CA3056726A1 - Tricyclic compounds for use in treatment of proliferative disorders - Google Patents

Info

Publication number

CA3056726A1

CA3056726A1 CA3056726A CA3056726A CA3056726A1 CA 3056726 A1 CA3056726 A1 CA 3056726A1 CA 3056726 A CA3056726 A CA 3056726A CA 3056726 A CA3056726 A CA 3056726A CA 3056726 A1 CA3056726 A1 CA 3056726A1

Authority

CA

Canada

Prior art keywords

alkyl

pyrido

solvate

hydrate

optionally substituted

Prior art date

2017-03-17

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.)

Pending

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• Global Dossier
• CIPO
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 297
• 230000002062 proliferating effect Effects 0.000 title claims description 20
• 150000003839 salts Chemical class 0.000 claims abstract description 215
• 239000012453 solvate Substances 0.000 claims abstract description 177
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 54
• 102100034607 Protein arginine N-methyltransferase 5 Human genes 0.000 claims abstract description 52
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 44
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 37
• 201000011510 cancer Diseases 0.000 claims abstract description 32
• 230000001404 mediated effect Effects 0.000 claims abstract description 12
• 101710084427 Protein arginine N-methyltransferase 5 Proteins 0.000 claims abstract 3
• 238000000034 method Methods 0.000 claims description 151
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 110
• -1 6-(cyclobutylamino)-N-(2-hydroxy-3-{5-methyl-1H,2H,3H,4H,5H-pyrido[4,3-b]indol-yl}propyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide Chemical compound 0.000 claims description 108
• 229910052736 halogen Inorganic materials 0.000 claims description 105
• 150000002367 halogens Chemical group 0.000 claims description 105
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 103
• 239000001257 hydrogen Substances 0.000 claims description 90
• 229910052739 hydrogen Inorganic materials 0.000 claims description 90
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 87
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 67
• 125000003118 aryl group Chemical group 0.000 claims description 61
• 150000002431 hydrogen Chemical group 0.000 claims description 61
• 125000001188 haloalkyl group Chemical group 0.000 claims description 57
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 47
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 37
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 30
• 125000001424 substituent group Chemical group 0.000 claims description 23
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
• 125000004429 atom Chemical group 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 19
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
• 238000001727 in vivo Methods 0.000 claims description 16
• 230000000694 effects Effects 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 229910052757 nitrogen Inorganic materials 0.000 claims description 11
• 230000014509 gene expression Effects 0.000 claims description 10
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 238000002560 therapeutic procedure Methods 0.000 claims description 8
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 7
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 238000000338 in vitro Methods 0.000 claims description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
• XFGGRVYEXSACGG-UHFFFAOYSA-N 6-(cyclobutylamino)-N-[2-hydroxy-3-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C1(CCC1)NC1=CC(=NC=N1)C(=O)NCC(CN1CC2=C(NC=3C=CC=CC2=3)CC1)O XFGGRVYEXSACGG-UHFFFAOYSA-N 0.000 claims description 4
• MOZRQAGODHFUAK-UHFFFAOYSA-N 6-(cyclobutylamino)-N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C1(CCC1)NC1=CC(=NC=N1)C(=O)NCC(CN1CC=2NC3=CC=CC=C3C=2CC1)O MOZRQAGODHFUAK-UHFFFAOYSA-N 0.000 claims description 4
• DOYGOTRVQLQXSK-UHFFFAOYSA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[2-hydroxy-3-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NCC(CN1CC2=C(NC=3C=CC=CC2=3)CC1)O DOYGOTRVQLQXSK-UHFFFAOYSA-N 0.000 claims description 4
• RUILVENRLKOEQO-UHFFFAOYSA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NCC(CN1CC=2NC3=CC=CC=C3C=2CC1)O RUILVENRLKOEQO-UHFFFAOYSA-N 0.000 claims description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• RUILVENRLKOEQO-LJQANCHMSA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[(2R)-2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NC[C@H](CN1CC=2NC3=CC=CC=C3C=2CC1)O RUILVENRLKOEQO-LJQANCHMSA-N 0.000 claims description 2
• RUILVENRLKOEQO-IBGZPJMESA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[(2S)-2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NC[C@@H](CN1CC=2NC3=CC=CC=C3C=2CC1)O RUILVENRLKOEQO-IBGZPJMESA-N 0.000 claims description 2
• HEIZPOCMYASBQF-UHFFFAOYSA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NCCCN1CC=2NC3=CC=CC=C3C=2CC1 HEIZPOCMYASBQF-UHFFFAOYSA-N 0.000 claims description 2
• FNDQIFHBWJDKML-UHFFFAOYSA-N [2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl] 3,4-dihydro-1H-isoquinoline-2-carboxylate Chemical compound C1N(CCC2=CC=CC=C12)C(=O)OCC(CN1CC=2NC3=CC=CC=C3C=2CC1)O FNDQIFHBWJDKML-UHFFFAOYSA-N 0.000 claims description 2
• HINOGIPUFJLPAK-UHFFFAOYSA-N [2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl] 3-phenylpyrrolidine-1-carboxylate Chemical compound C1(=CC=CC=C1)C1CN(CC1)C(=O)OCC(CN1CC=2NC3=CC=CC=C3C=2CC1)O HINOGIPUFJLPAK-UHFFFAOYSA-N 0.000 claims description 2
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 5
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
• WFSZLMCKQVAKIG-UHFFFAOYSA-N 2-(3-piperazin-1-ylpropyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole trihydrochloride Chemical compound Cl.Cl.Cl.C1N(CCC2=C1NC1=CC=CC=C21)CCCN2CCNCC2 WFSZLMCKQVAKIG-UHFFFAOYSA-N 0.000 claims 1
• IOXCOBDKZWKUOO-UHFFFAOYSA-N 2-(cyclobutylamino)-N-[2-hydroxy-3-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)propyl]-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide Chemical compound C1(CCC1)NC1=NC(=CC(=C1)C(=O)NCC(CN1CC2=C(NC=3C=CC=CC2=3)CC1)O)N1CCN(CC1)C IOXCOBDKZWKUOO-UHFFFAOYSA-N 0.000 claims 1
• KZVDWPDFXBFKKB-UHFFFAOYSA-N 2-(cyclobutylamino)-N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide Chemical compound C1(CCC1)NC1=NC(=CC(=C1)C(=O)NCC(CN1CC=2NC3=CC=CC=C3C=2CC1)O)N1CCN(CC1)C KZVDWPDFXBFKKB-UHFFFAOYSA-N 0.000 claims 1
• UFBDGQMBYWJUOT-UHFFFAOYSA-N 6-(cyclobutylamino)-N-[2-hydroxy-3-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)propyl]-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide Chemical compound C1(CCC1)NC1=CC(=NC(=N1)N1CCN(CC1)C)C(=O)NCC(CN1CC2=C(NC=3C=CC=CC2=3)CC1)O UFBDGQMBYWJUOT-UHFFFAOYSA-N 0.000 claims 1
• CCWDVVMHKNOXPU-UHFFFAOYSA-N 6-(cyclobutylamino)-N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide Chemical compound C1(CCC1)NC1=CC(=NC(=N1)N1CCN(CC1)C)C(=O)NCC(CN1CC=2NC3=CC=CC=C3C=2CC1)O CCWDVVMHKNOXPU-UHFFFAOYSA-N 0.000 claims 1
• YQFQACQEUDFVOC-UHFFFAOYSA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[2-hydroxy-3-(9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2-yl)propyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NCC(CN1CC=2N(C3=CC=CC=C3C=2CC1)C)O YQFQACQEUDFVOC-UHFFFAOYSA-N 0.000 claims 1
• FWEDLOSNMZRUNG-UHFFFAOYSA-N 6-[(1-acetylpiperidin-4-yl)amino]-N-[3-(3,4-dihydro-1H-pyrazino[1,2-a]indol-2-yl)-2-hydroxypropyl]pyrimidine-4-carboxamide Chemical compound C(C)(=O)N1CCC(CC1)NC1=CC(=NC=N1)C(=O)NCC(CN1CC=2N(C=3C=CC=CC=3C=2)CC1)O FWEDLOSNMZRUNG-UHFFFAOYSA-N 0.000 claims 1
• KIEBMLKNWHLABS-UHFFFAOYSA-N C1C2=CC=CC=C2CN1CCCN1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 Chemical compound C1C2=CC=CC=C2CN1CCCN1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 KIEBMLKNWHLABS-UHFFFAOYSA-N 0.000 claims 1
• CEFYRHKEFRHEIC-UHFFFAOYSA-N C1CC(C2=CC=CC=C2N2)=C2CN1CCCN(C)CC1=CC=CC=C1 Chemical compound C1CC(C2=CC=CC=C2N2)=C2CN1CCCN(C)CC1=CC=CC=C1 CEFYRHKEFRHEIC-UHFFFAOYSA-N 0.000 claims 1
• YKXWZQXJSLUKEV-UHFFFAOYSA-N C1CC(C2=CC=CC=C2N2)=C2CN1CCCN(C)CCC1=CC=CC=C1 Chemical compound C1CC(C2=CC=CC=C2N2)=C2CN1CCCN(C)CCC1=CC=CC=C1 YKXWZQXJSLUKEV-UHFFFAOYSA-N 0.000 claims 1
• LAEZOUGAISLBDR-UHFFFAOYSA-N C1CC=2OC3=CC=CC=C3C=2CN1CCCN(C)CC1=CC=CC=C1 Chemical compound C1CC=2OC3=CC=CC=C3C=2CN1CCCN(C)CC1=CC=CC=C1 LAEZOUGAISLBDR-UHFFFAOYSA-N 0.000 claims 1
• FISMYRQXBFPFIR-UHFFFAOYSA-N C1CC=2OC3=CC=CC=C3C=2CN1CCCN(C)CCC1=CC=CC=C1 Chemical compound C1CC=2OC3=CC=CC=C3C=2CN1CCCN(C)CCC1=CC=CC=C1 FISMYRQXBFPFIR-UHFFFAOYSA-N 0.000 claims 1
• VTCDQYAWFPIBBB-UHFFFAOYSA-N C=1C=CC=CC=1CCN(C)CCCN1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 Chemical compound C=1C=CC=CC=1CCN(C)CCCN1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 VTCDQYAWFPIBBB-UHFFFAOYSA-N 0.000 claims 1
• YGMOUIUWBGYGMW-UHFFFAOYSA-N C=1C=CC=CC=1CN(C)CCCN1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 Chemical compound C=1C=CC=CC=1CN(C)CCCN1CCC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1 YGMOUIUWBGYGMW-UHFFFAOYSA-N 0.000 claims 1
• CTSDFYHWEZHHFR-UHFFFAOYSA-N N-[2-hydroxy-3-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)propyl]-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide Chemical compound OC(CNC(C1=CC=C(C=C1)C(=O)N1C2COCC1CC2)=O)CN1CC2=C(NC=3C=CC=CC2=3)CC1 CTSDFYHWEZHHFR-UHFFFAOYSA-N 0.000 claims 1
• IJXFUGSRMZWZTG-UHFFFAOYSA-N N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-3,4-dihydro-1H-isoquinoline-2-carboxamide Chemical compound OC(CNC(=O)N1CC2=CC=CC=C2CC1)CN1CC=2NC3=CC=CC=C3C=2CC1 IJXFUGSRMZWZTG-UHFFFAOYSA-N 0.000 claims 1
• FDDDLKYUJOYUPP-UHFFFAOYSA-N N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-3-phenylpiperidine-1-carboxamide Chemical compound OC(CNC(=O)N1CC(CCC1)C1=CC=CC=C1)CN1CC=2NC3=CC=CC=C3C=2CC1 FDDDLKYUJOYUPP-UHFFFAOYSA-N 0.000 claims 1
• VXTOIHWDEBRQSW-UHFFFAOYSA-N N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-3-phenylpyrrolidine-1-carboxamide Chemical compound OC(CNC(=O)N1CCC(C1)C1=CC=CC=C1)CN1CCC2=C(C1)NC1=CC=CC=C21 VXTOIHWDEBRQSW-UHFFFAOYSA-N 0.000 claims 1
• CYMRXKIMQAVJSB-UHFFFAOYSA-N N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide Chemical compound OC(CNC(C1=CC=C(C=C1)C(=O)N1C2COCC1CC2)=O)CN1CC=2NC3=CC=CC=C3C=2CC1 CYMRXKIMQAVJSB-UHFFFAOYSA-N 0.000 claims 1
• PDHVRMGIMXWJJB-UHFFFAOYSA-N N-[2-hydroxy-3-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)propyl]-4-(morpholine-4-carbonyl)benzamide Chemical compound OC(CNC(C1=CC=C(C=C1)C(=O)N1CCOCC1)=O)CN1CC=2NC3=CC=CC=C3C=2CC1 PDHVRMGIMXWJJB-UHFFFAOYSA-N 0.000 claims 1
• BMVWYOJMXCGYLS-UHFFFAOYSA-N N-[2-hydroxy-3-(5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2-yl)propyl]-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide Chemical compound OC(CNC(C1=CC=C(C=C1)C(=O)N1C2COCC1CC2)=O)CN1CC2=C(N(C=3C=CC=CC2=3)C)CC1 BMVWYOJMXCGYLS-UHFFFAOYSA-N 0.000 claims 1
• CAMABNYAOJETNP-UHFFFAOYSA-N N-[2-hydroxy-3-(9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2-yl)propyl]-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide Chemical compound OC(CNC(C1=CC=C(C=C1)C(=O)N1C2COCC1CC2)=O)CN1CC=2N(C3=CC=CC=C3C=2CC1)C CAMABNYAOJETNP-UHFFFAOYSA-N 0.000 claims 1
• LALXXHGAQDGIOH-UHFFFAOYSA-N N1C2=CC=CC=C2C(CC2)=C1CN2CCCN1CC2=CC=CC=C2C1 Chemical compound N1C2=CC=CC=C2C(CC2)=C1CN2CCCN1CC2=CC=CC=C2C1 LALXXHGAQDGIOH-UHFFFAOYSA-N 0.000 claims 1
• NAHFFBVGHJZTNG-UHFFFAOYSA-N O1C2=CC=CC=C2C(C2)=C1CCN2CCCN1CC2=CC=CC=C2C1 Chemical compound O1C2=CC=CC=C2C(C2)=C1CCN2CCCN1CC2=CC=CC=C2C1 NAHFFBVGHJZTNG-UHFFFAOYSA-N 0.000 claims 1
• 230000002265 prevention Effects 0.000 abstract description 8
• 150000004677 hydrates Chemical class 0.000 abstract 1
• 125000000217 alkyl group Chemical group 0.000 description 154
• 239000011541 reaction mixture Substances 0.000 description 114
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 69
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 64
• 239000000243 solution Substances 0.000 description 63
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 56
• 230000002829 reductive effect Effects 0.000 description 56
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
• 101000924530 Homo sapiens Protein arginine N-methyltransferase 5 Proteins 0.000 description 50
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• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
• 238000005160 1H NMR spectroscopy Methods 0.000 description 36
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 241000689227 Cora <basidiomycete fungus> Species 0.000 description 36
• 208000035475 disorder Diseases 0.000 description 35
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• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 29
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
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• 239000007832 Na2SO4 Substances 0.000 description 27
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
• 229910052938 sodium sulfate Inorganic materials 0.000 description 27
• 235000011152 sodium sulphate Nutrition 0.000 description 27
• 125000006413 ring segment Chemical group 0.000 description 26
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
• 239000013058 crude material Substances 0.000 description 25
• HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 25
• 238000003786 synthesis reaction Methods 0.000 description 24
• 230000015572 biosynthetic process Effects 0.000 description 22
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• 125000004432 carbon atom Chemical group C* 0.000 description 21
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• 238000000746 purification Methods 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
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• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
• 210000004027 cell Anatomy 0.000 description 18
• 125000004122 cyclic group Chemical group 0.000 description 17
• 150000002148 esters Chemical class 0.000 description 17
• 239000003112 inhibitor Substances 0.000 description 17
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 201000010099 disease Diseases 0.000 description 16
• 229940002612 prodrug Drugs 0.000 description 16
• 239000000651 prodrug Substances 0.000 description 16
• UZFKIHMFDWGBKC-UHFFFAOYSA-N pyridine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=C1.NC(=O)C1=CC=NC=C1 UZFKIHMFDWGBKC-UHFFFAOYSA-N 0.000 description 16
• 238000003818 flash chromatography Methods 0.000 description 14
• 125000004438 haloalkoxy group Chemical group 0.000 description 14
• 239000012299 nitrogen atmosphere Substances 0.000 description 14
• 239000011698 potassium fluoride Substances 0.000 description 14
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