AU2014308703A1 - Furo- and thieno-pyridine carboxamide compounds useful as Pim kinase inhibitors - Google Patents

Info

Publication number

AU2014308703A1

AU2014308703A1 AU2014308703A AU2014308703A AU2014308703A1 AU 2014308703 A1 AU2014308703 A1 AU 2014308703A1 AU 2014308703 A AU2014308703 A AU 2014308703A AU 2014308703 A AU2014308703 A AU 2014308703A AU 2014308703 A1 AU2014308703 A1 AU 2014308703A1

Authority

AU

Australia

Prior art keywords

amino

pyridine

carboxamide

pyridin

nrc

Prior art date

2013-08-23

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.)

Abandoned

Links

• Espacenet
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 400
• DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 title abstract description 5
• YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 title abstract description 4
• 229940125670 thienopyridine Drugs 0.000 title abstract description 4
• 239000002175 thienopyridine Substances 0.000 title abstract description 4
• 229940043355 kinase inhibitor Drugs 0.000 title description 6
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 6
• 150000003839 salts Chemical class 0.000 claims abstract description 155
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 200
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 191
• 239000000203 mixture Substances 0.000 claims description 173
• -1 1H-pyrazol-4-yl ring Chemical group 0.000 claims description 170
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 108
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 103
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 102
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 102
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 100
• 229910052736 halogen Inorganic materials 0.000 claims description 95
• 101100240985 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) nrc-2 gene Proteins 0.000 claims description 94
• 150000002367 halogens Chemical class 0.000 claims description 88
• 125000001424 substituent group Chemical group 0.000 claims description 82
• 235000005152 nicotinamide Nutrition 0.000 claims description 76
• 239000011570 nicotinamide Substances 0.000 claims description 76
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 75
• 125000003118 aryl group Chemical group 0.000 claims description 69
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 62
• 238000000034 method Methods 0.000 claims description 59
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 58
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 50
• 125000004432 carbon atom Chemical group C* 0.000 claims description 50
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 48
• GENUAJKKXPWRAL-UHFFFAOYSA-N furo[3,2-b]pyridine-3-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=COC2=C1 GENUAJKKXPWRAL-UHFFFAOYSA-N 0.000 claims description 47
• 125000001072 heteroaryl group Chemical group 0.000 claims description 47
• 201000010099 disease Diseases 0.000 claims description 46
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 43
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 35
• 125000005843 halogen group Chemical group 0.000 claims description 34
• 206010028980 Neoplasm Diseases 0.000 claims description 33
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 33
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 30
• 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 29
• 125000006413 ring segment Chemical group 0.000 claims description 29
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
• 125000002950 monocyclic group Chemical group 0.000 claims description 27
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 229910052757 nitrogen Inorganic materials 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 25
• 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 23
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
• WCRHJCMVVHZBRK-UHFFFAOYSA-N thieno[3,2-b]pyridine-3-carboxamide Chemical compound S1C=C(C2=NC=CC=C21)C(=O)N WCRHJCMVVHZBRK-UHFFFAOYSA-N 0.000 claims description 23
• 201000011510 cancer Diseases 0.000 claims description 21
• 229910052801 chlorine Inorganic materials 0.000 claims description 21
• 229910052799 carbon Inorganic materials 0.000 claims description 20
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
• 125000004429 atom Chemical group 0.000 claims description 19
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
• 125000005842 heteroatom Chemical group 0.000 claims description 18
• 101100114828 Drosophila melanogaster Orai gene Proteins 0.000 claims description 17
• 229910052731 fluorine Inorganic materials 0.000 claims description 17
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 16
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
• 230000000694 effects Effects 0.000 claims description 14
• 101100297651 Mus musculus Pim2 gene Proteins 0.000 claims description 13
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 13
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 12
• 101100310928 Caenorhabditis elegans sra-6 gene Proteins 0.000 claims description 12
• 101150054691 PIM3 gene Proteins 0.000 claims description 12
• 125000003277 amino group Chemical group 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
• 125000001188 haloalkyl group Chemical group 0.000 claims description 11
• 206010028537 myelofibrosis Diseases 0.000 claims description 11
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
• 101100310927 Caenorhabditis elegans sra-4 gene Proteins 0.000 claims description 10
• 230000014509 gene expression Effects 0.000 claims description 9
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 8
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 8
• 101100310920 Caenorhabditis elegans sra-2 gene Proteins 0.000 claims description 8
• 229910052739 hydrogen Inorganic materials 0.000 claims description 8
• 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 7
• 208000017733 acquired polycythemia vera Diseases 0.000 claims description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 208000037244 polycythemia vera Diseases 0.000 claims description 7
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 6
• 101100005620 Caenorhabditis elegans cyb-3 gene Proteins 0.000 claims description 6
• 101100310926 Caenorhabditis elegans sra-3 gene Proteins 0.000 claims description 6
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 6
• 208000003476 primary myelofibrosis Diseases 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 5
• 208000026278 immune system disease Diseases 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
• XONRUCAPNUYQLL-SJORKVTESA-N CN1CCC(CC1)c1cnc2c(C(=O)Nc3cnccc3N3C[C@@H](N)C[C@H](C3)C(F)(F)F)c(N)oc2c1 Chemical compound CN1CCC(CC1)c1cnc2c(C(=O)Nc3cnccc3N3C[C@@H](N)C[C@H](C3)C(F)(F)F)c(N)oc2c1 XONRUCAPNUYQLL-SJORKVTESA-N 0.000 claims description 4
• ISNMLRIKECKKTQ-SJORKVTESA-N CN1CCN(Cc2cnc3c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@H](C4)C(F)(F)F)c(N)oc3c2)CC1 Chemical compound CN1CCN(Cc2cnc3c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@H](C4)C(F)(F)F)c(N)oc3c2)CC1 ISNMLRIKECKKTQ-SJORKVTESA-N 0.000 claims description 4
• MENUNSBFZDLLDG-MNOVXSKESA-N C[C@@H]1C[C@H](N)CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(OC(F)F)cnc12 Chemical compound C[C@@H]1C[C@H](N)CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(OC(F)F)cnc12 MENUNSBFZDLLDG-MNOVXSKESA-N 0.000 claims description 4
• OKXUEVXLKMRLBF-DOMZBBRYSA-N C[C@@H]1C[C@H](N)CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(cnc12)C1CC1 Chemical compound C[C@@H]1C[C@H](N)CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(cnc12)C1CC1 OKXUEVXLKMRLBF-DOMZBBRYSA-N 0.000 claims description 4
• ZEANPQMQVCLCFF-CJNGLKHVSA-N C[C@@H]1C[C@H](N)CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(cnc12)C1CCC1 Chemical compound C[C@@H]1C[C@H](N)CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(cnc12)C1CCC1 ZEANPQMQVCLCFF-CJNGLKHVSA-N 0.000 claims description 4
• 101100059439 Caenorhabditis elegans cyb-1 gene Proteins 0.000 claims description 4
• SSUDFYVQIIZVBA-UHFFFAOYSA-N ClC1=C(C2=NC=CC=C2S1)C(=O)N Chemical compound ClC1=C(C2=NC=CC=C2S1)C(=O)N SSUDFYVQIIZVBA-UHFFFAOYSA-N 0.000 claims description 4
• 101100012466 Drosophila melanogaster Sras gene Proteins 0.000 claims description 4
• 102000004190 Enzymes Human genes 0.000 claims description 4
• 108090000790 Enzymes Proteins 0.000 claims description 4
• 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 4
• 208000014767 Myeloproliferative disease Diseases 0.000 claims description 4
• NIDXDGAWKVAEJZ-MNOVXSKESA-N NC1=C(C2=NC=C(C=C2O1)C(F)(F)F)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N Chemical compound NC1=C(C2=NC=C(C=C2O1)C(F)(F)F)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N NIDXDGAWKVAEJZ-MNOVXSKESA-N 0.000 claims description 4
• ZCLQEQLXQWLAJS-PWSUYJOCSA-N NC1=C(C2=NC=C(C=C2O1)C(F)(F)F)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C)N Chemical compound NC1=C(C2=NC=C(C=C2O1)C(F)(F)F)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C)N ZCLQEQLXQWLAJS-PWSUYJOCSA-N 0.000 claims description 4
• IDUVTNWYLIGGJM-KGLIPLIRSA-N NC1=C(C2=NC=C(C=C2O1)CCC)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N Chemical compound NC1=C(C2=NC=C(C=C2O1)CCC)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N IDUVTNWYLIGGJM-KGLIPLIRSA-N 0.000 claims description 4
• GWIHJYSRUBNMKP-GARXDOFDSA-N NC1=C(C2=NC=C(C=C2O1)CN1CC(CC1)OC)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N Chemical compound NC1=C(C2=NC=C(C=C2O1)CN1CC(CC1)OC)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N GWIHJYSRUBNMKP-GARXDOFDSA-N 0.000 claims description 4
• CFTNUWZADFSSTB-KOLCDFICSA-N NC1=C(C2=NC=C(C=C2O1)Cl)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N Chemical compound NC1=C(C2=NC=C(C=C2O1)Cl)C(=O)NC=1C=NC=CC1N1C[C@H](C[C@H](C1)C(F)(F)F)N CFTNUWZADFSSTB-KOLCDFICSA-N 0.000 claims description 4
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• WZHSEVKZCUYEMD-CABCVRRESA-N N[C@H]1C[C@H](CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(cnc12)-c1cncnc1)C(F)(F)F Chemical compound N[C@H]1C[C@H](CN(C1)c1ccncc1NC(=O)c1c(N)oc2cc(cnc12)-c1cncnc1)C(F)(F)F WZHSEVKZCUYEMD-CABCVRRESA-N 0.000 claims description 4
• KDACVZQWBAKEFO-KGLIPLIRSA-N N[C@H]1C[C@H](CN(C1)c1ccncc1NC(=O)c1c(N)sc2cc(cnc12)N1CCOCC1)C(F)(F)F Chemical compound N[C@H]1C[C@H](CN(C1)c1ccncc1NC(=O)c1c(N)sc2cc(cnc12)N1CCOCC1)C(F)(F)F KDACVZQWBAKEFO-KGLIPLIRSA-N 0.000 claims description 4
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
• 108700020796 Oncogene Proteins 0.000 claims description 4
• 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 4
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 claims description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
• 201000006417 multiple sclerosis Diseases 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• PFDPPHIMKOMNSC-UHFFFAOYSA-N 2-cyclobutylfuro[3,2-b]pyridine-3-carboxamide Chemical compound C1(CCC1)C1=C(C2=NC=CC=C2O1)C(=O)N PFDPPHIMKOMNSC-UHFFFAOYSA-N 0.000 claims description 3
• NCLKCCDISBFXCW-UHFFFAOYSA-N 2-cyclopropylfuro[3,2-b]pyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C2=NC=CC=C2O1)C(=O)N NCLKCCDISBFXCW-UHFFFAOYSA-N 0.000 claims description 3
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• HBZCQJSSERIDSY-DVKDBIPTSA-N CCOC1CCN(Cc2cnc3c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@H](C4)C(F)(F)F)c(N)oc3c2)C1 Chemical compound CCOC1CCN(Cc2cnc3c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@H](C4)C(F)(F)F)c(N)oc3c2)C1 HBZCQJSSERIDSY-DVKDBIPTSA-N 0.000 claims description 3
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