BR112021007861A2 - compostos heterocíclicos substituídos por amida - Google Patents

Info

Publication number

BR112021007861A2

BR112021007861A2 BR112021007861-4A BR112021007861A BR112021007861A2 BR 112021007861 A2 BR112021007861 A2 BR 112021007861A2 BR 112021007861 A BR112021007861 A BR 112021007861A BR 112021007861 A2 BR112021007861 A2 BR 112021007861A2

Authority

BR

Brazil

Prior art keywords

substituted

alkyl

occurrence

independently

membered

Prior art date

2018-10-30

Links

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• -1 amide substituted heterocyclic compounds Chemical class 0.000 title claims description 110
• 150000001875 compounds Chemical class 0.000 claims abstract description 157
• 150000003839 salts Chemical class 0.000 claims abstract description 63
• 238000000034 method Methods 0.000 claims description 265
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 192
• 125000000623 heterocyclic group Chemical group 0.000 claims description 154
• 229910052739 hydrogen Inorganic materials 0.000 claims description 115
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 111
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 100
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 96
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 84
• 239000001257 hydrogen Substances 0.000 claims description 77
• 101150105130 RORB gene Proteins 0.000 claims description 72
• 150000002431 hydrogen Chemical class 0.000 claims description 71
• 229910052794 bromium Inorganic materials 0.000 claims description 65
• 229910052801 chlorine Inorganic materials 0.000 claims description 63
• 229910052731 fluorine Inorganic materials 0.000 claims description 63
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 58
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 58
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 57
• 201000010099 disease Diseases 0.000 claims description 50
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 46
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 38
• 201000006417 multiple sclerosis Diseases 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 33
• 229910052736 halogen Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical class 0.000 claims description 25
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 24
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 24
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 24
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 24
• 239000003814 drug Substances 0.000 claims description 22
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 20
• 208000023275 Autoimmune disease Diseases 0.000 claims description 17
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 14
• 201000004681 Psoriasis Diseases 0.000 claims description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
• 150000003852 triazoles Chemical group 0.000 claims description 14
• 125000001475 halogen functional group Chemical group 0.000 claims description 13
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 13
• 208000011231 Crohn disease Diseases 0.000 claims description 12
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
• 208000027866 inflammatory disease Diseases 0.000 claims description 11
• 238000002360 preparation method Methods 0.000 claims description 11
• 239000003937 drug carrier Substances 0.000 claims description 10
• WCYWZMWISLQXQU-FIBGUPNXSA-N trideuteriomethane Chemical compound [2H][C]([2H])[2H] WCYWZMWISLQXQU-FIBGUPNXSA-N 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 8
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 8
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 8
• 230000002757 inflammatory effect Effects 0.000 claims description 8
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 8
• 150000003217 pyrazoles Chemical group 0.000 claims description 8
• 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 7
• 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 6
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 6
• 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 5
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 5
• 206010039710 Scleroderma Diseases 0.000 claims description 4
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• 108010065637 Interleukin-23 Proteins 0.000 abstract description 40
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• 108010065805 Interleukin-12 Proteins 0.000 abstract description 36
• 102000013462 Interleukin-12 Human genes 0.000 abstract description 36
• 230000011234 negative regulation of signal transduction Effects 0.000 abstract description 3
• 150000001420 substituted heterocyclic compounds Chemical class 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 181
• 238000004128 high performance liquid chromatography Methods 0.000 description 149
• 150000002500 ions Chemical class 0.000 description 130
• 238000006243 chemical reaction Methods 0.000 description 100
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 90
• 239000000203 mixture Substances 0.000 description 88
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
• 235000019439 ethyl acetate Nutrition 0.000 description 81
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 74
• 239000000243 solution Substances 0.000 description 68
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 59
• 239000007787 solid Substances 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• 239000011541 reaction mixture Substances 0.000 description 45
• 239000000460 chlorine Substances 0.000 description 43
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 38
• 229910052938 sodium sulfate Inorganic materials 0.000 description 37
• 235000011152 sodium sulphate Nutrition 0.000 description 37
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 28
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 27
• 238000005160 1H NMR spectroscopy Methods 0.000 description 26
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
• 229910052757 nitrogen Inorganic materials 0.000 description 25
• 125000001424 substituent group Chemical group 0.000 description 25
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 24
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
• 239000012267 brine Substances 0.000 description 23
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
• 238000004519 manufacturing process Methods 0.000 description 22
• 230000026731 phosphorylation Effects 0.000 description 22
• 238000006366 phosphorylation reaction Methods 0.000 description 22
• 238000003818 flash chromatography Methods 0.000 description 21
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• 101100366892 Anopheles gambiae Stat gene Proteins 0.000 description 19
• 101100366894 Drosophila melanogaster Stat92E gene Proteins 0.000 description 19
• 125000003118 aryl group Chemical group 0.000 description 18
• 230000005587 bubbling Effects 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 235000019198 oils Nutrition 0.000 description 18
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
• AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 17
• 239000010410 layer Substances 0.000 description 16
• 239000000463 material Substances 0.000 description 16
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• 125000004429 atom Chemical group 0.000 description 14
• 229910000024 caesium carbonate Inorganic materials 0.000 description 14
• 238000001914 filtration Methods 0.000 description 14
• 125000001072 heteroaryl group Chemical group 0.000 description 14
• 229920006395 saturated elastomer Polymers 0.000 description 14
• 239000002253 acid Substances 0.000 description 13
• 229910052799 carbon Inorganic materials 0.000 description 13
• 125000005843 halogen group Chemical group 0.000 description 13
• 230000001404 mediated effect Effects 0.000 description 13
• 239000007832 Na2SO4 Substances 0.000 description 12
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• 125000002619 bicyclic group Chemical group 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
• 125000005842 heteroatom Chemical group 0.000 description 12
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 12
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
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• 238000003756 stirring Methods 0.000 description 12
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• DMYLUKNFEYWGCH-UHFFFAOYSA-N pyridazine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=N1 DMYLUKNFEYWGCH-UHFFFAOYSA-N 0.000 description 11
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 10
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• 102000004127 Cytokines Human genes 0.000 description 10
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• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
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