HUE035019T2 - New imidazole amines as modulators of kinase activity - Google Patents

Info

Publication number

HUE035019T2

HUE035019T2 HUE12761865A HUE12761865A HUE035019T2 HU E035019 T2 HUE035019 T2 HU E035019T2 HU E12761865 A HUE12761865 A HU E12761865A HU E12761865 A HUE12761865 A HU E12761865A HU E035019 T2 HUE035019 T2 HU E035019T2

Authority

HU

Hungary

Prior art keywords

imidazol

fluoro

piperidin

phenyl

trifluoromethyl

Prior art date

2011-09-12

Links

• Espacenet
• Global Dossier
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• -1 imidazole amines Chemical class 0.000 title description 111
• 230000000694 effects Effects 0.000 title description 10
• 108091000080 Phosphotransferase Proteins 0.000 title description 7
• 102000020233 phosphotransferase Human genes 0.000 title description 7
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims description 523
• 125000004429 atom Chemical group 0.000 claims description 63
• 150000003839 salts Chemical class 0.000 claims description 54
• 239000012453 solvate Substances 0.000 claims description 48
• 230000009021 linear effect Effects 0.000 claims description 46
• 125000004432 carbon atom Chemical group C* 0.000 claims description 44
• 238000006243 chemical reaction Methods 0.000 claims description 31
• 238000000034 method Methods 0.000 claims description 29
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 206010028980 Neoplasm Diseases 0.000 claims description 25
• 239000002253 acid Substances 0.000 claims description 21
• 201000011510 cancer Diseases 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 21
• 239000000460 chlorine Substances 0.000 claims description 19
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 19
• 229910052801 chlorine Inorganic materials 0.000 claims description 18
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 125000000623 heterocyclic group Chemical group 0.000 claims description 15
• 125000003118 aryl group Chemical group 0.000 claims description 14
• 239000004480 active ingredient Substances 0.000 claims description 12
• 125000001931 aliphatic group Chemical group 0.000 claims description 7
• 230000008569 process Effects 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
• 239000000651 prodrug Substances 0.000 claims description 5
• 229940002612 prodrug Drugs 0.000 claims description 5
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 125000002950 monocyclic group Chemical group 0.000 claims description 4
• 239000000126 substance Substances 0.000 claims description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
• 210000004556 brain Anatomy 0.000 claims description 3
• 230000011664 signaling Effects 0.000 claims description 3
• 150000001298 alcohols Chemical class 0.000 claims description 2
• 239000011780 sodium chloride Substances 0.000 claims description 2
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
• 230000036528 appetite Effects 0.000 claims 3
• 235000019789 appetite Nutrition 0.000 claims 3
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
• 206010052428 Wound Diseases 0.000 claims 2
• 208000027418 Wounds and injury Diseases 0.000 claims 2
• BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims 2
• BFTGQIQVUVTBJU-UHFFFAOYSA-N 5,6-dihydroimidazo[2,1-c][1,2,4]dithiazole-3-thione Chemical compound C1CN2C(=S)SSC2=N1 BFTGQIQVUVTBJU-UHFFFAOYSA-N 0.000 claims 1
• 241000251468 Actinopterygii Species 0.000 claims 1
• 206010011906 Death Diseases 0.000 claims 1
• RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims 1
• 241000764238 Isis Species 0.000 claims 1
• 239000004472 Lysine Substances 0.000 claims 1
• LTGPFZWZZNUIIK-LURJTMIESA-N Lysol Chemical compound NCCCC[C@H](N)CO LTGPFZWZZNUIIK-LURJTMIESA-N 0.000 claims 1
• 108091060294 Messenger RNP Proteins 0.000 claims 1
• 101100011750 Mus musculus Hsp90b1 gene Proteins 0.000 claims 1
• 240000009164 Petroselinum crispum Species 0.000 claims 1
• 240000004808 Saccharomyces cerevisiae Species 0.000 claims 1
• 101100296591 Schizosaccharomyces pombe (strain 972 / ATCC 24843) pck2 gene Proteins 0.000 claims 1
• 241001342990 Xylia Species 0.000 claims 1
• LUTSRLYCMSCGCS-BWOMAWGNSA-N [(3s,8r,9s,10r,13s)-10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,16-decahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(=O)CC=C3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 LUTSRLYCMSCGCS-BWOMAWGNSA-N 0.000 claims 1
• 150000005840 aryl radicals Chemical class 0.000 claims 1
• 210000005252 bulbus oculi Anatomy 0.000 claims 1
• 125000004122 cyclic group Chemical group 0.000 claims 1
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
• GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims 1
• 235000013305 food Nutrition 0.000 claims 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims 1
• 238000007654 immersion Methods 0.000 claims 1
• 230000000968 intestinal effect Effects 0.000 claims 1
• 239000006166 lysate Substances 0.000 claims 1
• 239000008267 milk Substances 0.000 claims 1
• 210000004080 milk Anatomy 0.000 claims 1
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• 108020004707 nucleic acids Proteins 0.000 claims 1
• 150000007523 nucleic acids Chemical class 0.000 claims 1
• 102000039446 nucleic acids Human genes 0.000 claims 1
• 230000000474 nursing effect Effects 0.000 claims 1
• 235000011197 perejil Nutrition 0.000 claims 1
• 238000000554 physical therapy Methods 0.000 claims 1
• 150000003254 radicals Chemical class 0.000 claims 1
• 229910052710 silicon Inorganic materials 0.000 claims 1
• 239000010703 silicon Substances 0.000 claims 1
• 238000006884 silylation reaction Methods 0.000 claims 1
• 101150117196 tra-1 gene Proteins 0.000 claims 1
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 421
• QPFXUEVSBFKNJV-UHFFFAOYSA-N 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidine Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 QPFXUEVSBFKNJV-UHFFFAOYSA-N 0.000 description 120
• SWAZPZDRQOTKRL-UHFFFAOYSA-N 5-bromo-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1Br SWAZPZDRQOTKRL-UHFFFAOYSA-N 0.000 description 114
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 68
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
• LPZBVVARVJQTAW-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C#N LPZBVVARVJQTAW-UHFFFAOYSA-N 0.000 description 55
• 239000011541 reaction mixture Substances 0.000 description 54
• LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 49
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
• ODHFZINJDDSFIB-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]pyrimidine-5-carboxamide Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C(N)=O ODHFZINJDDSFIB-UHFFFAOYSA-N 0.000 description 47
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 47
• 239000000203 mixture Substances 0.000 description 47
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 41
• 239000007787 solid Substances 0.000 description 35
• RYMJKFCEWNTOSX-UHFFFAOYSA-N 5-(4-fluorophenyl)-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C1=CC=C(F)C=C1 RYMJKFCEWNTOSX-UHFFFAOYSA-N 0.000 description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 34
• 239000000243 solution Substances 0.000 description 34
• KGAVPNAQEZTLRD-UHFFFAOYSA-N 6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-[5-(trifluoromethyl)pyridin-3-yl]imidazol-2-yl]piperidin-1-yl]-5-ethylpyrimidin-4-amine Chemical compound CCC1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C=NC=2)C(F)(F)F)CCN2CCC2)CC1 KGAVPNAQEZTLRD-UHFFFAOYSA-N 0.000 description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 29
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• 125000004076 pyridyl group Chemical group 0.000 description 27
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• 239000000047 product Substances 0.000 description 23
• GAYRMKRSQCSTHF-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-pyrrolidin-3-ylimidazol-2-yl]piperidin-1-yl]pyrimidine-5-carboxamide Chemical compound NC(=O)C1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C(F)=CC=2)C(F)(F)F)C2CNCC2)CC1 GAYRMKRSQCSTHF-UHFFFAOYSA-N 0.000 description 22
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• 238000004128 high performance liquid chromatography Methods 0.000 description 21
• 239000000543 intermediate Substances 0.000 description 20
• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 18
• 229910000024 caesium carbonate Inorganic materials 0.000 description 18
• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 18
• 239000002904 solvent Substances 0.000 description 18
• IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 17
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
• AHRQYOSAXZQCIG-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=C=NC=N[CH]1 AHRQYOSAXZQCIG-UHFFFAOYSA-N 0.000 description 17
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
• PDWXUDFNTMNSTQ-UHFFFAOYSA-N 6-[4-[1-[2-(cyclopropylamino)ethyl]-4-(4-fluoro-3-methylphenyl)imidazol-2-yl]piperidin-1-yl]-5-(1h-pyrazol-4-yl)pyrimidin-4-amine Chemical compound C1=C(F)C(C)=CC(C=2N=C(N(CCNC3CC3)C=2)C2CCN(CC2)C=2C(=C(N)N=CN=2)C2=CNN=C2)=C1 PDWXUDFNTMNSTQ-UHFFFAOYSA-N 0.000 description 14
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
• 241000124008 Mammalia Species 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 description 14
• 238000002360 preparation method Methods 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
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• ZRPHGTIRAHPTKO-UHFFFAOYSA-N 4-[1-[2-(azetidin-1-yl)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1C(N=C1C2CCNCC2)=CN1CCN1CCC1 ZRPHGTIRAHPTKO-UHFFFAOYSA-N 0.000 description 13
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• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 13
• HZKGNCGVQYKAAX-UHFFFAOYSA-N 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1C(N=C1C2CCNCC2)=CN1CCN1CCCC1 HZKGNCGVQYKAAX-UHFFFAOYSA-N 0.000 description 12
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• 239000008194 pharmaceutical composition Substances 0.000 description 11
• 238000002953 preparative HPLC Methods 0.000 description 11
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• 125000001424 substituent group Chemical group 0.000 description 10
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• FCQRMTUOEPBUDU-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine Chemical compound C1=CC(F)=CC=C1C(N=C1C2CCNCC2)=CN1CCN1CCCC1 FCQRMTUOEPBUDU-UHFFFAOYSA-N 0.000 description 7
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• DQSBRYJETNYGCI-UHFFFAOYSA-N 5-bromo-6-chloropyrimidin-4-amine Chemical compound NC1=NC=NC(Cl)=C1Br DQSBRYJETNYGCI-UHFFFAOYSA-N 0.000 description 7
• GFQGRBHYPKIIRV-UHFFFAOYSA-N 6-chloro-5-ethylpyrimidin-4-amine Chemical compound CCC1=C(N)N=CN=C1Cl GFQGRBHYPKIIRV-UHFFFAOYSA-N 0.000 description 7
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
• 150000001412 amines Chemical class 0.000 description 7
• 229910052786 argon Inorganic materials 0.000 description 7
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