TWI752961B - 經雜芳基取代之吡啶及使用方法 - Google Patents

Info

Publication number

TWI752961B

TWI752961B TW106118418A TW106118418A TWI752961B TW I752961 B TWI752961 B TW I752961B TW 106118418 A TW106118418 A TW 106118418A TW 106118418 A TW106118418 A TW 106118418A TW I752961 B TWI752961 B TW I752961B

Authority

TW

Taiwan

Prior art keywords

amino

dihydro

sulfonyl

phenyl

carbonyl

Prior art date

2016-06-03

Links

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• 238000000034 method Methods 0.000 title abstract description 115
• 125000001072 heteroaryl group Chemical group 0.000 title description 39
• 150000003222 pyridines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 351
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 120
• -1 2-( 2-Fluorobenzylamino)-5,5,7,7-tetramethyl-5,7-dihydro- 4H -thieno[2,3- c ]pyran-3-carboxamide Chemical compound 0.000 claims description 116
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 60
• 239000003814 drug Substances 0.000 claims description 59
• 150000003839 salts Chemical class 0.000 claims description 59
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 52
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 45
• 229940124597 therapeutic agent Drugs 0.000 claims description 34
• 239000003623 enhancer Substances 0.000 claims description 24
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 22
• 239000003795 chemical substances by application Substances 0.000 claims description 21
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 15
• 239000003937 drug carrier Substances 0.000 claims description 12
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
• 239000002253 acid Substances 0.000 claims description 10
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
• 150000001412 amines Chemical class 0.000 claims description 9
• WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
• 239000005711 Benzoic acid Substances 0.000 claims description 8
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 7
• 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 7
• 235000010233 benzoic acid Nutrition 0.000 claims description 7
• CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 7
• 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 5
• 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 5
• 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 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 229960004508 ivacaftor Drugs 0.000 claims description 4
• 235000001968 nicotinic acid Nutrition 0.000 claims description 4
• 239000011664 nicotinic acid Substances 0.000 claims description 4
• 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 3
• HBJVZQDLEBFKFM-FUHWJXTLSA-N 4-[(2R,4S)-4-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]oxan-2-yl]benzoic acid Chemical compound FC1(OC2=C(O1)C=CC(=C2)C1(CC1)C(=O)N[C@@H]1C[C@@H](OCC1)C1=CC=C(C(=O)O)C=C1)F HBJVZQDLEBFKFM-FUHWJXTLSA-N 0.000 claims description 3
• 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 3
• MLIHJZWVFLXBEU-AXECJNCJSA-N FC(OC1=CC2=C([C@H](C[C@H](O2)[C@@H]2CC[C@H](CC2)C(=O)O)NC(=O)[C@]2(COC=3C2=CC2=C(OC(O2)(F)F)C=3)C)C=C1)F Chemical compound FC(OC1=CC2=C([C@H](C[C@H](O2)[C@@H]2CC[C@H](CC2)C(=O)O)NC(=O)[C@]2(COC=3C2=CC2=C(OC(O2)(F)F)C=3)C)C=C1)F MLIHJZWVFLXBEU-AXECJNCJSA-N 0.000 claims description 3
• 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 3
• 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 3
• 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 3
• 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 3
• NHOUNZMCSIHKHJ-FQEVSTJZSA-N olacaftor Chemical compound C1(=CC=CC=C1)S(=O)(=O)NC(=O)C=1C(=NC(=CC=1)C1=CC(=CC(=C1)OCC(C)C)F)N1C(C[C@@H](C1)C)(C)C NHOUNZMCSIHKHJ-FQEVSTJZSA-N 0.000 claims description 3
• NSOMEXTZFRFPTE-UHFFFAOYSA-N 2-[[1-(hydroxymethyl)cyclopropanecarbonyl]amino]-5,5,7,7-tetramethyl-4h-thieno[2,3-c]pyran-3-carboxamide Chemical compound S1C=2C(C)(C)OC(C)(C)CC=2C(C(N)=O)=C1NC(=O)C1(CO)CC1 NSOMEXTZFRFPTE-UHFFFAOYSA-N 0.000 claims description 2
• FRQHPMBRRRGMIB-MIHVYDCKSA-N 3-[(2R,4R)-4-[[(1S)-1,5-dimethyl-2,3-dihydroindene-1-carbonyl]amino]-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid Chemical compound C[C@@]1(CCC2=CC(=CC=C12)C)C(=O)N[C@@H]1C[C@@H](OC2=C1C=CC(=C2)OC)C=1C=C(C(=O)O)C=CC=1 FRQHPMBRRRGMIB-MIHVYDCKSA-N 0.000 claims description 2
• ADNXFCXKAMMQNI-FUHWJXTLSA-N 3-[(2R,4S)-4-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]oxan-2-yl]benzoic acid Chemical compound FC1(OC2=C(O1)C=CC(=C2)C1(CC1)C(=O)N[C@@H]1C[C@@H](OCC1)C=1C=C(C(=O)O)C=CC=1)F ADNXFCXKAMMQNI-FUHWJXTLSA-N 0.000 claims description 2
• OOMFMAUDWWBORL-JRFVFWCSSA-N 3-[(2S,4R,6R)-4-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-6-phenyloxan-2-yl]benzoic acid Chemical compound FC1(OC2=C(O1)C=CC(=C2)C1(CC1)C(=O)N[C@H]1C[C@H](O[C@H](C1)C1=CC=CC=C1)C=1C=C(C(=O)O)C=CC=1)F OOMFMAUDWWBORL-JRFVFWCSSA-N 0.000 claims description 2
• GHTUXVKUVBQHIR-UHFFFAOYSA-N 3-amino-5-(3,3-difluoroazetidin-1-yl)sulfonyl-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)N1CC(C1)(F)F)C(=O)NCC(C(F)(F)F)O GHTUXVKUVBQHIR-UHFFFAOYSA-N 0.000 claims description 2
• UIGDHBJBRFGZNX-UHFFFAOYSA-N 3-amino-5-(3-fluorophenyl)sulfonyl-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=CC(=CC=C1)F)C(=O)NCC(C)(C)O UIGDHBJBRFGZNX-UHFFFAOYSA-N 0.000 claims description 2
• DAMDGCGBHYXPIN-UHFFFAOYSA-N 3-amino-5-(4,4-difluoropiperidin-1-yl)sulfonyl-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)N1CCC(CC1)(F)F)C(=O)NCC(C(F)(F)F)O DAMDGCGBHYXPIN-UHFFFAOYSA-N 0.000 claims description 2
• NAXPHBUQEPZMOO-UHFFFAOYSA-N 3-amino-5-(4-fluorophenyl)sulfonyl-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=CC=C(C=C1)F)C(=O)NCC1(CC1)O NAXPHBUQEPZMOO-UHFFFAOYSA-N 0.000 claims description 2
• UIZPMUABDHMTPW-JTQLQIEISA-N 3-amino-5-[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl-N-[[(3S)-oxolan-3-yl]methyl]pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=C(C=C(C=C1)OC(F)(F)F)F)C(=O)NC[C@H]1COCC1 UIZPMUABDHMTPW-JTQLQIEISA-N 0.000 claims description 2
• XKLDRUOEMRSYCZ-SNVBAGLBSA-N 3-amino-5-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)F)C(=O)NC[C@H](COC)O XKLDRUOEMRSYCZ-SNVBAGLBSA-N 0.000 claims description 2
• BBCXWIZINNMFPI-QMMMGPOBSA-N 3-amino-5-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)F)C(=O)NC[C@H](C)O BBCXWIZINNMFPI-QMMMGPOBSA-N 0.000 claims description 2
• QVMGWHKQDBERMR-SNVBAGLBSA-N 3-amino-5-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-N-[[(3R)-oxolan-3-yl]methyl]pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)F)C(=O)NC[C@@H]1COCC1 QVMGWHKQDBERMR-SNVBAGLBSA-N 0.000 claims description 2
• QVMGWHKQDBERMR-JTQLQIEISA-N 3-amino-5-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-N-[[(3S)-oxolan-3-yl]methyl]pyridine-2-carboxamide Chemical compound NC=1C(=NC=C(C=1)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)F)C(=O)NC[C@H]1COCC1 QVMGWHKQDBERMR-JTQLQIEISA-N 0.000 claims description 2
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