TWI752963B - 用於治療或預防與β-3腎上腺素受體相關病症之β-3腎上腺素受體調節劑 - Google Patents
用於治療或預防與β-3腎上腺素受體相關病症之β-3腎上腺素受體調節劑 Download PDFInfo
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- TWI752963B TWI752963B TW106118610A TW106118610A TWI752963B TW I752963 B TWI752963 B TW I752963B TW 106118610 A TW106118610 A TW 106118610A TW 106118610 A TW106118610 A TW 106118610A TW I752963 B TWI752963 B TW I752963B
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- methyl
- phenyl
- compound
- biphenyl
- pyridin
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- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 title claims abstract description 79
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 title claims abstract description 79
- 238000011282 treatment Methods 0.000 title claims abstract description 46
- 230000002265 prevention Effects 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 392
- 238000000034 method Methods 0.000 claims abstract description 105
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 102
- 206010019280 Heart failures Diseases 0.000 claims abstract description 94
- 208000035475 disorder Diseases 0.000 claims abstract description 87
- 230000001404 mediated effect Effects 0.000 claims abstract description 57
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 57
- 210000002216 heart Anatomy 0.000 claims abstract description 38
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 claims abstract description 22
- 206010007556 Cardiac failure acute Diseases 0.000 claims abstract description 20
- 230000002861 ventricular Effects 0.000 claims abstract description 17
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 16
- 206010024119 Left ventricular failure Diseases 0.000 claims abstract description 16
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 15
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 15
- 230000000747 cardiac effect Effects 0.000 claims abstract description 10
- 230000008816 organ damage Effects 0.000 claims abstract description 9
- 238000002583 angiography Methods 0.000 claims abstract description 8
- 238000002592 echocardiography Methods 0.000 claims abstract description 8
- 206010067125 Liver injury Diseases 0.000 claims abstract description 7
- 230000006378 damage Effects 0.000 claims abstract description 7
- 210000003709 heart valve Anatomy 0.000 claims abstract description 7
- 231100000234 hepatic damage Toxicity 0.000 claims abstract description 7
- 210000003734 kidney Anatomy 0.000 claims abstract description 7
- 230000008818 liver damage Effects 0.000 claims abstract description 7
- 230000033764 rhythmic process Effects 0.000 claims abstract description 7
- -1 C 1 -C 6 alkylene hydroxy, amine Chemical compound 0.000 claims description 1505
- 238000002360 preparation method Methods 0.000 claims description 155
- 239000000203 mixture Substances 0.000 claims description 130
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 96
- 150000003839 salts Chemical class 0.000 claims description 84
- 125000001424 substituent group Chemical group 0.000 claims description 83
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 39
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 150000004677 hydrates Chemical class 0.000 claims description 32
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 27
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 23
- 230000034994 death Effects 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 229940126601 medicinal product Drugs 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 15
- 239000002552 dosage form Substances 0.000 claims description 14
- 235000010290 biphenyl Nutrition 0.000 claims description 13
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 13
- 125000006798 (C1-C6) haloalkylamino group Chemical group 0.000 claims description 12
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
- 239000004305 biphenyl Substances 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 11
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 11
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 10
- 125000004533 benzofuran-5-yl group Chemical group O1C=CC2=C1C=CC(=C2)* 0.000 claims description 10
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 10
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 10
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 9
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 9
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims description 9
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 9
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims description 8
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 6
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 238000003384 imaging method Methods 0.000 claims description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 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 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 4
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- XWQVQSXLXAXOPJ-QNGMFEMESA-N 4-[[[6-[5-chloro-2-[[4-[[(2r)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]pyridin-4-yl]pyridin-2-yl]amino]methyl]oxane-4-carbonitrile Chemical compound C1CC(N[C@H](C)COC)CCC1NC1=CC(C=2N=C(NCC3(CCOCC3)C#N)C=CC=2)=C(Cl)C=N1 XWQVQSXLXAXOPJ-QNGMFEMESA-N 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 125000006309 butyl amino group Chemical group 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- XCYJZMGWFQAZOS-UHFFFAOYSA-N 2-cyanoethyl hypofluorite Chemical compound C(#N)CCOF XCYJZMGWFQAZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 2
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 125000006308 propyl amino group Chemical group 0.000 claims description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 3
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- WUMCTULJJWITJC-ACHIHNKUSA-N (2S)-1-[3-[1-(hydroxymethyl)cyclopropyl]sulfonylphenoxy]-3-[[(3S)-8-[3-[4-(propylaminomethyl)phenyl]phenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]propan-2-ol Chemical compound CCCNCC1=CC=C(C=C1)C1=CC(=CC=C1)S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COC2=CC(=CC=C2)S(=O)(=O)C2(CO)CC2)CC1 WUMCTULJJWITJC-ACHIHNKUSA-N 0.000 claims 1
- IRORSWUXZXYAMZ-ACHIHNKUSA-N (2S)-1-[3-[1-(hydroxymethyl)cyclopropyl]sulfonylphenoxy]-3-[[(3S)-8-[3-[4-[(2-methoxyethylamino)methyl]phenyl]phenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]propan-2-ol Chemical compound COCCNCC1=CC=C(C=C1)C1=CC(=CC=C1)S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COC2=CC(=CC=C2)S(=O)(=O)C2(CO)CC2)CC1 IRORSWUXZXYAMZ-ACHIHNKUSA-N 0.000 claims 1
- OTTAXHQDRZQBSM-NSOVKSMOSA-N (2S)-1-[[(3S)-8-[3-[4-(2-aminoethyl)phenyl]phenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]-3-[3-(1,1-difluoro-2-hydroxyethyl)sulfonylphenoxy]propan-2-ol Chemical compound NCCC1=CC=C(C=C1)C1=CC(=CC=C1)S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COC2=CC(=CC=C2)S(=O)(=O)C(F)(F)CO)CC1 OTTAXHQDRZQBSM-NSOVKSMOSA-N 0.000 claims 1
- RPZAVDKUZVJGBC-NSOVKSMOSA-N (2S)-1-[[(3S)-8-[3-[4-(aminomethyl)phenyl]-5-methoxyphenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]-3-(3-cyclopropylsulfonylphenoxy)propan-2-ol Chemical compound COC1=CC(=CC(=C1)S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COC2=CC(=CC=C2)S(=O)(=O)C2CC2)CC1)C1=CC=C(CN)C=C1 RPZAVDKUZVJGBC-NSOVKSMOSA-N 0.000 claims 1
- FEJYSMWXFZDMFI-ACHIHNKUSA-N (2S)-1-[[(3S)-8-[3-[4-(azetidin-1-ylmethyl)phenyl]phenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]-3-[3-[1-(hydroxymethyl)cyclopropyl]sulfonylphenoxy]propan-2-ol Chemical compound OCC1(CC1)S(=O)(=O)C1=CC=CC(OC[C@@H](O)CN[C@@H]2COC3(C2)CCN(CC3)S(=O)(=O)C2=CC=CC(=C2)C2=CC=C(CN3CCC3)C=C2)=C1 FEJYSMWXFZDMFI-ACHIHNKUSA-N 0.000 claims 1
- CZGOTIBAUNXPDM-LQJZCPKCSA-N (2S)-1-[[(3S)-8-[3-[4-(butylaminomethyl)phenyl]phenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]-3-[3-[1-(hydroxymethyl)cyclopropyl]sulfonylphenoxy]propan-2-ol Chemical compound CCCCNCC1=CC=C(C=C1)C1=CC(=CC=C1)S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COC2=CC(=CC=C2)S(=O)(=O)C2(CO)CC2)CC1 CZGOTIBAUNXPDM-LQJZCPKCSA-N 0.000 claims 1
- ZOUMUQSUBBTKJK-VMPREFPWSA-N (2S)-1-[[(3S)-8-[5-[4-(aminomethyl)-3-fluorophenyl]-2-ethoxyphenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]-3-[3-[1-(hydroxymethyl)cyclopropyl]sulfonylphenoxy]propan-2-ol Chemical compound CCOc1ccc(cc1S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COc2cccc(c2)S(=O)(=O)C2(CO)CC2)CC1)-c1ccc(CN)c(F)c1 ZOUMUQSUBBTKJK-VMPREFPWSA-N 0.000 claims 1
- MWQGFMMWRHXINT-VMPREFPWSA-N (2S)-1-[[(3S)-8-[5-[4-(aminomethyl)phenyl]-2-ethoxyphenyl]sulfonyl-1-oxa-8-azaspiro[4.5]decan-3-yl]amino]-3-[3-(methoxymethylsulfonyl)phenoxy]propan-2-ol Chemical compound CCOc1ccc(cc1S(=O)(=O)N1CCC2(C[C@@H](CO2)NC[C@H](O)COc2cccc(c2)S(=O)(=O)COC)CC1)-c1ccc(CN)cc1 MWQGFMMWRHXINT-VMPREFPWSA-N 0.000 claims 1
- GELMWIVBBPAMIO-UHFFFAOYSA-N 2-methylbutan-2-amine Chemical compound CCC(C)(C)N GELMWIVBBPAMIO-UHFFFAOYSA-N 0.000 claims 1
- COFZALLHGPEQAQ-RPWUZVMVSA-N 3-[[(3R)-3-[[(2S)-3-(3-cyclopropylsulfonylphenoxy)-2-hydroxypropyl]amino]-1-oxa-8-azaspiro[4.5]decan-8-yl]sulfonyl]-1-ethyl-8-methylquinolin-4-one Chemical compound C1(CC1)S(=O)(=O)C=1C=C(OC[C@H](CN[C@H]2COC3(C2)CCN(CC3)S(=O)(=O)C2=CN(C3=C(C=CC=C3C2=O)C)CC)O)C=CC=1 COFZALLHGPEQAQ-RPWUZVMVSA-N 0.000 claims 1
- GVCLNACSYKYUHP-UHFFFAOYSA-N 4-amino-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbothioamide Chemical compound C1=NC(N)=C2C(C(=S)N)=CN(COCCO)C2=N1 GVCLNACSYKYUHP-UHFFFAOYSA-N 0.000 claims 1
- NJIAKNWTIVDSDA-FQEVSTJZSA-N 7-[4-(1-methylsulfonylpiperidin-4-yl)phenyl]-n-[[(2s)-morpholin-2-yl]methyl]pyrido[3,4-b]pyrazin-5-amine Chemical compound C1CN(S(=O)(=O)C)CCC1C1=CC=C(C=2N=C(NC[C@H]3OCCNC3)C3=NC=CN=C3C=2)C=C1 NJIAKNWTIVDSDA-FQEVSTJZSA-N 0.000 claims 1
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Images
Classifications
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
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| DK3448859T3 (da) | 2017-03-20 | 2019-09-23 | Forma Therapeutics Inc | Pyrrolopyrrolsammensætninger som pyruvatkinase- (pkr) aktivatorer |
| JP7450610B2 (ja) | 2018-09-19 | 2024-03-15 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | ピルビン酸キナーゼｒの活性化 |
| WO2020061378A1 (en) | 2018-09-19 | 2020-03-26 | Forma Therapeutics, Inc. | Treating sickle cell disease with a pyruvate kinase r activating compound |
| MX2022003254A (es) | 2019-09-19 | 2022-04-18 | Forma Therapeutics Inc | Composiciones activadoras de piruvato cinasa r (pkr). |
| US12128035B2 (en) | 2021-03-19 | 2024-10-29 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
| JP2023024954A (ja) * | 2021-08-09 | 2023-02-21 | アリーナ ファーマシューティカルズ， インコーポレイテッド | ベータ－３アドレナリン作動性受容体に関連する障害の処置または予防に有用なベータ－３アドレナリン作動性受容体のモジュレーター |
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