CA3020792A1 - Conjugates comprising ripk2 inhibitors - Google Patents

Info

Publication number

CA3020792A1

CA3020792A1 CA3020792A CA3020792A CA3020792A1 CA 3020792 A1 CA3020792 A1 CA 3020792A1 CA 3020792 A CA3020792 A CA 3020792A CA 3020792 A CA3020792 A CA 3020792A CA 3020792 A1 CA3020792 A1 CA 3020792A1

Authority

CA

Canada

Prior art keywords

tert

dimethyl

methylpiperazin

pyrazol

quinazolin

Prior art date

2016-04-20

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
• Global Dossier
• CIPO
• Discuss

• 239000003112 inhibitor Substances 0.000 title claims abstract description 16
• 150000001875 compounds Chemical class 0.000 claims abstract description 319
• 238000000034 method Methods 0.000 claims abstract description 263
• 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 claims abstract description 70
• 101001109137 Homo sapiens Receptor-interacting serine/threonine-protein kinase 2 Proteins 0.000 claims abstract description 66
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 44
• 239000003814 drug Substances 0.000 claims abstract description 36
• 201000010099 disease Diseases 0.000 claims abstract description 35
• 230000001404 mediated effect Effects 0.000 claims abstract description 29
• 238000011282 treatment Methods 0.000 claims abstract description 26
• 230000000593 degrading effect Effects 0.000 claims abstract description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 132
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 103
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 86
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 78
• 150000003839 salts Chemical class 0.000 claims description 69
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 54
• 229910052757 nitrogen Inorganic materials 0.000 claims description 50
• -1 cyano, hydroxyl Chemical group 0.000 claims description 47
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 38
• 239000008194 pharmaceutical composition Substances 0.000 claims description 29
• 229910052736 halogen Inorganic materials 0.000 claims description 24
• 125000005647 linker group Chemical group 0.000 claims description 22
• 229940124597 therapeutic agent Drugs 0.000 claims description 20
• 150000002367 halogens Chemical class 0.000 claims description 18
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
• 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
• 125000005843 halogen group Chemical group 0.000 claims description 14
• 241000282414 Homo sapiens Species 0.000 claims description 13
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
• 125000003118 aryl group Chemical group 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 10
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 238000002560 therapeutic procedure Methods 0.000 claims description 7
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 4
• 125000003545 alkoxy group Chemical group 0.000 claims description 4
• 230000027455 binding Effects 0.000 claims description 4
• PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 claims description 4
• 125000004432 carbon atom Chemical group C* 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
• 229940043355 kinase inhibitor Drugs 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 4
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
• 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
• 125000002947 alkylene group Chemical group 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims description 2
• 239000001301 oxygen Substances 0.000 claims description 2
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 125000003003 spiro group Chemical group 0.000 claims description 2
• 101000733257 Homo sapiens Rho guanine nucleotide exchange factor 28 Proteins 0.000 claims 1
• 229910052717 sulfur Inorganic materials 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 71
• 230000000694 effects Effects 0.000 abstract description 9
• 230000008569 process Effects 0.000 abstract description 7
• 238000002360 preparation method Methods 0.000 abstract description 5
• 208000027866 inflammatory disease Diseases 0.000 abstract description 3
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 228
• 238000006243 chemical reaction Methods 0.000 description 181
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 162
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 160
• 239000000243 solution Substances 0.000 description 149
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 131
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 123
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 108
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 87
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 68
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 65
• 238000000746 purification Methods 0.000 description 63
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 55
• 235000002639 sodium chloride Nutrition 0.000 description 53
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 45
• 239000003607 modifier Substances 0.000 description 41
• 238000003818 flash chromatography Methods 0.000 description 37
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
• 238000002953 preparative HPLC Methods 0.000 description 36
• 239000012298 atmosphere Substances 0.000 description 35
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 33
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
• 235000019253 formic acid Nutrition 0.000 description 33
• 239000012044 organic layer Substances 0.000 description 33
• 239000011541 reaction mixture Substances 0.000 description 33
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 31
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
• 239000003039 volatile agent Substances 0.000 description 30
• 230000004054 inflammatory process Effects 0.000 description 29
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 28
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
• 239000012071 phase Substances 0.000 description 28
• 206010061218 Inflammation Diseases 0.000 description 27
• 239000012267 brine Substances 0.000 description 27
• 239000002253 acid Substances 0.000 description 26
• DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 24
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 23
• 239000002904 solvent Substances 0.000 description 23
• ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• 239000001099 ammonium carbonate Substances 0.000 description 21
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 21
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• 229910000027 potassium carbonate Inorganic materials 0.000 description 18
• 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 17
• 235000012538 ammonium bicarbonate Nutrition 0.000 description 17
• 239000003795 chemical substances by application Substances 0.000 description 17
• 239000012043 crude product Substances 0.000 description 17
• 235000011181 potassium carbonates Nutrition 0.000 description 17
• 239000007821 HATU Substances 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 235000009518 sodium iodide Nutrition 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
• RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 14
• 239000000047 product Substances 0.000 description 14
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• 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 description 11
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• 230000004044 response Effects 0.000 description 8
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