CA3201793A1 - Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator - Google Patents

Info

Publication number

CA3201793A1

CA3201793A1 CA3201793A CA3201793A CA3201793A1 CA 3201793 A1 CA3201793 A1 CA 3201793A1 CA 3201793 A CA3201793 A CA 3201793A CA 3201793 A CA3201793 A CA 3201793A CA 3201793 A1 CA3201793 A1 CA 3201793A1

Authority

CA

Canada

Prior art keywords

compound

independently selected

optionally substituted

pharmaceutically acceptable

therapeutic agent

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.)

Pending

Links

• Espacenet
• Global Dossier
• CIPO
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• 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 title abstract description 87
• 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 title abstract description 5
• 150000002678 macrocyclic compounds Chemical class 0.000 title description 16
• FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 title 1
• 238000000034 method Methods 0.000 claims abstract description 204
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 99
• 201000003883 Cystic fibrosis Diseases 0.000 claims abstract description 49
• 150000001875 compounds Chemical class 0.000 claims description 1186
• 150000003839 salts Chemical class 0.000 claims description 354
• 229910052736 halogen Inorganic materials 0.000 claims description 176
• 150000002367 halogens Chemical class 0.000 claims description 176
• 239000000203 mixture Substances 0.000 claims description 113
• 239000003814 drug Substances 0.000 claims description 112
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 108
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 94
• 229910052739 hydrogen Inorganic materials 0.000 claims description 85
• 239000001257 hydrogen Substances 0.000 claims description 82
• 125000000623 heterocyclic group Chemical group 0.000 claims description 81
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 79
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 78
• 125000004429 atom Chemical group 0.000 claims description 69
• 150000002431 hydrogen Chemical class 0.000 claims description 55
• -1 and Q) Chemical group 0.000 claims description 53
• 125000003118 aryl group Chemical group 0.000 claims description 51
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 39
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
• 125000003545 alkoxy group Chemical group 0.000 claims description 38
• FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 claims description 36
• 239000003795 chemical substances by application Substances 0.000 claims description 35
• OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 claims description 32
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 30
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 29
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 28
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
• 125000000217 alkyl group Chemical group 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
• 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 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 22
• 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 20
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
• 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 20
• 239000003937 drug carrier Substances 0.000 claims description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
• 229910052760 oxygen Inorganic materials 0.000 claims description 15
• 230000000694 effects Effects 0.000 claims description 14
• 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
• 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 11
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 239000003623 enhancer Substances 0.000 claims description 10
• 125000003003 spiro group Chemical group 0.000 claims description 10
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
• 239000002253 acid Substances 0.000 claims description 9
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 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
• 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 7
• 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
• 229940015640 navocaftor Drugs 0.000 claims description 7
• 150000007523 nucleic acids Chemical class 0.000 claims description 7
• 108020004707 nucleic acids Proteins 0.000 claims description 7
• 102000039446 nucleic acids Human genes 0.000 claims description 7
• 125000004043 oxo group Chemical group O=* 0.000 claims description 7
• 238000002560 therapeutic procedure Methods 0.000 claims description 7
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
• 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 6
• 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 6
• 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 description 6
• 229940126052 ENaC inhibitor Drugs 0.000 claims description 6
• XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 claims description 6
• 229960002576 amiloride Drugs 0.000 claims description 6
• 239000002713 epithelial sodium channel blocking agent Substances 0.000 claims description 6
• 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 6
• 229940070817 icenticaftor Drugs 0.000 claims description 6
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
• 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 5
• 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 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 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 4
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
• 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 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 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
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
• 102100030280 G-protein coupled receptor 39 Human genes 0.000 claims description 2
• 101001009541 Homo sapiens G-protein coupled receptor 39 Proteins 0.000 claims description 2
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 17
• 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 1
• XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 1
• QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 claims 1
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 1
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• 239000000556 agonist Substances 0.000 claims 1
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• 235000002639 sodium chloride Nutrition 0.000 description 320
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 237
• 239000007787 solid Substances 0.000 description 120
• 229910052734 helium Inorganic materials 0.000 description 119
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 96
• 239000012071 phase Substances 0.000 description 96
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
• 102100023419 Cystic fibrosis transmembrane conductance regulator Human genes 0.000 description 80
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• 125000004356 hydroxy functional group Chemical group O* 0.000 description 77
• 239000000843 powder Substances 0.000 description 77
• 238000006243 chemical reaction Methods 0.000 description 76
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• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 62
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• 239000000243 solution Substances 0.000 description 55
• 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 48
• 235000019253 formic acid Nutrition 0.000 description 48
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• 230000014759 maintenance of location Effects 0.000 description 40
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• 230000035772 mutation Effects 0.000 description 34
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• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 31
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• 230000002829 reductive effect Effects 0.000 description 26
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