CA2755554C - Pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses - Google Patents

Info

Publication number

CA2755554C

CA2755554C CA2755554A CA2755554A CA2755554C CA 2755554 C CA2755554 C CA 2755554C CA 2755554 A CA2755554 A CA 2755554A CA 2755554 A CA2755554 A CA 2755554A CA 2755554 C CA2755554 C CA 2755554C

Authority

CA

Canada

Prior art keywords

azabicyclo

oxa

phenyl

oct

pyrimidin

Prior art date

2009-04-17

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

Links

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• 150000003230 pyrimidines Chemical class 0.000 title abstract description 5
• 238000003786 synthesis reaction Methods 0.000 title description 20
• 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 title description 12
• 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 229
• 239000000203 mixture Substances 0.000 claims abstract description 153
• 150000003839 salts Chemical class 0.000 claims abstract description 27
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 213
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 196
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 190
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 179
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 168
• 239000004202 carbamide Substances 0.000 claims description 146
• -1 4-pyridyl- Chemical group 0.000 claims description 133
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 60
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 55
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 52
• 125000000623 heterocyclic group Chemical group 0.000 claims description 52
• 229910052757 nitrogen Inorganic materials 0.000 claims description 51
• 108091007960 PI3Ks Proteins 0.000 claims description 50
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 43
• 125000000217 alkyl group Chemical group 0.000 claims description 38
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 35
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 125000001424 substituent group Chemical group 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 34
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 31
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 24
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
• 125000004432 carbon atom Chemical group C* 0.000 claims description 18
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 125000003368 amide group Chemical group 0.000 claims description 14
• 229910052799 carbon Inorganic materials 0.000 claims description 14
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
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• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 12
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
• ULTTYPMRMMDONC-UHFFFAOYSA-N 5-[(2,5-dihydroxyphenyl)methyl-[(2-hydroxyphenyl)methyl]amino]-2-hydroxybenzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(N(CC=2C(=CC=CC=2)O)CC=2C(=CC=C(O)C=2)O)=C1 ULTTYPMRMMDONC-UHFFFAOYSA-N 0.000 claims description 10
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• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
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• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 239000011593 sulfur Chemical group 0.000 claims description 8
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• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
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• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
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• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 6
• VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 6
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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• WWXQFPSJFZXHEE-UHFFFAOYSA-N 1-[4-[4,6-bis(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-methylurea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(N2CC3CCC(O3)C2)=CC(N2CC3CCC(O3)C2)=N1 WWXQFPSJFZXHEE-UHFFFAOYSA-N 0.000 claims 1
• HQDFRJIZSFCGMB-UHFFFAOYSA-N 1-[4-[4,6-bis(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound C=1C=C(C=2N=C(C=C(N=2)N2CC3CCC(O3)C2)N2CC3CCC(O3)C2)C=CC=1NC(=O)NC1=CC=NC=C1 HQDFRJIZSFCGMB-UHFFFAOYSA-N 0.000 claims 1
• JATGKUYTHCYEKX-UHFFFAOYSA-N 1-[4-[4-(2-methylsulfonylethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl]phenyl]-3-pyridin-3-ylurea Chemical compound N=1C(NCCS(=O)(=O)C)=CC(N2C3CCC2COC3)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CN=C1 JATGKUYTHCYEKX-UHFFFAOYSA-N 0.000 claims 1
• FYCHZKJFIJTSTH-UHFFFAOYSA-N 1-[4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea Chemical compound N=1C(NC(C)C)=CC(N2C3COCC2COC3)=NC=1C(C=C1)=CC=C1NC(=O)NC(C=C1)=CC=C1N1CCN(C)CC1 FYCHZKJFIJTSTH-UHFFFAOYSA-N 0.000 claims 1
• WYOGWLUFUUMDGX-UHFFFAOYSA-N 1-[4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]-3-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]urea Chemical compound N=1C(NC(C)C)=CC(N2C3COCC2COC3)=NC=1C(C=C1)=CC=C1NC(=O)NC(C=C1)=CC=C1CN1CCN(C)CC1 WYOGWLUFUUMDGX-UHFFFAOYSA-N 0.000 claims 1
• KTJRELYXAMVFFF-UHFFFAOYSA-N 1-[4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound N=1C(NC(C)C)=CC(N2C3COCC2COC3)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=NC=C1 KTJRELYXAMVFFF-UHFFFAOYSA-N 0.000 claims 1
• CTMOHOOMAOPZFC-UHFFFAOYSA-N 1-[4-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(oxan-4-yl)pyrimidin-2-yl]phenyl]-3-pyridin-3-ylurea Chemical compound C=1C=CN=CC=1NC(=O)NC(C=C1)=CC=C1C(N=C(C=1)N2C3CCC2COC3)=NC=1C1CCOCC1 CTMOHOOMAOPZFC-UHFFFAOYSA-N 0.000 claims 1
• KKUIWWXQXSCKIE-UHFFFAOYSA-N 1-[4-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(oxan-4-ylamino)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound C=1C=C(C=2N=C(C=C(NC3CCOCC3)N=2)N2C3CCC2COC3)C=CC=1NC(=O)NC1=CC=NC=C1 KKUIWWXQXSCKIE-UHFFFAOYSA-N 0.000 claims 1
• NXJALMVTOLXOAT-UHFFFAOYSA-N 1-[4-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound N=1C(NC(C)C)=CC(N2C3CCC2COC3)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=NC=C1 NXJALMVTOLXOAT-UHFFFAOYSA-N 0.000 claims 1
• LMFFBOHRMSHFAG-UHFFFAOYSA-N 1-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound N=1C(NC(C)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=NC=C1 LMFFBOHRMSHFAG-UHFFFAOYSA-N 0.000 claims 1
• LYXFOYSJZFENMZ-UHFFFAOYSA-N 1-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound N=1C(C(F)(F)F)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=NC=C1 LYXFOYSJZFENMZ-UHFFFAOYSA-N 0.000 claims 1
• IOCRILFVUZQTFT-UHFFFAOYSA-N 1-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound C=1C=C(C=2N=C(C=C(N=2)N2CC3CCC(O3)C2)C=2C=CC=CC=2)C=CC=1NC(=O)NC1=CC=NC=C1 IOCRILFVUZQTFT-UHFFFAOYSA-N 0.000 claims 1
• LWBBUIRPDMIQQK-UHFFFAOYSA-N 1-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound C=1C=C(C=2N=C(C=CN=2)N2CC3CCC(O3)C2)C=CC=1NC(=O)NC1=CC=NC=C1 LWBBUIRPDMIQQK-UHFFFAOYSA-N 0.000 claims 1
• UKBPWWKTASOSAR-UHFFFAOYSA-N 1-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-(4-piperazin-1-ylphenyl)urea Chemical compound N=1C(CS(=O)(=O)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC(C=C1)=CC=C1N1CCNCC1 UKBPWWKTASOSAR-UHFFFAOYSA-N 0.000 claims 1
• ZJSQDHCQIVEFMQ-UHFFFAOYSA-N 1-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-phenylurea Chemical compound N=1C(CS(=O)(=O)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CC=C1 ZJSQDHCQIVEFMQ-UHFFFAOYSA-N 0.000 claims 1
• JBXIRTMNWYZXPG-UHFFFAOYSA-N 1-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-pyridin-3-ylurea Chemical compound N=1C(CS(=O)(=O)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CN=C1 JBXIRTMNWYZXPG-UHFFFAOYSA-N 0.000 claims 1
• IWXCLIQLKIDCKU-UHFFFAOYSA-N 1-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]-3-pyridin-4-ylurea Chemical compound N=1C(CS(=O)(=O)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1=CC=NC=C1 IWXCLIQLKIDCKU-UHFFFAOYSA-N 0.000 claims 1
• GGLXVPOMURNQOW-UHFFFAOYSA-N 1-[4-[5-chloro-4,6-bis(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl]phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(C(Cl)=C(N3C4CCC3COC4)N=2)N2C3CCC2COC3)C=C1 GGLXVPOMURNQOW-UHFFFAOYSA-N 0.000 claims 1
• CHGMYIRUDVREMN-UHFFFAOYSA-N 1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-[4-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]urea Chemical compound N=1C(NC(C)C)=CC(N2C3CCC2COC3)=NC=1C(C=C1)=CC=C1NC(=O)NC(C=N1)=CC=C1N1CCN(C)CC1 CHGMYIRUDVREMN-UHFFFAOYSA-N 0.000 claims 1
• STHHLVCQSLRQNI-UHFFFAOYSA-N 1-azabicyclo[3.2.1]octane Chemical compound C1C2CCN1CCC2 STHHLVCQSLRQNI-UHFFFAOYSA-N 0.000 claims 1
• AIKNLTUERQKODX-UHFFFAOYSA-N 1-cyclopropyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]urea Chemical compound N=1C(NC(C)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1CC1 AIKNLTUERQKODX-UHFFFAOYSA-N 0.000 claims 1
• KEYRMZQBHWQWDK-UHFFFAOYSA-N 1-cyclopropyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl]urea Chemical compound N=1C(C(F)(F)F)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1CC1 KEYRMZQBHWQWDK-UHFFFAOYSA-N 0.000 claims 1
• GFGWFZNHOWCYSJ-UHFFFAOYSA-N 1-cyclopropyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl]phenyl]urea Chemical compound C=1C=C(C=2N=C(C=C(N=2)N2CC3CCC(O3)C2)C=2C=CC=CC=2)C=CC=1NC(=O)NC1CC1 GFGWFZNHOWCYSJ-UHFFFAOYSA-N 0.000 claims 1
• MJLQEJWXQMHEBR-UHFFFAOYSA-N 1-cyclopropyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-propan-2-yloxypyrimidin-2-yl]phenyl]urea Chemical compound N=1C(OC(C)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1CC1 MJLQEJWXQMHEBR-UHFFFAOYSA-N 0.000 claims 1
• VNQYJBFIYYXCFQ-UHFFFAOYSA-N 1-cyclopropyl-3-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]urea Chemical compound N=1C(CS(=O)(=O)C)=CC(N2CC3CCC(O3)C2)=NC=1C(C=C1)=CC=C1NC(=O)NC1CC1 VNQYJBFIYYXCFQ-UHFFFAOYSA-N 0.000 claims 1
• VFFWXQFDHKUFRH-UHFFFAOYSA-N 1-ethyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C1=NC(N2CC3CCC(O3)C2)=CC(C=2C=CC=CC=2)=N1 VFFWXQFDHKUFRH-UHFFFAOYSA-N 0.000 claims 1
• UDCLHNOODSHYNR-UHFFFAOYSA-N 1-ethyl-3-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C1=NC(CS(C)(=O)=O)=CC(N2CC3CCC(O3)C2)=N1 UDCLHNOODSHYNR-UHFFFAOYSA-N 0.000 claims 1
• AYLAMPLUGKTQFB-UHFFFAOYSA-N 1-methyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(propan-2-ylamino)pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(NC(C)C)=CC(N2CC3CCC(O3)C2)=N1 AYLAMPLUGKTQFB-UHFFFAOYSA-N 0.000 claims 1
• LXHSOJWKRWWPQU-UHFFFAOYSA-N 1-methyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(N2CC3CCC(O3)C2)=CC(C(F)(F)F)=N1 LXHSOJWKRWWPQU-UHFFFAOYSA-N 0.000 claims 1
• GTVYRFHOBINLJG-UHFFFAOYSA-N 1-methyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(N2CC3CCC(O3)C2)=CC(C=2C=CC=CC=2)=N1 GTVYRFHOBINLJG-UHFFFAOYSA-N 0.000 claims 1
• BKYIHCQQAUTQHY-UHFFFAOYSA-N 1-methyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-propan-2-yloxypyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(OC(C)C)=CC(N2CC3CCC(O3)C2)=N1 BKYIHCQQAUTQHY-UHFFFAOYSA-N 0.000 claims 1
• CTEZMCHSUHDWJO-UHFFFAOYSA-N 1-methyl-3-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC=CC(N2CC3CCC(O3)C2)=N1 CTEZMCHSUHDWJO-UHFFFAOYSA-N 0.000 claims 1
• PPQURXVJQBDBCO-UHFFFAOYSA-N 1-methyl-3-[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NC)=CC=C1C1=NC(CS(C)(=O)=O)=CC(N2CC3CCC(O3)C2)=N1 PPQURXVJQBDBCO-UHFFFAOYSA-N 0.000 claims 1
• BXCQNBRVRCGRJP-UHFFFAOYSA-N 2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-n-propan-2-ylpyrimidin-4-amine Chemical compound N=1C(NC(C)C)=CC(N2C3COCC2COC3)=NC=1C1=CC=C(N)C=C1 BXCQNBRVRCGRJP-UHFFFAOYSA-N 0.000 claims 1
• WJNIYOBFNKKNJY-UHFFFAOYSA-N 2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-n-(oxan-4-yl)pyrimidin-4-amine Chemical compound C1=CC(N)=CC=C1C1=NC(NC2CCOCC2)=CC(N2C3CCC2COC3)=N1 WJNIYOBFNKKNJY-UHFFFAOYSA-N 0.000 claims 1
• SQGJVUOODZLQPA-UHFFFAOYSA-N 2-(4-aminophenyl)-n,n-diethyl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-amine Chemical compound N=1C(N(CC)CC)=CC(N2C3CCC2COC3)=NC=1C1=CC=C(N)C=C1 SQGJVUOODZLQPA-UHFFFAOYSA-N 0.000 claims 1
• NGDQYJVFOAGFBX-UHFFFAOYSA-N 2-(4-aminophenyl)-n-(2-methylsulfonylethyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-amine Chemical compound N=1C(NCCS(=O)(=O)C)=CC(N2C3CCC2COC3)=NC=1C1=CC=C(N)C=C1 NGDQYJVFOAGFBX-UHFFFAOYSA-N 0.000 claims 1
• CWOPCOPFSBNRIU-UHFFFAOYSA-N 2-(4-nitrophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-n-(oxan-4-yl)pyrimidin-4-amine Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=NC(NC2CCOCC2)=CC(N2C3CCC2COC3)=N1 CWOPCOPFSBNRIU-UHFFFAOYSA-N 0.000 claims 1
• IAGPASWODMJQQY-UHFFFAOYSA-N 2-hydroxyethyl n-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCCO)=CC=C1C1=NC(N2CC3CCC(O3)C2)=CC(C(F)(F)F)=N1 IAGPASWODMJQQY-UHFFFAOYSA-N 0.000 claims 1
• HWVSDPBBRMBNRX-UHFFFAOYSA-N 2-hydroxyethyl n-[4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCCO)=CC=C1C1=NC(N2CC3CCC(O3)C2)=CC(C=2C=CC=CC=2)=N1 HWVSDPBBRMBNRX-UHFFFAOYSA-N 0.000 claims 1
• QXFLWKCCFOARLQ-UHFFFAOYSA-N 4-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(oxan-4-yl)pyrimidin-2-yl]aniline Chemical compound C1=CC(N)=CC=C1C1=NC(C2CCOCC2)=CC(N2C3CCC2COC3)=N1 QXFLWKCCFOARLQ-UHFFFAOYSA-N 0.000 claims 1
• ARFWLBHEGJPPRB-UHFFFAOYSA-N 4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]aniline Chemical compound N=1C(CS(=O)(=O)C)=CC(N2CC3CCC(O3)C2)=NC=1C1=CC=C(N)C=C1 ARFWLBHEGJPPRB-UHFFFAOYSA-N 0.000 claims 1
• HSZHEUMJJBLBPN-UHFFFAOYSA-N 4-[4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl]aniline Chemical compound N=1C(CN(C)C)=CC(N2C3CCC2COC3)=NC=1C1=CC=C(N)C=C1 HSZHEUMJJBLBPN-UHFFFAOYSA-N 0.000 claims 1
• QSAGXQFBJSNDSW-UHFFFAOYSA-N 6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-2-(4-nitrophenyl)-n-propan-2-ylpyrimidin-4-amine Chemical compound N=1C(NC(C)C)=CC(N2C3COCC2COC3)=NC=1C1=CC=C([N+]([O-])=O)C=C1 QSAGXQFBJSNDSW-UHFFFAOYSA-N 0.000 claims 1
• ZXKMZSAHTOKHJI-UHFFFAOYSA-N 8-[6-(3,6-dihydro-2h-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octane Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=NC(N2C3CCC2COC3)=CC(C=2CCOCC=2)=N1 ZXKMZSAHTOKHJI-UHFFFAOYSA-N 0.000 claims 1
• OIFNQYRTFUIPME-UHFFFAOYSA-N 9-[6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=NC(Cl)=CC(N2C3COCC2COC3)=N1 OIFNQYRTFUIPME-UHFFFAOYSA-N 0.000 claims 1
• UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 1
• VPKQPEXRQNQPSJ-UHFFFAOYSA-N n,n-diethyl-2-(4-nitrophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-amine Chemical compound N=1C(N(CC)CC)=CC(N2C3CCC2COC3)=NC=1C1=CC=C([N+]([O-])=O)C=C1 VPKQPEXRQNQPSJ-UHFFFAOYSA-N 0.000 claims 1
• DDOBBODDOFXPAC-UHFFFAOYSA-N n-(2-methylsulfonylethyl)-2-(4-nitrophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-amine Chemical compound N=1C(NCCS(=O)(=O)C)=CC(N2C3CCC2COC3)=NC=1C1=CC=C([N+]([O-])=O)C=C1 DDOBBODDOFXPAC-UHFFFAOYSA-N 0.000 claims 1
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 1
• AGGXMNFMFVOREU-UHFFFAOYSA-N tert-butyl n-methyl-n-[[4-[[4-[4-(methylsulfonylmethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl]phenyl]carbamoylamino]phenyl]methyl]carbamate Chemical compound C1=CC(CN(C)C(=O)OC(C)(C)C)=CC=C1NC(=O)NC1=CC=C(C=2N=C(C=C(CS(C)(=O)=O)N=2)N2CC3CCC(O3)C2)C=C1 AGGXMNFMFVOREU-UHFFFAOYSA-N 0.000 claims 1
• UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 55
• 239000000470 constituent Substances 0.000 abstract description 7
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 441
• 239000000243 solution Substances 0.000 description 135
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
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