RU2012143689A - Спироциклические соединения и их применение в качестве терапевтических агентов и диагностических зондов - Google Patents
Спироциклические соединения и их применение в качестве терапевтических агентов и диагностических зондов Download PDFInfo
- Publication number
- RU2012143689A RU2012143689A RU2012143689/04A RU2012143689A RU2012143689A RU 2012143689 A RU2012143689 A RU 2012143689A RU 2012143689/04 A RU2012143689/04 A RU 2012143689/04A RU 2012143689 A RU2012143689 A RU 2012143689A RU 2012143689 A RU2012143689 A RU 2012143689A
- Authority
- RU
- Russia
- Prior art keywords
- oxa
- heptan
- morpholino
- azaspiro
- triazin
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract 17
- 239000003814 drug Substances 0.000 title 1
- 239000000523 sample Substances 0.000 title 1
- 229940124597 therapeutic agent Drugs 0.000 title 1
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract 26
- 239000001257 hydrogen Substances 0.000 claims abstract 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 18
- 150000002431 hydrogen Chemical group 0.000 claims abstract 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract 12
- 150000002367 halogens Chemical group 0.000 claims abstract 12
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract 7
- 125000004452 carbocyclyl group Chemical group 0.000 claims abstract 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract 6
- -1 methacryloyl Chemical group 0.000 claims 172
- 125000001072 heteroaryl group Chemical group 0.000 claims 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 12
- 125000003118 aryl group Chemical group 0.000 claims 11
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 9
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 7
- 125000000623 heterocyclic group Chemical group 0.000 claims 7
- 125000005647 linker group Chemical group 0.000 claims 7
- 150000003839 salts Chemical class 0.000 claims 7
- 239000012453 solvate Substances 0.000 claims 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 6
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims 6
- 150000001413 amino acids Chemical class 0.000 claims 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 6
- 125000004076 pyridyl group Chemical group 0.000 claims 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 4
- YLXFUFFEENJTSM-WLRTZDKTSA-N (e)-3-[[6-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-n,n-dimethylprop-2-en-1-amine Chemical compound C1N(S(=O)(=O)/C=C/CN(C)C)CC11CN(C=2N=C(N=C(N=2)N2CCOCC2)N2C3=CC=CC=C3N=C2C(F)F)C1 YLXFUFFEENJTSM-WLRTZDKTSA-N 0.000 claims 4
- OQEYBFLDTBSKDT-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]phenyl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CCOCC2)C=C1 OQEYBFLDTBSKDT-UHFFFAOYSA-N 0.000 claims 4
- SLWFMROOKYNKCW-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-yl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CCOCC2)C=N1 SLWFMROOKYNKCW-UHFFFAOYSA-N 0.000 claims 4
- SWVYUIBQZQZMIE-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyrimidin-2-yl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=NC=C(C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CCOCC2)C=N1 SWVYUIBQZQZMIE-UHFFFAOYSA-N 0.000 claims 4
- ZYKTZBLUXBSTGQ-UHFFFAOYSA-N 1-[6-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-chloroethanone Chemical compound C1=NC(N)=NC=C1C1=NC(N2CC3(CN(C3)C(=O)CCl)C2)=NC(N2CCOCC2)=N1 ZYKTZBLUXBSTGQ-UHFFFAOYSA-N 0.000 claims 4
- RCZNKLPZXMBEOE-UHFFFAOYSA-N 1-[6-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,6-diazaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound C1=NC(N)=NC=C1C1=NC(N2CC3(CN(C3)C(=O)C=C)C2)=NC(N2CCOCC2)=N1 RCZNKLPZXMBEOE-UHFFFAOYSA-N 0.000 claims 4
- XZPIJSOWXMUXIA-UHFFFAOYSA-N 1-[6-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,6-diazaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CC3(CN(C3)C(=O)C=C)C2)=NC=1N1CCOCC1 XZPIJSOWXMUXIA-UHFFFAOYSA-N 0.000 claims 4
- QOFYYRLHGYNMAY-UHFFFAOYSA-N 1-ethyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 QOFYYRLHGYNMAY-UHFFFAOYSA-N 0.000 claims 4
- FHPPGEYXCMHJPN-UHFFFAOYSA-N 1-ethyl-3-[5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-yl]urea Chemical compound C1=NC(NC(=O)NCC)=CC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 FHPPGEYXCMHJPN-UHFFFAOYSA-N 0.000 claims 4
- QKSBOAKCHDBTJX-UHFFFAOYSA-N 1-ethyl-3-[5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyrimidin-2-yl]urea Chemical compound C1=NC(NC(=O)NCC)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 QKSBOAKCHDBTJX-UHFFFAOYSA-N 0.000 claims 4
- WBHVIWTZHKYWMV-UHFFFAOYSA-N 1-methyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 WBHVIWTZHKYWMV-UHFFFAOYSA-N 0.000 claims 4
- JEICYXCIZSODCS-UHFFFAOYSA-N 2,6-dimethoxy-4-[5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]furan-2-yl]phenol Chemical compound COC1=C(O)C(OC)=CC(C=2OC(=CC=2)C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CC3CCC(O3)C2)=C1 JEICYXCIZSODCS-UHFFFAOYSA-N 0.000 claims 4
- MHJOLISBSJBKTP-UHFFFAOYSA-N 2,6-dimethoxy-4-[5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]furan-2-yl]phenol Chemical compound COC1=C(O)C(OC)=CC(C=2OC(=CC=2)C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CCOCC2)=C1 MHJOLISBSJBKTP-UHFFFAOYSA-N 0.000 claims 4
- FGWDPDRVMALKQQ-UHFFFAOYSA-N 4-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-6-[2-(difluoromethyl)benzimidazol-1-yl]-1,3,5-triazin-2-yl]morpholine Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CC3(CNC3)C2)=NC=1N1CCOCC1 FGWDPDRVMALKQQ-UHFFFAOYSA-N 0.000 claims 4
- ZLHFHDYHFFPWEN-UHFFFAOYSA-N 5-[2-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 ZLHFHDYHFFPWEN-UHFFFAOYSA-N 0.000 claims 4
- HDSVYQAJZCEMES-UHFFFAOYSA-N 5-[2-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyrimidin-2-amine Chemical compound FC(F)(F)C1=NC(N)=NC=C1C1=CC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 HDSVYQAJZCEMES-UHFFFAOYSA-N 0.000 claims 4
- RTDVHLWDOSQRBM-UHFFFAOYSA-N 5-[4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]pyrimidin-2-amine Chemical compound C1N(C)CC21CN(C=1N=C(N=C(N=1)N1CCOCC1)C=1C=NC(N)=NC=1)C2 RTDVHLWDOSQRBM-UHFFFAOYSA-N 0.000 claims 4
- CUEVGTVGJCCNLE-UHFFFAOYSA-N 5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 CUEVGTVGJCCNLE-UHFFFAOYSA-N 0.000 claims 4
- NCWCRJGZBXZSFU-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 NCWCRJGZBXZSFU-UHFFFAOYSA-N 0.000 claims 4
- WJLMOWBUJZVEQB-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine Chemical compound FC(F)(F)C1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 WJLMOWBUJZVEQB-UHFFFAOYSA-N 0.000 claims 4
- IHLJZIDKFWNTGW-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine Chemical compound C1=NC(N)=CC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 IHLJZIDKFWNTGW-UHFFFAOYSA-N 0.000 claims 4
- FDCFWOLVSCPZPM-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 FDCFWOLVSCPZPM-UHFFFAOYSA-N 0.000 claims 4
- BENZYCCSYXXLCM-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl]-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=NC(N2CC3(COC3)C2)=CC(N2CCOCC2)=N1 BENZYCCSYXXLCM-UHFFFAOYSA-N 0.000 claims 4
- NYFQPEZMHRTICP-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=CC(N2CCOCC2)=N1 NYFQPEZMHRTICP-UHFFFAOYSA-N 0.000 claims 4
- HQEPONXNCLIYJB-UHFFFAOYSA-N 5-[6-morpholin-4-yl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CC3(COC3)C2)=N1 HQEPONXNCLIYJB-UHFFFAOYSA-N 0.000 claims 4
- ZPOWJPOMPUHKPW-UHFFFAOYSA-N 5-[6-morpholin-4-yl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=CC(N2CCOCC2)=NC(N2CC3(COC3)C2)=N1 ZPOWJPOMPUHKPW-UHFFFAOYSA-N 0.000 claims 4
- PGPHXOGMZSAAHC-UHFFFAOYSA-N 6-[2-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CC3(COC3)C2)=CC=1N1CCOCC1 PGPHXOGMZSAAHC-UHFFFAOYSA-N 0.000 claims 4
- VQVDZAUJPNKGQL-UHFFFAOYSA-N 6-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2-oxa-6-azaspiro[3.3]heptane Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CC3(COC3)C2)=NC=1N1CCOCC1 VQVDZAUJPNKGQL-UHFFFAOYSA-N 0.000 claims 4
- MDOBZNMMEWMZDC-UHFFFAOYSA-N 6-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl]-2-oxa-6-azaspiro[3.3]heptane Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=CC(N2CCOCC2)=NC=1N(C1)CC21COC2 MDOBZNMMEWMZDC-UHFFFAOYSA-N 0.000 claims 4
- SGTSWFVOBPYMTJ-UHFFFAOYSA-N 6-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholin-4-ylpyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=CC(N2CC3(COC3)C2)=NC=1N1CCOCC1 SGTSWFVOBPYMTJ-UHFFFAOYSA-N 0.000 claims 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 4
- 108090001008 Avidin Proteins 0.000 claims 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 4
- 239000005977 Ethylene Substances 0.000 claims 4
- 108010090804 Streptavidin Proteins 0.000 claims 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 4
- PUHKUSYCOPZBGL-UHFFFAOYSA-N [2-methoxy-5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3CC4(COC4)C3)N3CC4CCC(O4)C3)C2=N1 PUHKUSYCOPZBGL-UHFFFAOYSA-N 0.000 claims 4
- PGZSVGZNVSYTHM-CALCHBBNSA-N [5-[4-[(3r,5s)-3,5-dimethylmorpholin-4-yl]-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3CC4(COC4)C3)N3[C@@H](COC[C@@H]3C)C)C2=N1 PGZSVGZNVSYTHM-CALCHBBNSA-N 0.000 claims 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 4
- 229960002685 biotin Drugs 0.000 claims 4
- 235000020958 biotin Nutrition 0.000 claims 4
- 239000011616 biotin Substances 0.000 claims 4
- 239000004202 carbamide Substances 0.000 claims 4
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims 4
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims 4
- 125000002228 disulfide group Chemical group 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 239000003550 marker Substances 0.000 claims 4
- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 claims 4
- HXCNWXXFEHKQMC-UHFFFAOYSA-N n-[2-[2-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,6-diazaspiro[3.3]heptan-6-yl]ethyl]prop-2-enamide Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CC3(CN(CCNC(=O)C=C)C3)C2)=NC=1N1CCOCC1 HXCNWXXFEHKQMC-UHFFFAOYSA-N 0.000 claims 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 150000002829 nitrogen Chemical class 0.000 claims 4
- 239000001301 oxygen Substances 0.000 claims 4
- 239000010802 sludge Substances 0.000 claims 4
- 239000007790 solid phase Substances 0.000 claims 4
- 229910052717 sulfur Inorganic materials 0.000 claims 4
- 239000011593 sulfur Substances 0.000 claims 4
- KTRSMJFXBRUEOW-UHFFFAOYSA-N 1-ethyl-3-[4-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 KTRSMJFXBRUEOW-UHFFFAOYSA-N 0.000 claims 3
- ZOOWSWDXGKELIV-UHFFFAOYSA-N 5-[2-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=CC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 ZOOWSWDXGKELIV-UHFFFAOYSA-N 0.000 claims 3
- FHKRRGHQZSKAQR-UHFFFAOYSA-N 5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine Chemical compound FC(F)(F)C1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=CC(N2CCOCC2)=N1 FHKRRGHQZSKAQR-UHFFFAOYSA-N 0.000 claims 3
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000002541 furyl group Chemical group 0.000 claims 3
- 125000002883 imidazolyl group Chemical group 0.000 claims 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims 3
- 239000002207 metabolite Substances 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- 239000000651 prodrug Substances 0.000 claims 3
- 229940002612 prodrug Drugs 0.000 claims 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 3
- 125000001424 substituent group Chemical group 0.000 claims 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 2
- QMGLZLGYZLHMIE-UHFFFAOYSA-N 1-methyl-3-[4-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 QMGLZLGYZLHMIE-UHFFFAOYSA-N 0.000 claims 2
- CDJKJHUNAOLZSC-UHFFFAOYSA-N 2,6-dimethoxy-4-[1-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]imidazol-4-yl]phenol Chemical compound COC1=C(O)C(OC)=CC(C=2N=CN(C=2)C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CC3CCC(O3)C2)=C1 CDJKJHUNAOLZSC-UHFFFAOYSA-N 0.000 claims 2
- PCCJBPIMDYFIGG-UHFFFAOYSA-N 2,6-dimethoxy-4-[1-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]imidazol-4-yl]phenol Chemical compound COC1=C(O)C(OC)=CC(C=2N=CN(C=2)C=2N=C(N=C(N=2)N2CC3(COC3)C2)N2CCOCC2)=C1 PCCJBPIMDYFIGG-UHFFFAOYSA-N 0.000 claims 2
- VCWVXIDQILXJFE-UHFFFAOYSA-N 3-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=C(N=1)N2CC3CCC(O3)C2)=NC=1N(C1)CC21COC2 VCWVXIDQILXJFE-UHFFFAOYSA-N 0.000 claims 2
- GVPHOBKSUXHPRY-UHFFFAOYSA-N 4-[3-(trifluoromethyl)diazirin-3-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1(C(F)(F)F)N=N1 GVPHOBKSUXHPRY-UHFFFAOYSA-N 0.000 claims 2
- PPRAAQHATXGYBW-UHFFFAOYSA-N 4-methyl-5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine Chemical compound CC1=CC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 PPRAAQHATXGYBW-UHFFFAOYSA-N 0.000 claims 2
- LICNKXQJGKHBKB-UHFFFAOYSA-N 4-methyl-5-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyrimidin-2-amine Chemical compound CC1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CC3CCC(O3)C2)=N1 LICNKXQJGKHBKB-UHFFFAOYSA-N 0.000 claims 2
- MMYZWPPNBQYXHH-UHFFFAOYSA-N 4-methyl-5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine Chemical compound CC1=CC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 MMYZWPPNBQYXHH-UHFFFAOYSA-N 0.000 claims 2
- XHEPEPWLWYVDET-UHFFFAOYSA-N 4-methyl-5-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]pyrimidin-2-amine Chemical compound CC1=NC(N)=NC=C1C1=NC(N2CC3(COC3)C2)=NC(N2CCOCC2)=N1 XHEPEPWLWYVDET-UHFFFAOYSA-N 0.000 claims 2
- CERXSOIRDZZUGF-UHFFFAOYSA-N 5-[4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1N(C)CC21CN(C=1N=C(N=C(N=1)N1CCOCC1)C=1C(=CC(N)=NC=1)C(F)(F)F)C2 CERXSOIRDZZUGF-UHFFFAOYSA-N 0.000 claims 2
- CJUCILOHKFTZRE-UHFFFAOYSA-N 5-[6-morpholin-4-yl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyrimidin-2-amine Chemical compound FC(F)(F)C1=NC(N)=NC=C1C1=CC(N2CCOCC2)=NC(N2CC3(COC3)C2)=N1 CJUCILOHKFTZRE-UHFFFAOYSA-N 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 2
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 2
- 125000001041 indolyl group Chemical group 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- UFWUDFNZMQIODW-UHFFFAOYSA-N n-[3-[4-morpholin-4-yl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl]phenyl]pyridine-3-carboxamide Chemical compound C=1C=CN=CC=1C(=O)NC(C=1)=CC=CC=1C(N=1)=NC(N2CC3(COC3)C2)=NC=1N1CCOCC1 UFWUDFNZMQIODW-UHFFFAOYSA-N 0.000 claims 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 2
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 2
- 125000005504 styryl group Chemical group 0.000 claims 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- XPBBOVRFBHWDGY-UHFFFAOYSA-N NC(N=C1)=NC=C1C1=NC(N(C2)CC22COC2)=NC=C1 Chemical compound NC(N=C1)=NC=C1C1=NC(N(C2)CC22COC2)=NC=C1 XPBBOVRFBHWDGY-UHFFFAOYSA-N 0.000 claims 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims 1
- FAUSIKJSTFZHHX-UHFFFAOYSA-N [2-methoxy-5-[4-morpholin-4-yl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3CC4(COC4)C3)N3CCOCC3)C2=N1 FAUSIKJSTFZHHX-UHFFFAOYSA-N 0.000 claims 1
- 125000004442 acylamino group Chemical group 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 230000003463 hyperproliferative effect Effects 0.000 claims 1
- 125000000842 isoxazolyl group Chemical group 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000003373 pyrazinyl group Chemical group 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000003831 tetrazolyl group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 125000001425 triazolyl group Chemical group 0.000 claims 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 abstract 1
- 101150065749 Churc1 gene Proteins 0.000 abstract 1
- 102100038239 Protein Churchill Human genes 0.000 abstract 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07—ORGANIC CHEMISTRY
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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| GB1004200.0 | 2010-03-15 | ||
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| PCT/IB2011/051047 WO2011114275A1 (en) | 2010-03-15 | 2011-03-11 | Spirocyclic compounds and their use as therapeutic agents and diagnostic probes |
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| UY34632A (es) | 2012-02-24 | 2013-05-31 | Novartis Ag | Compuestos de oxazolidin- 2- ona y usos de los mismos |
| US9296733B2 (en) | 2012-11-12 | 2016-03-29 | Novartis Ag | Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases |
| WO2014141104A1 (en) | 2013-03-14 | 2014-09-18 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh |
| UY35464A (es) | 2013-03-15 | 2014-10-31 | Araxes Pharma Llc | Inhibidores covalentes de kras g12c. |
| WO2014177060A1 (en) * | 2013-05-01 | 2014-11-06 | F.Hoffmann-La Roche Ag | Biheteroaryl compounds and uses thereof |
| CN103483345B (zh) * | 2013-09-25 | 2016-07-06 | 中山大学 | Pi3k激酶抑制剂、包含其的药物组合物及其应用 |
| JO3805B1 (ar) | 2013-10-10 | 2021-01-31 | Araxes Pharma Llc | مثبطات كراس جي12سي |
| CN104557871B (zh) * | 2013-10-28 | 2017-05-03 | 上海汇伦生命科技有限公司 | 具有螺环取代基的芳基吗啉类化合物，其制备方法和用途 |
| AU2015249376C1 (en) | 2014-04-25 | 2019-10-31 | 2Seventy Bio, Inc. | Improved methods for manufacturing adoptive cell therapies |
| WO2015164759A2 (en) | 2014-04-25 | 2015-10-29 | Bluebird Bio, Inc. | Mnd promoter chimeric antigen receptors |
| SG11201610170SA (en) * | 2014-06-06 | 2017-01-27 | Bluebird Bio Inc | Improved t cell compositions |
| CA2956002C (en) | 2014-07-24 | 2023-06-27 | Bluebird Bio, Inc. | Bcma chimeric antigen receptors |
| RU2017118562A (ru) | 2014-10-31 | 2018-11-30 | Индивиор ЮКей Лимитед | Соединения-антагонисты дофаминового d3-рецептора |
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| US11479755B2 (en) | 2015-12-07 | 2022-10-25 | 2Seventy Bio, Inc. | T cell compositions |
| EP3231799A1 (en) * | 2016-04-14 | 2017-10-18 | Universität Basel | 4-(azetidin-1-yl)pyrimidine derivatives with anti-mitotic and anti-proliferative activity |
| JP7093346B2 (ja) | 2016-11-04 | 2022-06-29 | ２セブンティ バイオ インコーポレイテッド | 抗ｂｃｍａ ｃａｒ ｔ細胞組成物 |
| JP2020502224A (ja) * | 2016-12-21 | 2020-01-23 | 日本たばこ産業株式会社 | ヤヌスキナーゼ阻害剤の結晶形 |
| EP3573970A1 (en) | 2017-01-26 | 2019-12-04 | Araxes Pharma LLC | 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer |
| WO2018140512A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused bicyclic benzoheteroaromatic compounds and methods of use thereof |
| EP3573964A1 (en) | 2017-01-26 | 2019-12-04 | Araxes Pharma LLC | Benzothiophene and benzothiazole compounds and methods of use thereof |
| US11279689B2 (en) | 2017-01-26 | 2022-03-22 | Araxes Pharma Llc | 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer |
| US11059819B2 (en) | 2017-01-26 | 2021-07-13 | Janssen Biotech, Inc. | Fused hetero-hetero bicyclic compounds and methods of use thereof |
| JP2020521740A (ja) | 2017-05-25 | 2020-07-27 | アラクセス ファーマ エルエルシー | 変異体ｋｒａｓ、ｈｒａｓまたはｎｒａｓの調節因子としてのキナゾリン誘導体 |
| MX2019013954A (es) | 2017-05-25 | 2020-08-31 | Araxes Pharma Llc | Inhibidores covalentes de kras. |
| RU2771201C2 (ru) * | 2017-11-06 | 2022-04-28 | Медшайн Дискавери Инк. | ПИРИДОПИРИМИДИНОВЫЕ СОЕДИНЕНИЯ, ВЫПОЛНЯЮЩИЕ ФУНКЦИЮ ДВОЙНЫХ ИНГИБИТОРОВ mTORC 1/2 |
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| KR20210045998A (ko) * | 2018-08-01 | 2021-04-27 | 아락세스 파마 엘엘씨 | 헤테로사이클릭 스피로 화합물 및 암 치료를 위한 그의 사용 방법 |
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| CA2445395C (en) * | 2001-04-27 | 2010-03-30 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compound and antitumor agent comprising the same as effective component |
| AU2006217742A1 (en) | 2005-02-25 | 2006-08-31 | Kudos Pharmaceuticals Limited | Hydrazinomethyl, HYDR zonomethyl and 5-membered heterocylic compounds which act as MTOR inhibitors and their use as anti cancer agents |
| GB0525081D0 (en) * | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
| JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | Pi-3 inhibitors and methods of use |
| EP2064203A1 (en) * | 2006-09-14 | 2009-06-03 | AstraZeneca AB | 2-benzimidaz0lyl-6-m0rph0lin0-4-piperidin-4-ylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders |
| WO2008032033A1 (en) | 2006-09-14 | 2008-03-20 | Astrazeneca Ab | 4-benzimidazolyl-2-morpholino-6-piperazinylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders |
| AU2008213808B2 (en) * | 2007-02-06 | 2011-11-10 | Novartis Ag | PI 3-kinase inhibitors and methods of their use |
| GB0721095D0 (en) * | 2007-10-26 | 2007-12-05 | Piramed Ltd | Pharmaceutical compounds |
| ES2548135T3 (es) * | 2008-05-13 | 2015-10-14 | Novartis Ag | Heterociclos condensados que contienen nitrógeno y composiciones de los mismos como inhibidores de quinasa |
| EP2294072B1 (en) | 2008-05-23 | 2017-03-29 | Wyeth LLC | Triazine compounds as p13 kinase and mtor inhibitors |
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2011
- 2011-03-11 BR BR112012023320A patent/BR112012023320A2/pt not_active IP Right Cessation
- 2011-03-11 MX MX2012010655A patent/MX2012010655A/es not_active Application Discontinuation
- 2011-03-11 US US13/635,016 patent/US20130040934A1/en not_active Abandoned
- 2011-03-11 SG SG2012068094A patent/SG184062A1/en unknown
- 2011-03-11 JP JP2012557645A patent/JP2013522286A/ja active Pending
- 2011-03-11 EP EP11715742A patent/EP2547684A1/en not_active Withdrawn
- 2011-03-11 RU RU2012143689/04A patent/RU2012143689A/ru not_active Application Discontinuation
- 2011-03-11 CN CN2011800239958A patent/CN102939292A/zh active Pending
- 2011-03-11 CA CA2791737A patent/CA2791737A1/en not_active Abandoned
- 2011-03-11 NZ NZ602292A patent/NZ602292A/en not_active IP Right Cessation
- 2011-03-11 KR KR1020127026689A patent/KR20130086520A/ko not_active Withdrawn
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| EP2547684A1 (en) | 2013-01-23 |
| CN102939292A (zh) | 2013-02-20 |
| GB201004200D0 (en) | 2010-04-28 |
| CA2791737A1 (en) | 2011-09-22 |
| WO2011114275A1 (en) | 2011-09-22 |
| ZA201206580B (en) | 2013-05-29 |
| US20130040934A1 (en) | 2013-02-14 |
| KR20130086520A (ko) | 2013-08-02 |
| AU2011228703A1 (en) | 2012-09-20 |
| NZ602292A (en) | 2014-08-29 |
| JP2013522286A (ja) | 2013-06-13 |
| SG184062A1 (en) | 2012-10-30 |
| MX2012010655A (es) | 2012-10-05 |
| BR112012023320A2 (pt) | 2016-05-24 |
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