CN116457355A - 2-氨基-3-羰基咪唑并吡啶和吡唑并吡啶化合物 - Google Patents
2-氨基-3-羰基咪唑并吡啶和吡唑并吡啶化合物 Download PDFInfo
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- CN116457355A CN116457355A CN202180063093.0A CN202180063093A CN116457355A CN 116457355 A CN116457355 A CN 116457355A CN 202180063093 A CN202180063093 A CN 202180063093A CN 116457355 A CN116457355 A CN 116457355A
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- China
- Prior art keywords
- pyridin
- amino
- imidazo
- methanone
- fluorocyclopropyl
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- 150000005229 pyrazolopyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims abstract description 9
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- -1 trimethylsilylethoxymethyl Chemical group 0.000 claims description 179
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 31
- 125000001188 haloalkyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 230000004770 neurodegeneration Effects 0.000 claims description 13
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 12
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 12
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 208000018737 Parkinson disease Diseases 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 10
- 125000001041 indolyl group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 9
- 208000001089 Multiple system atrophy Diseases 0.000 claims description 8
- 125000005082 alkoxyalkenyl group Chemical group 0.000 claims description 8
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 8
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 6
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 6
- 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 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000032859 Synucleinopathies Diseases 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 4
- 125000006419 fluorocyclopropyl group Chemical group 0.000 claims description 4
- VCCMONSCVWBBBE-UHFFFAOYSA-N 1-[2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]ethanone Chemical compound CC(C1=C(N)N=C(C=C2)N1C=C2C1=C(C)C(F)=CC=C1)=O VCCMONSCVWBBBE-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 201000002832 Lewy body dementia Diseases 0.000 claims description 3
- KZQFCWZXNMWZOB-YPMHNXCESA-N [2-amino-6-(3-fluoro-2-methylanilino)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(F)=CC=C1)=C1NC1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 KZQFCWZXNMWZOB-YPMHNXCESA-N 0.000 claims description 3
- QIMDSSSUNNRUNC-CABCVRRESA-N [2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C=CN2)C2=CC=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 QIMDSSSUNNRUNC-CABCVRRESA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- MLOHDFYHFUPTDD-RQJHMYQMSA-N (2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)Br)C2=N1 MLOHDFYHFUPTDD-RQJHMYQMSA-N 0.000 claims description 2
- OLIBZDJEUVXDFN-UHFFFAOYSA-N (2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)-cyclopropylmethanone Chemical compound NC1=C(C(C2CC2)=O)N(C=C(C=C2)Br)C2=N1 OLIBZDJEUVXDFN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 2
- VPLXKCZIPXBVBS-UHFFFAOYSA-N 2-amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C(N(C)C3CC3)=O)=C(N)N=C2C=C1 VPLXKCZIPXBVBS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- DNBNGQMFLPWXSX-WBVHZDCISA-N [(1S,2S)-2-fluorocyclopropyl]-[6-(3-fluoro-2-methylphenyl)-2-[2-(methylamino)ethylamino]imidazo[1,2-a]pyridin-3-yl]methanone Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(NCCNC)N=C2C=C1 DNBNGQMFLPWXSX-WBVHZDCISA-N 0.000 claims description 2
- SGJBEIVNMMAFLJ-HOCLYGCPSA-N [2-(dimethylamino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C([C@@H](C3)[C@H]3F)=O)=C(N(C)C)N=C2C=C1 SGJBEIVNMMAFLJ-HOCLYGCPSA-N 0.000 claims description 2
- SEKWNWIJEVPDOL-UHFFFAOYSA-N [2-amino-5-(6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-cyclopropylmethanone Chemical compound CC(C(C1=CC2=C(C(C3CC3)=O)C(N)=NN2C=C1)=C(C=NN1)C1=C1)=C1F SEKWNWIJEVPDOL-UHFFFAOYSA-N 0.000 claims description 2
- RCUCDTHDKHXRLX-ZJUUUORDSA-N [2-amino-6-(5-methyl-1,3-thiazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C2=CN3C(C([C@H](C4)[C@H]4F)=O)=C(N)N=C3C=C2)N=CS1 RCUCDTHDKHXRLX-ZJUUUORDSA-N 0.000 claims description 2
- PQRPLYJPGJOEMT-YPMHNXCESA-N [2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(F)=CC=C1)=C1C(C=C1F)=CN2C1=NC(N)=C2C([C@H](C1)[C@H]1F)=O PQRPLYJPGJOEMT-YPMHNXCESA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 2
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- IHVILBXERNRBLM-OCCSQVGLSA-N [2-amino-6-(6-fluoro-5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1)=C(C=CN1)C1=C1)=C1F IHVILBXERNRBLM-OCCSQVGLSA-N 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- ALTUGCQUDQMJSY-KGLIPLIRSA-N [2-amino-6-(1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(C=CN4)C4=CC=C3)C2=N1 ALTUGCQUDQMJSY-KGLIPLIRSA-N 0.000 claims 2
- VLXQNXAMUXAVGD-KGLIPLIRSA-N [2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CC=C4NC=CC4=C3)C2=N1 VLXQNXAMUXAVGD-KGLIPLIRSA-N 0.000 claims 2
- RWFQOFGSOZXTBN-OLZOCXBDSA-N [2-amino-6-(4-chloro-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CC=C4NC=CC4=C3Cl)C2=N1 RWFQOFGSOZXTBN-OLZOCXBDSA-N 0.000 claims 2
- XYAAWEWZLXWLEM-YPMHNXCESA-N [2-amino-6-(5-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(C=CN4)C4=CC=C3F)C2=N1 XYAAWEWZLXWLEM-YPMHNXCESA-N 0.000 claims 2
- NXXBJQRUQYBSCH-KGLIPLIRSA-N [2-amino-6-(5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC1=CC=C2NC=CC2=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 NXXBJQRUQYBSCH-KGLIPLIRSA-N 0.000 claims 2
- QNYNULCQERBVSI-KGLIPLIRSA-N [2-amino-6-(6-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(C=CN4)C4=CC(F)=C3)C2=N1 QNYNULCQERBVSI-KGLIPLIRSA-N 0.000 claims 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims 2
- QWHAWWLMSBTWOQ-ZBFHGGJFSA-N (2-amino-6-isoquinolin-4-ylimidazo[1,2-a]pyridin-3-yl)-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CN=CC4=CC=CC=C34)C2=N1 QWHAWWLMSBTWOQ-ZBFHGGJFSA-N 0.000 claims 1
- HVTKFTPRDSMTQO-CABCVRRESA-N (2-amino-6-quinolin-4-ylimidazo[1,2-a]pyridin-3-yl)-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CC=NC4=CC=CC=C34)C2=N1 HVTKFTPRDSMTQO-CABCVRRESA-N 0.000 claims 1
- LFEPESYTMOZGRB-ZJUUUORDSA-N (2-amino-6-thiophen-2-ylimidazo[1,2-a]pyridin-3-yl)-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CC=CS3)C2=N1 LFEPESYTMOZGRB-ZJUUUORDSA-N 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- BGDKIGANJLAOEO-UHFFFAOYSA-N 1-[2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-2,2-dimethylpropan-1-one Chemical compound CC(C)(C)C(C1=C(N)N=C(C=C2)N1C=C2C1=C(C)C(F)=CC=C1)=O BGDKIGANJLAOEO-UHFFFAOYSA-N 0.000 claims 1
- QGBIMKVLAHSIBN-UHFFFAOYSA-N 1-[2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]pentan-1-one Chemical compound CCCCC(C1=C(N)N=C(C=C2)N1C=C2C1=C(C)C(F)=CC=C1)=O QGBIMKVLAHSIBN-UHFFFAOYSA-N 0.000 claims 1
- VWJIHIHKMWZLHN-CVEARBPZSA-N 1-[4-[2-amino-3-[(1S,2S)-2-fluorocyclopropanecarbonyl]imidazo[1,2-a]pyridin-6-yl]-3-methylphenyl]ethanone Chemical compound CC(C(C=C1)=CC(C)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1)=O VWJIHIHKMWZLHN-CVEARBPZSA-N 0.000 claims 1
- YFEDQXVCBNMWTA-UHFFFAOYSA-N 2-amino-6-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]-N-cyclopropylimidazo[1,2-a]pyridine-3-carboxamide Chemical compound CN(C)C1=C2NN=CC2=C(C2=CN3C(C(NC4CC4)=O)=C(N)N=C3C=C2)C(Cl)=C1F YFEDQXVCBNMWTA-UHFFFAOYSA-N 0.000 claims 1
- NOXCGUHRILEXPM-UHFFFAOYSA-N 2-amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C(NC3CC3)=O)=C(N)N=C2C=C1 NOXCGUHRILEXPM-UHFFFAOYSA-N 0.000 claims 1
- FPPBJTWEVGSLQG-UHFFFAOYSA-N N'-acetyl-2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbohydrazide Chemical compound CC(NNC(C1=C(N)N=C(C=C2)N1C=C2C1=C(C)C(F)=CC=C1)=O)=O FPPBJTWEVGSLQG-UHFFFAOYSA-N 0.000 claims 1
- FWFFSIHMTIKWJZ-UHFFFAOYSA-N N-[3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl]acetamide Chemical compound CC(C1=C(NC(C)=O)N=C(C=C2)N1C=C2C1=C(C)C(F)=CC=C1)=O FWFFSIHMTIKWJZ-UHFFFAOYSA-N 0.000 claims 1
- MLOYFMHQCCGJHT-UHFFFAOYSA-N N-acetyl-N-[3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl]acetamide Chemical compound CC(C1=C(N(C(C)=O)C(C)=O)N=C(C=C2)N1C=C2C1=C(C)C(F)=CC=C1)=O MLOYFMHQCCGJHT-UHFFFAOYSA-N 0.000 claims 1
- WAKQJJBFCYVENN-HIFRSBDPSA-N [(1S,2S)-2-fluorocyclopropyl]-[6-(3-fluoro-2-methylphenyl)-2-(methylamino)imidazo[1,2-a]pyridin-3-yl]methanone Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(NC)N=C2C=C1 WAKQJJBFCYVENN-HIFRSBDPSA-N 0.000 claims 1
- XDBBQHKIOUSOOT-AEFFLSMTSA-N [(1S,2S)-2-fluorocyclopropyl]-[6-(3-fluoro-2-methylphenyl)-2-pyrrolidin-1-ylimidazo[1,2-a]pyridin-3-yl]methanone Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N3CCCC3)N=C2C=C1 XDBBQHKIOUSOOT-AEFFLSMTSA-N 0.000 claims 1
- JOTLDPFPPNGCOY-ZBFHGGJFSA-N [2-(2-aminoethylamino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(NCCN)N=C2C=C1 JOTLDPFPPNGCOY-ZBFHGGJFSA-N 0.000 claims 1
- JKKYEOPNCGASNE-AEFFLSMTSA-N [2-[2-(dimethylamino)ethylamino]-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(NCCN(C)C)N=C2C=C1 JKKYEOPNCGASNE-AEFFLSMTSA-N 0.000 claims 1
- MRKOSMWOCBVFFR-UHFFFAOYSA-N [2-amino-5-(1H-indol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-cyclopropylmethanone Chemical group NC1=NN(C=CC(C2=C(C=CN3)C3=CC=C2)=C2)C2=C1C(C1CC1)=O MRKOSMWOCBVFFR-UHFFFAOYSA-N 0.000 claims 1
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- ONHHCMNQEKOFKD-PWSUYJOCSA-N [2-amino-6-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CN=C4NC=CC4=C3F)C2=N1 ONHHCMNQEKOFKD-PWSUYJOCSA-N 0.000 claims 1
- TYLBYAVRATWHAP-KBPBESRZSA-N [2-amino-6-(4-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C=C(C=C1)F)=C1C1=CN2C(C([C@@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 TYLBYAVRATWHAP-KBPBESRZSA-N 0.000 claims 1
- TYLBYAVRATWHAP-KGLIPLIRSA-N [2-amino-6-(4-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C=C(C=C1)F)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 TYLBYAVRATWHAP-KGLIPLIRSA-N 0.000 claims 1
- CCXKUPSHRSMCJY-OCCSQVGLSA-N [2-amino-6-(4-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C=NN2)C2=CC=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 CCXKUPSHRSMCJY-OCCSQVGLSA-N 0.000 claims 1
- QIMDSSSUNNRUNC-LSDHHAIUSA-N [2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1R,2R)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C=CN2)C2=CC=C1C1=CN2C(C([C@@H](C3)[C@@H]3F)=O)=C(N)N=C2C=C1 QIMDSSSUNNRUNC-LSDHHAIUSA-N 0.000 claims 1
- QIMDSSSUNNRUNC-GJZGRUSLSA-N [2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C=CN2)C2=CC=C1C1=CN2C(C([C@@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 QIMDSSSUNNRUNC-GJZGRUSLSA-N 0.000 claims 1
- QIMDSSSUNNRUNC-HUUCEWRRSA-N [2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2R)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C=CN2)C2=CC=C1C1=CN2C(C([C@H](C3)[C@@H]3F)=O)=C(N)N=C2C=C1 QIMDSSSUNNRUNC-HUUCEWRRSA-N 0.000 claims 1
- YUUPZIDTBXFREH-UHFFFAOYSA-N [2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-(azetidin-3-yl)methanone Chemical compound CC1=C(C=CN2)C2=NC=C1C1=CN2C(C(C3CNC3)=O)=C(N)N=C2C=C1 YUUPZIDTBXFREH-UHFFFAOYSA-N 0.000 claims 1
- HZMXKJYWILACJU-OCCSQVGLSA-N [2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC1=C(C=CN2)C2=NC=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 HZMXKJYWILACJU-OCCSQVGLSA-N 0.000 claims 1
- BRAYDLROLFFJLQ-UHFFFAOYSA-N [2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-pyridin-2-ylmethanone Chemical compound CC1=C(C=CN2)C2=NC=C1C1=CN2C(C(C3=NC=CC=C3)=O)=C(N)N=C2C=C1 BRAYDLROLFFJLQ-UHFFFAOYSA-N 0.000 claims 1
- AZVOHUBRUPNJLD-UHFFFAOYSA-N [2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylmethanone Chemical compound CC1=C(C=CN2)C2=NC=C1C1=CN2C(C(C3=NC=CC=N3)=O)=C(N)N=C2C=C1 AZVOHUBRUPNJLD-UHFFFAOYSA-N 0.000 claims 1
- ZJRQFEQLRKQPHX-UHFFFAOYSA-N [2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-pyrimidin-4-ylmethanone Chemical compound CC1=C(C=CN2)C2=NC=C1C1=CN2C(C(C3=NC=NC=C3)=O)=C(N)N=C2C=C1 ZJRQFEQLRKQPHX-UHFFFAOYSA-N 0.000 claims 1
- FPASUGIQDVNAJD-UHFFFAOYSA-N [2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl]-pyrrolidin-3-ylmethanone Chemical compound CC1=C(C=CN2)C2=NC=C1C1=CN2C(C(C3CNCC3)=O)=C(N)N=C2C=C1 FPASUGIQDVNAJD-UHFFFAOYSA-N 0.000 claims 1
- VAHIDRGBKLBKRO-SJORKVTESA-N [2-amino-6-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C(C=C3)=CC=C3N3CCOCC3)C2=N1 VAHIDRGBKLBKRO-SJORKVTESA-N 0.000 claims 1
- KLLHQKVUCUPUTP-SJORKVTESA-N [2-amino-6-(4-piperazin-1-ylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C(C=C3)=CC=C3N3CCNCC3)C2=N1 KLLHQKVUCUPUTP-SJORKVTESA-N 0.000 claims 1
- NYVBMJDJLBFYJE-KGLIPLIRSA-N [2-amino-6-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C=CC(N)=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 NYVBMJDJLBFYJE-KGLIPLIRSA-N 0.000 claims 1
- AJJSJSANFGECNN-OCCSQVGLSA-N [2-amino-6-(5-amino-3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(F)=CC(N)=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 AJJSJSANFGECNN-OCCSQVGLSA-N 0.000 claims 1
- FEDABDYVDDOXHL-OCCSQVGLSA-N [2-amino-6-(5-chloro-1H-indol-3-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C(C3=C4)=CNC3=CC=C4Cl)C2=N1 FEDABDYVDDOXHL-OCCSQVGLSA-N 0.000 claims 1
- OWJLNSRWMYXIHK-SCZZXKLOSA-N [2-amino-6-(5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(C=NN4)C4=CC(F)=C3Cl)C2=N1 OWJLNSRWMYXIHK-SCZZXKLOSA-N 0.000 claims 1
- KGRLFIGDSJQVHD-SCZZXKLOSA-N [2-amino-6-(5-chloro-6-fluoro-7-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CSC1=C2NN=CC2=C(C2=CN3C(C([C@H](C4)[C@H]4F)=O)=C(N)N=C3C=C2)C(Cl)=C1F KGRLFIGDSJQVHD-SCZZXKLOSA-N 0.000 claims 1
- RDJKFSXNJUNBSZ-KGLIPLIRSA-N [2-amino-6-(5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C=CC(F)=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 RDJKFSXNJUNBSZ-KGLIPLIRSA-N 0.000 claims 1
- KGBZRVNPELDFII-UHFFFAOYSA-N [2-amino-6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-cyclopropylmethanone Chemical compound CC1=CC=C2NN=CC2=C1C1=CN2C(C(C3CC3)=O)=C(N)N=C2C=C1 KGBZRVNPELDFII-UHFFFAOYSA-N 0.000 claims 1
- VOMAEUOOABASDO-MFKMUULPSA-N [2-amino-6-(6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1)=C(C=NN1)C1=C1)=C1F VOMAEUOOABASDO-MFKMUULPSA-N 0.000 claims 1
- QWXRZVZHAHGULX-PWSUYJOCSA-N [2-amino-6-(6-fluoro-5-methyl-7-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1)=C(C=NN1)C1=C1SC)=C1F QWXRZVZHAHGULX-PWSUYJOCSA-N 0.000 claims 1
- PQKKJIPZYUKWGB-ZJUUUORDSA-N [2-amino-6-(furan-2-yl)imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=CC=CO3)C2=N1 PQKKJIPZYUKWGB-ZJUUUORDSA-N 0.000 claims 1
- UTIKNPGMNNGZLO-KGLIPLIRSA-N [2-amino-6-[2-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C(C=CC=C3)=C3OCCF)C2=N1 UTIKNPGMNNGZLO-KGLIPLIRSA-N 0.000 claims 1
- DULOVKJXJKWLMX-GJZGRUSLSA-N [2-amino-6-[2-(2-fluoroethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1R,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCF)C=CC=C3)C2=N1 DULOVKJXJKWLMX-GJZGRUSLSA-N 0.000 claims 1
- DULOVKJXJKWLMX-HUUCEWRRSA-N [2-amino-6-[2-(2-fluoroethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2R)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@@H]2F)=O)N(C=C(C=C2)C3=C(CCF)C=CC=C3)C2=N1 DULOVKJXJKWLMX-HUUCEWRRSA-N 0.000 claims 1
- DULOVKJXJKWLMX-CABCVRRESA-N [2-amino-6-[2-(2-fluoroethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCF)C=CC=C3)C2=N1 DULOVKJXJKWLMX-CABCVRRESA-N 0.000 claims 1
- SDJGNTWIRFSKOR-CABCVRRESA-N [2-amino-6-[2-(2-hydroxyethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCO)C=CC=C3)C2=N1 SDJGNTWIRFSKOR-CABCVRRESA-N 0.000 claims 1
- IPWHFZDYAAPZGG-CVEARBPZSA-N [2-amino-6-[2-(3-fluoropropyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCCF)C=CC=C3)C2=N1 IPWHFZDYAAPZGG-CVEARBPZSA-N 0.000 claims 1
- VHMOMVZMRCAZMN-CVEARBPZSA-N [2-amino-6-[2-(3-hydroxypropyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCCO)C=CC=C3)C2=N1 VHMOMVZMRCAZMN-CVEARBPZSA-N 0.000 claims 1
- UXJYUYXRQQNEOL-KGLIPLIRSA-N [2-amino-6-[2-(aminomethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NCC(C=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 UXJYUYXRQQNEOL-KGLIPLIRSA-N 0.000 claims 1
- CDPJULJJFQCIFP-YPMHNXCESA-N [2-amino-6-[2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(C(F)(F)F)C=CC=C3)C2=N1 CDPJULJJFQCIFP-YPMHNXCESA-N 0.000 claims 1
- WMIYLBSKCVBURG-OCCSQVGLSA-N [2-amino-6-[2-methyl-3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(C(F)(F)F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 WMIYLBSKCVBURG-OCCSQVGLSA-N 0.000 claims 1
- MXBKRPTXVUSIOB-KGLIPLIRSA-N [2-amino-6-[2-methyl-5-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C=CC(C(F)(F)F)=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 MXBKRPTXVUSIOB-KGLIPLIRSA-N 0.000 claims 1
- FSSPZXVQLIDAHN-MSOLQXFVSA-N [2-amino-6-[3-(4-methylpiperazin-1-yl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CN(CC1)CCN1C1=CC=CC(C2=CN3C(C([C@H](C4)[C@H]4F)=O)=C(N)N=C3C=C2)=C1 FSSPZXVQLIDAHN-MSOLQXFVSA-N 0.000 claims 1
- BVWOUCBWILYFMW-CABCVRRESA-N [2-amino-6-[3-(dimethylamino)-5-fluoro-2-methylphenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CC(C(N(C)C)=CC(F)=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 BVWOUCBWILYFMW-CABCVRRESA-N 0.000 claims 1
- XLGJTSLYVDTTID-GXTWGEPZSA-N [2-amino-6-[3-fluoro-2-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1R,2R)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@@H](C2)[C@@H]2F)=O)N(C=C(C=C2)C(C=CC=C3F)=C3OCCF)C2=N1 XLGJTSLYVDTTID-GXTWGEPZSA-N 0.000 claims 1
- XLGJTSLYVDTTID-TZMCWYRMSA-N [2-amino-6-[3-fluoro-2-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2R)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@@H]2F)=O)N(C=C(C=C2)C(C=CC=C3F)=C3OCCF)C2=N1 XLGJTSLYVDTTID-TZMCWYRMSA-N 0.000 claims 1
- XLGJTSLYVDTTID-OCCSQVGLSA-N [2-amino-6-[3-fluoro-2-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C(C=CC=C3F)=C3OCCF)C2=N1 XLGJTSLYVDTTID-OCCSQVGLSA-N 0.000 claims 1
- WWWAVQIPCBGBQY-HIFRSBDPSA-N [2-amino-6-[3-fluoro-2-(2-fluoroethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCF)C(F)=CC=C3)C2=N1 WWWAVQIPCBGBQY-HIFRSBDPSA-N 0.000 claims 1
- WRKFSKZUJIZTPL-HIFRSBDPSA-N [2-amino-6-[3-fluoro-2-(2-hydroxyethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCO)C(F)=CC=C3)C2=N1 WRKFSKZUJIZTPL-HIFRSBDPSA-N 0.000 claims 1
- PWGXDXXCDJRIPS-ZBFHGGJFSA-N [2-amino-6-[3-fluoro-2-(3-fluoropropyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCCF)C(F)=CC=C3)C2=N1 PWGXDXXCDJRIPS-ZBFHGGJFSA-N 0.000 claims 1
- OCOJRIWHVVPKLB-ZBFHGGJFSA-N [2-amino-6-[3-fluoro-2-(3-hydroxypropyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CCCO)C(F)=CC=C3)C2=N1 OCOJRIWHVVPKLB-ZBFHGGJFSA-N 0.000 claims 1
- VCDRSSKYCXPUEL-RISCZKNCSA-N [2-amino-6-[3-fluoro-2-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(CO)C(F)=CC=C3)C2=N1 VCDRSSKYCXPUEL-RISCZKNCSA-N 0.000 claims 1
- RVDBSKFDKAENMO-PWSUYJOCSA-N [2-amino-6-[3-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound NC1=C(C([C@H](C2)[C@H]2F)=O)N(C=C(C=C2)C3=C(C(F)(F)F)C(F)=CC=C3)C2=N1 RVDBSKFDKAENMO-PWSUYJOCSA-N 0.000 claims 1
- ZIVKMBQCVMJKDB-SWGAWFCGSA-N [2-amino-6-[3-fluoro-2-[(E)-2-methoxyethenyl]phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CO/C=C/C(C(F)=CC=C1)=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 ZIVKMBQCVMJKDB-SWGAWFCGSA-N 0.000 claims 1
- SKECAMNUWMQXMV-MSOLQXFVSA-N [2-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]imidazo[1,2-a]pyridin-3-yl]-[(1S,2S)-2-fluorocyclopropyl]methanone Chemical compound CN(CC1)CCN1C(C=C1)=CC=C1C1=CN2C(C([C@H](C3)[C@H]3F)=O)=C(N)N=C2C=C1 SKECAMNUWMQXMV-MSOLQXFVSA-N 0.000 claims 1
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Abstract
本公开提供了式(I)所示的化合物或其药学上可接受的盐、其立体异构体、包含该化合物的药物组合物,以及一种使用该化合物治疗或预防炎症和自身免疫性疾病,尤其是神经炎症性疾病的方法。
Description
相关申请的交叉引用
本申请要求于2020年9月15日提交的美国临时专利申请No.63/078,372的优先权。本段中确定的申请的全部公开内容通过引用并入本文。
技术领域
本公开总体涉及具有酶抑制活性的化合物、包含该化合物的药物组合物以及使用该化合物治疗疾病的方法。
背景技术
受体相互作用蛋白激酶(RIPK)是Ser/Thr和Tyr激酶家族,在炎症和先天免疫中发挥着重要作用。人们发现RIPK1和RIPK3的激酶活性对于多种刺激激活坏死性细胞死亡途径至关重要,多种刺激包括TNFα细胞因子家族、干扰素(IFN)和Toll样受体(TLR)配体(Christofferson and Yuan,2010;Vanlangenakker et al.,2012)。重要的是,RIPK1/3激酶与目前缺乏有效疗法的多种病理环境有关,包括中风、心肌梗塞、视网膜损伤、致命的全身炎症反应综合征(SIRS)和慢性肠道和皮肤炎症,以及急性胰腺炎(Linkermann andGreen,2014)。
RIPK2是另一种参与NF-κB激活、丝裂原活化蛋白激酶(MAPK)和细胞凋亡的RIP激酶。RIPK2的激酶活性对于通过NF-κB和MAPK JNK(‘Jun N-末端激酶’)的信号传导是可有可无的,但对于激活MAPK ERK2而言则是必需的。RIPK2最突出的功能是它介导来自NOD(“核苷酸结合寡聚化结构域”)蛋白NOD1和NOD2的信号转导,NOD1和NOD2是细胞溶质病原体识别受体,可激活促炎和抗菌反应以响应巨噬细胞中的细菌肽聚糖。NOD1和NOD2是由半胱天冬酶募集结构域(CARD)、核苷酸结合结构域和富含亮氨酸的重复序列组成的同源蛋白。在识别其配体后,NOD1或NOD2通过CARD-CARD同型相互作用募集RIPK2。这个过程促进了RIPK2的泛素化和TAK1和IKK复合物的激活,从而激活NF-κB和MAPK,以及由巨噬细胞产生促炎细胞因子。RIPK2还将各种泛素E3连接酶募集到NOD2复合物,包括XIAP(“X染色体连锁细胞凋亡抑制剂”)、cIAP1和cIAP2、PELL3和LUBAC。已经证明,XIAP缺乏会导致NOD1或NOD2介导的RIPK2泛素化和炎症信号传导受损。XIAP通过与RIPK2的激酶结构域结合而被募集到NOD2–RIPK2复合物中,这导致RIPK2的K63泛素化和LUBAC的募集;这有效激活了NF-κB和MAPK,以及在巨噬细胞中产生细胞因子。RIPK2的泛素化位点(Lys209、Lys410和Lys538)对其通过NOD1和NOD2介导信号传导的功能起着至关重要的作用。RIPK2的D146N激酶失活突变体保留了结合XIAP和激活NOD2信号传导的能力,这表明通过NOD1和NOD2进行信号传导时并不需要RIPK2的激酶活性。
由于NOD2-RIPK2通路在肉芽肿性炎症性疾病(包括炎症性肠病(IBD)中的作用,因此人们对其产生了特殊的兴趣。此类病理可能由通路的正向或负向失调引起(Caruso etal.,2014;Jostins et al.,2012;Philpott et al.,2014)。NOD2中的遗传变异是克罗恩病最强的易感因素(Hugot et al.,2001;Jostins et al.,2012;Ogura et al.,2001a)。克罗恩病相关突变会破坏NOD2与MDP的结合,可能会诱导来自包括NOD1在内的其他模式识别受体的过度炎症信号传导(Couturier-Maillard et al.,2013;Inohara et al.,2003)。相比之下,第二个主要克罗恩病易感因素ATG16L1的突变会破坏与NOD2的抑制性相互作用,从而增加RIPK2的激活(Sorbara et al.,2013)。在小儿克罗恩病中也有报道称RIPK2过度激活(Negroni et al.,2009)。此外,NOD2-RIPK2通路的功能获得与Blau综合征、早发性结节病、过敏性气道炎症和多发性硬化症有关(Goh et al.,2013;Jun et al.,2013;Shaw et al.,2011)。总体而言,这些数据确立了RIPK2作为了解IBD发病机制的关键分子以及将其确立为广泛的炎症和自身免疫性疾病(包括神经炎症性疾病)的潜在治疗靶点。
α-突触核蛋白是蛋白质大家族的一部分,包括β-和γ-突触核蛋白以及突触蛋白。α-突触核蛋白在与突触相关的正常状态下表达,且认为其在神经可塑性、学习和记忆中发挥作用。一些研究表明α-突触核蛋白在帕金森病发病机制中起着重要作用。增加蛋白质错误折叠和聚集的α-突触核蛋白的分子变化在疾病发病机制中具有直接作用。α-突触核蛋白的聚集有助于路易体和中性小体的形成,这是帕金森病和α-突触核蛋白病的病理标志。酪氨酸激酶c-abl的激活有助于α-突触核蛋白诱导的神经变性。
酪氨酸激酶c-abl是一种受到严格调控的非受体蛋白酪氨酸激酶,参与广泛的细胞过程,包括生长、存活和应激反应(Nat Rev Mol Cell Biol,2004,5:33-44)和c-abl参与调节多个细胞过程,并通过控制神经发生参与中枢神经系统的发育。最近,来自各种实验模型系统的越来越多的证据还表明,c-abl在阿尔茨海默病、帕金森病、尼曼-匹克C型疾病和tau蛋白疾病等神经退行性疾病中被激活(Human Molecular Genetics,2014,Vol.23,No.11)。
应激信号非受体酪氨酸激酶c-abl通过酪氨酸磷酸化将帕金森病与帕金森病的散发形式联系起来。c-abl对parkin的酪氨酸磷酸化是一种主要的翻译后修饰,可导致散发性帕金森病的parkin功能丧失和疾病进展。抑制c-abl为阻断帕金森病进展提供了新的治疗机会(The Journal of Neuroscience,2011,31(1):157-163)。肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病,其特征是运动神经元的进行性死亡。用小干扰RNA(siRNA)敲低c-abl也可以挽救ALS运动神经元变性(Imamura et al.,Sci.Transl.Med.9,2017)。多系统萎缩症(MSA)是一种罕见的、进展迅速的神经退行性疾病,目前没有任何治疗方法。在MSA中,α-突触核蛋白在黑质、纹状体、橄榄脑桥小脑结构和脊髓的神经元和少突胶质细胞中积累(J Neural Transm Vienna Austria 1996.2016;123(6))。
在转基因和慢病毒基因转移模型中,酪氨酸激酶抑制剂尼罗替尼的给药降低了c-abl活性并改善了α-突触核蛋白的自噬清除。小鼠前脑中c-abl的激活诱导海马体和纹状体中的神经变性。因此,通过磷酸化增加c-abl活性可能与在帕金森病和其他神经退行性疾病中检测到的α-突触核蛋白病理有关。(Hum Mol Genet.2013Aug 15)。c-Abl是α-突触核蛋白病、帕金森病、阿尔茨海默氏病、ALS、路易体痴呆和MSA的潜在治疗靶标。
发明内容
本公开提供了一种具有RIPK2和c-abl激酶抑制活性的化合物、包含该化合物的组合物以及可用于治疗炎症和/或自身免疫性疾病,尤其是神经炎症疾病的方法。在一个实施方案中,该化合物为式(I)所示的化合物:
在另一个实施方案中,本公开提供药物组合物,其包含治疗有效量的本文所述的化合物和药学上可接受的载体。
在另一个实施方案中,本公开提供了抑制或治疗神经退行性疾病的方法,包括向有此需要的受试者施用治疗有效量的一种或多种本文所述的化合物。
具体实施方式
以下描述本质上仅是示例,并不旨在限制本公开、应用或用途。
定义
为清楚起见,本文定义了本公开中使用的通用术语。
本说明书可互换地使用术语“取代基”、“基团”、“基团”、“部分”和“片段”。
如本文所用,术语“烯基”是指具有至少一个不饱和位点,即碳-碳,sp2双键的直链或支链的烃基。在一个实施方案中,烯基具有2至12个碳原子。在一些实施方案中,烯基为C2-C10烯基或C2-C6烯基。烯基的实例包括但不限于乙烯或乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、环戊烯基(-C5H7)和5-己烯基(-CH2CH2CH2CH2CH=CH2)。
如本文所用,术语“烷氧基”是RO-,其中R为烷基。烷氧基的非限制性实例包括甲氧基、乙氧基和丙氧基。
如本文所用,术语“烷氧基烷基”是指被烷氧基取代的烷基部分。烷氧基烷基的实例包括甲氧基甲基、甲氧基乙基、甲氧基丙基和乙氧基乙基。
如本文所用,术语“烷氧基羰基”为ROC(O)-,其中R为如本文所定义的烷基。在各种实施方案中,R为C1-C10烷基或C1-C6烷基。
如本文所用,术语“烷基”是指直链或支链烃基。在一个实施方案中,烷基具有1至12个碳原子。在一些实施方案中,烷基是C1-C10烷基或C1-C6烷基。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基和癸基。“低级烷基”是指具有1至4个碳原子的烷基。
如本文所用,如果使用术语“C1-C6”,则其表示碳原子数为1至6。例如,C1-C6烷基表示碳数为1至6的任何整数的烷基。
如本文所用,术语“烷基氨基”是指被一个或多个烷基取代的氨基。“N-(烷基)氨基”是RNH-,并且“N,N-(烷基)2氨基”为R2N-,其中R基团为本文所定义的烷基并且相同或不同。在各种实施方案中,R为C1-C10烷基或C1-C6烷基。烷基氨基的实例包括甲基氨基、乙基氨基、丙基氨基、丁基氨基、二甲基氨基、二乙基氨基和甲基乙基氨基。
如本文所用,术语“烷基氨基烷基”是指被烷基氨基取代的烷基部分,其中烷基氨基如本文所定义。烷基氨基烷基的实例包括甲基氨基甲基和乙基氨基甲基。
如本文所用,术语“炔基”是指具有至少一个不饱和位点即碳-碳-sp三键的直链或支链碳链基团。在一个实施方案中,炔基具有2至12个碳原子。在一些实施方案中,炔基为C2-C10炔基或C2-C6炔基。炔基的实例包括炔基(-C≡CH)和炔丙基(-CH2C≡CH)。
如本文所用,术语“芳基”指每个环中至多7个原子的任何单环或双环碳环,其中至少一个环是芳族的,或5至14个碳原子的芳环系系,该芳环体系包括与5或6元环烷基稠合的碳环芳族基团。芳基的代表性实例包括但不限于苯基、甲苯基、二甲苯基、萘基、四氢萘基、蒽基、芴基、茚基、薁基和茚满基。碳环芳族基团可以是未被取代的或任选地被取代的。
如本文所用,术语“环烷基”是包含至少一个饱和或部分不饱和的环结构并且经由环碳连接的烃基。在各种实施方案中,它是指饱和或部分不饱和的C3-C12环状部分,饱和或部分不饱和的C3-C12环状部分的实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。“环烷氧基”为RO-,其中R为环烷基。
如本文所用,术语“卤素”和“卤代”是指氯(-Cl)、溴(-Br)、氟(-F)或碘(-I)。“卤代烷氧基”是指被一个或多个卤素基团取代的烷氧基,并且卤代烷氧基的实例包括但不限于-OCF3、-OCHF2和-OCH2F。“卤代烷氧基烷基”是指被卤代烷氧基取代的烷基部分,其中卤代烷氧基如本文所定义。卤代烷氧基烷基的实例包括三氟甲氧基甲基、三氟乙氧基甲基和三氟甲氧基乙基。“卤代烷基”是指被一个或多个卤素基团取代的烷基部分。卤代烷基的实例包括-CF3和-CHF2。
如本文所用,术语“杂烷基”是指在链中具有2至14个碳(在一些实施方案中,2至10个碳)的直链或支链烷基,其中一个或多个碳已被杂原子取代,该杂原子选自S、O、P和N。示例性的杂烷基包括烷基醚、仲和叔烷基胺、酰胺、烷基硫化物等。
如本文所用,术语“杂环基”包括以下定义的杂芳基,并且是指具有2至14个环碳原子的饱和或部分不饱和的单环、双环或三环基团,除了环碳原子外,还有1-4个选自P、N、O和S的杂原子。在各个实施方案中,杂环基通过碳或通过杂原子连接至另一部分,并且任选地被碳或杂原子取代。杂环基的实例包括氮杂环丁烷基、苯并咪唑基、苯并呋喃基、苯并呋喃氮基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并恶唑基、咔唑基、咔啉基、肉桂啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基、吲哚嗪基、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、萘吡啶基、恶二唑基、恶唑基、恶唑啉、异恶唑啉、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四氢吡喃基、四氢硫吡喃基、四氢异喹啉基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、氮杂环丁烷基、1,4-二恶烷基、六氢氮杂吡啶基、哌嗪基、哌啶基、吡啶-2-基、吡咯烷基、吗啉基、硫代吗啉基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并恶唑基、二氢呋喃基、二氢咪唑基、二氢吲哚基二氢异恶唑基、二氢异噻唑基、二氢恶二唑基、二氢恶唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基和四氢噻吩基及其N-氧化物。“杂环基氧基”是RO-,其中R为杂环基。“杂环硫基”为RS-,其中R为杂环基。
如本文所用,术语“3元或4元杂环基”是指具有3或4个环原子的单环,其中至少一个环原子是选自N、O和S的杂原子。3-或4-元杂环基的非限制性实例包括吖丙啶基、2H-吖啶基、氧杂环烷基、噻喃基、氮杂环丁烷基、2,3-二乙酰氮、氮杂基、1,3-二氮杂环丁烷基、氧杂环丁烷基、2H-氧杂环丁烷基、硫杂环丁烷基和2H-噻吩基。
如本文所用,术语“杂芳基”是指在每个环中具有至多7个原子的单环、双环或三环,其中至少一个环是芳族的并且在环中包含1至4个选自以下的杂原子:杂芳基的非限制性实例包括吡啶基、噻吩基、呋喃基、嘧啶基、咪唑基、吡喃基、吡唑基、噻唑基、噻二唑基、异噻唑基、恶唑基、异恶唑基、吡咯基、哒嗪基、吡嗪基、喹啉基、异喹啉基、苯并呋喃基、二苯并呋喃基、二苯并噻吩基、苯并噻吩基、吲哚基、苯并噻唑基、苯并恶唑基、苯并咪唑基、异吲哚基、苯并三唑基、嘌呤基、噻萘基和吡嗪基。杂芳基的连接可以通过芳环发生,或者,如果杂芳基是双环或三环并且其中一个环不是芳族的或不含杂原子,则可以通过非芳环或不含杂原子的环进行连接。“杂芳基”也理解为包括任何含氮杂芳基的N-氧化物衍生物。“杂芳氧基”为RO-,其中R为杂芳基。
如本文所用,术语“羟基烷氧基”是指被羟基(-OH)取代的烷氧基,其中烷氧基如本文所定义。羟基烷氧基的一个实例是羟基乙氧基。
如本文所用,术语“羟烷基”是指被至少一个羟基取代的直链或支链的单价C1-C10烃基,羟烷基的实例包括但不限于羟甲基、羟乙基、羟丙基和羟丁基。
如本文所用,术语“药学上可接受的”是指适用于药物制剂,通常认为其用于这类用途是安全的,由国家或州政府的监管机构正式批准用于此类用途,或被列入美国药典或其他公认的用于动物,尤其是人类的药典。
如本文所用,术语“药学上可接受的载体”是指稀释剂、佐剂、赋形剂或载体,或药学上可接受的并与本发明的化合物一起给药的其他成分。
如本文所用,术语“药学上可接受的盐”是指可增强所需药理活性的盐。药学上可接受的盐的实例包括与无机酸或有机酸形成的酸加成盐、金属盐和胺盐。与无机酸形成的酸加成盐的实例包括与盐酸、氢溴酸、硫酸、硝酸和磷酸形成的盐。与有机酸例如乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、o-(4-羟基-苯甲酰基)-苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷二磺酸、2-羟基乙烷磺酸、苯磺酸、对氯苯磺酸、2-萘磺酸、对甲苯磺酸、樟脑磺酸、4-甲基-双环[2,2,2]辛-2-烯-1-羧酸、葡庚糖酸、4,4'-亚甲基双(3-羟基-2-萘甲酸)、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸和粘康酸形成的盐。金属盐的实例包括与钠、钾、钙、镁、铝、铁和锌离子形成的盐。胺盐的实例包括与氨和有机含氮碱形成的盐,其强度足以与羧酸形成盐。
如本文所用,术语“被取代”指上述任何基团(即烷基、芳基、杂芳基、杂环或环烷基),其中被取代部分的至少一个氢原子被取代基取代。在一个实施方案中,被取代的基团的每个碳原子被不超过两个取代基取代。在另一实施方案中,被取代的基团的每个碳原子被不多于一个取代基取代。在酮取代基的情况下,两个氢原子被氧取代,氧通过双键连接到碳上。除非特别规定,否则取代基包括卤代、羟基、(低级)烷基、卤代烷基、单烷基或二烷基氨基、芳基、杂环、-NO2、B(OH)2、BPin、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-NRaSO2Rb、-ORa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa、-OC(=O)NRaRb、-NRaSO2Rb、-PO3Ra、-PO(ORa)(ORb)、-SO2Ra、-S(O)Ra、-SO(N)Ra(例如,亚砜亚胺),-(Ra)S=NRb(例如,烃基硫亚胺)和-SRa,其中Ra和Rb相同或不同且独立地为氢、卤代、氨基、烷基、卤代烷基、芳基或杂环,或者其中Ra和Rb与它们所连接的氮原子一起形成杂环。Ra和Rb可以是基于它们所连接的原子的复数形式。
如本文所用,术语“治疗有效量”是指当应用于本发明的化合物时旨在表示足以改善、缓解、稳定、逆转、减缓或延缓疾病进展,或疾病症状的化合物的量。在一个实施方案中,本发明的方法提供化合物组合的施用。在这种情况下,“治疗有效量”是组合中足以引起预期生物学效应的本发明化合物的量。
如本文所用,术语“治疗”或“治疗中”是指改善或逆转疾病或病症的进展或严重程度,或改善或逆转此类疾病或病症的一种或多种症状或副作用。如本文所用,“治疗”或“治疗中”还指抑制或阻断,如延缓、阻止、抑制、阻碍疾病或病症的系统、病症或状态的进展。出于本发明的目的,“治疗”或“治疗中”还指获得有益或期望的临床结果的方法,其中“有益或期望的临床结果”包括但不限于症状的减轻、病症或疾病的程度减轻、疾病或病症状态稳定(即不恶化)、疾病或病症状态的延迟或减缓、疾病或病症状态的改善或缓和以及疾病或病症的部分或全部缓解。
在另一个实施方案中,式(I)所示的化合物用于调节RIPK2蛋白的活性。
如本文所用,术语“调节”是指改变蛋白激酶的催化活性。调节尤其指激活或抑制蛋白激酶的催化活性,这取决于蛋白激酶所暴露的化合物或盐的浓度,或更优选地,调节是指抑制蛋白激酶的催化活性。如本文所用的术语“催化活性”是指在蛋白激酶的直接或间接影响下酪氨酸、丝氨酸或苏氨酸的磷酸化速率。
激酶活性的药理学抑制剂主要分为三类:(1)I型或“DFG-in”ATP竞争性抑制剂,它直接与ATP结合位点的ATP竞争(即双重SRrc ABL抑制剂,达沙替尼,(2)II型或“DFG-out”ATP竞争性抑制剂,其除了结合ATP结合位点外,它还与相邻的疏水结合位点结合,该疏水结合位点仅在激酶处于失活构型时(即,激活环的定向在会阻止底物结合的构象中)(即伊马替尼、尼罗替尼)才可接近,以及(3)非ATP竞争性抑制剂,它们结合在影响激酶活性的ATP结合位点之外的位点(即,GNF-2)。
如本文所用,短语“一个或多个这个/该公开的化合物”包括式(I)所示的任何化合物,以及其包合物、水合物、溶剂化物或多晶型物。并且,即使术语“本公开的一个或多个化合物”未提及其药学上可接受的盐,该术语也包括其盐。在一个实施方案中,本公开的化合物包括立体化学纯的化合物,例如,那些基本上不含(例如,大于85%ee、大于90%ee、大于95%ee、大于97%ee或大于99%ee)的其他立体异构体。也就是说,如果根据本公开的式(I)所示的化合物或其盐是互变异构体和/或立体异构体(例如,几何异构体和构象异构体),则此类分离的异构体及其混合物也包括在本公开的范围内。如果本公开的化合物或其盐在其结构中具有不对称碳,则它们的活性旋光异构体及其外消旋混合物也包括在本公开的范围内。
如本文所用,术语“多晶型物”是指本公开化合物或其复合物的固体结晶形式。同一化合物的不同多晶型物可以表现出不同的物理、化学和/或光谱特性。不同的物理特性包括但不限于稳定性(例如,对热或光的稳定性)、压缩性和密度(在配方和产品制造方面很重要)和溶出度(会影响生物利用度)。稳定性差异可能是由化学反应性的变化(例如,不同的氧化,使得一种剂型在由一种多晶型物组成时比由另一种多晶型物组成时变色更快)或机械特性(例如,片剂在储存时碎裂作为动力学有利的多晶型物转变为热力学更稳定的多晶型物)或两者(例如,一种多晶型物的片剂在高湿度下更容易分解)所引起的。多晶型物的不同物理性质会影响它们的加工。例如,由于例如其颗粒的形状或尺寸分布,一种多晶型物可能比另一种多晶型物更可能形成溶剂化物或可能比另一种更难过滤或洗去杂质。
如本文所用,术语“溶剂化物”是指根据本公开所述的化合物或其盐,其还包括化学计量或非化学计量的通过非共价分子间力结合的溶剂。优选的溶剂易挥发、微量给药于人类是无毒和/或可接受的。
如本文所用,术语“水合物”是指根据本公开的化合物或其盐,其还包括通过非共价分子间力结合的化学计量或非化学计量的水。
如本文所用,术语“包合物”是指晶格形式的化合物或其盐,其包含空间(例如,通道),其中捕获有客体分子(例如,溶剂或水)。
本公开的化合物
本公开提供了式(I)所示的化合物:
或其药学上可接受的盐,其中:
R1和R2独立地为-H、C1-C6烷基、C3-C6碳环基、C1-C4烷酰基(即--(CO)C1-C4烷基)、-(CO)C3-C6碳环基、芳基,或杂芳基,其中每个碳任选地被一个或多个选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的基团取代;或者R1和R2共同形成一个5元杂环;
R3为-H、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-O-环烷基、-O-杂环基、-O-芳基、-O-杂芳基、-NRc-烷基、-NRc-环烷基、-NRc-杂环基、-NRc-芳基、-NRc-杂芳基、-NRc-NRcC(=O)Rc或-CF3,其中每个碳任选地被选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的一个或多个基团所取代;
R4和R5独立地为-H、-OH、卤素、C1-C6烷基、C1-C6烷氧基、芳基、杂芳基、杂环基或杂烷基、氨基、-SCH3或-CN;
R6选自-H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6碳环基、杂环基、芳基、杂芳基、-NRc-芳基、-NRc-杂芳基、-O-芳基、-O-杂芳基,其中R6任选被一个或多个基团所取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基、烷氧基烯基、-NO2、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-ORa、-SRa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa,和-OC(=O)NRaRb;
Ra和Rb独立地为-H、卤素、氨基、烷基或卤代烷基;
Rc为-H、C1-C3烷基或环丙基;和
X和Y独立地为碳或氮,其中当Y为C时,X为N,或当Y为N时,X为C。
在一些实施方案中,R3选自-H、甲基、异丙基、丁基、甲氧基、吡啶基、苯基、环丙基、环丁基、吡唑基、氮杂环丁基、嘧啶基、吡咯烷基、环丙基氨基和吲唑基,其中R3任选被选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的一个或多个基团取代。具有此类取代基的非限制性代表性化合物可在表1中找到。
在一些实施方案中,R6选自溴、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、氮杂吲哚基、吲哚基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、硫代苯基、呋喃基、恶唑基、噻唑基、恶二唑基、噻二唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、咪唑并吡啶基、咪唑并嘧啶基、咪唑并吡嗪基、吡咯三嗪基、吡唑并吡啶基、咪唑三嗪基、嘌呤基、吲唑基、苯并呋喃基、苯并噻吩、苯并恶唑啉基、苯并噻唑啉基、苯并咪唑基、氧吲哚啉基、喹啉基、氮杂喹啉基、异喹啉基、氮杂异喹啉基、喹唑啉基、氮杂喹唑啉基、喹喔啉基、氮杂喹喔啉基、萘基,其中R6任选被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、氨基烷基、烷基氨基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基和烷氧基烯基。具有此类取代基的非限制性代表性化合物可在表1中找到。
在一个实施方案中,式(I)所示的化合物选自根据式(II)所示的化合物及其药学上可接受的盐:
其中R3、R4、R5和R6定义如上。
在一些实施方案中,R3为氟代环丙基并且R6为吲哚基,吲哚基任选地被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、卤代烷基、羟烷基、氨基烷基和叔丁氧基羰基。具有此类取代基的非限制性代表性化合物可在表1中找到。
在一些实施方案中,R3为氟代环丙基,并且R6选自溴、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、氮杂吲哚基、吲哚基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、硫代苯基、呋喃基、恶唑基、噻唑基、恶二唑基、噻二唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、咪唑并吡啶基、咪唑并嘧啶基、咪唑并吡嗪基、吡咯并三嗪基、吡唑并吡啶基、咪唑并三嗪基、嘌呤基、吲唑基、苯并呋喃基、苯并噻吩、苯并恶唑啉基、苯并噻唑啉基、苯并咪唑基、氧代吲哚啉基、喹啉基、氮杂喹啉基、异喹啉基、氮杂异喹啉基、喹唑啉基、氮杂喹唑啉基、喹喔啉基、氮杂喹喔啉基、萘基,其中R6任选被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、氨基烷基、烷基氨基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基和烷氧基烯基。具有此类取代基的非限制性代表性化合物可在表1中找到。
在一些实施方案中,R3为环丙基并且R6选自选自溴、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、氮杂吲哚基、吲哚基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、硫代苯基、呋喃基、恶唑基、噻唑基、恶二唑基、噻二唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、咪唑并吡啶基、咪唑并嘧啶基、咪唑并吡嗪基、吡咯三嗪基、吡唑并吡啶基、咪唑并三嗪基、嘌呤基、吲唑基、苯并呋喃基、苯并噻吩、苯并恶唑啉基、苯并噻唑啉基、苯并咪唑基、氧代吲哚啉基、喹啉基、氮杂喹啉基、异喹啉基、氮杂异喹啉基、喹唑啉基、氮杂喹唑啉基、喹喔啉基、氮杂喹喔啉基、萘基,其中R6任选被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、氨基烷基、烷基氨基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基和烷氧基烯基。具有此类取代基的非限制性代表性化合物可在表1中找到。
在一些实施方案中,R3选自甲基、异丙基、丁基、甲氧基、吡啶基、苯基、环丁基、吡唑基、氮杂环丁基、嘧啶基、吡咯烷基、环丙基氨基和吲唑基,其中R3任选被一个或多个基团取代,这一个或多个基团选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基。具有此类取代基的非限制性代表性化合物可在表1中找到。
在另一个实施方案中,式(I)所示的化合物选自根据式(III)所示的化合物及其药学上可接受的盐:
其中R3、R4、R5和R6定义如上。具有此类取代基的非限制性代表性化合物可在表1中找到。
在一些实施方案中,式I所示的化合物具有R1和R2,它们独立地为-H、烷基、乙酰基、叔丁氧羰基、氨基乙基、二甲基氨基乙基或甲基氨基乙基;或者R1和R2一起形成一个5元杂环基团。具有此类取代基的非限制性代表性化合物可在表1中找到,其中R3至R6如上式(I)所定义。
本公开提供了上述化合物的药学上可接受的盐。药学上可接受的盐入如定义部分中所定义。在一些实施方案中,盐是盐酸盐、酒石酸盐、磷酸盐或马来酸盐。
使用根据本公开的化合物的医疗用途和治疗方法
本公开还提供了通过向受试者施用治疗有效量的一种或多种如上所述的化合物来治疗患有或易患此类疾病或病症的受试者的神经退行性疾病或病症的方法。在一个实施方案中,治疗是预防性治疗。在另一个实施方案中,治疗是姑息治疗。在另一个实施方案中,治疗是恢复性治疗。
1.疾病或病症
用于抑制RIPK2和c-abl活性的本公开化合物可用于治疗或预防神经退行性疾病或病症。该化合物可用于抑制或阻碍RIPK2和c-abl激酶活性,用于治疗神经退行性疾病或病症,或用于预防此类疾病的恶化。因此,本公开提供了一种抑制或阻碍细胞中RIPK2和c-abl活性的方法,其中使细胞与有效量的本公开化合物接触。在一个实施方案中,此类细胞存在于受试者(例如,阿尔茨海默病患者)中。在另一个实施方案中,提供了使用根据本公开的化合物治疗或预防受试者的炎症和/或自身免疫性疾病,尤其是神经炎症疾病或病症的医学用途。本公开的方法包括向需要治疗或预防的受试者施用含有治疗或预防有效量的RIPK2和c-abl抑制剂的药物组合物。炎症和自身免疫性疾病,尤其是神经炎症疾病或病症,包括但不限于α-突触核蛋白病、帕金森病、路易体痴呆、多系统萎缩症(MSA)、阿尔茨海默病或肌萎缩侧索硬化症(ALS)。
2受试者
根据本公开的待治疗的合适的受试者包括哺乳动物受试者。根据本公开的哺乳动物包括但不限于人、犬科动物、猫科动物、牛科动物、山羊科动物、马科动物、绵羊科动物、猪科动物、啮齿动物、兔类动物、灵长类动物等,并且包括子宫内的哺乳动物。受试者可以是任何性别,也可以处于任何发育阶段。在一个实施方案中,根据本公开的待治疗的合适受试者为人。
3.给药和剂量
本公开的化合物通常以治疗有效量施用。本公开的化合物可以通过任何合适的途径以适合这种途径的药物组合物的形式并且以对预期治疗有效的剂量施用。有效剂量通常为单次服用或拆分剂量服用约0.001至约100毫克/kg体重/天,优选约0.01至约50毫克/kg体重/天。根据年龄、物种和所治疗的疾病或病症的不同,低于该范围下限的剂量水平可能是合适的。在其他情况下,可以使用更大的剂量而不会产生有害的副作用。较大的剂量也可以分成几个较小的剂量,用于全天给药。确定合适剂量的方法是本公开所属领域中所公知的。例如,可以使用《雷明顿:药学的科学与实践》,Mack Publishing Co.,第20版,2000年。
药物组合物、剂型和给药途径
为了治疗上述疾病或病症,本文所述的化合物或其药学上可接受的盐可以按如下方式进行给药:
口服给药
本公开的化合物可以口服给药,包括通过吞咽给药,使得化合物进入胃肠道,或直接从口腔吸收到血流中(例如,口腔或舌下给药)。
用于口服给药的合适组合物包括固体、液体、凝胶或粉末制剂,并且具有诸如片剂、锭剂、胶囊剂、颗粒剂或粉末剂的剂型。
口服给药的组合物可以配制为立即释放或缓释,包括延迟或持续释放,任选地具有肠溶包衣。
液体制剂可包括溶液、糖浆和悬浮液,可用于软胶囊或硬胶囊。这样的制剂可以包括药学上可接受的载体,例如水、乙醇、聚乙二醇、纤维素或油。该制剂还可以包括一种或多种乳化剂和/或助悬剂。
在片剂剂型中,存在的药物量可以为剂型重量的约0.05%至约95%,更通常为约2%至约50%。此外,片剂可含有崩解剂,占剂型重量的约0.5%至约35%,更通常为约2%至约25%。崩解剂的实例包括但不限于乳糖、淀粉、羟基乙酸淀粉钠、交聚维酮、交联羧甲基纤维素钠、麦芽糖糊精或其混合物。
用于片剂的合适的润滑剂的含量按重量计可为约0.1%至约5%,包括但不限于滑石粉、二氧化硅、硬脂酸、钙、锌或硬脂酸镁、硬脂酰富马酸钠等。
用于片剂的合适的粘合剂包括但不限于明胶、聚乙二醇、糖、树胶、淀粉、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素等。用于片剂的合适的稀释剂包括但不限于甘露醇、木糖醇、乳糖、右旋糖、蔗糖、山梨糖醇、微晶纤维素和淀粉。
用于片剂的合适的增溶剂的量按重量计可约0.1%至约3%,并且包括但不限于聚山梨酯、月桂基硫酸钠、十二烷基硫酸钠、碳酸亚丙酯、二甘醇单乙醚、二甲基异山梨醇酯、聚乙二醇(天然或氢化)蓖麻油、HCORTM(Nikkol)、油酸酯、GelucireTM、辛酸/辛酸单/双甘油酯、山梨糖醇酐脂肪酸酯和Solutol HSTM。
肠胃外给药
本公开的化合物可以直接施用到血流,肌肉或内部器官中。肠胃外给药的合适方式包括静脉内给药、肌肉内给药、皮下动脉内给药、腹膜内给药、鞘内给药、颅内给药等。用于肠胃外给药的合适装置包括注射器(包括针头和无针头注射器)和输液方法。
用于肠胃外给药的组合物可以配制为立即释放或缓释,包括延迟或持续释放。大多数肠胃外制剂是含有赋形剂的水溶液,包括盐、缓冲剂和等渗剂。肠胃外制剂也可以脱水形式(例如,通过冻干)或作为无菌非水溶液制备。这些制剂可以与合适的介质,例如无菌水一起使用。增溶剂也可用于制备肠胃外溶液。
经皮给药
本公开的化合物可以局部施用于皮肤或经皮地施用。用于该局部给药的制剂可以包括洗剂、溶液、乳膏、凝胶、水凝胶、软膏、泡沫、植入物、贴剂等。用于局部给药制剂的药学上可接受的载体可以包括水、酒精、矿物油、甘油、聚乙二醇等。局部或经皮给药也可以通过电穿孔、离子电渗疗法、超声透入疗法等进行。
用于局部给药的组合物可以配制成立即释放或缓释,包括延迟释放或持续释放。
联合疗法
根据本公开的药物组合物可以包含一种或多种另外的治疗剂,例如,以提高功效或减少副作用。因此,在一些实施方案中,药物组合物还含有一种或多种选自活性成分的其他治疗剂,所述活性成分可用于治疗或抑制由RIPK和c-abl激酶直接或间接介导的疾病。此类活性成分的实例是但不限于治疗炎症和自身免疫性疾病或病症的药物。
制备药物组合物的参考文献
用于制备用于治疗或预防疾病或病症的药物组合物的方法是本公开所属领域中公知的。例如,根据《药物赋形剂手册》(第7版)、《雷明顿:药学的科学与实践》(第20版)、《药学技术百科全书》(第3版)或《缓释控释药物输送系统》(1978年)可以选择药学上可接受的赋形剂、载体、添加剂等,然后将其与本公开的化合物混合以制备药物组合物。
本公开提供了一种通过抑制RIPK2和c-abl活性而具有多种药理作用的化合物、以该化合物为有效药物的药物组合物、以及该化合物的医学用途,特别是用于治疗神经退行性疾病或病症,和一种治疗或预防的方法,该方法包括将所述化合物施用于需要这种治疗或预防的受试者。本公开的化合物及其药学上可接受的盐具有良好的安全性和对RIPK2和c-abl的高选择性,从而表现出优异的药物性质。
实施例
下文中,通过示例相当详细地描述本公开以帮助本领域技术人员理解本公开。然而,以下实施例是以说明的方式提供的,并不旨在限制本发明的范围。显然,在不脱离本发明的精神和范围或不牺牲其所有物质优势的情况下,可以进行各种改变。
式(I)所示的化合物的合成
从A到S的合成方法用于制备以下化合物。下文描述了本公开的一些化合物的说明性合成实例,并且可以通过与以下所述方法相类似的方法,使用不同的起始或反应材料来制备其他化合物。
合成方法A
实施例1(2-氨基-6-溴咪唑并[1,2-a]吡啶-3-基)(环丙基)甲酮
向环丙烷羧酸(3.17克,36.78毫摩尔,2.91毫升,1.3当量)的DMF(50毫升)溶液中加入EDCI(6.51克,33.95毫摩尔,1.2当量)、HOBt(4.59克,33.95毫摩尔,1.2当量)和TEA(8.59克,84.89毫摩尔,11.82毫升,3当量)。将混合物在15℃下搅拌1小时,然后加入6-溴咪唑并[1,2-a]吡啶-2-胺(6克,28.30毫摩尔,1当量)。将最终混合物在15℃下搅拌18小时。将混合物倒入水(200毫升)中,用乙酸乙酯(300毫升*3)萃取,用盐水(500毫升*2)洗涤有机相,用无水硫酸钠(Na2SO4)干燥,过滤并真空浓缩。残留物用乙酸乙酯(50毫升)研磨纯化,过滤并浓缩滤饼。得到黄色固体的实施例1(2.4克,8.25毫摩尔,收率30.28%,纯度96.3%)。
1H NMR(400MHz,DMSO-d6)δ9.70(d,J=1.2Hz,1H),7.60(dd,J=2.1,9.3Hz,1H),7.32(d,J=9.3Hz,1H),6.62(s,2H),2.46-2.37(m,1H),1.02-0.90(m,4H);LCMS(电喷雾)m/z 282.10(M+2H)+。
合成方法B
实施例6 1-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)乙烷-1-酮
步骤1)1-(2-氨基-6-溴咪唑并[1,2-a]吡啶-3-基)乙烷-1-酮
向6-溴咪唑并[1,2-a]吡啶-2-胺(260毫克,1.23毫摩尔,1当量)的DCM(20毫升)溶液中加入EDCI(358毫克,1.84毫摩尔,1.5当量)、HOBt(249毫克,1.84毫摩尔,1.5当量)和TEA(186毫克,1.84毫摩尔,256μL,1.5当量),将混合物在25℃下搅拌1小时,然后加入乙酸(81毫克,1.35毫摩尔、1.1当量)。将混合物在25℃下搅拌12小时。减压浓缩反应混合物以除去DCM溶液,得到残留物。通过硅胶层析纯化粗产物(产物在己烷/乙酸乙酯=1/2下得到),得到白色固体的化合物1(177毫克,0.67毫摩尔,收率57%)。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),7.61(dd,J=9.3,2.2Hz,1H),7.33(d,J=9.3Hz,1H),6.51(s,2H),2.43(s,3H)。
步骤2)1-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)乙烷-1-酮
在室温下向化合物1(150毫克,0.590毫摩尔,1当量)在二恶烷(6毫升)和H2O(2毫升)中的溶液中加入(3-氟-2-甲基苯基)硼酸(136毫克,0.883毫摩尔,1.5当量)、Na2CO3(125毫克,1.179毫摩尔,2.0当量)和Pd(dppf)Cl2(43毫克,0.06毫摩尔,0.1当量),微波下在120℃下加热30分钟,冷却至室温,通过硅藻土垫过滤以除去固体,并在乙酸乙酯和饱和碳酸氢钠水溶液之间进行分割。有机层用饱和氯化钠水溶液洗涤,分离,经无水Na2SO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=1/1)纯化残留物,得到象牙状固体的实施例6(122毫克,0.430毫摩尔,收率73%)。
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),7.51(dd,J=9.2,1.8Hz,1H),7.41(d,J=8.2Hz,1H),7.38-7.29(m,1H),7.23(t,J=8.5Hz,1H),7.16(d,J=7.1Hz,1H),6.47(s,2H),2.44(s,3H),2.16(d,J=2.2Hz,3H);LCMS(电喷雾)m/z 284.10(M+H)+。
合成方法C
实施例24(2-((2-(二甲基氨基)乙基)氨基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-
a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
向实施例5(100毫克,0.30毫摩尔,1当量)的DMF(1.5毫升)溶液中加入2-溴-N,N-二甲基乙烷-1-胺HBr(105毫克,0.45毫摩尔,1.5当量)、K2CO3(124毫克,0.90毫摩尔、3当量)和TBAB(9.6毫克,0.03毫摩尔,0.1当量)。将反应混合物在微波下加热至100℃持续30分钟。用10毫升水稀释反应混合物,并用乙酸乙酯(10毫升*2)萃取。合并的有机层用盐水(10毫升)洗涤,用Na2SO4干燥,过滤并浓缩滤液。通过硅胶柱层析(DCM中0至20%梯度MeOH)纯化残留物,得到实施例24(10毫克,收率8.3%)。
1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.22-8.09(m,2H),7.44-7.40(m,1H),7.35-7.28(m,1H),7.24-7.12(m,1H),5.37-5.16(m,1H),4.54(s,2H),4.09(d,J=4.9Hz,2H),3.17(d,J=3.8Hz,6H),2.83-2.66(m,4H),2.33-2.08(m,3H),1.96(dtd,J=23.5,6.8,3.2Hz,1H),1.33-1.23(m,1H);LCMS(电喷雾)m/z 399.2(M+H)+。
合成方法D
实施例28(2-氨基-6-(5-甲基噻唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-
氟环丙基)甲酮。
步骤1)2,2,2-三氟-N-(6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)咪唑并[1,2-a]吡啶-2-基)乙酰胺
在室温下,向N-(6-溴咪唑并[1,2-a]吡啶-2-基)-2,2,2-三氟乙酰胺(1.0克,3.24毫摩尔,1当量)的DMSO(30毫升)溶液中加入双(pinacolato)二硼(1.0克,4.21毫摩尔,1.3当量)、Pd(dppf)Cl2(234毫克,0.32毫摩尔,0.1当量)和KOAc(953毫克,9.72毫摩尔,3当量),然后在90℃下加热7小时,冷却至室温,通过硅藻土垫过滤以除去固体,并在乙酸乙酯和饱和碳酸氢钠水溶液之间分隔开来。有机层用饱和氯化钠水溶液洗涤,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=1/2)纯化残留物,得到米色固体的化合物2(602毫克,1.69毫摩尔,收率52.4%)。
步骤2)6-(5-甲基噻唑-4-基)咪唑并[1,2-a]吡啶-2-胺
向4-溴-5-甲基噻唑(200毫克,1.12毫摩尔,1当量)在二恶烷(4毫升)和H2O(1毫升)中的溶液中加入化合物2(598.35毫克,1.68毫摩尔,1.5当量)、Na2CO3(238.11毫克,2.25毫摩尔,2当量)和Pd(dppf)Cl2(82.19毫克,112.33μmol,0.1当量),然后将混合物在90℃下在N2下搅拌16小时。减压浓缩反应混合物以除去H2O和二恶烷溶液,得到残留物。通过反相快速色谱(MeCN/H2O,0.05%TFA,25%-30%)纯化残留物,得到产物。得到黄色固体的化合物3(80毫克,347.39μmol,收率30.93%)。
步骤3)(2-氨基-6-(5-甲基噻唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
向(1S,2S)-2-氟环丙烷-1-羧酸(31.64毫克,303.97μmol,1当量)的DCM(2毫升)溶液中加入EDCI(69.93毫克,364.76μmol,1.2当量)、HOBt(49.29毫克,364.75μmol,1.2当量)和TEA(92.27毫克,911.90μmol、126.92μL,3当量),将混合物在25℃下搅拌1小时,然后加入化合物3(70毫克,303.97μmol,1当量)。将混合物在25℃下搅拌11小时。减压浓缩反应混合物以除去DCM溶液,得到残留物。通过prep-HPLC纯化残留物(柱:Waters Xbridge 150*25mm*5um;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:15%-45%,10分钟)。得到白色固体的实施例28(53毫克,167.53μmol,收率55.12%。
1H NMR(400MHz,DMSO-d6)δ10.01-9.88(m,1H),8.99(br d,J=0.9Hz,1H),7.91-7.84(m,1H),7.44(br d,J=9.0Hz,1H),6.68(br s,2H),5.29-5.07(m,1H),2.68-2.58(m,5H),1.93-1.84(m,1H),1.20-1.08(m,1H);LCMS(电喷雾)m/z 317.20(M+H)+。
合成方法E
实施例33 N-(3-乙酰基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)乙酰胺
和实施例37 N-乙酰基-N-(3-乙酰基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)乙
酰胺
向实施例6(250毫克,0.88毫摩尔,1当量)的DCM(10毫升)溶液中加入T3P 50%溶液(842毫克,1.32毫摩尔,1.5当量)、TEA(295毫克,2.91毫摩尔,406μL,3.3当量),将混合物在0℃下搅拌1小时,然后加入乙酸(132毫克,2.21毫摩尔、2.5当量)。将混合物在25℃下搅拌15小时。减压浓缩反应混合物以除去DCM溶液,得到残留物。通过硅胶层析(己烷/乙酸乙酯=1/2)纯化粗产物,得到白色固体的实施例33(24.9毫克,0.077毫摩尔,收率8.7%)和实施例37(81.7毫克,0.222毫摩尔,收率25.3%)。
实施例33:1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.51(s,1H),7.81(d,J=9.3Hz,1H),7.68(dd,J=9.1,1.9Hz,1H),7.37(dd,J=14.0,8.0Hz,1H),7.28(t,J=8.5Hz,1H),7.20(d,J=7.7Hz,1H),2.44(s,3H),2.22-2.12(m,6H);LCMS(电喷雾)m/z 326.10(M+H)+:。
实施例37:1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ9.57(d,J=1.1Hz,1H),7.99-7.91(m,1H),7.80(dd,J=9.1,1.9Hz,1H),7.44-7.35(m,1H),7.34-7.26(m,1H),7.23(d,J=7.7Hz,1H),2.37(s,3H),2.35(s,6H),2.20(d,J=2.7Hz,3H);LCMS(电喷雾)m/z 368.10(M+H)+。
合成方法F
实施例54(6-(3-氟-2-甲基苯基)-2-(甲基氨基)咪唑并[1,2-a]吡啶-3-基)((1S,
2S)-2-氟环丙基)甲酮
实施例5实施例54
在-78℃下,向实施例5(50毫克,0.15毫摩尔,1当量)的THF(0.8毫升)溶液中滴加2M LDA的THF溶液(113μl,0.225毫摩尔,1.5当量)。30分钟后,加入MeI(20μl,0.3毫摩尔,2当量)。将反应混合物在-78℃下搅拌2小时。然后用10毫升水稀释混合物并用乙酸乙酯(10毫升*2)萃取。合并的有机层用盐水(10毫升)洗涤,用Na2SO4干燥,过滤并浓缩滤液。通过硅胶柱层析(DCM中0至10%梯度MeOH)纯化残留物,得到实施例54(3毫克,收率5.8%)。
1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),7.59-7.53(m,3H),7.35(dd,J=13.7,8.2Hz,1H),7.27-7.18(m,3H),5.28-5.08(m,1H),4.80(s,1H),3.07(d,J=4.4Hz,3H),2.31(d,J=18.7Hz,1H),2.18(d,J=2.2Hz,3H),1.91-1.76(m,1H),1.48(s,1H),1.17-1.08(m,1H);LCMS(电喷雾)m/z 342.10(M+H)+。
合成方法G
实施例55(2-(二甲氨基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮
在0℃下,向实施例5(50毫克,0.15毫摩尔,1当量)的DMF(0.8毫升)溶液中逐份加入NaH(9毫克,0.375毫摩尔,2.5当量)。30分钟后,加入MeI(30μl,0.45毫摩尔,3当量)。将反应混合物在0℃下搅拌2小时。然后用10毫升水稀释混合物,并用乙酸乙酯(10毫升*2)萃取。合并的有机层用盐水(10毫升)洗涤,用Na2SO4干燥,过滤并浓缩滤液。通过硅胶柱层析(DCM中0至8%梯度MeOH)纯化残留物,得到实施例55(18毫克,收率33.7%)。
1H NMR(400MHz,DMSO-d6)δ9.49(t,J=1.4Hz,1H),7.70-7.63(m,2H),7.35(dd,J=13.7,8.2Hz,1H),7.26(t,J=8.5Hz,1H),7.16(d,J=7.7Hz,1H),5.02(dd,J=67.3,1.9Hz,1H),3.07(d,J=12.6Hz,6H),2.16(d,J=2.2Hz,3H),1.73-1.63(m,1H),1.50(td,J=12.9,6.4Hz,1H);LCMS(电喷雾)m/z356.10(M+H)+。
合成方法H
实施例70(6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-
a]吡啶-2-基)氨基甲酸叔丁酯
步骤1)(6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-2-基)二甲酸叔丁酯
在室温下,向实施例5(500毫克,1.52毫摩尔,1当量)的THF(7毫升)溶液中加入TEA(0.414毫升,3.04毫摩尔,2当量)和DMAP(92毫克,0.76毫摩尔,0.5当量),然后冷却至0℃。然后,向反应混合物中缓慢加入Boc酸酐(499毫克,2.29毫摩尔,1.5当量),在室温下搅拌1小时。用乙酸乙酯萃取反应混合物并用水洗涤,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(产物在己烷/乙酸乙酯=1/2下得到)纯化残留物,得到白色固体的化合物4(720毫克,1.36毫摩尔,收率89.8%)。
步骤2)(6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-2-基)氨基甲酸叔丁酯
将化合物4(70毫克,0.132毫摩尔,1当量)的DCM(1.30毫升)溶液冷却至0℃,然后往其中滴加TFA(0.101毫升,1.32毫摩尔,10当量)。在室温下搅拌反应混合物30分钟。消耗化合物4后,浓缩反应混合物并用饱和碳酸氢钠水溶液中和。用乙酸乙酯萃取反应混合物,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(产物在己烷/乙酸乙酯=4/6下得到)纯化残留物,得到象牙状固体的实施例70(20毫克,0.046毫摩尔,收率35%)。
1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.47(d,J=1.2Hz,1H),7.80(d,J=9.2Hz,1H),7.68(dd,J=9.6,2.0Hz,1H),7.38-7.33(m,1H),7.27(t,J=8.8Hz,1H),7.20(d,J=7.6Hz,1H),5.06-4.83(m,1H),2.91-2.83(m,1H),2.17(d,J=2.0Hz,3H),1.91-1.80(m,1H),1.46(s,9H),1.28-1.21(m,1H);LCMS(电喷雾)m/z 428.20(M+H)+。
合成方法I
实施例71(6-(3-氟-2-甲基苯基)-2-(吡咯烷-1-基)咪唑并[1,2-a]吡啶-3-基)
((1S,2S)-2-氟环丙基)甲酮
在N2下,向实施例5(200毫克,611.01μmol,1当量)的甲苯(3毫升)溶液中加入DIPEA(157.94毫克,1.22毫摩尔,212.85μL,2当量)、DMAP(7.46毫克,61.10μmol,0.1当量)和1,4-二溴丁烷(791.55毫克,3.67毫摩尔,442.21μL,6当量)。将反应混合物在110℃下搅拌20小时。加入水(15毫升),并用EtOAc(10毫升*2)萃取水相。合并的有机相用饱和盐水(10毫升*2)洗涤并真空浓缩。通过反相快速色谱(MeCN/H2O,0.05%FA,70%-85%)纯化粗产物,得到浅黄色固体的实施例71(19.8毫克,50.20μmol,收率8.22%,纯度96.7%)。
1H NMR(400MHz,DMSO-d6)δ9.64-9.51(m,1H),8.44(br s,1H),7.64-7.55(m,2H),7.42-7.30(m,1H),7.29-7.22(m,1H),7.17(d,J=7.2Hz,1H),5.37-4.94(m,1H),4.05-3.73(m,2H),2.19(br s,1H),2.16(d,J=2.3Hz,3H),2.08(s,2H),2.04-1.96(m,2H),1.92(brdd,J=3.4,6.3Hz,1H),1.87-1.79(m,2H),1.30-1.11(m,1H);LCMS(电喷雾)m/z 382.00(M+H)+。
合成方法J
实施例87(6-(3-氟-2-甲基苯基)-2-((2-(甲基氨基)乙基)氨基)咪唑并[1,2-a]
吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
步骤1)(2-((6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-2-基)氨基)乙基)(甲基)氨基甲酸叔丁酯
在室温下,向实施例70(300毫克,0.701毫摩尔,1.5当量)的THF(3毫升)溶液中加入PPh3(183毫克,0.70毫摩尔,1.5当量)和(2-羟基乙基)(甲基)氨基甲酸叔丁酯(81毫克,0.467毫摩尔,1当量),然后冷却至0℃。然后,向反应混合物中缓慢加入DEAD(0.318毫升,0.701毫摩尔,1.5当量),在室温下搅拌3小时。用乙酸乙酯萃取反应混合物,用水洗涤,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析纯化残留物(产物在己烷/乙酸乙酯=6/4下得到),得到白色固体的化合物5(241毫克,0.412毫摩尔,收率88%)。
步骤2)(6-(3-氟-2-甲基苯基)-2-((2-(甲基氨基)乙基)氨基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
将化合物5(100毫克,0.171毫摩尔,1当量)的DCM(1.71毫升)溶液冷却至0℃,然后滴加TFA(0.261毫升,3.42毫摩尔,20当量)。将反应混合物在室温下搅拌3小时。消耗化合物5后,浓缩反应混合物并用饱和碳酸氢钠水溶液中和。用乙酸乙酯萃取反应混合物,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析纯化残留物(产物在DCM/甲醇=10/1下得到),得到象牙状固体的实施例87(37毫克,0.096毫摩尔,收率56%)。
1H NMR(400MHz,DMSO-d6)δ9.50(br s,1H),7.57-7.51(m,2H),7.36-7.31(m,1H),7.26-7.17(m,2H),5.27-5.07(m,1H),3.58(q,6.0Hz,2H),2.76(t,J=6.0Hz,2H),2.63-2.52(m,1H),2.33(s,3H),2.17(d,J=1.6Hz,3H),1.89-1.79(m,1H),1.24-1.10(m,1H);LCMS(电喷雾)m/z 385.15(M+H)+。
合成方法K
实施例88 N-(6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并
[1,2-a]吡啶-2-基)乙酰胺
向实施例5(78毫克,0.24毫摩尔,1当量)的DCM(3毫升)溶液中加入乙酸酐(49毫克,0.48毫摩尔,2.0当量)、DMAP(29毫克,0.12毫摩尔,0.5当量)和DIPEA(62毫克,0.49毫摩尔,2.0当量)。将混合物在25℃下搅拌16小时。在DCM和饱和碳酸氢钠水溶液之间分隔开来。有机层用饱和氯化钠水溶液洗涤,分离,经无水Na2SO4干燥,过滤,真空浓缩。通过硅胶层析纯化残留物(产物在己烷/乙酸乙酯=1/1下得到),得到象牙状固体的实施例88(19毫克,0.051毫摩尔,收率21%)。
1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),9.51(d,J=1.1Hz,1H),7.83(d,J=8.8Hz,1H),7.70(dd,J=9.3,1.6Hz,1H),7.43-7.32(m,1H),7.28(t,J=9.1Hz,1H),7.21(d,J=7.7Hz,1H),5.12-4.82(m,1H),2.87-2.73(m,1H),2.18(d,J=2.2Hz,3H),2.16(s,3H),1.92-1.75(m,1H),1.30-1.13(m,1H);LCMS(电喷雾)m/z 370.10(M+H)+。
合成方法L
实施例89(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,
2S)-2-氟环丙基)甲酮
步骤1)(2-氨基-6-溴咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
向6-溴咪唑并[1,2-a]吡啶-2-胺(5.81克,27.4毫摩尔,1当量)的DCM(500毫升)溶液中加入EDCI(7.88克,41.1毫摩尔,1.5当量)、HOBt(6.29克,41.1毫摩尔,1.5当量)和TEA(4.16克,41.1毫摩尔,5.73毫升,1.5当量),将混合物在25℃下搅拌1小时,然后加入(1S,2S)-2-氟环丙烷-1-羧酸(3.42克,32.9毫摩尔,1.2当量)。将混合物在25℃下搅拌11小时。减压浓缩反应混合物以除去DCM溶液,得到残留物。通过硅胶层析纯化粗产物(己烷/乙酸乙酯=1/2),得到白色固体的实施例2(6.03克,19.62毫摩尔,收率71.6%)。
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),7.63(d,J=9.2Hz,1H),7.34(d,J=10Hz,1H),6.71(s,2H),5.25-5.06(m,1H),2.62-2.51(m,1H),1.91-1.80(m,1H),1.18-1.09(m,1H);LCMS(电喷雾)m/z 299.00(M+H)+。
步骤2)(2-氨基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
在室温下,向实施例2(3.0克,10.06毫摩尔,1当量)的二恶烷(50毫升)溶液中加入4,4,4’,4’,5,5,5’-八甲基-2,2’-双(1,3,2-二氧杂硼烷)(3.32克,13.08毫摩尔,1.3当量),Pd(dppf)Cl2(736毫克,1.00毫摩尔,0.1当量)、KOAc(2.96克,30.20毫摩尔,3当量)并在90℃下加热7小时,冷却至室温,通过硅藻土垫过滤以去除固体,并在乙酸乙酯和饱和碳酸氢钠水溶液之间分隔开来。有机层用饱和氯化钠水溶液洗涤,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=1/2)纯化残留物,得到米色固体的化合物6(1.9克,5.504毫摩尔,收率54.7%)。
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),7.59(d,J=9.0Hz,1H),7.32(d,J=9.7Hz,1H),6.73(s,2H),5.23-5.05(m,1H),2.51-2.50(m,1H),1.90-1.81(m,1H),1.31(s,9H),1.15-1.06(m,1H);LCMS(电喷雾)m/z 346.10(M+H)+,264.10(M-82)+。
步骤3)(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
在室温下,向化合物6(600毫克,1.738毫摩尔,1当量)在二恶烷(7毫升)和水(1.75毫升)中的溶液中加入5-溴-4-甲基-1H-吲哚(365毫克,1.738毫摩尔,1当量)、Na2CO3(553毫克,5.21毫摩尔,3当量)和Pd(dppf)Cl2(127毫克,0.174毫摩尔,0.1当量),然后在微波下在100℃下加热1小时,冷却至室温,通过硅藻土垫过滤以除去固体,并在乙酸乙酯和饱和碳酸氢钠水溶液之间分隔开来。有机层用饱和氯化钠水溶液洗涤,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=1/1)纯化残留物,得到象牙状固体的实施例89(121毫克,0.347毫摩尔,收率19.9%)。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.47(s,1H),7.50(dd,J=9.1,1.9Hz,1H),7.41-7.32(m,2H),7.28(d,J=8.2Hz,1H),6.98(d,J=8.2Hz,1H),6.53(d,J=33.0Hz,3H),5.30-4.98(m,1H),2.60-2.49(m,1H),2.38(s,3H),1.90-1.68(m,1H),1.11-0.96(m,1H);LCMS(电喷雾)m/z 349.10(M+H)+。
合成方法M
实施例99(2-氨基-8-氟-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,
2S)-2-氟环丙基)甲酮
步骤1)N-(5-溴-3-氟吡啶-2-基)-4-甲基苯磺酰胺
在20℃下,向5-溴-3-氟吡啶-2-胺(10克,52.36毫摩尔,1当量)在吡啶(100毫升)中的溶液中加入TsCl(10.98克,57.59毫摩尔,1.1当量)。将混合物在90℃下搅拌16小时。用NaHCO3(200毫升)稀释混合物并用乙酸乙酯(300毫升)萃取。浓缩有机层。通过柱层析(SiO2,石油醚/乙酸乙酯=5/1至3/1)纯化残留物。得到黄色固体的化合物7(10克,28.97毫摩尔,收率55.33%)。
步骤2)(E)-2-(5-溴-3-氟-2-(甲苯基氨基)吡啶-1(2H)-基)乙酰胺
向化合物7(9克,26.07毫摩尔,1当量)的DMF(10毫升)溶液中加入DIPEA(3.71克,28.68毫摩尔,5.00毫升,1.1当量)和2-溴乙酰胺(3.96克,28.68毫摩尔,1.1当量)。将混合物在20℃下搅拌16小时。浓缩混合物。得到棕色固体的化合物8(10g,粗品)。
步骤3)N-(6-溴-8-氟咪唑并[1,2-a]吡啶-2-基)-2,2,2-三氟乙酰胺
向化合物8(5克,12.43毫摩尔,1当量)的DCE(10毫升)溶液中加入TFAA(31.33克,149.17毫摩尔,20.75毫升,12当量)。将混合物在60℃下搅拌3小时。用饱和NaHCO3中和混合物并用乙酸乙酯(300毫升)萃取。浓缩有机层。通过反相快速色谱法(0.1%FA条件,5-70%水/MeCN)纯化残留物并将其冻干,得到黄色固体的化合物9(2克,6.13毫摩尔,收率24.67%)。
步骤4)8-氟-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-胺
向化合物9(0.5克,1.53毫摩尔,1当量)在二恶烷(4毫升)和H2O(1毫升)中的溶液中加入(3-氟-2-甲基苯基)硼酸(283.30毫克,1.84毫摩尔,1.2当量)、Pd(dppf)Cl2(112.21毫克,153.35μmol,0.1当量)和Na2CO3(487.61毫克,4.60毫摩尔,3当量)。将混合物在90℃下搅拌16小时并浓缩。通过反相快速色谱法(0.1%FA条件,5-70%水/MeCN)纯化残留物并将其冻干,得到白色固体的化合物10(0.35克,1.35毫摩尔,收率88.03%)。
步骤5)(2-氨基-8-氟-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
向化合物10(60.22毫克,578.58μmol,1当量)的DCM(4毫升)溶液中加入EDCI(133.10毫克,694.30μmol,1.2当量)、HOBt(93.82毫克,694.30μmol,1.2当量)和TEA(70.26毫克,694.30μmol,96.64μL,1.2当量)。将混合物在20℃下搅拌1小时,然后加入(1S,2S)-2-氟环丙烷-1-羧酸(0.15克,578.58μmol,1当量)。将混合物在20℃下搅拌15小时并浓缩。通过反相快速色谱法(0.1%FA条件,5-70%H2O/MeCN)纯化残留物并将其冻干,得到实施例99(68毫克,185.50μmol,收率32.06%,纯度94.2%,白色固体)。
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.62-7.59(m,1H),7.36-7.19(m,3H),6.87(s,1H),5.29-5.10(m,1H),2.61-2.52(m,1H),2.19(s,3H),1.89-1.84(m,1H),1.17-1.13(m,1H);LCMS(电喷雾)m/z 346.10(M+H)+。
合成方法N
实施例107 2-氨基-N-环丙基-6-(3-氟-2-甲基苯基)-N-甲基咪唑并[1,2-a]吡
啶-3-甲酰胺
步骤1)6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-胺
向6-溴咪唑并[1.2-a]吡啶-2-胺(324毫克,1.53毫摩尔,1当量)在二恶烷(4毫升)和H2O(1毫升)中的溶液中加入(3-氟-2-甲基苯基)硼酸(283.30毫克,1.84毫摩尔,1.2当量)、pd(dppf)Cl2(112.21毫克,153.35μmol,0.1当量)和Na2CO3(487.61毫克,4.60毫摩尔,3当量)。将混合物在90℃下搅拌16小时。浓缩混合物。通过反相快速色谱法(0.1%FA条件,5-70%H2O/MeCN)纯化残留物并将其冻干,得到白色固体的化合物11(107毫克,1.07毫摩尔,收率70.00%)。
步骤2(6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)氨基甲酸二叔丁酯
在室温下,向化合物11(500毫克,2.07毫摩尔,1当量)的THF(10毫升)溶液中加入TEA(0.577毫升,4.14毫摩尔,2当量)和DMAP(126毫克,1.03毫摩尔,0.5当量),然后冷却至0℃。然后,向反应混合物中缓慢加入Boc酸酐(903毫克,4.14毫摩尔,2.0当量),在室温下搅拌混合物1小时。用乙酸乙酯萃取反应混合物并用水洗涤,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=6/4)纯化残留物,得到白色固体的化合物12(445毫克,1.00毫摩尔,收率48%)。
步骤3)2-(二(叔丁氧基羰基)氨基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-羧酸
将化合物12(200毫克,0.453毫摩尔,1当量)的THF(2.26毫升)溶液冷却至-78℃,然后向其中滴加LDA(0.906毫升,1.81毫摩尔,4当量),然后在相同温度下搅拌30分钟。逐份加入干冰,在-78℃下搅拌反应混合物2小时。然后用冰淬灭反应混合物,用DCM萃取,用水(100毫升)洗涤合并的有机相,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(DCM/甲醇=10/1)纯化粗产物,得到白色固体的化合物13(81毫克,0.166毫摩尔,收率36%)。
步骤4)(3-(环丙基(甲基)氨基甲酰基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)氨基甲酸二叔丁酯
向化合物13(81毫克,0.164毫摩尔,1当量)是DMF(0.8毫升)溶液中加入N-甲基环丙胺(17毫克,0.247毫摩尔,1.5当量)、EDCI(62毫克,0.328毫摩尔,2.0当量),HOBt(44毫克,0.328毫摩尔,2当量)和TEA(0.068毫升,0.492毫摩尔,3当量),将混合物在50℃下搅拌2小时。用乙酸乙酯萃取反应混合物,合并的有机相用饱和氯化钠水溶液(100毫升)洗涤,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=6/4)纯化粗产物,得到白色固体的化合物14(49毫克,0.090毫摩尔,收率55%)。
步骤5)2-氨基-N-环丙基-6-(3-氟-2-甲基苯基)-N-甲基咪唑并[1,2-a]吡啶-3-甲酰胺
向化合物14(45毫克,0.083毫摩尔,1当量)的DCM(0.4毫升)溶液中滴加4N HCl二恶烷(0.2毫升,0.835毫摩尔,10当量)。将反应混合物在室温下搅拌1小时。消耗化合物14后,浓缩反应混合物并用饱和碳酸氢钠水溶液中和。用乙酸乙酯萃取反应混合物,分离,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(DCM/甲醇=8/1)纯化残留物,得到象牙状固体的实施例107(22毫克,0.065毫摩尔,收率78%)。
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.35-7.25(m,3H),7.21(t,J=9.0Hz,1H),7.14(d,J=7.2Hz,1H),5.71(s,2H),2.94(s,3H),2.91-2.84(m,1H),2.16(s,3H),0.60-0.51(m,4H);LCMS(电喷雾)m/z 339.10(M+H)+。
合成方法O
实施例112N’-乙酰基-2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-碳酰肼
向化合物13(84毫克,0.155毫摩尔,1当量)的DCM(0.8毫升)溶液中加入乙酰酰肼(13.7毫克,0.186毫摩尔,1.2当量)、EDCI(46毫克,0.232毫摩尔,1.5当量)和HOBt(31.4毫克,0.232毫摩尔,1.5当量),混合物在25℃下搅拌16小时。用DCM(3毫升)萃取反应混合物,并用1N HCl水溶液(3毫升)洗涤合并的有机相,用无水MgSO4干燥,过滤,真空浓缩。通过硅胶层析(二氯甲烷/甲醇=8/2)纯化粗产物,得到白色固体的实施例112(4.6毫克,0.013毫摩尔,收率8.6%)。
1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.10(s,1H),9.06(t,J=1.4Hz,1H),7.39(d,J=1.1Hz,2H),7.33-7.16(m,3H),6.18(s,2H),2.16(d,J=2.2Hz,3H),1.90(s,3H);LCMS(电喷雾)m/z 342.10(M+H)+。
合成方法P
实施例135 2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-羧酸甲酯
步骤1)N-(6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)乙酰胺
向化合物11(58毫克,0.24毫摩尔,1当量)的DCM(3毫升)溶液中加入乙酸酐(49毫克,0.48毫摩尔,2.0当量)、DMAP(29毫克,0.12毫摩尔,0.5当量)和DIPEA(62毫克,0.48毫摩尔,2.0当量)。将混合物在25℃下搅拌16小时。将混合物在DCM和饱和碳酸氢钠水溶液之间分隔开来。有机层用饱和氯化钠水溶液洗涤,分离,用无水Na2SO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=1/1)纯化残留物,得到象牙状固体的化合物15(38毫克,0.13毫摩尔,收率56%)
步骤2)N-(3-溴-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)乙酰胺
向化合物15(30毫克,0.105毫摩尔,1当量)在MeCN(1毫升)中的溶液中加入N-溴代琥珀酰亚胺(18.6毫克,0.105毫摩尔,1.0当量),将混合物在0℃下搅拌2小时。用DCM(3毫升)萃取反应混合物,用H2O洗涤合并的有机相,用无水MgSO4干燥,过滤,真空浓缩。获得象牙状固体的化合物16(32毫克,0.09毫摩尔,收率86%)。
步骤3)2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-羧酸甲酯
向化合物16(300毫克,828.28μmol,1当量)在MeOH(10毫升)中的溶液中加入TEA(252毫克,2.48毫摩尔,346μL,3当量)和Pd(dppf)Cl2(61毫克,82.83μmol,0.1当量),并将反应混合物在80℃下在CO气氛(50psi)下搅拌12小时。将反应混合物过滤并浓缩,得到残留物。经柱层析(硅胶,石油醚:乙酸乙酯=1:1至0:1)Prep HPLC(柱:Waters Xbridge 150*25mm*5um;流动相:[水(10mM NH4HCO3)-ACN];B%:30%-63%,9分钟)纯化残留物,然后将其冻干。获得白色固体的实施例135(5.2毫克,17.37μmol,收率2.10%,纯度100%)。
1H NMR(400MHz,DMSO-d6)δ8.93(br s,1H),7.48-7.43(m,1H),7.42-7.38(m,1H),7.37-7.30(m,1H),7.27-7.21(m,1H),7.17(d,J=7.7Hz,1H),6.40(s,2H),3.82(s,3H),2.17(d,J=2.3Hz,3H);LCMS(电喷雾)m/z 300.10(M+H)+
合成方法Q
实施例148(2-氨基-6-((3-氟-2-甲基苯基)氨基)咪唑并[1,2-a]吡啶-3-基)
((1S,2S)-2-氟环丙基)甲酮
步骤1)2,2,2-三氟-N-(6-((3-氟-2-甲基苯基)氨基)咪唑并[1,2-a]吡啶-2-基)乙酰胺
向N-(6-溴咪唑并[1,2-a]吡啶-2-基)-2,2,2-三氟乙酰胺(500毫克,1.62毫摩尔,1当量)和3-氟-2-甲基苯胺(243.74毫克,1.95毫摩尔,221.58μL,1.2当量)在1,4-二恶烷(10毫升)中的溶液中加入BrettPhos Pd G3(147.13毫克,162.31μmol,0.1当量)和t-BuONa(2M,1.62毫升,2当量)。将混合物在90℃下在N2下搅拌12小时。将反应混合物在乙酸乙酯(100毫升*3)和H2O(100毫升*3)之间分隔开来。分离有机相,用NaCl(100毫升)洗涤,经Na2SO4干燥,过滤并减压浓缩,得到残留物。通过柱层析(SiO2,石油醚/乙酸乙酯=3/1至0/1)纯化残留物。得到棕色胶质的化合物17(100毫克,283.86μmol,收率17.49%)。
步骤2)N6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2,6-二胺
向化合物17(100毫克,283.86μmol,1当量)在MeOH(5毫升)和H2O(1毫升)中的溶液中加入K2CO3(117.69毫克,851.58μmol,3当量)。将混合物在70℃下搅拌12小时。将反应混合物在乙酸乙酯(50毫升*3)和H2O(50毫升*3)之间分隔开来。分离有机相,用NaCl(50毫升)洗涤,用Na2SO4干燥,过滤并减压浓缩,得到残留物。通过柱层析(SiO2,石油醚/乙酸乙酯=3/1至0/1)纯化残留物。获得棕色固体的化合物18(20毫克,78.04μmol,收率27.49%)。
步骤3)(2-氨基-6-((3-氟-2-甲基苯基)氨基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮
向化合物18(20毫克,78.04μmol,1当量)和(1S,2S)-2-氟环丙烷-1-羧酸(8.12毫克,78.04μmol,1当量)在DCM(3毫升)中的溶液中加入EDCI(14.96毫克,78.04μmol,1当量)和HOBt(10.55毫克,78.04μmol,1当量)。将混合物在25℃下搅拌12小时。减压蒸发溶剂。通过柱层析(SiO2,石油醚/乙酸乙酯=1/0-1/1)纯化残留物,粗产物通过反相HPLC(0.1%FA条件)纯化。得到棕色固体的实施例148(0.5毫克,1.46μmol,收率1.87%)。
1H NMR(400MHz,DMSO-d6)δ9.46-9.28(m,1H),7.57(s,1H)7.37-7.33(m,1H)7.33-7.29(m,1H),7.09-7.02(m,1H),6.74-6.70(m,1H),6.68-6.65(m,1H),6.42(br s,1H),5.25-5.01(m,1H),2.12(d,J=1.59Hz,3H),1.88-1.75(m,1H),1.14-1.02(m,2H);LCMS(电喷雾)m/z 343.10(M+H)+。
合成方法R
实施例151(3S,4R)-4-甲基四氢呋喃-3-基2-氨基-6-(5-氯-6-氟-7-(甲硫基)-
1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-羧酸酯
步骤1)N-(6-(5-氯-6-氟-7-(甲硫基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-2-基)-2,2,2-三氟乙酰胺
在20℃下,在N2下,向化合物2(938毫克,2.64毫摩尔,2当量)和4-溴-5-氯-6-氟-7-(甲硫基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(500毫克,1.32毫摩尔,1当量)在二恶烷(25毫升)和H2O(5毫升)中的混合物中一次性加入Pd(dppf)Cl2(97毫克,132.00μmol,0.1当量)以及Na2CO3(420毫克,3.96毫摩尔,3当量)。将混合物加热至80℃并搅拌3小时。过滤反应混合物,然后用H2O(20毫升)稀释并用乙酸乙酯(30毫升*3)萃取。合并的有机层用Na2SO4干燥,过滤并减压浓缩,得到残留物。经柱层析(SiO2,石油醚/乙酸乙酯=20/1至1/1)纯化残留物。得到红色油状化合物19(400毫克,757.69μmol,收率57.40%)。
步骤2)6-(5-氯-6-氟-7-(甲硫基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-2-胺
在20℃下,在N2下,向化合物19(350毫克,662.98μmol,1当量)在MeOH(20毫升)和H2O(5毫升)中的混合物中一次性加入K2CO3(458毫克,3.31毫摩尔,5当量)。将混合物加热至70℃持续16小时。用20毫升水稀释反应混合物,并用乙酸乙酯(30毫升*3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残留物。通过反相HPLC(0.1%FA条件)纯化粗产物。获得棕色固体的化合物20(118毫克,273.20μmol,收率41.21%)。
步骤3)(3S,4R)-4-甲基四氢呋喃-3-基2-氨基-6-(5-氯-6-氟-7-(甲硫基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-羧酸酯
在20℃下,在N2下,向化合物20(80毫克,185.22μmol,1当量)和(3S,4R)-4-甲基四氢呋喃-3-基(4-硝基苯基)碳酸酯(248毫克,926.10μmol,5当量)在THF(10毫升)中的混合物中一次性加入DIPEA(144毫克,1.11毫摩尔,193.57μL,6当量)。然后将混合物加热至80℃并搅拌24小时。将反应混合物冷却至20℃,然后用水(20毫升)淬灭,然后用乙酸乙酯(30毫升*3)萃取混合物。合并的有机层用NaCl溶液(30毫升*1)洗涤,用Na2SO4干燥,过滤并减压浓缩,得到残留物。经柱层析(SiO2,石油醚/乙酸乙酯=5/1至0/1)纯化残留物。得到黄色油状化合物21(54毫克,粗品)。
步骤4)(3S,4R)-4-甲基四氢呋喃-3-基2-氨基-6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-羧酸酯
在0℃下并在N2下,向化合物21(54毫克,96.42μmol,1当量)在二恶烷(2毫升)中的混合物中滴加HCl/二恶烷(4M,0.5毫升,20.74当量)。将混合物在0℃下搅拌0.1小时。通过在0℃加入Et3N/MeOH(0.5毫升/0.5毫升)淬灭反应混合物,然后减压浓缩得到残留物。通过反相HPLC(0.1%FA条件)纯化粗产物。得到棕色固体的实施例151(5.1毫克,10.72μmol,收率11.11%)。
1H NMR(400MHz,DMSO-d6)δ13.82(s,1H)9.15(s,1H)8.08(s,1H)7.64(d,J=9.11,1H)7.53(d,J=9.05Hz,1H)6.29-6.56(m,2H)5.01-5.10(m,1H)3.80-4.03(m,4H)2.56-2.64(m,4H)1.05(d,J=7.09Hz,3H);LCMS(电喷雾)m/z 476.00(M+H)+。
合成方法S
实施例153(2-氨基-5-(6-氟-5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]吡啶-3-基)
(环丙基)甲酮
步骤1)N-(5-溴-3-(环丙烷羰基)吡唑并[1,5-a]吡啶-2-基)-2,2,2-三氟乙酰胺
在室温下,向N-(5-溴吡唑并[1,5-a]吡啶-2-基)-2,2,2-三氟乙酰胺(200毫克,0.65毫摩尔,1.0当量)在DCM(13毫升)中的溶液中加入环丙烷酰氯(81毫克,0.78毫摩尔,1.2当量)、TiCl4(493毫克,2.601毫摩尔,4.0当量),然后在80℃下加热16小时。将混合物冷却至室温,用饱和NaHCO3猝灭并用DCM(3X100毫升)萃取。有机层用饱和氯化钠水溶液洗涤,分离,用无水Na2SO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=3/1)纯化残留物,得到棕色固体的化合物22(169毫克,0.449毫摩尔,收率69%)。
1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.84(dd,J=7.1,2.2Hz,1H),8.38(d,J=2.2Hz,1H),7.40(dd,J=7.7,2.2Hz,1H),2.56-2.48(m,1H),1.09-1.00(m,2H),1.00-0.93(m,2H)。
步骤2)(2-氨基-5-(6-氟-5-甲基-2-(四氢-2H-吡喃-2-基)-2H-吲唑-4-基)吡唑并[1,5-a]吡啶-3-基)(环丙基)甲酮
在室温下,向化合物22(80毫克,0.21毫摩尔,1.0当量)在二恶烷(2毫升)和H2O(1毫升)中的溶液中加入6-氟-5-甲基-2-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)-2H-吲唑(115毫克,0.32毫摩尔,1.5当量)、Na2CO3(45毫克,0.43毫摩尔,2.0当量)和Pd(dppf)Cl2(16毫克,0.02毫摩尔,0.1当量),然后在100℃下加热16小时。将混合物冷却至室温,通过硅藻土垫过滤以除去固体,并在乙酸乙酯和饱和碳酸氢钠水溶液之间分隔开来。有机层用饱和氯化钠水溶液洗涤,分离,用无水Na2SO4干燥,过滤,真空浓缩。通过硅胶层析(己烷/乙酸乙酯=1/1)纯化残留物,得到象牙状固体的化合物23(44毫克,0.101毫摩尔,收率48%)。
1H NMR(400MHz,DMSO-d6)δ8.67(d,J=7.7Hz,1H),7.94(d,J=1.1Hz,1H),7.85(s,1H),7.70(d,J=10.4Hz,1H),7.01(dd,J=6.7,2.1Hz,1H),6.66(s,2H),5.84(dd,J=9.9,2.7Hz,1H),3.94-3.84(m,1H),3.84-3.69(m,1H),2.49-2.45(m,1H),2.45-2.30(m,1H),2.24(d,J=2.7Hz,3H),2.13-1.89(m,2H),1.84-1.66(m,1H),1.66-1.50(m,2H),1.05-0.91(m,2H),0.91-0.80(m,2H)。
步骤3)(2-氨基-5-(6-氟-5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]吡啶-3-基)(环丙基)甲酮
向化合物23(40毫克,0.09毫摩尔,1.0当量)的DCM(1毫升)溶液中加入TFA(316毫克,2.77毫摩尔,30.0当量)。将混合物在25℃下搅拌3小时。用饱和NaHCO3水溶液将反应混合物调节至pH7。用水(20毫升)稀释混合物并用乙酸乙酯萃取。合并的有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩,得到残留物。通过硅胶层析(己烷/乙酸乙酯=1/3)纯化残留物,得到象牙状固体的实施例153(21.2毫克,0.061毫摩尔,收率66%)。
1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),8.66(d,J=6.6Hz,1H),7.95(s,1H),7.81(s,1H),7.42(d,J=9.9Hz,1H),7.02(dd,J=7.1,1.6Hz,1H),6.66(s,2H),2.49-2.43(m,1H),2.24(d,J=2.7Hz,3H),1.03-0.92(m,2H),0.92-0.82(m,2H);LCMS(电喷雾)m/z350.10(M+H)+。
下表1显示了实施例的化合物以及用于制备化合物的一般合成方法和表征数据。
表1实施例化合物
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化合物评估here
RIP2激酶测定
GST标记的重组人RIP2(25ng)在缓冲液(40mM Tris,7.5;20mM MgCl2;0.1毫克/毫升BSA;50μM DTT)中与5μL化合物(0.5% DMSO)、5μL MBP(0.5μg/μl)和5μL ATP(25μM)一起孵育。通过将反应混合物在96孔板中于30℃下孵育60分钟来开始测定。孵育结束后,加入25μL ADP-Glo试剂,反应在30℃孵育40分钟以终止反应并降解残留的ATP。然后通过每孔添加50μL检测试剂将ADP产物转化为ATP。在室温下孵育30分钟后,使用Molecular device I3X读板器检测发光。使用在GraphPad Prism 7软件和SigmaPlot 13.0中实施的软件程序,根据一系列抑制百分比值计算得到IC50值,其中在抑制剂浓度范围内测定得到该一系列抑制百分比值。
c-Abl激酶测定
ADP-Glo检测试剂盒购自Promega。氯化镁(MgCl2)、牛血清白蛋白(BSA)、乙二醇-双(β-氨基乙基醚)-N,N,N’,N’-四乙酸(EGTA)、tween-20、1,4-二硫苏糖醇(DTT)和二甲基亚砜(DMSO)购自Sigma-Aldrich。HEPES缓冲液购自Gibco。ABL1激酶和Abltide购自Signalchem。
c-Abl激酶活性通过Promega的ADP-GloTM测定法测量。在此测定中,His标记的重组人ABL1(0.25ng/μl)在缓冲液(50mM HEPES,7.5;10mM MgCl2;1mM EGTA;0.05% BSA;0.01% Tween-20;2mM DTT)中与5μL化合物(0.5% DMSO)、5μL Abltide(0.01μg/μl)和5μLATP(25μM)一起孵育。通过将反应混合物在96孔板中于30℃下孵育30分钟来开始测定。孵育结束后,加入25μL ADP-Glo试剂,反应在室温下孵育40分钟以终止反应并降解残留的ATP。然后通过每孔添加50μL检测试剂将ADP产物转化为ATP。在室温下孵育30分钟后,使用Molecular device I3X读板器检测发光。使用在GraphPad Prism 7软件和SigmaPlot 13.0中实施的软件程序,根据一系列抑制百分比值计算得到IC50值,其中在抑制剂浓度范围内测定得到该一系列抑制百分比值。
BV-2细胞分泌IL-6
BV-2小鼠小胶质细胞由韩国科学技术研究院(KIST)的Bae博士友情提供。将BV-2细胞解冻并悬浮在补充有10%胎牛血清(FBS)和1%青霉素/链霉素的Dulbecco改良eagle培养基(DMEM)中。将细胞以2X104个细胞/孔的密度接种到96孔板中,并使其附着24小时。实验当天,对不同浓度的FB化合物进行处理,并用10μg/ml L18-MDP刺激细胞。孵育24小时后,收集上清液用于细胞因子测定。
在刺激后24小时后,根据制造商的建议,使用IL-6ELISA试剂盒(R&D系统)测量细胞因子分泌。使用SpectraMax i3X酶标仪(酶标仪)测量450nm处的吸光度。减去仅含有培养基孔的值,并计算相对于DMSO/L18-MDP处理的对照(100%)的每种化合物浓度的抑制百分比。使用GraphPad Prism 7软件和SigmaPlot 13.0中实施的软件根据一系列活性百分比值计算得出IC50值。
表2显示了本发明化合物的IC50值,其中+表示>1000nM,++表示501-1000nM,+++表示101-500nM,++++表示1-100nM。
表2.BV-2细胞的体外激酶活性和IL-6分泌。
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-;未测试。
Claims (24)
1.一种式(I)所示的化合物:
或其药学上可接受的盐,其中:
R1和R2独立地为-H、C1-C6烷基、C3-C6碳环基、C1-C4烷酰基、-(CO)C3-C6碳环基、芳基,或杂芳基,其中每个R1和R2任选地被一个或多个选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的基团取代;或者R1和R2共同形成一个5元杂环;
R3为-H、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-O-环烷基、-O-杂环基、-O-芳基、-O-杂芳基、-NRc-烷基、-NRc-环烷基、-NRc-杂环基、-NRc-芳基、-NRc-杂芳基、-NRc-NRc C(=O)Rc或-CF3,其中R3任选地被一个或多个选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的基团所取代;
R4和R5独立地为-H、-OH、卤素、C1-C6烷基、C1-C6烷氧基、芳基、杂芳基、杂环基或杂烷基、氨基、-SCH3或-CN;
R6选自-H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6碳环基、杂环基、芳基、杂芳基、-NRc-芳基、-NRc-杂芳基、-O-芳基、-O-杂芳基,其中R6任选被一个或多个基团所取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基、烷氧基烯基、-NO2、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-ORa、-SRa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa,和-OC(=O)NRaRb;
Ra和Rb独立地为-H、卤素、氨基、烷基或卤代烷基;
Rc为-H、C1-C3烷基或环丙基;和
当Y为C时,X为N,或当Y为N时,X为C。
2.根据权利要求1所述的化合物,其特征在于,R3选自-H、甲基、异丙基、丁基、甲氧基、吡啶基、苯基、环丙基、环丁基、吡唑基、氮杂环丁基、嘧啶基、吡咯烷基、环丙基氨基和吲唑基,其中R3任选被一个或多个选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的基团取代。
3.根据权利要求1或2所述的化合物,其特征在于,R6选自溴、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、氮杂吲哚基、吲哚基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、硫代苯基、呋喃基、恶唑基、噻唑基、恶二唑基、噻二唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、咪唑并吡啶基、咪唑并嘧啶基、咪唑并吡嗪基、吡咯三嗪基、吡唑并吡啶基、咪唑三嗪基、嘌呤基、吲唑基、苯并呋喃基、苯并噻吩、苯并恶唑啉基、苯并噻唑啉基、苯并咪唑基、氧吲哚啉基、喹啉基、氮杂喹啉基、异喹啉基、氮杂异喹啉基、喹唑啉基、氮杂喹唑啉基、喹喔啉基、氮杂喹喔啉基、萘基,其中R6任选被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、氨基烷基、烷基氨基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基和烷氧基烯基。
4.根据权利要求1至3中任一项所述的化合物,其特征在于,其选自式(II)所示的化合物及其药学上可接受的盐:
R3为-H、烷基、环烷基、杂环基、芳基、杂芳基、-O-环烷基、-O-杂环基、-O-芳基、-O-杂芳基、-NRc-烷基、-NRc-环烷基、-NRc-杂环基、-NRc-芳基、-NRc-杂芳基、-NRc-NRc C(=O)Rc或-CF3,其中R3任选地被选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的一个或多个基团所取代;
R4和R5独立地为-H、-OH、卤素、C1-C6烷基、C1-C6烷氧基、芳基、杂芳基、杂环基或杂烷基、氨基、-SCH3或-CN;
R6选自-H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6碳环基、杂环基、芳基、杂芳基、-NRc-芳基、-NRc-杂芳基、-O-芳基、-O-杂芳基,其中R6任选被一个或多个基团所取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基、烷氧基烯基、-NO2、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-ORa、-SRa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa,和-OC(=O)NRaRb;
Ra和Rb独立地为-H、卤素、氨基、烷基或卤代烷基;和
Rc为-H、C1-C3烷基或环丙基。
5.根据权利要求4所述的化合物,其特征在于,R3为氟代环丙基并且R6为吲哚基,吲哚基任选地被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、卤代烷基、羟烷基、氨基烷基和叔丁氧基羰基。
6.根据权利要求1-5中任一项所述的化合物,其特征在于,其选自:
(2-氨基-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-6-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-7-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-8-氟-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氯-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-8-氟-6-(1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-甲基-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氟-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氯-1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(6-氟-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(6-氟-5-甲基-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1R,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1R,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2R)-2-氟环丙基)甲酮;
3-(2-氨基-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-6-基)-1H-吲哚-1-羧酸叔丁酯;和
(2-氨基-6-(1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮。
7.根据权利要求1-5中任一项所述的化合物,其特征在于,其选自:
(2-氨基-6-(4-甲基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氯-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(6-氟-5-甲基-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-甲基-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氟-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(6-氟-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;和
(2-氨基-6-(6-氟-5-甲基-1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮。
8.根据权利要求4所述的化合物,其特征在于,R3为氟代环丙基,并且R6选自溴、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、氮杂吲哚基、吲哚基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、硫代苯基、呋喃基、恶唑基、噻唑基、恶二唑基、噻二唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、咪唑并吡啶基、咪唑并嘧啶基、咪唑并吡嗪基、吡咯并三嗪基、吡唑并吡啶基、咪唑并三嗪基、嘌呤基、吲唑基、苯并呋喃基、苯并噻吩、苯并恶唑啉基、苯并噻唑啉基、苯并咪唑基、氧代吲哚啉基、喹啉基、氮杂喹啉基、异喹啉基、氮杂异喹啉基、喹唑啉基、氮杂喹唑啉基、喹喔啉基、氮杂喹喔啉基、萘基,其中R6任选被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、氨基烷基、烷基氨基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基和烷氧基烯基。
9.根据权利要求8所述的化合物,其特征在于,其选自:
(2-氨基-6-溴咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2,3-二甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2,5-二甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2,4-二甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-氟-6-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-甲基-3-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-氟-6-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-甲基噻唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-甲基噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(噻唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3,4-二氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-氯苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2R)-2-氟环丙基)甲酮;
1-(4-(2-氨基-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-6-基)-3-甲基苯基)乙烷-1-酮;
(2-氨基-6-(4-吗啉苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-氯-3-氟苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-甲基-5-(三氟甲基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(S)-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(2,2-二氟环丙基)甲酮;
(2-氨基-6-(4-(哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(7-(二甲基氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(苯并呋喃-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氯-7-(二甲基氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氟-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-甲基异噻唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吲唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氯-1H-吲唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-吲唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-8-氟-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-8-氟-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-苯并[d]咪唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-甲基-1H-苯并[d]咪唑-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H吡咯并[2,3-b]吡啶-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1,4-二甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
2-氨基-6-(3-氟-2-甲基苯基)-N-((1R,2S)-2-氟环丙基)咪唑并[1,2-a]吡啶-3-甲酰胺;
(2-氨基-6-(1H吡咯并[2,3-b]吡啶-3-基)咪唑并[1,2-a]吡啶-3-烷基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(喹啉-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(喹啉-3-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(异喹啉-4-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(邻甲苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;(2-氨基-6-(2-(2-氟乙氧基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(2-氟乙氧基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
2-(2-氨基-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-6-基)-1H-吡咯-1-羧酸叔丁酯;
3-(2-氨基-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-6-基)-1H-吡咯-1-羧酸叔丁酯;
(2-氨基-6-(3-氟-2-(3-羟丙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吡咯-2-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(1H-吡咯-3-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(2-羟乙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(羟甲基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(2-羟乙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(3-羟丙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(2-氟乙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(3-氟丙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(3-氟丙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氨基-5-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(4-氨基-2-氟-5-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(2-氟乙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-(2-氨基-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-6-基)苄基)氨基甲酸叔丁酯;
(2-氨基-6-(2-(氨基甲基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(2-氟乙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(2-(2-氟乙基)苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(2-氟乙氧基)苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氨基-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(2-氨基-6-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-((E)-2-甲氧基乙烯基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-乙烯基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氟-2-甲基-3-(甲基氨基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-(二甲基氨基)-5-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-((3-氟-2-甲基苯基)氨基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-氨基-6-(3-氟-2-(2-氟乙氧基)苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2R)-2-氟环丙基)甲酮;
(2-氨基-6-(5-氨基-3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;和
(2-氨基-6-(3-氟-2-甲基苯氧基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮。
10.根据权利要求1至4中任一项所述的化合物,其特征在于,R3为环丙基并且R6选自选自溴、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、氮杂吲哚基、吲哚基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、硫代苯基、呋喃基、恶唑基、噻唑基、恶二唑基、噻二唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、咪唑并吡啶基、咪唑并嘧啶基、咪唑并吡嗪基、吡咯三嗪基、吡唑并吡啶基、咪唑并三嗪基、嘌呤基、吲唑基、苯并呋喃基、苯并噻吩、苯并恶唑啉基、苯并噻唑啉基、苯并咪唑基、氧代吲哚啉基、喹啉基、氮杂喹啉基、异喹啉基、氮杂异喹啉基、喹唑啉基、氮杂喹唑啉基、喹喔啉基、氮杂喹喔啉基、萘基,其中R6任选被一个或多个基团取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、氨基烷基、烷基氨基、三甲基甲硅烷基乙氧基甲基、吗啉基、哌嗪基、甲基哌嗪基和烷氧基烯基。
11.根据权利要求10所述的化合物,其特征在于,其选自:
(2-氨基-6-溴咪唑并[1,2-a]吡啶-3-基)(环丙基)甲酮;
(2-氨基-6-(4-甲基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基](环丙基)甲酮;
(2-氨基-6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-基)(环丙基)甲酮;和
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(环丙基)甲酮。
12.根据权利要求1至4中任一项所述的化合物,其特征在于,R3选自甲基、异丙基、丁基、甲氧基、吡啶基、苯基、环丁基、吡唑基、氮杂环丁基、嘧啶基、吡咯烷基、环丙基氨基和吲唑基,其中R3任选被一个或多个基团取代,这一个或多个基团选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基。
13.根据权利要求12所述的化合物,其特征在于,其选自:
1-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)乙烷-1-酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(吡啶-2-基)甲酮;(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(苯基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(环丁基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(1-甲基-1H-吡唑-4-基)甲酮;
1-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)-2,2-二甲基丙烷-1-酮;
1-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)戊烷-1-酮;
2-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-羰基)氮杂环丁烷-1-羧酸叔丁酯;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(3,3-二氟环丁基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(氮杂环丁烷-2-基)甲酮;
3-(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-羰基)氮杂环丁烷-1-羧酸叔丁酯;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(氮杂环丁烷-3-基)甲酮;
(2-氨基-6-(1H-吲哚-5-基)咪唑并[1,2-a]吡啶-3-基)(吡啶-2-基)甲酮;
(2-氨基-6-(1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(吡啶-2-基)甲酮;
(2-氨基-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(吡啶-2-基)甲酮;
(2-氨基-6-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(吡啶-2-基)甲酮;
(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(嘧啶-2-基)甲酮;(2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)(嘧啶-4-基)甲酮;(2-氨基-6-(1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(嘧啶-4-基)甲酮;
(2-氨基-6-(1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(嘧啶-2-基)甲酮;
(2-氨基-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(氮杂环丁烷-3-基)甲酮;
(2-氨基-6-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(氮杂环丁烷-3-基)甲酮;
(2-氨基-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(嘧啶-4-基)甲酮;
(2-氨基-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(嘧啶-2-基)甲酮;
(2-氨基-6-(1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(氮杂环丁烷-3-基)甲酮;
(2-氨基-6-(1H吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(吡咯烷-3-基)甲酮;
(2-氨基-6-(4-甲基-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(吡咯烷-3-基)甲酮;
(2-氨基-6-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)咪唑并[1,2-a]吡啶-3-基)(吡咯烷-3-基)甲酮;
2-氨基-N-环丙基-6-(3-氟-2-甲基苯基)-N-甲基咪唑并[1,2-a]吡啶-3-甲酰胺;2-氨基-N-环丙基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-甲酰胺;
N’-乙酰基-2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-碳酰肼;
2-氨基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-羧酸甲酯;
2-氨基-6-(5-氯-7-(二甲基氨基)-6-氟-1H-吲唑-4-基)-N-环丙基咪唑并[1,2-a]吡啶-3-甲酰胺;和
(3S,4R)-4-甲基四氢呋喃-3-基2-氨基-6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡啶-3-羧酸酯。
14.根据权利要求1所述的化合物,其特征在于,其选自式(III)所示的化合物及其药学上可接受的盐:
其中R3为-H、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-O-环烷基、-O-杂环基、-O-芳基、-O-杂芳基、-NRc-烷基、-NRc-环烷基、-NRc-杂环基、-NRc-芳基、-NRc-杂芳基、-NRc-NRc C(=O)Rc或-CF3,其中每个碳任选地被选自卤素、烷基、羟烷基、卤代烷基和单烷基氨基烷基的一个或多个基团所取代;
R4和R5独立地为-H、-OH、卤素、C1-C6烷基、C1-C6烷氧基、芳基、杂芳基、杂环基或杂烷基、氨基、-SCH3或-CN;
R6选自-H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6碳环基、杂环基、芳基、杂芳基、-NRc-芳基、-NRc-杂芳基、-O-芳基、-O-杂芳基,其中R6任选被一个或多个基团所取代,这一个或多个基团选自卤素、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、三甲基甲硅烷基乙氧基甲基、-NO2、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-ORa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa,和-OC(=O)NRaRb;
Ra和Rb独立地为-H、卤素、氨基、烷基或卤代烷基;
Rc为-H、C1-C3烷基或环丙基。
15.根据权利要求14所述的化合物,其特征在于,其为
(2-氨基-5-(1H-吲哚-4-基)吡唑并[1,5-a]吡啶-3-基)(环丙基)甲酮;
(2-氨基-5-(6-氟-5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]吡啶-3-基)(环丙基)甲酮;或
(2-氨基-5-(3-氟-2-甲基苯基)吡唑并[1,5-a]吡啶-3-基)(环丙基)甲酮。
16.根据权利要求1所述的化合物,其特征在于,R1和R2独立地为-H、烷基、乙酰基、叔丁氧羰基、氨基乙基、二甲基氨基乙基或甲基氨基乙基;或者R1和R2共同形成一个5元杂环。
17.根据权利要求16所述的化合物,其特征在于,其选自:
(2-((2-(二甲基氨基)乙基)氨基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-((2-氨基乙基)氨基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
N-乙酰基-N-(3-乙酰基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)乙酰胺;(6-(3-氟-2-甲基苯基)-2-(甲基氨基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(2-(二甲基氨基)-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-3-基)((1R,2S)-2-氟环丙基)甲酮;
(6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-2-基)氨基甲酸叔丁酯;
(6-(3-氟-2-甲基苯基)-2-(吡咯烷-1-基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
(6-(3-氟-2-甲基苯基)-2-((2-(甲基氨基)乙基)氨基)咪唑并[1,2-a]吡啶-3-基)((1S,2S)-2-氟环丙基)甲酮;
N-(6-(3-氟-2-甲基苯基)-3-((1S,2S)-2-氟环丙烷-1-羰基)咪唑并[1,2-a]吡啶-2-基)乙酰胺;和
N-(3-乙酰基-6-(3-氟-2-甲基苯基)咪唑并[1,2-a]吡啶-2-基)乙酰胺。
18.根据权利要求1至17中任一项所述的化合物,其特征在于,所述盐为盐酸盐、酒石酸盐、磷酸盐或马来酸盐。
19.一种药物组合物,其包含治疗有效量的如权利要求1至17中任一项所述的化合物或其药学上可接受的盐,以及至少一种药学上可接受的载体。
20.根据权利要求19所述的药物组合物,其特征在于,还包含一种或多种可用于治疗神经退行性疾病的活性成分。
21.一种治疗受试者炎症和自身免疫性疾病的方法,包括:
向有此需要的受试者施用治疗有效量的如权利要求1至17中任一项所述的化合物或其药学上可接受的盐。
22.根据权利要求21所述的方法,其特征在于,所述炎症和自身免疫性疾病为神经炎症疾病。
23.根据权利要求21或22所述的方法,其特征在于,所述神经炎症疾病为α-突触核蛋白病、帕金森病、路易体痴呆、多系统萎缩症(MSA)、阿尔茨海默病或肌萎缩侧索硬化症(ALS)。
24.根据权利要求21至23中任一项所述的方法,其特征在于,所述受试者为人。
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US4097483A (en) | 1974-11-01 | 1978-06-27 | Kyorin Pharmaceutical Co., Ltd. | Pyrazolo 1,5-a!pyridines |
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US20130331378A1 (en) | 2011-01-26 | 2013-12-12 | Kissei Pharmaceutical Co., Ltd. | Pyrazolopyridine derivative or pharmacologically acceptable salt thereof |
US20150158868A1 (en) | 2013-12-06 | 2015-06-11 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
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