WO2007082805A1 - Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors - Google Patents
Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors Download PDFInfo
- Publication number
- WO2007082805A1 WO2007082805A1 PCT/EP2007/050136 EP2007050136W WO2007082805A1 WO 2007082805 A1 WO2007082805 A1 WO 2007082805A1 EP 2007050136 W EP2007050136 W EP 2007050136W WO 2007082805 A1 WO2007082805 A1 WO 2007082805A1
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- WO
- WIPO (PCT)
- Prior art keywords
- bis
- chloro
- phenyl
- dihydro
- ethoxy
- Prior art date
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- 239000012819 MDM2-Inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 125000003545 alkoxy group Chemical group 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 21
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 18
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 18
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- PVVXZVITTYNLIH-IOWSJCHKSA-N 2-[4-[(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-1-morpholin-4-ylethanone Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1 PVVXZVITTYNLIH-IOWSJCHKSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 230000003993 interaction Effects 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 7
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 238000003821 enantio-separation Methods 0.000 claims description 5
- 239000011737 fluorine Chemical group 0.000 claims description 5
- 229910052731 fluorine Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- -1 ethoxy, isopropoxy Chemical group 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- ANUBQOWOEIFOCJ-XZWHSSHBSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(2-ethoxypyridin-3-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-1-morpholin-4-ylethanone Chemical compound CCOC1=NC=CC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1 ANUBQOWOEIFOCJ-XZWHSSHBSA-N 0.000 claims description 3
- BBURSNGPNNXZBY-WUFINQPMSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(2-ethoxypyridin-3-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n,n-dimethylacetamide Chemical compound CCOC1=NC=CC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1 BBURSNGPNNXZBY-WUFINQPMSA-N 0.000 claims description 3
- FQSCZFHMPZKFPA-URLMMPGGSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-1-morpholin-4-ylethanone Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)=C1OCC FQSCZFHMPZKFPA-URLMMPGGSA-N 0.000 claims description 3
- BMPLFFGITZVCDB-IOWSJCHKSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n,n-bis(2-methoxyethyl)acetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)N(CCOC)CCOC)CC2)=C1OCC BMPLFFGITZVCDB-IOWSJCHKSA-N 0.000 claims description 3
- AUCYFLMSVPKIHP-BQTLCQCVSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n-(1-methoxypropan-2-yl)acetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)NC(C)COC)CC2)=C1OCC AUCYFLMSVPKIHP-BQTLCQCVSA-N 0.000 claims description 3
- BXKALESCEUCENS-URLMMPGGSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n-(2-cyanoethyl)-n-methylacetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)N(C)CCC#N)CC2)=C1OCC BXKALESCEUCENS-URLMMPGGSA-N 0.000 claims description 3
- QKIYWLBZEVPFFM-RRPNLBNLSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n-methoxy-n-methylacetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)N(C)OC)CC2)=C1OCC QKIYWLBZEVPFFM-RRPNLBNLSA-N 0.000 claims description 3
- JMAUGCYRNWSXKB-URLMMPGGSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n-methyl-n-propan-2-ylacetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)N(C)C(C)C)CC2)=C1OCC JMAUGCYRNWSXKB-URLMMPGGSA-N 0.000 claims description 3
- VWMPHUCGQIYXNE-WUFINQPMSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n-tert-butylacetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(=O)NC(C)(C)C)CC2)=C1OCC VWMPHUCGQIYXNE-WUFINQPMSA-N 0.000 claims description 3
- CXSPLDJANPLGTQ-LOSJGSFVSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]acetamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC(N)=O)CC2)=C1OCC CXSPLDJANPLGTQ-LOSJGSFVSA-N 0.000 claims description 3
- JXCDGNQSEATOOW-RRPNLBNLSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(4-ethoxy-2-methylsulfanylpyrimidin-5-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-n,n-dimethylacetamide Chemical compound CCOC1=NC(SC)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1 JXCDGNQSEATOOW-RRPNLBNLSA-N 0.000 claims description 3
- UJDMWMZJYDECAI-WUFINQPMSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-[4-ethoxy-2-(trifluoromethyl)pyrimidin-5-yl]-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-1-morpholin-4-ylethanone Chemical compound CCOC1=NC(C(F)(F)F)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1 UJDMWMZJYDECAI-WUFINQPMSA-N 0.000 claims description 3
- XPZGWKIAYANWCX-LOSJGSFVSA-N 4-[(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CC(=O)NCC1 XPZGWKIAYANWCX-LOSJGSFVSA-N 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- INZVVEULORRXRB-IZZNHLLZSA-N [(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazol-1-yl]-(4-methylpiperazin-1-yl)methanone Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(C)CC1 INZVVEULORRXRB-IZZNHLLZSA-N 0.000 claims description 3
- APYXNSUSOYWZBJ-XZWHSSHBSA-N [(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazol-1-yl]-(4-pyrrolidin-1-ylpiperidin-1-yl)methanone Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCC(N2CCCC2)CC1 APYXNSUSOYWZBJ-XZWHSSHBSA-N 0.000 claims description 3
- DIASRMDOXVBRGS-URLMMPGGSA-N [(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1 DIASRMDOXVBRGS-URLMMPGGSA-N 0.000 claims description 3
- ZIZCGXQKKDWXLN-WUFINQPMSA-N [(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazol-1-yl]-[4-(dimethylamino)piperidin-1-yl]methanone Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCC(N(C)C)CC1 ZIZCGXQKKDWXLN-WUFINQPMSA-N 0.000 claims description 3
- UNZQNUHUVZKIOT-RRPNLBNLSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(2,4-diethoxypyrimidin-5-yl)-4,5-dihydroimidazol-1-yl]-[4-(2-methylsulfonylethyl)piperazin-1-yl]methanone Chemical compound CCOC1=NC(OCC)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1 UNZQNUHUVZKIOT-RRPNLBNLSA-N 0.000 claims description 3
- WTSLAMQJHPVJNX-LOSJGSFVSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazol-1-yl]-(4-ethylsulfonylpiperazin-1-yl)methanone Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC2)S(=O)(=O)CC)=C1OCC WTSLAMQJHPVJNX-LOSJGSFVSA-N 0.000 claims description 3
- OBFFIPPSRQMASO-IZZNHLLZSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazol-1-yl]-[4-(2-methylsulfonylethyl)piperazin-1-yl]methanone Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CCS(C)(=O)=O)CC2)=C1OCC OBFFIPPSRQMASO-IZZNHLLZSA-N 0.000 claims description 3
- SVBWBTDLQPSRAF-RRPNLBNLSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CCCS(C)(=O)=O)CC2)=C1OCC SVBWBTDLQPSRAF-RRPNLBNLSA-N 0.000 claims description 3
- YYEILWPPWQPSRX-RRPNLBNLSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(4-ethoxy-2-methylpyrimidin-5-yl)-4,5-dihydroimidazol-1-yl]-[4-(2-methylsulfonylethyl)piperazin-1-yl]methanone Chemical compound CCOC1=NC(C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1 YYEILWPPWQPSRX-RRPNLBNLSA-N 0.000 claims description 3
- NFFDLGKCBWKZRR-IZZNHLLZSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(4-ethoxy-2-methylsulfanylpyrimidin-5-yl)-4,5-dihydroimidazol-1-yl]-[4-(2-methylsulfonylethyl)piperazin-1-yl]methanone Chemical compound CCOC1=NC(SC)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1 NFFDLGKCBWKZRR-IZZNHLLZSA-N 0.000 claims description 3
- BWARELALGBCBIF-LOSJGSFVSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-[4-ethoxy-2-(trifluoromethyl)pyrimidin-5-yl]-4,5-dihydroimidazol-1-yl]-[4-(2-methylsulfonylethyl)piperazin-1-yl]methanone Chemical compound CCOC1=NC(C(F)(F)F)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1 BWARELALGBCBIF-LOSJGSFVSA-N 0.000 claims description 3
- QNQZCGYPMWAJSH-WUFINQPMSA-N [4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-(3,5-dimethyl-1,2-oxazol-4-yl)methanone Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CC2)C(=O)C2=C(ON=C2C)C)=C1OCC QNQZCGYPMWAJSH-WUFINQPMSA-N 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
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- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 208000037841 lung tumor Diseases 0.000 claims description 3
- NVPMSTGDKJNDLE-IZZNHLLZSA-N n-[2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(3-ethoxythiophen-2-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]ethyl]methanesulfonamide Chemical compound C1=CSC(C=2N([C@@H]([C@@H](N=2)C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CCNS(C)(=O)=O)CC2)=C1OCC NVPMSTGDKJNDLE-IZZNHLLZSA-N 0.000 claims description 3
- 208000023958 prostate neoplasm Diseases 0.000 claims description 3
- XFGWLMFBRUBNCD-RRPNLBNLSA-N 1-[4-[(4s,5r)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]ethanone Chemical compound CCOC1=NC(C(C)(C)C)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(C(C)=O)CC1 XFGWLMFBRUBNCD-RRPNLBNLSA-N 0.000 claims description 2
- NRZDSQQKLXURGB-URLMMPGGSA-N 2-[4-[(4s,5r)-4,5-bis(4-chlorophenyl)-2-(4-ethoxy-2-methylsulfanylpyrimidin-5-yl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]-1-morpholin-4-ylethanone Chemical compound CCOC1=NC(SC)=NC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1 NRZDSQQKLXURGB-URLMMPGGSA-N 0.000 claims description 2
- CUMCMYMKECWGHO-UHFFFAOYSA-N 3-methyl-1,2-oxazole Chemical compound CC=1C=CON=1 CUMCMYMKECWGHO-UHFFFAOYSA-N 0.000 claims description 2
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- RDMGHFFQFTYQMF-RRPNLBNLSA-N [(4s,5r)-4,5-bis(4-chlorophenyl)-2-(2-ethoxypyridin-3-yl)-4,5-dihydroimidazol-1-yl]-[4-(2-methylsulfonylethyl)piperazin-1-yl]methanone Chemical compound CCOC1=NC=CC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1 RDMGHFFQFTYQMF-RRPNLBNLSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 238000004519 manufacturing process Methods 0.000 claims 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07703687A EP1979338A1 (en) | 2006-01-18 | 2007-01-08 | Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors |
AU2007207052A AU2007207052B2 (en) | 2006-01-18 | 2007-01-08 | CIS-4, 5-biaryl-2-heterocyclic-imidazolines as MDM2 inhibitors |
JP2008550710A JP2009523751A (en) | 2006-01-18 | 2007-01-08 | Cis-4,5-biaryl-2-heterocyclic-imidazoline as an MDM2 inhibitor |
CA002636824A CA2636824A1 (en) | 2006-01-18 | 2007-01-08 | Cis-4,5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors |
BRPI0710477-4A BRPI0710477A2 (en) | 2006-01-18 | 2007-01-08 | cis-4,5-biaryl - 2-heterocyclic imidazolines as mdm2 inhibitors |
CN2007800022507A CN101370799B (en) | 2006-01-18 | 2007-01-08 | Cis-4, 5-biaryl-2-heterocyclic-imidazolines as MDM2 inhibitors |
IL192635A IL192635A0 (en) | 2006-01-18 | 2008-07-03 | Cis-4,5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US75977006P | 2006-01-18 | 2006-01-18 | |
US60/759,770 | 2006-01-18 |
Publications (1)
Publication Number | Publication Date |
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WO2007082805A1 true WO2007082805A1 (en) | 2007-07-26 |
Family
ID=37983391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2007/050136 WO2007082805A1 (en) | 2006-01-18 | 2007-01-08 | Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors |
Country Status (12)
Country | Link |
---|---|
US (1) | US7705007B2 (en) |
EP (1) | EP1979338A1 (en) |
JP (1) | JP2009523751A (en) |
KR (1) | KR101015073B1 (en) |
CN (1) | CN101370799B (en) |
AR (1) | AR059040A1 (en) |
AU (1) | AU2007207052B2 (en) |
BR (1) | BRPI0710477A2 (en) |
CA (1) | CA2636824A1 (en) |
IL (1) | IL192635A0 (en) |
TW (1) | TW200738695A (en) |
WO (1) | WO2007082805A1 (en) |
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WO2008125487A1 (en) * | 2007-04-12 | 2008-10-23 | F. Hoffmann-La Roche Ag | Diphenyl-dihydro-imidazopyridinones |
JP2010540675A (en) * | 2007-10-09 | 2010-12-24 | エフ.ホフマン−ラ ロシュ アーゲー | Chiral cis-imidazoline |
WO2011045257A1 (en) * | 2009-10-14 | 2011-04-21 | F. Hoffmann-La Roche Ag | Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions |
US8084479B2 (en) | 2006-01-18 | 2011-12-27 | Amgen Inc. | Thiazole compounds and methods of use |
WO2017201449A1 (en) | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
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- 2007-01-08 EP EP07703687A patent/EP1979338A1/en not_active Withdrawn
- 2007-01-08 BR BRPI0710477-4A patent/BRPI0710477A2/en not_active IP Right Cessation
- 2007-01-08 CA CA002636824A patent/CA2636824A1/en not_active Abandoned
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- 2007-01-08 WO PCT/EP2007/050136 patent/WO2007082805A1/en active Application Filing
- 2007-01-08 AU AU2007207052A patent/AU2007207052B2/en not_active Expired - Fee Related
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- 2007-01-16 AR ARP070100184A patent/AR059040A1/en not_active Application Discontinuation
- 2007-01-17 US US11/654,102 patent/US7705007B2/en not_active Expired - Fee Related
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Cited By (10)
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US8084479B2 (en) | 2006-01-18 | 2011-12-27 | Amgen Inc. | Thiazole compounds and methods of use |
WO2008125487A1 (en) * | 2007-04-12 | 2008-10-23 | F. Hoffmann-La Roche Ag | Diphenyl-dihydro-imidazopyridinones |
US7625895B2 (en) | 2007-04-12 | 2009-12-01 | Hoffmann-Le Roche Inc. | Diphenyl-dihydro-imidazopyridinones |
JP2010540675A (en) * | 2007-10-09 | 2010-12-24 | エフ.ホフマン−ラ ロシュ アーゲー | Chiral cis-imidazoline |
WO2011045257A1 (en) * | 2009-10-14 | 2011-04-21 | F. Hoffmann-La Roche Ag | Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions |
US8017607B2 (en) | 2009-10-14 | 2011-09-13 | Hoffmann-La Roche Inc. | N-substituted-pyrrolidines as inhibitors of MDM2-P-53 interactions |
WO2017201449A1 (en) | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
US9988368B1 (en) | 2017-06-16 | 2018-06-05 | Unity Biotechnology, Inc. | Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use |
US10329279B2 (en) | 2017-06-16 | 2019-06-25 | Unity Biotechnology, Inc. | Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use |
WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
Also Published As
Publication number | Publication date |
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TW200738695A (en) | 2007-10-16 |
CA2636824A1 (en) | 2007-07-26 |
KR20080085045A (en) | 2008-09-22 |
US20070167437A1 (en) | 2007-07-19 |
KR101015073B1 (en) | 2011-02-16 |
BRPI0710477A2 (en) | 2011-08-16 |
US7705007B2 (en) | 2010-04-27 |
AU2007207052A1 (en) | 2007-07-26 |
EP1979338A1 (en) | 2008-10-15 |
IL192635A0 (en) | 2009-02-11 |
AR059040A1 (en) | 2008-03-12 |
AU2007207052B2 (en) | 2012-07-12 |
JP2009523751A (en) | 2009-06-25 |
CN101370799B (en) | 2012-09-05 |
CN101370799A (en) | 2009-02-18 |
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