DK2307409T3 - Pyrrolopyridines as kinase inhibitors - Google Patents

Info

Publication number

DK2307409T3

DK2307409T3 DK09747404.3T DK09747404T DK2307409T3 DK 2307409 T3 DK2307409 T3 DK 2307409T3 DK 09747404 T DK09747404 T DK 09747404T DK 2307409 T3 DK2307409 T3 DK 2307409T3

Authority

DK

Denmark

Prior art keywords

alkyl

hydrogen

mmol

certain embodiments

phenyl

Prior art date

2008-05-13

Links

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• 229940043355 kinase inhibitor Drugs 0.000 title description 2
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
• 150000005255 pyrrolopyridines Chemical class 0.000 title 1
• -1 -SO2R1 Chemical group 0.000 claims description 245
• 239000001257 hydrogen Substances 0.000 claims description 244
• 229910052739 hydrogen Inorganic materials 0.000 claims description 244
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 223
• 125000000217 alkyl group Chemical group 0.000 claims description 186
• 150000001875 compounds Chemical class 0.000 claims description 183
• 229910052736 halogen Inorganic materials 0.000 claims description 171
• 150000002367 halogens Chemical class 0.000 claims description 171
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 136
• 125000004429 atom Chemical group 0.000 claims description 103
• 150000002431 hydrogen Chemical class 0.000 claims description 101
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 96
• 125000001072 heteroaryl group Chemical group 0.000 claims description 90
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 89
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 87
• 229920006395 saturated elastomer Polymers 0.000 claims description 82
• 125000003118 aryl group Chemical group 0.000 claims description 75
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 73
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 67
• 125000000623 heterocyclic group Chemical group 0.000 claims description 66
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 54
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 52
• 150000003839 salts Chemical class 0.000 claims description 47
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 37
• 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 32
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 32
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 22
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 19
• 125000003342 alkenyl group Chemical group 0.000 claims description 18
• 229910052801 chlorine Inorganic materials 0.000 claims description 18
• 229910052731 fluorine Inorganic materials 0.000 claims description 18
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 229910052794 bromium Inorganic materials 0.000 claims description 13
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 10
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 229910052702 rhenium Inorganic materials 0.000 claims description 8
• 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 7
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 6
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 5
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 5
• 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 4
• 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 3
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000001847 2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 3
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 229910052799 carbon Inorganic materials 0.000 claims description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 227
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• 239000007787 solid Substances 0.000 description 187
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• 238000006243 chemical reaction Methods 0.000 description 143
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• 238000000034 method Methods 0.000 description 130
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 106
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 100
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 94
• 239000000243 solution Substances 0.000 description 88
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 79
• 238000005160 1H NMR spectroscopy Methods 0.000 description 76
• 125000004043 oxo group Chemical group O=* 0.000 description 76
• 230000014759 maintenance of location Effects 0.000 description 69
• 239000002904 solvent Substances 0.000 description 68
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 62
• 238000003818 flash chromatography Methods 0.000 description 56
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 53
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 49
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 47
• 239000012071 phase Substances 0.000 description 46
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 44
• 229910052938 sodium sulfate Inorganic materials 0.000 description 44
• 235000011152 sodium sulphate Nutrition 0.000 description 44
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
• 239000012267 brine Substances 0.000 description 43
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 43
• 230000002441 reversible effect Effects 0.000 description 41
• 125000004070 6 membered heterocyclic group Chemical group 0.000 description 38
• WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 38
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• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 29
• 238000001914 filtration Methods 0.000 description 29
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 28
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• 229910052757 nitrogen Inorganic materials 0.000 description 19
• MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-dihydropyridine Chemical compound C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 description 18
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