MD3687506T2 - Benzofuran, benzopirol, benzotiofen substituiţi și inhibitori ai complementului înrudiți structural - Google Patents
Benzofuran, benzopirol, benzotiofen substituiţi și inhibitori ai complementului înrudiți structural Download PDFInfo
- Publication number
- MD3687506T2 MD3687506T2 MDE20201202T MDE20201202T MD3687506T2 MD 3687506 T2 MD3687506 T2 MD 3687506T2 MD E20201202 T MDE20201202 T MD E20201202T MD E20201202 T MDE20201202 T MD E20201202T MD 3687506 T2 MD3687506 T2 MD 3687506T2
- Authority
- MD
- Moldova
- Prior art keywords
- phenyl
- mmol
- alkyl
- ethyl
- carboxamido
- Prior art date
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- 239000004074 complement inhibitor Substances 0.000 title description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical class CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 235
- 238000000034 method Methods 0.000 claims abstract description 207
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
- 201000010099 disease Diseases 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 230000004154 complement system Effects 0.000 claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- -1 cyano, hydroxy Chemical group 0.000 claims description 336
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 56
- 208000011038 Cold agglutinin disease Diseases 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 230000002159 abnormal effect Effects 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 206010052779 Transplant rejections Diseases 0.000 claims description 6
- 238000003860 storage Methods 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 5
- 208000004451 Membranoproliferative Glomerulonephritis Diseases 0.000 claims description 5
- 208000000733 Paroxysmal Hemoglobinuria Diseases 0.000 claims description 5
- 102100036050 Phosphatidylinositol N-acetylglucosaminyltransferase subunit A Human genes 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 5
- 206010028417 myasthenia gravis Diseases 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 201000003045 paroxysmal nocturnal hemoglobinuria Diseases 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 208000035913 Atypical hemolytic uremic syndrome Diseases 0.000 claims description 4
- 208000029713 Catastrophic antiphospholipid syndrome Diseases 0.000 claims description 4
- 206010009868 Cold type haemolytic anaemia Diseases 0.000 claims description 4
- 206010018370 Glomerulonephritis membranoproliferative Diseases 0.000 claims description 4
- 208000008795 neuromyelitis optica Diseases 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 49
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 230000001594 aberrant effect Effects 0.000 abstract 1
- 239000000651 prodrug Substances 0.000 abstract 1
- 229940002612 prodrug Drugs 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 366
- 238000002360 preparation method Methods 0.000 description 262
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 249
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 249
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 224
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 215
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 190
- 238000010626 work up procedure Methods 0.000 description 184
- 238000000746 purification Methods 0.000 description 175
- 239000007787 solid Substances 0.000 description 173
- 238000005160 1H NMR spectroscopy Methods 0.000 description 169
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 164
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 152
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 124
- 238000003818 flash chromatography Methods 0.000 description 124
- 239000000377 silicon dioxide Substances 0.000 description 121
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 114
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 105
- 235000019439 ethyl acetate Nutrition 0.000 description 100
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 93
- 239000002253 acid Substances 0.000 description 83
- 230000002441 reversible effect Effects 0.000 description 82
- 239000012071 phase Substances 0.000 description 79
- 238000004128 high performance liquid chromatography Methods 0.000 description 77
- 239000011734 sodium Substances 0.000 description 72
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 68
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 66
- 239000000460 chlorine Substances 0.000 description 63
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 54
- UELJXCRPLCATAK-UHFFFAOYSA-N ethyl 2-(2-aminophenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC=C1N UELJXCRPLCATAK-UHFFFAOYSA-N 0.000 description 50
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 49
- 238000010438 heat treatment Methods 0.000 description 48
- 238000004440 column chromatography Methods 0.000 description 47
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 46
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 37
- 229920000642 polymer Polymers 0.000 description 36
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 34
- 235000019798 tripotassium phosphate Nutrition 0.000 description 34
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- 239000007821 HATU Substances 0.000 description 27
- NPTBTFRGCBFYPZ-UHFFFAOYSA-N [3-(aminomethyl)phenyl]boronic acid;hydrochloride Chemical compound [Cl-].[NH3+]CC1=CC=CC(B(O)O)=C1 NPTBTFRGCBFYPZ-UHFFFAOYSA-N 0.000 description 25
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
- PRSVMYFVRJZAAR-UHFFFAOYSA-N ethyl 2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate Chemical compound CCOC(=O)C1=NC(Cl)=NN2C=CC=C12 PRSVMYFVRJZAAR-UHFFFAOYSA-N 0.000 description 18
- IUHXZUIOPHLKSJ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NCC=1C=C(C=CC1)OB(O)O Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC1)OB(O)O IUHXZUIOPHLKSJ-UHFFFAOYSA-N 0.000 description 16
- 150000003840 hydrochlorides Chemical class 0.000 description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- 238000004293 19F NMR spectroscopy Methods 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- KPHUVXZUQPTRAN-UHFFFAOYSA-N Cl.NCC=1C=C(C=CC1)OB(O)O Chemical compound Cl.NCC=1C=C(C=CC1)OB(O)O KPHUVXZUQPTRAN-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- 125000002950 monocyclic group Chemical group 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- UCAJPHQTEWYXEA-UHFFFAOYSA-N triazine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NN=N1 UCAJPHQTEWYXEA-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 10
- 238000000576 coating method Methods 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 9
- XTRBBJJVAIWTPL-UHFFFAOYSA-N ethyl 2-(2-hydroxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC=C1O XTRBBJJVAIWTPL-UHFFFAOYSA-N 0.000 description 9
- BZGPZFRKDKHUSA-UHFFFAOYSA-N 2-(2-hydroxyphenyl)ethyl acetate Chemical compound CC(=O)OCCC1=CC=CC=C1O BZGPZFRKDKHUSA-UHFFFAOYSA-N 0.000 description 8
- VSTFMZCQGKRKIK-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-1-(cyclopropylmethyl)indole-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=C2C=CN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)O)CC1CC1 VSTFMZCQGKRKIK-UHFFFAOYSA-N 0.000 description 8
- UEPHLBLJNSZIHS-UHFFFAOYSA-N 2-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid Chemical compound N(C(=O)OC(C)(C)C)CC1=CC(C2=NN3C(=CC=C3)C(=N2)C(=O)O)=CC=C1 UEPHLBLJNSZIHS-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- HGXJOXHYPGNVNK-UHFFFAOYSA-N butane;ethenoxyethane;tin Chemical compound CCCC[Sn](CCCC)(CCCC)C(=C)OCC HGXJOXHYPGNVNK-UHFFFAOYSA-N 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 8
- JNFKSGSGSKSMEH-UHFFFAOYSA-N (4-bromo-1-methylindol-6-yl)methanol Chemical compound BrC1=C2C=CN(C2=CC(=C1)CO)C JNFKSGSGSKSMEH-UHFFFAOYSA-N 0.000 description 7
- XDEKDSSHITVNAW-SFHVURJKSA-N (S)-N-[(7-bromo-1-benzofuran-3-yl)methyl]-2-methylpropane-2-sulfinamide Chemical compound BrC1=CC=CC=2C(=COC=21)CN[S@@](=O)C(C)(C)C XDEKDSSHITVNAW-SFHVURJKSA-N 0.000 description 7
- NZJRBBRRIDIEBW-SFHVURJKSA-N (S)-N-[(7-bromo-1-benzofuran-3-yl)methylidene]-2-methylpropane-2-sulfinamide Chemical compound BrC1=CC=CC=2C(=COC=21)C=N[S@@](=O)C(C)(C)C NZJRBBRRIDIEBW-SFHVURJKSA-N 0.000 description 7
- VXPGKMODPKNPLM-UHFFFAOYSA-N 1-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]-2,7-naphthyridine-3-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C1=NC(=CC2=CC=NC=C12)C(=O)O VXPGKMODPKNPLM-UHFFFAOYSA-N 0.000 description 7
- OFNYPLXPVPMRRR-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-1-(cyclopropylmethyl)indazole-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=C2C=NN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)O)CC1CC1 OFNYPLXPVPMRRR-UHFFFAOYSA-N 0.000 description 7
- AFJSKODMUGCDEH-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]furo[3,2-d]pyrimidine-2-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C=1C2=C(N=C(N=1)C(=O)NC1=C(C=CC=C1)CC(=O)O)C=CO2 AFJSKODMUGCDEH-UHFFFAOYSA-N 0.000 description 7
- YJZDLVUQJZRLQI-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]naphthalene-2-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=CC(=CC2=CC=CC=C12)C(=O)NC1=C(C=CC=C1)CC(=O)O YJZDLVUQJZRLQI-UHFFFAOYSA-N 0.000 description 7
- BFUBRQZKPVKQND-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]thieno[2,3-d]pyrimidine-2-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C=1C2=C(N=C(N=1)C(=O)NC1=C(C=CC=C1)CC(=O)O)SC=C2 BFUBRQZKPVKQND-UHFFFAOYSA-N 0.000 description 7
- IVVXWOZVIYPBAK-UHFFFAOYSA-N 2-[2-[[7-[3-(aminomethyl)phenyl]-1-benzofuran-5-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=CC(=CC=2C=COC=21)C(=O)NC1=C(C=CC=C1)CC(=O)O IVVXWOZVIYPBAK-UHFFFAOYSA-N 0.000 description 7
- SFRSTFCEQZZZGU-UHFFFAOYSA-N 2-[2-[[7-[3-(aminomethyl)phenyl]furo[2,3-c]pyridine-5-carbonyl]amino]thiophen-3-yl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C=1N=C(C=C2C=1OC=C2)C(=O)NC=1SC=CC=1CC(=O)O SFRSTFCEQZZZGU-UHFFFAOYSA-N 0.000 description 7
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 7
- DBJJVAICOCRELY-UHFFFAOYSA-N 4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C=1C2=C(N=C(N=1)C(=O)O)COC2 DBJJVAICOCRELY-UHFFFAOYSA-N 0.000 description 7
- LXQMDZWHHKBXSZ-UHFFFAOYSA-N 4-bromo-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine-6-carboxylic acid Chemical compound BrC1=C2C(=NC(=C1)C(=O)O)N(C=C2)S(=O)(=O)C1=CC=C(C)C=C1 LXQMDZWHHKBXSZ-UHFFFAOYSA-N 0.000 description 7
- VYAXCZJJLOTMNJ-UHFFFAOYSA-N 4-bromo-1-methylindole-6-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2N(C)C=CC2=C1Br VYAXCZJJLOTMNJ-UHFFFAOYSA-N 0.000 description 7
- QMBPONMULUIKJC-UHFFFAOYSA-N [4-bromo-1-(4-methylphenyl)sulfonylindol-6-yl]methanol Chemical compound BrC1=C2C=CN(C2=CC(=C1)CO)S(=O)(=O)C1=CC=C(C)C=C1 QMBPONMULUIKJC-UHFFFAOYSA-N 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- IXQBRVDFAOVOIB-UHFFFAOYSA-N tert-butyl N-[[3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)phenyl]methyl]carbamate Chemical compound ClC=1N=C(C2=C(N=1)COC2)C=1C=C(CNC(OC(C)(C)C)=O)C=CC=1 IXQBRVDFAOVOIB-UHFFFAOYSA-N 0.000 description 7
- WLPKMVJRZMCQLN-UHFFFAOYSA-N tert-butyl N-[[3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)phenyl]methyl]carbamate Chemical compound C12=C(N=C(N=C2C=CO1)Cl)C1=CC(CNC(=O)OC(C)(C)C)=CC=C1 WLPKMVJRZMCQLN-UHFFFAOYSA-N 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- JBVLLDHDYZFTPU-UHFFFAOYSA-N (7-bromo-1-benzofuran-5-yl)methanol Chemical compound OCC1=CC(Br)=C2OC=CC2=C1 JBVLLDHDYZFTPU-UHFFFAOYSA-N 0.000 description 6
- AYSHVCBHDRAKRX-UHFFFAOYSA-N 1-methyl-4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]indole-6-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C1=C2C=CN(C2=CC(=C1)C(=O)O)C AYSHVCBHDRAKRX-UHFFFAOYSA-N 0.000 description 6
- LITNZJDPZQUBMY-UHFFFAOYSA-N 2,4-dichloro-7-(cyclopropylmethyl)pyrrolo[2,3-d]pyrimidine Chemical compound ClC=1N=C(C2=C(N=1)N(C=C2)CC1CC1)Cl LITNZJDPZQUBMY-UHFFFAOYSA-N 0.000 description 6
- KJWUDEMKWXYFEG-UHFFFAOYSA-N 2-[2-[[2-[3-(aminomethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C=1N=C(C2=C(N=1)CCC2)C(=O)NC1=C(C=CC=C1)CC(=O)O KJWUDEMKWXYFEG-UHFFFAOYSA-N 0.000 description 6
- NSINEABXUPNTCG-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)-5-fluorophenyl]-1H-indole-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=C(C=1)F)C1=C2C=CNC2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)O NSINEABXUPNTCG-UHFFFAOYSA-N 0.000 description 6
- GBLJQXVQQQHEPP-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-1-methylindole-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=C2C=CN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)O)C GBLJQXVQQQHEPP-UHFFFAOYSA-N 0.000 description 6
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- CXMRVVLZUVIIAF-UHFFFAOYSA-N ethyl 2-[2-[[1-[3-(aminomethyl)phenyl]-2,7-naphthyridine-3-carbonyl]amino]phenyl]acetate Chemical compound NCC=1C=C(C=CC=1)C1=NC(=CC2=CC=NC=C12)C(=O)NC1=C(C=CC=C1)CC(=O)OCC CXMRVVLZUVIIAF-UHFFFAOYSA-N 0.000 description 5
- HSKYEBKIDRHYFX-UHFFFAOYSA-N ethyl 2-[2-[[4-[3-(aminomethyl)phenyl]-1H-indole-6-carbonyl]amino]phenyl]acetate Chemical compound NCC=1C=C(C=CC=1)C1=C2C=CNC2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC HSKYEBKIDRHYFX-UHFFFAOYSA-N 0.000 description 5
- SUMVWZBLFVDVQF-UHFFFAOYSA-N ethyl 2-[2-[[4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]naphthalene-2-carbonyl]amino]phenyl]acetate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C1=CC(=CC2=CC=CC=C12)C(=O)NC1=C(C=CC=C1)CC(=O)OCC SUMVWZBLFVDVQF-UHFFFAOYSA-N 0.000 description 5
- IDUZDMGXDWZRIG-UHFFFAOYSA-N ethyl 2-[2-[[4-bromo-1-(4-methylphenyl)sulfonylindol-6-yl]methoxy]phenyl]acetate Chemical compound BrC1=C2C=CN(C2=CC(=C1)COC1=C(C=CC=C1)CC(=O)OCC)S(=O)(=O)C1=CC=C(C)C=C1 IDUZDMGXDWZRIG-UHFFFAOYSA-N 0.000 description 5
- DBQVDJIXRWITMI-UHFFFAOYSA-N ethyl 2-[2-[[6-[3-(aminomethyl)phenyl]imidazo[1,2-b]pyridazine-8-carbonyl]amino]phenyl]acetate Chemical compound CCOC(=O)CC1=C(NC(=O)C2=CC(=NN3C=CN=C23)C2=CC(CN)=CC=C2)C=CC=C1 DBQVDJIXRWITMI-UHFFFAOYSA-N 0.000 description 5
- AROHFJLROKDZCF-UHFFFAOYSA-N ethyl 2-[2-[[7-[3-(aminomethyl)-1-benzofuran-7-yl]-1-benzofuran-5-yl]methoxy]phenyl]acetate Chemical compound NCC1=COC2=C1C=CC=C2C1=CC(=CC=2C=COC=21)COC1=C(C=CC=C1)CC(=O)OCC AROHFJLROKDZCF-UHFFFAOYSA-N 0.000 description 5
- SWCRKYJFGOXHCJ-UHFFFAOYSA-N ethyl 2-[2-[[7-[3-(aminomethyl)phenyl]-2,3-dihydro-1-benzofuran-5-yl]methoxy]phenyl]acetate Chemical compound NCC=1C=C(C=CC=1)C1=CC(=CC=2CCOC=21)COC1=C(C=CC=C1)CC(=O)OCC SWCRKYJFGOXHCJ-UHFFFAOYSA-N 0.000 description 5
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- SBULWLFAUYIREX-UHFFFAOYSA-N ethyl 4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]thieno[2,3-d]pyrimidine-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C=1C2=C(N=C(N=1)C(=O)OCC)SC=C2 SBULWLFAUYIREX-UHFFFAOYSA-N 0.000 description 5
- OMJHCMDWXLFNGB-UHFFFAOYSA-N ethyl 4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]thieno[3,2-d]pyrimidine-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C=1C2=C(N=C(N=1)C(=O)OCC)C=CS2 OMJHCMDWXLFNGB-UHFFFAOYSA-N 0.000 description 5
- SGXDTAILTLUZDS-UHFFFAOYSA-N methyl 1-methyl-4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]indole-6-carboxylate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C1=C2C=CN(C2=CC(=C1)C(=O)OC)C SGXDTAILTLUZDS-UHFFFAOYSA-N 0.000 description 5
- BWQBYHGDMBHIIQ-UHFFFAOYSA-N methyl 2-(2-aminophenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1N BWQBYHGDMBHIIQ-UHFFFAOYSA-N 0.000 description 5
- 150000002894 organic compounds Chemical class 0.000 description 5
- 244000052769 pathogen Species 0.000 description 5
- 239000012286 potassium permanganate Substances 0.000 description 5
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- AFZGILJOJCNFGQ-UHFFFAOYSA-N tert-butyl N-[[3-[2-(1-ethoxyethenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl]phenyl]methyl]carbamate Chemical compound C(C)OC(=C)C=1N=C(C2=C(N=1)COC2)C=1C=C(CNC(OC(C)(C)C)=O)C=CC=1 AFZGILJOJCNFGQ-UHFFFAOYSA-N 0.000 description 5
- XIBJUDLPKWXZFP-UHFFFAOYSA-N tert-butyl N-[[3-[2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate Chemical compound OCC1=NN2C(C(=N1)C=1C=C(CNC(OC(C)(C)C)=O)C=CC=1)=CC=C2 XIBJUDLPKWXZFP-UHFFFAOYSA-N 0.000 description 5
- GTJOFCVYQLMVRA-UHFFFAOYSA-N tert-butyl N-[[3-[2-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidin-4-yl]phenyl]methyl]carbamate Chemical compound ClC=1N=C(C2=C(N=1)N(C=C2)S(=O)(=O)C1=CC=C(C)C=C1)C=1C=C(CNC(OC(C)(C)C)=O)C=CC=1 GTJOFCVYQLMVRA-UHFFFAOYSA-N 0.000 description 5
- AFINYMZHAFIKJM-UHFFFAOYSA-N tert-butyl N-[[3-[4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]phenyl]methyl]carbamate Chemical compound N(C(=O)OC(C)(C)C)CC1=CC(C2=NN3C(C(=N2)CO)=CC=C3)=CC=C1 AFINYMZHAFIKJM-UHFFFAOYSA-N 0.000 description 5
- MYWHHESLIVRSTI-UHFFFAOYSA-N tert-butyl N-[[3-[7-(cyclopropylmethyl)-2-(1-ethoxyethenyl)pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]methyl]carbamate Chemical compound C1(CC1)CN1C=CC2=C1N=C(N=C2C=1C=C(CNC(OC(C)(C)C)=O)C=CC=1)C(=C)OCC MYWHHESLIVRSTI-UHFFFAOYSA-N 0.000 description 5
- ZKQCAOYXQPEPFL-UHFFFAOYSA-N tert-butyl N-[[3-[7-(cyclopropylmethyl)-2-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]methyl]carbamate Chemical compound C1(CC1)CN1C=CC2=C1N=C(N=C2C=1C=C(CNC(OC(C)(C)C)=O)C=CC=1)CO ZKQCAOYXQPEPFL-UHFFFAOYSA-N 0.000 description 5
- PHYODHNMTXXDRS-UHFFFAOYSA-N 2-[2-[[2-[3-(aminomethyl)-2-fluorophenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carbonyl]amino]phenyl]acetic acid Chemical compound NCC1=CC=CC(=C1F)C1=NN2C=CC=C2C(=N1)C(=O)NC1=C(CC(O)=O)C=CC=C1 PHYODHNMTXXDRS-UHFFFAOYSA-N 0.000 description 4
- JXEWQAUQMIYWAM-UHFFFAOYSA-N 2-[2-[[2-[3-(aminomethyl)-5-fluorophenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carbonyl]amino]phenyl]acetic acid Chemical compound NCC1=CC(F)=CC(=C1)C1=NN2C=CC=C2C(=N1)C(=O)NC1=C(CC(O)=O)C=CC=C1 JXEWQAUQMIYWAM-UHFFFAOYSA-N 0.000 description 4
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- FVSLUEMQOQOWFB-UHFFFAOYSA-N 2-[2-[[2-[3-(aminomethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carbonyl]amino]-4-methylphenyl]acetic acid Chemical compound CC1=CC(NC(=O)C2=NC(=NN3C=CC=C23)C2=CC(CN)=CC=C2)=C(CC(O)=O)C=C1 FVSLUEMQOQOWFB-UHFFFAOYSA-N 0.000 description 4
- SVHALKDXKCDJGH-UHFFFAOYSA-N 2-[2-[[2-[3-(aminomethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carbonyl]amino]phenyl]acetic acid Chemical compound NCC1=CC=CC(=C1)C1=NN2C=CC=C2C(=N1)C(=O)NC1=C(CC(O)=O)C=CC=C1 SVHALKDXKCDJGH-UHFFFAOYSA-N 0.000 description 4
- YBGCIKZBLTZKNH-UHFFFAOYSA-N 2-[2-[[2-[5-(aminomethyl)-2-fluorophenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carbonyl]amino]phenyl]acetic acid Chemical compound NCC1=CC(=C(F)C=C1)C1=NN2C=CC=C2C(=N1)C(=O)NC1=C(CC(O)=O)C=CC=C1 YBGCIKZBLTZKNH-UHFFFAOYSA-N 0.000 description 4
- UTJRPNXALHOPBZ-UHFFFAOYSA-N 2-[2-[[4-[2-(aminomethyl)-3-fluoropyridin-4-yl]-1H-indol-6-yl]methoxy]phenyl]acetic acid Chemical compound NCC1=NC=CC(=C1F)C1=C2C=CNC2=CC(=C1)COC1=C(C=CC=C1)CC(=O)O UTJRPNXALHOPBZ-UHFFFAOYSA-N 0.000 description 4
- ZFTWPHPMCOWYLP-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-6-yl]methoxy]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=C2C(=NC(=C1)COC1=C(C=CC=C1)CC(=O)O)N(C=C2)S(=O)(=O)C1=CC=C(C)C=C1 ZFTWPHPMCOWYLP-UHFFFAOYSA-N 0.000 description 4
- PTMNHZGCUPETOY-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-1H-indazole-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=C2C=NNC2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)O PTMNHZGCUPETOY-UHFFFAOYSA-N 0.000 description 4
- JNQRWVTUXOVKMT-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=C2C(=NC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)O)NC=C2 JNQRWVTUXOVKMT-UHFFFAOYSA-N 0.000 description 4
- RSLZWKWSLOFVPQ-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]-7-(cyclopropylmethyl)pyrrolo[2,3-d]pyrimidin-2-yl]methoxy]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C=1C2=C(N=C(N=1)COC1=C(C=CC=C1)CC(=O)O)N(C=C2)CC1CC1 RSLZWKWSLOFVPQ-UHFFFAOYSA-N 0.000 description 4
- UQOTYZCMBYSQIH-UHFFFAOYSA-N 2-[2-[[4-[3-(aminomethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-2-carbonyl]amino]phenyl]acetic acid Chemical compound NCC1=CC=CC(=C1)C1=NC(=NN2C=CC=C12)C(=O)NC1=C(CC(O)=O)C=CC=C1 UQOTYZCMBYSQIH-UHFFFAOYSA-N 0.000 description 4
- BSMQRYBXJCYLGQ-UHFFFAOYSA-N 2-[2-[[7-[3-(aminomethyl)phenyl]-1-benzofuran-5-yl]methoxy]phenyl]acetic acid Chemical compound NCC=1C=C(C=CC=1)C1=CC(=CC=2C=COC=21)COC1=C(C=CC=C1)CC(=O)O BSMQRYBXJCYLGQ-UHFFFAOYSA-N 0.000 description 4
- LRIMOILXHQQLDF-UHFFFAOYSA-N 2-[2-[[8-[3-(aminomethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl]amino]phenyl]acetic acid Chemical compound NCC1=CC=CC(=C1)C1=CC(=CN2C=NN=C12)C(=O)NC1=C(CC(O)=O)C=CC=C1 LRIMOILXHQQLDF-UHFFFAOYSA-N 0.000 description 4
- ZBEMQMNZOCEAFY-UHFFFAOYSA-N 4-bromo-1-(4-methylphenyl)sulfonylindole-6-carboxylic acid Chemical compound BrC1=C2C=CN(C2=CC(=C1)C(=O)O)S(=O)(=O)C1=CC=C(C)C=C1 ZBEMQMNZOCEAFY-UHFFFAOYSA-N 0.000 description 4
- PXTZUYPPAYUOEY-UHFFFAOYSA-N 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid Chemical compound ClC1=NC(C(=O)O)=CC2=C1OC=C2 PXTZUYPPAYUOEY-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001299 aldehydes Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 150000001540 azides Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
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- 238000009792 diffusion process Methods 0.000 description 4
- JYVDOLNSEMNFQM-UHFFFAOYSA-N ethyl 2-[2-[(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carbonyl)amino]phenyl]acetate Chemical compound BrC1=C2C(=NC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)NC=C2 JYVDOLNSEMNFQM-UHFFFAOYSA-N 0.000 description 4
- CMVLVHVSSRYFTG-UHFFFAOYSA-N ethyl 2-[2-[(7-bromo-1,2-dimethylbenzimidazole-5-carbonyl)amino]phenyl]acetate Chemical compound CCOC(=O)CC1=C(NC(=O)C2=CC(Br)=C3N(C)C(C)=NC3=C2)C=CC=C1 CMVLVHVSSRYFTG-UHFFFAOYSA-N 0.000 description 4
- GGRGMGATGZVYIH-UHFFFAOYSA-N ethyl 2-[2-[(7-chlorofuro[2,3-c]pyridine-5-carbonyl)amino]phenyl]acetate Chemical compound ClC=1N=C(C=C2C=1OC=C2)C(=O)NC1=C(C=CC=C1)CC(=O)OCC GGRGMGATGZVYIH-UHFFFAOYSA-N 0.000 description 4
- PHKZRCRFGZGHEW-UHFFFAOYSA-N ethyl 2-[2-[[1-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]-2,7-naphthyridine-3-carbonyl]amino]phenyl]acetate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C1=NC(=CC2=CC=NC=C12)C(=O)NC1=C(C=CC=C1)CC(=O)OCC PHKZRCRFGZGHEW-UHFFFAOYSA-N 0.000 description 4
- ZYWSHQKWMWXBJG-UHFFFAOYSA-N ethyl 2-[2-[[1-methyl-4-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]indole-6-carbonyl]amino]phenyl]acetate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C1=C2C=CN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)C ZYWSHQKWMWXBJG-UHFFFAOYSA-N 0.000 description 4
- XOLNDHHAVIMOAZ-UHFFFAOYSA-N ethyl 2-[2-[[4-[3-(aminomethyl)-2-fluorophenyl]-1H-indole-6-carbonyl]amino]phenyl]acetate Chemical compound NCC=1C(=C(C=CC=1)C1=C2C=CNC2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)F XOLNDHHAVIMOAZ-UHFFFAOYSA-N 0.000 description 4
- ZRQJCASOHUFWDJ-UHFFFAOYSA-N ethyl 2-[2-[[4-[3-(aminomethyl)phenyl]-2-(cyclopropylmethyl)indazole-6-carbonyl]amino]phenyl]acetate Chemical compound NCC=1C=C(C=CC=1)C=1C2=CN(N=C2C=C(C=1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)CC1CC1 ZRQJCASOHUFWDJ-UHFFFAOYSA-N 0.000 description 4
- JKDNDKAEWQMHTO-UHFFFAOYSA-N ethyl 2-[2-[[4-bromo-1-(cyclopropylmethyl)indazole-6-carbonyl]amino]phenyl]acetate Chemical compound BrC1=C2C=NN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)CC1CC1 JKDNDKAEWQMHTO-UHFFFAOYSA-N 0.000 description 4
- FWKPTLKXIMBFPW-UHFFFAOYSA-N ethyl 2-[2-[[4-bromo-1-(cyclopropylmethyl)indole-6-carbonyl]amino]phenyl]acetate Chemical compound BrC1=C2C=CN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)CC1CC1 FWKPTLKXIMBFPW-UHFFFAOYSA-N 0.000 description 4
- MXFNAVJACZPQFY-UHFFFAOYSA-N ethyl 2-[2-[[6-[3-(aminomethyl)phenyl]imidazo[1,2-a]pyridine-8-carbonyl]amino]phenyl]acetate Chemical compound CCOC(=O)CC1=C(NC(=O)C2=CC(=CN3C=CN=C23)C2=CC(CN)=CC=C2)C=CC=C1 MXFNAVJACZPQFY-UHFFFAOYSA-N 0.000 description 4
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- DCDVWJFXIQQTPT-UHFFFAOYSA-N ethyl 2-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate Chemical compound C(C)(C)(C)OC(=O)NCC=1C=C(C=CC=1)C=1N=C(C2=C(N=1)CCC2)C(=O)OCC DCDVWJFXIQQTPT-UHFFFAOYSA-N 0.000 description 4
- CJXIVWAUMJVSGE-UHFFFAOYSA-N ethyl 2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate Chemical compound CCOC(=O)C1=NC(Cl)=NN2C(C=O)=CC=C12 CJXIVWAUMJVSGE-UHFFFAOYSA-N 0.000 description 4
- NTSFKZFTXTWRLH-UHFFFAOYSA-N ethyl 7-formyl-2-[3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate Chemical compound C1=CC=C(C=C1C=1N=C(C=2N(C(C=O)=CC=2)N=1)C(=O)OCC)CNC(=O)OC(C)(C)C NTSFKZFTXTWRLH-UHFFFAOYSA-N 0.000 description 4
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- 210000001539 phagocyte Anatomy 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
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- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 4
- ZFCHNZDUMIOWFV-UHFFFAOYSA-M pyrimidine-2-carboxylate Chemical compound [O-]C(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-M 0.000 description 4
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- RRPZOPXCIUIHKM-UHFFFAOYSA-N tert-butyl N-[[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1F RRPZOPXCIUIHKM-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
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- WAXCJTJJNHRMAF-UHFFFAOYSA-N ethyl 2-[2-[[2-[3-(aminomethyl)-2-fluorophenyl]pyrrolo[2,1-f][1,2,4]triazine-4-carbonyl]amino]phenyl]acetate Chemical compound CCOC(=O)CC1=C(NC(=O)C2=NC(=NN3C=CC=C23)C2=C(F)C(CN)=CC=C2)C=CC=C1 WAXCJTJJNHRMAF-UHFFFAOYSA-N 0.000 description 2
- MNHMYOUZVWBRIB-UHFFFAOYSA-N ethyl 2-[2-[[4-[3-(aminomethyl)phenyl]-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-6-yl]methoxy]phenyl]acetate Chemical compound NCC=1C=C(C=CC=1)C1=C2C(=NC(=C1)COC1=C(C=CC=C1)CC(=O)OCC)N(C=C2)S(=O)(=O)C1=CC=C(C)C=C1 MNHMYOUZVWBRIB-UHFFFAOYSA-N 0.000 description 2
- PLFZKRXXMYWLLC-UHFFFAOYSA-N ethyl 2-[2-[[4-[3-(aminomethyl)phenyl]-1-(cyclopropylmethyl)indazole-6-carbonyl]amino]phenyl]acetate Chemical compound NCC=1C=C(C=CC=1)C1=C2C=NN(C2=CC(=C1)C(=O)NC1=C(C=CC=C1)CC(=O)OCC)CC1CC1 PLFZKRXXMYWLLC-UHFFFAOYSA-N 0.000 description 2
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- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZCFOCWSOLOVVCA-UHFFFAOYSA-K tripotassium sodium phosphate Chemical compound [Na+].[K+].[K+].[K+].[O-]P([O-])([O-])=O ZCFOCWSOLOVVCA-UHFFFAOYSA-K 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K31/4164—1,3-Diazoles
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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| US201862654108P | 2018-04-06 | 2018-04-06 | |
| PCT/US2019/026054 WO2019195720A1 (en) | 2018-04-06 | 2019-04-05 | Substituted benzofuran, benzopyrrole, benzothiophene, and structurally related complement inhibitors |
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| MDE20220940T MD3939658T2 (ro) | 2018-04-06 | 2019-04-05 | Benzopirol substituit și inhibitori ai complementului înrudiți structural |
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| MDE20220940T MD3939658T2 (ro) | 2018-04-06 | 2019-04-05 | Benzopirol substituit și inhibitori ai complementului înrudiți structural |
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| TWI873092B (zh) | 2018-04-06 | 2025-02-21 | 美商百歐克斯製藥公司 | 取代的苯并呋喃、苯并吡咯、苯并噻吩及結構相關的補體抑制劑 |
| KR20220041846A (ko) * | 2019-07-31 | 2022-04-01 | 바이오크리스트파마슈티컬즈,인코포레이티드 | 경구 보체 인자 d 억제제에 대한 투약 요법 |
| AR120173A1 (es) | 2019-10-09 | 2022-02-02 | Biocryst Pharm Inc | Inhibidores del factor d del complemento para administración oral |
| PY2062527A (es) * | 2019-10-09 | 2021-09-23 | Biocryst Pharm Inc | Inhibidores del factor d del complemento para administración oral |
| CN115362162A (zh) | 2020-02-20 | 2022-11-18 | 艾其林医药公司 | 用于治疗补体因子d介导的障碍的杂芳基化合物 |
| AR121715A1 (es) * | 2020-04-03 | 2022-06-29 | Biocryst Pharm Inc | Pirrolopirimidinaminas como inhibidores del sistema del complemento |
| US20230391758A1 (en) * | 2020-09-18 | 2023-12-07 | Merck Sharp & Dohme Llc | Modified benzofuran-carboxamides as glucosylceramide synthase inhibitors |
| TW202304890A (zh) * | 2021-04-14 | 2023-02-01 | 美商百歐克斯製藥公司 | Klk5雙環雜芳香族抑制劑 |
| TW202330489A (zh) * | 2021-10-21 | 2023-08-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 稠合環類化合物、其製備方法及其在醫藥上的應用 |
| AR129422A1 (es) * | 2022-05-25 | 2024-08-21 | Univ Leuven Kath | Nuevos derivados para tratar trastornos mediados por trpm3 |
| EP4622643A1 (en) * | 2022-11-22 | 2025-10-01 | Maze Therapeutics, Inc. | Inhibitors of solute carrier family 6a member 19 (slc6a19) and methods of use thereof |
| TW202434204A (zh) * | 2023-01-06 | 2024-09-01 | 美商百歐克斯製藥公司 | 用於治療補體介導之疾病之口服劑型及口服給藥方案 |
| KR102925481B1 (ko) * | 2023-09-05 | 2026-02-10 | 광주과학기술원 | 신규 화합물 및 이의 건선 치료 용도 |
| WO2025080823A1 (en) | 2023-10-11 | 2025-04-17 | Regeneron Pharmaceuticals, Inc. | Treatment of macular degeneration with complement factor d (cfd) inhibitors |
| CN119504834B (zh) * | 2024-11-21 | 2025-10-17 | 南开大学 | 一种以含硅基团为疏水标签的pd-l1蛋白降解剂及其制备方法、药物组合物和应用 |
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| LU84979A1 (fr) | 1983-08-30 | 1985-04-24 | Oreal | Composition cosmetique ou pharmaceutique sous forme aqueuse ou anhydre dont la phase grasse contient un polyether oligomere et polyethers oligomeres nouveaux |
| LU86084A1 (fr) | 1985-09-20 | 1987-04-02 | Faco Sa | Apparei de massage electrique |
| US5102417A (en) | 1985-11-07 | 1992-04-07 | Expandable Grafts Partnership | Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft |
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| TWI873092B (zh) | 2018-04-06 | 2025-02-21 | 美商百歐克斯製藥公司 | 取代的苯并呋喃、苯并吡咯、苯并噻吩及結構相關的補體抑制劑 |
| KR20220041846A (ko) | 2019-07-31 | 2022-04-01 | 바이오크리스트파마슈티컬즈,인코포레이티드 | 경구 보체 인자 d 억제제에 대한 투약 요법 |
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