CA3045371C - Inhibitors of influenza virus replication and uses thereof - Google Patents

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Publication number

CA3045371C

CA3045371C CA3045371A CA3045371A CA3045371C CA 3045371 C CA3045371 C CA 3045371C CA 3045371 A CA3045371 A CA 3045371A CA 3045371 A CA3045371 A CA 3045371A CA 3045371 C CA3045371 C CA 3045371C

Authority

CA

Canada

Prior art keywords

alkylene

cooh

membered

compound

alkyl

Prior art date

2016-12-15

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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• 241000712461 unidentified influenza virus Species 0.000 title claims abstract description 50
• 239000003112 inhibitor Substances 0.000 title abstract description 9
• 230000029812 viral genome replication Effects 0.000 title abstract description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 467
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 53
• 206010022000 influenza Diseases 0.000 claims abstract description 32
• 125000002947 alkylene group Chemical group 0.000 claims description 232
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 177
• -1 propinyl Chemical group 0.000 claims description 171
• 125000000623 heterocyclic group Chemical group 0.000 claims description 164
• 125000000217 alkyl group Chemical group 0.000 claims description 78
• 125000001424 substituent group Chemical group 0.000 claims description 77
• 150000003839 salts Chemical class 0.000 claims description 72
• 125000001072 heteroaryl group Chemical group 0.000 claims description 69
• 229910052801 chlorine Inorganic materials 0.000 claims description 62
• 229910052731 fluorine Inorganic materials 0.000 claims description 61
• 125000003118 aryl group Chemical group 0.000 claims description 60
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 59
• 229910052794 bromium Inorganic materials 0.000 claims description 57
• 229910052757 nitrogen Inorganic materials 0.000 claims description 57
• 125000004432 carbon atom Chemical group C* 0.000 claims description 56
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 49
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
• 229910052805 deuterium Inorganic materials 0.000 claims description 44
• 125000002837 carbocyclic group Chemical group 0.000 claims description 41
• 150000001204 N-oxides Chemical class 0.000 claims description 39
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 39
• 229910052739 hydrogen Inorganic materials 0.000 claims description 38
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 38
• 239000012453 solvate Substances 0.000 claims description 38
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
• 239000003814 drug Substances 0.000 claims description 32
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 30
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 29
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 27
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 26
• 230000009385 viral infection Effects 0.000 claims description 26
• 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims description 25
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 25
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 25
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 25
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 22
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 20
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 19
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 19
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 19
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 19
• 125000001425 triazolyl group Chemical group 0.000 claims description 19
• 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 18
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 18
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 18
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 18
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 18
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 18
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 18
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 18
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 18
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 18
• 125000002971 oxazolyl group Chemical group 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 18
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 18
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 18
• 125000000335 thiazolyl group Chemical group 0.000 claims description 18
• 125000001544 thienyl group Chemical group 0.000 claims description 18
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 16
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
• 241000700605 Viruses Species 0.000 claims description 14
• 239000003795 chemical substances by application Substances 0.000 claims description 14
• 239000003937 drug carrier Substances 0.000 claims description 14
• 125000002541 furyl group Chemical group 0.000 claims description 14
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 13
• 125000002757 morpholinyl group Chemical group 0.000 claims description 13
• 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
• 125000004193 piperazinyl group Chemical group 0.000 claims description 13
• 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 13
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 13
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 12
• 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims description 12
• 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims description 12
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 12
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 11
• 201000010099 disease Diseases 0.000 claims description 11
• 125000001188 haloalkyl group Chemical group 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
• 229940124597 therapeutic agent Drugs 0.000 claims description 11
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 10
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
• 229930192474 thiophene Natural products 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
• 239000003981 vehicle Substances 0.000 claims description 10
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
• JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims description 9
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 9
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 9
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 9
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 9
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 9
• RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 9
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 9
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
• 150000003536 tetrazoles Chemical class 0.000 claims description 9
• 150000003852 triazoles Chemical class 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
• 208000035475 disorder Diseases 0.000 claims description 8
• 230000002401 inhibitory effect Effects 0.000 claims description 8
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 8
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
• 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 7
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 7
• 125000001041 indolyl group Chemical group 0.000 claims description 7
• 125000001624 naphthyl group Chemical group 0.000 claims description 7
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 7
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 7
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 7
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 6
• 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 6
• 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 6
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 6
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 125000005936 piperidyl group Chemical group 0.000 claims description 6
• 125000005493 quinolyl group Chemical group 0.000 claims description 6
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 6
• 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 6
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
• 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 5
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 5
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
• 125000005954 phenoxathiinyl group Chemical group 0.000 claims description 5
• 229910052702 rhenium Inorganic materials 0.000 claims description 5
• 229910052721 tungsten Inorganic materials 0.000 claims description 5
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
• UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 4
• QNRRHYPPQFELSF-CNYIRLTGSA-N Laninamivir Chemical compound OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O QNRRHYPPQFELSF-CNYIRLTGSA-N 0.000 claims description 4
• DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical group C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 4
• 229960003805 amantadine Drugs 0.000 claims description 4
• ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims description 4
• 229950008454 favipiravir Drugs 0.000 claims description 4
• 229950004244 laninamivir Drugs 0.000 claims description 4
• 229960003752 oseltamivir Drugs 0.000 claims description 4
• 229960001084 peramivir Drugs 0.000 claims description 4
• 229960000888 rimantadine Drugs 0.000 claims description 4
• ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 claims description 4
• 229960001028 zanamivir Drugs 0.000 claims description 4
• KZIMLUFVKJLCCH-UHFFFAOYSA-N 5-[2-(1h-imidazol-5-yl)ethylamino]-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)NCCC1=CNC=N1 KZIMLUFVKJLCCH-UHFFFAOYSA-N 0.000 claims description 3
• 229940124873 Influenza virus vaccine Drugs 0.000 claims description 3
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 3
• 101150007594 cin-4 gene Proteins 0.000 claims description 3
• 229960003971 influenza vaccine Drugs 0.000 claims description 3
• 229960000329 ribavirin Drugs 0.000 claims description 3
• HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 3
• KUWCILGWLAWLGB-SFJHCMNLSA-N stachyflin Chemical compound O1C2=C3CNC(=O)C3=CC(O)=C2C[C@]2(C)[C@@H](C)CC[C@@H]3[C@]12CC[C@H](O)C3(C)C KUWCILGWLAWLGB-SFJHCMNLSA-N 0.000 claims description 3
• KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 claims description 3
• 229960004626 umifenovir Drugs 0.000 claims description 3
• 229950005327 laninamivir octanoate hydrate Drugs 0.000 claims description 2
• UKTIJASCFRNWCB-RMIBSVFLSA-N laninamivir octanoate hydrate Chemical compound CCCCCCCC(=O)OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O UKTIJASCFRNWCB-RMIBSVFLSA-N 0.000 claims 1
• VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims 1
• XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 16
• 238000002360 preparation method Methods 0.000 abstract description 13
• 239000000203 mixture Substances 0.000 description 248
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
• 239000007787 solid Substances 0.000 description 103
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
• 239000000243 solution Substances 0.000 description 94
• 235000002639 sodium chloride Nutrition 0.000 description 77
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 75
• 150000002500 ions Chemical class 0.000 description 73
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 71
• 239000000706 filtrate Substances 0.000 description 70
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 64
• 238000010898 silica gel chromatography Methods 0.000 description 62
• 239000002904 solvent Substances 0.000 description 62
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 58
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 52
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 50
• 239000000460 chlorine Substances 0.000 description 50
• 239000012044 organic layer Substances 0.000 description 49
• 239000004698 Polyethylene Substances 0.000 description 48
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 47
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
• 238000000034 method Methods 0.000 description 41
• 239000000651 prodrug Substances 0.000 description 40
• 229940002612 prodrug Drugs 0.000 description 40
• 239000011541 reaction mixture Substances 0.000 description 39
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
• 239000002585 base Substances 0.000 description 38
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
• 238000006243 chemical reaction Methods 0.000 description 35
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 34
• 239000002207 metabolite Substances 0.000 description 34
• 239000003054 catalyst Substances 0.000 description 33
• YSEQNZOXHCKLOG-UHFFFAOYSA-N 2-methyl-octanoic acid Chemical compound CCCCCCC(C)C(O)=O YSEQNZOXHCKLOG-UHFFFAOYSA-N 0.000 description 32
• 229910000027 potassium carbonate Inorganic materials 0.000 description 32
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
• 239000002253 acid Substances 0.000 description 26
• PNKGHXVHKCJNBW-UHFFFAOYSA-N bicyclo[2.2.2]octane-3-carboxylic acid Chemical compound C1CC2C(C(=O)O)CC1CC2 PNKGHXVHKCJNBW-UHFFFAOYSA-N 0.000 description 24
• 235000015320 potassium carbonate Nutrition 0.000 description 24
• 229920006395 saturated elastomer Polymers 0.000 description 23
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
• 238000005160 1H NMR spectroscopy Methods 0.000 description 20
• 230000005587 bubbling Effects 0.000 description 20
• 238000006069 Suzuki reaction reaction Methods 0.000 description 19
• 235000017557 sodium bicarbonate Nutrition 0.000 description 19
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
• 239000000126 substance Substances 0.000 description 19
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 18
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