了本标题化合物279(300mg,30%产率)。1H NMR:(300MHz,DMSO-d6,δppm):7.87(d,J=8.4Hz,2H),7.29(d,J=7.9Hz,2H),6.98(s,2H),3.92(s,2H),2.03(s,3H)。
步骤3. 4-(5-乙酰基氨基-4-氰基-3-甲基-噻吩-2-基甲基)-苯甲酸280
在室温,向4-(5-氨基-4-氰基-3-甲基-噻吩-2-基甲基)-苯甲酸279(230mg,0.86mmol)在丙酮(5ml)-二氯甲烷(5ml)的溶剂混合物内的溶液中加入乙酰氯(0.305ml,4.3mmol)。在相同条件下搅拌2小时后,形成了本标题化合物280的沉淀,收集,并干燥(200mg,75%产率)。[M-1]313.1。
步骤4:N-(2-氨基-苯基)-4-(5-乙酰基氨基-4-氰基-3-甲基-噻吩-2-基甲
基)-苯甲酰胺(281)
按照类似于实施例92步骤2中描述的方法,但是用280代替143,以25%的产率获得了本标题化合物281。1H NMR(DMSO)δ(ppm):9.61(s,1H);7.91(d,J=7.9Hz,2H),7.34(d,J=8.4Hz,2H),7.15(d,J=7.5Hz,1H),6.96(t,J=6.6Hz,1H),6.77(d,J=7.0Hz,1H),6.59(t,J=7.9Hz,1H),4.89(s,2H),4.10(s,2H),2.19(s,3H),2.16(s,3H).[M+1]405.0。
反应方案50
实施例166
步骤1. 4-(N-羟基脒基甲基)-苯甲酸(282)
将4-氰基甲基苯甲酸(2.07g,12.86mmol)、NH2OH.HCl(1.79g,25.71mmol)和氢氧化钾(2.16g,38.57mmol)在70ml乙醇中的悬浮液回流36小时,倒入100ml水内,用浓HCl酸化(pH 5-6)。真空除去EtOH,用另外100ml水处理剩余悬浮液。收集所形成的沉淀,并干燥,获得了本标题化合物282。[M+1]195.1。
步骤2. 4-(5-甲基-[1,2,4]恶二唑-3-基甲基)-苯甲酸(283)
将4-(N-羟基脒基甲基)-苯甲酸282(388mg,2.0mmol)在吡啶(8ml)中的溶液用乙酸酐(0.283ml,3.0mmol)处理。将所得溶液回流6小时,真空蒸发,用水研制剩余固体,通过过滤收集,干燥,通过硅胶柱色谱纯化,依次用EtOAc、EtOAc-MeOH(10∶1)和EtOAc-MeOH(1∶1)洗脱,获得了283(164mg,38%产率)。[M-1]-217.1
步骤3. N-(2-氨基-苯基)-4-(5-甲基-[1,2,4]恶二唑-3-基甲基)-苯甲酰胺
(284)
为了制备本标题化合物284,采用类似于实施例92步骤2中描述的方法,但是用283代替143,获得了本标题化合物284。1H NMR:(DMSO)δ(ppm):9.62(s,1H),7.93(d,J=7.9Hz,2H),7.42(d,J=8.4Hz,1H),7.16(d,J=7.5Hz,1H),6.97(t,J=7.9Hz,1H),6.78(d,J=7.5Hz,1H),6.60(t,J=7.9Hz,1H),4.92(s,2H),4.14(s,2H),2.55(s,3H)。[M+1]+309.2
反应方案51
i:乙酰基丙酮/EtOH;
ii:HOBt/EDCxHCl然后1,2-二氨基苯
实施例167
步骤1:4-(3,5-二甲基-吡唑-1-基)-苯甲酸(285)
将4-肼基-苯甲酸(0.60g,3.95mmol)和乙酰基丙酮(0.405ml,3.95mmol)在乙醇(20ml)中的溶液回流1小时。真空除去乙醇,用水研制剩余固体,通过过滤收集,获得了285(0.71mg,83%产率)。[M-1]-215.1。
步骤2.N-(2-氨基-苯基)-4-(3,5-二甲基-吡唑-1-基)-苯甲酰胺(286)
为了制备本标题化合物286,采用类似于实施例92步骤2中描述的方法,但是用285代替143,以34%的产率获得了本标题化合物286(通过色谱法纯化,用CH2Cl2-甲醇,19∶1洗脱)。1H NMR:(DMSO)δ(ppm):9.73(s,1H);8.09(d,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),7.17(d,J=7.5Hz,1H),6.98(t,J=7.0Hz,1H),6.78(d,J=7.9Hz,1H),6.60(t,J=7.5Hz,1H),6.13(s,1H),4.92(s,2H),2.37(s,3H),2.20(s,3H).[M+1]+303.3
反应方案52
a.2.5%Pd(OAc)2/nBu4NCl(1eq)/KOAc(3eq)/2.5%PPh3/DMF/80℃
b.3-4%Pd(OAc)2/9%PPh3/Ag2CO3(2eq)/CH3CN/80℃
c.LiOH·H2O/THF-H2O(2∶1)
d.1,2-苯二胺/BOP/Et3N/DMF
e.PtO2/H2(1atm)/AcOEt
实施例168
步骤1:2-(3,4,5-三甲氧基-苯基)-2,3-二氢-呋喃(287)
向5-碘-1,2,3-三甲氧基苯(900mg,3.06mmol)和2,3-二氢呋喃(1.16mL,15.3mmol)在无水DMF(8mL)内的溶液中加入PPh3(20mg,0.077mmol)、KOAc(901mg,9.18mmol)、n-Bu4NCl(850mg,3.06mmol)和Pd(OAc)2(17mg,0.077mmol)。将该反应混合物在80℃搅拌18小时。将该反应混合物用AcOEt和水稀释。分离后,将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:20/80),获得了本标题化合物287(311mg,1.32mmol,43%产率)。1H NMR:(300MHz,CDCl3)δ(ppm):6.59(s,2H),6.45(m,1H),5.45(dd,J=10.5,8.4Hz,1H),4.97(m,1H),3.87(s,6H),3.84(s,3H),3.06(m,1H),2.62(m,1H)。
步骤2:4-[5-(3,4,5-三甲氧基-苯基)-2,5-二氢-呋喃-2-基]-苯甲酸乙酯
(288)
向287(200mg,0.846mmol)和4-碘-苯甲酸乙酯(468mg,1.69mmol)在无水乙腈(4mL)内的溶液中加入PPh3(20mg,0.076mmol)、Ag2CO3(467mg,1.69mmol)和Pd(OAc)2(7mg,0.03mmol)。将该反应混合物在80℃搅拌18小时。将该反应混合物经由硅藻土过滤,用AcOEt洗涤。加入水,分离各相。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:30/70),获得了本标题化合物288(280mg,0.728mmol,86%产率)。1H NMR(300MHz,CDCl3)δ(ppm):8.05(d,J=7.5Hz,2H),7.45(d,J=7.5Hz,2H),6.61(s,2H),6.18-5.95(m,4H),4.38(q,J=7.0Hz,2H),3.88(s,6H),3.84(s,3H),1.39(t,J=7.0Hz)。
步骤3:N-(2-氨基-苯基)-4-[5-(3,4,5-三甲氧基-苯基)-2,5-二氢-呋喃-2-
基]-苯甲酰胺(289)
按照类似于实施例1步骤4、5中描述的方法,但是用288代替6,以48%的产率获得了本标题化合物289。1H NMR(DMSO)δ(ppm):8.00(s,1H),7.91(d,J=7.9Hz,2H),7.48(d,J=7.9Hz,2H),7.33(d,J=7.5Hz,1H),7.09(t,J=7.5Hz,1H),6.92-6.82(m,2H),6.61(s,2H),6.14-5.99(m,4H),3.89(s,6H),3.84(s,3H).
实施例169
步骤1:N-(2-氨基-苯基)-4-[5-(3,4,5-三甲氧基-苯基)-四氢-呋喃-2-基]-苯
甲酰胺.(290)
向289(43mg,0.096mmol)在AcOEt(4mL)内的脱气溶液中加入PtO2(3mg,0.01mmol),将该反应混合物在室温于1atm的H2压力下搅拌16小时。用氮气吹扫该反应烧瓶,然后将该反应混合物经由硅藻土过滤,用MeOH洗涤,浓缩。通过快速硅胶色谱将残余粗产物纯化3次(MeOH/DCM:2/98,AcOEt/DCM:30/70和AcOEt/CHCl3:30/70),获得了本标题化合物290(10mg,0.22mmol,23%产率)。1H NMR-(CDCl3)δ(ppm):8.10(s,1H),7.91(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),7.34(d,J=7.5Hz,1H),7.10(t,J=7.5Hz,1H),6.96-6.85(m,2H),6.64(s,2H),5.33(t,J=7.0Hz,1H),5.21(t,J=7.0Hz,1H),3.89(s,6H),3.85(s,3H),2.59-2.40(m,2H),2.09-1.88(m,2H)。
反应方案53
a.三丁基(乙烯基)锡/Pd(PPh3)4/甲苯/100℃
b.m-CPBA/CHCl3/r.t.
c.3,4,5-三甲氧基苯胺/CoCl2/CH3CN
d.TFA/DCM
e.1,1’-羰基二咪唑/DCM/r.t.
f.1,1’-羰基二咪唑/Et3N/甲苯/THF/90℃
实施例169
步骤1:[2-(4-乙烯基-苯甲酰基氨基)-苯基]-氨基甲酸叔丁酯(291)
按照类似于实施例143步骤2中描述的方法,但是用184代替221,以90%的产率获得了本标题化合物291,为深黄色油状物。1H NMR:(300MHz,CDCl3)δ(ppm):9.18(s,1H),7.94(d,J=8.5Hz,2H);7.77(d,J=7.5Hz,1H),7.49(d,J=8.5Hz,2H),7.30-7.10(m,3H),6.89(s,1H),6.77(dd,J=17.4,11.0Hz,1H),5.87(d,J=17.4Hz,1H),5.39(d,J=11.0Hz,1H),1.52(s,9H)。
步骤2:[2-(4-环氧乙烷基-苯甲酰基氨基)-苯基]-氨基甲酸叔丁酯(292)
向291(4.1g,12.1mmol)在无水CHCl3(60mL)内的溶液中加入m-CPBA 70%(3.6g,14.5mmol)。将该反应混合物在室温搅拌5小时,然后再加入m-CPBA(0.6g,2.4mmol),继续搅拌1小时。再加入一定量的m-CPBA(0.6g,2.4mmol),将该反应混合物搅拌16小时。加入氯仿和10%NaHCO3溶液,分离各相。将有机层用水和盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:1/3),获得了本标题化合物292(2.86g,8.07mmol,66%产率)。1H NMR(300MHz,CDCl3)δ(ppm):9.20(s,1H),7.95(d,J=8.1Hz,2H),7.86-7.75(m,1H),7.38(d,J=8.1Hz,2H),7.26-7.10(m,3H),6.84-6.70(m,1H),3.93(t,J=3.0Hz,1H),3.20(t,J=5.0Hz,1H),2.80(dd,J=5.0,3.0Hz,1H),1.52(s,9H)。
步骤3:(2-{4-[1-羟基-2-(3,4,5-三甲氧基-苯基氨基)-乙基]-苯甲酰基氨
基}-苯基)-氨基甲酸叔丁酯(295)和(2-{4-[2-羟基-1-(3,4,5-三甲氧基-苯
基氨基)-乙基]-苯甲酰基氨基}-苯基)-氨基甲酸叔丁酯(293)
向CoCl2(8mg,0.06mmol)在无水乙腈(10mL)内的搅拌着的溶液中加入292(1g,2.8mmol),然后加入3,4,5-三甲氧基苯胺(516mg,2.8mmol),让该反应混合物在室温反应16小时,然后将其在60℃加热5小时。将该反应混合物在AcOEt与水之间分配,分离各相。用盐水洗涤有机层,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(AcOEt/己烷:1/1),获得了化合物s293和295(合并的:1.07g,1.99mmol,71%产率,292/295比例=5/1),通过快速硅胶色谱分离(AcOEt/己烷:1/1)。1H NMR(300MHz,CDCl3)δ(ppm):
化合物292:9.21(s,1H),7.92(d,J=8.1Hz,2H),7.73(d,J=6.6Hz,1H),7.46(d,J=8.1Hz,2H),7.28-7.10(m,3H),6.90(s,1H),5.83(s,2H),4.54-4.44(m,1H),3.93(dd,J=8.1,3.9Hz,1H),3.84-3.72(m,1H),3.71(s,3H),3.66(s,6H),1.47(s,9H).
化合物295:9.22(s,1H),7.91(d,J=8.1Hz,2H),7.77(d,J=7.2Hz,1H),7.46(d,J=8.1Hz,2H),7.30-7.21(m,3H),6.88(s,1H),6.15(s,2H),5.16-5.06(m,1H),3.81(s,6H), 3.78(s,3H),3.50-3.25(m,2H),1.51(s,9H)。
步骤4:N-(2-氨基-苯基)-4-[2-羟基-1-(3,4,5-三甲氧基-苯基氨基)-乙基]-
苯甲酰胺(294)
按照类似于实施例42步骤3中描述的方法,但是用293代替46,以50%的产率获得了本标题化合物294。1H NMR(DMSO)δ(ppm):8.36(s,1H),7.74(d,J=6.9Hz,2H),7.30(d,J=7.8Hz,2H),7.1 8(d,J=6.9Hz,1H),7.00(t,J=7.2Hz,1H),6.72(m,2H),5.69(s,2H),4.34(m,1H),4.02-3.52(m,2H),3.66(s,3H),3.57(s,6H)。
实施例170
步骤1:N-(2-氨基-苯基)-4-[2-氧代-3-(3,4,5-三甲氧基-苯基)-恶唑烷-4-
基]-苯甲酰胺(296)
向293(200mg,0.372mmol)在甲苯(5mL)和THF(1mL)内的溶液中加入1,1’-羰基二咪唑(72mg,0.45mmol),然后加入Et3N(156μL,1.12mmol),将该混合物在室温搅拌5小时,然后在90℃搅拌48小时。将该反应混合物用AcOEt稀释,加入饱和NH4Cl溶液,分离各相。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(DCM/AcOEt:80/20),获得了所需化合物(120mg,0.21mmol,57%产率)。1H NMR(DMSO)δ(ppm):9.37(s,1H),7.98(d,J=8.1Hz,2H),7.76(d,J=7.5Hz,1H),7.41(d,J=8.1Hz,2H),7.25-15(m,3H),6.88(s,1H),6.61(s,2H),5.40(dd,J=8.7,6.0Hz,1H),4.79(t,J=8.7Hz,1H),4.19(dd,J=8.7,6.01H),3.75(s,3H),3.72(s,6H),1.47(s,9H)。
按照类似于实施例42步骤3中描述的方法,但是用上面的化合物代替46,以81%的产率获得了本标题化合物296。1H NMR(DMSO)δ(ppm):8.03(s,1H),7.91(d,J=8.1Hz,2H),7.41(d,J=8.1Hz,2H),7.30(d,J=7.5Hz,1H),7.07(t,J=7.5Hz,1H),6.82(d,J=7.5Hz,2H),6.61(s,2H),5.40(dd,J=8.7,6.0Hz,1H),4.78(t,J=8.7Hz,1H),4.18(dd,J=8.7,6.0Hz,1H),3.75(s,3H),3.71(s,6H)。
实施例171
步骤1:N-(2-氨基-苯基)-4-[2-氧代-3-(3,4,5-三甲氧基-苯基)-恶唑烷-5-
基]-苯甲酰胺(297)
向295(130mg,0.242mmol)在DCM(2mL)内的溶液中加入1,1’-羰基二咪唑(47mg,0.29mmol),将该混合物在室温搅拌16小时。减压除去DCM,加入AcOEt和饱和NH4Cl溶液,并分离各相。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(己烷/AcOEt:30/70),获得了所需化合物(80mg,0.14mmol,58%产率)。1H NMR(DMSO)δ(ppm):9.39(s,1H),8.04(d,J=8.1Hz,2H),7.84(d,J=7.5Hz,1H),7.52(d,J=8.1Hz,2H),7.26-7.12(m,3H),6.86-6.74(m,3H),5.70(t,J=8.4Hz,1H),4.24(t,J=8.7Hz,1H),3.97-3.87(m,1H),3.87(s,6H),3.82(s,3H),1.52(s,9H)。
按照类似于实施例42步骤3中描述的方法,但是用上面的化合物代替46,以94%的产率获得了本标题化合物297。1H NMR(DMSO)δ(ppm):8.38(s,1H),7.97(d,J=7.5Hz,2H),7.47(d,J=8.1Hz,2H),7.35(d,J=7.0Hz,1H),7.08(t,J=7.0Hz,1H),6.97-6.87(m,2H),6.79(s,2H),5.66(t,J=8.1Hz,1H),4.41(t,J=9.0Hz,1H),3.9 1(t,J=7.8Hz,1H),3.86(s,6H),3.82(s,3H)。
反应方案54
a.CeCl3七水合物/NaN3/CH3CN-H2O(9∶1)/回流
b.H2/Pd/C(10%)/MeOH
c.3,4-二甲氧基苯甲酰氯/Et3N/DCM/-20℃
d.Burgess试剂/THF/70℃
e.TFA/DCM
反应方案55
实施例172
步骤1:{2-[4-(1-叠氮基-2-羟基-乙基)-苯甲酰基氨基]-苯基}-氨基甲酸
叔丁酯(298)和{2-[4-(2-叠氮基-1-羟基-乙基)-苯甲酰基氨基]-苯基}-氨
基甲酸叔丁酯(302)
向292(210mg,0.59mmol)在乙腈(9mL)和水(1mL)内的溶液中加入CeCl3七水合物(110mg,0.296mmol),然后加入NaN3(42mg,0.65mmol)。将该反应混合物回流3小时,然后减压除去乙腈。就残余物用DCM稀释,用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱法纯化(AcOEt/己烷:1/1),获得了本标题化合物298和302的1∶1混合物(合并的:187mg,0.47mmol,80%产率),通过快速硅胶色谱分离(AcOEt/己烷:2/5)。
化合物298:1H NMR:(300MHz,CDCl3/CD3OD)δ(ppm):7.95(d,J=8.1Hz,2H),7.70-7.63(m,1H),7.43(d,J=8.1Hz,2H),7.36-7.29(m,1H),7.24-7.14(m,2H),4.69(dd,J=7.5,4.8Hz,1H),3.80-3.65(m,2H),1.49(s,9H).
化合物302:1H NMR:(300MHz,CDCl3)δ(ppm):9.28(s,1H),7.86(d,J=8.4Hz,2H),7.71(d,J=7.5Hz,1H),7.38(d,J=8.4Hz,2H),7.25-7.08(m,3H),7.01(s,1H),4.87(dd,J=6.9,5.1Hz,1H),3.47-3.38(m,2H),3.32-3.21(bs,1H),1.50(s,9H)。
步骤2:{2-[4-(1-氨基-2-羟基-乙基)-苯甲酰基氨基]-苯基}-氨基甲酸叔
丁酯(299)
向298(156mg,0.39mmol)在MeOH(2mL)内的溶液中加入Pd/C10%(20mg,0.02mmol)。将该反应混合物在1atm的H2压力下于室温搅拌16小时,然后用氮气吹扫。通过经由硅藻土过滤除去钯,将MeOH减压蒸发,获得了本标题化合物299(88mg,0.24mmol,60%产率),其不用纯化直接使用。1H NMR(300MHz,CDCl3)δ(ppm):9.24(s,1H),7.90(d,J=7.8Hz,2H),7.71(d,J=6.6Hz,1H),7.40(d,J=7.8Hz,2H),7.31-7.10(m,3H),7.06-6.94(m,1H),4.12(dd,J=7.5,4.5Hz,1H),3.74(dd,J=7.8,5.4Hz,1H),3.64-3.51(m,1H),2.64(s,3H),1.49(s,9H)。
步骤3:(2-{4-[1-(3,4-二甲氧基-苯甲酰基氨基)-2-羟基-乙基]-苯甲酰基
氨基}-苯基)-氨基甲酸叔丁酯(300)
在-20℃,向299(88mg,0.24mmol)在无水DCM(2mL)内的搅拌着的溶液中加入3,4-二甲氧基苯甲酰氯(50mg,0.25mmol),然后加入Et3N(37μL,0.26mmol)。让该反应混合物温热至室温,然后搅拌48小时。加入饱和NH4Cl溶液,然后加入DCM,并分离各相。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(MeOH/DCM:4/96),获得了本标题化合物300(91mg,0.17mmol,71%产率)。1H NMR(300MHz,CDCl3)δ(ppm):9.29(s,1H),7.81(d,J=8.1Hz,2H),7.65-7.58(m,1H),7.46(m,7H),6.80(d,J=8.1Hz,1H),5.20-5.10(m,1H),3.95-3.78(m,2H),3.88(s,3H)3.84(s,3H),1.47(s,9H).
步骤4:N-(2-氨基-苯基)-4-[2-(3,4-二甲氧基-苯基)-4,5-二氢-恶唑-4-基]-
苯甲酰胺(301)
向300(91mg,0.17mmol)在无水THF(2mL)内的溶液中加入Burgess试剂(44mg,0.19mmol),将该混合物在70℃搅拌2小时。将该反应混合物在AcOEt与水之间分配,并分离各相。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。通过快速硅胶色谱纯化残余粗产物(MeOH/DCM:3/97),获得了Boc-保护的中间体(75mg,0.14mmol,85%产率)。1H NMR(CDCl3)δ(ppm):9.31(s,1H),7.94(d,J=8.4Hz,2H),7.72(d,J=7.5Hz,1H),7.66(d,J=8.1Hz,1H),7.61(s,1H),7.39(d,J=8.1Hz,2H),7.27(d,J=6.0Hz,1H),7.23-7.08(m,3H),6.93(d,J=8.7Hz,1H),5.43(t,J=9.0Hz,1H),4.84(t,J=9.3Hz,1H),4.26(t,J=8.4Hz,1H),3.95(s,3H),3.94(s,3H),1.50(s,9H)。
按照类似于实施例42步骤3中描述的方法,但是用上面的化合物代替46,以82%的产率获得了本标题化合物301。1H NMR(CDCl3)δ(ppm):8.01(s,1H),7.89(d,J=7.9Hz,2H),7.65(dd,J=8.4,1.5Hz,1H),7.60(d,J=1.5Hz,1H),7.41(d,J=7.9Hz,2H),7.32(d,J=7.9Hz,1H),7.08(t,J=6.6Hz,1H),6.92(d,J=8.4Hz,1H),6.84(d,J=7.9Hz,2H),5.43(dd,J=9.7,8.4Hz,1H),4.83(dd,J=9.7,8.4Hz,1H),4.25(t,J=8.1Hz,1H),3.94(s,3H),3.93(s,3H)。
实施例173
步骤1:{2-[4-(2-氨基-1-羟基-乙基)-苯甲酰基氨基]-苯基}-氨基甲酸叔
丁酯(303)
采用实施例172步骤2中描述的相同方法,由302以94%的产率获得了本标题化合物303。化合物303不用进一步纯化直接用于下一步骤。
步骤2:2-{4-[2-(3,4-二甲氧基-苯甲酰基氨基)-1-羟基-乙基]-苯甲酰基氨
基}-苯基)-氨基甲酸叔丁酯(304)
采用实施例172步骤3中描述的相同方法,由303和3,4-二甲氧基苯甲酰氯以40%的产率获得了本标题化合物304。1H NMR(CDCl3)δ(ppm):9.31(s,1H),7.78(d,J=8.1Hz,2H),7.68(d,J=6.9Hz,1H),7.38(d,J=1.8Hz,1H),7.33(d,J=8.1Hz),7.30-7.06(m,4H),7.00-6.93(m,1H),6.79(d,J=8.4Hz,1H),4.89-4.82(m,1H),3.88(s,3H),3.86(s,3H),3.85-3.73(m,1H),3.44-3.32(m,1H),1.46(s,9H).
步骤3:N-(2-氨基-苯基)-4-[2-(3,4-二甲氧基-苯基)-4,5-二氢-恶唑-5-基]-
苯甲酰胺(305)
按照类似于实施例172步骤4、5中描述的方法,但是用304代替300,以63%的产率获得了本标题化合物305。1H NMR(CDCl3)δ(ppm):8.02(s,1H),7.93(d,J=8.1Hz,2H),7.63(dd,J=8.4,1.8Hz,1H),7.60(s,1H),7.44(d,J=8.1Hz,2H),7.33(d,J=7.5Hz,1H),7.09(t,J=7.5Hz,1H),6.91(d,J=8.1Hz,1H),6.85(d,J=8.1Hz,2H),5.74(dd,J=10.0,7.8Hz,1H),4.51(dd,J=14.5,10.0Hz,1H),4.00-3.90(m,7H)。
反应方案57
实施例178
步骤1:[2-(4-甲酰基-苯甲酰基氨基)-苯基]-氨基甲酸叔丁酯(315)
向4-羧基苯甲醛(6g,40mmol)在二氯甲烷(10mL)内的悬浮液中加入亚硫酰氯(4.1mL,56mmol,1.4当量),然后滴加DMF(1mL)。将该混合物回流4小时,将过量亚硫酰氯和DMF减压除去。向(2-氨基苯基)-氨基甲酸叔丁酯(8.32g,40mmol,1当量)在二氯甲烷(80mL)内的于0℃搅拌着的溶液中加入4-甲酰基苯甲酰氯在二氯甲烷(20mL)中的悬浮液,然后加入二异丙基乙基胺(3.61mL,20mmol,1当量)。将该混合物在0℃搅拌30分钟,然后在室温搅拌30分钟。就该残余粗产物用二氯甲烷(300mL)稀释,用水洗涤。将合并的有机层干燥(MgSO4),过滤并真空浓缩。通过硅胶柱色谱纯化该残余粗产物(用20%乙酸乙酯在己烷中的混合物洗脱),获得了6.1g(45%产率)N-酰苯胺315。1H NMR(CDCl3):δ10.18(s,1H),9.64(brs,1H),8.20(d,J=7.9Hz,2H),8.06(d,J=7.9Hz,2H),7.96(d,J=7.9Hz,1H),7.28-7.38(m,1H),7.24(d,J=4.4Hz,1H),6.84(s,1H),6.81(d,J=8.8Hz,1H),1.58(s,9H)。
步骤2:(2-{4-[(3,4-二甲氧基苯基氨基)-甲基]-苯甲酰基氨基}-苯基)-氨
基甲酸叔丁酯(316)
按照类似于实施例144步骤3中描述的方法,但是用上面的化合物代替226,以定量产率获得了本标题化合物316。1H NMR(CDCl3):δ9.21(brs,1H),8.01(d,J=7.9Hz,2H),7.86(d,J=7.0Hz,1H),7.55 (d,J=8.3Hz,2H),7.20-7.34(m,3H),6.89(brs,1H),6.81(d,J=8.8Hz,1H),6.37(d,J=2.2Hz,1H),6.23(dd,J=2.6,8.3Hz,1H),4.45(s,2H),3.89(s,3H),3.88(s,3H),1.58(s,9H)。
步骤3:N-(2-氨基苯基)-4-[1-(3,4-二甲氧基苯基)-3-(4-甲基硫基苯基)-脲
基甲基]-苯甲酰胺317
向N-酰苯胺316(500mg,1.047mmol)在氯仿/THF(1∶1,10mL)内的溶液中加入异氰酸酯(169μL,1.205mmol,1.15当量)。将该混合物在室温于氮气氛下搅拌过夜,将该残余粗产物浓缩,通过硅胶柱色谱纯化(用40%乙酸乙酯在己烷中的混合物洗脱),获得了606mg(90%产率)所需化合物。1H NMR(CDCl3):δ9.25(s,1H),7.96(d,J=8.3Hz,2H),7.85(d,J=7.0Hz,1H),7.44(d,J=8.3Hz,2H),7.20-7.36(m,6H),6.93(d,J=3.5Hz,1H),6.90(s,1H),6.75(dd,J=2.2,8.3Hz,1H),6.68(dd,J=2.6Hz,1H),6.33(s,1H),5.0(s,2H),3.97(s,3H),3.85(s,3H),2.51(s,3H),1.57(s,9H)。
按照类似于实施例42步骤3中描述的方法,但是用上面的化合物代替46,以85%的产率获得了本标题化合物317。1H NMR(DMSO-d6):δ.10.14(brs,1H),7.99(d,J=7.9Hz,2H),7.93(s,1H),7.49(d,J=8.35Hz,4H),7.39(d,J=7.5Hz,1H),7.10-7.30(2m,5H),6.97(dd,J=2.2,8.35Hz,1H),6.77(dd,J=2.2,8.35Hz,1H),5.02(s,2H),3.80(s,3H),3.77(s,3H),2.48(s,3H)。
反应方案58
实施例179
步骤1:N-(2-氨基-苯基)-6-氯-烟酰胺(318)
按照实施例42步骤2中描述的方法,由80%的产率获得了本标题化合物318。LRMS=计算值:246.69,实测值:247.7。
步骤2:N-(2-氨基-苯基)-6-(喹啉-2-基硫基)-烟酰胺(319)
按照实施例45步骤1中描述的方法,但是用318代替3,4,5-三甲氧基苄基胺,以20%的产率获得了本标题化合物319。1H NMR:(CD3OD-d6)δ(ppm):9.08(d,J=1.9Hz,1H),8.35-8.25(m,2H),7.99-7.56(m,7H),7.23(dd,J=1.2,7.9Hz,1H),7.12(dd J=1.4,7.9,14.0Hz,1H),6.93(dd,J=1.2,8.0Hz,1H),6.79(ddd,J=1.4,7.7,13.7Hz,1H)。
反应方案59
步骤1:4-[(4-吗啉-4-基-苯基氨基)-甲基]-苯甲酸(402a).
在室温将4-甲酰基苯甲酸(2.53g;16.8mmol;1当量)、4-吗啉苯胺(3g;16.8mmol;1当量)和Bu2SnCl2(510mg;1.68mmol;0.1当量)在无水THF(20ml)中的悬浮液用PhSiH3(3.31ml;16.8mmol;1当量)处理12小时。将该反应过滤,用MeOH洗涤固体产物。该反应的产量是5.25g(99%)。LRMS:计算值:312.37;实测值:313.2。
步骤2:N-(2-氨基-苯基)-4-[(4-吗啉-4-基-苯基氨基)-甲基]-苯甲酰胺
(402)
向酸402a(2.61g;8.36mmol;1当量)、1,2-苯二胺(903mg;8.36mmol;1当量)和BOP(3.70g;8.36mmol;1当量)在无水DMF(20ml)内的溶液中加入Et3N(4.64ml;33.4mmol;4当量)。搅拌过夜后,将大部分DMF减压除去,通过色谱法纯化(Hex∶EtAcO:1∶2/EtAcO)。以70%的产率获得了晶体402(2.35g)。1H-NMR(300.07MHz;DMSO-d6)δ(ppm):9.65(s,1H),7.97(d,J=7.9,2H),7.53(d,J=7.9,2H),7.22(d,J=7.5,1H),7.03(dd,J=7.0,7.5,1H),6.83(d,J=7.9,1H),6.77(d,J=8.8,2H),6.65(dd,J=7.5,7.0,1H),6.57(d,J=8.8,2H),4.93(bs,2H),4.36(d,J=5.7,2H),3.75(m,4H),2.93(m,4H).LRMS:计算值:402.49;实测值:403.4。
反应方案60
实施例283a
步骤1.4-[(3.4-二甲氧基苯基氨基)-甲基]-苯甲酸(424a)
在50mL烧瓶内,将4-氨基藜芦醚(1.53g,10mmol)、4-甲酰基-苯甲酸(1.50g,10mmol)、二氯化二丁基锡(304mg,1mmol)、苯基甲硅烷(2.47ml,20mmol)在无水THF(10mL)和DMA(10ml)中的混合物于室温搅拌过夜。除去溶剂后,将该残余粗产物溶解在乙酸乙酯(100ml)中,然后用饱和NaHCO3水溶液(50ml×3)洗涤。将合并的水层用6%NaHSO4酸化至pH=4。将所得白色悬浮液过滤,然后用水(5ml×3)洗涤滤饼。用冷冻干燥器将滤饼干燥,获得所需的酸(1.92g,67%),为白色固体产物。LRMS=288(MH)+。
步骤2.N-(2-氨基苯基)-4-[(3,4-二甲氧基苯基氨基)-甲基]-苯甲酰胺
(424b)
在150ml烧瓶内,将酸(1.92g,6.69mmol)、苯并三唑-1-基氧基-三(二甲基氨基)磷六氟磷酸盐(BOP,3.26g,7.37mmol)÷三乙胺(1.87ml,13.4mmol)、邻苯二胺(1.30g,12.02mmol)在二氯甲烷(67ml)中的混合物于室温搅拌2小时。除去溶剂后,将残余粗产物溶解在EtOAc(100ml)中,然后用饱和NaHCO3溶液和盐水50ml洗涤。将合并的有机层用Na2SO4干燥,将滤液浓缩至干。通过色谱法纯化粗产物(二氧化硅柱,55%-70%EtOAc在1%Et3N的己烷溶液中的混合物),然后将所需级份浓缩至干。将残余物悬浮在最少量的乙酸乙酯中,然后过滤,获得了终产物(1.49g,59%)。1H NMR(300MHz,DMSO-d6)δ(ppm):9.65(s,1H),7.98(d,J=7.9Hz,2H),7.54(d,J=7.9Hz,2H),7.22(d,J=7.9Hz,1H),7.02(dd,J=7.9,7.9Hz,1H),6.83(d,J=7.9Hz,1H),6.72(d,J=8.79Hz,1H),6.45(dd,J=7.5,7.5Hz,1H),6.39(d,J=2.2Hz,1H),6.01-6.08(m,2H),4.94(s,2H,NH2),4.36(d,J=6.16Hz,2H),3.72(s,3H),3.65(s,3H)。
实施例283b
步骤1:N-(4-氨基噻吩-3-基)-4-[(3,4-二甲氧基苯基氨基)-甲基]-苯甲酰
胺:
将酸424a(1040mg;3.62mmol);3,4-二氨基噻吩二盐酸盐(1017mg;5.44mmol;1.50当量)和BOP(1770mg;4.0mmol;1.1当量)悬浮在MeCN中,用三乙胺(4mL;29mmol)处理,在室温搅拌18小时;浓缩,通过硅胶柱色谱纯化(用50%EtOAc在DCM中的混合物洗脱),获得了527mg(1.37mmol;38%产率)化合物424c,其纯度为90%。1H-NMR(300.07MHz;DMSO-d6)δ(ppm):8.56(s,1H),7.78(d,J=7.9Hz,2H),7.43(d,J=3.5Hz,1H),7.38(d,J=7.9Hz,2H),6.73(d,J=8.8Hz,1H),6.33(d,J=3.5Hz,1H),6.58(d,J=2.6Hz,1H),6.13(dd,J=2.6,8.3Hz,1H),4.33(s,2H),3.80(s,3H),3.78(s,3H).LRMS:计算值:383.4642;实测值:384.2(M+H);406.2(M+Na)和192.6(M+2H)/2。
反应方案61
步骤1:甲基-(5-硝基苯并噻唑-2-基)-胺(456a)
将2-氟-5-硝基苯胺(861mg;5.52mmol;1.02当量);Im2CS(960.3mg;5.39mmol)和无水K2CO3(1.45g)的混合物悬浮在无水DME(10mL)中,在室温于氮气氛下搅拌90分钟。将该黄色悬浮液用DME(10mL)稀释以增加流动性,然后加入40%MeNH2在水中的溶液(4.0mL;46.5mmol;8.6当量)。将该系统加热至65℃,在该温度下搅拌3.5小时,冷却,用乙酸乙酯稀释,用饱和NaCl洗涤(X2)。常规后处理操作之后,经由硅胶柱色谱纯化该深色粗产物混合物(依次用50%EtOAc在己烷中的混合物和5%MeOH在DCM中的混合物洗脱),获得了836.8mg(4.0mmol;72%产率)化合物456a。
步骤2:N-甲基-苯并噻唑-2,5-二胺(456b)
将硝基化合物456a(593mg;2.83mmol);SnCl2(4.02g;20.8mmol;7.35当量)和NH4OAc(4.5g)悬浮在THF∶MeOH∶H2O=1∶1∶1(60mL)中,在70℃搅拌2小时,冷却,用乙酸乙酯稀释,依次用饱和NaHCO3和盐水洗涤;干燥(MgSO4),过滤并浓缩。残余物(443mg;2.43mmol;87%)表现出一致的光谱以及适于合成目的的纯度,因此不用进一步纯化直接用于下一步骤。
步骤3:4-[(2-甲基氨基苯并噻唑-5-基氨基)-甲基]-苯甲酸(456c)
将苯胺456b(509mg;2.8mmol);4-甲酰基苯甲酸(426mg;2.8mmol)和Bu2SnCl2(198mg;0.65mmol;23%mol)在DME(14mL)中的溶液于室温搅拌3分钟,用纯净的PhSiH3(0.6mL;4.7mmol;1.7mmol)处理,让其反应18小时。用MeOH处理该过量硅烷后,将该混合物浓缩,通过硅胶柱色谱纯化(洗脱用5%MeOH在DCM中的溶液),获得了729mg(2.54mmol;91%产率)酸456c。
步骤4:N-(2-氨基苯基)-4-[(2-甲基氨基苯并噻唑-5-基氨基)-甲基]-苯
甲酰胺(456)
将酸456c(729mg;2.54mmol)、1,2-苯二胺(376mg;3.47mmol;1.36当量)和BOP(1.43g;3.23mmol;1.27当量)的混合物溶解在乙腈(15mL)中,用三乙胺(3mL)处理,并搅拌过夜。用甲醇处理该反应混合物,浓缩,通过硅胶柱色谱纯化(40%EtOAc在DCM中的混合物),将所得产物从DCM中结晶,获得了358mg(0.88mmol;35%产率)纯的化合物456。1H-NMR(300MHz;DMSO-d6)δ(ppm):9.57(s,1H),7.92(d,J=7.9Hz,2H),7.66(d,J=4.8Hz,1H),7.48(d,J=8.3Hz,2H),7.26(d,J=8.3Hz,1H),7.15(d,J=7.9Hz,1H),6.95(t,J=7.5Hz,1H),6.76 4.87(bs,2H),6.58(t,J=7.5Hz,1H),6.54(d,J=1.8Hz,1H),6.13(dd,J=1.8,8.3Hz,1H),6.27(t,J=5.7Hz,1H),4.87(bs,2H),4.36(d,J=5.7Hz,2H),2.85(d,J=4.8Hz,3H).LRMS:计算值:403.5008,实测值:404.2(M+NH)和202.6(M+2H)/2。
反应方案62
实施例235
步骤1:4-(5-甲氧基-1H-苯并咪唑-2-基-硫基甲基)-苯甲酸甲酯(376a)
向5-甲氧基-2-硫代苯并噻唑(2.00g,11.1mmol)在无水DMF(40ml)内的溶液中加入4-(溴甲基)-苯甲酸甲酯(2.54g,11.1mmol)。将该反应混合物在室温搅拌16小时。将DMF蒸发,把残余物在乙酸乙酯中研制30分钟,然后过滤,并干燥。分离出HBr盐形式的所需化合物:98%产率,(4.44g)。1H NMR:(DMSO)δ(ppm):7.90(d,J=8.8Hz,2H),7.56-7.52(m,3H),7.09(d,J=2.2Hz,1H),7.01(dd,J=8.8,2.2Hz,1H),4.73(s,2H),3.82(s,6H).MS:(计算值)328.1,(实测值),329.2(MH)+。
步骤2:4-(5-甲氧基-1H-苯并咪唑-2-基-硫基甲基)-苯甲酸(376b)
将LiOH.H2O(1.02g,24.4mmol)在水(15ml)中的溶液加到376a(3.99g,9.75mmol)在THF(10ml)内的悬浮液中。将该反应混合物在室温搅拌16小时。用HCl 1M将该反应混合物酸化至pH 4。在0℃将所需产物研制20分钟,然后过滤,并干燥。获得了化合物376b,为白色粉末(100%产率,3.05g)。1H NMR:(DMSO)δ(ppm):12.85(bs,1H),7.86(d,J=8.1Hz,2H),7.53(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,1H),6.97(d,J=2.2Hz,1H),6.76(dd,J=8.8,2.2Hz,1H),4.60(s,2H),3.82(s,3H).MS:(计算值)314.1,(实测值),315.1(MH)+。
步骤3:N-(2-氨基-苯基)-4-(5-甲氧基-1H-苯并咪唑-2-基-硫基申基)-苯甲
酰胺(376)
按照实施例1步骤5中描述的方法,但是用4-(5-甲氧基-1H-苯并咪唑-2-基-硫基甲基)-苯甲酸2代替7,获得了本标题化合物376,为白色粉末:36%产率(933mg)。1H NMR:(DMSO)δ(ppm):12.42(bs,1H),9.57(bs,1H),7.89(d,J=8.1Hz,2H),7.55(d,J=8.1Hz,2H),7.34(d,J=8.8Hz,1H),7.14(d,J=7.3Hz,1H),6.98-6.93(m,2H),6.77-6.55(m,2H),6.58(dd,J=7.3,7.3Hz,1H),4.87(s,2H),4.59(s,2H),3.77(s,3H).MS:(计算值)404.1,(实测值),405.4(MH)+。
实施例180-328
实施例180-327(化合物320-468)是用实施例85-179中描述的制备化合物126-319的相同方法(反应方案11-58)制得的。
实施例329-344
实施例329-344(化合物470-485)是用实施例1-143中描述的制备化合物8-224的相同方法(反应方案1-32)制得的。
反应方案63
实施例345
步骤1:3-(4-溴-苯基)-丙烯酸甲酯(486)
在0℃于氮气氛下,向无水i-Pr2NH(758μl,5.40mmol)在无水THF(25ml)内的搅拌着的溶液中缓慢地加入n-BuLi溶液(2.22ml,5.54mmol,2.5M在己烷中的溶液)。30分钟后,将LDA冷却至-78℃,滴加无水乙酸甲酯(430μl,5.40mmol)。30分钟后,缓慢地加入4-溴苯甲醛(500mg,2.70mmol)在无水THF(10ml)中的溶液。30分钟后,加入2-氯-4,6-二甲氧基-1,3,5-三嗪(569mg,3.24mmol)在无水THF(15ml)中的溶液。然后让该混合物温热至室温并保持过夜。形成了悬浮液。将该反应混合物倒入饱和NH4Cl水溶液内,并用AcOEt稀释。分离后,将有机层依次用H2O和盐水洗涤,用MgSO4干燥,过滤并浓缩。通过快速硅胶色谱纯化粗产物(AcOEt/己烷:10/90),获得了本标题产物486(394mg,1.9mmol,61%产率),为无色固体结晶。1H NMR(300MHz,CDCl3)δ(ppm):7.63(d,J=16.2Hz,1H),AB系统(δA=7.53,δB=7.39,J=8.4Hz,4H),6.43(d,J=15.8Hz,1H),3.82(s,3H)。
步骤2:3-[4-(3,4,5-三甲氧基-苯基氨基)-苯基]-丙烯酸甲酯(487)
用氮气将Cs2CO3(378mg,1.16mmol)、Pd(OAc)2(6mg,0.025mmol)、(rac)-BINAP(23mg,0.037mmol)的混合物吹扫10分钟。分别加入486(200mg,0.83mmol)、3,4,5-三甲氧基苯胺(182mg,0.99mmol)和无水甲苯(5ml)。将该反应混合物在100℃于氮气氛下加热24小时。然后让其冷却至室温,用AcOEt稀释,依次用饱和NaHCO3水溶液、H2O、饱和NH4Cl、H2O和盐水洗涤,用无水MgSO4干燥,过滤并浓缩。然后通过快速硅胶色谱纯化该残余粗产物(AcOEt/己烷:40/60),获得了本标题化合物487(280mg,0.82mmol,98%产率),为黄色油状物。1H NMR(300MHz,CDCl3)δ(ppm):7.64(d,J=16.2Hz,1H),7.43(bd,J=7.9Hz,2H),7.12-6.86(m,2H),6.60-6.20(m,3H,included at 6.29,d,J=15.8Hz),3.84(s,9H),3.80(s,3H)。
步骤3:N-(2-氨基-苯基)-3-[4-(3,4,5-三甲氧基-苯基氨基)-苯基]-丙烯酰
胺(488)
采用与实施例1步骤4和5相同的方法,在2个步骤中由487制得了本标题化合物488。1H NMR(300MHz,DMSO-d6)δ(ppm):9.29(s,1H),8.48(s,1H),7.60-7.42(m,3H),7.38(d,J=7.5Hz,1H),7.12(d,J=8.4Hz,2H),6.94(t,J=7.5Hz,1H),6.78(d,J=7.9Hz,1H),6.71(d,J=15.8Hz,1H),6.61(t,J=7.1Hz,1H),6.47(s,2H),4.97(s,2H),3.79(s,6H),3.66(s,3H)。
反应方案64
实施例346
步骤1:3-(4-甲酰基-3-甲氧基-苯基)-丙烯酸叔丁酯489
采用实施例53步骤1中描述的方法,但是用4-羟基-2-甲氧基-苯甲醛代替84,然后采用实施例42步骤2中描述的方法,但是用上面的化合物代替42,以29%的产率获得了本标题化合物489。LRMS=计算值:262,实测值:263.2(M+H+)。
步骤2:3-{3-甲氧基-4-[(3,4,5-三甲氧基-苯基氨基)-甲基]-苯基}-丙烯酸
叔丁酯490
按照实施例144步骤3中描述的方法,但是用489代替4-甲酰基苯甲醛,以69%的产率获得了本标题化合物490。LRMS=计算值:429,实测值:430.5(M+H+)。
步骤3:N-(2-氨基-苯基)-3-{3-甲氧基-4-[(3,4,5-三甲氧基-苯基氨基)-甲
基]-苯基}-丙烯酰胺491
按照实施例42步骤3、4中描述的方法,但是用490代替46,以67%的产率获得了本标题化合物491。1H NMR(CDCl3),δ(ppm):8.08(s,1H),7.74(d,J=15.4Hz,1H),7.30(m,1H),7.06(m,3H);6.80(m,3H),6.70(d,J=15.4Hz,1H),5.98(s,2H),4.40(s,2H);4.12(bs,3H),3.94(s,3H),3.84(s,3H),3.77(s,6H)。
反应方案65
实施例436
步骤1:5-甲基-苯并呋喃-2-甲酸甲酯(583)
将5-甲基水杨醛(1.0mg,7.5mmol)、K2CO3(1.55g,11.0mmol)和Bu4NBr(322mg,1mmol)在甲苯(30ml)中的搅拌着的悬浮液用溴丙二酸二甲酯(1.06ml,8.0mmol)处理。用迪安斯榻克分水器将该悬浮液加热回流20小时。将该棕色悬浮液冷却至25℃,并真空浓缩。将残余物置于DCM中,并过滤。将滤液用H2O、1N NaOH和盐水洗涤。用硫酸镁将有机层干燥,过滤并浓缩。通过柱色谱法纯化残余粗产物(10%乙酸乙酯/己烷),获得了本标题化合物583(600mg,42%产率)。LRMS:190.2(计算值);191.1(实测值)。
步骤2:5-溴甲基-苯并呋喃-2-甲酸甲酯(585)
将583(500mg,2.63mmol)、N-溴琥珀酰亚胺(561mg,3.15mmol)和1,1’-偶氮二(环己烷甲腈)(Vazo)(63mg,0.26mmol)在15ml CCl4中的混合物加热回流过夜。将该混合物冷却至室温,加入水,用DCM萃取。将有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩。通过柱色谱法纯化该残余粗产物(30%乙酸乙酯/己烷),获得了本标题化合物585(680mg,96%产率)。1H NMR:(CDCl3)δ(ppm):7.79(s,1H),7.70-7.52(m,3H),4.69(s,2H),4.06(s,3H),3.72(s,2H).LRMS:268.2(计算值);269.1(实测值)。
步骤3:5-[(3,4-二甲氧基-苯基氨基)-甲基]-苯并呋喃-2-甲酸甲酯(586)
按照实施例47步骤2中描述的方法,但是用585代替63,以40%的产率获得了本标题化合物586。LRMS:341(计算值);342.3(实测值)。
步骤4:5-[(3,4-二甲氧基-苯基氨基)-甲基]-苯并呋喃-2-甲酸(2-氨基-苯
基)-酰胺(587)
按照实施例1步骤4、5中描述的方法,但是用585代替6,以29%的产率获得了本标题化合物587。1H NMR:(DMSO)δ(ppm):9.83(s,1H),7.75(s,1H),7.64(s,1H),7.62(d,J=8.0Hz,1H),7.47(d,J=9.0Hz,1H),7.18(d,J=8.0Hz,1H),6.97(t,J=7.5Hz,1H),6.78(d,J=8.0Hz,1H),6.65(d,J=8.5Hz,1H),6.59(t,J=7.5Hz,1H),6.33(s,1H),6.04(d,J=8.0Hz,1H),5.92(d,J=5.5Hz,1H),4.93(s,2H),4.31(d,J=5.5Hz,1H),2.82(s,3H),2.76(s,3H).LRMS:417.46(计算值);418.4(实测值)。
实施例437
步骤1:5-硝基-苯并[b]噻吩-2-甲酸甲酯(584)
在5℃,将5-硝基-2-氯-苯甲醛(4.0g,21.6mmol)在DMF(40ml)内的搅拌着的悬浮液用K2CO3(3.52g,25.5mmol)处理,然后用甘醇酸甲酯(1.93ml,21.6mmol)处理。将所得溶液温热至25℃,搅拌20小时。然后将该溶液倒入250ml冰水内,通过过滤收集所形成的沉淀。从EtOAc中结晶,获得了细的浅橙色针状物584(3.54g,69%)。LRMS237.0(计算值);238.1(实测值).1H NMR:(DMSO)δ(ppm):9.00(d,J=2.2Hz,1H),8.45(s,1H),8.39-8.30(m,2H),3.93(s,3H)。
步骤2:5-氨基-苯并[b]噻吩-2-甲酸甲酯(588)
将584(3.52g,14.8mmol)在甲醇(100ml)中的悬浮液用Fe粉(6.63g,118.7mmol)处理。将所得悬浮液加热至回流,用15分钟缓慢地加入12M HCl(8.5ml)。将所得深绿色悬浮液回流3小时,然后冷却,浓缩。将残余物置于EtOAc中,依次用饱和NaHCO3水溶液和盐水洗涤,用MgSO4干燥,过滤并浓缩,获得了(2.57g,84%)。1H NMR:(DMSO)δ(ppm):7.92(s,1H),7.65(d,J=8.8Hz,1H),7.05(d,J=1.5Hz,1H),6.88(dd,J=1.8,8.4Hz,1H),5.27(s,2H),3.85(s,3H).LRMS:207.0(计算值);208.1(实测值)。
步骤3:5-(3,4,5-三甲氧基-苄基氨基)-苯并[b]噻吩-2-甲酸甲酯(589)
按照实施例144步骤3中描述的方法,但是用588代替226,以68%的产率获得了本标题化合物589。(DMSO)δ(ppm):7.94(s,1H),7.69(d,J=8.8Hz,1H),7.02-6.99(m,2H),6.73(s,2H),6.41(t,J=5.7Hz,1H),4.21(d,J=5.9Hz,2H),3.84(s,3H),3.75(s,6H),3.62 (s,3H).LRMS:387.1(计算值);388.3(实测值)。
步骤4:5-(3,4,5-三甲氧基-苄基氨基)-苯并[b]噻吩-2-甲酸(2-氨基-苯基)-
酰胺(590)
按照实施例1步骤4、5中描述的方法,但是用589代替6,以%的产率获得了本标题化合物590。1H NMR:(DMSO)δ(ppm):7.79(s,1H),7.60(d,J=8.8Hz,1H),7.00-6.95(m,2H),6.74(s,2H),4.32(s,2H),3.80(s,6H),3.73(s,3H)。
实施例347-425
实施例347-425(化合物492-570)是按照实施例40-346中描述的制备化合物44-491的相同方法(反应方案3-64)制得的。
测定实施例1
抑制组蛋白脱乙酰化酶的酶活性
人HDAC-1
用从杆状病毒昆虫细胞表达系统表达和纯化的克隆重组人HDAC-1酶筛选HDAC抑制剂。对于脱乙酰化酶,将20,000cpm的[3H]-代谢标记的乙酰化组蛋白底物(M.Yoshida等人,J.Biol.Chem.265(28):17174-17179(1990))与30μg克隆重组hHDAC-1于37℃培养10分钟。通过加入乙酸(0.04M,终浓度)和HCl(250mM,终浓度)来停止该反应。用乙酸乙酯萃取该混合物,通过闪烁计数来定量测定释放的[3H]-乙酸。为了进行抑制测定,将酶与化合物在4℃预培养30分钟以开始酶测定。如下所述确定关于HDAC酶抑制剂的IC50值:获得各化合物的剂量反应曲线,确定产生50%最大抑制的抑制剂浓度。代表性化合物的IC50值列在表5的第三栏中。
MTT测定
在用化合物处理的前一天,将HCT116细胞(2000/孔)置于96-孔组织培养平板中。将不同浓度的化合物加到细胞中。将细胞在5%CO2培养器中于37℃培养72小时。将MTT(3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴化物,Sigma)以0.5mg/ml的终浓度加入,与细胞培养4小时,然后向培养的细胞中加入一体积的加溶缓冲液(50%N,N-二甲基甲酰胺,20%SDS,pH 4.7)。培养过夜后,使用MR700平板读数器(Dynatech Laboratories Inc.),通过在570nM的比色读数(使用在630nM的读数作为参照)定量测定加溶的染料。依据相关细胞系(cell line)的标准生长曲线将OD值转化成细胞数目。将细胞数目减至溶剂处理细胞的数目的50%的浓度确定为MTT IC50。代表性化合物的IC50值列在表5的第四栏中。
3.通过免疫印迹测定全细胞中的组蛋白H4乙酰基化
将在培养基中生长的T24人膀胱癌细胞与HDAC抑制剂一起培养16小时。培养结束后,按照M.Yoshida等人描述的方法(J.Biol.Chem.265(28):17174-17179(1990))从细胞中提取组蛋白。将总共20g组蛋白负载到SDS/PAGE上,并转移到硝基纤维素膜上。用乙酰化组蛋白H-4的特异性多克隆抗体(Upstate Biotech Inc.)探测所述膜,然后加入与次级抗体缀合的辣根过氧化物酶(Sigma)。使用Kodak膜(Eastman Kodak)检测增强的化学荧光(ECL)(Amersham)。通过测光密度术定量测定乙酰化H-4信号。代表性数据列在表5的第五栏中。数据是以将乙酰化H-4信号有效地降低50%的浓度(EC50)给出的。
表5a:抑制组蛋白脱乙酰化酶
(na=不能获得;99=>25μM)
表5b
(na=不能获得)
表5c
表5d
表5e
表5f
测定实施例2
组蛋白脱乙酰化酶抑制剂在体内对人肿瘤异种移植物的抗肿瘤作用
给8-10周大小的雌性BALB/c裸鼠(Taconic Labs,GreatBarrington,NY)在侧腹区域皮下注射2×106个预处理的HCT116人结肠直肠癌细胞。在相同株系的裸鼠中通过最少3次连续肿瘤移植来进行这些预处理。然后,切下约30mg肿瘤片断,在Forene麻醉下(AbbottLabs,Geneve,Switzerland)在左侧腹皮下移植到小鼠中。当肿瘤达到100mm3的平均体积时,通过每日静脉内、皮下或腹膜内注射组蛋白脱乙酰化酶抑制剂在适当载体例如PBS、DMSO/水或Tween 80/水中的溶液来治疗小鼠,开始剂量为10mg/kg。通过依据标准方案的剂量反应实验来确定HDAC抑制剂的最佳剂量。依据标准方法(例如Meyer等人,Int.J.Cancer 43:851-856(1989)),注射后每隔一天计算一次肿瘤体积。与仅用载体(即没使用HDAC抑制剂)治疗的对照相比,用本发明HDAC抑制剂治疗使得肿瘤重量和体积显著减小。此外,在测定时,与对照相比,组蛋白乙酰化水平显著增加。所选化合物的数据列在表6中。图1显示了化合物106的完整实验结果,该化合物将肿瘤生长抑制了80%。图2-10显示了所测试的其它化合物的结果。
表6
在HCT 116结肠直肠肿瘤模型中的体内抗肿瘤活性
化合物 | %肿瘤生长抑制 |
106 | 80a |
126 | 62b |
9 | 51b |
87 | 30b |
157 | 66a |
167 | 58a |
15 | 26b |
168 | 26b |
16 | 50b |
154 | 23a |
98 | 52a |
a:20mg/kg i.p.
b:40mg/kg i.p.
表7
组蛋白脱乙酰化酶抑制剂对裸鼠异种移植物模型的抗肿瘤作用
%肿瘤生长抑制 | |||||
cpd | A 549(p.o.) | SW48 p.o.) | A 549(i.p.) | HCT 116(i.p.) | SW48(i.p.) |
106 | 40%(70mg/kg) | 16%(60mg/kg) | - | - | - |
164 | 42%(70mg/kg) | 62%(60mg/kg) | - | 37%(20mg/kg) | 99%(25mg/kg) |
228 | 45%(70mg/kg) | 25%(60mg/kg) | 64%(20mg/kg) | 45%(20mg/kg) | 68%(20mg/kg) |
424b | 67%(50mg/kg) | 78%(30mg/kg) | 60%(50mg/kg) | 77%(75mg/kg) | 68%(25mg/kg) |
测定实施例3
组蛋白脱乙酰化酶抑制剂和组蛋白脱乙酰化酶反义低聚核苷酸在体内对肿瘤细胞的联合抗肿瘤作用
该实施例的目的是举例说明联合使用本发明组蛋白脱乙酰化酶抑制剂与组蛋白脱乙酰化酶反义低聚核苷酸在提高抑制哺乳动物中肿瘤生长方面的能力。优选地,反义低聚核苷酸与HDAC抑制剂抑制了相同组蛋白脱乙酰化酶的表达和活性。
如实施例126所述,每天用含有约0.1mg-约30mg/kg体重的组蛋白脱乙酰化酶反义低聚核苷酸的盐水制剂治疗携带移植的HCT116肿瘤(平均体积为100mm3)的小鼠。每天用含有约0.01mg-约5mg/kg体重的HDAC抑制剂的可药用制剂治疗第二组小鼠。
某些小鼠既接受反义低聚核苷酸,也接受HDAC抑制剂。在这些小鼠中,一组可接受经由尾静脉同时静脉内给予的反义低聚核苷酸和HDAC抑制剂。另一组可接受经由尾静脉给予的反义低聚核苷酸和皮下给予的HDAC抑制剂。还有一组可接受都是皮下给予的反义低聚核苷酸和HDAC抑制剂。类似地建立对照组小鼠,它们不接受任何治疗(例如仅接受盐水),仅接受错配的反义低聚核苷酸,不抑制组蛋白脱乙酰化酶活性的对照化合物,和错配的反义核苷酸和对照化合物。
用卡钳测定肿瘤体积。与对照相比,用反义低聚核苷酸加上本发明组蛋白脱乙酰化酶蛋白抑制剂治疗使得肿瘤重量和体积显著减小。
Claims (132)
1.式(1)组蛋白脱乙酰化酶抑制剂
或其可药用盐,其中
R3和R4独立地选自氢、L1、Cy1和-L1-Cy1,其中
L1是C1-C6烷基、C2-C6杂烷基或C3-C6链烯基;且
Cy1是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;或者
R3和R4与相邻氮原子一起形成5-、6-或7-元环,其中所述环原子独立地选自C、O、S和N,并且其中所述环可任选被取代,和任选形成二环环系的一部分,或任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环和环系可任选被取代;
Y1选自-N(R1)(R2)、-CH2-C(O)-N(R1)(R2)、卤素和氢,其中
R1和R2独立地选自氢、L1、Cy1和-L1-Cy1,其中
L1是C1-C6烷基、C2-C6杂烷基或C3-C6链烯基;
Cy1是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;或者
R1和R2与相邻氮原子一起形成5-、6-或7-元环,其中所述环原子独立地选自C、O、S和N,并且其中所述环可任选被取代,和任选形成二环环系的一部分,或任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环和环系可任选被取代;
Y2是化学键或N(R0),其中R0选自氢、烷基、芳基、芳烷基和酰基;
Ak1是C1-C6亚烷基、C1-C6-亚杂烷基(优选其中一个-CH2-被-NH-替代的C1-C6-亚杂烷基,更优选-NH-CH2-)、C2-C6亚链烯基或C2-C6亚炔基;
Ar1是亚芳基或亚杂芳基,每一所述基团可任选被取代;且
Z1选自
其中Ay1是芳基或杂芳基,所述基团可任选被取代。
2.权利要求1的化合物,其中Ay1是苯基或噻吩基,所述基团分别被-OH或-NH2取代。
3.权利要求2的化合物,其中所述氨基或羟基取代基在与Ay2连接的氮的邻位。
4.权利要求1的化合物,其中Ay1是邻苯胺、邻苯酚、3-氨基-2-噻吩基或3-羟基-2-噻吩基。
6.权利要求1的化合物,其中Ar1是亚苯基。
7.权利要求1的化合物,其中Ak1是亚烷基。
8.权利要求1的化合物,其中Ak1是亚甲基。
9.权利要求1的化合物,其中Y2是-NH-。
10.权利要求1的化合物,其中Y1是-N(R1)(R2)或-CH2-C(O)-N(R1)(R2)。
11.权利要求10的化合物,其中R1和/或R2是氢。
12.权利要求10的化合物,其中R1和/或R2是C1-C6烷基或C2-C6链烯基。
13.权利要求10的化合物,其中R1和/或R2是烯丙基。
14.权利要求10的化合物,其中R1和/或R2是芳基、杂芳基、芳烷基或杂芳烷基,每一所述基团的环可任选被取代,并任选与一个或两个芳基环稠合。
15.权利要求14的化合物,其中R1和/或R2独立地为苯基、吡啶基或吡咯基。
16.权利要求10的化合物,其中R1和/或R2独立地为环烷基,所述基团可任选被取代,并任选与一个或两个芳基环稠合。
17.权利要求16的化合物,其中R1和/或R2独立地为环丙基、环戊基或环己基,每一所述基团可任选被取代,并任选与一个或两个芳基环稠合。
18.权利要求16的化合物,其中R1和/或R2独立地为环丙基、环戊基或环己基。
19.权利要求1的化合物,其中R3和/或R4是氢。
20.权利要求1的化合物,其中R3和/或R4独立地为C1-C6烷基或C2-C6链烯基。
21.权利要求20的化合物,其中R3和/或R4是烯丙基。
22.权利要求1的化合物,其中R3和/或R4独立地为芳基、杂芳基、芳烷基或杂芳烷基,每一所述基团的环可任选被取代,并任选与一个或两个芳基环稠合。
23.权利要求22的化合物,其中R3和/或R4独立地为苯基、吡啶基或吡咯基。
24.权利要求1的化合物,其中R3和/或R4独立地为环烷基。
25.权利要求24的化合物,其中R3和/或R4独立地为环丙基、环戊基或环己基,所述基团可任选被取代,并任选与一个或两个芳基环稠合。
26.权利要求24的化合物,其中R3和/或R4独立地为环丙基、环戊基或环己基。
27.权利要求1的化合物,其中L1是C1-C6烷基、C2-C6杂烷基或C3-C6链烯基。
28.权利要求27的化合物,其中L1是C1-C6亚烷基。
29.权利要求27的化合物,其中L1是亚甲基或亚乙基。
30.权利要求27的化合物,其中L1是烯丙基。
31.权利要求1的化合物,其中Cy1是杂环基,所述基团可任选被取代,并任选与一个或两个芳基环稠合。
32.权利要求31的化合物,其中Cy1是哌啶、吡咯烷、哌嗪或吗啉,每一所述环可任选被取代,并任选与一个或两个芳基环稠合。
33.权利要求31的化合物,其中Cy1是哌啶、吡咯烷、哌嗪或吗啉。
34.权利要求1的化合物,其中Cy1是环烷基。
35.权利要求34的化合物,其中Cy1是环丙基、环戊基或环己基。
36.权利要求1的化合物,其中Cy1是芳基或杂芳基,每一所述基团可任选被取代,并任选与一个或两个芳基环稠合。
37.权利要求36的化合物,其中Cy1是苯基、吡啶基或吡咯基,每一所述基团可任选被取代,并任选与一个或两个芳基环稠合。
38.权利要求36的化合物,其中Cy1是苯基、吡啶基或吡咯基。
39.权利要求36的化合物,其中Cy1与一个或两个苯环稠合。
40.权利要求1的化合物,其中Cy1具有1-约5个独立地选自C1-C4烷基、C1-C4烷氧基和卤素的取代基。
41.权利要求40的化合物,其中所述独立选择的取代基是甲基、甲氧基和氟。
42.权利要求1的化合物,其中R1和R2和/或R3和R4与相邻氮原子一起形成5-或6-元环,其中所述环原子独立地选自C、O和N,并且其中所述环可任选被取代,并任选与一个或两个芳基环稠合。
43.权利要求42的化合物,其中所述5-或6-元环是吡咯烷、哌啶、哌嗪或吗啉,并且其中每个环可任选被取代,并任选与芳基环稠合。
44.权利要求43的化合物,其中所述芳基环是苯。
45.权利要求43的化合物,其中所述取代基包括芳基或C3-C12环烷基环,每一所述基团可任选被取代,并任选与C3-C12环烷基、芳基、杂芳基或杂环稠合。
46.权利要求44的化合物,其中所述基团是苯基、苯基甲基和苯基乙基,所述基团的苯基环可任选与C1-C12环烷基环、芳基环或杂环稠合。
47.式1(a)组蛋白脱乙酰化酶抑制剂化合物:
或可药用盐,其中
J是C1-C3-烃基、-N(R20)-、-N(R20)-CH2-、-O-或-O-CH2-;
R20是-H或-Me;
X和Y独立地选自-NH2、环烷基、杂环基、芳基、杂芳基和A-(C1-C6-烷基)n-B-;
A是H、C1-C6-烷氧基、环烷基、杂环基、芳基或杂芳基;
B是-NH-、-O-或一个键;且
n是0(在这种情况下A直接键合到B上)或1。
48.权利要求47的化合物,其中A是任选被一个或多个选自卤素和甲氧基的基团取代的苯基,且B是-NH-。
49.权利要求47的化合物,其中A选自环丙基、吡啶基和茚满基。
50.权利要求47的化合物,其中J是-NH-CH2-、-O-CH2-、-N(CH3)-CH2-、-CH=CH-或-CH2-CH2-。
51.权利要求47的化合物,其中R20是-H。
53.权利要求47的化合物,其中J、X和Y选自下列组合:
54.式(2)组蛋白脱乙酰化酶抑制剂
或其可药用盐,其中
Cy2是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;
X1选自共价键、M1-L2-M1和L2-M2-L2,其中
L2在每次出现时独立地选自化学键、C1-C4亚烷基、C2-C4亚链烯基和C2-C4亚炔基,条件是:当X1是M1-L2-M1时,L2不是化学键;
M1在每次出现时独立地选自-O-、-N(R7)-、-S-、-S(O)-,S(O)2-、-S(O)2N(R7)-、-N(R7)-S(O)2-、-C(O)-、-C(O)-NH-,-NH-C(O)-、-NH-C(O)-O-和-O-C(O)-NH-,其中R7选自氢、烷基、芳基、芳烷基、酰基、杂环基和杂芳基;且
M2选自M1、亚杂芳基和亚杂环基,任一所述环可任选被取代;
Ar2是亚芳基或亚杂芳基,每一所述基团可任选被取代;
R5和R6独立地选自氢、烷基、芳基和芳烷基;
q是0或1;且
Ay2是5-6元环烷基、杂环基或杂芳基,所述基团被氨基或羟基取代(这些基团优选在与Ay2连接的酰胺氮的邻位),并且还任选被另外的基团取代;
条件是:当Cy2是萘基,X1是-CH2-,Ar2是苯基,R5和R6是H,且q是0或1时,Ay2不是苯基或邻羟基苯基。
55.权利要求54的化合物,其中当Ay2是任选被卤素、硝基或甲基取代的邻苯酚,Ar2是任选取代的苯基,X1是-O-、-CH2-、-S-、-S-CH2-、-S(O)-、-S(O)2-、-C(O)-或-OCH2-时,Cy2不是任选取代的苯基或萘基。
56.权利要求54的化合物,其中当Ay2是任选被卤素、C1-C6-烷基、C1-C6-烷氧基或-NO2取代的邻苯胺基,q是0,Ar2是苯基,且X1是-CH2-时,Cy2不是取代的吡啶酮(吡啶酮的取代基不限于本文描述的取代基)。
57.权利要求54的化合物,其中当X1是-CH2-,Ar2是任选取代的苯基,q是1,且R6是H时,则Cy2不是任选取代的咪唑。
58.权利要求54的化合物,其中当Ar2是被氨基或羟基取代的苯基,X1是C0-C8-烷基-X1a-C0-C8-烷基,其中X1a是-CH2-、-O-、-S-、-NH-、-C(O)-时,Cy2不是任选取代的萘基或二氢萘或四氢萘。
59.权利要求54的化合物,其中当Ay2是邻苯酚,Ar2是取代的苯基,X1是-O-、-S-、-CH2-、-O-CH2-、-S-CH2-或-C(O)-,且R5和R6是H时,Cy2不是任选取代的萘基。
60.权利要求54的化合物,其中当Ay2是邻苯胺基,q是0,Ar2是未取代的苯基,X1是-CH2-时,Cy2不是取代的6-氢咪唑并[5,4-d]哒嗪-7-酮-1-基或取代的6-氢咪唑并[5,4-d]哒嗪-7-硫酮-1-基。
61.权利要求54的化合物,其中Ay2是苯基或噻吩基,所述基团分别被-OH或-NH2取代。
62.权利要求54的化合物,其中所述氨基或羟基优选在与Ay2连接的氮的邻位。
63.权利要求54的化合物,其中Ay2是邻苯胺、邻苯酚、3-氨基-2-噻吩基或3-羟基-2-噻吩基。
64.权利要求54的化合物,其中
q是1;
M1在每次出现时选自-N(R7)-、-S-、-C(O)-NH-和-O-C(O)-NH-,其中R7选自氢、烷基、芳基、芳烷基和酰基;且
Ay2是任选取代的苯胺基。
65.权利要求64的化合物,其中Ay2的-NH2在与Ay2连接的氮原子的邻位。
66.权利要求65的化合物,其中R5和R6独立地选自氢和 C1-C4烷基。
67.权利要求65的化合物,其中R5和R6是氢。
70.权利要求54的化合物,其中Ar2选自亚苯基、亚吡啶基、亚嘧啶基和亚喹啉基。
71.权利要求54的化合物,其中X1式化学键。
72.权利要求54的化合物,其中X1是L2-M2-L2,且M2选自-NH-、-N(CH3)-、-S-、-C(O)-N(H)-和-O-C(O)-N(H)-。
73.权利要求54的化合物,其中X1是L2-M2-L2,其中至少一个出现的L2为化学键。
74.权利要求54的化合物,其中X1是L2-M2-L2,其中至少一个出现的L2为亚烷基,优选亚甲基。
75.权利要54的化合物,其中X1是L2-M2-L2,其中至少一个出现的L2为亚链烯基。
76.权利要54的化合物,其中X1是M1-L2-M1,且M1选自-NH-、-N(CH3)-、-S-和-C(O)-N(H)-。
77.权利要54的化合物,其中Cy2是分别任选被取代的芳基或杂芳基。
78.权利要54的化合物,其中Cy2是分别任选被取代的苯基、吡啶基、咪唑基或喹啉基。
79.权利要54的化合物,其中Cy2是杂环基。
81.权利要求54的化合物,其中Cy2具有1-3个独立地选自下列的取代基:烷基、烷氧基、氨基、硝基、卤素、卤代烷基和卤代烷氧基。
82.权利要求54的化合物,其中所述取代基选自甲基、甲氧基、氟、三氟甲基、三氟甲氧基、硝基、氨基、氨基甲基和羟基甲基。
83.权利要求54的化合物,其中所述化合物是式(2a)化合物:
其中
Ara是苯基或噻吩基;
R6是H或C1-C6-烷基(优选-CH3);
Y和Z独立地为-CH=或-N=;
W是卤素、(V’-L4)t-V-L3-;
L3是一个键、-C1-C6-烃基、-(C1-C3-烃基)m1-X’-(C1-C3-烃基)m2、-NH-(C0-C3-烃基)、(C1-C3-烃基)-NH-或-NH-(C1-C3-烃基)-NH-;
m1和m2独立地为0或1;
X’是-N(R21)-、-C(O)N(R21)-、N(R21)C(O)-、-O-或-S-;
R21是-H、V”-(C1-C6-烃基)c;
L4是(C1-C6-烃基)a-M-(C1-C6-烃基)b;
a和b独立地为0或1;
M是-NH-、-NHC(O)-、-C(O)NH-、-C(O)-、-SO2-、-NHSO2-或-SO2NH-;
V、V’和V”独立地选自环烷基、杂环基、芳基和杂芳基;
t是0或1;
或者,W、其所键合的环C以及Y一起形成单环环烷基、杂环基、芳基或杂芳基;且
其中A和Ara环可任选被1-3个独立地选自甲基、羟基、甲氧基、卤素和氨基的取代基进一步取代。
84.权利要求83的化合物,其中:
Y和Z是-CH=,且R6是H;
W是V-L3;
L3是-NH-CH-或-CH-NH-;
V是苯基,所述苯基可任选被1-3个独立地选自下列的基团取代:卤素、羟基、C1-C6-烃基、C1-C6-烃氧基或烃硫基(特别是甲氧基或甲硫基),其中每一所述烃基可任选被一个或多个选自卤素、亚硝基、氨基、磺酰胺基和氰基的基团取代;且
Ara是苯基,并且与其键合的氨基彼此呈邻位关系。
87.权利要求83的化合物,其中A和Ara环没有被进一步取代。
89.权利要求88的化合物,其中所述酰胺氮与键合在Ara上的氨基氮彼此呈邻位关系。
91.权利要求90的化合物,其中Ay2选自:
和
92.权利要求90的化合物,其中Cy2是苯基、吡啶基、嘧啶基、苯并咪唑基、苯并噻唑基、噻吩基、四氢喹唑啉基或1,3-二氢喹唑啉-2,4-二酮,每一所述基团可任选被1-3个CH3O-取代。
93.权利要求90的化合物,其中Cy2是被1-3个CH3O-取代的苯基。
94.式(3)组蛋白脱乙酰化酶抑制剂:
或其可药用盐,其中
Ar3是亚芳基或亚杂芳基,任一所述基团可任选被取代;
Cy3是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或者与一个或多个饱和或部分不饱和环烷基环或杂环稠合,每一所述环可任选被取代;
条件是当Cy3是在环中具有-C(O)-、-C(S)-、-S(O)-或-S(O)2-的环基团时,Cy3不被包含芳基或杂芳基环的基团取代;且
X2选自化学键、L3、W1-L3、L3-W1、W1-L3-W1和L3-W1-L3,其中
W1在每次出现时为S、O或N(R9),其中R9选自氢、烷基、芳基和芳烷基;且
L3是C1-C4亚烷基、C2-C4亚链烯基或C2-C4亚炔基;
条件是X2不包含-C(O)-、-C(S)-、-S(O)-或-S(O)2-基团;
并且条件还是:当Cy3是吡啶时,X2是L3、W1-L3或L3-W1。
96.权利要求94的化合物,其中X2选自L3、W1-L3、L3-W1、W1-L3-W1和L3-W1-L3。
97.权利要求94的化合物,其中当X2是化学键时,Ar3不是
或
且Cy3不是取代或未取代的二氮杂卓或苯并呋喃基团。
98.权利要求95的化合物,其中Q在每次出现时为C(R8),其中R8选自氢、烷基、芳基、芳烷基、烷氧基、氨基、硝基、卤素、卤代烷基和卤代烷氧基。
99.权利要求95的化合物,其中1-约3个Q是氮。
100.权利要求94的化合物,其中Ar3选自亚苯基、亚吡啶基、亚噻唑基和亚喹啉基。
101.权利要求94的化合物,其中X2是化学键。
102.权利要求94的化合物,其中X2是非环烃基。
103.权利要求94的化合物,其中X2是亚烷基。
104.权利要求94的化合物,其中X2是亚甲基或亚乙基。
105.权利要求94的化合物,其中X2是亚链烯基或亚炔基。
106.权利要求102的化合物,其中烃链中的一个碳被-NH-或-S-代替。
107.权利要求94的化合物,其中X2是W1-L3-W1,且W1是-NH-或-N(CH3)-。
108.权利要求94的化合物,其中Cy3是环烷基。
109.权利要求94的化合物,其中Cy3是环己基。
110.权利要求94的化合物,其中Cy3是芳基或杂芳基,每一所述基团可任选被取代,并任选与一个或两个芳基环稠合。
111.权利要求94的化合物,其中Cy3是苯基、吡啶基、嘧啶基、咪唑基、噻唑基、噁二唑基、喹啉基或芴基,每一所述基团可任选被取代,并任选与一个或两个芳基环稠合。
112.权利要求94的化合物,其中Cy3环基团与苯环稠合。
113.权利要求94的化合物,其中Cy3具有1-3个独立地选自下列的取代基:烷基、烷氧基、芳基、芳烷基、氨基、卤素、卤代烷基和羟基烷基。
114.权利要求113的化合物,其中所述取代基选自甲基、甲氧基、氟,三氟甲基、氨基、硝基、氨基甲基、羟基甲基和苯基。
115.权利要求94的化合物,其中Cy3具有1-3个式-K1-N(H)(R10)取代基,其中
K1是化学键或C1-C4亚烷基;
R10选自Z’和-Ak2-Z’,其中
Ak2是C1-C4亚烷基;且
Z’是环烷基、芳基、杂芳基或杂环基,每一所述基团可任选被取代,并且每一所述基团可任选与一个或多个芳基或杂芳基环或一个或多个饱和或部分不饱和环烷基或杂环稠合。
117.权利要求94的化合物,其中Cy3是杂环基,每一所述基团可任选被取代,并任选与一个或两个芳基环稠合。
118.权利要求94的化合物,其中Cy3选自
和
119.权利要求117的化合物,其中Cy3的杂环与苯环稠合。
120.权利要求94的化合物,其中当Ar4是亚喹喔啉基时,X3不是-CH(OH)-。
123.权利要求54的化合物,其中
Ay2是邻苯胺基;
q是0;且
X1是M1-L2-M1或L2-M2-L2。
124.权利要求123的化合物,其中Ar2是芳基或杂芳基;且Cy2-X1-选自
a)A1-L1-B1-,其中A1是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L1是-(CH2)0-1NH(CH2)0-1-、-NHC(O)-或-NHCH2-;且其中B1是苯基或共价键;
b)A2-L2-B2-,其中A2是CH3(C=CH2)-、任选取代的环烷基、任选取代的烷基或任选取代的芳基;其中L2是-C≡C-;且其中B2是共价键;
c)A3-L3-B3-,其中A3是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L3是共价键;且其中B3是-CH2NH-;
d)A4-L4-B4-,其中A4是任选取代的芳基;其中L4是-NHCH2-;且其中B4是噻吩基;
e)A5-L5-B5-,其中A5是任选取代的杂芳基或任选取代的杂环基;其中L5是共价键;且其中B5是-SCH2-;
f)吗啉基-CH2-;
g)任选取代的芳基;
h)A6-L6-B6-,其中A6是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L6是共价键;且其中B6是-NHCH2-;
i)A7-L7-B7-,其中A7是任选取代的杂芳基或任选取代的杂环基;其中L7是共价键;且其中B7是-CH2-;
j)任选取代的杂芳基或任选取代的杂环基;
k)A8L8-B8-,其中A8是任选取代的苯基;其中L8是共价键;且其中B8是-O-;
l)A9-L9-B9-,其中A9是任选取代的芳基;其中L9是共价键;且其中B9是呋喃基;
m)A10-L10-B10-,其中A10是任选取代的杂芳基或任选取代的杂环基;其中L10是-CH(CH2CH3)-;且其中B10是-NHCH2-;
n)A11-L11-B11-,其中A11是任选取代的杂芳基或任选取代的杂环基;其中L11是共价键;且其中B11是-OCH2-;
o)A12-L12-B12-,其中A12是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L12是-NHC(O)-;且其中B12是-N(任选取代的芳基)CH2-;
p)A13-L13-B13-,其中A12是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L13是共价键;且其中B13是-NHC(O)-;
q)A14-L14-B14-,其中A14是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L14是-NHC(O)(任选取代的杂芳基);且其中B14是-S-S-;
r)F3CC(O)NH-;
s)A15-L15-B15-,其中A15是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L15是-(CH2)0-1NH(任选取代的杂芳基)-;且其中B15是-NHCH2-;
t)A16-L16-B16-,其中A16是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L16是共价键;且其中B16是-N(任选取代的烷基)CH2-;和
u)A16-L16-B16-,其中A16是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中L16是共价键;且其中B16是-(任选取代的芳基-(CH2)2-N-。
125.权利要求123的化合物,其中Cy2-X1-选自
a)D1-E1-F1-,其中D1是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E1是-CH2-或共价键;且其中B1是共价键;
b)D2-E2-F2-,其中D2是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E2是-NH(CH2)0-2-;且其中F2是共价键;
c)D3-E3-F3-,其中D3是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E3是-(CH2)0-2NH-;且其中F3是共价键;
d)D4-E4-F4-,其中D4是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E4是-S(CH2)0-2-;且其中F4是共价键;
e)D5-E5-F5-,其中D5是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E5是-(CH2)0-2S-;且其中F5是共价键;和
f)D6-E6-F6-,其中D6是任选取代的芳基、任选取代的杂芳基或任选取代的杂环基;其中E6是-NH(CH2)0-2NH-;且其中F6是共价键。
127.权利要求126的化合物,其中Y、Z和W是一个下列组合:
130.选自列在表2a-b、3a-d、4a-c和5a-5f中的化合物或其可药用盐的组蛋白脱乙酰化酶抑制剂。
131.组合物,其中包含权利要求1-130任一项的化合物和可药用载体。
132.抑制细胞中组蛋白脱乙酰化酶的方法,所述方法包括将细胞与权利要求1-130任一项的化合物接触。
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- 2002-09-12 BR BR0212510-2A patent/BR0212510A/pt not_active IP Right Cessation
- 2002-09-12 CN CN201010195036A patent/CN101851173A/zh active Pending
- 2002-09-12 JP JP2003528544A patent/JP3795044B2/ja not_active Expired - Fee Related
- 2002-09-12 KR KR1020107019027A patent/KR20100107509A/ko not_active Application Discontinuation
- 2002-09-12 CN CN028226909A patent/CN1578663B/zh not_active Expired - Lifetime
- 2002-09-12 CA CA2465978A patent/CA2465978C/en not_active Expired - Fee Related
- 2002-09-12 WO PCT/US2002/029017 patent/WO2003024448A2/en active Application Filing
- 2002-09-12 KR KR10-2004-7003794A patent/KR20040048411A/ko active Search and Examination
- 2002-09-12 EP EP02763627A patent/EP1429765A2/en not_active Withdrawn
- 2002-09-12 MX MXPA04002397A patent/MXPA04002397A/es active IP Right Grant
- 2002-09-12 AU AU2002327627A patent/AU2002327627B2/en not_active Ceased
- 2002-09-12 US US10/242,304 patent/US7595343B2/en not_active Expired - Fee Related
-
2005
- 2005-03-18 JP JP2005080310A patent/JP2005255683A/ja active Pending
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2010
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Also Published As
Publication number | Publication date |
---|---|
CN1578663B (zh) | 2011-05-25 |
JP2010168382A (ja) | 2010-08-05 |
WO2003024448A3 (en) | 2003-11-13 |
KR20100107509A (ko) | 2010-10-05 |
AU2002327627B2 (en) | 2006-09-14 |
JP2005255683A (ja) | 2005-09-22 |
JP2005508905A (ja) | 2005-04-07 |
KR20040048411A (ko) | 2004-06-09 |
CA2465978A1 (en) | 2003-03-27 |
US7595343B2 (en) | 2009-09-29 |
WO2003024448A2 (en) | 2003-03-27 |
CA2465978C (en) | 2015-04-07 |
MXPA04002397A (es) | 2004-12-02 |
JP3795044B2 (ja) | 2006-07-12 |
EP1429765A2 (en) | 2004-06-23 |
CN101851173A (zh) | 2010-10-06 |
BR0212510A (pt) | 2004-08-24 |
US20040106599A1 (en) | 2004-06-03 |
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