KR20230113309A - P2x3 억제제로서 아미노 퀴나졸린 유도체 - Google Patents

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Publication number

KR20230113309A

KR20230113309A KR1020237018300A KR20237018300A KR20230113309A KR 20230113309 A KR20230113309 A KR 20230113309A KR 1020237018300 A KR1020237018300 A KR 1020237018300A KR 20237018300 A KR20237018300 A KR 20237018300A KR 20230113309 A KR20230113309 A KR 20230113309A

Authority

KR

South Korea

Prior art keywords

fluorophenyl

methyl

quinazolin

alkyl

ethyl

Prior art date

2020-11-27

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

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• CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 title abstract description 7
• 102100040460 P2X purinoceptor 3 Human genes 0.000 title description 4
• 239000003112 inhibitor Substances 0.000 title description 3
• 101710189970 P2X purinoceptor 3 Proteins 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 246
• 206010011224 Cough Diseases 0.000 claims abstract description 46
• 238000011282 treatment Methods 0.000 claims abstract description 36
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
• 208000006673 asthma Diseases 0.000 claims abstract description 14
• 201000010099 disease Diseases 0.000 claims abstract description 13
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 12
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 12
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 11
• -1 -NH-C(O)R 1 Chemical group 0.000 claims description 99
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 41
• 125000001072 heteroaryl group Chemical group 0.000 claims description 35
• 125000003118 aryl group Chemical group 0.000 claims description 33
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 29
• 125000005843 halogen group Chemical group 0.000 claims description 26
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 24
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 18
• 229910052757 nitrogen Inorganic materials 0.000 claims description 18
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
• 208000013116 chronic cough Diseases 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 16
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 208000009079 Bronchial Spasm Diseases 0.000 claims description 7
• 208000014181 Bronchial disease Diseases 0.000 claims description 7
• 206010006482 Bronchospasm Diseases 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
• 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 230000000642 iatrogenic effect Effects 0.000 claims description 4
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
• YUTUWCKCXVDZKP-UHFFFAOYSA-N CC(C=C1)=CN=C1C(C=C12)=CC(OCC(F)F)=C1N=CN=C2NCC1=CC=C(C)N=N1 Chemical compound CC(C=C1)=CN=C1C(C=C12)=CC(OCC(F)F)=C1N=CN=C2NCC1=CC=C(C)N=N1 YUTUWCKCXVDZKP-UHFFFAOYSA-N 0.000 claims description 3
• 238000011321 prophylaxis Methods 0.000 claims description 3
• CVXGFTCNUQQCKY-QGZVFWFLSA-N 6-(4-fluorophenyl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-8-morpholin-4-ylsulfonylquinazolin-4-amine Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)S(=O)(=O)N1CCOCC1)N[C@H](C)C=1N=NC(=CC=1)C CVXGFTCNUQQCKY-QGZVFWFLSA-N 0.000 claims description 2
• MZLKYBKWPSGBOI-QGZVFWFLSA-N 6-(4-fluorophenyl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-8-piperazin-1-ylsulfonylquinazolin-4-amine Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)S(=O)(=O)N1CCNCC1)N[C@H](C)C=1N=NC(=CC=1)C MZLKYBKWPSGBOI-QGZVFWFLSA-N 0.000 claims description 2
• ZQKHPHVBLCWOHR-UHFFFAOYSA-N CC1=CC=C(CNC(C2=CC(C(C=C3)=CC=C3F)=C3)=NC=NC2=C3OCC(F)F)N=N1 Chemical compound CC1=CC=C(CNC(C2=CC(C(C=C3)=CC=C3F)=C3)=NC=NC2=C3OCC(F)F)N=N1 ZQKHPHVBLCWOHR-UHFFFAOYSA-N 0.000 claims description 2
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• UAIJDYVQJJSSTA-PWSAKUHLSA-N C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2S(C)=O Chemical compound C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2S(C)=O UAIJDYVQJJSSTA-PWSAKUHLSA-N 0.000 claims description 2
• AWCMVDHMNTWASX-FJNJALAMSA-N C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2S(C1COC1)=O Chemical compound C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2S(C1COC1)=O AWCMVDHMNTWASX-FJNJALAMSA-N 0.000 claims description 2
• YSMLRYZOEYSPRK-CQSZACIVSA-N C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2SC Chemical compound C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2SC YSMLRYZOEYSPRK-CQSZACIVSA-N 0.000 claims description 2
• CKHFGHWVDRBEIZ-OAHLLOKOSA-N C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2SC1COC1 Chemical compound C[C@H](C1=CC=C(C)N=N1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2SC1COC1 CKHFGHWVDRBEIZ-OAHLLOKOSA-N 0.000 claims description 2
• VQEZUUOLCIEPKL-GFCCVEGCSA-N C[C@H](C1=CN=C(C(F)(F)F)N=C1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2OCC(F)F Chemical compound C[C@H](C1=CN=C(C(F)(F)F)N=C1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2OCC(F)F VQEZUUOLCIEPKL-GFCCVEGCSA-N 0.000 claims description 2
• 208000014085 Chronic respiratory disease Diseases 0.000 claims description 2
• 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 2
• JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 2
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
• 230000000241 respiratory effect Effects 0.000 claims description 2
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 6
• YWWYRHQDMDMIRC-OAHLLOKOSA-N 6-(4-fluorophenyl)-N,N-dimethyl-4-[[(1R)-1-(6-methylpyridazin-3-yl)ethyl]amino]quinazoline-8-sulfonamide Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)S(=O)(=O)N(C)C)N[C@H](C)C=1N=NC(=CC=1)C YWWYRHQDMDMIRC-OAHLLOKOSA-N 0.000 claims 2
• XGKUGULTUTWOLU-MRXNPFEDSA-N C[C@H](C1=CN=C(C(F)(F)F)N=C1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2OC(CC1)CCN1C(C)=O Chemical compound C[C@H](C1=CN=C(C(F)(F)F)N=C1)NC(C1=CC(C(C=C2)=CC=C2F)=C2)=NC=NC1=C2OC(CC1)CCN1C(C)=O XGKUGULTUTWOLU-MRXNPFEDSA-N 0.000 claims 2
• BQFNJNBPNARBNE-UHFFFAOYSA-N 6-(4-fluorophenyl)-8-[(3-methyloxetan-3-yl)methoxy]-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)OCC1(COC1)C)NCC=1N=NC(=CC=1)C BQFNJNBPNARBNE-UHFFFAOYSA-N 0.000 claims 1
• OITDELSYLCLRLI-OAHLLOKOSA-N 6-(4-fluorophenyl)-8-morpholin-4-ylsulfonyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]quinazolin-4-amine Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)S(=O)(=O)N1CCOCC1)N[C@H](C)C=1C=NC(=NC=1)C(F)(F)F OITDELSYLCLRLI-OAHLLOKOSA-N 0.000 claims 1
• BRNLTJHIGKXWIY-UHFFFAOYSA-N 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(oxetan-3-yloxy)quinazolin-4-amine Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)OC1COC1)NCC=1N=NC(=CC=1)C BRNLTJHIGKXWIY-UHFFFAOYSA-N 0.000 claims 1
• LCHXKQARHDPLKJ-LLVKDONJSA-N 6-(4-fluorophenyl)-N-methyl-4-[[(1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]amino]quinazoline-8-sulfonamide Chemical compound FC1=CC=C(C=C1)C=1C=C2C(=NC=NC2=C(C=1)S(=O)(=O)NC)N[C@H](C)C1=NOC(=N1)C LCHXKQARHDPLKJ-LLVKDONJSA-N 0.000 claims 1
• NVOVQUQQAKYERI-UHFFFAOYSA-N CC(C)(C)OC(N(C1)CC1OC(C=C(C=C12)C(C=C3)=CC=C3F)=C1N=CN=C2NCC1=CC=C(C)N=N1)=O Chemical compound CC(C)(C)OC(N(C1)CC1OC(C=C(C=C12)C(C=C3)=CC=C3F)=C1N=CN=C2NCC1=CC=C(C)N=N1)=O NVOVQUQQAKYERI-UHFFFAOYSA-N 0.000 claims 1
• DXSWFQUGGOIZDZ-UHFFFAOYSA-N CC1=CC=C(CNC(C2=CC(C(C=C3)=CC=C3F)=C3)=NC=NC2=C3OC(CC2)CCN2C(OC)=O)N=N1 Chemical compound CC1=CC=C(CNC(C2=CC(C(C=C3)=CC=C3F)=C3)=NC=NC2=C3OC(CC2)CCN2C(OC)=O)N=N1 DXSWFQUGGOIZDZ-UHFFFAOYSA-N 0.000 claims 1
• GODBCLKNKNAVPH-UHFFFAOYSA-N CC1=CC=C(CNC(C2=CC(C(C=C3)=CC=C3F)=C3)=NC=NC2=C3OC(CC2)CN2C(OC)=O)N=N1 Chemical compound CC1=CC=C(CNC(C2=CC(C(C=C3)=CC=C3F)=C3)=NC=NC2=C3OC(CC2)CN2C(OC)=O)N=N1 GODBCLKNKNAVPH-UHFFFAOYSA-N 0.000 claims 1
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• 238000000034 method Methods 0.000 abstract description 126
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