AU2021383176A1 - Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator - Google Patents

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Publication number

AU2021383176A1

AU2021383176A1 AU2021383176A AU2021383176A AU2021383176A1 AU 2021383176 A1 AU2021383176 A1 AU 2021383176A1 AU 2021383176 A AU2021383176 A AU 2021383176A AU 2021383176 A AU2021383176 A AU 2021383176A AU 2021383176 A1 AU2021383176 A1 AU 2021383176A1

Authority

AU

Australia

Prior art keywords

compound

independently selected

optionally substituted

therapeutic agent

pharmaceutically acceptable

Prior art date

2020-11-18

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.)

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• 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 title abstract description 100
• 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 title abstract description 98
• 150000002678 macrocyclic compounds Chemical class 0.000 title description 19
• FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 title description 2
• 238000000034 method Methods 0.000 claims abstract description 196
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 104
• 201000003883 Cystic fibrosis Diseases 0.000 claims abstract description 39
• 150000001875 compounds Chemical class 0.000 claims description 1162
• 150000003839 salts Chemical class 0.000 claims description 353
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 179
• 229910052736 halogen Inorganic materials 0.000 claims description 176
• 150000002367 halogens Chemical class 0.000 claims description 176
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 126
• 239000003814 drug Substances 0.000 claims description 114
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 107
• 125000000623 heterocyclic group Chemical group 0.000 claims description 95
• 229910052739 hydrogen Inorganic materials 0.000 claims description 82
• 239000001257 hydrogen Substances 0.000 claims description 82
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 74
• 125000004429 atom Chemical group 0.000 claims description 68
• 150000002431 hydrogen Chemical class 0.000 claims description 60
• 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 52
• -1 and Q) Chemical group 0.000 claims description 45
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 41
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 36
• 239000003795 chemical substances by application Substances 0.000 claims description 33
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 30
• WOXOLLSAICIZNO-UHFFFAOYSA-N [5-[3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridin-2-yl]-1,3,4-oxadiazol-2-yl]methanol Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=CC=C(C=C1)OC(F)(F)F)C1=NN=C(O1)CO WOXOLLSAICIZNO-UHFFFAOYSA-N 0.000 claims description 24
• HBZAZSCNDMDWEU-WREZULKGSA-N 3,5-diamino-6-chloro-n-[n'-[4-[4-[2-[hexyl-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]amino]ethoxy]phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide Chemical compound C1=CC(OCCN(CCCCCC)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)=CC=C1CCCCNC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N HBZAZSCNDMDWEU-WREZULKGSA-N 0.000 claims description 23
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
• 239000003937 drug carrier Substances 0.000 claims description 20
• IGEOJNMYRZUKIK-IBGZPJMESA-N N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide Chemical compound C[C@@H]1CN(C2=NC(=CC=C2C(=O)NS(=O)(=O)C2=CC=CC=C2)N2C=CC(OCCC3(CC3)C(F)(F)F)=N2)C(C)(C)C1 IGEOJNMYRZUKIK-IBGZPJMESA-N 0.000 claims description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
• PURKAOJPTOLRMP-ASMGOKTBSA-N n-[2-tert-butyl-4-[1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-yl]-5-hydroxyphenyl]-4-oxo-1h-quinoline-3-carboxamide Chemical compound C1=C(O)C(C(C([2H])([2H])[2H])(C([2H])([2H])[2H])C([2H])([2H])[2H])=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-ASMGOKTBSA-N 0.000 claims description 16
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
• XPEHHUISIBFLHX-RAIGVLPGSA-N O[C@H](C)C1=NN=C(O1)[C@@H]1C[C@H](C1)NC(=O)C1=CC(=NO1)C1=CC=CC=C1 Chemical compound O[C@H](C)C1=NN=C(O1)[C@@H]1C[C@H](C1)NC(=O)C1=CC(=NO1)C1=CC=CC=C1 XPEHHUISIBFLHX-RAIGVLPGSA-N 0.000 claims description 15
• 230000000694 effects Effects 0.000 claims description 14
• 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 14
• NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 13
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 11
• 239000003623 enhancer Substances 0.000 claims description 10
• 125000003003 spiro group Chemical group 0.000 claims description 10
• QUDOHCFOJCNKPK-QGZVFWFLSA-N 8-methyl-2-(3-methyl-1-benzofuran-2-yl)-5-[(1R)-1-(oxan-4-yl)ethoxy]quinoline-4-carboxylic acid Chemical compound O1CCC(CC1)[C@@H](C)OC1=C2C(=CC(=NC2=C(C=C1)C)C=1OC2=C(C=1C)C=CC=C2)C(=O)O QUDOHCFOJCNKPK-QGZVFWFLSA-N 0.000 claims description 9
• QVDYQHXNAQHIKH-TZIWHRDSSA-N galicaftor Chemical compound FC1(OC2=C(O1)C=CC(=C2)C1(CC1)C(=O)N[C@@H]1C[C@@H](OC2=CC(=CC=C12)OC(F)F)C1=CC=C(C(=O)O)C=C1)F QVDYQHXNAQHIKH-TZIWHRDSSA-N 0.000 claims description 9
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 9
• YFEYDNAKCSOOOG-YCXOGWGTSA-N (2S,3R,4S,5S)-3-tert-butyl-4-[[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methoxy]-5-(2-methylphenyl)-1-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1OCC=1C(=NC=C(C=1)C(F)(F)F)OC)C1=C(C=CC=C1)C)C(=O)[C@H]1OCCCC1)C(=O)O YFEYDNAKCSOOOG-YCXOGWGTSA-N 0.000 claims description 8
• KJBRSTPUILEBDR-DBMIJKFDSA-N (2r,3s,4r,5r,6s)-5-amino-6-[(1r,2r,3s,4r,6s)-4,6-diamino-2-[(2s,3r,4s,5r)-5-[(1s)-1-aminoethyl]-3,4-dihydroxyoxolan-2-yl]oxy-3-hydroxycyclohexyl]oxy-2-[(1r)-1-hydroxyethyl]oxane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H]([C@@H](N)C)O[C@H]1O[C@H]1[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H]([C@@H](C)O)O2)N)[C@@H](N)C[C@@H](N)[C@@H]1O KJBRSTPUILEBDR-DBMIJKFDSA-N 0.000 claims description 8
• XRPSUWYWZUQALB-UHFFFAOYSA-N 2-[7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2-yl]-n-methyl-n-(2-methyl-1,3-benzoxazol-6-yl)acetamide Chemical compound N=1N(CC(=O)N(C)C=2C=C3OC(C)=NC3=CC=2)C(=O)C2=CC(OCC)=CC=C2C=1C1=CC=CC(F)=C1 XRPSUWYWZUQALB-UHFFFAOYSA-N 0.000 claims description 8
• UMOGNCVNHXWFIX-VIFPVBQESA-N 3-amino-N-[(2S)-2-hydroxypropyl]-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=CC=C(C=C1)OC(F)(F)F)C(=O)NC[C@H](C)O UMOGNCVNHXWFIX-VIFPVBQESA-N 0.000 claims description 8
• GHTGYZMBQPXTCQ-UHFFFAOYSA-N CC1(C)Cc2c(sc(NC(=O)c3ccn[nH]3)c2C(N)=O)C(C)(C)O1 Chemical compound CC1(C)Cc2c(sc(NC(=O)c3ccn[nH]3)c2C(N)=O)C(C)(C)O1 GHTGYZMBQPXTCQ-UHFFFAOYSA-N 0.000 claims description 8
• 229940126130 GLPG2451 Drugs 0.000 claims description 8
• TYQIFWXBQYAKCR-UHFFFAOYSA-N N-[5-hydroxy-2,4-bis(trimethylsilyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide Chemical compound C[Si](C)(C)C1=CC(=C(NC(=O)C2=CNC3=C(C=CC=C3)C2=O)C=C1O)[Si](C)(C)C TYQIFWXBQYAKCR-UHFFFAOYSA-N 0.000 claims description 8
• XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 claims description 8
• 229960002576 amiloride Drugs 0.000 claims description 8
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 229940070817 icenticaftor Drugs 0.000 claims description 8
• 229940015640 navocaftor Drugs 0.000 claims description 8
• 125000004043 oxo group Chemical group O=* 0.000 claims description 8
• ZYOATBKPEFZNGP-UHFFFAOYSA-N 3,5-diamino-6-chloro-n-[n'-[4-[4-(2,3-dihydroxypropoxy)phenyl]butyl]carbamimidoyl]pyrazine-2-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.N1=C(Cl)C(N)=NC(N)=C1C(=O)NC(=N)NCCCCC1=CC=C(OCC(O)CO)C=C1 ZYOATBKPEFZNGP-UHFFFAOYSA-N 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 150000007523 nucleic acids Chemical class 0.000 claims description 7
• 102000039446 nucleic acids Human genes 0.000 claims description 7
• 108020004707 nucleic acids Proteins 0.000 claims description 7
• 238000002560 therapeutic procedure Methods 0.000 claims description 7
• MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical compound FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 claims description 6
• 102000003787 Anoctamin-1 Human genes 0.000 claims description 6
• 108090000160 Anoctamin-1 Proteins 0.000 claims description 6
• 229940126052 ENaC inhibitor Drugs 0.000 claims description 6
• 229940123084 GPR39 agonist Drugs 0.000 claims description 6
• MVRHVFSOIWFBTE-INIZCTEOSA-N N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide Chemical compound CN1N=C(C(=C1)S(=O)(=O)NC(=O)C=1C(=NC(=CC=1)N1N=C(C=C1)OCC(C(F)(F)F)(C)C)N1C(C[C@@H](C1)C)(C)C)C MVRHVFSOIWFBTE-INIZCTEOSA-N 0.000 claims description 6
• 239000002713 epithelial sodium channel blocking agent Substances 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 claims description 6
• UFSKUSARDNFIRC-UHFFFAOYSA-N lumacaftor Chemical compound N1=C(C=2C=C(C=CC=2)C(O)=O)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 UFSKUSARDNFIRC-UHFFFAOYSA-N 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 3
• ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 3
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 17
• FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 4
• HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 3
• USHQRIKZLHNPQR-SNVBAGLBSA-N 3-amino-6-methoxy-n-[(2r)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide Chemical compound COC1=NC(C(=O)NC[C@@](C)(O)C(F)(F)F)=C(N)C=C1C(F)(F)F USHQRIKZLHNPQR-SNVBAGLBSA-N 0.000 claims 2
• FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 2
• 230000008569 process Effects 0.000 abstract description 22
• 235000002639 sodium chloride Nutrition 0.000 description 320
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 240
• 229910052740 iodine Inorganic materials 0.000 description 124
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• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 96
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• 239000000203 mixture Substances 0.000 description 91
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