TWI623537B - 1,5-萘啶衍生物與含此之melk抑制劑 - Google Patents
1,5-萘啶衍生物與含此之melk抑制劑 Download PDFInfo
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- TWI623537B TWI623537B TW106119610A TW106119610A TWI623537B TW I623537 B TWI623537 B TW I623537B TW 106119610 A TW106119610 A TW 106119610A TW 106119610 A TW106119610 A TW 106119610A TW I623537 B TWI623537 B TW I623537B
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- TW
- Taiwan
- Prior art keywords
- group
- naphthyridin
- alkyl
- amino
- hydroxyphenyl
- Prior art date
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- 229940124787 MELK inhibitor Drugs 0.000 title description 3
- 150000005055 1,5-naphthyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 592
- 150000003839 salts Chemical class 0.000 claims description 142
- 125000001424 substituent group Chemical group 0.000 claims description 119
- 125000003118 aryl group Chemical group 0.000 claims description 99
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 99
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 81
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 63
- 125000003545 alkoxy group Chemical group 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 50
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 48
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 48
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 150000001412 amines Chemical class 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 125000003386 piperidinyl group Chemical group 0.000 claims description 37
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 35
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 31
- 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 31
- 206010028980 Neoplasm Diseases 0.000 claims description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 29
- 125000003342 alkenyl group Chemical group 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 28
- 125000004193 piperazinyl group Chemical group 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- XTHDCRACMUNCHP-UHFFFAOYSA-N 1-[6-chloro-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound C1CC(CN(C)C)CCC1NC1=C(C(C)=O)C=NC2=CC=C(Cl)N=C12 XTHDCRACMUNCHP-UHFFFAOYSA-N 0.000 claims description 25
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 25
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 24
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 18
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 17
- 206010006187 Breast cancer Diseases 0.000 claims description 14
- 208000026310 Breast neoplasm Diseases 0.000 claims description 14
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 206010005003 Bladder cancer Diseases 0.000 claims description 10
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 10
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 10
- BXOBQDOEBJELFC-UHFFFAOYSA-N acetaldehyde;dihydrochloride Chemical compound Cl.Cl.CC=O BXOBQDOEBJELFC-UHFFFAOYSA-N 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 10
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 8
- HOLHYSJJBXSLMV-UHFFFAOYSA-N 2,6-dichlorophenol Chemical group OC1=C(Cl)C=CC=C1Cl HOLHYSJJBXSLMV-UHFFFAOYSA-N 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- ABFWLWFSFQECIW-UHFFFAOYSA-N 1-[4-[[6-(3-aminopiperidin-1-yl)pyridin-3-yl]amino]-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1ccc(nc1)N1CCCC(N)C1)-c1cc(Cl)c(O)c(Cl)c1 ABFWLWFSFQECIW-UHFFFAOYSA-N 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- OFXPODQSPOUHEV-UHFFFAOYSA-N 1-[6-(3-chloro-4-hydroxy-5-methoxyphenyl)-4-[[6-[2-(dimethylamino)ethoxy]pyridin-3-yl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound COc1cc(cc(Cl)c1O)-c1ccc2ncc(C(C)=O)c(Nc3ccc(OCCN(C)C)nc3)c2n1 OFXPODQSPOUHEV-UHFFFAOYSA-N 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- DJTWSDDNMRSYIX-UHFFFAOYSA-N 1-[4-[[6-(3-aminopiperidin-1-yl)pyridin-3-yl]amino]-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1ccc(nc1)N1CCCC(N)C1)-c1cc(F)c(O)c(Cl)c1 DJTWSDDNMRSYIX-UHFFFAOYSA-N 0.000 claims description 5
- DJTWSDDNMRSYIX-MRXNPFEDSA-N 1-[4-[[6-[(3R)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1ccc(nc1)N1CCC[C@@H](N)C1)-c1cc(F)c(O)c(Cl)c1 DJTWSDDNMRSYIX-MRXNPFEDSA-N 0.000 claims description 5
- ABFWLWFSFQECIW-INIZCTEOSA-N 1-[4-[[6-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1ccc(nc1)N1CCC[C@H](N)C1)-c1cc(Cl)c(O)c(Cl)c1 ABFWLWFSFQECIW-INIZCTEOSA-N 0.000 claims description 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
- NMHHOPOQZMKQGJ-KRWDZBQOSA-N [4-[[6-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]-cyclopropylmethanone Chemical compound N[C@H]1CCCN(C1)c1ccc(Nc2c(cnc3ccc(nc23)-c2cc(F)c(O)c(Cl)c2)C(=O)C2CC2)cn1 NMHHOPOQZMKQGJ-KRWDZBQOSA-N 0.000 claims description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- ABFWLWFSFQECIW-MRXNPFEDSA-N 1-[4-[[6-[(3R)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1ccc(nc1)N1CCC[C@@H](N)C1)-c1cc(Cl)c(O)c(Cl)c1 ABFWLWFSFQECIW-MRXNPFEDSA-N 0.000 claims description 4
- DJTWSDDNMRSYIX-INIZCTEOSA-N 1-[4-[[6-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1ccc(nc1)N1CCC[C@H](N)C1)-c1cc(F)c(O)c(Cl)c1 DJTWSDDNMRSYIX-INIZCTEOSA-N 0.000 claims description 4
- DKZYXHCYPUVGAF-UHFFFAOYSA-N 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN(C)CC1CCC(CC1)Nc1c(cnc2ccc(nc12)-c1cc(Cl)c(O)c(Cl)c1)C(C)=O DKZYXHCYPUVGAF-UHFFFAOYSA-N 0.000 claims description 4
- YPWDIJBYLGCHOL-UHFFFAOYSA-N 2-chloro-4-[8-[[4-(dimethylamino)cyclohexyl]amino]-7-methylsulfonyl-1,5-naphthyridin-2-yl]-6-fluorophenol Chemical compound CN(C)C1CCC(CC1)Nc1c(cnc2ccc(nc12)-c1cc(F)c(O)c(Cl)c1)S(C)(=O)=O YPWDIJBYLGCHOL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- NHIOHZSWBYQOAB-KRWDZBQOSA-N [4-[[6-[(3S)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]-cyclopropylmethanone Chemical compound N[C@H]1CCCN(C1)c1ccc(Nc2c(cnc3ccc(nc23)-c2cc(Cl)c(O)c(Cl)c2)C(=O)C2CC2)cn1 NHIOHZSWBYQOAB-KRWDZBQOSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- VWUVJSLUODCSBG-UHFFFAOYSA-N 1-[4-[[2-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl]amino]-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1cnc(nc1)N1CCC(N)C1)-c1cc(Cl)c(O)c(Cl)c1 VWUVJSLUODCSBG-UHFFFAOYSA-N 0.000 claims description 3
- QZNPHEDOLUEBNA-UHFFFAOYSA-N 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[3-(2-pyrrolidin-1-ylethyl)anilino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1Nc1cccc(CCN2CCCC2)c1)-c1cc(Cl)c(O)c(Cl)c1 QZNPHEDOLUEBNA-UHFFFAOYSA-N 0.000 claims description 3
- MFVYUXAOMUYLIA-UHFFFAOYSA-N 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[4-[(4-methylpiperazin-1-yl)methyl]anilino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN1CCN(Cc2ccc(Nc3c(cnc4ccc(nc34)-c3cc(Cl)c(O)c(Cl)c3)C(C)=O)cc2)CC1 MFVYUXAOMUYLIA-UHFFFAOYSA-N 0.000 claims description 3
- HSFDFPJOXXVPJT-UHFFFAOYSA-N 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN1CCC(CC1)n1cc(Nc2c(cnc3ccc(nc23)-c2cc(Cl)c(O)c(Cl)c2)C(C)=O)cn1 HSFDFPJOXXVPJT-UHFFFAOYSA-N 0.000 claims description 3
- CTNSVHJCMGFELJ-UHFFFAOYSA-N 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[6-[2-(dimethylamino)ethoxy]pyridin-3-yl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN(C)CCOc1ccc(Nc2c(cnc3ccc(nc23)-c2cc(Cl)c(O)c(Cl)c2)C(C)=O)cn1 CTNSVHJCMGFELJ-UHFFFAOYSA-N 0.000 claims description 3
- DNNXPAGXQYNMMV-UHFFFAOYSA-N 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[6-[3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-yl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN(C)C1CCN(C1)c1ccc(Nc2c(cnc3ccc(nc23)-c2cc(Cl)c(O)c(Cl)c2)C(C)=O)cn1 DNNXPAGXQYNMMV-UHFFFAOYSA-N 0.000 claims description 3
- SSQWHXJDSBZJSV-UHFFFAOYSA-N 1-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-4-[(1-methylpiperidin-4-yl)amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN1CCC(CC1)Nc1c(cnc2ccc(nc12)-c1cc(F)c(O)c(Cl)c1)C(C)=O SSQWHXJDSBZJSV-UHFFFAOYSA-N 0.000 claims description 3
- SRDLLLPPROJEOX-UHFFFAOYSA-N 1-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-4-[4-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)c1cnc2ccc(nc2c1N1CCC(CCN2CCCC2)CC1)-c1cc(F)c(O)c(Cl)c1 SRDLLLPPROJEOX-UHFFFAOYSA-N 0.000 claims description 3
- OBVDIKLQRBFRGG-UHFFFAOYSA-N 1-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-4-[[6-[2-(dimethylamino)ethylamino]pyridin-3-yl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CN(C)CCNc1ccc(Nc2c(cnc3ccc(nc23)-c2cc(F)c(O)c(Cl)c2)C(C)=O)cn1 OBVDIKLQRBFRGG-UHFFFAOYSA-N 0.000 claims description 3
- IXXPMKUZHVTLBD-UHFFFAOYSA-N 1-[6-pyrrolidin-1-yl-4-[[4-(pyrrolidin-1-ylmethyl)cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone Chemical compound CC(=O)C1=CN=C2C=CC(N3CCCC3)=NC2=C1NC(CC1)CCC1CN1CCCC1 IXXPMKUZHVTLBD-UHFFFAOYSA-N 0.000 claims description 3
- PNYOHCRQQXZIPN-UHFFFAOYSA-N 2,6-dichloro-4-[8-[4-[(dimethylamino)methyl]anilino]-7-methylsulfonyl-1,5-naphthyridin-2-yl]phenol Chemical compound CN(C)Cc1ccc(Nc2c(cnc3ccc(nc23)-c2cc(Cl)c(O)c(Cl)c2)S(C)(=O)=O)cc1 PNYOHCRQQXZIPN-UHFFFAOYSA-N 0.000 claims description 3
- ZEYDOWYBOKJJSQ-UHFFFAOYSA-N 2-chloro-4-[8-[4-[(dimethylamino)methyl]anilino]-7-methylsulfonyl-1,5-naphthyridin-2-yl]-6-fluorophenol Chemical compound CN(C)Cc1ccc(Nc2c(cnc3ccc(nc23)-c2cc(F)c(O)c(Cl)c2)S(C)(=O)=O)cc1 ZEYDOWYBOKJJSQ-UHFFFAOYSA-N 0.000 claims description 3
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- DKZYXHCYPUVGAF-WOVMCDHWSA-N CN(C)C[C@H]1CC[C@H](CC1)Nc1c(cnc2ccc(nc12)-c1cc(Cl)c(O)c(Cl)c1)C(C)=O Chemical compound CN(C)C[C@H]1CC[C@H](CC1)Nc1c(cnc2ccc(nc12)-c1cc(Cl)c(O)c(Cl)c1)C(C)=O DKZYXHCYPUVGAF-WOVMCDHWSA-N 0.000 claims description 3
- JNXJTOCIMIRWJN-WKILWMFISA-N CN(C)[C@H]1CC[C@@H](CC1)Nc1c(cnc2ccc(nc12)-c1cc(Cl)c(O)c(Cl)c1)C(C)=O Chemical compound CN(C)[C@H]1CC[C@@H](CC1)Nc1c(cnc2ccc(nc12)-c1cc(Cl)c(O)c(Cl)c1)C(C)=O JNXJTOCIMIRWJN-WKILWMFISA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- NHIOHZSWBYQOAB-QGZVFWFLSA-N [4-[[6-[(3R)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]-cyclopropylmethanone Chemical compound N[C@@H]1CCCN(C1)c1ccc(Nc2c(cnc3ccc(nc23)-c2cc(Cl)c(O)c(Cl)c2)C(=O)C2CC2)cn1 NHIOHZSWBYQOAB-QGZVFWFLSA-N 0.000 claims description 3
- NMHHOPOQZMKQGJ-QGZVFWFLSA-N [4-[[6-[(3R)-3-aminopiperidin-1-yl]pyridin-3-yl]amino]-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl]-cyclopropylmethanone Chemical compound N[C@H]1CN(CCC1)C1=CC=C(C=N1)NC1=C(C=NC2=CC=C(N=C12)C1=CC(=C(C(=C1)F)O)Cl)C(=O)C1CC1 NMHHOPOQZMKQGJ-QGZVFWFLSA-N 0.000 claims description 3
- MRYAZOKFKBERRP-UHFFFAOYSA-N [6-(3-chloro-5-fluoro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]-cyclopropylmethanone Chemical compound CN(C)CC1CCC(CC1)Nc1c(cnc2ccc(nc12)-c1cc(F)c(O)c(Cl)c1)C(=O)C1CC1 MRYAZOKFKBERRP-UHFFFAOYSA-N 0.000 claims description 3
- 201000011199 bladder lymphoma Diseases 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- WEXLLFSLHVKYLS-UHFFFAOYSA-N 1-[4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-6-(1h-pyrazol-4-yl)-1,5-naphthyridin-3-yl]ethanone Chemical compound C1CC(CN(C)C)CCC1NC1=C(C(C)=O)C=NC2=CC=C(C3=CNN=C3)N=C12 WEXLLFSLHVKYLS-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
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- 239000006166 lysate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
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- 108020004999 messenger RNA Proteins 0.000 description 1
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- NYBQXBOSQNTGPL-UHFFFAOYSA-N methane methanesulfonic acid Chemical compound S(C)(=O)(=O)O.C.C NYBQXBOSQNTGPL-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical class OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- WDZVYHXDNNXLFP-UHFFFAOYSA-N pyridin-3-yl carbamate Chemical compound NC(=O)OC1=CC=CN=C1 WDZVYHXDNNXLFP-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- BLFKPWSRRGIALQ-UHFFFAOYSA-N pyrrolidin-3-yl carbamate Chemical compound NC(=O)OC1CCNC1 BLFKPWSRRGIALQ-UHFFFAOYSA-N 0.000 description 1
- KFTZCNLLRKFMQH-UHFFFAOYSA-N pyrrolidin-3-ylcarbamic acid Chemical compound OC(=O)NC1CCNC1 KFTZCNLLRKFMQH-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 150000003254 radicals Chemical class 0.000 description 1
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- 239000002151 riboflavin Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
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- 238000010008 shearing Methods 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GNLNGVZPEKSDAR-UHFFFAOYSA-N tert-butyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate Chemical compound CC1=NN(C(=O)OC(C)(C)C)C(C)=C1B1OC(C)(C)C(C)(C)O1 GNLNGVZPEKSDAR-UHFFFAOYSA-N 0.000 description 1
- XUEZIWUUCPQAJI-QFIPXVFZSA-N tert-butyl N-[(3S)-1-[5-[[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclobutanecarbonyl)-1,5-naphthyridin-4-yl]amino]pyridin-2-yl]piperidin-3-yl]carbamate Chemical compound C(C)(C)(C)OC(N[C@@H]1CN(CCC1)C1=NC=C(C=C1)NC1=C(C=NC2=CC=C(N=C12)C1=CC(=C(C(=C1)F)O)Cl)C(=O)C1CCC1)=O XUEZIWUUCPQAJI-QFIPXVFZSA-N 0.000 description 1
- FEYLUKDSKVSMSZ-UHFFFAOYSA-N tert-butyl n-(4-aminocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(N)CC1 FEYLUKDSKVSMSZ-UHFFFAOYSA-N 0.000 description 1
- NBTNDUBSJWWOMC-GFCCVEGCSA-N tert-butyl n-[(3r)-1-(5-aminopyridin-2-yl)piperidin-3-yl]carbamate Chemical compound C1[C@H](NC(=O)OC(C)(C)C)CCCN1C1=CC=C(N)C=N1 NBTNDUBSJWWOMC-GFCCVEGCSA-N 0.000 description 1
- NBTNDUBSJWWOMC-LBPRGKRZSA-N tert-butyl n-[(3s)-1-(5-aminopyridin-2-yl)piperidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCCN1C1=CC=C(N)C=N1 NBTNDUBSJWWOMC-LBPRGKRZSA-N 0.000 description 1
- HMMYZMWDTDJTRR-UHFFFAOYSA-N tert-butyl n-[(4-aminocyclohexyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCC(N)CC1 HMMYZMWDTDJTRR-UHFFFAOYSA-N 0.000 description 1
- QFRRVRBQMHXWFP-UHFFFAOYSA-N tert-butyl n-[1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]-n-methylcarbamate Chemical compound C1C(N(C)C(=O)OC(C)(C)C)CCN1C1=CC=C(N)C=N1 QFRRVRBQMHXWFP-UHFFFAOYSA-N 0.000 description 1
- SSZKBGFWNFAXNC-UHFFFAOYSA-N tert-butyl n-[4-(2-aminoethyl)cyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(CCN)CC1 SSZKBGFWNFAXNC-UHFFFAOYSA-N 0.000 description 1
- SGNKPJPMWHKOJO-UHFFFAOYSA-N tert-butyl n-[4-(hydroxymethyl)cyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(CO)CC1 SGNKPJPMWHKOJO-UHFFFAOYSA-N 0.000 description 1
- XYKYUXYNQDXZTD-UHFFFAOYSA-N tert-butyl n-methyl-n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1CCNC1 XYKYUXYNQDXZTD-UHFFFAOYSA-N 0.000 description 1
- WUOQXNWMYLFAHT-UHFFFAOYSA-N tert-butyl n-piperidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCCNC1 WUOQXNWMYLFAHT-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002100 tumorsuppressive effect Effects 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本發明有關於通式(I)之化合物。
Description
本發明係關於一種具抑制MELK活性之1,5-萘啶衍生物、一種製備該衍生物之方法,及一種含有該化合物作為活性成份之醫藥組合物。
MELK,母源性胚胎拉鏈狀白胺酸蛋白質激酶(maternal embryonic leucine zipper kinase),在先前已鑑別為snf1/AMPK絲胺酸-蘇胺酸激酶家族之一新成員,其係涉及哺乳動物胚胎發育(Heyer BS et al.,Dev Dyn.1999 Aug 215(4):344-51)。該基因顯示在幹細胞更新(Nakano I et al.,J Cell Biol.2005 Aug 1,170(3):413-27)、細胞周期行進(cell-cycle progression)(Blot J et al.,Dev Biol.2002 J15,241(2):327-38;Seong HA et al.,Biochem J.2002 Feb 1,361(Pt 3):597-604)及前mRNA剪切(Vulsteke V et al.,J Biol Chem.2004 Mar 5,279(10):8642-7.Epub 2003 Dec 29)扮演重要角色。此外,最近藉由使用含有23,040個基因的整個基因組cDNA微陣列晶片進行基因表現晶片分析,顯示在乳癌中,MELK受到正調控(Lin ML et al.,Breast Cancer Res.2007;9(1):R17,
WO2006/016525,WO2008/023841)。事實上,在數種癌細胞中,例如肺癌、膀胱癌、淋巴癌、及子宮頸癌細胞當中,MELK是受到正調控(參見WO2004/031413、WO2007/013665,及WO2006/085684,並揭示在此納入當做參考)。對於多種人類組織及癌細胞株的北方墨點分析顯示:MELK在大部分的乳癌細胞及細胞株中以顯著高水準過度表現,但在正常的重要器官中則不會表現(心臟、肝臟、肺臟及腎臟)(WO2006/016525)。再者,以siRNA抑制MELK表現顯示會顯著抑制人類乳癌細胞的生長。因此,有人認為MELK是治療廣泛的癌症類型的癌症療法的適當標靶。
本案發明人致力於開發有效的MELK抑制劑,且發現有一化合物可以選擇性地抑制MELK的活性。
本發明係關於以下(1)至(24):(1)一種通式(I)化合物或其醫藥上可接受之鹽:
其中,X1選自下列所組成之群:直接鍵結、-NR12-、-O-及-S-;R12選自下列所組成之群:氫原子、C1-C6烷基及C3-C10環烷基;Q1選自下列所組成之群:C3-C10環烷基、C6-C10芳基、5-
至10-員雜芳基、3-至10-員非芳香雜環基、(C3-C10環烷基)-C1-C6烷基、(C6-C10芳基)-C1-C6烷基、(5-至10-員雜芳基)-C1-C6烷基及(3-至10-員非芳香雜環基)-C1-C6烷基;其Q1選擇性地由分別選自A1之一或多個取代基取代;X2選自下列所組成之群:-CO-、-S-、-SO-及-SO2-;R11選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基;其中R11選擇性地由分別選自A2之一或多個取代基取代;R5選自下列所組成之群:鹵原子、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A3之一或多個取代基取代;R2、R3及R4分別選自下列所組成之群:氫原子、鹵原子及C1-C6烷基;A1及A3分別選自下列所組成之群:鹵原子、氰基、-COOR13、-CONR14R15、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR16R17、-OR18、-S(O)nR19、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;A2分別選自下列所組成之群:鹵原子、氰基、C3-C10環烷基、羧基、甲醯氧基、(C1-C6烷基)羰醯氧基、羥基、C1-C6烷氧基、胺基、C1-C6烷基胺基及二(C1-C6烷基)胺基;
R13、R14及R15分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;或R14及R15經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇性地由分別選自A4之一或多個取代基取代;R16及R18分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR20;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;R17選自下列所組成之群:氫原子及C1-C6烷基,其選擇性地由分別選自A4之一或多個取代基取代,或R16至R17經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇性地由分別選自A4之一或多個取代基取代;R19選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基及5-至10-員雜芳基;其中該烷基、環烷基、芳基、雜芳基選擇性地由分別選自A4之一或多個取代基取代;R20選自下列所組成之群:氫原子、-NR14R15、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;
n為整數,分別選自0至2;A4分別選自下列所組成之群:鹵原子、氰基、-COOR21、-CONR22R23、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR24R25、-OR26、-S(O)nR27、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;R21、R22及R23分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基,其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;或R22至R23經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A5之一或多個取代基取代;R24及R26分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR28;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;R25選自下列所組成之群:氫原子及選擇地由分別選自A5之一或多個取代基取代之C1-C6烷基;或R24及R25經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A5之一或多個取代基取代;R27選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10
芳基、及5-至10-員雜芳基;其中該烷基、環烷基、芳基及雜芳基選擇地由分別選自A5之一或多個取代基取代;R28分別選自下列所組成之群:氫原子、-NR22R23、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;A5分別選自下列所組成之群:鹵原子、氰基、-COOR31、-CONR32R33、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR34R35、-OR36、-S(O)nR37、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基,雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;R31、R32及R33分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A6之一或多個取代基取代;或R32至R33經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A6之一或多個取代基取代;R34及R36分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR38;其中該烷基、烯基、炔基、環烷基、芳基,雜芳基、及雜環基選擇地由分別
選自A6之一或多個取代基取代;R35選自下列所組成之群:氫原子選擇地由分別選自A6之一或多個取代基取代之C1-C6烷基;或R34及R35經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A6之一或多個取代基取代;R37選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基及5-至10-員雜芳基;其中該烷基、環烷基、芳基、及雜芳基選擇地由分別選自A6之一或多個取代基取代;R38分別選自下列所組成之群:氫原子、-NR32R33、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A6之一或多個取代基取代;A6分別選自下列所組成之群:鹵原子、氰基、羧基、-COOR41、-CONR42R43、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR44R45、-OR46、S(O)nR47、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基,雜芳基,及雜環基選擇性地以一或多個取代基取代,該取代基分別選自下列所組成之群:鹵原子、羥基、C1-C6烷氧基、胺基、C1-C6烷基胺基及二(C1-C6烷基)胺基;R41、R42及R43分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基,雜芳基、及雜環基選擇性地以一或
多個取代基取代,該取代基分別選自下列所組成之群:鹵原子、羥基、C1-C6烷氧基、胺基、C1-C6烷基胺基及二(C1-C6烷基)胺基;R44及R46分別選自下列所組成之群:氫原子、C1-C6烷基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR48;R45選自下列所組成之群:氫原子及C1-C6烷基;R47選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基及5-至10-員雜芳基;以及R48分別選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基。
根據上述(1)之化合物或其醫藥可接受鹽類,其中Q1選自下列所組成之群:C5-C7環烷基、苯基、吡啶基(pyridyl)、吡唑基(pyrazolyl)、嘧啶基(pyrimidinyl)、及哌啶基(piperidyl);其中Q1選擇地由分別選自A1之一或多個取代基取代。
據上述(1)或(2)之化合物或其醫藥可接受鹽類,其中X2選自下列所組成之群:-CO-及-SO2-;;以及R11選自下列所組成之群:C1-C6烷基及C3-C7環烷基,其選擇性地以一或多個取代基取代,該取代基分別選自下列所組成之群:羥基及鹵原子。
據上述(1)至(3)之化合物或其醫藥可接受鹽類,其中R5係以一或多個取代基取代之苯基,該取代基分別選自下列所組成之群:羥基,鹵原子、C1-C6烷基及C1-C6烷氧基,其
中該烷基及烷氧基選擇性地以一或多個鹵原子取代。
據上述(1)至(4)之化合物或其醫藥可接受鹽類,其中R2係氫原子。
據上述(1)至(5)之化合物或其醫藥可接受鹽類,其中R3係氫原子。
據上述(1)至(6)之化合物或其醫藥可接受鹽類,其中R4係氫原子。
據上述(1)至(7)之化合物或其醫藥可接受鹽類,其中X1係-NH-。
據上述(1)至(8)之化合物或其醫藥可接受鹽類,其中Q1選擇的取代基選自下列所組成之群:羥基、胺基、C1-C6烷氧基、C1-C6烷基胺基、二(C1-C6烷基)胺基、胺基-C1-C6烷基、(C1-C6烷基胺基)-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、胺基-C1-C6烷氧基、(C1-C6烷基胺基)-C1-C6烷氧基、二(C1-C6烷基)胺基-C1-C6烷氧基、羥基-C1-C6烷基、(C1-C6烷氧基)-C1-C6烷基、羧基-C1-C6烷基、[(C1-C6烷氧基)羰基]-C1-C6烷基、氨基甲醯基-C1-C6烷基、[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基、[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基、(C1-C6烷基)羰基胺基、N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基、吡咯啶基(pyrrolidinyl)、哌啶基(piperidyl)、及哌嗪基(piperazinyl);其中該群之定義為Q1選擇的取代基選擇性地以一取代基取代,該取代基選下列所組成之群:胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、
哌啶基及哌嗪基;以及其中該吡咯啶基、哌啶基及哌嗪基定義為Q1選擇的取代基,選擇性地以一取代基取代,該取代基選下列所組成之群:C1-C6烷基、胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基。
根據上述(1)之化合物或其醫藥可接受鹽類,其中Q1選擇的取代基選自下列所組成之群:羥基、胺基、二(C1-C6烷基)胺基、C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷氧基、二(C1-C6烷基)胺基、[(胺基-C1-C6烷基)羰基]胺基、N-(C1-C6烷基)哌啶基、二(C1-C6烷基)胺基-吡咯啶-1-基、胺基-吡咯啶-1-基、(吡咯啶-1-基)-C1-C6烷基、(C1-C6烷基)胺基-哌啶-1-基、胺基-哌啶-1-基、羥基-C1-C6烷基、[二(C1-C6烷基)胺基-C1-C6烷基]胺基、[4-(C1-C6烷基)-哌嗪-1-基]-C1-C6烷基、(哌嗪-1-基)-C1-C6烷基、吡咯啶基羰基-胺基、(羥基-吡咯啶-1-基)-C1-C6烷基、嗎啉基-C1-C6烷基、[N-(羥基-C1-C6烷基)-N-(C1-C6烷基)胺基]-C1-C6烷基及(CD3)2N-C1-C6烷基。
據上述(1)所述選自下列所組成之群之化合物或其醫藥可接受鹽類:1-(6-氯-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(二甲基胺基)環己基)胺基)-1,5-萘啶(naphthyridin)-3-基)乙酮(ethanone);1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-(二甲基胺基)環己基)
胺基)-1,5-萘啶-3-基)乙酮;環丙基(6-(3,5-二氯-4-羥基苯基)-4-(4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)甲酮;(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-((4-((二甲基胺基)甲基)-環己基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(2-(二甲基胺基)乙基)-環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-(4-((二甲基胺基)甲基)環己基胺基)-6-(4-羥基-3-(三氟甲氧基)-苯基)-1,5-萘啶-3-基)乙酮;2,6-二氯-4-(8-((4-((二甲基胺基)甲基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-((4-((二甲基胺基)甲基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-((4-((二甲基胺基)甲基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;2,6-二氯-4-(8-((4-(二甲基胺基)環己基)胺基)-7-(甲基磺
醯基)-1,5-萘啶-2-基)酚;2,6-二氯-4-(8-((4-((二甲基胺基)甲基)苯基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-((4-((二甲基胺基)甲基)苯基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-((4-((二甲基胺基)甲基)苯基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((3-(2-(吡咯啶-1-基)乙基)苯基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(3-(2-(吡咯啶-1-基)乙基)苯基胺基)-1,5-萘啶-3-基)乙酮,1-(6-(3,5-二氯-4-羥基苯基)-4-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;2,6-二氯-4-(8-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-7-(甲基-磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((1-甲基哌啶-4-基)甲基胺
基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-((二甲基胺基-d6)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)苯基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)苯基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-((4-(2-(二甲基胺基)乙基)苯基)-胺基)-1,5-萘啶-3-基)乙酮;2-氯-4-(8-((4-(二甲基胺基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(2-(吡咯啶-1-基)乙基)哌啶-1-基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(2-(吡咯啶-1-基)乙基)哌啶-1-基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙基胺基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙基胺
基)-吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;(S)-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮(methanone);1-(4-((2-(3-胺基吡咯啶-1-基)嘧啶-5-基)胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-(4-(4-((二甲基胺基)甲基)環己基胺基)-6-(1H-吡唑-4-基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(羥基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基]-2-羥基乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(1-甲基哌啶-4-基胺基)-1,5-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(1-甲基哌啶-4-基胺基)-1,5-萘啶-3-基)乙酮;1-{6-[3,5-二氯-4-羥基苯基]-4-[4-(嗎啉基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(((2-羥基乙基)(甲基)胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(((2-羥基乙基)(甲基)胺基)-甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氟-4-羥基苯基)-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((6-(3-(二甲基胺基)吡咯啶
-1-基)吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((6-(3-(二甲基胺基)吡咯啶-1-基)-吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(6-(3-(甲基胺基)吡咯啶-1-基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(6-(3-(甲基胺基)吡咯啶-1-基)-吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(1H-苯並[d]咪唑-5-基)-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-((4-((二甲基胺基)甲基)環己基胺基)-6-(吡啶-4-基)-1,5-萘啶-3-基)乙酮;5-(7-乙醯基-8-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)-嘧啶-2-甲腈;1-(6-(3,5-二甲基-1H-吡唑-4-基)-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-(4-((二甲基胺基)甲基)環己基胺基)-6-(4-羥基-3,5-二甲基-苯基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(吡咯啶-1-基甲基)苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(吡咯啶-1-基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(吡咯啶-1-基甲基)環己基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)
環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;1-(4-(4-胺基環己基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-[4-(4-胺基環己基胺基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基]乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-環己基胺基)-1,5-萘啶-3-基)乙酮;N-(4-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)-環己基)-2-胺基-3-甲基丁醯胺;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(哌嗪-1-基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;N-(4-((3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基)胺基)環己基)-2-胺基丙醯胺;N-(4-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)-環己基)-2-胺基丙醯胺;(S)-N-((1R,4S)-4-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-
萘啶-4-基-胺基)環己基)吡咯啶-2-羧醯胺;(S)-N-((1R,4S)-4-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)環己基)吡咯啶-2-羧醯胺;1-(6-(3-羥基吡咯啶-1-基)-4-(4-((3-羥基吡咯啶-1-基)甲基)環己基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(吡咯啶-1-基)-4-(4-(吡咯啶-1-基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;N-(4-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基)-環己基)-2-胺基-3-甲基丁醯胺;[6-(3-氯-5-氟-4-羥基苯基)-4-[4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基](環丙基)甲酮;環丙基[6-(3,5-二氯-4-羥基苯基)-4-[4-(二甲基胺基)環己基-胺基]-1,5-萘啶-3-基]甲酮;1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(1H-吡咯[2,3-b]吡啶-5-基)-1,5-萘啶-3-基)乙酮;(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}(環丙基)甲酮;1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(4-甲氧基苯基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-甲氧基苯基)-4-{4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]乙酮;1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(6-羥基吡啶-3-基)-1,5-萘啶-3-基)乙酮;5-(7-乙醯基-8-{4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘
啶-2-基)2-氰吡啶(picolinotrile);1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{[4-(二甲基胺基)環己基]甲基-胺基}-1,5-萘啶-3-基)乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-{[4-(二甲基胺基)環己基]-甲基胺基}-1,5-萘啶-3-基]乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-(4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-(4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-{順-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{順-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基}乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;(R)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;(R)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(二甲基胺基)環己
基]胺基}-1,5-萘啶-3-基)-2-羥基乙酮二鹽酸鹽;1-[6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]-2-羥基乙酮二鹽酸鹽;1-[6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]1-丙酮二鹽酸鹽;1-[6-(3,5-二氯-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]1-丙酮二鹽酸鹽;(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽;(S)-1-(4{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽;1-[6-(3,5-二氯-4-羥基苯基)-4-({4-[((R)-3-氟吡咯啶-1-基)甲基]環己基}胺基)-1,5-萘啶-3-基]乙酮二鹽酸鹽;(S)-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丁基)甲酮二鹽酸鹽;(6-(3,5-二氯-4-羥基苯基)-4-((4-[(二甲基胺基)甲基{環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮二鹽酸鹽;(6-(3-氯-5-氟-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮二鹽酸鹽;(S)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丁基)甲酮;(R)-1-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽;(R)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-
二氯-4-羥基苯基)-1,5-萘啶-3-基)-2-甲基1-丙酮三鹽酸鹽;1-[6-(3,5-二氯-5-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮二鹽酸鹽;1-[6-氯-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮二鹽酸鹽;以及其可接其醫藥上可接受之鹽。
根據上述(1)之化合物或其醫藥可接受鹽類,其選自下列所組成之群;下列化合物:1-(6-(3,5-二氯-4-羥基苯基)-4-(反-(4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮;環丙基(6-(3,5-二氯-4-羥基苯基)-4-(反-4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)甲酮;(6-(3-氯-5-氟-4-羥基苯基)-4-(反-4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((反-4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((反-4-((二甲基胺基)甲基)-環己基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((反-4-(2-(二甲基胺基)乙基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;(S)-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]-2-羥基乙酮;
1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基}(環丙基)甲酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基}乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;及其可接其醫藥上可接受之鹽。
一種含有如(1)至(12)所述之化合物或其醫藥上可接受之鹽任一為活性成分的醫藥組合物。
一種含有如(1)至(12)所述之化合物或其醫藥上可接受之鹽任一為活性成分的MELK抑制劑。
一種含有如(1)至(12)所述之化合物或其醫藥上可接受之鹽任一為活性成分的MELK表現調節劑。
一種含有如(1)至(12)所述之化合物或其醫藥上可接受之鹽任一為活性成分的抗腫瘤劑。
一種治療和/或預防涉及MELK過量表現之疾病的
藥劑,其包括如(1)至(12)所述之化合物或其醫藥上可接受之鹽任一作為活性成分。
如(17)所述之治療和/或預防藥劑,其中該疾病為癌症。
如(18)所述之治療和/或預防藥劑,其中該癌症選自下列所組成之群:乳癌、肺癌、膀胱癌、淋巴癌及子宮癌。
一種治療和/或預防涉及MELK過量表現之疾病的方法,其包括對一有需要之受試者投予一有效量之如(1)至(12)所述之化合物或其醫藥上可接受之鹽。
一種如(1)至(12)所述之化合物或其醫藥上可接受之鹽用於治療和/或預防涉及MELK過量表現之疾病。
一種如(1)至(12)所述之化合物或其醫藥上可接受之鹽在製備治療和/或預防涉及MELK過量表現之疾病的藥劑中的應用。
一種製備如(1)至(12)所述之通式(I)化合物或醫藥上可接受之鹽之方法:
其中R5為選擇性地經一或多個取代基取代之苯基,該取代基分別選自A3;以及Q1、X1、X2、R11、R2、R3、R4及A3為如(1)至(10)所述任一所定義之基團,其包括:使通式(II)化合物與通式(III)化合物反應,
其中Q1、X1、X2、R11、R2、R3及R4為上述定義之基團,但條件是該基團可有一或多個保護基團,及X11為鹵原子如氯原子;
其中R5為上述定義,但條件是R5基團可有一或多個保護基團,且R51及R52分別選自下列所組成之群:C1-C6烷基或R51及R52經由硼原子彼此鍵結在一起形成選擇性地經一或多個取代基取代之5-至7-環環硼酸酯,該取代基分別選自下列所組成之群:C1-C6烷基。
一種通式(II)化合物或其醫藥上可接受之鹽:
其中Q1、X1、X2、R11、R2、R3及R4如(1)至(10)所述之一之基團,但條件是該基團可有一或多個保護基團及X11為鹵原子。
本發明之一態樣係提供一種通式(I)化合物或其醫藥上可接受之鹽:
其中,X1為-NH-;Q1為選自下列所組成之群:C5-C7環烷基、苯基、吡啶基、吡唑基、嘧啶基及哌啶基;其中Q1選擇性地經一或多個取代基取代,該取代基分別選自A1;X2為選自下列所組成之群:-CO-及-SO2-;R11為選自下列所組成之群:C1-C6烷基及C3-C7環烷基,其選擇性地經一或多個取代基取代,該取代基分別選自下列所組成之群:羥基及鹵原子;R5為經一或多個取代基取代之苯基,該取代基分別選自下列所組成之群:羥基、鹵原子、C1-C6烷基及C1-C6烷氧基,其中該烷基及烷氧基選擇性地經一或多個鹵原子取代;R2、R3及R4為氫原子;A1分別選自下列所組成之群:羥基、胺基、C1-C6烷氧基、C1-C6烷基胺基、二(C1-C6烷基)胺基、胺基-C1-C6烷基、(C1-C6烷基胺基)-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、胺基-C1-C6烷氧基、(C1-C6烷基胺基)-C1-C6烷氧基、二(C1-C6烷基)胺基-C1-C6烷氧基、羥基-C1-C6烷基、(C1-C6烷氧基)-C1-C6烷基、羧基-C1-C6烷基、[(C1-C6烷氧基)羰基]-C1-C6烷基、氨基甲醯基-C1-C6烷基、[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基、[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基、(C1-C6烷基)羰基
胺基、N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基、吡咯啶基、哌啶基及哌嗪基;其中該吡咯啶基、哌啶基及哌嗪基定義為A1選擇性地經一個取代基取代,該取代基選自下列所組成之群:C1-C6烷基、胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基;以及其中該基團之烷基官能基定義為A1選擇性地選擇性地經一個取代基取代,該取代基選自下列所組成之群:胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基。
本發明之又一態樣係提供一種通式(I)化合物或其醫藥上可接受之鹽::
其中,X1為-NH-;及Q1選自下列所組成之群:C5-C7環烷基,如環己基及吡啶基;其中Q1選擇性地經一或多個取代基取代,該取代基分別選自A1;A1分別選自下列所組成之群:羥基、胺基、C1-C6烷氧基、C1-C6烷基胺基、二i(C1-C6烷基)胺基、胺基-C1-C6烷基、(C1-C6烷基胺基)-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、胺基-C1-C6烷氧基、(C1-C6烷基胺基)-C1-C6烷氧基、二(C1-C6烷基)
胺基-C1-C6烷氧基、羥基-C1-C6烷基、(C1-C6烷氧基)-C1-C6烷基、羧基-C1-C6烷基、[(C1-C6烷氧基)羰基]-C1-C6烷基、氨基甲醯基-C1-C6烷基、[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基、[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基、(C1-C6烷基)羰基胺基、N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基、吡咯啶基、哌啶基及哌嗪基;其中該吡咯啶基、哌啶基及哌嗪基定義為A1選擇性地經一個取代基取代,該取代基選自下列所組成之群:C1-C6烷基、胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基;及其中該基團之烷基官能基定義為A1選擇性地選擇性地經一個取代基取代,該取代基選自下列所組成之群:胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基;X2選自下列所組成之群:-CO-;及R11選自下列所組成之群:C1-C6烷基及C3-C7環烷基、其選擇性地經一個取代基取代,該取代基選自下列所組成之群:羥基及鹵原子;R2、R3及R4為氫原子;及R5為經一羥基及二鹵原子取代之苯基。
前述通式(I)之定義態樣之一,Q1選擇的取代基為選自下列所組成之群:羥基、胺基、二(C1-C6烷基)胺基、C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷氧基、二(C1-C6烷基)胺基、[(胺基-C1-C6烷基)羰基]胺基、N-(C1-C6烷基)哌啶基、二(C1-C6烷基)胺基-吡咯啶-1-基、胺基-吡咯啶-1-基、(吡咯啶-1-基)-C1-C6烷基、(C1-C6烷
基)胺基-哌啶-1-基、胺基-哌啶-1-基、羥基-C1-C6烷基、[二(C1-C6烷基)胺基-C1-C6烷基]胺基、[4-(C1-C6烷基)-哌嗪-1-基]-C1-C6烷基、(哌嗪-1-基)-C1-C6烷基、吡咯啶基羰基-胺基、(羥基-吡咯啶-1-基)-C1-C6烷基、嗎啉基-C1-C6烷基、[N-(羥基-C1-C6烷基)-N-(C1-C6烷基)胺基]-C1-C6烷基及(CD3)2N-C1-C6烷基。
另一態樣,X1為-NH-;及Q1選自下列所組成之群:C5-C7環烷基,如環己基及吡啶基;其中Q1擇性地選擇性地經一個取代基取代,該取代基選自A1;A1分別選自下列所組成之群:羥基、胺基、C1-C6烷氧基、C1-C6烷基胺基、二(C1-C6烷基)胺基、胺基-C1-C6烷基、(C1-C6烷基胺基)-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、胺基-C1-C6烷氧基、(C1-C6烷基胺基)-C1-C6烷氧基、二(C1-C6烷基)胺基-C1-C6烷氧基、羥基-C1-C6烷基、(C1-C6烷氧基)-C1-C6烷基、羧基-C1-C6烷基、[(C1-C6烷氧基)羰基]-C1-C6烷基、氨基甲醯基-C1-C6烷基、[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基、[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基、(C1-C6烷基)羰基胺基、N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基、吡咯啶基、哌啶基及哌嗪基;其中該吡咯啶基、哌啶基及哌嗪基定義為A1選擇性地經一個取代基取代,該取代基選自下列所組成之群:C1-C6烷基、胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基;及其中該基團之烷基官能基定義為A1選擇性地經一個取代
基取代,該取代基選自下列所組成之群:胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基。
另一態樣,X1為-NH-;Q1選自下列所組成之群:下列通式之環己基及吡啶基
其中R61為胺基-哌啶-1-基、(C1-C6烷基)胺基-哌啶-1-基及二(C1-C6烷基)胺基-C1-C6烷基;及R62選自下列所組成之群:二(C1-C6烷基)胺基及二(C1-C6烷基)胺基-C1-C6烷基。一實施例中,R61為3-胺基-哌啶-1-基及R62為二甲基胺基或二甲基胺基-甲基。
另一態樣,X1為直接鍵結;及Q1選自下列所組成之群:5-環含氮芳香雜環基,如吡咯基、吡唑基及咪唑基及3-至10-環含氮非芳香雜環基,如吡咯啶基、哌啶基、哌嗪基及嗎啉基,其中該雜芳基或雜環基之氮原子鍵結至該萘啶環;其中Q1選擇性地經一或多個取代基取代,該取代基分別選自A1。
又一態樣,X1為直接鍵結;及Q1選自下列所組成之群:5-環含氮芳雜環基,如吡咯基、吡唑基、咪唑基及3-至10-環含氮非芳香雜環基,如吡咯啶基、哌啶基、哌嗪基及嗎啉基,其中該雜芳基或雜環基之氮原子鍵結至該萘啶環;其中Q1選擇性地經一或多個取代基取代,該取代基分別選自A1;A1分別選自下列所組成之群:羥基、胺基、C1-C6烷氧基、
C1-C6烷基胺基、二(C1-C6烷基)胺基、胺基-C1-C6烷基、(C1-C6烷基胺基)-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、胺基-C1-C6烷氧基、(C1-C6烷基胺基)-C1-C6烷氧基、二(C1-C6烷基)胺基-C1-C6烷氧基、羥基-C1-C6烷基、(C1-C6烷氧基)-C1-C6烷基、羧基-C1-C6烷基、[(C1-C6烷氧基)羰基]-C1-C6烷基、氨基甲醯基-C1-C6烷基、[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基、[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基、(C1-C6烷基)羰基胺基、N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基、吡咯啶基、哌啶基及哌嗪基;其中該吡咯啶基、哌啶基及哌嗪基定義為A1選擇性地經一個取代基取代,該取代基選自下列所組成之群:C1-C6烷基、胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基;及其中該基團之烷基官能基定義為A1選擇性地經一個取代基取代,該取代基選自下列所組成之群:胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基。
另一態樣,X2選自下列所組成之群:-CO-;及R11選自下列所組成之群:C1-C6烷基及C3-C7環烷基、其選擇性地經一個取代基取代,該取代基選自下列所組成之群:羥基及鹵原子。
另一態樣,X2為-CO-;及R11選自下列所組成之群:甲基、羥基甲基及環丙基。
另一態樣,R5為經一羥基及二鹵原子取代之苯基。
另一態樣,R5選自下列所組成之群:3,5-二氯-4-
羥基苯基、3,5-二氟-4-羥基苯基及3-氯-5-氟-4-羥基苯基。
本發明態樣之一係提供一種選自下列所組成之群的化合物或其醫藥上可接受之鹽:下列化合物:1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮;1-{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基}乙酮;1-{6-(3-氯-5-氟-4-羥基苯基)-4-[反-4-(二甲基胺基)環己基-胺基]-1,5-萘啶-3-基}乙酮;環丙基(6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)甲酮;(6-(3-氯-5-氟-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基)環己基胺基]-1,5-萘啶-3-基}(環丙基)甲酮;1-{6-(3,5-二氯-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基}乙酮;1-{6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基}乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-({反-4-[2-(二甲基胺基)乙基]環己基}-胺基)-1,5-萘啶-3-基]乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-{反-4-[2-(二甲基胺基)乙基]-環己基胺基}-1,5-萘啶-3-基)乙酮;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-[4-羥基
-3-(三氟-甲氧基)苯基]-1,5-萘啶-3-基)乙酮;2,6-二氯-4-(8-{反-4-[(二甲基胺基)甲基]環己基胺基}-7-(甲基-磺醯基)-1,5-萘啶-2-基)酚;6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-3-甲基磺醯基-1,5-萘啶;6-(3-氯-4-羥基-5-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-3-甲基磺醯基-1,5-萘啶;2,6-二氯-4-{8-[反-4-(二甲基胺基)環己基胺基]-7-(甲基磺醯基)-1,5-萘啶-2-基}酚;2,6-二氯-4-(8-(4-((二甲基胺基)甲基)苯基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-(4-((二甲基胺基)甲基)苯基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-(4-((二甲基胺基)甲基)苯基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;1-(6-(3,5-二氯-4-羥基苯基)-4-(3-(2-(吡咯啶-1-基)乙基)苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(3-(2-(吡咯啶-1-基)乙基)苯基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(6-(2-(二甲基胺基)-乙氧基)吡啶-3-基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙氧基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-(6-(2-(二甲基胺基)乙
氧基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;2,6-二氯-4-(8-(6-(2-(二甲基胺基)乙氧基)吡啶-3-基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-(6-(2-(二甲基胺基)乙氧基)吡啶-3-基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-(6-(2-(二甲基胺基)乙氧基)吡啶-3-基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((1-甲基哌啶-4-基)甲基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(反-4-((二甲基胺基-d6)-甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(2-(二甲基胺基)-乙基)苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(2-(二甲基胺基)乙基)苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-(4-(2-(二甲基胺基)乙基)苯基-胺基)-1,5-萘啶-3-基)乙酮;2-氯-4-(8-(反-4-(二甲基胺基)環己基胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;1-(6-(3,5-二氯-4-羥基苯基)-4-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)苯基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲
基)-苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(2-(吡咯啶-1-基)乙基)哌啶-1-基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(2-(吡咯啶-1-基)乙基)哌啶-1-基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙基胺基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙基胺基)-吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;(S)-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(4-(2-(3-胺基吡咯啶-1-基)嘧啶-5-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(1H-吡唑-4-基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(羥基甲基)環己基]胺基}-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]-2-羥基乙酮;1-{6-(3,5-二氯-4-羥基苯基)-4-[(1-甲基哌啶-4-基)胺基]-1,5-萘啶-3-基}乙酮;1-{6-(3-氯-5-氟-4-羥基苯基)-4-[(1-甲基哌啶-4-基)胺基]-1,5-萘啶-3-基}乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(嗎啉基甲基)環己
基]-胺基}-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-(反-4-{[(2-羥基乙基)(甲基)胺基]-甲基}環己基胺基)-1,5-萘啶-3-基]-乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-(反-4-{[(2-羥基乙基)(甲基)-胺基]甲基}環己基胺基)-1,5-萘啶-3-基]-乙酮;1-(6-(3,5-二氟-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-{6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-{6-[3-(二甲基胺基)吡咯啶-1-基]-吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-{6-[3-(甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-{6-[3-(甲基胺基)-吡咯啶-1-基]-吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮;1-(6-(1H-苯並[d]咪唑-5-基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基)乙酮;1-{4-[4-(反-4-二甲基胺基)甲基環己基胺基]-6-(吡啶-4-基)-1,5-萘啶-3-基}乙酮;5-(7-乙醯基-8-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-2-基)嘧啶-2-甲腈;1-(6-(3,5-二甲基-1H-吡唑-4-基)-4-{反-4-[(二甲基胺基)-甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(4-羥基
-3,5-二甲基-苯基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-{6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮;1-{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(吡咯啶-1-基甲基)-環己基-胺基]-1,5-萘啶-3-基}乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-{[反-4-(吡咯啶-1-基甲基)環己基]胺基}-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(4-甲基哌嗪-1-基)-甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮;1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;1-{4-[反-(4-胺基環己基)胺基]-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基}乙酮;1-{4-[反-(4-胺基環己基)胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-{反-4-[(4-甲基哌嗪-1-基)-甲基]環己基胺基}-1,5-萘啶-3-基)乙酮;N-(反-4-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]-胺基}環己基)-2-胺基-3-甲基丁醯胺;1-{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(哌嗪-1-基甲基)-環己基-胺基]-1,5-萘啶-3-基}乙酮;(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二
氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)乙酮;N-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]-環己基}-2-胺基丙醯胺;N-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-基-胺基]環己基}-2-胺基丙醯胺;(S)-N-{4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-基-胺基-胺基]環己基}吡咯啶-2-吡咯啶;(S)-N-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-基-胺基胺基]環己基}吡咯啶-2-吡咯啶;1-(6-(3-羥基吡咯啶-1-基)-4-{反-4-[(3-羥基吡咯啶-1-基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮;1-{6-(吡咯啶-1-基)-4-[反-4-(吡咯啶-1-基甲基)-環己基胺基]-1,5-萘啶-3-基}乙酮;N-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]-環己基}-2-胺基-3-甲基丁醯胺;環丙基{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(二甲基胺基)環己基-胺基]-1,5-萘啶-3-基}甲酮;1-[6-(3-氯-5-氟-4-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基]乙酮;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(1H-吡咯[2,3-b]-吡啶-5-基)-1,5-萘啶-3-基)乙酮;(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟
-4-羥基-苯基)-1,5-萘啶-3-基}(環丙基)甲酮;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(4-甲氧基苯基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]乙酮;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(6-羥基吡啶-3-基)-1,5-萘啶-3-基)乙酮;5-(7-乙醯基-8-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-2-基)2-氰吡啶;1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(4-羥基苯基)-1,5-萘啶-3-基)乙酮二鹽酸鹽;1-[6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(二甲基胺基)環己基]甲基-胺基}-1,5-萘啶-3-基]乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-{[反-4-(二甲基胺基)環己基]-甲基胺基}-1,5-萘啶-3-基]乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮;1-{6-(3-氯-5-氟-4-羥基苯基)-4-({順-4-[(二甲基胺基)甲基]-環己基}胺基)-1,5-萘啶-3-基}乙酮;1-{6-(3,5-二氯-4-羥基苯基)-4-({順-4-[(二甲基胺基)甲基]-環己基}胺基)-1,5-萘啶-3-基}乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二
氯-4-羥基-苯基)-1,5-萘啶-3-基}乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;以及其醫藥可接受之鹽。
本發明另一態樣係提供通式(1)之化合物或選自下列所組成之群之醫藥可接受鹽類:下列化合物:1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮;環丙基(6-(3,5-二氯-4-羥基苯基)-4-(4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)甲酮;(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((二甲基胺基)甲基)環己基-胺基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]-2-羥基乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;
1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基}(環丙基)甲酮;1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基}乙酮;1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;以及其醫藥可接受鹽類。
本發明態樣之一係提供一製備(1)至(12)所述之通式(I)化合物或其醫藥可接受鹽類之方法:
其中X1為-NH-;及X2、R11、R2、R3及R4定義為(1)至(10)所述或先前所述之基團,其包括:使通式(IV)化合物與通式(V)化合物反應,
其中X2、R11、R2、R3及R4為先前所定義之基團,但條
件是該基團可有一或多個保護基團;及X11及X12分別選自鹵原子,如氯原子;Q1-NH2 (V)
其中Q1為先前所定義之基團,但條件是該基團可有一或多個保護基團;獲得一通式(II)之化合物。
本發明另一態樣係提供一製備(1)至(11)所述之通式(I)化合物或其醫藥可接受鹽類之方法:
其中X1為-NH-;R5為選擇性地經一或多個取代基取代之苯基,該取代基分別選自A3;及Q1、X1、X2、R11、R2、R3及R4為如(1)至(10)所述任一所定義之基團,其包括:使通式(IV)化合物與通式(V)化合物反應,
其中X2、R11、R2、R3及R4為上述定義之基團,但條件是該基團可有一或多個保護基團,及X11及X12分別選自鹵
原子,如氯原子;Q1-NH2 (V)
其中Q1為先前所定義之基團,但條件是該基團可有一或多個保護基團;獲得一通式(II)之化合物;
以及,使通式(II)化合物與通式(III)化合物反應,
其中Q1、X1、X2、R11、R2、R3及R4為先前所定義之基團,但條件是該基團可有一或多個保護基團及X11鹵原子;
其中R5為先前所定義,但條件是R5基團可有一或多個保護基團;及R51及R52分別選自下列所組成之群:C1-C6烷基或R51及R52經由硼原子彼此鍵結在一起形成選擇性地經一或多個取代基取代之5-至7-環環硼酸酯,該取代基分別選自下列所組成之群:C1-C6烷基。
態樣之一,保護-NH-及/或-NH2保護基團選自下列
所組成之群:C1-C6烷基羰基(如乙醯基)、C1-C6烷氧基羰基(如甲氧基羰基、乙氧基羰基及叔丁氧羰基)、苯基(C1-C6烷氧基)羰基(如苯甲氧基羰基)、(C1-C6烷氧基1)C1-C6烷基(如甲氧基甲基)、苯基(C1-C6烷氧基)甲基(如苯甲氧基甲基)及(苯基)C1-C6烷基(如苄基);及保護羥基保護基團選自下列所組成之群:C1-C6烷基羰基(如乙醯基)、C1-C6烷氧基羰基(如甲氧基羰基、乙氧基羰基及叔丁氧羰基)、苯基(C1-C6烷氧基)羰基(如苯甲氧基羰基)、(C1-C6烷氧基1)C1-C6烷基(如甲氧基甲基)、苯基(C1-C6烷氧基)甲基(如苯甲氧基甲基)、(苯基)C1-C6烷基(如苄基)、三(C1-C6烷基)甲矽烷基(如三甲基甲矽烷基及叔丁二甲基甲矽烷基)、二(C1-C6烷基)苯基甲矽烷基、(C1-C6烷基)二苯基甲矽烷基及三苯基甲矽烷基。又該羧基基團可以C1-C6烷基(如甲基及乙基)、(苯基)C1-C6烷基(如苄基)、(C1-C6烷氧基1)C1-C6烷基(如甲氧基甲基)或苯基(C1-C6烷氧基)C1-C6烷基(如苯甲氧基甲基)保護形成相對應之酯。
本發明態樣之一係提供一種通式(II)化合物或其醫藥上可接受之鹽:
其中Q1、X1、X2、R11、R2、R3及R4如(1)至(10)所述之一之基團,但條件是-含NH-及/or-NH2基團可有一或多個保
護基團,該保護基團選自下列所組成之群:C1-C6烷基羰基(如乙醯基)、C1-C6烷氧基羰基(如甲氧基羰基、乙氧基羰基及叔丁氧羰基)、苯基(C1-C6烷氧基)羰基(如苯甲氧基羰基)、(C1-C6烷氧基1)C1-C6烷基(如甲氧基甲基)、苯基(C1-C6烷氧基)甲基(如苯甲氧基甲基)及苄基;及X11為鹵原子。
圖1為說明實施例6化合物體外抗增殖活性系列圖片(a)-(e)。該圖指出實施例6化合物對各類型人類癌細胞株之生長抑制效果;(a)A549(肺癌)、(b)T47D(乳癌)、(c)DU4475(乳癌)及(d)22Rv1(前列腺癌)細胞株其MELK高表現,而(e)HT1197(膀胱癌)細胞株其MELK表現幾乎偵測不到。
圖2為說明異種移植模型系列圖片(a)-(h),其顯示實施例6對各類型人類癌細胞株異種移植之有效性。具(a,b)MDA-MB-231(三陰性乳癌)、(c,d)A549(肺癌)、(e)DU145(前列腺癌)或(f)MIAPaCa-2(胰臟癌)裸鼠以給定濃度之載體對照或實施例6化合物治療14。劑量為(a)對MDA-MB-231者靜脈注射每兩日一次20mg/kg或(b)每日口服一次10mg/kg;(c)對A549者靜脈注射每日一次1、5或10mg/kg或(d)口服每日一次5或10mg/kg;(e)對DU145者口服每日一次10mg/kg;及(f)對MIAPaCa-2者口服每日一次10mg/kg。以平均腫瘤量±SD(n=6每處理組)表示;(g)自A549及PC-14異種移植小鼠腫瘤樣本之溶解物以抗-MELK及抗-ACTB抗體進行免疫墨點;(h)實施例6化合物以口服具PC-14(MELK-陰性膀胱癌
細胞株)投予劑量每日一次10mg/kg。以平均腫瘤量±SD(n=3每處理組)表示。i.v.q.2d;靜脈注射每二日一次;i.v.q.d.;靜脈注射每日一次、p.o.q.d.;口服每日一次。
圖3為說明實施例6對於異種移植模型小鼠體重影響之系列圖片(a)-(f)。具(a,b)MDA-MB-231(MELK-陽性、三陰性乳癌)、(c,d)A549(肺癌)、(e)DU145(前列腺癌)、or(f)MIAPaCa-2(胰臟癌)細胞株裸鼠以載體對照或實施例6化合物給藥14天。以平均相對體重±SD(n=6每處理組)相較投藥前平均體重表示。投藥14天後平均相對體重為:(a)0.93,對MDA-MB-231者靜脈注射每兩日一次20mg/kg;(b)0.89,對MDA-MB-231者每日口服一次10mg/kg;(c)1.06,對A549者靜脈注射每日一次1mg/kg;1.03,對A549靜脈注射每日一次5mg/kg;及1.00,對A549靜脈注射每日一次10mg/kg;(d)0.99,對A549者口服每日一次5mg/kg;及0.98,對A549口服每日一次10mg/kg;(e)0.96,對DU1459者口服每日一次10mg/kg;(f)0.97,對MIAPaCa-2者口服每日一次10mg/kg。i.v.q.2d;靜脈注射每二日一次;i.v.q.d.;靜脈注射每日一次、p.o.q.d.;口服每日一次。
本發明之一目的係提供一種具抑制MELK活性之化合物及包括該化合物醫藥可接受鹽類,其可用於治療增殖性疾病,如癌症。本發明另一目的係提供一種治療和/或預防增殖性疾病之方法。本發明又一目的係提供一種製備該化合物之方法。
以下以通式(I)代表的化合物,將稱為化合物(I)。同樣方式應用在以其他通式編號的化合物。需注意:在此及附屬的申請專利範圍中使用的單數形「一(a)」、「一(an)」,及「該(the)」,除非在內文中明確指明,否則包括複數的含意。因此,比如當指出一「群組」,係代表一或更多群組。
上述通式之每一基團定義如下:
該“C1-C6烷基”及“C1-C6烷氧基”、“C1-C6烷基胺基”、“二(C1-C6烷基)胺基”、(C1-C6烷基)羰基及類似物中C1-C6烷基部份意指具一至六個碳原子之直鍊或支鍊烷基基團。具體來說,該“C1-C6烷基”及“C1-C6烷基部份”案例包括,但不定限於,甲基、乙基、丙基、異丙基、丁基、異丁基、仲丁基、叔-丁基、戊基、1-甲基丁基、1-乙基丙基、2-甲基丁基、異戊基、叔-戊基、1,2-二甲基丙基、新戊基、己基、1-甲基戊基、1-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、異己基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、1-異丙基丙基、1-乙基-1-甲基丙基、2,3-二甲基丁基、3,3-二甲基丁基、2,2-二甲基丁基、2-乙基丁基、及3-乙基丁基。
該“C2-C6烯基”、及“C2-C6烯氧基”及類似物之C2-C6烯基部份意指具二至六個碳原子及一至三個雙鍵之直鍊或支鍊烷基基團。具體來說,該“C1-C6烯基”及“C1-C6烯基部份”案例包括,但不定限於,乙烯基、1-丙烯-1-基、2-丙烯-1-基(allyl)、丙烯-2-基、1-丁烯-1-基、2-丁烯-1-基及1,3-丁烯-1-基。
該“C2-C6炔基”及“C2-C6炔氧基”及類似物之C2-C6
炔基部份意指具二至六個碳原子及一至三個三鍵之直鍊或支鍊烷基基團。具體來說,該“C1-C6炔基”及該“C1-C6炔基部份”案例包括,但不定限於,乙炔基、1-丙炔-1-基、2-丙炔-1-基(propargyl))、丙炔-2-基、1-丁炔-1-基、2-丁炔-1-基及1,3-丁炔-1-基。
說明書中,在每一個基團中C1-C6烷基部份除另有所註否則如上“C1-C6烷基部份”所定義。含複數C1-C6烷基部份基團案例中,該C1-C6烷基部份可為一樣或不同。
“C1-C6烷氧基”具體案例包括,但不定限於,甲氧基、乙氧基、丙氧基、異丙氧基、異丁氧基、叔-丁氧基、丁氧基、戊氧基及己氧基。
該“C1-C6烷氧基羰基”意指-C(=O)O-(C1-C6烷基)之單鍵基團。“C1-C6烷氧基羰基”具體案例包括,但不定限於,甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙氧基羰基、異丁氧基羰基、叔丁氧羰基、丁氧基羰基、戊氧基羰基及己氧基羰基。
該“(C1-C6烷基)羰基”意指-C(=O)-(C1-C6烷基)之單鍵基團。“C1-C6烷基羰基”具體案例包括,但不定限於,甲基羰基(即乙醯基)、乙基羰基、丙基羰基、異丙基羰基、異丁基羰基、叔-丁基羰基、丁基羰基、戊基羰基及己基羰基。
“C1-C6烷基胺基”具體案例包括,但不定限於,甲基胺基、乙基胺基、丙基胺基、異丙基胺基、丁基胺基、異丁基胺基、仲丁基胺基及叔-丁基胺基、戊基胺基。
“二(C1-C6烷基)胺基”烷基部份可為一樣或不同。
“二(C1-C6烷基)胺基”具體案例包括,但不定限於,二甲基胺基、二乙基胺基、二丙基胺基、二異丙基胺基、二丁基胺基、二異丁基胺基、二(仲丁基)胺基、二(叔-丁基)胺基、二戊基胺基、乙基(甲基)胺基、丙基(甲基)胺基、異丙基(甲基)胺基、丁基(甲基)胺基、異丁基(甲基)胺基、仲丁基(甲基)胺基、叔-丁基(甲基)胺基及戊基(甲基)胺基。
通式:-S(O)nR19代表-SR19(n=0)、-SOR19(n=1)及-SO2R19(n=2)及案例包括,但不定限於,“C1-C6烷基硫”,如甲基硫、乙基硫及異丙基硫、“C1-C6烷基磺醯基”,如甲基磺醯基、乙基磺醯基及異丙基磺醯基及“C1-C6烷基亞磺醯基”,如甲基亞磺醯基、乙基亞磺醯基及異丙基亞磺醯基。此可應用於通式-S(O)nR27及-S(O)nR37定義。
“鹵原子”具體案例包括氟、氯、溴及碘原子。
“C3-C10環烷基”意指具三至十個碳原子之飽合單環碳氫基團及具四至十個碳原子其當二或多個飽合單環碳氫化合物分享二或多個碳原子時形成之橋接環碳氫基團。“C3-C10環烷基”亦包括與芳香或非芳香碳環結合形成雙環之環烷基。具體來說,“C3-C10環烷基”具體案例包括,但不定限於,飽合單環碳氫基團,如環丙基、環丁基、環戊基、環己基、環庚基及環辛基及橋接環碳氫基團,如金鋼烷基。
“C6-C10芳基”意指具六至十個碳原子之芳香碳環基團,並包括與芳香或非芳香碳環結合形成雙環基團之環烷基。具體案例包括,但不定限於,苯基、1-萘基、2-萘基及2,3-二氫-1H-茚基。
“5-至10-員雜芳基”意指具一或多個雜原子之芳香雜環基團,較佳為1至三個雜原子,其選自下列所組成之群:氮原子、氧原子及硫原子。“5-至10-員雜芳基”包括與芳香或非芳香碳環結合或與芳香或非芳香雜環結合形成雙環基團之芳香雜環烷基,亦包括與與芳香或非芳香雜環結合形成雙環基團之芳香碳環基團。具體案例包括,但不定限於,呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、異噁唑基、噁二唑基、噻唑基、異噻唑基、噻二唑基、三唑基、四唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、三嗪基、苯並呋喃基、苯並硫苯基、苯並噁唑基、苯並噻唑基、異吲哚基、吲哚基、1H-吲唑基、苯並咪唑基、苯並三唑基、噁唑並嘧啶基、噻唑並嘧啶基、吡咯吡啶亞基、吡咯嘧啶基、咪唑並吡啶基、嘌呤基、喹啉基、異喹啉基、噌嗪基、酚嗪基、喹唑啉基、喹喔啉基、萘啶基、吡哆並嘧啶基、[1,2,4]三唑並[1,5-a]吡啶基及吡咯[2,3-b]吡啶基。特別地,噻吩基、吡咯基、咪唑基、異噁唑基、吡啶基、嘧啶基、吡唑基、1H-吲唑基、苯並咪唑基、[1,2,4]三唑並[1,5-a]吡啶基或吡咯[2,3-b]吡啶基為較佳。
“3-至10-員非芳香雜環基”意指具一或多個雜原子之非芳香雜環基團,較佳為1至三個雜原子,其選自下列所組成之群:氮原子、氧原子及硫原子。“3-至10-員非芳香雜環基”包括與芳香或非芳香碳環結合或與芳香或非芳香雜環結合形成雙環基團之非芳香雜環烷基,亦包括與與芳香或非芳香雜環結合形成雙環基團之非芳香碳環基團。具體案例包括,但不定限於,吖丙啶基、氮雜環丁基、吡咯啶基、哌啶基(包
括哌啶基)、氮雜環庚烷基、1,2,5,6-四氫吡啶基、1,2,3,6-四氫吡啶基、咪唑烷基、吡唑烷基、哌嗪基、同哌嗪基、吡唑啉基、環氧乙基、四氫呋喃基、四氫-2H-吡喃基、5,6-二氫-2H-吡喃基、噁唑烷基、嗎啉基(包括嗎啉基)、四氫硫苯基、四氫-2H-硫吡喃基、硫噁唑烷基、硫嗎啉基、2H-噁唑基、2H-硫噁唑基、二氫吲哚基、二氫異吲哚基、二氫苯並呋喃基、苯並咪唑烷基、2,3-二氫苯並咪唑基、2,3-二氫苯並噁唑基、二氫苯並硫噁唑基、苯並二歐索林基、四氫喹啉基、四氫異喹啉基、二氫-2H-苯並二氫吡喃基、二氫-1H-苯並二氫吡喃基、二氫-2H-硫苯並二氫吡喃基、二氫-1H-硫苯並二氫吡喃基、四氫喹喔啉基、四氫喹唑啉基、二氫苯並二氧雜環己基、氧雜環丁基、1,2-二氫吡啶基、1-氮雜二環[2.2.2]辛-3-基、2,5-氮雜二環[2.2.1]庚基|、8-氮雜二環[3.2.1]辛基、哌啶-4-螺-3’-吡咯啶-1-基及異吲哚基。特別地,氮雜環丁基、吡咯啶基、哌啶基、哌啶基、哌嗪基、嗎啉基、嗎啉基、1,2-二氫吡啶基、1,2,5,6-四氫吡啶基、1-氮雜二環[2.2.2]辛-3-基、2,5-氮雜二環[2.2.1]庚基、8-氮雜二環[3.2.1]辛基、2,3-二氫苯並咪唑基、或哌啶-4-螺-3’-吡咯啶-1-基為較佳。
“3-至10-員含氮雜環基”意指具一氮原子及一或多個額外雜原子之芳香或非芳香雜環基團,較佳為一至三個雜原子,其選自下列所組成之群:氮原子、氧原子及硫原子。“3-至10-員含氮雜環基”包括與芳香或非芳香碳環結合或與芳香或非芳香雜環結合形成雙環基團之雜環基。具體案例包括吖丙啶基、氮雜環丁基、吡咯基、吡咯啶基、哌啶基(包括哌啶
基)、氮雜環庚烷基、咪唑基、吡唑基、三唑基、四唑基、哌嗪基及嗎啉基。
“(C3-C10環烷基)-C1-C6烷基”具體案例包括(C3-C10環烷基)-C1-C2烷基、亦即(C3-C10環烷基)-甲基如環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基及環辛基甲基;1-(C3-C10環烷基)-乙基如1-環丙基乙基、1-環丁基乙基、1-環戊基乙基、1-環己基乙基、1-環庚基乙基及1-環辛基乙基;及2-(C3-C10環烷基)-乙基如2-環丙基乙基、2-環丁基乙基、2-環戊基乙基、2-環己基乙基、2-環庚基乙基及2-環辛基乙基。“(C6-C10芳基)-C1-C6烷基”具體案例包括(C6-C10芳基)-C1-C2烷基、亦即(C6-C10芳基)-甲基、如苯基、2-苯基乙基及1-苯基乙基。(5-至10-員雜芳基)-C1-C6烷基具體案例包括(5-至10-員雜芳基)-C1-C2烷基、亦即(5-至10-員雜芳基)-甲基如吡啶基甲基、亦即吡啶-2-基甲基、吡啶-3-基甲基及吡啶-4-基甲基。“(3-至10-員非芳香雜環基)-C1-C6烷基”具體案例包括亦即(3-至10-員非芳香雜環基)-C1-C2烷基、(3-至10-員非芳香雜環基)-甲基如哌啶基甲基、亦即哌啶-1-基甲基(即哌啶基甲基)、哌啶-2-基甲基、哌啶-3-基甲基,及哌啶-4-基甲基;哌嗪基甲基、亦即哌嗪-1-基甲基及哌嗪-2-基甲基;及嗎啉基甲基、亦即嗎啉-2-基甲基、嗎啉-3-基甲基及嗎啉-4-基甲基(即嗎啉基甲基)。
胺基-C1-C6烷基具體案例包括胺基甲基、1-胺基乙基、2-胺基乙基、1-胺基丙基、2-胺基丙基、3-胺基丙基。(C1-C6烷基胺基)-C1-C6烷基具體案例包括,但不定限於,(甲基胺
基)-C1-C6烷基如(甲基胺基)甲基、1-(甲基胺基)乙基、2-(甲基胺基)乙基、1-(甲基胺基)丙基、2-(甲基胺基)丙基、3-(甲基胺基)丙基及(C1-C6烷基胺基)-甲基如(甲基胺基)甲基、(乙基胺基)甲基、(丙基胺基)甲基、(異丙基胺基)甲基、(丁基胺基)甲基、(異丁基胺基)甲基、(仲丁基胺基)甲基、(叔-丁基胺基)甲基及(戊基胺基)甲基。二(C1-C6烷基)胺基-C1-C6烷基具體案例包括,但不定限於,(二甲基胺基)-C1-C6烷基如(二甲基胺基)甲基、1-(二甲基胺基)乙基、2-(二甲基胺基)乙基、1-(二甲基胺基)丙基、2-(二甲基胺基)丙基、3-(二甲基胺基)丙基及二(C1-C6烷基)胺基-甲基如(二甲基胺基)甲基、(二乙基胺基)甲基、(二丙基胺基)甲基、(二異丙基胺基)甲基、(二丁基胺基)甲基、(二異丁基胺基)甲基、[二(仲丁基)胺基]-甲基、[(叔-丁基)胺基]甲基、(二戊基胺基)甲基、[乙基(甲基)胺基]甲基、[丙基(甲基)胺基]甲基、[異丙基(甲基)胺基]甲基、[丁基(甲基)胺基]甲基、[異丁基(甲基)胺基]甲基、[仲丁基(甲基)胺基]甲基、[叔-丁基(甲基)胺基]甲基及[戊基(甲基)胺基]甲基。
胺基-C1-C6烷氧基具體案例包括胺基甲氧基、1-胺基乙氧基、2-胺基乙氧基、1-胺基丙氧基、2-胺基丙氧基、3-胺基丙氧基。(C1-C6烷基胺基)-C1-C6烷氧基具體案例包括,但不定限於,(甲基胺基)-C1-C6烷氧基如(甲基胺基)甲氧基、1-(甲基胺基)乙氧基、2-(甲基胺基)乙氧基、1-(甲基胺基)丙氧基、2-(申基胺基)丙氧基、3-(甲基胺基)丙氧基及(C1-C6烷基胺基)-甲氧基如(甲基胺基)甲氧基、(乙基胺基)甲氧
基、(丙基胺基)甲氧基、(異丙基胺基)甲氧基、(丁基胺基)甲氧基、(異丁基胺基)甲氧基、(仲丁基胺基)甲氧基、(叔-丁基胺基)甲氧基及(戊基胺基)甲氧基。二(C1-C6烷基)胺基-C1-C6烷氧基具體案例包括,但不定限於,(二甲基胺基)-C1-C6烷氧基如(二甲基胺基)甲氧基、1-(二甲基胺基)乙氧基、2-(二甲基胺基)乙氧基、1-(二甲基胺基)丙氧基、2-(二甲基胺基)丙氧基、3-(二甲基胺基)丙氧基及二(C1-C6烷基)胺基-甲氧基如(二甲基胺基)甲氧基、(二乙基胺基)甲氧基、(二丙基胺基)甲氧基、(二異丙基胺基)甲氧基、(二丁基胺基)甲氧基、(二異丁基胺基)甲氧基、[二(仲丁基)胺基]-甲氧基、[二(叔-丁基)胺基]甲氧基、(二戊基胺基)甲氧基、[乙基(甲基)胺基]甲氧基、[丙基(甲基)胺基]甲氧基、[異丙基(甲基)胺基]甲氧基、[丁基(甲基)胺基]甲氧基、[異丁基(甲基)胺基]甲氧基、[仲丁基(甲基)胺基]甲氧基、[叔-丁基(甲基)胺基]甲氧基及[戊基(甲基)胺基]甲氧基。
羥基-C1-C6烷基具體案例包括羥基甲基、1-羥基乙基、2-羥基乙基、1-羥基丙基、2-羥基丙基、3-羥基丙基。(C1-C6烷氧基)-C1-C6烷基具體案例包括,但不定限於,甲氧基-C1-C6烷基如甲氧基甲基、1-(甲氧基)乙基、2-(甲氧基)乙基、1-(甲氧基)丙基、2-(甲氧基)丙基、3-(甲氧基)丙基及(C1-C6烷氧基)-甲基如(甲氧基)甲基、(乙氧基)甲基、(丙氧基)甲基、(異丙氧基)甲基、(丁氧基)甲基、(異丁氧基)甲基、(仲-丁氧基)甲基、(叔-丁氧基)甲基及(戊氧基)甲基。
羧基-C1-C6烷基具體案例包括,但不定限於,羧基甲基、1-羧基乙基、2-羧基乙基、1-羧基丙基、2-羧基丙基及3-
羧基丙基。[(C1-C6烷氧基)羰基]-C1-C6烷基具體案例包括,但不定限於,甲氧基羰基-C1-C6烷基如甲氧基羰基-甲基、1-(甲氧基羰基)乙基、2-(甲氧基羰基)乙基、1-(甲氧基羰基)丙基、2-(甲氧基羰基)丙基及3-(甲氧基羰基)丙基;及[(C1-C6烷氧基)羰基]-甲基如(甲氧基羰基)甲基、1-(甲氧基羰基)乙基、2-(甲氧基羰基)乙基、1-(甲氧基羰基)丙基、2-(甲氧基羰基)丙基及3-(甲氧基羰基)丙基。
氨基甲醯基-C1-C6烷基具體案例包括,但不定限於,氨基甲醯基甲基、1-氨基甲醯基乙基、2-氨基甲醯基乙基、1-氨基甲醯基丙基、2-氨基甲醯基丙基及3-氨基甲醯基丙基。[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基具體案例包括,但不定限於,N-甲基氨基甲醯基-C1-C6烷基如N-甲基氨基甲醯基-甲基、1-(N-甲基氨基甲醯基)乙基、2-(N-甲基氨基甲醯基)乙基、1-(甲基氨基甲醯基)丙基、2-(N-甲基氨基甲醯基)丙基及3-(N-甲基氨基甲醯基)丙基;及[N-(C1-C6烷基)氨基甲醯基]-甲基如(N-甲基氨基甲醯基)甲基、(N-乙基氨基甲醯基)甲基、(N-丙基氨基甲醯基)甲基、(N-異丙基氨基甲醯基)甲基、(N-丁基氨基甲醯基)甲基、[N-(叔-丁基)氨基甲醯基]甲基及[N-(仲丁基)氨基甲醯基]甲基。[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基具體案例包括,但不定限於,(N,N-二甲基氨基甲醯基)-C1-C6烷基如(N,N-二甲基氨基甲醯基)甲基、1-(N,N-二甲基氨基甲醯基)乙基、2-(N,N-二甲基氨基甲醯基)乙基、1-(N,N-二甲基氨基甲醯基)丙基、2-(N,N-二甲基氨基甲醯基)丙基及3-(N,N-二甲基氨基甲醯基)丙基;及[N,N-
二(C1-C6烷基)氨基甲醯基]-甲基如(N,N-二甲基氨基甲醯基)甲基、(N,N-二乙基氨基甲醯基)甲基、(N,N-二丙基氨基甲醯基)甲基、(N,N-二異丙基氨基甲醯基)甲基、(N,N-二丁基氨基甲醯基)甲基、(N,N-二異丁基氨基甲醯基)甲基、[N,N-二(仲丁基)氨基甲醯基]甲基、[N,N-二(叔-丁基)氨基甲醯基]甲基、(N,N-二戊基氨基甲醯基)甲基、[N-乙基-N-(甲基)氨基甲醯基]甲基、[N-丙基-N-(甲基)氨基甲醯基]甲基、[N-異丙基-N-(甲基)氨基甲醯基]甲基、[N-丁基-N-(甲基)氨基甲醯基]甲基、[N-異丁基-N-(甲基)氨基甲醯基]甲基、[N-仲丁基-N-(甲基)氨基甲醯基]甲基、[N-叔-丁基-N-(甲基)氨基甲醯基]甲基及[N-戊基-N-(甲基)氨基甲醯基]甲基。
(C1-C6烷基)羰基胺基具體案例包括,但不定限於,甲基羰基胺基、乙基羰基胺基、丙基羰基胺基、異丙基羰基胺基、丁基羰基胺基、異丁基羰基胺基、仲丁基羰基胺基、叔-丁基羰基胺基及戊基羰基胺基。N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基具體案例包括,但不定限於,N-乙醯基-N-(C1-C6烷基)胺基如N-乙醯基-N-甲基胺基、N-乙醯基-N-乙基胺基、N-乙醯基-N-丙基胺基、N-乙醯基-N-異丙基胺基、N-乙醯基-N-丁基胺基、N-乙醯基-N-異丁基胺基、N-乙醯基-N-仲丁基胺基、N-乙醯基-N-叔-丁基胺基及N-乙醯基-N-戊基胺基;及N-(C1-C6烷基)羰基-N-(甲基)胺基如N-乙醯基-N-(甲基)胺基、N-乙基羰基-N-(甲基)胺基、N-丙基羰基-N-(甲基)胺基、N-異丙基羰基-N-(甲基)胺基、N-異丁基羰基-N-(甲基)胺基、N-叔-丁基羰基-N-(甲基)胺基、N-丁基羰基-N-(甲基)
胺基、N-戊基羰基-N-(甲基)胺基及N-己基羰基-N-(甲基)胺基。
5-至7-環環硼酸酯具體案例為如下通式:
化合物(I)醫藥上可接受之鹽意指如、醫藥上可接受之酸加成鹽、胺基酸加成鹽等。化合物(I)醫藥上可接受之酸加成鹽具體案例包括無機酸鹽,如鹽酸鹽,硫酸鹽,及磷酸鹽、有機酸鹽,如醋酸、馬來酸、富馬酸、檸檬酸等;以及醫藥上可接受之胺基酸加成鹽具體案例包括如離胺酸、甘胺酸、苯基丙胺酸、天門冬醯胺酸或麩胺酸之加成鹽。特別地,化合物(I)醫藥上可接受之鹽包括鹽酸鹽、二鹽酸鹽及三鹽酸鹽。
涉及MELK過量表現之疾病,其可以含有本發明化合物或其醫藥可接受之鹽治療和/或預防,具體案例包括,但不定限,癌、乳癌、膀胱癌、子宮頸癌、膽管細胞癌、慢性骨髓性白血病(CML)、大腸直腸癌、子宮內膜異位瘤、食道癌、胃癌、肝癌、非小細胞肺癌(NSCLC)、淋巴癌、骨肉瘤、卵巢癌、胰臟癌、前列腺癌、腎細胞癌及小細胞肺癌(SCC)。可治療和/或預防之癌案例包括,但不定限,乳癌、膀胱癌、子宮頸癌、膽管細胞癌、CML、大腸直腸癌、子宮內膜異位瘤、食道癌、胃癌、肝癌、NSCLC、淋巴癌、骨肉瘤、卵巢癌、胰臟癌、前列腺癌、腎細胞癌及SCC、但不定限於此。
化合物(I)包括可有立體異構物,如位向異構物(regioisomer)、幾合異構物、光學異構物及互變異構體之化
合物,且所有可能的包含此等的異構物及其混合物都包括在本發明。
化合物(I)亦包括據有一或多個微量穩定同位素或放射性同位素,如2H、3H、13C、14C、15N、18O等、其可以化合物與上述一或多個異構物之傳統方法製備而成。
又,化合物(I)及其在醫藥上可接受之鹽,可以與水或各種其他溶劑一起形成溶劑化物的形式存在,且此等溶劑化物也包含在本發明。
本發明化合物(I)之具體例如表1所示。但是,本發明之化合物不限於此等。
化合物(I)及其在醫藥上可接受之鹽,可以單獨投予;但是,一般希望以各種形式的醫藥配方提供。此種醫藥配
方係用在動物或人類。
本發明之醫藥配方可只包含有效成分化合物(I)或其在醫藥上可接受之鹽,或為與任何其他的治療用的有效成分的混合物。再者,此等醫藥配方可利用在藥物配方的技術領域中周知的任何方法製造,藉由將該有效成分與一或更多形式的醫藥上可接受的載體(例如,稀釋劑、溶劑及賦形劑)混合在一起而製作。
理想上,係使用對於治療最為有效的投予路徑,例如包括口服途徑,或非口服途徑,例如靜脈內途徑。
投予的劑型,例如錠劑及注射劑。
錠劑及適用於口服投予者,可使用賦形劑例如乳糖、崩散劑例如澱粉、潤滑劑例如硬脂酸鎂,及黏結劑例如羥基丙基纖維素製造。
注射劑及此等適用於非口服投予者,可使用例如溶劑或稀釋劑例如鹽溶液、葡萄糖溶液,或鹽水及葡萄糖溶液的混合物製備。
化合物(I)或其在醫藥上可接受之鹽之劑量,以及投藥的次數,取決於投予形式、病患的年紀與體重、欲治療的症狀的本性或嚴重度等,但通常口服投予時,針對1名成人,為0.01mg至1000mg,較佳為0.05mg至100mg的範圍,且投予次數為1日1次至數次。若為非口服投予例如靜脈內投予的情形,對於1名成人以0.001mg至1000mg,或較佳為0.01mg至100mg,投予1次至數次。然而,此等劑量或投藥次數會取決於上述各種情況而改變。
製備上述化合物之方法如下所示。
通式-X2-R1如前定義、如(C1-C6烷基)羰基、(C3-C10環烷基)羰基、(C1-C6烷基)磺醯基及(C3-C10環烷基)磺醯基;其中該烷基羰基、環烷基羰基、烷基磺醯基及環烷基磺醯基選擇性地經一或多個鹵原子取代。-X2-R11具體案包括乙醯基、乙基羰基、環丙基羰基、甲基磺醯基、乙基磺醯基、環丙基磺醯基、氯乙醯基、1-氯乙基羰基、2-氯乙基羰基、氯環丙基羰基、氯甲基磺醯基、1-氯乙基磺醯基、2-氯乙基磺醯基及氯環丙基磺醯基。
2-氯-5-胺基吡啶A藉酯B及原甲酸三乙酯存在下加熱轉換成烯烴異構物混合物之濃縮產物C(流程1)。市售、文獻已知、使用已知文獻方法製備之各種酯可應用於該反應。中間物C加入至熱DowthermTM A以促成閉環並獲得1、5-萘啶D。D以氧氯化磷處理獲得關鍵中間物E(流程1)。
流程2
流程2說明獲得關鍵中間物E替代合成方法。市售2-甲氧基-5-胺基吡啶F藉酯B及原甲酸三乙酯存在下加熱轉換成烯烴異構物混合物之濃縮產物C(流程2)。中間物G加入至熱DowthermTM A以促成閉環並獲得1、5-萘啶H。H之6-位去甲基化係在回流的乙腈以三甲基甲矽烷基氯及碘化鈉處理,得到中間物I,其無需純化,可與氧氯化磷反應以得關鍵中間物E(流程2)。
通式-X1-Q1定義如前、如C5-C7環烷基胺基、苯基胺基、吡啶基胺基、吡唑基胺基、嘧啶基胺基、哌啶基胺基、吡咯啶-1-基、哌啶-1-基、哌嗪-1-基及嗎啡啉-1-基,其選擇性地經一或多個取代基取代,該取代基分別選自如前所定義之A1。
通式-R5除鹵原子,定義如前,如C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中
該環烷基、芳基、雜芳基及雜環基選擇性地選擇性地經一或多個取代基取代,該取代基分別選自如前所定義之A3。R5具體案例包括選擇性地經一或三個取代基取代之苯基,該取代基分別選自A3、如3、5-二氯-4-羥基苯基、3,5-二氟-4-羥基苯基及3-氯-5-氟-4-羥基苯基.
標的化合物製備說明如流程3。中間物E之4-位與如定義H-X1-Q1化合物反應以置入X1-Q1所示之取代基。產出之中間物K(屬於分類為通式(II)之化合物)之6-位與R5-B(OR51)OR52(屬於分類為通式(III)之化合物)反應以置入R5所示之取代基。
為置入胺基於1,5-萘啶環之4-位,E在鹼存在下以適當的胺加熱以獲得中間物L,其屬通式(II)(流程4)。市售、文獻已知、使用已知文獻方法製備之各種胺可應用於該反應。將中間物L與硼酸酯N進行鈴木偶聯反應,以獲得屬通式(I)之化合物。市售、文獻已知、使用已知文獻方法製備之各種硼酸酯可應用於該反應。在流程4,硼酸酯N製備其藉由使芳
基溴M與雙戊醯二硼於有機鈀存在下反應以獲得屬通式(I)之化合物。假如需要,鈴木偶聯反應後,去保護基團以獲得標的化合物。
在流程4,A3代表如前所述苯環上選擇的取代基,m表示選自0至5整數,較佳選自1至3。
以下實施例中的關注中間體及化合物,除非有特別指明,否則可利用一般的用在合成有機化學的分離及純化方法單離及純化,例如包括過濾、萃取、清洗、乾燥、濃縮、再結晶,及各種形式的層析。或者,可將中間物用在次一反應而不經純化。
以下,將對於本發明參照實施例以具體說明,但是本發明的範圍不限於此。
又,於以下實施例中,除非特別指明,若定義的基團在製造方法的條件下有改變或不適於實施該方法,該關注的化合物可藉由使用合成有機化學中通常使用的引入或移除保護基的方法製造(例如,“Protective Groups in Organic Synthesis”,T.W.Greene,John Wiley & Sons Inc.,1999)。再者,反應處理的順序,例如取代基之引入,可視需要改變。
實施例S
一般流程I(4-位元取代)
對於中間體E(1.0當量)於二氧陸圜或二氧陸圜及DMF(2:1)混合物之懸浮液,加入必要的胺(1.0-2.0當量)、N,N-二異丙基乙胺(2.0-5.0當量),及微細粉碎的K2CO3(2.0-3.0當量),將反應混合物於60-100℃加熱16小時或直到E耗盡(以
LCMS分析監控)。將反應混合物冷卻,以飽和重碳酸鈉水溶液稀釋,並以乙酸乙酯萃取。將合併的有機層以無水硫酸鈉乾燥,過濾,濃縮濾液。將殘渣以管柱層析純化(二氧化矽,甲醇/二氯甲烷),以獲得所要產物L。
一般流程II(6-位元取代)
對於中間體L(1.0當量)、必要的有機硼酸酯(1.5-2.0當量)及Pd(dppf)Cl2(0.1-0.2當量)於二氧陸圜(0.1-0.2M)之懸浮液,加入Cs2CO3(1.0M於水,3.0-4.0eq)。將反應混合物以氮氣脫氣,並於80℃攪拌2-24小時。將反應混合物冷卻,以飽和重碳酸鈉水溶液稀釋,並以3:1氯仿/異丙醇萃取。將合併的有機層以無水硫酸鈉乾燥,過濾,濃縮濾液。將殘渣以層析法純化(使用甲醇/二氯甲烷之正相層析或使用水/含0.025% TFA之逆相層析),以獲得標的產物。以管柱層析純化(二氧化矽,0-20%甲醇/二氯甲烷),以獲得所要產物。
有些情形中,將產物於甲醇中稀釋,接著加入過量HCl(2.0-5.0當量,如在乙醚、甲醇、二氧陸圜或水之溶液)。5分鐘後,該混合物濃縮乾燥,獲得所望化合物之HCl鹽。
一般流程III(硼酸酯合成)
對於適當的芳基溴(1.0當量)、雙戊醯二硼(1.5-2.0當量)及KOAc(2.0-3.0當量)於二氧陸圜(0.1-0.2M)之懸浮液,加入Pd(dppf)Cl2(0.05-0.1當量)。將反應混合物以氮氣脫氣,再於80℃加熱2-16小時。將反應混合物冷卻,濃縮,濃縮濾液。將殘渣以層析法純化(二氧化矽、乙酸乙酯/己烷),以獲得所要產物M。
一般流程IV-1(boc-去保護實驗步驟)
對於經boc保護之胺於THF、甲醇或甲醇/二氯甲烷(0.1M)之懸浮液,加入過量HCl水溶液(2.0-5.0當量,如在乙醚、甲醇、二氧陸圜或水之溶液)。將該反應混合物於室溫或加熱(50-70℃)直到以LCMS分析觀察到反應完全為止。將該反應混合物冷卻並濃縮,以獲得所望化合物之HCl鹽
一般流程IV-2(boc-去保護實驗步驟)
對於經boc保護之化合物於THF之溶液,加入過量TFA(2.0-10當量),並將該反應混合物於室溫或50-70℃加熱直到以LCMS分析觀察到反應完全為止。將該反應混合物濃縮,將殘留物物於甲醇中稀釋,接著加入過量HCl(2.0-5.0當量,如在乙醚、甲醇、二氧陸圜或水之溶液)。5分鐘後,該混合物濃縮乾燥,獲得所望化合物之HCl鹽。
一般流程V
1,4-二氧陸圜及N,N-二甲基甲醯胺(2:1)混合物之{4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]環己基}甲基甲磺酸(1.0mmol)溶液加入必要的胺(2.0-4.0當量),三乙基胺或N,N-二異丙基乙基胺(2.0-3.0當量)及碘化鉀(cat.);該反應混合物於85℃攪拌加熱18小時。將該反應混合物冷卻並以水及乙酸乙酯稀釋。分層後,該乙酸乙酯層以硫酸鈉乾燥,濃縮,濃縮濾液。將殘渣以層析法純化(二氧化矽,己烷或二氯甲烷/乙酸乙酯),以獲得所要產物。
一般流程VI
1-(4-((4-胺基環己基)胺基)-6-氯-1,5-萘啶-3-基)乙酮鹽
酸鹽(1.0mmol)於DMF(0.1M)之溶液加入必要的胺基酸(1.2mmol),二異丙基乙基胺(5.0當量)及HATU(2-(7-Aza-1H-苯並三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯)(1.2當量)。該反應混合物於室溫攪拌加熱18小時。將該反應混合物冷卻並以水及乙酸乙酯稀釋。分層後,該乙酸乙酯層以硫酸鈉乾燥,濃縮,濃縮濾液。將殘渣以層析法純化(二氧化矽,己烷或二氯甲烷/乙酸乙酯),以獲得所要產物。
滯留時間t R以表示,HPLC分析以下列條件執行:管柱:Gemini-NXTM C18 column 150 x 4.6mm,5 micro 100 A(Phenomenex);移動相:[洗脫劑A]水w/0.05% CF3COOH;[洗脫劑B]乙腈w/0.05% CF3COOH;流速:1mL/min溫度:室溫偵測波長:223nm或254nm梯度操作:
實施例1
1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)-乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(360mg,1.5mmol)與反-4-[(二甲基胺基)甲基]環己胺二醋酸鹽(500mg,1.8mmol)反應以獲得黃色固體所要之產物(340mg,63%)d:1H NMR(500MHz,CDCl3)δ 10.89(s,1H),8.93(s,1H),8.07(d,J=8.6Hz,1H),7.51(d,J=8.6Hz,1H),5.16-4.96(m,1H),2.67(s,3H),2.34-2.24(m,2H),2.22(s,6H),2.14(d,J=7.1Hz,2H),1.98-1.89(m,2H),1.56-1.47(m,1H),1.41-1.32(m,2H),1.28-1.10(m,2H);ESI MS m/z 361[M+H]+;HPLC 98.8%(AUC),t R=8.42min.
實施例2
1-{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-{6-氯-4-[反-4-(二甲基胺基)環己基 胺基)-1,5-萘啶-3-基)乙酮(61mg,0.16mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物
(76mg,90%):1H NMR(500MHz,CD3OD)δ 9.17(s,1H),8.47(d,J=9.0Hz,1H),8.36(d,J=8.9Hz,1H),8.10(s,2H),5.65-5.55(m,1H),3.52-3.43(m,1H),2.91(s,6H),2.76(s,3H),2.66-2.56(m,xH),2.33-2.26(m,2H),1.88-1.71(m,4H).ESI MS m/z 473[M+H]+;HPLC>99%(AUC),t R=9.51min.
實施例3
1-{6-(3-氯-5-氟-4-羥基苯基)-4-[反-4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-{6-氯-4-[反-4-(二甲基胺基)環己基 胺基)-1,5-萘啶-3-基)乙酮(45mg,0.12mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(47mg,0.17mmol)反應,,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(6.9mg,11%):1H NMR(500MHz,CD3OD)δ 9.17(s,1H),8.47(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.00(s,1H),7.91(dd,J=11.4,2.2Hz,1H),5.69-5.59(m,1H),3.52-3.45(m,1H),2.92(s,6H),2.76(s,3H),2.63-2.56(m,2H),2.33-2.26(m,2H),1.89-1.71(m,4H).ESI MS m/z 457[M+H]+;HPLC>99%(AUC),t R=9.32min.
實施例4
環丙基(6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)
甲基]-環己基胺基}-1,5-萘啶-3-基)甲酮二鹽酸鹽
按一般流程II,(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基 胺基}-1,5-萘啶-3-基)(環丙基)甲酮(60mg,0.16mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(66mg,73%):1H NMR(500MHz,CD3OD)δ 9.41(s,1H),8.46(d,J=8.9Hz,1H),8.34(d,J=8.9Hz,1H),8.12(s,2H),5.74-5.64(m,1H),3.09(d,J=6.6Hz,2H),2.93(s,6H),2.92-2.85(s,1H),2.47-2.40(m,2H),208-1.96(m,3H),1.72-1.60(m,2H),1.47-1.34(m,2H),1.32-1.18(m,4H).ESI MS m/z 513[M+H]+;HPLC>99%(AUC),t R=9.67min.
實施例5
(6-(3-氯-5-氟-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基)(環丙基)甲酮二鹽酸鹽
按一般流程II,(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基 胺基}-1,5-萘啶-3-基)(環丙基)甲酮(60mg,0.16mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(54mg,61%):1H NMR(500MHz,CD3OD)δ 9.41(s,1H),8.45(d,J=8.9Hz,1H),8.34(d,J=8.9Hz,1H),8.02(t,J=1.9Hz,1H),7.88(dd,J=11.6,2.2Hz,1H),5.73-5.64(m,1H),3.09(d,J=6.6Hz,2H),2.94(s,6H),2.93-2.83(m,1H),2.48-2.40(m,2H),2.10-1.96(m,3H),1.73-1.61(m,2H),1.46-1.34(m,2H),1.34-1.18(m,4H).ESI MS m/z 497[M+H]+;HPLC>99%(AUC),t R=10.26min.
實施例6
1-{6-(3,5-二氯-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基 胺基}-1,5-萘啶-3-基)乙酮(20mg,0.055mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(29mg,0.10mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(18mg,58%):1H NMR(500MHz,CD3OD)δ 9.14(s,
1H),8.46(d,J=9.1Hz,1H),8.33(d,J=9.1Hz,1H),8.12(s,2H),5.75-5.67(m,1H),3.09(d,J=6.6Hz,2H),2.94(s,6H),2.76(s,3H),2.48-2.41(m,2H),2.09-1.98(m,1H),1.75-1.63(m,1H),1.48-1.36(m,2H).ESI MS m/z 487[M+H]+;HPLC>99%(AUC),t R=9.67min.
實施例7
1-{6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}-胺基)-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基 胺基}-1,5-萘啶-3-基)乙酮(20mg,0.055mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(27mg,0.10mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(16mg,52%)as a light yellow solid:1H NMR(500MHz,CD3OD)δ 9.15(s,1H),8.45(d,J=9.1Hz,1H),8.33(d,J=9.0Hz,1H),8.02(t,J=1.9Hz,1H),7.88(dd,J=11.5,2.2Hz,1H),5.75-5.65(m,1H),3.09(d,J=6.6Hz,2H),2.94(s,6H),2.76(s,3H),2.45(d,J=12.5Hz,2H),2.11-2.01(m,3H),1.75-1.63(m,2H),1.47-1.36(m,2H).ESI MS m/z 471[M+H]+;HPLC>99%(AUC),t R=9.66min.
實施例8
1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基 胺基}-1,5-萘啶-3-基)乙酮(20mg,0.055mmol)與-氯-6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(28mg,1.0mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(18mg,59%):1H NMR(500MHz,CD3OD)δ 9.13(s,1H),8.49(d,J=8.9Hz,1H),8.32(d,J=9.1Hz,1H),7.81(d,J=2.1Hz,1H),7.58(d,J=2.1Hz,1H),5.80-5.70(m,1H),4.03(s,3H),3.08(d,J=6.6Hz,2H),2.93(s,6H),2.76(s,3H),2.49-2.39(m,2H),2.08-1.96(m,3H),1.72-1.62(m,2H),1.47-1.35(m,2H).ESI MS m/z 483[M+H]+;HPLC>99%(AUC),t R=9.62min.
實施例9
1-[6-(3,5-二氯-4-羥基苯基)-4-({反-4-[2-(二甲基胺基)乙基]環己基}胺基)-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基 胺基}-1,5-萘啶-3-基)乙酮(50mg,0.13mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(58mg,0.2mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(64mg,83%):1H NMR(500MHz,CD3OD)δ 9.13(s,1H),8.46(d,J=9.1Hz,1H),8.33(d,J=9.0Hz,1H),8.13(s,1H),5.74-5.64(m,1H),3.27-3.18(m,2H),2.91(s,6H),2.75(s,3H),2.45-2.35(m,2H),2.05-1.98(m,2H),1.78-1.70(m,2H),1.66-1.52(m,3H),1.45-1.35(m,2H).ESI MS m/z 501[M+H]+;HPLC>99%(AUC),t R=10.22min.
實施例10
1-(6-(3-氯-5-氟-4-羥基苯基)-4-{反-4-[2-(二甲基胺基)乙基]-環己基胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-(反-4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)乙酮(50mg,0.13mmol)與
2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(55mg,0.2mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(58mg,78%):1H NMR(500MHz,CD3OD)δ 9.13(s,1H),8.45(d,J=8.9Hz,1H),8.32(d,J=8.9Hz,1H),8.04(t,J=1.8Hz,1H),7.89(dd,J=11.6,2.2Hz,1H),5.73-5.63(m,1H),3.27-3.18(m,2H),2.91(s,6H),2.75(s,3H),2.44-2.37(m,2H),2.05-1.98(m,2H),1.78-1.69(m,2H),1.67-1.51(m,3H),1.44-1.34(m,2H).ESI MS m/z 485[M+H]+;HPLC>99%(AUC),t R=9.91min.
實施例11
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-[4-羥基-3-(三氟甲氧基)-苯基]-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基 胺基}-1,5-萘啶-3-基)乙酮(55mg,0.15mmol)與4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2-(三氟甲氧基)酚(68mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(71mg,79%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=8.9Hz,1H),8.32(d,J=9.0Hz,1H),8.04-7.97(m,2H),7.21(d,J=8.6Hz,1H),5.70-5.60(m,
1H),3.07(d,J=6.6Hz,2H),2.94(s,6H),2.76(s,3H),2.50-2.40(m,2H),2.08-1.97(m,3H),1.74-1.62(m,2H),1.39-1.27(m,2H).ESI MS m/z 503[M+H]+;HPLC>99%(AUC),t R=9.80min.
實施例12
2,6-二氯-4-(8-{反-4-[(二甲基胺基)甲基]環己基胺基}-7-(甲基磺醯基)-1,5-萘啶-2-基)酚二鹽酸鹽
按一般流程II,6-氯-N-{反-4-[(二甲基胺基)甲基]-環己基}-3-(甲基磺醯基)-1,5-萘啶-4-胺(56mg,0.14mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.21mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(43mg,51%):1H NMR(500MHz,CD3OD)δ 8.90(s,1H),8.51(d,J=9.0Hz,1H),8.35(d,J=9.0Hz,1H),8.14(s,2H),5.76-5.66(m,1H),3.38(s,3H),3.09(d,J=6.7Hz,2H),2.94(s,6H),2.50-2.43(m,2H),2.08-1.96(m,3H),1.74-1.64(m,2H),1.47-1.35(m,2H).ESI MS m/z 523[M+H]+;HPLC>99%(AUC),t R=10.04min.
實施例13
6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]
環己基}-胺基)-3-甲基磺醯基-1,5-萘啶二鹽酸鹽
按一般流程II,6-氯-N-{反-4-[(二甲基胺基)甲基]-環己基}-3-(甲基磺醯基)-1,5-萘啶-4-胺(61mg,0.15mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(63mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(52mg,59%):1H NMR(500MHz,CD3OD)δ 8.90(s,1H),8.50(d,J=8.9Hz,1H),8.35(d,J=9.0Hz,1H),8.04(t,J=1.8Hz,1H),7.90(dd,J=11.5,2.2Hz,1H),5.775.67(m,1H),3.38(s,3H),3.09(d,J=6.6Hz,2H),2.94(s,6H),2.51-2.44(m,2H),2.08-1.97(m,3H),1.76-1.64(m,2H),1.46-1.34(m,2H).ESI MS m/z 507[M+H]+;HPLC 99.0%(AUC),t R=9.81min.
實施例14
6-(3-氯-4-羥基-5-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-3-甲基磺醯基-1,5-萘啶-二鹽酸鹽
按一般流程II,6-氯-N-{反-4-[(二甲基胺基)甲基]-環己基}-3-(甲基磺醯基)-1,5-萘啶-4-胺(24mg,0.061mmol)與2-氯-6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(28mg,0.10mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(23mg,64%):1H NMR(500MHz,CD3OD)δ 8.89(s,1H),8.54(d,J=9.1Hz,1H),8.34(d,J=9.0Hz,1H),7.83(d,J=2.0Hz,1H),7.60(d,J=2.0Hz,1H),5.83-5.73(m,1H),4.04(s,3H),3.38(s,3H),3.08(d,J=6.6Hz,2H),2.93(s,6H),2.50-2.43(m,2H),2.07-1.95(m,3H),1.73-1.63(m,2H),1.46-1.35(m,2H).ESI MS m/z 519[M+H]+;HPLC>99%(AUC),t R=9.77min.
實施例15
2,6-二氯-4-{8-[反-4-(二甲基胺基)環己基胺基]-7-(甲基磺醯基)-1,5-萘啶-2-基}酚二鹽酸鹽
按一般流程II,反-N1-[6-氯-3-(甲基磺醯基)-1,5-萘啶-4-yl]-N4,N4-二甲基環己烷-1,4-二胺(40mg,0.10mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(43mg,0.15mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(45mg,75%):1H NMR(500MHz,CD3OD)δ 8.93(s,1H),8.51(d,J=8.9Hz,1H),8.37(d,J=8.9
Hz,1H),8.12(s,2H),5.65-5.55(m,1H),3.50-3.41(m,1H),3.39(s,3H),2.91(s,6H),2.67-2.57(m,2H),2.33-2.27(m,2H),1.87-1.73(m,4H).ESI MS m/z 509[M+H]+;HPLC98.0%(AUC),t R=9.95min.
實施例16
2,6-二氯-4-(8-{4-[(二甲基胺基)甲基]苯基胺基}-7-(甲基磺醯基)-1,5-萘啶-2-基)酚二鹽酸鹽
按一般流程II,6-氯-N-{4-[(二甲基胺基)甲基]苯基}-3-(甲基磺醯基)-1,5-萘啶-4-胺(50mg,0.14mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.21mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(35mg,42%):1H NMR(500MHz,CD3OD)δ 9.12(s,1H),8.47(d,J=9.1Hz,1H),8.38(d,J=9.2Hz,1H),7.63(d,J=9.0Hz,2H),7.59-7.52(m,2H),7.34(s,2H),4.43(s,2H),3.48(s,3H),2.86(s,6H).;ESI MS m/z 517[M+H]+;HPLC>99%(AUC),t R=11.03min.
實施例17
2-氯-4-(8-{4-[(二甲基胺基)甲基]苯基胺基}-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚 二鹽酸鹽
按一般流程II,6-氯-N-{4-[(二甲基胺基)甲基]苯基}-3-(甲基磺醯基)-1,5-萘啶-4-胺(50mg,0.14mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(58mg,0.21mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(51mg,63%):1H NMR(500MHz,CD3OD)δ 9.12(s,1H),8.46(d,J=9.0Hz,1H),8.37(d,J=9.1Hz,1H),7.68-7.61(m,2H),7.60-7.53(m,2H),7.22(t,J=1.8Hz,1H),7.06(dd,J=11.9,2.2Hz,1H),4.43(s,2H),3.48(s,3H),2.88(s,6H).;ESI MS m/z 501[M+H]+;HPLC>99%(AUC),t R=10.68min.
實施例18
2-氯-4-(8-{4-[(二甲基胺基)甲基]苯基胺基}-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚二鹽酸鹽
按一般流程II,6-氯-N-{4-[(二甲基胺基)甲基]苯基}-3-(甲基磺醯基)-1,5-萘啶-4-胺(50mg,0.14mmol)與
2-氯-6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(60mg,0.21mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(44mg,54%):1H NMR(500MHz,CD3OD)δ 9.11(s,1H),8.50(d,J=9.0Hz,1H),8.36(d,J=9.0Hz,1H),7.62-7.50(m,4H),7.34(d,J=2.1Hz,1H),6.68(d,J=2.0Hz,1H),4.40(s,2H),3.92(s,3H),3.47(s,3H),2.83(s,6H);ESI MS m/z 513[M+H]+;HPLC>99%(AUC),t R=10.56min.
實施例19
1-[6-(3,5-二氯-4-羥基苯基)-4-{3-[2-(吡咯啶-1-基)乙基]苯基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{3-[2-(吡咯啶-1-基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮(59mg,0.15mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(67mg,75%)as:1H NMR(500MHz,D2O)δ 9.13(s,1H),8.13(d,J=9.0Hz,1H),8.01(d,J=9.1Hz,1H),7.64(t,J=7.8Hz,1H),7.41(d,J=7.4Hz,1H),7.32(d,J=7.9Hz,1H),6.79(s,1H),6.66(br s,2H),3.36-3.27(m,2H),2.78(s,3H),2.74-2.64(m,2H),2.62-2.42(m,4H),1.87-1.72(m,4H).;ESI
MS m/z 521[M+H]+;HPLC 98.9%(AUC),t R=10.34min.
實施例20
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{3-[2-(吡咯啶-1-基)乙基]苯基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{3-[2-(吡咯啶-1-基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮(59mg,0.15mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(63mg,72%):1H NMR(500MHz,CD3OD)δ 9.30(s,1H),8.43(d,J=9.0Hz,1H),8.34(d,J=8.9Hz,1H),7.54-7.30(m,4H),7.23(br s,1H),7.13(br s,1H),3.68-3.60(m,2H),3.35-3.23(m,2H),3.11-2.99(m,4H),2.80(br s,3H),2.19-2.07(m,2H),2.05-1.96(m,2H).;ESI MS m/z 505[M+H]+;HPLC>99%(AUC),t R=10.17min.
實施例21
1-[6-(3,5-二氯-4-羥基苯基)-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮(50mg,0.13mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(56mg,0.20mmol)f反應,隨後二鹽酸鹽形成,獲得黃橘色固體之所要產物(63mg,83%):1H NMR(500MHz,CD3OD)δ 9.35(s,1H),8.46(d,J=9.0Hz,1H),8.37(d,J=9.0Hz,1H),8.24(d,J=2.7Hz,1H),7.78(dd,J=8.8,2.7Hz,1H),7.44(br s,2H),7.02(d,J=8.8Hz,1H),4.72-4.66(m,2H),3.64-3.58(m,2H),3.00(s,6H),2.84(s,3H).;ESI MS m/z 512[M+H]+;HPLC 99%(AUC),t R=9.73min.
實施例22
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{6-[2-(二甲基胺基)乙
氧基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮(50mg,0.13mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(53mg,0.20mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(40mg,54%):1H NMR(500MHz,CD3OD)δ 9.35(br s,1H),8.45(d,J=9.0Hz,1H),8.37(d,J=8.9Hz,1H),8.28(d,J=2.6Hz,1H),7.76(dd,J=8.8,2.7Hz,1H),7.35(br s,1H),7.10(br s,1H),7.01(d,J=8.8Hz,1H),4.74-4.68(m,2H),3.66-3.60(m,2H),3.02(s,6H),2.84(s,3H).;ESI MS m/z 496[M+H]+;HPLC 98.3%(AUC),t R=9.47min.
實施例23
1-[6-(3-氯-4-羥基-5-甲氧基苯基)-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮(20mg,0.052mmol)與2-氯-6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(28mg,0.10mmol)反應,隨後二鹽酸鹽形成,獲得橘固體之所要產物(22mg,74%):1H NMR(500MHz,CD3OD)δ 9.33(s,1H),8.47(d,J=9.0Hz,1H),8.35(d,J=9.0Hz,1H),8.26(d,J=2.7Hz,1H),7.74(dd,J=8.8,2.7Hz,1H),7.29(br s,1H),
6.96(d,J=8.8Hz,1H),6.85(br s,1H),4.70-4.64(m,2H),3.95(s,3H),3.62-3.56(m,2H),2.99(s,6H),2.83(s,3H).;ESI MS m/z 508[M+H]+;HPLC>99%(AUC),t R=9.36min.
實施例24
2,6-二氯-4-(8-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-7-(甲基磺醯基)-1,5-萘啶-2-基)酚鹽酸鹽
按一般流程II,1-[6-(3-氯-4-羥基-5-甲氧基苯基)-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮(60mg,0.14mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(70mg,79%)as a yellow solid:1H NMR(500MHz,CD3OD)δ 9.11(s,1H),8.49(d,J=9.1Hz,1H),8.39(d,J=9.0Hz,1H),8.28(d,J=2.7Hz,1H),7.83(dd,J=8.8,2.8Hz,1H),7.46(s,2H),7.03(d,J=8.8Hz,1H),4.71-4.65(m,2H),3.63-3.57(m,2H),3.49(s,3H),3.00(s,6H);ESI MS m/z 548[M+H]+;HPLC>99%(AUC),t R=10.87min.
實施例25
2-氯-4-(8-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺
基}-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚二鹽酸鹽
按一般流程II,1-[6-(3-氯-4-羥基-5-甲氧基苯基)-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮(50mg,0.16mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(58mg,80%):1H NMR(500MHz,CD3OD)δ 9.11(s,1H),8.48(d,J=9.1Hz,1H),8.38(d,J=9.0Hz,1H),8.32(d,J=2.7Hz,1H),7.81(dd,J=8.8,2.7Hz,1H),7.38(t,J=1.8Hz,1H),7.11(dd,J=11.8,2.2Hz,1H),7.02(d,J=8.7Hz,1H),4.74-4.68(m,2H),3.66-3.60(m,2H),3.49(s,3H),3.02(s,6H).;ESI MS m/z 532[M+H]+;HPLC>99%(AUC),t R=10.51min.
實施例26
2-氯-4-(8-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚
按一般流程II,1-[6-(3-氯-4-羥基-5-甲氧基苯基)-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮(49mg,0.12mmol)與2-氯-6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(50mg,0.18mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(56mg,78%):1H NMR(500MHz,CD3OD)δ 9.09(s,1H),8.49(d,J=9.0Hz,1H),8.37(d,J=9.0Hz,1H),8.30(d,J=2.6Hz,1H),7.78(dd,J=8.8,2.8Hz,1H),7.28(d,J=2.1Hz,1H),6.96(d,J=8.8Hz,1H),6.88(d,J=2.0Hz,1H),4.68-4.62(m,2H),3.96(s,3H),3.62-3.54(m,2H),3.49(s,3H),2.98(s,6H).;ESI MS m/z 544[M+H]+;HPLC 99%(AUC),t R=10.23min.
實施例27
1-(6-(3,5-二氯-4-羥基苯基)-4-((1-甲基哌啶-4-基)甲基胺基)-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-{6-氯-4-[(1-甲基哌啶-4-基)甲
基胺基]-1,5-萘啶-3-基}乙酮(60mg,0.18mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(78mg,0.27mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(7.3mg,7.6%):1H NMR(500MHz,CD3OD)δ 9.18(s,1H),8.48(d,J=9.0Hz,1H),8.35(d,J=8.9Hz,1H),8.11(s,2H),4.60(d,J=7.1Hz,2H),3.65-3.59(m,2H),3.09(td,J=13.0,2.8Hz,2H),2.88(s,3H),2.77(s,3H),2.34(br s,1H),2.27(d,J=14.7Hz,2H),1.80-1.67(m,2H);ESI MS m/z 459[M+H]+;HPLC>99%(AUC),t R=9.39min.
實施例28
1-[6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮(153mg,0.42mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(180mg,0.63mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(164mg,69%):1H NMR(500MHz,CD3OD)δ 9.15(s,1H),8.46(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.12(s,2H),5.76-5.71(m,1H),3.09(d,J=6.6Hz,2H),2.76(s,3H),
2.50-2.40(m,2H),2.08-1.98(m,3H),1.74-1.64(m,2H),1.47-1.37(m,2H).;ESI MS m/z 493[M+H]+;HPLC>99%(AUC),t R=9.83min.
實施例29
1-[6-(3,5-二氯-4-羥基苯基)-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮(40mg,0.11mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(43mg,0.15mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(17mg,28%):1H NMR(500MHz,CD3OD)δ 9.30(s,1H),8.43(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),7.52(br s,2H),7.42(d,J=8.5Hz,2H),7.37(d,J=8.5Hz,2H),3.40-3.32(m,2H),3.22-3.13(m,2H),2.96(s,6H),2.79(s,3H).;ESI MS m/z 495[M+H]+;HPLC>99%(AUC),t R=9.91min.
實施例30
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮(40mg,0.11mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(41mg,0.15mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(13mg,22%):1H NMR(500MHz,CD3OD)δ 9.29(s,1H),8.42(d,J=9.1Hz,1H),8.32(d,J=9.0Hz,1H),7.44(d,J=8.5Hz,2H),7.41-7.35(m,3H),7.11(br s,1H),3.43-3.36(m,2H),3.23-3.13(m,2H),2.98(s,6H),2.80(s,3H).;ESI MS m/z 479[M+H]+;HPLC>99%(AUC),t R=9.67min.
實施例31
1-[6-(3-氯-4-酚-5-甲氧基苯基)-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮(40mg,0.11mmol)與2-氯
-6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(57mg,0.20mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(40mg,66%):1H NMR(500MHz,CD3OD)δ 9.30(s,1H),8.47(d,J=9.1Hz,1H),8.35(d,J=9.1Hz,1H),7.41(d,J=8.6Hz,2H),7.38(d,J=8.6Hz,2H),7.33(br s,1H),6.88(br s,1H),3.95(s,3H),3.35-3.30(m,2H),3.20-3.12(m,2H),2.98(s,6H),2.81(s,3H).;ESI MS m/z 491[M+H]+;HPLC>99%(AUC),t R=9.62min.
實施例32
2-氯-4-{8-[反-4-(二甲基胺基)環己基胺基]-7-(甲基磺醯基)-1,5-萘啶-2-基}-6-氟酚
按一般流程II,反-N 1-(6-氯-3-(甲基磺醯基)-1,5-萘啶-4-yl)-N 4,N 4-二甲基環己烷-1,4-二胺(28mg,0.073mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(41mg,0.15mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(30mg,72%):1H NMR(500MHz,CD3OD)δ 8.92(s,1H),8.51(d,J=9.0Hz,1H),8.37(d,J=8.9Hz,1H),8.02(t,J=1.7Hz,1H),7.92(dd,J=11.5,2.2Hz,1H),5.64(br s,1H),3.52-3.42(m,1H),3.39(s,3H),2.91(s,6H),2.65-2.55(m,2H),2.33-2.26(m,2H),1.88-1.72(m,4H).;
ESI MS m/z 493[M+H]+;HPLC 98.3%(AUC),t R=9.62min.
實施例33
1-[6-(3,5-二氯-4-羥基苯基)-4-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基胺基]-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-{6-氯-4-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基胺基)-1,5-萘啶-3-基)]乙酮(77mg,0.21mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(87mg,0.30mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(67mg,57%):1H NMR(500MHz,D2O)δ 9.14(s,1H),8.15(d,J=9.0Hz,1H),7.99(d,J=8.9Hz,1H),7.73(d,J=2.8Hz,1H),7.51(br s,1H),6.97(br s,2H),4.44-4.32(m,1H),3.50(d,J=12.5Hz,2H),3.07(t,J=13.0Hz,2H),2.80(s,3H),2.78(s,3H),2.15-1.92(m,4H).;ESI MS m/z 511[M+H]+;HPLC>99%(AUC),t R=9.37min.
實施例34
1-(6-(3,5-二氯-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-苯基胺基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-(4-((4-甲基哌嗪-1-基)甲基)-苯基胺基)-1,5-萘啶-3-基)乙酮(74mg,0.18mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(78mg,0.27mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(84mg,77%):1H NMR(500MHz,CD3OD)δ 9.33(s,1H),8.45(d,J=9.1Hz,1H),8.36(d,J=9.0Hz,1H),7.70(d,J=8.1Hz,2H),7.49(d,J=8.1Hz,2H),7.38(br s,2H),4.45(s,2H),3.55(br s,8H),2.99(s,3H),2.81(s,3H).;ESI MS m/z 536[M+H]+;HPLC>99%(AUC),t R=9.57min.
實施例35
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{4-[(4-甲基哌嗪-1-基)甲基]苯基胺基}-1,5-萘啶-3-基]乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[(4-甲基哌嗪-1-基)甲基]苯基 胺基}-1,5-萘啶-3-基)乙酮(74mg,0.18mmol)與
2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(74mg,0.27mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(96mg,93%):1H NMR(500MHz,CD3OD)δ 9.32(s,1H),8.44(d,J=9.1Hz,1H),8.34(d,J=9.1Hz,1H),7.65(d,J=7.6Hz,2H),7.48(d,J=8.0Hz,2H),7.31(br s,1H),7.12(br s,1H),4.26(br s,2H),3.45(br s,8H),2.97(s,3H),2.80(s,3H);ESI MS m/z 520[M+H]+;HPLC>99%(AUC),t R=9.37min.
實施例36
1-[6-(3,5-二氯-4-羥基苯基)-4-{4-[2-(吡咯啶-1-基)乙基]哌啶-1-基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[2-(吡咯啶-1-基)乙基]哌啶-1-基}-1,5-萘啶-3-基)乙酮(60mg,0.16mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(54mg,60%):1H NMR(500MHz,CD3OD)δ 8.91(s,1H),8.46(d,J=9.1Hz,1H),8.35(d,J=8.9Hz,1H),8.16(s,2H),4.63(br s,2H),3.70-3.54(m,4H),3.32-3.24(m,2H),3.13-3.03(m,2H),2.67(s,3H),2.22-1.96(m,7H),1.82-1.69(m,
4H).;ESI MS m/z[M+H]+;HPLC>99%(AUC),t R=9.75min.
實施例37
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{4-[2-(吡咯啶-1-基)乙基]哌啶-1-基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[2-(吡咯啶-1-基)乙基]哌啶-1-基}-1,5-萘啶-3-基)乙酮(60mg,0.16mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(73mg,83%):1H NMR(500MHz,CD3OD)δ 8.91(s,1H),8.45(d,J=9.0Hz,1H),8.35(d,J=8.9Hz,1H),8.04(t,J=1.8Hz,1H),7.89(dd,J=11.7,2.2Hz,1H),4.66(br s,2H),3.69-3.54(m,4H),3.33-3.23(m,2H),3.13-3.03(m,2H),2.67(s,3H),2.22-1.96(m,7H),1.81-1.68(m,4H).;ESI MS m/z 497[M+H]+;HPLC>99%(AUC),t R=9.65min.
實施例38
1-[6-(3,5-二氯-4-羥基苯基)-4-{6-[2-(二甲基胺基)乙基胺基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮三鹽酸鹽
按一般流程II,1-[6-(3,5-二氯-4-羥基苯基)-4-{6-[2-(二甲基胺基)乙基胺基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮(69mg,0.18mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(78mg,0.27mmol)反應,隨後三鹽酸鹽形成,獲得黃橘色固體之所要產物(87mg,78%)as a yellow-orange solid:1H NMR(500MHz,D2O)δ 9.22(s,1H),8.22(d,J=8.9Hz,1H),8.02(d,J=9.1Hz,1H),7.92(d,J=2.5Hz,1H),7.59-7.53(m,1H),6.98(s,2H),6.79(d,J=9.4Hz,1H),3.67(t,J=6.4Hz,2H),3.23(t,J=6.4Hz,2H),2.82(s,6 H),2.80(s,3H).;ESI MS m/z 511[M+H]+;HPLC>99%(AUC),t R=9.13min.
實施例39
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{6-[2-(二甲基胺基)乙基胺基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮三鹽酸鹽
按一般流程II,1-[6-(3,5-二氯-4-羥基苯基)-4-{6-[2-(二甲基胺基)乙基胺基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮(69mg,0.18mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(74mg,0.27mmol)反應,隨後三鹽酸鹽形成,獲得黃橘色固體之所要產物(71mg,66%):1H NMR(500MHz,CD3OD)δ 9.40(s,1H),8.49(d,J=9.0Hz,1H),8.41(d,J=9.1Hz,1H),8.23(d,J=2.5Hz,1H),7.87(dd,J=9.4,2.5Hz,1H),7.42(br s,2H),7.06(d,J=9.4Hz,1H),3.91(t,J=6.4Hz,2H),3.47(t,J=6.4Hz,2H),2.99(s,6H),2.85(s,3H).;ESI MS m/z 495[M+H]+;HPLC 98.9%(AUC),t R=8.97min.
實施例40
(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基}(環丙基)甲酮三鹽酸鹽
按一般流程IV-2,(S)-叔-丁基1-{5-[3-(環丙羰基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]吡啶-2-基}哌啶-3-基氨基甲酸酯(73mg,0.11mmol)與TFA(3mL)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(31mg,42%)as:1H NMR(500MHz,CD3OD)δ 9.52(br s,1H),8.51(d,J=
9.0Hz,1H),8.42(d,J=9.0Hz,1H),8.23(d,J=2.6Hz,1H),7.88(dd,J=9.4,2.7Hz,1H),7.69(br s,2H),7.24(d,J=9.5Hz,1H),4.37(d,J=10.9Hz,1H),4.05-3.95(m,1H),3.50-3.33(m,3H),2.90(br s,1H),2.27-2.17(m,1H),2.06-1.96(m,1H),1.86-1.74(m,2H),1.37-1.18(m,4H).;ESI MS m/z 549[M+H]+;HPLC 95.4%(AUC),t R=10.09min.
實施例41
1-{4-[2-(3-胺基吡咯啶-1-基)嘧啶-5-基胺基]-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基}乙酮三鹽酸鹽
按一般流程IV-1,叔-丁基1-{5-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]嘧啶-2-基}吡咯啶-3-基氨基甲酸酯(123mg,0.20mmol)與6N HCl(2mL)反應,隨後三鹽酸鹽形成,獲得淡橘色固體之所要產物(62mg,50%):1H NMR(500MHz,CD3OD)δ 9.36(br s,1H),8.51-8.35(m,3H),7.51(br s,2H),4.12-3.97(m,2H),3.89-3.84(m,1H),3.80-3.69(m,2H),2.84(br s,3H),2.58-2.48(m,1H),2.28-2.17(m,1H).;ESI MS m/z 510[M+H]+;HPLC 95.6%(AUC),t R=9.18min.
實施例42
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(1H-吡唑-4-基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮(55mg,0.15mmol)與叔-丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-羧酸(66mg,0.225mmol)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(32mg,42%):1H NMR(300MHz,CD3OD)δ 9.10(s,1H),8.34(s,2H)8.30-8.23(m,2H),5.64(m,1H),3.14(d,J=6.7Hz,2H),2.94(s,6H),2.75(s,3H),2.47(d,J=13.0Hz,2H),2.09-1.97(m,3H),1.73-1.61(m,2H),1.45-1.33(m,2H);ESI MS m/z 393[M+H]+;HPLC 98.3%(AUC),t R=8.60min.
實施例43
1-(6-{3,5-二氯-4-羥基苯基)-4-[反-4-(羥基甲基)環己基]胺基}-1,5-萘啶-3-基)乙酮鹽酸鹽
按一般流程II,1-{6-氯-4-[4-(羥基甲基)環己基
胺基]-1,5-萘啶-3-基}乙酮(34mg,0.10mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(44mg,0.15mmol)反應,隨後鹽酸鹽形成,獲得橘色固體之所要產物(40mg,80%):1H NMR(500MHz,DMSO-d 6)δ 11.83(d,J=8.0Hz,1H),10.91(s,1H),9.22(s,1H),8.61(d,J=8.9Hz,1H),8.50(d,J=9.0Hz,1H),8.16(s,2H),5.55-5.45(m,1H),3.28(d,J=6.5Hz,2H),2.76(s,3H),2.25-2.23(m,2H),1.96-1.88(m,2H),1.50-1.42(m,3H),1.17-1.12(m,2H);ESI MS m/z 460[M+H]+;HPLC 96.8%(AUC),t R=11.64min.
實施例44
1-[6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]-2-羥基乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)-2-羥基乙酮(18mg,0.048mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(18mg,0.062mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(9.1mg,33%).1H NMR(500MHz,CD3OD)δ 9.13(s,1H),8.47(d,J=8.9Hz,1H),8.33(d,J=8.9Hz,1H),8.13(s,2H),5.78-5.68(m,1H),4.91(s,2H),3.10(d,J=6.7
Hz,2H),2.94(s,6H),2.49-2.42(m,2H),2.10-2.00(m,3H),1.76-1.66(m,2H),1.48-1.36(m,2H).;ESI MS m/z 503[M+H]+;HPLC>99%(AUC),t R=9.40min.
實施例45
1-{6-(3,5-二氯-4-羥基苯基)-4-[(1-甲基哌啶-4-基)胺基]-1,5-萘啶-3-基}乙酮
按一般流程II,1-{6-氯-4-[(1-甲基哌啶-4-基)胺基]-1,5-萘啶-3-基}乙酮(70mg,0.22mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(95mg,0.33mmol)反應,獲得黃色固體所要之產物(52mg,53%):1H NMR(500MHz,CD3OD)δ 8.85(s,1H),8.09-8.01(m,2H),7.94(s,2H),5.74-5.70(m,1H),2.95-2.92(m,2H),2.68(s,3H),2.51(t,J=11.7Hz,2H),2.37(s,3H),2.33-2.25(m,2H),1.73-1.71(m,2H);ESI MS m/z 445[M+H]+;HPLC>99%(AUC),t R=9.03min.
實施例46
1-{6-(3-氯-5-氟-4-羥基苯基)-4-[(1-甲基哌啶-4-基)胺基]-1,5-萘啶-3-基}乙酮
按一般流程II,1-{6-氯-4-[(1-甲基哌啶-4-基)胺基]-1,5-萘啶-3-基}乙酮(69mg,0.22mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(88mg,0.32mmol)反應,獲得黃色固體所要之產(44mg,47%):1H NMR(500MHz,CD3OD+D2O)δ 8.94(s,1H),8.15(s,2H),7.92(s,1H),7.74(dd,J=12.0,2.2Hz,1H),5.70-5.62(m,1H),3.17-3.12(m,2H),2.71(s,3H),2.69-2.64(m,2H),2.53(s,3H),2.37-2.35(m,2H),1.85-1.82(m,2H);ESI MS m/z 429[M+H]+;HPLC>99%(AUC),t R=8.80min.
實施例47
1-[6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(嗎啉基甲基)環己基]胺基}-1,5-萘啶-3-基]乙酮
按一般流程II,1-(6-氯-4-{[4-(嗎啉基甲基)環己基]-胺基}-1,5-萘啶-3-基)乙酮(85mg,0.21mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(91mg,0.31mmol)反應,獲得橘色固體所要之產(59mg,53%):1H NMR
(500MHz,CDCl3)δ 11.18-11.16(m,1H),8.95(s,1H),8.21(d,J=8.8Hz,1H),7.99(s,2H),7.94(d,J=8.8Hz,1H),5.51-5.42(m,1H),3.71(t,J=4.7Hz,4H),2.70(s,3H),2.41-2.43(m,4H),2.34-2.32(m,2H),2.23-2.22(m,2H),2.02-1.95(m,2H),1.62-1.58(m,1H),1.46-1.39(m,2H),1.28-1.15(m,2H);ESI MS m/z 529[M+H]+;HPLC 98.2%(AUC),t R=9.93min.
實施例48
1-[6-(3,5-二氯-4-羥基苯基)-4-(反-4-{[(2-羥基乙基)(甲基)胺基]甲基}-環己基胺基)-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-[6-氯-4-(4-{[(2-羥基乙基)(甲基)-胺基]甲基}環己基胺基)-1,5-萘啶-3-基]乙酮(70mg,0.18mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(76mg,0.27mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(68mg,64%):1H NMR(500MHz,CD3OD)δ 9.15(s,1H),8.46(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.12(s,2H),5.74-5.71(m,1H),3.90(t,J=5.0Hz,2H),3.39-3.37(m,1H),3.28-3.26(m,2H),3.06-3.02(m,1H),2.97(s,3H),2.76(m,3H),2.46-2.43(m,2H),2.13-2.03(m,3H),1.69-1.66(m,2H),1.44-1.42(m,2H);ESI MS m/z 517
[M+H]+;HPLC>99%(AUC),t R=9.74min.
實施例49
1-[6-(3-氯-5-氟-4-羥基苯基)-4-(反-4-{[(2-羥基乙基)(甲基)胺基]-甲基}環己基胺基)-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-[6-氯-4-(4-{[(2-羥基乙基)(甲基)胺基]-甲基}環己基胺基)-1,5-萘啶-3-基]乙酮(30mg,0.076mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(31mg,0.11mmol)反應,隨後二鹽酸鹽形成,獲得淡黃色固體之所要產物(32mg,73%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.03(s,1H),7.89(d,J=11.5Hz,1H),5.74-5.71(m,1H),3.90(t,J=5.1Hz,2H),3.45-3.32(m,1H),3.30-3.26(m,2H),3.07-3.04(m,1H),2.97(s,3H),2.76(s,3H),2.45(s,2H),2.17-2.02(m,3H),1.70-1.62(m,2H),1.48-1.36(m,2H);ESI MS m/z 501[M+H]+;HPLC 98.2%(AUC),t R=9.54min.
實施例50
1-[6-(3,5-二氟-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基)乙酮(65mg,0.18mmol)與2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(69mg,0.27mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(87mg,90%):1H NMR(500MHz,CD3OD)δ 9.13(s,1H),8.44(d,J=9.0Hz,1H),8.35(d,J=9.0Hz,1H),7.78(dd,J=7.8,1.7Hz,2H),5.66-5.62(m,1H),3.09(d,J=6.6Hz,2H),2.94(s,6H),2.76(s,3H),2.47-2.44(m,2H),2.08-2.04(m,3H),1.72-1.68(m,2H),1.37-1.28(m,2H);ESI MS m/z 455[M+H]+;HPLC>99%(AUC),t R=9.49min.
實施例51
1-[6-(3,5-二氯-4-羥基苯基)-4-{6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{6-[3-(二甲基胺基)吡咯啶-1-基]-吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮(55mg,0.134mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊
環-2-基)酚(58mg,0.20mmol)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(75mg,86%):1H NMR(300MHz,CD3OD)δ 9.41(s,1H),8.55-8.38(m,2H),8.30(d,J=2.4Hz,1H),7.97(dd,J=9.5,2.4Hz,1H),7.54(s,2H),7.05(d,J=9.5Hz,1H),4.20-4.16(m,2H),4.02-3.86(m,2H),3.80-3.70(m,1H),3.03(s,6H),2.85(s,3H),2.82-2.68(m,1H),2.39-2.52(m,1H);ESI MS m/z 537[M+H]+;HPLC>99%(AUC),t R=9.08min.
實施例52
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基]乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮(55mg,0.134mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(55mg,0.20mmol)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(85mg,99%):1H NMR(300MHz,CD3OD)δ 9.41(s,1H),8.54-8.37(m,2H),8.29(d,J=2.3Hz,1H),7.99(dd,J=9.5,2.3Hz,1H),7.39-7.35(m,2H),7.10(d,J=9.5Hz,1H),4.29-4.11(m,2H),4.03-3.85(m,2H),3.75-
3.71(m,1H),3.03(s,6H),2.85(s,3H),2.71-2.82(s,1H);ESI MS m/z 521[M+H]+;HPLC>99%(AUC),t R=8.90min.
實施例53
1-(6-(3,5-二氯-4-羥基苯基)-4-{6-[3-(甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程D-1,叔-丁基1-{5-[3-乙醯基-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-4-基胺基]吡啶-2-基}吡咯啶-3-基(甲基)氨基甲酸酯(0.183mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘黃色固體之所要產物(57mg,49%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.37(s,1H),8.49(d,J=8.9Hz,1H),8.40(d,J=8.9Hz,1H),8.24(d,J=2.5Hz,1H),7.88(dd,J=9.4,2.5Hz,1H),7.57(s,2H),6.96(d,J=9.4Hz,1H),4.13-4.00(m,2H),3.92-3.79(m,2H),3.66-3.73(m,1H),2.83(s,6H),2.72-2.60(m,1H),2.45-2.34(m,1H);ESI MS m/z 523[M+H]+;HPLC>99%(AUC),t R=8.97min.
實施例54
1-(6-(3-氯-5-氟-4-羥基苯基)-4-{6-[3-(甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程D-1,叔-丁基1-{5-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基]-1,5-萘啶-4-基胺基}吡啶-2-基)吡咯啶-3-基(甲基)氨基甲酸酯(0.189mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(73mg,63%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.34(s,1H),8.46(d,J=9.0Hz,1H),8.38(d,J=9.0Hz,1H),8.22(d,J=2.5Hz,1H),7.82(dd,J=9.4,2.5Hz,1H),7.40(s,1H),7.32(d,J=11.8Hz,1H),6.92(d,J=9.4Hz,1H),4.16-3.97(m,2H),3.90-3.78(m,2H),3.75-3.65(m,1H),2.83(s,6H),2.72-2.60(m,1H),2.42-3.34(m,1H);ESI MS m/z 507[M+H]+;HPLC>99%(AUC),t R=8.72min.
實施例55
1-(6-(1H-苯並[d]咪唑-5-基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮(68mg,0.188mmol)
與5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-苯並[d]imidazole(69mg,0.282mmol)反應,隨後三鹽酸鹽形成,獲得黃棕色固體之所要產物(76mg,73%):1H NMR(500MHz,CD3OD)δ 9.49(s,1H),9.19(s,1H),8.63(d,J=8.9Hz,1H),8.56(s,1H),8.46(d,J=8.9Hz,1H),8.37(d,J=8.5Hz,1H),8.19(d,J=8.5Hz,1H),5.65-5.55(m,1H),3.15(d,J=6.9Hz,2H),2.93(s,6H),2.78(s,3H),2.52-2.48(m,2H),2.07-1.95(m,3H),1.76-1.64(m,2H),1.43-1.31(m,2H);ESI MS m/z 443[M+H]+;HPLC 97.7%(AUC),t R=8.20min.
實施例56
1-{4-[4-(反-4-二甲基胺基)甲基環己基胺基]-6-(吡啶-4-基)-1,5-萘啶-3-基}乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-(反-4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮(89mg,0.247mmol)與4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶(45mg,0.370mmol)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(108mg,85%):1H NMR(500MHz,CD3OD)δ 9.28-9.20(m,3H),8.81(d,J=8.9Hz,1H),8.74-8.69(m,2H),8.57(d,J=8.9Hz,1H),5.51-5.43(m,1H),3.17(d,J=6.7Hz,2H),2.94(s,6H),2.78(s,3H),2.52-2.44(m,2H),2.08-1.97(m,3H),
1.77-1.65(m,2H),1.42-1.33(m,2H);ESI MS m/z 404[M+H]+;HPLC 95.6%(AUC),t R=7.62min.
實施例57
5-(7-乙醯基-8-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-2-基)嘧啶-2-甲腈
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮(87mg,0.24mmol)與5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)嘧啶-2-甲腈(83mg,0.36mmol)以獲得黃色固體之所要產物(24mg,23%):1H NMR(500MHz,CD3OD+TFA-d)δ 9.62(s,2H),9.23(s,1H),8.68(d,J=8.9Hz,1H),8.51(d,J=8.9Hz,1H),5.52-5.41(m,1H),3.12(d,J=6.8Hz,2H),2.94(s,6H),2.77(s,3H),2.51-2.42(m,2H),2.08-1.94(m,3H),1.88-1.65(m,2H),1.37-1.25(m,2H);ESI MS m/z 430[M+H]+;HPLC>99%(AUC),t R=8.73min.
實施例58
1-(6-(3,5-二甲基-1H-吡唑-4-基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程D-1,叔-丁基4-(7-乙醯基-8-{反-4-[(二甲基胺基)-甲基]環己基}胺基)-1,5-萘啶-2-基)-3,5-二甲基-1H-吡唑-1-羧酸(0.25mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得黃色泡沒之所要產物(96mg,72%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.17(s,1H),8.36(d,J=8.8Hz,1H),8.08(d,J=8.8Hz,1H),5.64-5.52(m,1H),3.05(d,J=6.7Hz,2H),2.90(s,6H),2.76(s,3H),2.47(s,6H),2.38-2.29(m,2H),1.99-1.87(m,3H),1.68-1.52(m,2H),1.21-1.07(m,2H);ESI MS m/z 421[M+H]+;HPLC>99%(AUC),t R=8.45min.
實施例59
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(4-羥基-3,5-二甲基苯基)-1,5-萘啶-3-基)乙酮二氯
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮(60mg,0.166mmol)
與2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(62mg,0.25mmol)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(41mg,48%):1H NMR(500MHz,CD3OD)δ 9.10(s,1H),8.39(d,J=9.0Hz,1H),8.26(d,J=9.0Hz,1H),7.72(s,2H),5.82-5.73(m,1H),3.06(d,J=6.6Hz,2H),2.93(s,6H),2.75(s,3H),2.49-2.42(m,2H),2.35(s,6H),2.09-1.98(m,3H),1.73-1.60(m,2H),1.40-1.27(m,2H);ESI MS m/z 447[M+H]+;HPLC 98.4%(AUC),t R=9.81min.
實施例60
1-(6-(3,5-二氯-4-羥基苯基)-4-[4-(吡咯啶-1-基甲基)苯基胺基]-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-{6-氯-4-[4-(吡咯啶-1-基甲基)苯基胺基]-1,5-萘啶-3-基}乙酮(72mg,0.189mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(82mg,0.284mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(50mg,45%):1H NMR(500MHz,CD3OD)δ 9.34(s,1H),8.44(d,J=8.9Hz,1H),8.36(d,J=8.9Hz,1H),7.68-7.62(m,2H),7.54-7.47(m,2H),7.40(br s,2H),4.49(s,2H),3.53-3.44(m,2H),3.25-3.17(m,2H),2.81(s,3H),2.24-2.14(m,2H),1.92-2.05(m,2H);ESI MS m/z 507[M+H]+;
HPLC>99%(AUC),t R=10.07min.
實施例61
1-{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(吡咯啶-1-基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-{6-氯-4-[反-4-(吡咯啶-1-基甲基)-環己基胺基]-1,5-萘啶-3-基}乙酮(67mg,0.17mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(58mg,0.21mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(36mg,36%):1H NMR(300MHz,CD3OD)δ 9.15(s,1H),8.47(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.12(s,2H),5.75-5.67(m,1H),3.72-3.65(m,2H),3.17-3.06(m,4H),2.76(s,3H),2.48-2.40(m,2H),2.20-1.99(m,6H),1.73-1.61,(m,2H),1.47-1.36(m,2H);ESI MS m/z 513[M+H]+;HPLC 95.7%(AUC),t R=10.21min.
實施例62
1-(6-(3-氯-5-氟-4-羥基苯基)-4-{[反-4-(吡咯啶-1-基甲基)環己基]胺基}-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{[反-4-(吡咯啶-1-基甲基)-環己基]胺基}-1,5-萘啶-3-基)乙酮(86mg,0.22mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(90mg,0.33mmol)反應,隨後二鹽酸鹽形成,獲得淡棕色固體之所要產物(75mg,69%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.02(s,1H),7.88(dd,J=11.5,2.0Hz,1H),5.74-5.64(m,1H),3.74-3.68(m,2H),3.18-3.10(m,4H),2.76(s,3H),2.47-2.41(m,2H),2.22-1.98(m,7H),1.74-1.62(m,2H),1.47-1.34(m,2H);ESI MS m/z 497[M+H]+;HPLC 96.6%(AUC),t R=9.90min.
實施例63
1-(6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(4-甲基哌嗪-1-基)甲基]環己基-胺基}-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[(4-甲基哌嗪-1-基)
甲基]-環己基 胺基}-1,5-萘啶-3-基)乙酮(32mg,0.076mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(26mg,0.092mmol)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(31mg,67%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.46(d,J=8.9Hz,1H),8.33(d,J=8.9Hz,1H),8.10(s,2H),5.73-5.68(m,1H),3.75(br s,8H),3.16(br s,2H),3.02(s,3H),2.76(s,3H),2.46-2.42(m,2H),2.22-2.14(m,2H),2.10-2.00(m,1H),1.72-1.63(m,2H),1.46-1.37(m,2H);ESI MS m/z 542[M+H]+;HPLC 96.7%(AUC),t R=9.37min.
實施例64
1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程IV-2,叔-丁基[1-(5-{[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(0.20mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(31mg,30%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.38(s,1H),8.49(d,J=9.0Hz,1H),8.41(d,J=9.0Hz,1H),8.25(d,J=2.6Hz,1H),7.92-7.86(m,1H),7.58(s,2H),7.24(d,J=9.5Hz,1H),4.41-4.34(m,1H),4.03-3.96(m,1H),3.53-3.32(m,4H),
2.84(s,3H),2.24-2.21(m,1H),2.05-1.97(m,1H),1.84-1.76(m,2H);ESI MS m/z 523[M+H]+;HPLC 98.0%(AUC),t R=9.48min.
實施例65
1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程IV-2,叔-丁基[1-(5-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(0.20mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(33mg,33%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.38(s,1H),8.48(d,J=9.5Hz,1H),8.41(d,J=9.5Hz),8.25(d,J=2.5Hz,1H),7.91(dd,J=9.5,2.5Hz,1H),7.41-7.37(m,2H),7.28(d,J=9.5Hz,1H),4.37(d,J=10.7Hz,1H),4.03-3.99(m,1H),3.52-3.32(m,3H),2.84(s,3H),2.28-2.20(m,1H),2.08-1.98(m,1H),1.84-1.78(m,2H);ESI MS m/z 507[M+H]+;HPLC>99%(AUC),t R=9.38min.
實施例66
1-{4-[反-(4-胺基環己基)胺基]-6-(3,5-二氯-4-羥基苯
基)-1,5-萘啶-3-基}-乙酮二鹽酸鹽
按一般流程IV-2,叔-丁基(4-{[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基]胺基}環己基)氨基甲酸酯(0.23mmol)與TFA(2mL)反應,隨後二鹽酸鹽形成,獲得灰色固體之所要產物(32mg,27%兩個步驟以上):1H NMR(300MHz,D2O)δ 8.96(s,1H),8.18-8.00(m,2H),7.53(s,2H),3.28-3.23(m,1H),2.68(s,3H),2.28-2.24(m,2H),2.16-2.13(m,2H),1.76-1.64(m,2H),1.57-1.45(m,2H);ESI MS m/z 445[M+H]+;HPLC 98.4%(AUC),t R=9.34min.
實施例67
1-{4-[反-(4-胺基環己基)胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程IV-2,叔-丁基(4-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}環己基)氨基甲酸酯(0.20mmol)與TFA(2mL)反應,隨後二鹽酸鹽形成,獲得白色固體之所要產物(45mg,45%兩個步驟以上):1H NMR
(500MHz,D2O)δ 8.99(s,1H),8.13(d,J=9.0Hz,1H),8.03(d,J=9.0Hz,1H),7.40-7.34(m,2H),4.91-4.94(m,1H),3.35-3.28(m,1H),2.72(s,3H),2.30-2.22(m,2H),2.21-2.14(m,2H),1.75-1.68(m,2H),1.56-1.48(m,2H);ESI MS m/z 429[M+H]+;HPLC>99%(AUC),t R=9.10min.
實施例68
1-(6-(3-氯-5-氟-4-羥基苯基)-4-{反-4-[(4-甲基哌嗪-1-基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{4-[(4-甲基哌嗪-1-基)甲基]-環己基 胺基}-1,5-萘啶-3-基)乙酮(53mg,0.13mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(41mg,0.152mmol)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(11mg,14%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=9.0Hz,1H),8.32(d,J=9.0Hz,1H),8.02(s,1H),7.88(dd,J=11.4,2.2Hz,1H),5.75-5.65(m,1H),3.70(br s,8H),3.10(br s,2H),3.01(s,3H),2.75(s,3H),2.46-2.42(m,2H),2.16-2.13(m,2H),2.05-2.02(m,1H),1.73-1.61(m,2H),1.46-1.35(m,2H);ESI MS m/z 526[M+H]+;HPLC>99%(AUC),t R=9.14min.
實施例69
N-(反-4-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}-環己基)-2-胺基-3-甲基丁醯胺二鹽酸鹽
按一般流程IV-2,叔-丁基[1-(反-4-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}環己基胺基)-3-甲基-1-二氧硼戊環-2-基]氨基甲酸酯(0.19mmol)與TFA(2mL)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(35mg,30%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.44(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.00(s,1H),7.87(dd,J=11.4,2.2Hz,1H),5.63-5.57(m,1H),3.88-3.83(m,1H),3.62(d,J=6.0Hz,1H),2.76(s,3H),2.51-2.40(m,2H),2.10-2.12(m,3H),1.81-1.53(m,4H),1.08(t,J=7.4Hz,6H);ESI MS m/z 528[M+H]+;HPLC98.9%(AUC),t R=9.99min.
實施例70
1-{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(哌嗪-1-基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮三鹽酸鹽
按一般流程IV-2,叔-丁基4-((4-((3-乙醯基-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-4-基)胺基)環己基)甲基)哌嗪-1-羧酸(0.298mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(84mg,47%兩個步驟以上):1H NMR(500MHz,D2O)δ 9.00(s,1H),8.22-8.11(m,2H),7.59(s,2H),5.06(m,1H),4.76-4.71(m,1H),4.66(s,1H),3.60(s,8H),3.15(d,J=6.7Hz,2H),2.74(s,3H),2.25-2.23(m,2H),2.02-1.97(m,2H),1.60-1.58(m,2H),1.24-1.20(m,2H);ESI MS m/z 528[M+H]+;HPLC 98.0%(AUC),t R=9.29min.
實施例71
(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程IV-2,(S)-叔-丁基[1-(5-{[3-乙醯基-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)
哌啶-3-基]氨基甲酸酯(0.197mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得黃色固體之所要產物(42mg,33%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.39(s,1H),8.49(d,J=9.0Hz,1H),8.41(d,J=9.0Hz,1H),8.25(d,J=2.6Hz,1H),7.92(dd,J=9.5,2.6Hz,1H),7.57(s,2H),7.27(d,J=9.5Hz,1H),4.37(d,J=10.9Hz,1H),4.02-3.99(m,1H),3.52-3.32(m,3H),2.84(s,3H),2.24-2.22(m,1H),2.07-1.95(m,1H),1.82-1.77(m,2H);ESI MS m/z 523[M+H]+;HPLC 97.5%(AUC),t R=9.56min.
實施例72
(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程IV-2,(S)-叔-丁基[1-(5-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(0.20mm01)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘黃色固體之所要產物(42mg,34%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.30(s,1H),8.45(d,J=9.0Hz,1H),8.35(d,J=9.0Hz,1H),8.19(d,J=2.6Hz,1H),7.68(dd,J=9.2,2.6Hz,1H),7.45(br s,1H),7.27
(br s,1H),7.05(d,J=9.2Hz,1H),4.43-4.36(m,1H),3.94-3.92(m,1H),3.44-3.32(m,3H),2.81(s,3H),2.23-2.15(m,1H),2.05-1.91(m,1H),1.77-1.73(m,2H);ESI MS m/z 507[M+H]+;HPLC>99%(AUC),t R=9.57min.
實施例73
N-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]-環己基}-2-胺基丙醯胺二鹽酸鹽
按一般流程IV-1,粗叔-丁基1-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]環己基胺基}-1-氧代丙-2-基氨基甲酸酯(0.13mmol)與HCl(5mL,2M乙醚)反應,以獲得棕色固體所要之產物(32mg,41%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=8.5Hz,1H),8.34(d,J=8.5Hz,1H),8.10(s,2H),5.65-5.55(m,1H),3.90(q,J=6.9Hz,1H),3.85-3.76(m,1H),2.76(s,3H),2.50-2.39(m,2H),2.21-2.10(m,2H),1.78-1.69(m,2H),1.65-1.52(m,2H),1.51(d,J=6.9Hz,3H);ESI MS m/z 516[M+H]+;HPLC>99%(AUC),t R=9.65min.
實施例74
N-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-
基胺基]-環己基}-2-胺基丙醯胺二鹽酸鹽
按一般流程IV-1,叔-丁基1-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-基胺基]環己基胺基}-1-氧代丙-2-基氨基甲酸酯(0.13mmol)與HCl(5mL,2M乙醚)反應,以獲得白色固體所要之產物(6.0mg,8%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.44(d,J=8.9Hz,1H),8.33(d,J=8.9Hz,1H),8.00(t,J=1.8Hz,1H),7.87(dd,J=11.6,1.8Hz,1H),5.65-5.57(m,2H),3.94-3.77(m,2H),2.76(s,3H),2.50-2.40(s,2H),2.20-2.12(m,2H),1.78-1.58(m,2H),1.61-1.52(m,2H),1.51(d,J=7.1Hz,3H);ESI MS m/z 500[M+H]+;HPLC 99.0%(AUC),t R=9.59min.
實施例75
(S)-N-{4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-基胺基]-環己基}吡咯啶-2-醯胺二鹽酸鹽
按一般流程IV-1,(S)-叔-丁基2-{4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-yl胺基]環己基氨基甲醯基}吡咯啶-1-羧酸(0.19mmol)與HCl(5mL,2M乙醚)反應,以獲得灰白色固體所要之產物(70mg,58%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.09(s,2H),5.66-5.53(m,1H),4.24(dd,J=8.5,6.9Hz,1H),3.90-3.77(m,1H),3.46-3.30(m,2H),2.76(s,3H),2.51-2.40(m,3H),2.22-1.94(m,5H),1.80-1.53(m,4H);ESI MS m/z 542[M+H]+;HPLC98.9%(AUC),t R=9.88min.
實施例76
(S)-N-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-基胺基]-環己基}吡咯啶-2-醯胺二鹽酸鹽
按一般流程IV-1,叔-丁基1-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-4-基胺基]環己基胺基}-1-氧代丙-2-基氨基甲酸酯(0.19mmol)與HCl(5mL,2M乙醚)反應,以獲得灰白色固體所要之產物(46mg,45%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.44(d,J=8.9Hz,1H),8.33(d,J=8.9Hz,1H),8.00(t,J=1.8Hz,
1H),7.87(dd,J=11.4,1.8Hz,1H),5.69-5.52(m,1H),4.23(dd,J=8.5,6.9Hz,1H),3.80-3.88(m,1H),3.47-3.32(m,2H),2.75(s,3H),2.51-2.39(m,3H),2.20-2.13(m,2H),2.12-1.95(m,3H),1.81-1.68(m,2H),1.67-1.52(m,2H);ESI MS m/z 527[M+H]+;HPLC>99%(AUC),t R=9.69min.
實施例77
1-(6-(3-羥基吡咯啶-1-基)-4-{反-4-[(3-羥基吡咯啶-1-基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮
按一般流程V,{4-[(3-乙醯基-6-氯-1,5-萘啶-反-4-yl)-胺基]環己基甲基 甲磺酸(170mg,0.41mmol)與3-吡咯啶醇(680mg,7.8mmol)反應,以獲得橘棕色固體所要之產物(33mg,17%):1H NMR(500MHz,CD3OD)δ 8.64(s,1H),7.85(d,J=9.2Hz,1H),7.04(d,J=9.2Hz,1H),5.63-5.55(m,1H),4.61-4.54(m,1H),4.40-4.30(m,1H),3.79-3.65(m,3H),3.60-3.52(m,1H),2.88-2.80(m,1H),2.79-2.70(m,1H),2.63(s,2H),2.63-2.53(m,1H),2.53-2.48(m,1H),2.47-2.35(m,2H),2.30-2.05(m,6H),2.00-1.89(m,2H),1.75-1.70(m,1H),1.62-1.52(m,1H),1.40-1.31(m,2H),1.21-1.10(m,2H);ESI MS m/z 454[M+H]+;HPLC 98.1%
(AUC),t R=8.66min.
實施例78
1-{6-(吡咯啶-1-基)-4-[反-4-(吡咯啶-1-基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮
按一般流程V,{4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]-環己基}甲基 甲磺酸(180mg,0.437mmol)與吡咯啶(34mg,0.48mmol)反應,以獲得棕色固體所要之產物(34mg,18%):1H NMR(500MHz,CD3OD)δ 8.63(s,1H),7.83(d,J=9.2Hz,1H),7.02(d,J=9.2Hz,1H),5.57(br s,1H),3.61-3.53(m,4H),2.63(s,6H),2.45(d,J=7.0Hz,2H),2.30-2.18(m,2H),2.14-2.04(m,4H),1.98-1.91(m,2H),1.89-1.80(m,4H),1.68-1.55(m,1H),1.40-1.28(m,2H),1.18-1.08(m,2H);ESI MS m/z 422[M+H]+;HPLC 97.5%(AUC),t R=9.68min.
實施例79
N-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]-環己基}-2-胺基-3-甲基丁醯胺二鹽酸鹽
按一般流程IV-2,叔-丁基1-(4-(3-乙醯基-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-4-基胺基)環己基胺基)-3-甲基-1-二氧硼戊環-2-基氨基甲酸酯(0.19mmol)與HCl(5mL,2M乙醚)反應,以獲得灰白色固體所要之產物(55mg,47%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.10(s,2H),5.67-5.53(m,1H),3.91-3.80(m,1H),3.62(d,J=6.0Hz,1H),2.76(s,3H),2.49-2.40(m,2H),2.25-2.10(m,3H),1.81-1.54(m,4H),1.07(dd,J=9.0,6.9Hz,6H);ESI MS m/z 544[M+H]+;HPLC 99.0%(AUC),t R=10.15min.
實施例80
環丙基{6-(3,5-二氯-4-羥基苯基)-4-[反-4-(二甲基胺基)-環己基胺基]-1,5-萘啶-3-基}甲酮二鹽酸鹽
按一般流程II,{6-氯-4-[反-4-(二甲基胺基)環己基-胺基]-1,5-萘啶-3-基}(環丙基)甲酮(50mg,0.13mmol)
與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(65g,84%):1H NMR(500MHz,CD3OD)δ 9.43(s,1H),8.46(d,J=9.0Hz,1H),8.36(d,J=9.0Hz,1H),8.11(s,2H),5.64-5.54(m,1H),3.51-3.44(m,1H),2.91(s,6H),2.93-2.89(m,1H),2.63-2.56(m,2H),2.32-2.24(m,2H),1.87-1.68(m,4H),1.33-1.18(m,4H).;ESI MS m/z 499[M+H]+;HPLC>99%(AUC),t R=10.12min.
實施例81
1-[6-(3-氯-5-氟-4-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,{6-氯-4-[反-4-(二甲基胺基)環己基-胺基]-1,5-萘啶-3-基}(環丙基)甲酮(50mg,0.13mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(61mg,0.23mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(58g,78%):1H NMR(500MHz,CD3OD)δ 9.43(s,1H),8.46(d,J=8.9Hz,1H),8.36(d,J=9.0Hz,1H),8.00(t,J=1.9Hz,1H),7.91(dd,J=11.6,2.2Hz,1H),5.66-5.56(m,1H),3.53-3.43(m,1H),2.91(s,6H),2.93-2.86(m,1H),2.62-2.54(m,2H),2.33-2.23(m,2H),1.88-1.69
(m,4H),1.33-1.18(m,4H).ESI MS m/z 483[M+H]+;HPLC>99%(AUC),t R=9.84min.
實施例82
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(1H-吡咯[2,3-b]吡啶-5-基)-1,5-萘啶-3-基)乙酮三鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮(60mg,0.17mmol)與5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡咯[2,3-b]吡啶(60mg,0.25mmol)反應,隨後三鹽酸鹽形成,獲得灰白色固體之所要產物(7.5mg,9%):1H NMR(500MHz,CD3OD)δ 9.19(s,1H),9.08(s,2H),8.65(d,J=8.9Hz,1H),8.44(d,J=8.9Hz,1H),7.72(d,J=3.7Hz,1H),6.91(d,J=3.6Hz,1H),5.69-5.59(m,1H),3.18(d,J=6.8Hz,2H),2.94(s,6H),2.77(s,3H),2.55-2.45(m,2H),2.08-1.98(m,3H),1.76-1.64(m,2H),1.48-1.36(m,2H).ESI MS m/z 443[M+H]+;HPLC>99%(AUC),t R=9.25min.
實施例83
(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}(環丙基)甲酮
按一般流程IV-2,(S)-叔-丁基1-{5-[6-(3-氯-5-氟-4-羥基-苯基)-3-(環丙羰基)-1,5-萘啶-4-基胺基)吡啶-2-基]哌啶-3-基氨基甲酸酯(100mg,0.16mmol)與TFA(3mL)反應,以獲得橘紅色固體所要之產物(33mg,40%):1H NMR(500MHz,CD3OD)δ 9.15(s,1H),8.06(d,J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),7.94(d,J=2.7Hz,1H),7.40(s,1H),7.33(dd,J=9.0,2.8Hz,1H),6.94(dd,J=12.6,2.3Hz,1H),6.69(d,J=8.9Hz,1H),4.20-4.10(m,1H),3.87-3.77(m,1H),3.30-3.21(m,1H),3.13-3.03(m,2H),2.91-2.83(m,1H),2.17-2.06(m,1H),1.90-1.82(m,1H),1.77-1.51(m,2H),1.43-1.04(m,4H);ESI MS m/z 533[M+H]+;HPLC>99%(AUC),t R=9.97min.
實施例84
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(4-甲氧基苯基)-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)
甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮(72g,0.20mmol)與(4-甲氧基苯基)硼酸(45g,0.30mmol)反應,隨後二鹽酸鹽形成,獲得橘色固體之所要產物(80mg,79%):1H NMR(300MHz,CD3OD)δ 9.13(s,1H),8.45(d,J=9.0Hz,1H),8.31(d,J=9.0Hz,1H),8.15-8.03(m,2H),7.24-7.12(m,2H),5.73-5.59(m,1H),3.91(s,3H),3.13(d,J=6.7Hz,2H),2.94(s,6H),2.75(s,3H),2.50-2.42(m,2H),2.09-1.96(m,3H),1.77-1.60(m,2H),1.45-1.25(m,2H);ESI MS m/z 433[M+H]+;HPLC>99%(AUC),t R=9.83min.
實施例85
1-[6-(3,5-二氯-4-甲氧基苯基)-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮(77g,0.21mmol)與(3,5-二氯-4-甲氧基苯基)硼酸(70g,0.32mmol)反應,隨後二鹽酸鹽形成,獲得棕色固體之所要產物(80g,66%):1H NMR(300MHz,CD3OD)δ 9.18(s,1H),8.52(d,J=9.0Hz,1H),8.39(d,J=9.0Hz,1H),8.20(s,2H),5.74-5.59(m,1H),3.99(s,3H),3.09(d,J=6.6Hz,2H),2.94(s,6H),2.76(s,3H),2.48-2.40(m,2H),2.10-2.00(m,3H),1.79-1.61(m,2H),
1.50-1.31(m,2H);ESI MS m/z 501[M+H]+;HPLC>99%(AUC),t R=10.49min.
實施例86
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(6-羥基吡啶-3-基)-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮(74g,0.21mmol)與(6-羥基吡啶-3-基)硼酸(43g,0.31mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(49g,48%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.41-8.29(m,4H),6.76(d,J=9.5Hz,1H),5.58-5.50(m,1H),3.13(d,J=6.7Hz,2H),2.94(s,6H),2.75(s,3H),2.49-2.40(m,2H),2.08-2.00(m,3H),1.73-1.61(m,2H),1.39-1.27(m,2H);ESI MS m/z 420[M+H]+;HPLC>99%(AUC),t R=8.43min.
實施例87
5-(7-乙醯基-8-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-2-基)2-氰吡啶二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮(77g,0.21mmol)與5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)2-氰吡啶(72g,0.32mmol)反應,隨後二鹽酸鹽形成,獲得淡棕色固體之所要產物(100g,95%):1H NMR(500MHz,CD3OD)δ 9.46(d,J=2.2Hz,1H),9.21(s,1H),8.70(dd,J=8.2,2.2Hz,1H),8.63(d,J=8.9Hz,1H),8.47(d,J=8.9Hz,1H),8.17(d,J=8.2Hz,1H),5.58-5.50(m,1H),3.14(d,J=6.8Hz,2H),2.94(s,6H),2.77(s,3H),2.49-2.42(m,2H),2.05-1.97(m,3H),1.75-1.65(m,2H),1.39-1.27(m,2H);ESI MS m/z 429[M+H]+;HPLC 96.2%(AUC),t R=8.88min.
實施例88
1-(4-{反-4-[(二甲基胺基)甲基]環己基胺基}-6-(4-羥基苯基)-1,5-萘啶-3-基)乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮(76g,0.21mmol)與
(4-羥基苯基)硼酸(43g,0.32mmol)反應,隨後二鹽酸鹽形成,獲得黃色固體之所要產物(35g,34%):1H NMR(500MHz,CD3OD)δ 9.11(s,1H),8.41(d,J=8.9Hz,1H),8.28(d,J=8.9Hz,1H),8.03-7.97(m,2H),7.04-6.98(m,2H),5.73-5.62(m,1H),3.11(d,J=6.8Hz,2H),2.94(s,6H),2.75(s,3H),2.50-2.42(m,2H),2.06-1.99(m,3H),1.73-1.61(m,2H),1.40-1.27(m,2H);ESI MS m/z 419[M+H]+;HPLC>99%(AUC),t R=9.24min.
實施例89
1-[6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(二甲基胺基)環己基]-甲基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{[反-4-(二甲基胺基)環己基]甲基胺基}-1,5-萘啶-3-基)乙酮(100mg,0.27mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(86g,0.30mmol)反應,隨後二鹽酸鹽形成,獲得淺黃色固體之所要產物(50mg,38%):1H NMR(500MHz,CD3OD)δ 9.14(s,1H),8.45(dd,J=9.0,1.5Hz,1H),8.37(d,J=9.1Hz,1H),8.08(d,J=2.1Hz,2H),4.51(dd,J=7.2,1.9Hz,2H),3.33-3.24(m,1H),2.87(s,6H),2.78(s,3H),2.30-2.20(m,
4H),2.03(dtd,J=18.7,7.3,6.9,3.4Hz,1H),1.65(qd,J=13.2,12.3,3.8Hz,2H),1.42(qd,J=14.6,13.8,3.6Hz,2H),0.14-0.06(m,2H);ESI MS m/z 487[M+H]+;HPLC 95.0%(AUC),t R=9.74min.
實施例90
1-[6-(3-氯-5-氟-4-羥基苯基)-4-{[反-4-(二甲基胺基)-環己基]甲基胺基}-1,5-萘啶-3-基]乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{[反-4-(二甲基胺基)環己基]-甲基胺基}-1,5-萘啶-3-基)乙酮(100g,0.27mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(85g,0.30mmol)反應,隨後二鹽酸鹽形成,獲得白色固體之所要產物(50g,38%):1H NMR(500MHz,CD3OD)δ 9.12(s,1H),8.43(d,J=9.0Hz,1H),8.36(d,J=8.9Hz,1H),8.01-7.95(m,1H),7.87(dd,J=11.5,2.2Hz,1H),4.51(d,J=7.0Hz,2H),4.25(d,J=6.7Hz,1H),3.27(dt,J=12.2,3.3Hz,1H),2.87(s,3H),2.77(d,J=16.7Hz,6H),2.28-2.19(m,1H),2.09-1.95(m,1H),1.84(s,1H),1.64(qd,J=12.8,12.1,3.7Hz,1H),1.41(qd,J=14.0,13.3,3.4Hz,1H),1.27(dd,J=23.6,12.3Hz,1H);ESI MS m/z 471[M+H]+;HPLC 98.9%(AUC),
t R=8.55min.
實施例91
1-[6-(3,5-二氯-4-羥基苯基)-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]-乙酮鹽酸鹽
按一般流程II,1-[6-氯-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮(160mg,0.50mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(165mg,0.60mmol)反應,隨後鹽酸鹽形成,獲得淺黃色固體之所要產物(120mg,56%):1H NMR(500MHz,CD3OD)δ 9.11(s,1H),8.44(d,J=9.0Hz,1H),8.30(d,J=9.0Hz,1H),8.00(t,J=1.9Hz,1H),7.87(dd,J=11.5,2.3Hz,1H),5.60(tt,J=10.5,4.2Hz,1H),3.75(tt,J=9.6,4.2Hz,1H),2.75(s,3H),2.42-2.35(m,2H),2.14-2.06(m,2H),1.74-1.54(m,4H);ESI MS m/z 430[M+H]+;HPLC>99%(AUC),t R=10.9min.
實施例92
1-[6-(3-氯-5-氟-4-羥基苯基)-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮鹽酸鹽
按一般流程II,1-[6-氯-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮(160mg,0.50mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(160g,0.60mmol)反應,隨後鹽酸鹽形成,獲得灰白色固體之所要產物(120mg,57%):1H NMR(500MHz,CD3OD)δ 9.11(s,1H),8.45(d,J=9.1Hz,1H),8.30(d,J=9.0Hz,1H),8.11(s,2H),5.60(dq,J=10.1,4.5Hz,1H),4.94-4.83(m,1H),3.75(tt,J=7.6,3.9Hz,1H),3.66(s,2H),3.41-3.31(m,1H),2.75(s,3H),2.38(dd,J=9.0,5.3Hz,2H),2.14-2.07(m,2H),2.03(s,1H),1.74-1.57(m,4H);ESI MS m/z 446[M+H]+;HPLC 96.7%(AUC),t R=11.1min.
實施例93
1-{6-(3-氯-5-氟-4-羥基苯基)-4-({順-4-[(二甲基胺基)甲基]環己基}-胺基)-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{順-4-[(二甲基胺基)甲基]-環己基 胺基}-1,5-萘啶-3-基)乙酮(120mg,0.30mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(100mg,0.30mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(150mg,81%):1H NMR(500MHz,CD3OD)δ
9.17(s,1H),8.46(d,J=9.0Hz,1H),8.45-8.30(m,1H),7.99(q,J=2.7,1.7Hz,1H),7.90-7.82(m,1H),5.93(p,J=4.2Hz,1H),3.20(d,J=7.1Hz,2H),2.95(s,6H),2.78(s,3H),2.15(dddt,J=44.4,14.7,11.4,4.1Hz,3H),2.01-1.86(m,2H),1.61(dtd,J=14.3,10.8,3.6Hz,3H),1.20(s,1H);ESI MS m/z 471[M+H]+;HPLC 95.7%(AUC),t R=9.9min.
實施例94
1-{6-(3,5-二氯-4-羥基苯基)-4-({順-4-[(二甲基胺基)甲基]-環己基}胺基)-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{順-4-[(二甲基胺基)甲基]-環己基 胺基}-1,5-萘啶-3-基)乙酮(120mg,0.30mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(100mg,0.30mmol)反應,隨後二鹽酸鹽形成,獲得灰白色固體之所要產物(150mg,81%):1H NMR(500MHz,CD3OD)δ 9.17(s,1H),8.47(d,J=9.0Hz,1H),8.34(d,J=8.9Hz,1H),8.11(s,2H),5.92(p,J=4.4Hz,1H),3.21(d,J=7.2Hz,2H),2.96(s,6H),2.78(s,3H),2.25-2.05(m,3H),1.99-1.88(m,2H),1.62(dtd,J=14.1,11.2,10.8,3.7Hz,3H),1.20(s,1H);ESI MS m/z 487[M+H]+;HPLC 96.5%(AUC),t R=9.9min.
實施例95
(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基}乙酮三鹽酸鹽
按一般流程IV-2,(R)-叔-丁基1-(5-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯(60mg,0.10mmol)與TFA(1.5mL)反應,以獲得黃棕色固體之所要產物(37mg,74%):1H NMR(500MHz,CD3OD)δ 9.28(s,1H),8.49-8.31(m,2H),8.16(d,J=2.7Hz,1H),7.63(dd,J=9.1,2.8Hz,1H),7.51(s,2H),6.98(d,J=9.1Hz,1H),4.40(dd,J=12.7,3.6Hz,1H),3.93(d,J=13.4Hz,1H),3.41-3.19(m,3H),2.80(s,3H),2.16(m,1H),1.97-1.89(m,1H),1.78-1.65(m,2H);ESI MS m/z 523[M+H]+;HPLC 98.1%(AUC),t R=9.87min.
實施例96
(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮
按一般流程IV-2,(R)-叔-丁基1-(5-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯(100mg,0.16mmol)與TFA(2.0mL)反應,以獲得黃棕色固體之所要產物(56mg,67%):1H NMR(500MHz,CD3OD)δ 9.27(s,1H),8.40(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.16(d,J=2.7Hz,1H),7.59(dd,J=9.1,2.8Hz,1H),7.44(s,1H),7.20(d,J=11.7Hz,1H),6.97(d,J=9.1Hz,1H),4.39(dd,J=12.6,3.4Hz,1H),3.38-3.94(m,2H),3.43-3.21(m,5H),2.79(s,3H),2.17(m,,2H),1.93(m,1H),1.80-1.66(m,2H).;ESI MS m/z 507[M+H]+;HPLC 98.8%(AUC),t R=9.34min.
實施例97
乙基2-(乙氧基亞甲基)-3-氧代丁酸
乙基乙醯醋酸(100g,0.77mol),原甲酸三乙酯(130g,0.92mol),及乙酸酐(150g,1.5mol)混合物以具蒸餾裝置之圓底燒瓶於135℃加熱6-18小時,以收集反應過程所產生之乙醇。將反應混合物冷卻,濃縮。將殘留物高真空蒸餾,以獲得淡黃色油物之所要產物(100g,70%):ESI MS m/z
187[M+H]+.
實施例98
乙基2-[(6-氯吡啶-3-基胺基)亞甲基)]-3-氧代丁酸
乙基2-(乙氧基亞甲基)-3-氧代丁酸(48g,0.26mol)及2-氯-5-胺基吡啶(33g,0.26mol)於氯苯(150mL)之混合物以具蒸餾裝置之圓底燒瓶於135℃加熱4小時,以收集反應過程所產生之乙醇。將反應混合物冷卻,濃縮。將殘留物於二乙基乙醚磨碎、過濾,獲得灰白色固體之所要產物(55g,79%):1H NMR(500MHz,CDCl3)δ 12.76(d,12.3Hz,1H),8.42(s,1H),8.38(s,1H),8.31(d,J=2.8Hz,1H),7.52-7.48(m,1H),7.37-7.34(m,1H),4.30(q,J=7.1Hz,2H),2.56(s,1H),1.35(t,J=7.1Hz,3H);ESI MS m/z 269[M+H]+.
實施例99
乙基2-[(6-甲氧基吡啶-3-基胺基)亞甲基]-3-氧代丁酸
乙基2-(乙氧基亞甲基)-3-氧代丁酸(100g,0.54mol)及2-甲氧基-5-胺基吡啶(67g,0.54mol)於氯苯(500mL)之混合物以具蒸餾裝置之圓底燒瓶於135℃加熱4小時,以收集反應過程所產生之乙醇。將反應混合物冷卻,濃縮。將殘留物於二乙基乙醚磨碎、過濾,獲得灰白色固體之所要產
物(120g,84%):1H NMR(500MHz,CDCl3)δ 12.74(d,12.3Hz,1H),8.35(d,J=13.0Hz,1H),8.07(d,J=2.8Hz,1H),7.55(d,J=8.8,2.9Hz,,1H),6.79(d,J=8.8Hz,1H),4.30(q,J=7.1Hz,2H),2.55(s,3H),1.33(t,J=7.1Hz,1H);ESI MS m/z 265[M+H]+.
實施例100
1-(4-羥基-6-甲氧基-1,5-萘啶-3-基)乙酮
含有DowthermTM A(500mL)燒瓶於250℃以超過3至5分鐘分批加入乙基2-[(6-甲氧基吡啶-3-基胺基)亞甲基]-3-氧代丁酸(75g,0.28mol)。該反應混合物另攪拌30-60分鐘。該反應混合物自熱源移開,冷卻至室溫,以己烷稀釋以促使沉澱。過濾該固體物,以己烷及乙腈清洗,真空乾燥,以獲得灰白色固體所要之產物(60g,46%):1H NMR(500MHz,DMSO-d6)δ 12.48(bs,1H),8.45(d,J=5.2Hz,1H),8.00(d,J=8.9Hz,1H),7.40-7.37(m,1H),7.21(d,J=8.9Hz,1H),7.01-6.99(m,1H),3.96(s,3H),2.61(s,3H);ESI MS m/z 219[M+H]+.
實施例101
1-(4,6-二氯-1,5-萘啶-3-基)乙酮
按流程1合成途徑製備:
含有DowthermTM A(500mL)燒瓶於250℃以超過3至5分鐘分批加入乙基2-[(6-氯吡啶-3-基胺基)亞甲基]-3-氧代丁酸(10g,27mmol)。該反應混合物另攪拌30-45分鐘。該反應混合物自熱源移開,冷卻至室溫,以己烷稀釋以促使沉澱。濾該固體物,以己烷清洗,真空乾燥,以獲得中間物1-(6-氯-4-羥基-1,5-萘啶-3-基)乙酮,其於乾淨氧氯化磷及催化的N,N-二甲基甲醯胺於70℃攪拌4小時。該反應物冷卻,緩慢倒入至大力攪拌之冰冷飽合硫代硫酸鈉及乙酸乙酯溶液,分層,該有基層以硫酸鈉乾燥,過濾,濃縮濾液。該殘留物以管柱層析法(二氧化矽,己烷/乙酸乙酯)純化,以獲得棕色固體之所要產物(3g,46%兩個步驟以上):ESI MS m/z 241[M+H]+.
按流程2合成途徑製備:
乙基2-[(6-甲氧基吡啶-3-基胺基)亞甲基]-3-氧代丁酸(70g,0.32mol)於乙腈(800ml)懸浮液加入三甲基甲矽烷基氯(173g,1.6mol)及碘化鈉(140g,0.96mol)。該反應混合物於回流下加熱2小時。該反應混合物冷卻至室溫,加入飽合硫代硫酸鈉溶液。該混合物濃縮以移去乙腈,以鹽水稀釋。過濾該固體物,乾燥,以獲得中間物1-(4,6-二羥基-1,5-萘啶-3-基)乙酮。此中間物懸浮於二氯乙烷(350mL),隨後加入氧氯化磷(200mL)及催化的N,N-二甲基甲醯胺。該反應混合物於80℃攪拌3小時。該反應混合物冷卻至室溫,緩慢倒入至冰涼飽合碳酸氫鈉或3N氫氧化鈉溶液驟冷。該驟冷反應混合物濃縮以移去二氯乙烷。該產生之固體物過濾,以層析法
(二氧化矽,己烷/乙酸乙酯)純化,獲得棕色固體之所要之產物(50g,74%兩步驟以上):1H NMR(300MHz,CDCl3)δ 9.00(s,1H),8.38(d,J=8.8Hz,1H),7.74(d,J=8.8Hz,1H),4.30(q,J=7.1Hz,2H),3.28-3.18(m,1H),1.36(t,J=7.1Hz,3H),ESI MS m/z 241[M+H]+.
實施例102
甲基3-(6-氯吡啶-3-基胺基)-2-(環丙羰基)丙烯酸
甲基3-環丙基-3-氧代丙酸(7.2g,50mmol),原甲酸三乙酯(13mL,75mmol)及2-氯-5-胺基吡啶(6.4g,50mmol)混合物以具短徑蒸餾裝置之圓底燒瓶於145℃加熱3小時,以收集反應過程所產生之乙醇。將反應混合物冷卻,濃縮。該殘留物以層析法(二氧化矽,己烷/乙酸乙酯)純化,以獲得淡黃色油之所要之產物(4.2g,28%):1H NMR(300MHz,CDCl3)δ 12.78(d,12.5Hz,1H),8.40-8.34(m,1H),8.28(d,J=2.9Hz,1H),7.51-7.44(m,1H),7.35(d,J=8.6Hz,1H),4.30(q,J=7.1Hz,2H),3.28-3.18(m,1H),1.36(t,J=7.1Hz,3H),1.17-1.09(m,2H),1.02-0.86(m,2H).ESI MS m/z 281[M+H]+.
實施例103
環丙基(4,6-二氯-1,5-萘啶-3-基)甲酮
含有DowthermTM A(500mL)燒瓶於250℃以超過3至5分鐘分批加入甲基3-(6-氯吡啶-3-基胺基)-2-(環丙羰基)丙烯酸(4.2g,15mmol)。該反應混合物另攪拌30-45分鐘。該反應混合物自熱源移開,冷卻至室溫,以己烷稀釋以促使沉澱。過濾該固體物,以己烷清洗,真空乾燥,以獲得中間物(6-氯-4-羥基-1,5-萘啶-3-基)(環丙基)甲酮,其於乾淨氧氯化磷及催化的N,N-二甲基甲醯胺於70℃攪拌4小時。該反應物冷卻,緩慢倒入至大力攪拌之冰冷飽合硫代硫酸鈉及乙酸乙酯溶液,分層,該有基層以硫酸鈉乾燥,過濾,濃縮。該殘留物以層析法(二氧化矽,二氯甲烷/乙酸乙酯)純化,以獲得棕色固體之所要產物(0.78g,20%兩個步驟以上):1H NMR(500MHz,CDCl3)δ 8.93(s,1H),8.39(d,J=8.7Hz,1H),7.74(d,J=8.8Hz,1H),2.65(t,J=7.7,4.5Hz,1H),1.52-1.42(m,2H),1.32-1.22(m,2H);ESI MS m/z 268[M+H]+.
實施例104
乙基3-(6-氯吡啶-3-基胺基)-2-(甲基磺醯基)丙烯酸
乙基3-乙氧基-2-(甲基磺醯基)丙烯酸(7.0g,32mmol)及2-氯-5-胺基吡啶(4.1g,32mmol)於氯苯(16mL)之混合物以具蒸餾裝置之圓底燒瓶於135℃加熱3小時,以收
集反應過程所產生之乙醇。將反應混合物冷卻,濃縮。將殘留物以層析法(二氧化矽,二氯甲烷/乙酸乙酯)純化,以獲得淡黃色油之所要之產物(8.2g,84%):1H NMR(500MHz,CDCl3)δ 10.61(d,13.4Hz,1H),8.34(d,J=13.4Hz,1H),8.27(d,J=2.9Hz,1H),7.50(dd,J=8.6,3.0Hz,1H),7.37(d,J=8.6Hz,1H),4.41(q,J=7.2Hz,2H),3.18(s,3H),1.42(t,J=7.2Hz,3H);ESI MS m/z 305[M+H]+.
實施例105
2,8-二氯-7-(甲基磺醯基)-1,5-萘啶
含有DowthermTM A(500mL)燒瓶於250℃以超過3至5分鐘分批加入乙基3-(6-氯吡啶-3-基胺基)-2-(甲基磺醯基)丙烯酸(8.2g,30mmol)。該反應混合物另攪拌30-45分鐘。該反應混合物自熱源移開,冷卻至室溫,以己烷稀釋以促使沉澱。過濾該固體物,以己烷清洗,真空乾燥,以獲得中間物6-氯-3-(甲基磺醯基)-1,5-萘啶-4-醇,其於乾淨氧氯化磷(31mL)及催化的N,N-二甲基甲醯胺於70℃攪拌4小時。該反應物冷卻,緩慢倒入至大力攪拌之冰冷飽合硫代硫酸鈉及乙酸乙酯溶液,分層,該有機層以硫酸鈉乾燥,過濾,濃縮。該殘留物以層析法(二氧化矽,己烷/乙酸乙酯)純化,以獲得棕色固體之所要產物(2.7g,33%兩個步驟以上):1H NMR(500MHz,CDCl3)δ 9.50(s,1H),8.46(d,J=8.8Hz,1H),7.83(d,J=8.8Hz,1H),3.41(s,3H);ESI MS m/z 278[M+H]+.
實施例106
2-氯-1-(4,6-二氯-1,5-萘啶-3-基)乙酮
將1-(4,6-二氯-1,5-萘啶-3-基)乙酮(3.0g,12mmol)於THF(120mL)溶液加入苯基三甲基氨二氯碘酸(4.3g,12mmol)。該反應混合物於70℃攪拌5小時。該反應物冷卻,以飽合碳酸氫鈉溶液稀及以二氯甲烷萃取。該合併有機層以無水硫酸鈉乾燥,過濾,濾液濃縮。該殘留物以管狀層析法(二氧化矽,二氯甲烷/乙酸乙酯)純化,以獲得灰白色固體所要之產物(1.1g,32%).ESI MS m/z 275[M+H]+.
實施例107
2-(4,6-二氯-1,5-萘啶-3-基)-2-氧代乙酸乙酯
將醋酸(0.32mL,5.5mmol)及N,N-二異丙基乙基胺(0.87mL,5.0mmol)於丙酮(20mL)溶液加入2-氯-1-(4,6-二氯-1,5-萘啶-3-基)乙酮(0.26g,0.96mmol)。該反應混合物於室溫攪拌4小時。該反應物以飽合碳酸氫鈉溶液稀及以二氯甲烷萃取。該合併有機層以無水硫酸鈉乾燥,過濾,濾液濃縮。該殘留物以管狀層析法(二氧化矽,二氯甲烷/乙酸乙酯)純化,以獲得白色固體所要之產物(0.12g,42%).ESI MS m/z 299[M+H]+.
實施例108
苯基4-[(二甲基胺基)甲基]環己基氨基甲酸酯
將市售苯基4-(胺基甲基)環己基-氨基甲酸酯(15g,57mmol)於(15 0mL)懸浮液加入甲醛(14mL,0.17mol,37%溶液)及甲酸(6.5mL,0.17mol),該混合物回流加熱2小時,冷卻至室溫,以2N NaOH中和,以CH2Cl2萃取。有機萃取物以無水硫酸鈉乾燥,過濾,濃縮,以得到黃褐色蠟狀固體之所要產物。(16g,96%).:APCI MS m/z 291[C17H26N2O2+H]+.
實施例109
反-4-[(二甲基胺基)甲基]環己胺二醋酸鹽
將含有Pd/C(1.5g,Degussa type E101)於甲醇/醋酸(100mL,3:1)燒瓶加入於甲醇/醋酸(300mL,3:1)之苯基4-[(二甲基胺基)甲基]環己基氨基甲酸酯(16g,54mmol)。該反應混合物在H2(1atm)氣體存在下於室溫攪拌6小時。該反應混合物以矽藻土過濾。將濾液濃縮,與甲苯共沸。該稠密油物於真空乾燥,以得蠟狀固體之所要產物(18g,粗),無需純化:1H NMR(300MHz,CD3OD)δ 3.11-2.98(m,1H),2.78(d,J=7.0Hz,2H),2.69(s,6H),2.07(br d,J=13.9Hz,4H),
2.02-1.86(m,2H),1.92(s,6H),1.79-1.67(m,1H),1.53-1.35(m,2H),1.20-1.05(m,2H).
實施例110
叔-丁基[反-4-(吡咯啶-1-基甲基)環己基]氨基甲酸酯
將反-4-((叔丁氧羰基)胺基)環己基)甲基 甲磺酸(1.8g,6.0mmol),K2CO3(1.7g,12mmol)及KI(600mg,3.6mmol)於乙腈(30mL)懸浮液逐滴加入吡咯啶(5.0mL,60mmol)。該反應混合物於85℃加熱16小時。該溶液冷卻至室溫,以飽合NaHCO3溶液稀釋,以CHCl3/異丙醇(3:1)混合物萃取。該合併有機層以硫酸鈉乾燥,過濾,濾液濃縮。該殘留物以層析法(二氧化矽,甲醇/二氯甲烷)純化,以獲得白色固體所要之產物(1.3g,76%).ESI MS m/z 283[C16H30N2O2+H]+
實施例111
反-4-(吡咯啶-1-基甲基)環己胺 二鹽酸鹽
將叔-丁基(反-4-(吡咯啶-1-基甲基)環己基)氨基甲酸酯(1.3g,4.5mmol)於THF(15mL)溶液加入6N HCl(6mL)水溶液及水(6mL)。該反應混合物於65℃加熱攪拌3小時。該反應混合物冷卻至室溫,濃縮,以獲得灰白色固體所要之產
物(1.2g,>99%).ESI MS m/z 183[C11H22FN2+H]+
實施例112
叔-丁基(反-4-[2-(二甲基胺基)乙基]環己基}氨基甲酸酯
將叔-丁基[反-4-(2-胺基乙基)環己基]氨基甲酸酯(970mg,4.0mmol)及para甲醛(360mg,12mmol)於甲醇(40mL)懸浮液加入氰基硼氫化鈉(750mg,12mmol)及醋酸(1滴)。產生之懸浮液於室溫攪拌16小時,以飽合NaHCO3溶液稀釋,以CHCl3/異丙醇(3:1)混合物萃取。該合併有機層以無水硫酸鈉乾燥,過濾,濃縮濾液。該殘留物以層析法(二氧化矽,甲醇/二氯甲烷)純化,以獲得白色固體所要之產物(340mg,31%).ESI MS m/z 271[C15H30N2O2+H]+
實施例113
反-4-[2-(二甲基胺基)乙基]環己胺 二鹽酸鹽
按一般流程IV-1,叔-丁基{反-4-[2-(二甲基胺基)乙基]-環己基}氨基甲酸酯(330mg,1.2mmol)與6N HCl(2mL)反應,以獲得粘無色油狀所要之產物,無需純化。
實施例114
N2-[2-(二甲基胺基)乙基)吡啶-2,5-二胺
將2-氯-5-硝基吡啶(500mg,3.1mmol)於THF(30mL)溶液加入N1,N1-二甲基乙烷-1,2-二胺(310mg,3.5mmol)及三乙基胺(0.64mL,4.6mmol)。該反應混合物於室溫攪拌16小時。該反應混合物濃縮,該殘留物溶解於二氯甲烷,以1N HCl水溶液及水清洗。該有機層以無水硫酸鈉乾燥,過濾,濃縮濾液。該殘留物溶解於四氫呋喃(30mL),以氮除氣,以10wt.% Pd/C(0.3g)催化反應。該反應混合物置於氫氣(40Psi)下,直到以LCMS分析觀察到反應完全為止。該反應混合物以矽藻土過濾。將濾液濃縮,得到紫色固體之所要產物(280mg,50%):ESI MS m/z 181[C9H16N4+H]+.
實施例115
6-[2-(二甲基胺基)乙氧基]吡啶-3-胺
將2-氯-5-硝基吡啶(500mg,3.1mmol)於二氧陸圜(30mL)溶液在室溫加入2-(二甲基胺基)乙醇(309mg,3.5mmol)及60wt.% NaH(0.15g,3.7mmol)。該反應混合物於室溫攪拌,直到以LCMS分析觀察到反應完全為止。該反應混合物倒入至冰冷水,該產物以二氯甲烷萃取。該有機層以硫酸鈉乾燥,過濾。將濾液濃縮。該殘留物溶解於四氫呋喃
(30mL),以氮除氣,以10wt.% Pd/C(0.3g)催化反應。該反應混合物置於氫氣(40Psi)下,直到以LCMS分析觀察到反應完全為止。該反應混合物以矽藻土過濾。將濾液濃縮,得到紫色固體之所要產物t(340mg,61%):ESI MS m/z 182[C9H15N3O+H]+.
實施例116
叔-丁基[1-(5-胺基吡啶-2-基)吡咯啶-3-基](甲基)氨基甲
酸酯
市售叔-丁基 甲基(吡咯啶-3-基)氨基甲酸酯(1.0g,5.0mmol)於THF(25mL)溶液加入三乙基胺(0.70mL,5.0mmol)及2-氯-5-硝基吡啶(500mg,3.1mmol)。該反應混合物室溫攪拌16小時。該反應混合物以飽合NaHCO3溶液稀釋,以萃取乙酸乙酯。該有機層以硫酸鈉乾燥,過濾,濃縮濾液。該殘留物以層析法(二氧化矽,乙酸乙酯/己烷)純化,以獲得黃色固體所要之產物(1.0g,quant.)。該固體物溶解於四氫呋喃(50mL),以氮除氣,以10wt.% Pd/C(0.5g)催化反應。該反應混合物置於氫氣(1atm)下,直到以LCMS分析觀察到反應完全為止。該反應混合物以矽藻土過濾。將濾液濃縮,得到紅色油狀之所要產物(940mg,100%)ESI MS m/z 293[C15H24N4O2+H]+
實施例117
叔-丁基{反-4-[(二甲基-d 6-胺基)甲基]環己基}氨基甲酸酯
將反-4-[(叔丁氧羰基)胺基)環己基]甲基 甲磺酸(310mg,1.0mmol),KI(330mg,2.0mmol)及N,N-二異丙基乙基胺(1.8mL,10mmol)於乙腈(4mL)懸浮液加入二甲基-d 6-胺 鹽酸鹽(350mg,4.0mmol)。該反應瓶於CEM®微波100℃加熱1小時。該反應混合物冷卻,以飽合NaHCO3溶液稀釋,以乙酸乙酯萃取。該有機層以硫酸鈉乾燥,過濾,濃縮濾液,得淺棕色固體之所要產物(240mg,90%).ESI MS m/z 263[C14H22D6N2O2+H]+
實施例118
反-4-[(二甲基胺基-d 6)甲基]環己胺 二鹽酸鹽
將叔-丁基{反-4-[(二甲基-d 6-胺基)甲基]環己基}氨基甲酸酯(750mg,2.9mmol)於THF(10mL)溶液加水(5mL)及HCl(6.0M in H2O,5.0mL,30mmol)。產生之溶液於65℃加熱攪拌2小時,濃縮,乾燥,以得白色半固體,無須進一步純化或解析。
實施例119
叔-丁基 反-4-(二甲基胺基)環己基氨基甲酸酯
將叔-丁基 反-4-胺基環己基氨基甲酸酯(750mg,3.5mmol)、對甲醛(320mg,10mmol)及氰基硼氫化鈉(660mg,13mmol)於甲醇(30mL)溶液加入醋酸(催化的)。該反應於室溫攪拌18小時。該反應混合物以水及二氯甲烷稀釋,分層。該溶液層以1M氫氧化鈉調整至pH 10,以二氯甲烷萃取。該合併有機層以硫酸鈉乾燥,過濾,濃縮濾液,得白色固體所要之產物(800mg,95%):ESI MS m/z 243[C13H26N2O2+H]+.
實施例120
反-N 1,N 1-二甲基環己烷-1,4-二胺
將叔-丁基 反-4-(二甲基胺基)環己基氨基甲酸酯(800mg,3.3mmol)溶液加入TFA(5mL),該反應混合物於75℃攪拌18小時。濃縮該反應混合物,該殘留物上載至SCX®離子交換管柱,以甲醇清洗,隨後以7N氨於甲醇清洗,得所要之產物。將含該產物之部份濃縮之乾,得橘色油狀之遊離鹼形式的所要產物(400mg,85%):ESI MS m/z 143[C8H18N2+H]+.
實施例121
6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-胺
將2-氯-5-硝基吡啶(500mg,3.1mmol)於THF(30mL)溶液加入N,N-二甲基吡咯啶-3-胺(400mg,3.5mmol)及三乙基胺(0.64mL,4.6mmol)。該反應混合物於室溫攪拌16小時。該反應混合物濃縮至乾。該殘留物溶解於二氯甲烷及以1N HCl溶液及水清洗。該有機層以無水硫酸鈉乾燥,過濾。將濾液濃縮至乾。該殘留物溶解於四氫呋喃(30mL),以氮除氣,以10wt.% Pd/C(0.3g)催化反應。該反應混合物置於氫氣(40Psi)下,直到以LCMS分析觀察到反應完全為止。該反應混合物以矽藻土過濾。將濾液濃縮,得到紫色固體之所要產物(360mg,56%):ESI MS m/z 207[C11H18N4+H]+.
實施例122
叔-丁基1-(5-胺基吡啶-2-基)哌啶-3-基氨基甲酸酯
將2-氯-5-硝基吡啶(500mg,3.1mmol)於THF(30mL)溶液加入叔-丁基 哌啶-3-基氨基甲酸酯(700mg,3.5mmol)及三乙基胺(0.64mL,4.6mmol)。該反應混合物於室溫攪拌16小時。該反應混合物濃縮至乾。該殘留物溶解於二氯甲烷及以1N HCl溶液及水清洗。該有機層以無水硫酸
鈉乾燥,過濾。將濾液濃縮至乾。該殘留物溶解於四氫呋喃(30mL),以氮除氣,以10wt.% Pd/C(0.3g)催化反應。該反應混合物置於氫氣(40Psi)下,直到以LCMS分析觀察到反應完全為止。該反應混合物以矽藻土過濾。將濾液濃縮,得到紫色固體之所要產物(850mg,93%):ESI MS m/z 293[C15H24N4O2+H]+.
實施例123
(S)-叔-丁基1-(5-胺基吡啶-2-基)哌啶-3-基氨基甲酸酯
將2-氯-5-硝基吡啶(500mg,3.1mmol)於THF(30mL)溶液加入(S)-叔-丁基 哌啶-4-基氨基甲酸酯(700mg,3.5mmol)及三乙基胺(0.64mL,4.6mmol)該反應混合物於室溫攪拌16小時。該反應混合物濃縮至乾。該殘留物溶解於二氯甲烷及以1N HCl溶液及水清洗。該有機層以無水硫酸鈉乾燥,過濾。將濾液濃縮至乾。該殘留物溶解於四氫呋喃(30mL),以氮除氣,以10wt.% Pd/C(0.3g)催化反應。該反應混合物置於氫氣(40Psi)下,直到以LCMS分析觀察到反應完全為止。該反應混合物以矽藻土過濾。將濾液濃縮,得到紫色固體之所要產物(945mg,quant.):ESI MS m/z 293[C15H24N4O2+H]+.
實施例124
叔-丁基4-(4-硝基-1H-吡唑-1-基)哌啶-1-羧酸
將硝基吡唑(3.0g,25mmol),叔-丁基 4-羥基哌啶-1-羧酸(6.0g,30mmol)及三苯基膦(7.9g,30mmol)於THF(200mL)溶液在室溫加入二異丙基偶氮基二羧酸(6.0g,30mmol)。該反應混合物於室溫攪拌16小時。該反應混合物濃縮,該殘留物以層析法(二氧化矽,己烷/乙酸乙酯)純化,得到白色固體之所要產物(4.2g,57%):
實施例125
1-(1-甲基哌啶-4-基)-1H-吡唑-4-胺
將氫化鋁鋰(0.32g,8.4mmol)於THF(15mL)懸浮液加入叔-丁基4-(4-硝基-1H-吡唑-1-基)哌啶-1-羧酸(500mg,1.7mmol)於THF(10mL)溶液。該反應混合物於60℃攪拌16小時。將該反應混合物冷卻至0℃,緩慢先後加入乙醇(0.3mL)、水(0.3mL)、3N NaOH溶液(0.3mL)使之驟冷。所產生之混合物攪拌30分鐘,過濾。將濾液濃縮至乾,得所要之產物(280mg),無需純化:ESI MS m/z 181[M+H]+.
實施例126
2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚
將含4-溴-2,6-二氯酚(45g,0.20mol)、KOAc(39g,0.40mol)、雙戊醯二硼(61g,0.22mol)及Pd(dppf)Cl2(8.1g,0.010mol)燒瓶加入1,4-二氧陸圜(1200mL).該反應混合物以氮除氣,於90℃攪拌16小時。將該反應混合物冷卻,以二氯甲烷稀釋,過濾。將濾液濃縮至乾。該殘留物以層析法(二氧化矽,己烷/乙酸乙酯)純化,得黃色油狀物,以己烷處理,過濾該所產生之固體,得白色固體之所要產物(24g,44%):1H NMR(500MHz,CDCl3)δ 7.57(t,J=1.3Hz,1H),7.42(dd,J=10.2,1.3Hz,1H),1.33(s,12H).
實施例127
2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚
按實施例106之步驟,4-溴-2-氯-6-氟酚(270mg,1.2mmol)與雙戊醯二硼(305mg,1.2mmol)及Pd(dppf)Cl2(98mg,0.12mmol)反應,以獲得無色油狀所要之產物(340mg,quant.):1H NMR(500MHz,CDCl3)δ 7.57(t,J=1.3Hz,1H),7.42(dd,J=10.2,1.3Hz,1H),1.33(s,12H).
實施例128
1-{6-氯-4-[反-4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基}乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與反-N1,N1-二甲基環己烷-1,4-二胺 二鹽酸鹽(336mg,1.6mmol)反應,以獲得淺棕色固體所要之產物(156mg,38%):.1H NMR(500MHz,CDCl3)δ 10.88(br s,1H),8.94(s,1H),8.08(d,J=8.7Hz,1H),7.53(d,J=8.8Hz,1H),5.07-4.92(m,1H),2.67(s,3H),2.34(s,6H),2.39-2.32(m,2 H),2.31-2.22(m,1 H),2.07-1.99(m,2H),1.56-1.35(m,4H);ESI MS m/z 347[M+H]+
實施例129
(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)(環丙基)甲酮
按一般流程I,環丙基(4,6-二氯-1,5-萘啶-3-基)-甲酮(267mg,1.0mmol)與反-4-[(二甲基胺基)甲基]
環己胺二醋酸鹽(270mg,1.0mmol)反應,以獲得灰白色固體所要之產物(150mg,39%):1H NMR(500MHz,CDCl3)δ 10.85(br s,1H),9.19(s,1H),8.08(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),4.97(br s,1H),2.72-2.62(m,1H),2.31-2.24(m,2H),2.22(s,6H),2.13(d,J=7.2Hz,2H),1.96-1.89(m,2H),1.55-1.46(m,1 H),1.36(qd,J=12.4,3.3Hz,2H),1.28-1.22(m,2H),1.21-1.09(m,2H),1.08-1.02(m,2H);ESI MS m/z 387[M+H].+
實施例130
1-(6-氯-4-{反-4-[2-(二甲基胺基)乙基]環己基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與反-4-[2-(二甲基胺基)乙基]環己胺 二鹽酸鹽(300mg,1.2mmol)反應,以獲得灰白色固體所要之產物(140mg,36%):1H NMR(500MHz,CDCl3)δ 10.88(br s,1H),8.93(s,1H),8.07(d,J=8.7Hz,1H),7.52(d,J=8.8Hz,1H),5.04-4.96(m,1H),2.67(s,3H),2.36-2.22(m,4H),2.24(s,6 H),1.93-1.83(dd,J=13.9,3.5Hz,2H),1.49-1.31(m,5H),1.27-1.15(m,2H);ESI MS m/z 375[M+H]+
實施例131
1-(6-氯-4-{順-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(500mg,2.1mmol)與順-4-[(二甲基胺基)甲基]環己胺(300mg,2.0mmol)反應,以獲得黃色固體所要之產物(400mg,55%):ESI MS m/z 361[M+H]+;
實施例132
6-氯-N-{反-4-[(二甲基胺基)甲基]環己基}-3-(甲基磺醯基)-1,5-萘啶-4-胺
按一般流程I,2,8-二氯-7-(甲基磺醯基)-1,5-萘啶(150mg,0.54mmol)與反-4-[(二甲基胺基)甲基]環己胺二醋酸鹽(190mg,0.68mmol)反應,以獲得淺黃色固體所要之產物(150mg,68%):1H NMR(500MHz,CDCl3)δ 8.84(s,1H),8.14(d,J=8.8Hz,1H),7.70-7.60(m,1H),7.57(d,
J=8.8Hz,1H),5.05-4.95(m,1H),3.09(s,3H),2.34-2.24(m,8H),2.18(d,J=7.0Hz,2H),2.00-1.92(m,2H),1.57-1.50(m,1H),1.42-1.30(m,2H),1.24-1.12(m,2H);ESI MS m/z 397[M+H]+
實施例133
反-N1-[6-氯-3-(甲基磺醯基)-1,5-萘啶-4-基]-N4,N4-二甲基環己烷-1,4-二胺
按一般流程I,2,8-二氯-7-(甲基磺醯基)-1,5-萘啶(140mg,0.52mmol)與反-N1,N1-二甲基環己烷-1,4-二胺二鹽酸鹽(140mg,0.65mmol)反應,以獲得灰白色固體所要之產物(68mg,34%):1H NMR(500MHz,CDCl3)δ 8.85(s,1H),8.15(d,J=8.8Hz,1H),7.66(d,J=7.7Hz,1H),7.58(d,J=8.8Hz,1H),5.06-4.96(m,1H),3.09(s,3H),2.33(s,6H),2.33-2.28(m,2 H),2.27-2.17(m,1 H),2.06-1.99(m,2H),1.56-1.32(m,4H);ESI MS m/z 383[M+H]+
實施例134
6-氯-N-{4-[(二甲基胺基)甲基]苯基}-3-(甲基磺醯基)-1,5-萘啶-4-胺
按一般流程I,2,8-二氯-7-(甲基磺醯基)-1,5-萘啶(150mg,0.53mmol)與4-[(二甲基胺基)甲基]苯胺(120mg,0.80mmol)反應,以獲得黃色固體所要之產物(150mg,80%):1H NMR(500MHz,CDCl3)δ 9.05(s,1H),8.95(s,1H),8.18(d,J=8.8Hz,1H),7.52(d,J=8.7Hz,1H),7.34-7.27(m,2H),7.12-7.04(m,2H),3.49(s,2H),3.17(s,3H),2.30(s,6H);ESI MS m/z 391[M+H]+
實施例135
1-(6-氯-4-{3-[2-(吡咯啶-1-基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與3-[2-(吡咯啶-1-基)乙基]苯胺(240mg,1.3mmol)反應,以獲得黃色固體所要之產物(230mg,57%):1H NMR(500MHz,CDCl3)δ 10.79(br s,1H),8.99(s,1H),8.16(d,J=8.7Hz,1H),7.52(d,J=8.8Hz,1H),7.29-7.20(m,
1H),7.07(d,J=7.7Hz,1H),7.03-6.96(m,2H),2.85-2.77(m,2H),2.72-2.66(m,2H),2.59-2.49(m,4H),2.53(s,3 H),1.84-1.74(m,4H);ESI MS m/z 395[M+H]+
實施例136
1-(6-氯-4-{6-[2-(二甲基胺基)乙氧基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(170mg,0.71mmol)與6-[2-(二甲基胺基)乙氧基]吡啶-3-胺(160mg,0.90mmol)反應,以獲得淺棕色固體所要之產物(120mg,44%):1H NMR(500MHz,CDCl3)δ 11.63(br s,1H),9.08(s,1H),8.11(d,J=8.8Hz,1H),7.99(d,J=2.7Hz,1H),7.47(d,J=8.7Hz,1H),7.41(dd,J=8.8,2.8Hz,1H),6.80(d,J=8.7Hz,1H),4.46(t,J=5.6Hz,2H),2.76(t,J=5.6Hz,2H),2.74(s,3H),2.36(s,6H);ESI MS m/z 386[M+H]+
實施例137
6-氯-N-(6-(2-(二甲基胺基)乙氧基)吡啶-3-基)-3-(甲基磺醯基)-1,5-萘啶-4-胺
按一般流程I,2,8-二氯-7-(甲基磺醯基)-1,5-萘啶(150mg,0.54mmol)與6-[2-(二甲基胺基)乙氧基]吡啶-3-胺(120mg,0.65mmol)反應,以獲得淺黃色固體所要之產物(160mg,70%);.1H NMR(500MHz,CDCl3)δ 9.03(s,1H),8.98(s,1H),8.17(d,J=8.8Hz,1H),7.98(d,J=2.8Hz,1H),7.52(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.8Hz,1H),6.82(d,J=8.8Hz,1H),4.46(t,J=5.5Hz,2H),3.20(s,3H),2.76(t,J=5.6Hz,2H),2.37(s,6H);ESI MS m/z 422[M+H]+
實施例138
1-[6-氯-4-(反-4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(480mg,2.0mmol)與反-4-胺基環己ol(287mg,2.5mmol)反應,以獲得橘紅色固體所要之產物(500mg,78%):1H NMR(500MHz,CDCl3)δ 10.90(s,1H),8.95(s,1H),8.09(d,J=8.7Hz,1H),7.53(d,J=8.7Hz,1H),5.10(tdt,J=11.2,8.0,3.9Hz,1H),3.76(tt,J=10.0,4.3Hz,1H),2.68(s,3H),2.33-2.24(m,
2H),2.13-2.04(m,2H),1.63-1.41(m,8H);ESI MS m/z 320[M+H]+
實施例139
1-(6-氯-4-{[反-4-(二甲基胺基)環己基]甲基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(300mg,1.2mmol)與反-4-(胺基甲基)-N,N-二甲基環己胺(350mg,1.5mmol)反應,以獲得橘紅色固體所要之產物(400mg,86%):1H NMR(300MHz,CD3OD)δ 8.95(s,1H),8.11(d,J=8.8Hz,1H),7.69(d,J=8.8Hz,1H),4.07(d,J=6.5Hz,2H),2.69(s,3H),2.32(s,6H),2.13-1.95(m,4H),1.43-1.08(m,4H);ESI MS m/z 361[M+H]+
實施例140
1-{6-氯-4-[(1-甲基哌啶-4-基)甲基胺基]-1,5-萘啶-3-基}乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與(1-甲基哌啶-4-基)甲胺(160mg,1.3mmol)反應,以獲得淺黃棕色固體所要之產物(170mg,49%):1H NMR(500MHz,CDCl3)δ 11.06(br s,1H),8.95(s,1H),8.10(d,J=8.8Hz,1H),7.53(d,J=8.7Hz,1H),4.13(t,J=6.4Hz,2H),2.99-2.92(m,2H),2.69(s,3H),2.32(s,3H),2.07-1.98(m,2H),1.97-1.89(m,2H),1.85-1.75(m,1H),1.57-1.47(m,2H);ESI MS m/z 333[M+H]+
實施例141
(S)-叔-丁基1-{5-[3-(環丙羰基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]吡啶-2-基}哌啶-3-基氨基甲酸酯
按一般流程II,(S)-叔-丁基1-{5-[6-氯-3-(環丙羰基)-1,5-萘啶-4-基胺基]吡啶-2-基}哌啶-3-基氨基甲酸酯(98mg,0.19mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(87mg,0.30mmol)反應,以獲得紅棕色固體所要之產物(73mg,60%):1H NMR(500MHz,CDCl3)δ 11.55(br s,1H),9.29(s,1H),8.25(d,J=8.8Hz,1H),8.03(d,J=2.7Hz,1H),7.92(d,J=8.8Hz,1H),7.46(s,2H),7.32(dd,J=9.0,2.8Hz,1H),6.67(d,J=9.0Hz,1H),4.78-4.72(m,
1H),3.87-3.69(m,3H),3.29-3.07(m,2H),2.79-2.71(m,1H),1.98-1.69(m,2H),1.45(s,9H),1.31-1.22(m,2H),1.16-1.06(m,2H);ESI MS m/z 649[M+H]+
實施例142
(S)-叔-丁基1-{5-[6-氯-3-(環丙羰基)-1,5-萘啶-4-基胺基]-吡啶-2-基}哌啶-3-基氨基甲酸酯
按一般流程I,環丙基(4,6-二氯-1,5-萘啶-3-基)-甲酮(267mg,1.0mmol)與(S)-叔-丁基1-(5-胺基吡啶-2-基)-哌啶-3-基氨基甲酸酯(340mg,1.2mmol)反應,以獲得棕色固體所要之產物(329mg,63%):1H NMR(500MHz,CDCl3)δ 10.19(br s,1H),9.03(s,1H),8.17(d,J=8.8Hz,1H),8.04(d,J=2.8Hz,1H),7.53(d,J=8.8Hz,1H),7.31-7.25(m,1H),6.70(d,J=9.1Hz,1H),4.78(br s,1H),3.83-3.62(m,3H),3.47-3.25(m,2H),2.55-2.47(m,1H),1.97-1.83(m,2H),1.73-1.58(m,1H),1.45(s,9H),1.12-1.04(m,2H),1.00-0.90(m,2H);ESI MS m/z 523[M+H]+
實施例143
1-(6-氯-4-(反-4-((二甲基胺基-d 6)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(100mg,0.42mmol)與反-4-[(二甲基胺基-d 6)甲基]環己胺(87mg,0.37mmol)反應,以獲得淺棕色固體所要之產物(85mg,63%):1H NMR(500MHz,CD3OD)δ 8.96(s,1H),8.11(d,J=8.8Hz,1H),7.70(d,J=8.7Hz,1H),5.08-4.98(m,1H),2.68(s,3H),2.34-2.24(m,4H),2.00-1.91(m,2H),1.68-1.53(m,1H),1.46-1.36(m,2H),1.25-1.15(m,2H);ESI MS m/z 367[M+H]+
實施例144
1-(6-氯-4-{4-[2-(二甲基胺基)乙基]苯基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(150mg,0.64mmol)與4-[2-(二甲基胺基)乙基)苯胺(110mg,0.64mmol)反應,以獲得黃色固體所要之產物(143mg,60%):1H NMR(500MHz,CDCl3)δ 10.86(br s,1H),8.99(s,
1H),8.14(d,J=8.8Hz,1H),7.50(d,J=8.8Hz,1H),7.22-7.15(m,2H),7.11-7.04(m,2H),2.87(t,J=8.1Hz,2H),2.70-2.60(m,2H),2.55(s,3H),2.39(s,6 H);ESI MS m/z 369[M+H]+
實施例145
反-N1-[6-氯-3-(甲基磺醯基)-1,5-萘啶-4-基]-N4,N4-二甲基環己烷-1,4-二胺
按一般流程I,2,8-二氯-7-(甲基磺醯基)-1,5-萘啶(140mg,0.52mmol)與反-N1,N1-二甲基環己烷-1,4-二胺 二鹽酸鹽(140mg,0.65mmol)反應,以獲得灰白色固體所要之產物(68mg,34%):ESI MS m/z 383[M+H]+
實施例146
1-{6-氯-4-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基胺基]-1,5-萘啶-3-基}乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與1-(1-甲基哌啶-4-基)-1H-吡唑-4-胺(216mg,1.2mmol)反應,以獲得淺橘色固體所要之產物(304mg,76%):1H NMR(500MHz,CDCl3)δ 8.99(s,1H),8.12(d,J=8.7Hz,1H),7.56-7.48(m,2H),7.42(d,J=0.6Hz,1H),4.18-4.11(m,1H),3.00(d,J=11.4Hz,2H),2.67(s,3H),2.34(s,3H),2.26-2.02(m,6H);ESI MS m/z 385[M+H]+
實施例147
叔-丁基1-{5-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-yl胺基]嘧啶-2-基}吡咯啶-3-基氨基甲酸酯
按一般流程II,叔-丁基1-[5-(3-乙醯基-6-氯-1,5-萘啶-4-yl胺基)嘧啶-2-基]吡咯啶-3-基氨基甲酸酯(120mg,0.25mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(110mg,0.38mmol)反應,以獲得橘色固體之所要產物(120mg,80%):1H NMR(500MHz,CDCl3)δ 12.02(s,1H),9.12(s,1H),8.28-8.20(m,3H),7.93(d,J=8.8Hz,1H),7.39(s,2H),4.72(br s,1H),4.36(br s,1H),3.86(br s,1H),3.65(br s,2H),3.40(br s,1H),2.80(s,3H),2.28(br s,1H),2.03-1.93(m,1H),1.48(s,9H);ESI MS m/z 610[M+
H]+
實施例148
叔-丁基1-[5-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)嘧啶-2-基]吡咯啶-3-基氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(300mg,1.2mmol)與叔-丁基1-(5-胺基嘧啶-2-基)吡咯啶-3-基氨基甲酸酯(380mg,1.4mmol)反應,以獲得黃橘色固體所要之產物(468mg,78%):1H NMR(500MHz,CDCl3)δ 11.72(s,2H),9.09(s,2H),8.21(s,3H),8.11(d,J=8.7Hz,2H),7.48(d,J=8.8Hz,2H),7.26(s,2H),4.70(s,2H),4.38(s,2H),3.90(dd,J=11.6,6.1Hz,2H),3.78-3.66(m,4H),3.52(dd,J=11.6,4.3Hz,2H),2.77(s,5H),2.31(dq,J=13.4,7.2Hz,2H),1.57(s,2H),1.47(s,17H),1.19(s,1H);ESI MS m/z 484[M+H]+
實施例149
1-(6-氯-4-{4-[(4-甲基哌嗪-1-基)甲基]苯基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與4-[(4-甲基哌嗪-1-基)甲基]苯胺(260mg,1.3mmol)反應,以獲得黃色固體所要之產物(250mg,58%):1H NMR(500MHz,CDCl3)δ 11.04(br s,1H),9.01(s,1H),8.14(d,J=8.7Hz,1H),7.49(d,J=8.7Hz,1H),7.30(d,J=8.0Hz,2H),7.10(d,J=8.0Hz,2H),3.52(s,2H),2.58(s,3H),2.48(br s,8H),2.30(s,3H);ESI MS m/z 410[M+H]+
實施例150
1-(6-氯-4-{4-[2-(吡咯啶-1-基)乙基]哌啶-1-基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與4-[2-(吡咯啶-1-基)乙基]哌啶(230mg,1.3mmol)反應,以獲得黃色固體所要之產物(190mg,47%):1H NMR(500MHz,CDCl3)δ 8.74(s,1 H),8.18(d,J=8.8Hz,
1H),7.53(d,J=8.7Hz,1H),3.98-3.90(m,2H),3.32-3.23(m,2H),2.58-2.50(m,6H),2.55(s,3H),1.86-1.53(m,11H);ESI MS m/z 387[M+H]+
實施例151
1-(6-氯-4-{6-[2-(二甲基胺基)乙基胺基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(300mg,1.2mmol)與N2-[2-(二甲基胺基)乙基]吡啶-2,5-二胺(320mg,1.5mmol)反應,以獲得橘色固體所要之產物(210mg,37%):1H NMR(500MHz,CDCl3)δ 11.41(br s,1H),9.02(s,1H),8.13-8.07(m,1H),7.95(d,J=2.5Hz,1H),7.47(dd,J=8.7,1.1Hz,1H),7.29-7.23(m,1H),6.44(d,J=8.8Hz,1H),5.12(t,J=5.1Hz,1H),3.41(q,J=5.7Hz,2H),2.69(s,3H),2.60(t,J=6.0Hz,2H),2.30(s,6H);ESI MS m/z 385[M+H].+
實施例152
1-[6-氯-4-(1-甲基哌啶-4-基胺基)-1,5-萘啶-3-基]乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(220mg,0.91mmol)與1-甲基piperi二n-4-胺(160mg,1.4mmol)反應,以獲得淺棕色固體所要之產物(200mg,69%):1H NMR(500MHz,CDCl3)δ 10.98(s,1H),8.96(s,1H),8.10(d,J=8.7Hz,1H),7.53(d,J=8.7Hz,1H),5.11(br s,1H),2.98-2.870(m,2H),2.69(s,3H),2.41-2.28(m,5H),2.28-2.20(m,2H),1.85-1.73(m,2H);ESI MS m/z 319[M+H]+ ;ESI MS m/z 319[M+H]+
實施例153
(S)-叔-丁基1-[5-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)吡啶-2-基]哌啶-3-基氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(260mg,1.1mmol)與(S)-叔-丁基1-(5-胺基吡啶-2-基)哌啶-3-基氨基甲酸酯(470mg,1.6mmol)反應,以獲得橘紅色固體所要之產物(350mg,65%):1H NMR(300MHz,CDCl3)δ 11.48(s,1H),9.04(s,1H),8.10(d,J=8.7Hz,1H),8.01(d,J=
2.8Hz,1H),7.46(d,J=8.7Hz,1H),7.31(dd,J=9.0,2.8Hz,1H),6.73(d,J=9.0Hz,1H),4.80(br s,1H),3.85-3.62(m,3H),3.55-3.25(m,3H),2.71(s,3H),1.96-1.84(m,1H),1.82-1.70(m,1H),1.72-1.55(m,1H),1.45(s,9H);ESI MS m/z 497[M+H]+
實施例154
1-{6-氯-4-[反-4-(羥基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(200mg,0.83mmol)與(反-4-胺基環己基)甲醇(130mg,1.0mmol)反應,以獲得橘黃色固體所要之產物(180mg,65%):1H NMR(500MHz,CDCl3)δ 10.90(s,1H),8.94(s,1H),8.08(d,J=8.7Hz,1H),7.52(d,J=8.7Hz,1H),5.10-4.92(m,1H),3.58-3.47(m,2H),2.68(s,3H),2.37-2.23(m,2H),2.01-1.89(m,2H),1.65-1.51(m,1H),1.42-1.30(m,2H),1.29-1.18(m,2H);ESI MS m/z 334[M+H]+
實施例155
{6-氯-4-[反-4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基}(環丙基)甲酮
按一般流程I,環丙基(4,6-二氯-1,5-萘啶-3-基)甲酮(243mg,0.91mmol)與反-N1,N1-二甲基環己烷-1,4-二胺(168mg,1.2mmol)反應,以獲得淺黃色固體所要之產物(150mg,44%).1H NMR(500MHz,氯form-d)δ 10.83(br s,1H),9.20(s,1H),8.09(d,J=8.7Hz,1H),7.52(d,J=8.8Hz,1H),4.98(br s,1H),2.71-2.63(m,1H),2.33(s,6H),2.34-2.29(m,2H),2.28-2.19(m,1H),2.06-1.97(m,2H),1.54-1.33(m,4H),1.31-1.22(m,2H),1.11-1.01(m,2H).ESI MS m/z 373[M+H]+.
實施例156
{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]環己基}甲基甲磺酸
將1-{6-氯-4-[反-4-(羥基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮(140mg,0.42mmol)於二氯甲烷(10mL)溶液加入三乙基胺(0.12mL,0.84mmol)及甲烷磺醯基 氯(65μL,0.84mmol)。該反應混合物於室溫攪拌4小時。該反應混合物以飽合NaHCO3溶液稀釋,分層,該有機層濃縮得到
黃色固體所要之粗產物(180mg),無需進一部純化:1H NMR(500MHz,CDCl3)δ 10.90(br s,1H),8.95(s,1H),8.09(d,J=8.7Hz,1H),7.53(d,J=8.7Hz,1H),5.10-4.95(m,1H),4.11(d,J=6.5Hz,2H),3.03(s,3H),2.68(s,3H),2.39-2.26(m,2H),2.01-1.92(m,2H),1.90-1.78(m,1H),1.47-1.24(m,4H);ESI MS m/z 412[M+H]+
實施例157
叔-丁基4-{[反-4-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)環己基]甲基}哌嗪-1-羧酸
按一般流程V,{4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]-環己基}甲基 甲磺酸(170mg,0.42mmol)與叔-丁基4-[(反-4-胺基環己基)甲基]哌嗪-1-羧酸(93mg,0.50mmol)反應,以獲得黃色固體所要之產物(150mg,73%).ESI MS m/z 502[M+H]+
實施例158
1-{6-氯-4-[反-4-(嗎啉基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮
按一般流程V,{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)-胺基]環己基}甲基 甲磺酸(230mg,0.56mmol)與嗎啉(72mg,0.84mmol)反應,以獲得黃色固體所要之產物(85mg,38%):1H NMR(300MHz,CDCl3)δ 10.90(br s,1H),8.94(s,1H),8.08(d,J=8.7Hz,1H),7.52(d,J=8.7Hz,1H),5.11-4.88(m,1H),3.77-3.65(m,4H),2.68(s,3H),2.46-2.38(m,4H),2.36-2.21(m,2H),2.21-2.15(m,2H),2.01-1.89(m,2H),1.64-1.50(m,1H),1.46-1.07(m,4H);ESI MS m/z 403[M+H]+
實施例159
1-[6-氯-4-(反-4-{[(2-羥基乙基)(甲基)胺基]甲基]環己基胺基)-1,5-萘啶-3-基]乙酮
按一般流程V,{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)-胺基]環己基}甲基 甲磺酸(240mg,0.58mmol)與2-甲基胺基乙醇(88mg,1.2mmol)反應,以獲得黃色固體所要之產物(110mg,47%):1H NMR(300MHz,CDCl3)δ 10.89(s,
1H),8.94(s,1H),8.08(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),5.09-4.88(m,1H),3.63(t,J=5.3Hz,2H),2.68(s,3H),2.59(br s,2H),2.31(br s,7H),2.04-1.91(m,2H),1.68-1.50(m,1H),1.48-1.07(m,4H;ESI MS m/z 391[M+H]+
實施例160
1-{6-氯-4-[反-4-(吡咯啶-1-基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(220mg,0.92mmol)與4-(吡咯啶-1-基甲基)環己胺(200mg,1.1mmol)反應,以獲得棕色固體所要之產物(67mg,19%):.1H NMR(300MHz,CDCl3)δ 10.88(br s,1H),8.93(s,1H),8.07(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),5.09-4.88(m,1H),2.66(br s,7H),2.46(d,J=7.1Hz,2H),2.37-2.25(m,2H),2.08-1.76(m,6H),1.72-1.55(m,1H),1.51-1.12(m,4H);ESI MS m/z 387[M+H]+
實施例161
叔-丁基1-[5-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)吡啶-2-基]-哌啶-3-基氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(610mg,2.5mmol)與叔-丁基1-(5-胺基吡啶-2-基)哌啶-3-基氨基甲酸酯(590mg,3.0mmol)反應,以獲得橘紅色固體所要之產物(420mg,35%):1H NMR(500MHz,CDCl3)δ 11.47(s,1H),9.01(s,1H),8.09(d,J=8.7Hz,1H),8.01(d,J=2.6Hz,1H),7.45(d,J=8.7Hz,1H),7.34-7.28(m,1H),6.72(d,J=9.1Hz,1H),4.95-4.90(m,1H),3.85-3.67(m,3H),3.47-3.27(m,2H),2.69(s,3H),1.97-1.88(m,1H),1.86-1.75(m,1H),1.73-1.59(m,2H),1.45(s,9H);ESI MS m/z 497[M+H]+
實施例162
1-(6-氯-4-{反-4-[(4-甲基哌嗪-1-基)甲基]環己基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與反-4-[(4-甲基哌嗪-1-基)甲基]環己胺
(330mg,1.6mmol)反應,以獲得黃色固體所要之產物(32mg,7%):1H NMR(300MHz,CDCl3)δ 10.93-10.89(m,1H),8.95(s,1H),8.11(d,J=8.7Hz,1H),7.53(d,J=8.7Hz,1H),5.09-4.90(m,1H),3.31(br s,4H),2.90(br s,4H),2.75(s,3H),2.68(s,3H),2.43-2.24(m,4H),1.99-1.87(m,2H),1.62-1.46(m,1H),1.47-1.07(m,4H);ESI MS m/z 416[M+H]+
實施例163
叔-丁基{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]環己基}氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(480mg,2.0mmol)與叔-丁基(反-4-胺基環己基)氨基甲酸酯(430mg,2.0mmol)反應,以獲得淺橘色固體所要之產物(600mg,71%):1H NMR(500MHz,CDCl3)δ 10.91(br s,1H),8.96(s,1H),8.10(d,J=8.8Hz,1H),7.54(d,J=8.8Hz,1H),5.10-4.99(m,1H),4.48(br s,1H),3.55(br s,1H),2.69(s,3H),2.34-2.25(m,2H),2.19-2.10(m,2H),1.56-1.45(m,2H),1.47(s,9H),1.44-1.33(m,2H);ESI MS m/z 419[M+H]+
實施例164
2-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘
啶-3-基)-2-氧代乙酸乙酯
按一般流程I,2-(4,6-二氯-1,5-萘啶-3-基)-2-氧代乙酸乙酯(101mg,0.33mmol)與反-4-[(二甲基胺基)甲基]環己 胺(67mg,0.43mmol)反應,以獲得灰白色固體所要之產物(90mg,65%).ESI MS m/z 419[M+H]+.
實施例165
1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)-2-羥基乙酮
將2-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)-2-氧代乙酸乙酯(90mg,0.22mmol)於甲醇溶液加入新鮮磨碎碳酸鉀(90mg,0.65mmol)。該反應混合物室溫攪拌30分鐘,以飽合NaHCO3溶液稀釋,以乙酸乙酯萃取。有機層以無水硫酸鈉乾燥,過濾,濃縮濾液。該殘留物以管柱層析法(二氧化矽,二氯甲烷/甲醇)純化,以獲得黃色固體所要之產物(18mg,22%).ESI MS m/z 377[M+H]+.
實施例166
1-{4-[(4-胺基環己基)胺基]-6-氯-1,5-萘啶-3-基}乙酮二鹽酸鹽
按一般流程IV-1,叔-丁基{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-yl)胺基]環己基}氨基甲酸酯(360mg,0.86mmol)與HCl(5mL,2M乙醚)反應,以獲灰白色固體所要之產物(190mg,56%).ESI MS m/z 318[M+H]+
實施例167
1-{6-氯-4-[4-(吡咯啶-1-基甲基)苯基胺基]-1,5-萘啶-3-基}乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(200mg,0.83mmol)與4-(吡咯啶-1-基甲基)苯胺(310mg,1.24mmol)反應,以獲得棕橘色固體所要之產物(78mg,25%):1H NMR(300MHz,CDCl3)δ 11.06(s,1H),9.03(s,1H),8.15(d,J=8.7Hz,1H),7.50(d,J=8.7Hz,1H),7.41(d,J=8.3Hz,2H),7.13(d,J=8.3Hz,2H),3.85(br s,2H),2.80(br s,
4H),2.60(s,3H),1.92(br s,4H);ESI MS m/z 381[M+H]+
實施例168
叔-丁基1-[5-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)吡啶-2-基]-吡咯啶-3-基(甲基)氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(200mg,0.83mmol)與叔-丁基1-(5-胺基吡啶-2-基)吡咯啶-3-基(甲基)氨基甲酸酯(360mg,1.2mmol)反應,以獲得暗紅色固體所要之產物(360mg,85%):1H NMR(500MHz,CDCl3)δ 11.39(s,1H),9.02(s,1H),8.10(d,J=8.7Hz,1H),8.02(d,J=2.6Hz,1H),7.47(d,J=8.7Hz,1H),7.32(dd,J=8.8,2.6Hz,1H),6.37(d,J=8.8Hz,1H),4.91(br s,1H),3.73-3.62(m,2H),3.51-3.38(m,2H),2.83(s,3H),2.68(s,3H),2.28-2.06(m,2H),1.49(s,9H);ESI MS m/z 497[M+H]+
實施例169
1-(6-氯-4-{6-[3-(二甲基胺基)吡咯啶-1-基]吡啶-3-基胺基}-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(250mg,1.0mmol)與N,N-二甲基吡咯啶-3-胺(260mg,1.2mmol)反應,以獲得橘色固體所要之產物(380mg,89%):1H NMR(300MHz,CDCl3)δ 11.35(s,1H),9.00(s,1H),8.10(d,J=8.7Hz,1H),8.02(dd,J=2.7,0.7Hz,1H),7.47(d,J=8.7Hz,1H),7.30(dd,J=8.9,2.7Hz,1H),6.35(d,J=8.9Hz,1H),3.88-3.77(m,1H),3.62-3.72(m,1H),3.49-3.37(m,1H),3.33-3.22(m,1H),2.94-2.76(m,1H),2.68(s,3H),2.34(s,6H),2.34-2.18(m,1H),2.06-1.89(m,1H);ESI MS m/z 411[M+H]+
實施例170
叔-丁基4-[7-乙醯基-8-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-2-基]-3,5-二甲基-1H-吡唑-1-羧酸
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基)乙酮(92mg,0.25mmol)與
叔-丁基3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-羧酸(120mg,0.37mmol)得棕色固體所要粗產物(100mg),無需進一部純化:ESI MS m/z 521[M+H]+
實施例171
叔-丁基1-(5-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基)-吡啶-2-基)吡咯啶-3-基(甲基)氨基甲酸酯
按一般流程II,叔-丁基1-(5-(3-乙醯基-6-氯-1,5-萘啶-4-yl胺基)-吡啶-2-基)吡咯啶-3-基(甲基)氨基甲酸酯(91mg,0.183mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(79mg,0.273mmol)得橘色固體所要粗產物(72mg),無需進一部純化:ESI MS m/z 623[M+H]+
實施例172
叔-丁基1-(5-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)吡啶-2-基)吡咯啶-3-基(甲基)氨基甲酸酯
按一般流程II,叔-丁基1-[5-(3-乙醯基-6-氯-1,5-萘啶-4-yl胺基)-吡啶-2-基]吡咯啶-3-基(甲基)氨基甲酸酯(94mg,0.19mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(77mg,0.28mmol)得橘色固體所要粗產物(79mg)無需進一部純化:ESI MS m/z 607[M+H]+
實施例173
叔-丁基(1-{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]環己基-胺基}-3-甲基-1-二氧硼戊環-2-基)氨基甲酸酯
按一般流程VI,1-{4-[(4-胺基環己基)胺基]-6-氯-1,5-萘啶-3-基}乙酮二鹽酸鹽(300mg,0.94mmol)與2-[(叔丁氧羰基)胺基]-3-甲基丁酸(310mg,1.4mmol)反應,以獲得白色固體所要之產物(320mg,65%).ESI MS m/z 518[M+H]+
實施例174
叔-丁基1-{反-4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基]環己基胺基}-3-甲基-1-二氧硼戊環-2-基氨基甲酸酯
按一般流程II,叔-丁基(1-{反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]環己基胺基}-3-甲基-1-二氧硼戊環-2-基)氨基甲酸酯s(100mg,0.19mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(50mg,0.23mmol)得灰白色固體所要粗產物(115mg):ESI MS m/z 628[M+H]+.
實施例175
叔-丁基 反-4-{[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基]胺基環己基}氨基甲酸酯
按一般流程II,叔-丁基 反-4-[(3-乙醯基-6-氯-1,5-萘啶-4-yl)-胺基環己基]氨基甲酸酯(100mg,0.23mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(81mg,0.28mmol)得所要粗產物,無需進一步純化:ESI MS m/z 545[M+H]+.
實施例176
(R)-叔-丁基1-(5-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(340mg,1.4mmol)與(R)-叔-丁基1-(5-胺基吡啶-2-基)哌啶-3-基氨基甲酸酯(500mg,1.7mmol)反應,以獲得棕橘色固體所要之產物(410mg,58%).ESI MS m/z 497[M+H]+
實施例177
(R)-叔-丁基1-(5-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯
按一般流程II,(R)-叔-丁基1-(5-(3-乙醯基-6-氯-1,5-萘啶-4-yl胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯(200mg,0.40mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(170mg,0.60mmol)反應,以獲得橘色固體所要之產物(210mg,85%).ESI MS m/z 623[M+H]+
實施例178
(R)-叔-丁基1-(5-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯
按一般流程II,(R)-叔-丁基1-(5-(3-乙醯基-6-氯-1,5-萘啶-4-yl胺基)吡啶-2-基)哌啶-3-基氨基甲酸酯(200mg,0.40mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(165mg,0.60mmol)反應,以獲得黃橘色固體所要之產物(125g,51%).ESI MS m/z 607[M+H]+
實施例179
叔-丁基[1-(5-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-yl]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,叔-丁基(1-{5-[(3-乙醯基-6-氯-1,5-萘啶-4-yl)胺基]吡啶-2-基}哌啶-3-基)氨基甲酸酯(100mg,0.20mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.24mmol)得所要粗產物,無需進一步純化:ESI MS m/z 607[M+H]+.
實施例180
叔-丁基[1-(5-{[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-yl]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,叔-丁基(1-{5-[(3-乙醯基-6-氯-1,5-萘啶-4-yl)胺基]吡啶-2-基}哌啶-3-基)氨基甲酸酯(100mg,0.20mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(68mg,0.24mmol)得所要粗產物(45mg),無需進一步純化:ESI MS m/z 623[M+H]+.
實施例181
叔-丁基1-{4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-基胺基]環己基胺基}-3-甲基-1-二氧硼戊環-2-基氨基甲酸酯
按一般流程II,將叔-丁基[1-({4-[(3-乙醯基-6-氯-1,5-萘啶-反-4-yl)胺基]環己基}胺基)-3-甲基-1-二氧硼戊環-2-基]氨基甲酸酯(100mg,0.19mmol)與2,6-二氯
-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,得棕色固體粗產物(80mg),無需進一步純化:ESI MS m/z 644[M+H]+
實施例182
叔-丁基1-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]環己基胺基}-1-氧代丙-2-基氨基甲酸酯
按一般流程II,叔-丁基1-[反-4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基胺基]-1-氧代丙-2-基氨基甲酸酯(65mg,0.13mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(45mg,0.16mmol)得所要粗產物,無需進一步純化
實施例183
叔-丁基1-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-yl胺基]環己基胺基}-1-氧代丙-2-yl氨基甲酸酯
按一般流程II,叔-丁基1-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基胺基]-1-氧代丙-2-基氨基甲酸酯(68mg,0.13mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(43mg,0.16mmol)得所要粗產物,無需進一步純化
實施例184
(S)-叔-丁基2-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-yl胺基]環己基氨基甲醯基}吡咯啶-1-羧酸
按一般流程II,將(S)-叔-丁基2-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基氨基甲醯基]吡咯啶-1-羧酸(100mg,0.19mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(63mg,0.23mmol)反應,得棕色固體所要粗產物(75mg),無需進一步純化:ESI MS m/z 626[M+H]+
實施例185
(S)-叔-丁基2-{4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-yl胺基]-環己基氨基甲醯基}吡咯啶-1-羧酸
按一般流程II,(S)-叔-丁基2-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-基胺基)環己基氨基甲醯基]吡咯啶-1-羧酸(100mg,0.195mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(66mg,0.234mmol)反應,得黃色固體所要粗產物(113mg),無需進一步純化。
實施例186
(S)-叔-丁基2-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)-環己基氨基甲醯基]吡咯啶-1-羧酸
按一般流程V,1-[4-(反-4-胺基環己基)胺基)-6-氯-1,5-萘啶-3-基]乙酮二鹽酸鹽(220mg,0.564mmol)與(S)-1-(叔丁氧羰基)吡咯啶-2-羧酸(145mg,0.676mmol)反應,以獲得灰白色固體所要之產物(290mg,99%).ESI MS m/z 518[M+H]+
實施例187
叔-丁基1-[4-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)環己基胺基]-1-氧代丙-2-yl氨基甲酸酯
按一般流程V,{1-[4-(反-4-胺基環己基)胺基]-6-氯-1,5-萘啶-3-基}乙酮二鹽酸鹽(130mg,0.35mmol)與2-(叔丁氧羰基胺基)丙酸(78mg,0.42mmol)反應,以獲得黃色固體所要之產物(130mg,79%).ESI MS m/z 490[M+H]+
實施例188
(S)-叔-丁基[1-(5-{[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,(S)-叔-丁基(1-{5-[(3-乙醯基-6-氯-1,5-萘啶-4-基)胺基]吡啶-2-基}哌啶-3-基)氨基甲酸酯(100mg,0.20mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(82mg,0.30mmol)反應,得所要粗產物(72mg),無需進一步純化:ESI MS m/z 607[M+H]+.
實施例189
(S)-叔-丁基[1-(5-{[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,(S)-叔-丁基(1-{5-[(3-乙醯基-6-氯-1,5-萘啶-4-基)-胺基]吡啶-2-基}哌啶-3-基)氨基甲酸酯(98mg,0.20mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(85mg,0.30mmol)反應,得粗產物(56mg),無需進一步純化。:ESI MS m/z 625[M+H]+.
實施例190
(S)-叔-丁基[1-(5-{[3-(環丙基羰基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,(S)-叔-丁基1-{5-[6-氯-3-(環丙羰基)-1,5-萘啶-4-基胺基]吡啶-2-基}哌啶-3-基氨基甲酸酯(131mg,0.25mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-
二氧硼戊環-2-基)酚(102mg,0.38mmol)反應,以獲得橘色固體所要之產物(100mg,63%).ESI MS m/z 633[M+H]+.
實施例191
叔-丁基4-({反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]環己基}甲基)哌嗪-1-羧酸
按一般流程II,叔-丁基4-{[反-4-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)環己基]甲基}哌嗪-1-羧酸(150mg,0.30mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(130mg,0.45mmol)反應,得所要粗產物(170mg),無需進一步純化:ESI MS m/z 628[M+H]+.
實施例192
叔-丁基1-{4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-基胺基]環己基胺基}-3-甲基-1-二氧硼戊環-2-基氨基甲酸酯
按一般流程B,叔-丁基(1-{4-[(3-乙醯基-6-氯-1,5-萘啶-反-4-yl)胺基環己基]胺基}-3-甲基-1-二氧硼戊環-2-基)氨基甲酸酯(100mg,0.19mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.23mmol)反應,得棕色固體所要粗產物(80mg).ESI MS m/z 644[M+H]+
實施例193
叔-丁基1-{反-4-[3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基]環己基胺基}-1-氧代丙-2-yl氨基甲酸酯
按一般流程B,叔-丁基1-[反-4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基胺基]-1-氧代丙-2-yl氨基甲酸酯(65mg,0.13mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(45mg,0.16mmol)反應,得所要粗產物。
實施例194
叔-丁基1-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-基胺基]環己基胺基}-1-氧代丙-2-基氨基甲酸酯
按一般流程B,叔-丁基1-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基胺基]-1-氧代丙-2-yl氨基甲酸酯(68mg,0.13mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(43mg,0.16mmol)反應,得所要粗產物(170mg),無需進一步純化或性質分析
實施例195
(S)-叔-丁基2-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)-環己基氨基甲醯基]吡咯啶-1-羧酸
按一般流程D,1-[4-(反-4-胺基環己基)胺基]-6-氯-1,5-萘啶-3-基)乙酮二鹽酸鹽(220mg,0.564mmol)與(S)-1-(叔丁氧羰基)吡咯啶-2-羧酸(145mg,0.676mmol)反應,以獲得灰白色固體所要之產物(290mg,99%)ESI MS m/z 518[M+H]+
實施例196
(S)-叔-丁基2-{4-[3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-反-4-yl胺基]環己基氨基甲醯基}吡咯啶-1-羧酸
按一般流程B,(S)-叔-丁基2-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基氨基甲醯基]吡咯啶-1-羧酸(100mg,0.19mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(63mg,0.23mmol)反應,得所要粗產物(75mg),無需進一步純化或性質分析:ESI MS m/z 626[M+H]+
實施例197
叔-丁基1-[4-(3-乙醯基-6-氯-1,5-萘啶-4-基胺基)環己基胺基]-1-氧代丙-2-yl氨基甲酸酯
按一般流程C,1-[4-(反-4-胺基環己基)胺基]-6-氯-1,5-萘啶-3-基)乙酮二鹽酸鹽(130mg,0.35mmol)與2-(叔丁氧羰基胺基)丙酸(78mg,0.42mmol)反應,以獲得黃色固體所要之產物(130mg,79%).ESI MS m/z 490[M+H]+
實施例198
(S)-叔-丁基2-(4-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-反-4-yl胺基)環己基氨基甲醯基)吡咯啶-1-羧酸
按一般流程B,(S)-叔-丁基2-[4-(3-乙醯基-6-氯-1,5-萘啶-反-4-yl胺基)環己基氨基甲醯基]吡咯啶-1-羧酸(100mg,0.19mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(66mg,0.23mmol)反應,得黃色固體所要粗產物(113mg),無需進一步純化或性質分析.
實施例199
叔-丁基[反-4-(二甲基胺基)環己基]甲基氨基甲酸酯
將叔-丁基[反-4-胺基環己基]甲基氨基甲酸酯(1.15g,5.00mmol),對甲醛(454mg,15.0mmol),及氰基硼氫化鈉(940mg,15.0mmol)於甲醇(40mL)溶液加入醋酸(催化)。該反應於室溫攪拌18小時。該反應混合物以水驟冷,濃縮去甲醇。以1M氫氧化鈉溶液調整該溶液層pH至10,隨著以二氯甲烷萃取。該有機層以無水硫酸鈉乾燥,過濾,濃縮,
以獲得黏稠油狀所要之產物(1.2g,96%):ESI MS m/z 257[C14H28N2O2+H]+.
實施例200
反-4-(胺基甲基)-N,N-二甲基環己胺
按一般流程IV-1,叔-丁基[反-4-(二甲基胺基)環己基]甲基 氨基甲酸酯(1.2g,4.8mmol)與3M鹽酸(10mL)反應,得到白色固體所要產物之二鹽酸鹽(1.2g,>99%):ESI MS m/z 230[C9H20N2+H]+.
實施例201
(R)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮
按一般流程IV-2,(R)-叔-丁基[1-(5-{[3-(環丙羰基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基}胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(0.12g,0.18mmol,)與TFA(2mL)反應。該產物所產生之三氟醋酸鹽轉換成游離鹼,以獲得橘色固體所要之產物(67mg,67%):1H NMR(500MHz,CD3OD)δ
9.17(s,1H),8.09(d,J=9.0Hz,1H),8.03(d,J=9.0Hz,1H),7.92(d,J=2.5Hz,1H),7.44(s,2H),7.37(dd,J=9.0,2.5Hz,1H),6.70(d,J=9.0Hz,1H),4.16-4.13(m,1H),3.87-3.84(m,1H),3.27-3.21(m,1H),3.09-3.05(m,2H),2.89-2.86(m,1H),2.18-2.08(m,1H),1.90-1.81(m,1H),1.73-1.58(m,2H),1.21-1.08(m,4H);ESI MS m/z 549[M+H]+;HPLC>99%(AUC),t R=10.15min.
實施例202
(R)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮
按一般流程IV-2,(R)-叔-丁基[1-(5-{[3-(環丙羰基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(0.98g,0.16mmol)與TFA(2mL)反應。該產物所產生之三氟醋酸鹽轉換成游離鹼,以獲得橘色固體所要之產物(58mg,71%):1H NMR(500MHz,CD3OD)δ 9.18(s,1H),8.09(d,J=9.0Hz,1H),8.04(d,J=9.0Hz,1H),7.97(d,J=2.0Hz,1H),7.37(dd,J=9.0,2.0Hz,1H),6.97(d,J=13.0Hz,1H),6.75(d,J=9.0Hz,1H),4.18-4.15(m,1H),3.83-3.81(m,1H),3.31-3.22(m,1H),3.15-3.05(m,2H),2.91-2.85(m,1H),2.12-2.08(m,1H),1.91-1.83(m,1H),1.71-
1.58(m,2H),1.25-1.08(m,4H);ESI MS m/z 533[M+H]+;HPLC 99.0%(AUC),t R=9.18min.
實施例203
1-[6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(二甲基胺基)環己基]胺基}-1,5-萘啶-3-基)-2-羥基乙酮二鹽酸鹽
按一般流程II,2-[(叔-丁基二甲基甲矽烷基)oxy)]-1-{6-氯-4-[(反-4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮(44mg,0.093mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(43mg,0.15mmol),隨後形成二鹽酸鹽,得黃色固體產物(10mg,20%):1H NMR(500MHz,CD3OD)δ 9.15(s,1H),8.47(d,J=9.0Hz,1H),8.35(d,J=9.0Hz,1H),8.11(s,2H),5.68-5.60(m,1H),4.92(s,2H),3.51-3.42(m,1H),2.92(s,6H),2.63-2.59(m,2H),2.33-2.28(m,2H),1.88-1.73(m,4H);ESI MS m/z 489[M+H]+;HPLC>99%(AUC),t R=9.16min.
實施例204
1-[6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]-2-羥基乙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)-2-羥基乙酮(49mg,0.13mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(53mg,0.12mmol),隨後形成二鹽酸鹽,得灰白色固體產物(31mg,42%):1H NMR(500MHz,CD3OD)δ 9.12(s,1H),8.45(d,J=9.0Hz,1H),8.32(d,J=9.0Hz,1H),8.03(s,1H),7.89(d,J=11.0Hz,1H),5.80-5.65(m,1H),4.91(s,2H),3.13-3.05(m,2H),2.94(s,6H),2.50-2.43(m,2H),2.12-1.98(m,2H),1.78-1.65(m,2H),1.48-1.35(m,2H);ESI MS m/z 487[M+H]+;HPLC>99%(AUC),t R=9.26min.
實施例205
1-[6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]1-丙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基)-2-羥基乙酮(170mg,0.50
mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(170mg,0.60mmol)反應。分離純化後,得灰白色固體之二鹽酸鹽(31mg,42%):1H NMR(500MHz,CD3OD)δ 9.17(s,1H),8.44(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.02(d,J=2.0Hz,1H),7.88(dd,J=11.5,2.0Hz,1H),5.72-5.53(m,1H),3.20(q,J=7.0Hz,2H),3.13-3.08(m,2H),2.94(s,6H),2.50-2.43(m,2H),2.12-2.00(m,3H),1.78-1.65(m,2H),1.48-1.35(m,2H),1.25(t,J=7.0Hz,3H);ESI MS m/z 485[M+H]+;HPLC>99%(AUC),t R=9.96min.
實施例206
1-[6-(3,5-二氯-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]1-丙酮二鹽酸鹽
按一般流程II,1-(6-氯-4-{反-4-[(二甲基胺基)甲基]環 己基胺基}-1,5-萘啶-3-基)-2-羥基乙酮(170mg,0.50mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(170mg,0.60mmol)反應。分離純化後,得白色固體之二鹽酸鹽(45mg,14%):1H NMR(500MHz,CD3OD)δ 9.17(s,1H),8.45(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.11(s,2H),5.75-5.66(m,1H),3.20(q,J=7.0Hz,2H),3.13-3.08(m,
2H),2.94(s,6H),2.50-2.41(m,2H),2.10-2.00(m,3H),1.74-1.62(m,2H),1.48-1.36(m,2H),1.25(t,J=7.0Hz,3H);ESI MS m/z 501[M+H]+;HPLC>99%(AUC),t R=10.17min.
實施例207
(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽
按一般流程IV-2,(S)-叔-丁基(1-(5-((6-(3,5-二氯-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(0.195mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘棕色固體之所要產物(78mg,62%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.32(s,1H),8.47(d,J=9.0Hz,1H),8.37(d,J=9.0Hz,1H),8.20(d,J=2.5Hz,1H),7.76(dd,J=9.0,2.5Hz,1H),7.61(s,2H),7.11(d,J=9.0Hz,1H),4.41-4.38(m,1H),3.97-3.95(m,1H),3.48-3.16(m,5H),2.24-2.15(m,1H),2.03-1.91(m,1H),1.82-1.74(m,2H),1.32-1.19(m,3H);ESI MS m/z 537[M+H]+;HPLC>99%(AUC),t R=9.92min.
實施例208
(S)-1-(4{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯
-5-氟-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽
按一般流程IV-2,(S)-叔-丁基[1-(5-{[6-(3-氯-5-氟-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基]胺基]吡啶-2-基)哌啶-3-基]氨基甲酸酯(0.21mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得綠棕色固體之所要產物(67mg,52%):1H NMR(500MHz,CD3OD)δ 9.32(s,1H),8.46(d,J=9.0Hz,1H),8.37(d,J=9.0Hz,1H),8.21(d,J=2.5Hz,1H),7.75(dd,J=9.3,2.5Hz,1H),7.63-7.26(m,2H),7.12(d,J=9.3Hz,1H),4.39(d,J=10.5Hz,1H),4.01-3.96(m,1H),3.48-3.16(m,5H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.82-1.71(m,2H),1.32-1.19(m,3H);ESI MS m/z 521[M+H]+;HPLC>99%(AUC),tR=9.75min.
實施例209
1-[6-(3,5-二氯-4-羥基苯基)-4-({4-[((R)-3-氟吡咯啶-1-基)甲基]環己基}胺基)-1,5-萘啶-3-基]乙酮
按一般流程II,1-(6-氯-4-((4-(((R)-3-氟吡咯啶-1-基)甲基)環己基)胺基)-1,5-萘啶-3-基)乙酮(58mg,0.143mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(62mg,0.21mmol)反應,以獲得橘色固體所要之產物(52mg,60%):1H NMR(500MHz,CD3OD)δ 9.15(s,1H),8.46(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.12(s,2H),5.74-5.69(m,1H),5.53-5.43(m,1H),4.12-3.84(m,2H),3.31-3.17(m,2H),2.76(s,3H),2.50-2.43(m,2H),2.18-1.96(m,3H),1.74-1.62(m,2H),1.50-1.38(m,2H);ESI MS m/z 531[M+H]+;HPLC 96.7%(AUC),tR=10.05min.
實施例210
(S)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丁基)甲酮三鹽酸鹽
按一般流程IV-2,(S)-叔-丁基[1-(5-{[6-(3-氯-5-氟-4-羥基苯基)-3-(環丁烷羰基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(0.20mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘棕色固體之所要產物(94mg,72%兩個步驟以上):1H NMR(500MHz,CD3OD)δ 9.10(s,1H),8.45(d,J=9.0Hz,1H),8.36(d,J=9.0Hz,1H),8.22(d,J=3.0Hz,1H),7.74(dd,J=9.3,3.0Hz,1H),7.63-7.23(m,2H),
7.10(d,J=9.3Hz,1H),4.40(d,J=10.5Hz,1H),4.38-4.23(m,1H),4.03-3.92(m,1H),3.45-3.36(m,2H),2.60-2.36(m,4H),2.26-2.13(m,2H),2.03-1.90(m,2H),1.81-1.70(m,2H);ESI MS m/z 547[M+H]+;HPLC 98.2%(AUC),t R=10.33min.
實施例211
(6-(3,5-二氯-4-羥基苯基)-4-((4-[(二甲基胺基)甲基{環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮
按一般流程II,(6-氯-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮(40mg,0.10mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(43mg,0.15mmol)反應,以獲得淺黃色固體所要之產物(53mg,68%):1H NMR(500MHz,CD3OD)δ 8.93(s,1H),8.45(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.12(s,2H),5.76-5.65(m,1H),4.30-4.20(m,1H),3.12-3.07(m,2H),2.95(s,6H),2.52-2.41(m,4H),2.39-2.34(m,2H),2.22-2.12(m,1H),2.09-2.00(m,2H),1.98-1.90(m,1H),1.76-1.64(m,2H),1.49-1.36(m,2H);ESI MS m/z 527[M+H]+;HPLC>99%(AUC),tR=10.72min.
實施例212
(6-(3-氯-5-氟-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮
按一般流程II,(6-氯-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮(65mg,0.16mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(65mg,0.24mmol)反應,以獲得淺黃色固體所要之產物(72mg,77%):1H NMR(500MHz,CD3OD)δ 8.93(s,1H),8.44(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.02(s,1H),7.88(dd,J=11.5,2.0Hz,1H),5.74-5.64(m,1H),4.29-4.19(m,1H),3.12-3.07(m,2H),2.95(s,6H),2.52-2.41(m,4H),2.39-2.34(m,2H),2.24-2.12(m,1H),2.09-1.98(m,2H),1.98-1.89(m,1H),1.78-1.66(m,2H),1.49-1.35(m,2H);ESI MS m/z 511[M+H]+;HPLC>99%(AUC),tR=10.52min.
實施例213
(R)-1-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽
按一般流程IV-2,(R)-叔-丁基(1-(5-((6-(3-氯-5-氟-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(120mg,0.19mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘棕色固體之所要產物(78mg,65%):1H NMR(500MHz,CD3OD)δ 9.38(s,1H),8.48(d,J=9.0Hz,1H),8.41(d,J=9.0Hz,1H),8.25(d,J=2.5Hz,1H),7.90(dd,J=9.5,2.5Hz,1H),7.56-7.30(m,2H),7.27(d,J=9.5Hz,1H),4.43-4.32(m,1H),4.08-3.96(m,1H),3.53-3.38(m,3H),3.29-3.20(m,2H),2.29-2.20(m,1H),2.09-1.98(m,1H),1.88-1.74(m,2H),1.38-1.21(m,3H);ESI MS m/z 521[M+H]+;HPLC 97.6%(AUC),t R=9.86min.
實施例214
(R)-1-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽
按一般流程IV-2,(R)-叔-丁基[1-(5-{[3-(環丙羰基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(80mg,0.12mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(48mg,62%):1H NMR(500MHz,CD3OD)δ 9.39(s,1H),8.49(d,J=9.5Hz,1H),8.42(d,J=9.0Hz,1H),8.26(d,J=2.0Hz,1H),
7.92(dd,J=9.5,2.0Hz,1H),7.58(s,2H),7.28(d,J=9.5Hz,1H),4.42-4.32(m,1H),4.16-3.96(m,1H),3.52-3.22(m,5H),2.29-2.18(m,1H),2.08-1.98(m,1H),1.88-1.75(m,2H),1.37-1.20(m,3H);ESI MS m/z 537[M+H]+;HPLC98.0%(AUC),t R=9.92min
實施例215
(R)-1-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)-2-甲基1-丙酮三鹽酸鹽
按一般流程IV-2,(R)-叔-丁基(1-(5-((6-(3-氯-5-氟-4-羥基苯基)-3-異丁醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(168mg,0.26mmol)與TFA(2mL)反應,隨後三鹽酸鹽形成,獲得橘色固體之所要產物(110mg,78%):1H NMR(500MHz,CD3OD)δ 9.31(s,1H),8.35(s,2H),8.18(d,J=2.5Hz,1H),7.64(d,J=9.0,2.5Hz,1H),7.38(bs,1H),7.22-7.12(m,1H),7.02(d,J=9.0Hz,1H),4.44-4.32(m,1H),3.98-3.90(m,1H),3.82-3.70(m,1H),3.46-3.22(m,3H),2.22-2.12(m,1H),2.01-1.88(m,1H),1.80-1.68(m,2H),1.36-1.20(m,6H);ESI MS m/z 535[M+H]+;HPLC>99%(AUC),t R=10.07min.
實施例216
1-[6-(3,5-二氯-5-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮二鹽酸鹽
按一般流程II,1-[6-氯-4-({反-4-[(二甲基胺基)甲基]環 己基}胺基)-1,5-萘啶-3-基)-2-甲基1-丙酮(0.25g,0.64mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(0.28g,0.96mmol).After work up及purification the二鹽酸鹽salt was formed反應,以獲得黃色固體所要之產物(150mg,41%):1H NMR(500MHz,CD3OD)δ 9.23(s,1H),8.45(d,J=9.0Hz,1H),8.35(d,J=9.0Hz,1H),8.10(s,2H),5.77-5.63(m,1H),3.83-3.71(m,1H),3.11-3.04(m,2H),2.94(s,6H),2.47-2.42(m,1H),2.08-2.00(m,3H),1.73-1.65(m,2H),1.50-1.37(m,2H),1.36-1.24(m,6H);ESI MS m/z 515[M+H]+;HPLC 98.7%(AUC),t R=10.57min.
實施例217
1-[6-氯-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮
按一般流程II,1-[6-氯-4-({反-4-[(二甲基胺基)甲基]環 己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮(0.25g,0.64mmol)與3,5-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(0.26g,0.96mmol).After work up及purification the二鹽酸鹽salt was formed反應,以獲得淺棕色固體所要之產物(175mg,46%):1H NMR(500MHz,CD3OD)δ 9.22(s,1H),8.45(d,J=9.0Hz,1H),8.34(d,J=9.0Hz,1H),8.03(d,J=2.0,2H),7.88(dd,J=11.5,2.0Hz,1H),5.75-5.68(m,1H),3.83-3.74(m,1H),3.13-3.08(m,2H),2.94(s,6H),2.50-2.38(m,2H),2.12-1.99(m,3H),1.78-1.65(m,2H),1.49-1.37(m,2H),1.33-1.25(m,6H);ESI MS m/z 499[M+H]+;HPLC 97.5%(AUC),t R=10.24min.
實施例218
(R)-叔-丁基[1-(5-{[3-(環丙羰基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,(R)-叔-丁基[1-(5-{[6-氯-3-(環
丙羰基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(150mg,0.29mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(120mg,0.43mmol)反應,得橘色固體產物(119mg,64%):ESI MS m/z 649[M+H]+.
實施例219
(R)-叔丁基[1-(5-{[6-氯-3-(環丙羰基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程I,4,6-二氯-1,5-萘啶-3-基(環丙基)甲酮(400mg,1.5mmol)與(R)-叔-丁基[1-(5-胺基吡啶-2-基)哌啶-3-yl]氨基甲酸酯(550mg,1.9mmol)反應,得橘色泡沫產物(600mg,76%):ESI MS m/z 523[M+H]+.
實施例220
(R)-叔-丁基[1-(5-{[3-(環丙羰基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯
按一般流程II,(R)-叔-丁基[1-(5-{[6-氯-3-(環
丙羰基)-1,5-萘啶-4-基]胺基}吡啶-2-基)哌啶-3-基]氨基甲酸酯(150mg,0.29mmol)與2-氯6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(120mg,0.43mmol)反應,得橘紅色固體產物(100mg,54%):ESI MS m/z 633[M+H]+.
實施例221
2-((叔-丁基二甲基甲矽烷基)氧基)-1-(6-氯-4-((反-4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮
按一般流程I,2-((叔-丁基二甲基甲矽烷基)氧基)-1-(4,6-二氯-1,5-萘啶-3-基)乙酮(87mg,0.23mmol)與反-二甲基環己烷-1,4-二胺(50mg,0.35mmol)反應,得到淺黃油狀產物(44mg,40%):ESI MS m/z 477[M+H]+.
實施例222
2-((叔-丁基二甲基甲矽烷基)oxy)-1-(4,6-二氯-1,5-萘啶-3-基)乙酮
將1-(4,6-二氯-1,5-萘啶-3-基)-2-羥基乙酮(128mg,0.5mmol)於DMF(5mL)溶液0℃下加入咪唑(68mg,1.0mmol)及叔-丁基二甲基甲矽烷基氯(90mg,0.6
mmol)。該混合物攪拌3小時,倒至NaHCO3(飽合),以乙酸乙酯萃取。該有機層以Na2SO4乾燥,濃縮,以層析法純化,得淺黃色油狀產物(87mg,47%):ESI MS m/z 371[M+H]+.
實施例223
1-(6-氯-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)1-丙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)1-丙酮(255mg,1.0mmol)與反-4-((二甲基胺基)甲基)環己胺(310mg,2.0mmol)反應,得白色固體產物(350mg,93%):ESI MS m/z 375[M+H]+.
實施例224
1-(4,6-二氯-1,5-萘啶-3-基)1-丙酮
將1-(4-羥基-6-甲氧基-1,5-萘啶-3-基)1-丙酮(5.2g,22.4mmol)於乙腈(100ml)懸浮液加入三甲基甲矽烷基氯(12g,112mmol)及碘化鈉(10g,67mmol)。該反應混合物於回流下加熱16小時。將該反應混合物冷卻至室溫,加入飽合硫酸鈉溶液。該混合物濃縮移去乙腈,以鹽水稀釋。固體過濾,
乾燥,得中間物1-(4,6-二羥基-1,5-萘啶-3-基)1-丙酮。此中間物懸浮於二氯乙烷(10mL),隨後加入氧氯化磷(10mL)及催化的N,N-二甲基甲醯胺。該反應混合物於80℃攪拌2小時。該反應混合物冷卻至室溫,緩慢倒入至冰涼飽合碳酸氫鈉或3N氫氧化鈉溶液驟冷。該驟冷反應混合物濃縮以移去二氯乙烷。該產生之固體物過濾收集,以層析法(二氧化矽,己烷/乙酸乙酯)純化,,獲得棕色固體之所要之產物(3.2g,56%兩步驟以上):ESI MS m/z 255[M+H]+.
實施例225
1-(4-羥基-6-甲氧基-1,5-萘啶-3-基)1-丙酮
含有DowthermTM A(200mL)燒瓶於250℃以超過3至5分鐘分批加入乙基2-[(6-氯吡啶-3-yl胺基)亞甲基]-3-氧代丁酸(10g,36mmol)。該反應混合物另攪拌30-45分鐘。該反應混合物自熱源移開,冷卻至室溫,以己烷稀釋以促使沉澱。過濾該固體物,以己烷清洗,真空乾燥,以獲得棕色固體所要之產物(5.0g,粗產物):ESI MS m/z 241[M+H]+.
實施例226
乙基2-(((6-甲氧基吡啶-3-基)胺基)亞甲基)-3-氧代戊酸
乙基2-(((6-甲氧基吡啶-3-基)胺基)亞甲基)-3-氧
代戊酸以實施例99所述條件,使用2-甲氧基-5-胺基吡啶及乙基2-(乙氧基亞甲基)-3-氧代戊酸製備。
實施例227
(S)-叔-丁基(1-(5-((6-(3,5-二氯-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程II,(S)-叔-丁基(1-(5-((6-氯-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(100mg,0.20mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(85mg,0.30mmol)反應,得該產物(100mg),無需進一步純化:ESI MS m/z 637[M+H]+.
實施例228
(S)-叔-丁基(1-(5-((6-氯-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)1-丙酮(250mg,0.98mmol)與(S)-叔-丁基1-(5-胺基吡啶-2-基)哌
啶-3-基氨基甲酸酯(430mg,1.5mmol)反應,以獲得暗棕色固體所要之產物(550mg,粗產物):1H NMR(500MHz,CDCl3)δ 11.29(s,1H),9.03(s,1H),8.11(d,J=9.0Hz,1H),8.01(d,J=3.0Hz,1H),7.47(d,J=9.0Hz,1H),7.31-7.29(m,1H),6.72(d,J=9.0Hz,1H),4.79(br s,1H),3.90-3.61(m,4H),3.51-3.25(m,2H),3.07(q,J=7.0Hz,2H),1.96-1.84(m,1H),1.82-1.70(m,1H),1.72-1.55(m,1H),1.45(s,9H),1.26(t,J=7.0Hz,3H);ESI MS m/z 511[M+H]+
實施例229
(S)-叔-丁基(1-(5-((6-(3-氯-5-氟-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程II,(S)-叔-丁基(1-(5-((6-氯-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(100mg,0.20mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(83mg,0.31mmol)反應,得該產物(102mg),無需進一步純化:ESI MS m/z 621[M+H]+.
實施例230
1-(6-氯-4-((4-(((R)-3-氟吡咯啶-1-基)甲基)環己基)胺基)-1,5-萘啶-3-基)乙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)乙酮(240mg,1.0mmol)與4-(((R)-3-氟吡咯啶-1-基)甲基)環己胺(100mg,0.5mmol)反應,得棕色固體產物(61mg,15%):ESI MS m/z 405[M+H]+.
實施例231
4-(((R)-3-氟吡咯啶-1-基)甲基)環己胺
4-(((R)-3-氟吡咯啶-1-基)甲基)環己胺以實施例117及118所述條件使用反-4-[(叔丁氧羰基)胺基)環己基]甲基甲磺酸及(R)-3-氟吡咯啶製備。
實施例232
(S)-叔-丁基(1-(5-((6-(3-氯-5-氟-4-羥基苯基)-3-(環丁烷羰基)-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程II,(S)-叔-丁基(1-(5-((6-氯-3-(環丁烷羰基)-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(110mg,0.20mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(82mg,0.30mmol)反應,得該產物(134mg),無需進一步純化:ESI MS m/z 647[M+H]+.
實施例233
(S)-叔-丁基(1-(5-((6-氯-3-(環丁烷羰基)-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程I,環丁基(4,6-二氯-1,5-萘啶-3-基)甲酮(200mg,0.71mmol)與(S)-叔-丁基1-(5-胺基吡啶-2-基)哌啶-3-基氨基甲酸酯(311mg,1.1mmol)反應,以獲得橘色固體所要之產物(350mg,78%):1H NMR(300MHz,CDCl3)δ 11.52(s,1H),8.88(s,1H),8.08(d,J=8.7Hz,1H),8.02(d,J=2.7Hz,1H),7.45(d,J=8.7Hz,1H),7.31(dd,J=9.0,2.7Hz,1H),6.72(d,J=9.0Hz,1H),4.81(br s,1H),4.15-3.97(m,1H),3.91-3.60(m,3H),3.58-3.31(m,2H),2.54-2.21(m,4H),2.20-2.00(m,1H),2.00-1.85(m,2H),1.82-1.63(m,2H),1.51(s,9H);ESI MS m/z 537[M+H]+.
實施例234
環丁基(4,6-二氯-1,5-萘啶-3-基)甲酮
環丁基(4,6-二氯-1,5-萘啶-3-基)甲酮以實施例101(流程2)所述條件下,使用環丁基(4-羥基-6-甲氧基-1,5-萘啶-3-基)甲酮製備。
實施例235
環丁基(4-羥基-6-甲氧基-1,5-萘啶-3-基)甲酮
環丁基(4-羥基-6-甲氧基-1,5-萘啶-3-基)甲酮以實施例100所述條件下,使用乙基2-(環丁烷羰基)-3-((6-甲氧基吡啶-3-基)胺基)丙烯酸製備。
實施例236
乙基2-(環丁烷羰基)-3-((6-甲氧基吡啶-3-基)胺基)丙烯酸
乙基2-(環丁烷羰基)-3-((6-甲氧基吡啶-3-基)胺基)丙烯酸以實施例99所述條件下,使用2-甲氧基-5-胺基吡啶及乙基2-(環丁烷羰基)-3-乙氧基丙烯酸製備。
實施例237
(6-氯-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮
(6-氯-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮以實施例131所述條件下,使用環丁基(4,6-二氯-1,5-萘啶-3-基)甲酮及反-4-((二甲基胺基)甲基)環己胺製備。
實施例238
(R)-叔-丁基(1-(5-((6-(3-氯-5-氟-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程II,(R)-叔-丁基(1-(5-((6-氯-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(175mg,0.34mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(140mg,0.51mmol)反應,以獲得固體所要之產物(120mg,57%):ESI MS m/z 621[M+H]+.
實施例239
(R)-叔-丁基(1-(5-((6-氯-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)1-丙酮(500mg,1.96mmol)與(R)-叔-丁基(1-(5-胺基吡啶-2-基)哌啶-3-基)氨基甲酸酯(860mg,2.94mmol)反應,以獲得淺棕色固體所要之產物(850mg,84%):ESI MS m/z 511[M+H]+.
實施例240
(R)-叔-丁基(1-(5-((6-(3,5-二氯-4-羥基苯基)-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程II,(R)-叔-丁基(1-(5-((6-氯-3-丙醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(175mg,0.34mmol)與2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(149mg,0.51mmol)反應,以獲得固體所要之產物(100mg,46%):ESI MS m/z 637[M+H]+.,
實施例241
(R)-叔-丁基(1-(5-((6-(3-氯-5-氟-4-羥基苯基)-3-異丁醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程II,(R)-叔-丁基(1-(5-((6-氯-3-異丁醯基-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯(225mg,0.63mmol)與2-氯-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)酚(175mg,0.66mmol)反應,以獲得固體形式之所要產物(168mg,62%):ESI MS m/z 635[M+H]+.
實施例242
(R)-叔-丁基(1-(5-((6-氯-3-異butyryl-1,5-萘啶-4-基)胺基)吡啶-2-基)哌啶-3-基)氨基甲酸酯
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)-2-甲基1-丙酮(500mg,1.85mmol)與(R)-叔-丁基(1-(5-胺基吡啶-2-基)哌啶-3-基)氨基甲酸酯(815mg,2.78mmol)反應,以獲得紅色固體所要之產物(880mg,88%):ESI MS m/z 525[M+H]+.
實施例243
1-(4,6-二氯-1,5-萘啶-3-基)-2-甲基1-丙酮
將1-(4,6-二羥基-1,5-萘啶-3-基)-2-甲基1-丙酮(15.5g,63.0mmol)於乙腈(250ml)懸浮液加入三甲基甲矽烷基氯(20.5g,189mmol)及碘化鈉(28.3g,189mmol)。該反應混合物於回流下加熱3小時。該反應混合物冷卻至室溫,加入飽合硫代硫酸鈉溶液。該混合物濃縮以移去乙腈,以鹽水稀釋。過濾該固體物,乾燥,以獲得中間物1-(4-羥基-6-甲氧基-1,5-萘啶-3-基)-2-甲基1-丙酮。此中間物懸浮於氧氯化磷(60mL)及催化N,N-二甲基甲醯胺。該反應混合物於70℃攪拌30分鐘。該反應混合物冷卻至室溫,緩慢倒入至冰涼飽合碳酸氫鈉或3N氫氧化鈉溶液驟冷。該驟冷反應混合物濃縮以移去二氯乙烷。該產生之固體物過濾收集,以層析法(二氧化矽,己烷/乙酸乙酯)純化,獲得黃色固體之所要之產物(12.0g,75%兩步驟以上):ESI MS m/z 255[M+H]+.
實施例244
1-(4-羥基-6-甲氧基-1,5-萘啶-3-基)-2-甲基1-丙酮
含有DowthermTM A(400mL)燒瓶於250℃以超過3至5分鐘分批加入乙基2-(((6-甲氧基吡啶-3-基)胺基)亞甲基)-4-甲基-3-氧代戊酸(11.5g,39.3mmol)。該反應混合物另攪拌30-45分鐘。該反應混合物自熱源移開,冷卻至室溫,以己烷稀釋以促使沉澱。過濾該固體物,以己烷清洗,真空乾
燥,以獲得黃棕色固體所要之產物(13.7g,粗產物):ESI MS m/z 247[M+H]+.
實施例245
乙基2-(((6-甲氧基吡啶-3-基)胺基)亞甲基)-4-甲基-3-氧代戊酸
乙基2-(((6-甲氧基吡啶-3-基)胺基)亞甲基)-4-甲基-3-氧代戊酸以實施例99所述條件下,使用2-甲氧基-5-胺基吡啶及乙基2-(乙氧基亞甲基)-4-甲基-3-氧代戊酸製備。
實施例246
1-(6-氯-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)-2-甲基1-丙酮
按一般流程I,1-(4,6-二氯-1,5-萘啶-3-基)-2-甲基1-丙酮(500mg,1.85mmol)與反-4-((二甲基胺基)甲基)環己胺(436mg,2.78mmol)反應,得白色固體產物(640mg,89%):ESI MS m/z 389[M+H]+.
本申請案之本發明化合物非限定於上述實施例說明,亦可參考以上述實施例等使用相似或類同方法合成。
接下來,化合物(I)之藥物活性敘述於試驗實施例。
[試驗實施例]
激酶試驗
(2)MELK的活性,係使用螢光素異硫氰酸酯標定(FITC-標定)的組蛋白H3勝肽當成基質,於存在或不存在化合物之下決定。FITC-標定的組蛋白H3勝肽磷酸化的程度,係利用固定化金屬離子親和性系螢光極化(IMAP)技術(Sportsman JR,et al.,Assay Drug Dev.Technol.2:205-14,2004)使用IMAP FP Progressive Bin二ng System(Molecular Devices Corporation)測量。將測試化合物溶於DMSO使濃度為12.5mM,然後系列稀釋直到DMSO濃度在試驗中成為1%。將系列稀釋的化合物、0.8ng/micro-L PBK(Carna Biosciences)與100nM FITC-標定的組蛋白H3勝肽,於反應緩衝液中(20mM HEPES,0.01% Tween-20,0.3mM MgCl 2,2mM二硫蘇糖醇,50micro-M ATP,pH 7.4),在室溫反應1小時。將反應藉由添加3倍試驗體積的進展結合溶液而中止。於室溫溫育0.5小時後,以Wallac EnVision 2103多標記讀取儀(PerkinElmer)測量螢光極化。IC50值,係使用SigmaPlot,10.0版(Systat Software,Inc.),以非線性四參數擬合計算。
本發明的典型化合物的IC 50值,如下表2所示:
西方墨點分析
為了評估數個細胞株中的MELK的表現狀態,使用從此等
細胞收集的粗製細胞溶解物實施西方墨點分析。使用抗MELK抗體(選殖體31,BD Biosciences)使表現可見化。乳癌細胞株22Rv1、T47D、A549與DU4475顯著表現MELK,而膀胱癌細胞株與HT-1197未顯示表現MELK。
細胞系試驗
使用22Rv1、T47D、A549、DU4475針對其標靶專一性細胞毒殺性,評估對於MELK的有效候選抑制劑,並使用HT-1197細胞當成負面控制。將100micro-L的細胞懸浮液接種在96孔微滴定盤(ViewPlate-96FTC,PerkinElmer)。22Rv1、T47D、A549、DU4475與HT-1197的起始細胞濃度,各為3,000個細胞/井、2,000個細胞/井,及2,500個細胞/井。細胞生長使用Cell Counting Kit-8(DOJINDO),於暴露於候選抑制劑72小時後決定。使用IC50當做此等抑制劑的抗增殖活性的指標,並以系列稀釋法(0、1.5625、3.125、6.25、12.5、25、50與100micro-M)計算。正確的IC50值如上述所計算。
本發明的典型化合物的IC 50值,如下表3所示:
NT:未測試
實施例6化合物之生長抑制效果更進一步以各種癌細胞
株生長進行評估。使用A549(肺癌),T47D(乳癌),DU4475(乳癌),及22Rv1(前列腺癌)癌細胞進行體外抗增殖試驗,其MELK高度表現,分別顯示6.7,4.3,2.3,及6.0nM IC50值(圖1a-d)。另外,HT1197(膀胱癌)癌細胞,其MELK幾乎偵測不到,顯示97nM IC50值(圖1e),此清礎暗喻本化合物之MELK-依賴生長抑制效果。
異種移植模型抗腫瘤試驗
MDA-MB-231細胞株注射至NOD.CB17-Prkdc scid /J小鼠(Charles River Laboratory)乳腺脂肪。A549,MIAPaCa-2及PC-14細胞株(1 x 107個細胞)皮下注射至BALB/cSLC-nu/nu雌鼠(Japan SLC,Inc.)左脇。DU145細胞株皮下注射至BALB/cSLC-nu/nu雄鼠(Japan SLC,Inc.)右脇。當MDA-MB-231,A549,DU145,MIAPaCa-2,及PC-14異種移植已分別達平均量100,210,110,250,及250mm3,動物隨機分6小鼠一群(除PC-14,使用3小鼠一群)。採用口服者,化合物以0.5%甲基纖維素載體製成,按指示劑量及服用時間給藥。採用靜脈注射者,化合物調配成5%葡萄糖,注射至小鼠尾靜脈。兩種給藥途徑採每kg體重給藥量10mL。濃度如主文及圖所指示。腫瘤量每隔一天使用卡尺量測。該結果以公式長x寬2 x 1/2轉換成腫瘤量(mm3)。以小鼠重量作為同日耐受性指標。A549異種移植動物試驗委外KAC Co.,Ltd.(Shiga,Japan)按其「實驗動物飼養管理及使用指南」執行;其它動物試驗委外OncoTherapy Science,Inc按其「實驗動物飼養管理及使用指南」執行。腫瘤生長抑制(TGI)按公式{1-(T-T 0)/(C-C 0)}×100計算,
其中T及T 0分為實驗組第14天及第0天之腫瘤量;C-C 0分為對照組。所有值以平均±SD表示。以學生t-檢定計算統計顯著性,顯著水準為p<0.05。
本發明人後續以MDA-MB-231細胞株(MELK-陽性,三陰性乳癌細胞株)異種移植模型進行實施例6化合物之體內抗腫瘤效果。該化合物投予至小鼠,該小鼠移植模型14天後腫瘤大小達約100mm3(參閱方法)。該腫瘤大小作為藥物反應(生長抑制(TGI))之替代指標(Surrogate Marker)。實施例6每日靜脈注射20mg/kg,其TGI結果為73%(圖2a)。由於本化合物生體利用率期望非常高(資料未顯示),本化合物期望用於口服。每日口服一次10mg/kg,其TGI結果為72%(圖2b)。由於對於各種癌細胞株具高生長抑制效果,再使用不同類型癌細胞株進行體內生長抑制效果評估,發現實施例6對多種癌種類在劑量依賴下,無或僅一點體重降低,顯示顯著腫瘤生長抑制(圖2及圖3)。如,A549(肺癌)異種移植小鼠每日靜脈注射一次實施例1,5,及10mg/kg分別顯示TGI 51,91,及108(圖2c)及每日口服一次5及10mg/kg分別顯示TGI 95及124%(圖2d)。此外,本發明進行DU145(前列腺癌)及MIAPaCa-2(胰臟癌)異種移植模型,每日口服一次10mg/kg,分別顯示TGI 106及87%(圖2e及f)。為進一步確認MELK-特異體內腫瘤抑制效果,本發明人進行PC-14肺癌細胞株,其MELK表現幾乎無法偵測(圖2g)。每日口服一次實施例6 10mg/kg14天後,顯示對PC-14異種移植無腫瘤抑制效果(圖2h),再次支持實施例6MELK-
依賴抗腫瘤活性。
產業利用性
本發明提供一種具有MELK作用的新穎的喹啉衍生物。本發明的化合物可當做抑制MELK的醫藥組合物。此種醫藥組合物適於治療或預防癌症。
Claims (13)
- 一種通式(I)化合物或其醫藥上可接受之鹽,其中,X1係單鍵或-NH-;Q1選自下列所組成之群:C5-C7環烷基、苯基、吡啶基、吡唑基、嘧啶基、哌啶基及(C6-C10芳基)-C1-C6烷基;其中Q1選擇性地由分別選自A1之一或多個取代基取代;X2係-SO2-;R11選自下列所組成之群:C1-C6烷基及C3-C10環烷基,其選擇性地以一或多個取代基取代,分別選自下列所組成之群:羥基及鹵原子;R5選自下列所組成之群:鹵原子、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該芳基、雜芳基及雜環基選擇性地由分別選自A3之一或多個取代基取代;R2、R3及R4係氫原子;A1及A3分別選自下列所組成之群:鹵原子、氰基、-COOR13、-CONR14R15、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR16R17、-OR18、-S(O)nR19、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;R13、R14及R15分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;或R14及R15經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇性地由分別選自A4之一或多個取代基取代;R16及R18分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR20;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;R17選自下列所組成之群:氫原子及C1-C6烷基,其選擇性地由分別選自A4之一或多個取代基取代,或R16至R17經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇性地由分別選自A4之一或多個取代基取代;R19選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基及5-至10-員雜芳基;其中該烷基、環烷基、芳基、雜芳基選擇性地由分別選自A4之一或多個取代基取代;R20選自下列所組成之群:氫原子、-NR14R15、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇性地由分別選自A4之一或多個取代基取代;n為選自0至2之整數;A4分別選自下列所組成之群:鹵原子、氰基、-COOR21、-CONR22R23、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR24R25、-OR26、-S(O)nR27、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;R21、R22及R23分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基,其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;或R22至R23經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A5之一或多個取代基取代;R24及R26分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR28;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;R25選自下列所組成之群:氫原子及選擇地由分別選自A5之一或多個取代基取代之C1-C6烷基;或R24及R25經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A5之一或多個取代基取代;R27選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基、及5-至10-員雜芳基;其中該烷基、環烷基、芳基及雜芳基選擇地由分別選自A5之一或多個取代基取代;R28分別選自下列所組成之群:氫原子、-NR22R23、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A5之一或多個取代基取代;A5分別選自下列所組成之群:鹵原子、氰基、-COOR31、-CONR32R33、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR34R35、-OR36、-S(O)nR37、C3-C10環烷基、C6-C20芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A6之一或多個取代基取代;R31、R32及R33分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A6之一或多個取代基取代;或R32至R33經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A6之一或多個取代基取代;R34及R36分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR38;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基、及雜環基選擇地由分別選自A6之一或多個取代基取代;R35選自下列所組成之群:氫原子選擇地由分別選自A6之一或多個取代基取代之C1-C6烷基;或R34及R35經由氮原子彼此鍵結在一起形成3-至10-員含氮雜環基,其選擇地由分別選自A6之一或多個取代基取代;R37選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基及5-至10-員雜芳基;其中該烷基、環烷基、芳基、及雜芳基選擇地由分別選自A6之一或多個取代基取代;R38分別選自下列所組成之群:氫原子、-NR32R33、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基、雜芳基及雜環基選擇地由分別選自A6之一或多個取代基取代;A6分別選自下列所組成之群:鹵原子、氰基、羧基、-COOR41、-CONR42R43、甲醯基、(C1-C6烷基)羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、硝基、-NR44R45、-OR46、S(O)nR47、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基羰基、烷基、烯基、炔基、環烷基、芳基、雜芳基、及雜環基選擇性地以一或多個取代基取代,該取代基分別選自下列所組成之群:鹵原子、羥基、C1-C6烷氧基、胺基、C1-C6烷基胺基及二(C1-C6烷基)胺基;R41、R42及R43分別選自下列所組成之群:氫原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基;其中該烷基、烯基、炔基、環烷基、芳基,雜芳基、及雜環基選擇性地以一或多個取代基取代,該取代基分別選自下列所組成之群:鹵原子、羥基、C1-C6烷氧基、胺基、C1-C6烷基胺基及二(C1-C6烷基)胺基;R44及R46分別選自下列所組成之群:氫原子、C1-C6烷基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基、3-至10-員非芳香雜環基及-COR48;R45選自下列所組成之群:氫原子及C1-C6烷基;R47選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基及5-至10-員雜芳基;以及R48分別選自下列所組成之群:C1-C6烷基、C3-C10環烷基、C6-C10芳基、5-至10-員雜芳基及3-至10-員非芳香雜環基其中5-至10-員雜芳基具有一或多個雜原子,其選自下列所組成之群:氮原子、氧原子及硫原子,以及3-至10-員非芳香雜環基具有一或多個雜原子,其選自下列所組成之群:氮原子、氧原子及硫原子。
- 如申請專利範圍第1項所述之化合物或其醫藥上可接受之鹽,其中Q1選自下列所組成之群:C5-C7環烷基、苯基、吡啶基、吡唑基、嘧啶基、及哌啶基;其中Q1選擇地由分別選自A1之一或多個取代基取代。
- 如申請專利範圍第1或2項所述之化合物或其醫藥上可接受之鹽,其中R5係以一至三個取代基取代之苯基,該取代基分別選自下列所組成之群:羥基、鹵原子、C1-C6烷基及C1-C6烷氧基,其中該烷基及烷氧基選擇性地以一或多個鹵原子取代。
- 如申請專利範圍第1或2項所述之化合物或其醫藥上可接受之鹽,其中X1係-NH-。
- 如申請專利範圍第1或2項所述之化合物或其醫藥上可接受之鹽,其中Q1的選擇性取代基選自下列所組成之群:羥基、胺基、C1-C6烷氧基、C1-C6烷基胺基、二(C1-C6烷基)胺基、胺基-C1-C6烷基、(C1-C6烷基胺基)-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、胺基-C1-C6烷氧基、(C1-C6烷基胺基)-C1-C6烷氧基、二(C1-C6烷基)胺基-C1-C6烷氧基、羥基-C1-C6烷基、(C1-C6烷氧基)-C1-C6烷基、羧基-C1-C6烷基、[(C1-C6烷氧基)羰基]-C1-C6烷基、氨基甲醯基-C1-C6烷基、[N-(C1-C6烷基)氨基甲醯基]-C1-C6烷基、[N,N-二(C1-C6烷基)氨基甲醯基]-C1-C6烷基、(C1-C6烷基)羰基胺基、N-(C1-C6烷基)羰基-N-(C1-C6烷基)胺基、吡咯啶基、哌啶基、及哌嗪基;其中定義為Q1的選擇性取代基之吡咯啶基、哌啶基、及哌嗪基可選擇性地以一取代基取代,該取代基選自下列所組成之群:C1-C6烷基、胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基;以及其中定義為Q1的選擇性取代基之烷基部分可選擇性地以一取代基取代,該取代基選下列所組成之群:胺基、C1-C6烷基胺基、二(C1-C6烷基)胺基、羥基、C1-C6烷氧基、吡咯啶基、哌啶基及哌嗪基。
- 如申請專利範圍第5項所述之化合物或其醫藥上可接受之鹽,其中Q1的選擇性取代基為選自下列所組成之群:羥基、胺基、二(C1-C6烷基)胺基、C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷基、二(C1-C6烷基)胺基-C1-C6烷氧基、二(C1-C6烷基)胺基、[(胺基-C1-C6烷基)羰基]胺基、N-(C1-C6烷基)哌啶基、二(C1-C6烷基)胺基-吡咯啶-1-基、胺基-吡咯啶-1-基、(吡咯啶-1-基)-C1-C6烷基、(C1-C6烷基)胺基-哌啶-1-基、胺基-哌啶-1-基、羥基-C1-C6烷基、[二(C1-C6烷基)胺基-C1-C6烷基]胺基、[4-(C1-C6烷基)-哌嗪-1-基]-C1-C6烷基、(哌嗪-1-基)-C1-C6烷基、吡咯啶基羰基-胺基、(羥基-吡咯啶-1-基)-C1-C6烷基、嗎啉基-C1-C6烷基、[N-(羥基-C1-C6烷基)-N-(C1-C6烷基)胺基]-C1-C6烷基及(CD3)2N-C1-C6烷基。
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如申請專利範圍第1項所述之化合物或其醫藥可接受鹽,其中該化合物為選自下列所組成之群:1-(6-氯-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮;環丙基(6-(3,5-二氯-4-羥基苯基)-4-(4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)甲酮;(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-((4-((二甲基胺基)甲基)-環己基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(2-(二甲基胺基)乙基)-環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-(4-((二甲基胺基)甲基)環己基胺基)-6-(4-羥基-3-(三氟甲氧基)-苯基)-1,5-萘啶-3-基)乙酮;2,6-二氯-4-(8-((4-((二甲基胺基)甲基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-((4-((二甲基胺基)甲基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-((4-((二甲基胺基)甲基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;2,6-二氯-4-(8-((4-(二甲基胺基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2,6-二氯-4-(8-((4-((二甲基胺基)甲基)苯基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-((4-((二甲基胺基)甲基)苯基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-((4-((二甲基胺基)甲基)苯基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((3-(2-(吡咯啶-1-基)乙基)苯基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(3-(2-(吡咯啶-1-基)乙基)苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;2,6-二氯-4-(8-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-7-(甲基-磺醯基)-1,5-萘啶-2-基)酚;2-氯-4-(8-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;2-氯-4-(8-((6-(2-(二甲基胺基)乙氧基)吡啶-3-基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-甲氧基酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((1-甲基哌啶-4-基)甲基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-((二甲基胺基-d6)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)苯基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((4-(2-(二甲基胺基)乙基)苯基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-4-羥基-5-甲氧基苯基)-4-((4-(2-(二甲基胺基)乙基)苯基)-胺基)-1,5-萘啶-3-基)乙酮;2-氯-4-(8-((4-(二甲基胺基)環己基)胺基)-7-(甲基磺醯基)-1,5-萘啶-2-基)-6-氟酚;1-(6-(3,5-二氯-4-羥基苯基)-4-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-yl)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(2-(吡咯啶-1-基)乙基)哌啶-1-基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(2-(吡咯啶-1-基)乙基)哌啶-1-基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙基胺基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(6-(2-(二甲基胺基)乙基胺基)-吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;(S)-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(4-((2-(3-胺基吡咯啶-1-基)嘧啶-5-基)胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-(4-(4-((二甲基胺基)甲基)環己基胺基)-6-(1H-吡唑-4-yl)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(羥基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{4-[(二甲基胺基)甲基]-環己基胺基}-1,5-萘啶-3-基]-2-羥基乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(1-甲基哌啶-4-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(1-甲基哌啶-4-基胺基)-1,5-萘啶-3-基)乙酮;1-{6-[3,5-二氯-4-羥基苯基]-4-[4-(嗎啉基甲基)環己基胺基]-1,5-萘啶-3-基}乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(((2-羥基乙基)(甲基)胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(((2-羥基乙基)(甲基)胺基)-甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氟-4-羥基苯基)-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((6-(3-(二甲基胺基)吡咯啶-1-基)吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((6-(3-(二甲基胺基)吡咯啶-1-基)-吡啶-3-基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(6-(3-(甲基胺基)吡咯啶-1-基)吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(6-(3-(甲基胺基)吡咯啶-1-基)-吡啶-3-基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(1H-苯並[d]咪唑-5-基)-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-((4-((二甲基胺基)甲基)環己基胺基)-6-(吡啶-4-基)-1,5-萘啶-3-基)乙酮;5-(7-乙醯基-8-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-2-基)-嘧啶-2-甲腈;1-(6-(3,5-二甲基-1H-吡唑-4-yl)-4-(4-((二甲基胺基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-(4-((二甲基胺基)甲基)環己基胺基)-6-(4-羥基-3,5-二甲基-苯基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(吡咯啶-1-基甲基)苯基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(吡咯啶-1-基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-(吡咯啶-1-基甲基)環己基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;1-(4-(4-胺基環己基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-[4-(4-胺基環己基胺基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基]乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-(4-((4-甲基哌嗪-1-基)甲基)-環己基胺基)-1,5-萘啶-3-基)乙酮;N-(4-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)-環己基)-2-胺基-3-甲基丁醯胺;1-(6-(3,5-二氯-4-羥基苯基)-4-(4-(哌嗪-1-基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;N-(4-((3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基)胺基)環己基)-2-胺基丙醯胺;N-(4-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)-環己基)-2-胺基丙醯胺;(S)-N-((1R,4S)-4-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基-胺基)環己基)吡咯啶-2-羧醯胺;(S)-N-((1R,4S)-4-(3-乙醯基-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-4-基胺基)環己基)吡咯啶-2-羧醯胺;1-(6-(3-羥基吡咯啶-1-基)-4-(4-((3-羥基吡咯啶-1-基)甲基)環己基-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(吡咯啶-1-基)-4-(4-(吡咯啶-1-基甲基)環己基胺基)-1,5-萘啶-3-基)乙酮;N-(4-(3-乙醯基-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-4-基胺基)-環己基)-2-胺基-3-甲基丁醯胺;[6-(3-氯-5-氟-4-羥基苯基)-4-[4-(二甲基胺基)環己基胺基]-1,5-萘啶-3-基](環丙基)甲酮;環丙基[6-(3,5-二氯-4-羥基苯基)-4-[4-(二甲基胺基)環己基-胺基]-1,5-萘啶-3-基]甲酮;1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(1H-吡咯[2,3-b]吡啶-5-基)-1,5-萘啶-3-基)乙酮;(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}(環丙基)甲酮;1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(4-甲氧基苯基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-甲氧基苯基)-4-{4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]乙酮;1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(6-羥基吡啶-3-基)-1,5-萘啶-3-基)乙酮;5-(7-乙醯基-8-{4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-2-基)2-氰吡啶(picolinonitrile);1-(4-{4-[(二甲基胺基)甲基]環己基胺基}-6-(4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{[4-(二甲基胺基)環己基]甲基-胺基}-1,5-萘啶-3-基)乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-{[4-(二甲基胺基)環己基]-甲基胺基}-1,5-萘啶-3-基]乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-(4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-(4-羥基環己基胺基)-1,5-萘啶-3-基]乙酮;1-[6-(3-氯-5-氟-4-羥基苯基)-4-{順-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]乙酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{順-4-[(二甲基胺基)甲基]環己基-胺基}-1,5-萘啶-3-基]乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基}乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;及其醫藥上可接受之鹽。
- 如申請專利範圍第1項所述之化合物或其醫藥上可接受之鹽,其中該化合物選自由下列所組成之群:1-(6-(3,5-二氯-4-羥基苯基)-4-(反-(4-(二甲基胺基)環己基)胺基)-1,5-萘啶-3-基)乙酮;環丙基(6-(3,5-二氯-4-羥基苯基)-4-(反-4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)甲酮;(6-(3-氯-5-氟-4-羥基苯基)-4-(反-4-((二甲基胺基)甲基)-環己基胺基)-1,5-萘啶-3-基)(環丙基)甲酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((反-4-((二甲基胺基)甲基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3-氯-5-氟-4-羥基苯基)-4-((反-4-((二甲基胺基)甲基)-環己基)胺基)-1,5-萘啶-3-基)乙酮;1-(6-(3,5-二氯-4-羥基苯基)-4-((反-4-(2-(二甲基胺基)乙基)環己基)-胺基)-1,5-萘啶-3-基)乙酮;(S)-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{反-4-[(二甲基胺基)甲基]環己基胺基}-1,5-萘啶-3-基]-2-羥基乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)乙酮;1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-1-(4-(6-(3-胺基哌啶-1-基)吡啶-3-基胺基)-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基)乙酮;(S)-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基-苯基)-1,5-萘啶-3-基}(環丙基)甲酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3,5-二氯-4-羥基-苯基)-1,5-萘啶-3-基}乙酮;(R)-1-{4-[6-(3-胺基哌啶-1-基)吡啶-3-基胺基]-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基}乙酮;(R)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;(R)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丙基)甲酮;1-[6-(3,5-二氯-4-羥基苯基)-4-{[反-4-(二甲基胺基)環己基]胺基}-1,5-萘啶-3-基)-2-羥基乙酮二鹽酸鹽;1-[6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]-2-羥基乙酮二鹽酸鹽;1-[6-(3-氯-5-氟-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]1-丙酮二鹽酸鹽;1-[6-(3,5-二氯-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基)]1-丙酮二鹽酸鹽;(S)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽;(S)-1-(4{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽;1-[6-(3,5-二氯-4-羥基苯基)-4-({4-[((R)-3-氟吡咯啶-1-基)甲基]環己基}胺基)-1,5-萘啶-3-基]乙酮二鹽酸鹽;(S)-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丁基)甲酮二鹽酸鹽;(6-(3,5-二氯-4-羥基苯基)-4-((4-[(二甲基胺基)甲基{環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮二鹽酸鹽;(6-(3-氯-5-氟-4-羥基苯基)-4-((4-((二甲基胺基)甲基)環己基)胺基)-1,5-萘啶-3-基)(環丁基)甲酮二鹽酸鹽;(S)-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3-氯-5-氟-4-羥基苯基)-1,5-萘啶-3-基)(環丁基)甲酮;(R)-1-(4-((6-(3-胺基哌啶-1-基)吡啶-3-基)胺基)-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)1-丙酮三鹽酸鹽;(R)-1-(4-{[6-(3-胺基哌啶-1-基)吡啶-3-基]胺基}-6-(3,5-二氯-4-羥基苯基)-1,5-萘啶-3-基)-2-甲基1-丙酮三鹽酸鹽;1-[6-(3,5-二氯-5-4-羥基苯基)-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮二鹽酸鹽;1-[6-氯-4-({反-4-[(二甲基胺基)甲基]環己基}胺基)-1,5-萘啶-3-基]-2-甲基1-丙酮二鹽酸鹽;及其醫藥上可接受之鹽。
- 一種醫藥組合物,其係包含如申請專利範圍第1至7項中任一項之化合物或其在醫藥上可接受之鹽作為有效成分。
- 一種如申請專利範圍第1至8項中任一項之化合物或其在醫藥上可接受之鹽之用途,係用於製造癌症的治療劑;其中上述癌症係選自下列所組成之群:乳癌、膀胱癌、子宮頸癌、膽管細胞癌、慢性骨髓性白血病(CML)、大腸直腸癌、子宮內膜異位瘤、食道癌、胃癌、肝癌、非小細胞肺癌(NSCLC)、淋巴瘤、骨肉瘤、卵巢癌、胰臟癌、前列腺癌、腎細胞癌及小細胞肺癌(SCC)。
- 如申請專利範圍第10項所述之用途,其中該癌症係選自下列所組成之群:乳癌、肺癌、膀胱癌、淋巴瘤及子宮癌。
- 一種製備如申請專利範圍第1至4項中任一項所述之通式(I)化合物或醫藥上可接受之鹽之方法,Q1、X1、X2、R11、R2、R3、R4及R5為如申請專利範圍第1至6項所述任一所定義之基團,該方法包括:使通式(II)化合物與通式(III)化合物反應,其中Q1、X1、X2、R11、R2、R3及R4為上述定義之基團,但條件是該基團可有一或多個保護基團,及X11為鹵原子;其中R5為上述定義,但條件是R5基團可有一或多個保護基團,且R51及R52分別選自下列所組成之群:C1-C6烷基,或R51及R52經由硼原子彼此鍵結在一起形成選擇性地經一或多個取代基取代之5-至7-員環硼酸酯,該取代基分別選自下列所組成之群:C1-C6烷基;其中該保護基團為:用以保護-NH-及/或-NH2之基團,其選自下列所組成之群:C1-C6烷基羰基、C1-C6烷氧基羰基、苯基(C1-C6烷氧基)羰基、(C1-C6烷氧基)C1-C6烷基、苯基(C1-C6烷氧基)甲基及(苯基)C1-C6烷基;或用以保護羥基之基團,其選自下列所組成之群:C1-C6烷基羰基、C1-C6烷氧基羰基、苯基(C1-C6烷氧基)羰基、(C1-C6烷氧基)C1-C6烷基、苯基(C1-C6烷氧基)甲基、(苯基)C1-C6烷基、三(C1-C6烷基)甲矽烷基、二(C1-C6烷基)苯基甲矽烷基、(C1-C6烷基)二苯基甲矽烷基及三苯基甲矽烷基;或用以保護羧基之基團,其選自下列所組成之群:C1-C6烷基、(苯基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基及苯基(C1-C6烷氧基)C1-C6烷基,以形成相對應的酯。
- 一種通式(II)化合物或其醫藥上可接受之鹽,其中Q1、X1、X2、R11、R2、R3及R4如申請專利範圍第1至6項所述任一項之基團,但條件是該基團可有一或多個保護基團及X11為鹵原子;其中該保護基團為:用以保護-NH-及/或-NH2之基團,其選自下列所組成之群:C1-C6烷基羰基、C1-C6烷氧基羰基、苯基(C1-C6烷氧基)羰基、(C1-C6烷氧基)C1-C6烷基、苯基(C1-C6烷氧基)甲基及(苯基)C1-C6烷基;或用以保護羥基之基團,其選自下列所組成之群:C1-C6烷基羰基、C1-C6烷氧基羰基、苯基(C1-C6烷氧基)羰基、(C1-C6烷氧基)C1-C6烷基、苯基(C1-C6烷氧基)甲基、(苯基)C1-C6烷基、三(C1-C6烷基)甲矽烷基、二(C1-C6烷基)苯基甲矽烷基、(C1-C6烷基)二苯基甲矽烷基及三苯基甲矽烷基;或用以保護羧基之基團,其選自下列所組成之群:C1-C6烷基、(苯基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基及苯基(C1-C6烷氧基)C1-C6烷基,以形成相對應的酯。
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US20110150831A1 (en) * | 2009-11-26 | 2011-06-23 | Aeterna Zentaris Gmbh | Novel naphthyridine derivatives and the use thereof as kinase inhibitors |
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