CA2712959C - Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity - Google Patents

Info

Publication number

CA2712959C

CA2712959C CA2712959A CA2712959A CA2712959C CA 2712959 C CA2712959 C CA 2712959C CA 2712959 A CA2712959 A CA 2712959A CA 2712959 A CA2712959 A CA 2712959A CA 2712959 C CA2712959 C CA 2712959C

Authority

CA

Canada

Prior art keywords

title compound

oxo

carboxylic acid

dihydro

pyridin

Prior art date

2008-01-22

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

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• 108010019244 Checkpoint Kinase 1 Proteins 0.000 title abstract description 27
• 230000002401 inhibitory effect Effects 0.000 title abstract description 4
• 102000006459 Checkpoint Kinase 1 Human genes 0.000 title description 26
• NRGVEGWSRITVOR-UHFFFAOYSA-N 3-(1h-indol-2-yl)-1h-pyridin-2-one Chemical class OC1=NC=CC=C1C1=CC2=CC=CC=C2N1 NRGVEGWSRITVOR-UHFFFAOYSA-N 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 526
• -1 hydroxy, methyl Chemical group 0.000 claims abstract description 61
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
• 239000001257 hydrogen Substances 0.000 claims abstract description 51
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 31
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 17
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 16
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 7
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 4
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 4
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 claims abstract 4
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 claims abstract 3
• 229910052757 nitrogen Inorganic materials 0.000 claims description 84
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 47
• 239000000203 mixture Substances 0.000 claims description 36
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
• 206010028980 Neoplasm Diseases 0.000 claims description 19
• 230000000694 effects Effects 0.000 claims description 18
• 238000011282 treatment Methods 0.000 claims description 17
• 125000001424 substituent group Chemical group 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 15
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• 201000011510 cancer Diseases 0.000 claims description 11
• 125000001153 fluoro group Chemical group F* 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 239000001301 oxygen Substances 0.000 claims description 11
• 125000000623 heterocyclic group Chemical group 0.000 claims description 10
• 125000002950 monocyclic group Chemical group 0.000 claims description 9
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 239000005864 Sulphur Substances 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 238000001959 radiotherapy Methods 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 231100000433 cytotoxic Toxicity 0.000 claims description 4
• 230000001472 cytotoxic effect Effects 0.000 claims description 4
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• 208000023275 Autoimmune disease Diseases 0.000 claims description 3
• 125000000217 alkyl group Chemical group 0.000 claims description 3
• 238000002512 chemotherapy Methods 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 2
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
• 206010052779 Transplant rejections Diseases 0.000 claims description 2
• 239000000824 cytostatic agent Substances 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 206010025135 lupus erythematosus Diseases 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 201000006417 multiple sclerosis Diseases 0.000 claims description 2
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
• 210000000056 organ Anatomy 0.000 claims description 2
• 201000008482 osteoarthritis Diseases 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 9
• 102000001253 Protein Kinase Human genes 0.000 claims 4
• 108060006633 protein kinase Proteins 0.000 claims 4
• GEBXRQMORXJPGN-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]-n-[6-oxo-5-[5-(piperidin-1-ylmethyl)-1h-indol-2-yl]-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1=CC(C)=CC=C1CN1N=CC(C(=O)NC=2C=C(C(=O)NC=2)C=2NC3=CC=C(CN4CCCCC4)C=C3C=2)=C1 GEBXRQMORXJPGN-UHFFFAOYSA-N 0.000 claims 1
• YRNZHBVRTDDGNB-UHFFFAOYSA-N 1-benzyl-n-[5-(1h-indol-2-yl)-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1NC(=O)C(C=2NC3=CC=CC=C3C=2)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 YRNZHBVRTDDGNB-UHFFFAOYSA-N 0.000 claims 1
• DISCGKGWZKLOSH-UHFFFAOYSA-N 1-benzyl-n-[5-[5-(2,2-dimethyl-3-piperidin-1-ylpropoxy)-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1CCCCN1CC(C)(C)COC(C=C1C=2)=CC=C1NC=2C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 DISCGKGWZKLOSH-UHFFFAOYSA-N 0.000 claims 1
• ZSYVTFSMHIZBJT-UHFFFAOYSA-N 1-benzyl-n-[5-[5-(2,2-dimethyl-3-pyrrolidin-1-ylpropoxy)-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1CCCN1CC(C)(C)COC(C=C1C=2)=CC=C1NC=2C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 ZSYVTFSMHIZBJT-UHFFFAOYSA-N 0.000 claims 1
• DKDWHPAIWPQMDV-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[(4-fluoropiperidin-1-yl)methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1CC(F)CCN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 DKDWHPAIWPQMDV-UHFFFAOYSA-N 0.000 claims 1
• QENZBLJVRSQXHR-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[(4-methylpiperidin-1-yl)methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1CC(C)CCN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 QENZBLJVRSQXHR-UHFFFAOYSA-N 0.000 claims 1
• OUZSVHBSAIWGAB-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[1-(dimethylamino)-2-methylpropan-2-yl]oxy-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1C2=CC(OC(C)(C)CN(C)C)=CC=C2NC=1C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 OUZSVHBSAIWGAB-UHFFFAOYSA-N 0.000 claims 1
• WMBKHLMCZPQUSY-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[3-(diethylamino)-2,2-dimethylpropoxy]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1C2=CC(OCC(C)(C)CN(CC)CC)=CC=C2NC=1C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 WMBKHLMCZPQUSY-UHFFFAOYSA-N 0.000 claims 1
• REQMZUHAMVOEON-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[3-(dimethylamino)-2,2-dimethylpropoxy]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1C2=CC(OCC(C)(C)CN(C)C)=CC=C2NC=1C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 REQMZUHAMVOEON-UHFFFAOYSA-N 0.000 claims 1
• PZNCUDMYMQBNPI-OAQYLSRUSA-N 1-benzyl-n-[5-[5-[[(2r)-2-methylpiperidin-1-yl]methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C[C@@H]1CCCCN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 PZNCUDMYMQBNPI-OAQYLSRUSA-N 0.000 claims 1
• ITWISLBDFHAZFK-OYRHEFFESA-N 1-benzyl-n-[5-[5-[[(2r,6s)-2,6-dimethylmorpholin-4-yl]methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 ITWISLBDFHAZFK-OYRHEFFESA-N 0.000 claims 1
• KIBWTTYZBWVWLR-SZPZYZBQSA-N 1-benzyl-n-[5-[5-[[(2r,6s)-2,6-dimethylpiperidin-1-yl]methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C[C@H]1CCC[C@@H](C)N1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 KIBWTTYZBWVWLR-SZPZYZBQSA-N 0.000 claims 1
• PZNCUDMYMQBNPI-NRFANRHFSA-N 1-benzyl-n-[5-[5-[[(2s)-2-methylpiperidin-1-yl]methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C[C@H]1CCCCN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 PZNCUDMYMQBNPI-NRFANRHFSA-N 0.000 claims 1
• MHLUPVPNKGOJPG-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[[1-(diethylaminomethyl)cyclopropyl]methoxy]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1C=C2NC(C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)=CC2=CC=1OCC1(CN(CC)CC)CC1 MHLUPVPNKGOJPG-UHFFFAOYSA-N 0.000 claims 1
• NOMVGDXJBPVSOA-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[[[3-(dimethylamino)-2,2-dimethylpropyl]-ethylamino]methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1C2=CC(CN(CC)CC(C)(C)CN(C)C)=CC=C2NC=1C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 NOMVGDXJBPVSOA-UHFFFAOYSA-N 0.000 claims 1
• OEKPFDMUKNSTBS-UHFFFAOYSA-N 1-benzyl-n-[6-oxo-5-[5-(piperidin-1-ylmethyl)-1h-indol-2-yl]-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1=NN(CC=2C=CC=CC=2)C=C1C(=O)NC(C=1)=CNC(=O)C=1C(NC1=CC=2)=CC1=CC=2CN1CCCCC1 OEKPFDMUKNSTBS-UHFFFAOYSA-N 0.000 claims 1
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
• 239000002254 cytotoxic agent Substances 0.000 claims 1
• APAITVFDOPBSBV-UHFFFAOYSA-N n-[5-[5-[(4-fluoropiperidin-1-yl)methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]-1-(1-phenylethyl)pyrazole-4-carboxamide Chemical compound C1=C(C(=O)NC=2C=C(C(=O)NC=2)C=2NC3=CC=C(CN4CCC(F)CC4)C=C3C=2)C=NN1C(C)C1=CC=CC=C1 APAITVFDOPBSBV-UHFFFAOYSA-N 0.000 claims 1
• WZFHXTBJQNYCNB-BHIFYINESA-N n-[5-[5-[[(2r,6s)-2,6-dimethylmorpholin-4-yl]methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]-1-[(1r)-1-phenylethyl]pyrazole-4-carboxamide Chemical compound C1([C@@H](C)N2N=CC(=C2)C(=O)NC=2C=C(C(=O)NC=2)C=2NC3=CC=C(CN4C[C@@H](C)O[C@@H](C)C4)C=C3C=2)=CC=CC=C1 WZFHXTBJQNYCNB-BHIFYINESA-N 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 abstract 1
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 369
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 243
• 239000007787 solid Substances 0.000 description 220
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 215
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 188
• 238000002474 experimental method Methods 0.000 description 156
• 238000005160 1H NMR spectroscopy Methods 0.000 description 153
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• 238000002360 preparation method Methods 0.000 description 80
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• 239000000706 filtrate Substances 0.000 description 13
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• 238000000746 purification Methods 0.000 description 12
• AGBUHNSJFSPPNR-UHFFFAOYSA-N tert-butyl 5-(2-tert-butylsilyloxypropan-2-yl)indole-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C=CC2=CC(=CC=C12)C(O[SiH2]C(C)(C)C)(C)C AGBUHNSJFSPPNR-UHFFFAOYSA-N 0.000 description 12
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