KR20240130085A - 트리시클릭 유도체 억제제, 이의 제조 방법 및 응용 - Google Patents
트리시클릭 유도체 억제제, 이의 제조 방법 및 응용 Download PDFInfo
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- KR20240130085A KR20240130085A KR1020247020514A KR20247020514A KR20240130085A KR 20240130085 A KR20240130085 A KR 20240130085A KR 1020247020514 A KR1020247020514 A KR 1020247020514A KR 20247020514 A KR20247020514 A KR 20247020514A KR 20240130085 A KR20240130085 A KR 20240130085A
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- South Korea
- Prior art keywords
- alkyl
- cyano
- cycloalkyl
- aryl
- membered
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 45
- 239000003112 inhibitor Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- -1 amino, hydroxyl Chemical group 0.000 claims description 1014
- 125000000217 alkyl group Chemical group 0.000 claims description 484
- 125000000623 heterocyclic group Chemical group 0.000 claims description 294
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 246
- 125000001072 heteroaryl group Chemical group 0.000 claims description 245
- 125000003118 aryl group Chemical group 0.000 claims description 223
- 125000003545 alkoxy group Chemical group 0.000 claims description 182
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 146
- 229910052805 deuterium Inorganic materials 0.000 claims description 146
- 229910052736 halogen Inorganic materials 0.000 claims description 136
- 150000002367 halogens Chemical class 0.000 claims description 136
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 127
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 108
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 100
- 125000000304 alkynyl group Chemical group 0.000 claims description 97
- 125000003342 alkenyl group Chemical group 0.000 claims description 96
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 239000001257 hydrogen Substances 0.000 claims description 92
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 89
- 150000002431 hydrogen Chemical class 0.000 claims description 82
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 77
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 74
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 72
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 71
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 66
- 229910020008 S(O) Inorganic materials 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 65
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 65
- 125000004043 oxo group Chemical group O=* 0.000 claims description 63
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 60
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 60
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 57
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 51
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
- 125000001188 haloalkyl group Chemical group 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 27
- 125000004429 atom Chemical group 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 26
- 125000005605 benzo group Chemical group 0.000 claims description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 18
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 18
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000001301 oxygen Substances 0.000 claims description 17
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000001425 triazolyl group Chemical group 0.000 claims description 9
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 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 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007821 HATU Substances 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 229940122339 MALT1 inhibitor Drugs 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 3
- TWJGQZBSEMDPQP-UHFFFAOYSA-N 2-chloro-n-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1,2,4-triazol-1-yl]phenyl]acetamide Chemical compound C=1C=C(NC(=O)CCl)C=CC=1N1N=C(OCCOC)N=C1C1=CC=C(Cl)C(Cl)=C1 TWJGQZBSEMDPQP-UHFFFAOYSA-N 0.000 claims description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 3
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 201000003791 MALT lymphoma Diseases 0.000 claims description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 201000003444 follicular lymphoma Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract 2
- 238000004949 mass spectrometry Methods 0.000 description 226
- 238000006243 chemical reaction Methods 0.000 description 168
- 239000000243 solution Substances 0.000 description 168
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 158
- 239000000047 product Substances 0.000 description 147
- 238000010189 synthetic method Methods 0.000 description 105
- 239000003480 eluent Substances 0.000 description 89
- 238000010898 silica gel chromatography Methods 0.000 description 88
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 82
- 230000002829 reductive effect Effects 0.000 description 77
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- 239000000203 mixture Substances 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- 239000000706 filtrate Substances 0.000 description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 239000012043 crude product Substances 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000012141 concentrate Substances 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 125000006413 ring segment Chemical group 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 11
- WHTGDIMWBUVWJS-UHFFFAOYSA-N 2-bromo-5-nitro-3-(trifluoromethyl)pyridine Chemical compound [O-][N+](=O)C1=CN=C(Br)C(C(F)(F)F)=C1 WHTGDIMWBUVWJS-UHFFFAOYSA-N 0.000 description 10
- CMRLHUOJMKQVJD-UHFFFAOYSA-N 3-chloro-4-(triazol-2-yl)aniline Chemical compound ClC1=CC(N)=CC=C1N1N=CC=N1 CMRLHUOJMKQVJD-UHFFFAOYSA-N 0.000 description 10
- NPJPEHDOKYYYRI-UHFFFAOYSA-N 4-(triazol-2-yl)-3-(trifluoromethyl)aniline Chemical compound N=1N(N=CC=1)C1=C(C=C(N)C=C1)C(F)(F)F NPJPEHDOKYYYRI-UHFFFAOYSA-N 0.000 description 10
- XQEBWVOBGCAVBT-UHFFFAOYSA-N 5-chloro-6-pyrazol-1-ylpyridin-3-amine Chemical compound ClC1=CC(N)=CN=C1N1N=CC=C1 XQEBWVOBGCAVBT-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000003282 alkyl amino group Chemical group 0.000 description 10
- 125000004414 alkyl thio group Chemical group 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 125000005366 cycloalkylthio group Chemical group 0.000 description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 10
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 10
- OPEZLLCPUDLUFV-UHFFFAOYSA-N 2-chloro-5-nitro-3-(trifluoromethyl)pyridine Chemical compound [O-][N+](=O)C1=CN=C(Cl)C(C(F)(F)F)=C1 OPEZLLCPUDLUFV-UHFFFAOYSA-N 0.000 description 9
- RWISYPZSGXHJNJ-UHFFFAOYSA-N 6-(triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine Chemical compound NC1=CC(=C(N=C1)N1N=CC=N1)C(F)(F)F RWISYPZSGXHJNJ-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 150000007942 carboxylates Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000003003 spiro group Chemical group 0.000 description 9
- XLPDVAVQKGDHNO-UHFFFAOYSA-N 2,3-dichloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CN=C(Cl)C(Cl)=C1 XLPDVAVQKGDHNO-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- NYEBLPXQZSUILV-UHFFFAOYSA-N 5-bromo-7-chloropyrazolo[1,5-a]pyridine Chemical compound Clc1cc(Br)cc2ccnn12 NYEBLPXQZSUILV-UHFFFAOYSA-N 0.000 description 7
- SPVSXXFBKUTYGT-UHFFFAOYSA-N 5-chloro-6-(triazol-2-yl)pyridin-3-amine Chemical compound ClC=1C=C(C=NC=1N1N=CC=N1)N SPVSXXFBKUTYGT-UHFFFAOYSA-N 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- SMTNVUNCVXQSME-UHFFFAOYSA-N 7-bromo-3,4-dihydro-2H-1,4-benzoxazin-5-amine Chemical compound NC1=CC(Br)=CC2=C1NCCO2 SMTNVUNCVXQSME-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 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 6
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- FHCNMPYMCKHBTK-UHFFFAOYSA-N methyl 3-hydroxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(O)=C1[N+]([O-])=O FHCNMPYMCKHBTK-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 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 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- YTXAYGAYACWVGD-UHFFFAOYSA-N palladium;hydrate Chemical compound O.[Pd] YTXAYGAYACWVGD-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- YOWGRWHKDCHINP-UHFFFAOYSA-N tributyl(1,3-oxazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CO1 YOWGRWHKDCHINP-UHFFFAOYSA-N 0.000 description 1
- GVZFDPPAJXHNGL-UHFFFAOYSA-N trifluoromethyl trifluoromethanesulfonate Chemical compound FC(F)(F)OS(=O)(=O)C(F)(F)F GVZFDPPAJXHNGL-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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
- C07D487/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A61K31/4192—1,2,3-Triazoles
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- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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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
- C07D471/04—Ortho-condensed systems
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- 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
- C07D498/06—Peri-condensed systems
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Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111655759.X | 2021-12-30 | ||
| CN202111655759 | 2021-12-30 | ||
| CN202210249052 | 2022-03-14 | ||
| CN202210249052.7 | 2022-03-14 | ||
| CN202211064934 | 2022-08-31 | ||
| CN202211064934.2 | 2022-08-31 | ||
| PCT/CN2022/143665 WO2023125877A1 (zh) | 2021-12-30 | 2022-12-29 | 三并环类衍生物抑制剂、其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
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| KR20240130085A true KR20240130085A (ko) | 2024-08-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1020247020514A Pending KR20240130085A (ko) | 2021-12-30 | 2022-12-29 | 트리시클릭 유도체 억제제, 이의 제조 방법 및 응용 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20250059196A1 (https=) |
| EP (1) | EP4458819A4 (https=) |
| JP (1) | JP2025501056A (https=) |
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| TW202515550A (zh) * | 2023-06-29 | 2025-04-16 | 大陸商上海翰森生物醫藥科技有限公司 | 三并環類抑制劑與抗癌劑在製備抗腫瘤藥物中的聯合應用 |
| CN121285553A (zh) * | 2023-06-29 | 2026-01-06 | 上海翰森生物医药科技有限公司 | 一种三并环类衍生物抑制剂的晶型及其制备方法 |
| CN117534669A (zh) * | 2023-11-01 | 2024-02-09 | 上海凌凯医药科技有限公司 | 五元氮杂环并吡啶醇的制备方法 |
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| US9812645B2 (en) | 2015-02-13 | 2017-11-07 | Flexterra, Inc. | Perylene-based semiconductors |
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| US10689366B2 (en) | 2016-11-01 | 2020-06-23 | Cornell University | Compounds for MALT1 degredation |
| TWI795381B (zh) | 2016-12-21 | 2023-03-11 | 比利時商健生藥品公司 | 作為malt1抑制劑之吡唑衍生物 |
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| WO2018226150A1 (en) | 2017-06-05 | 2018-12-13 | Medivir Aktiebolag | Pyrazolopyrimidine as malt-1 inhibitors |
| JPWO2019039429A1 (ja) | 2017-08-22 | 2020-07-30 | 日本曹達株式会社 | 環状アミン化合物および有害生物防除剤 |
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| EP3810609B1 (en) * | 2018-06-18 | 2024-06-12 | Janssen Pharmaceutica NV | Pyrazole derivatives as malt1 inhibitors |
| KR20210069079A (ko) | 2018-09-28 | 2021-06-10 | 얀센 파마슈티카 엔.브이. | 모노아실글리세롤 리파아제 조절제 |
| TWI848400B (zh) | 2018-11-28 | 2024-07-11 | 日商武田藥品工業股份有限公司 | 雜環化合物及醫藥 |
| CN109665987B (zh) * | 2018-12-28 | 2022-02-18 | 河南大学 | 萘内酰亚胺-多胺缀合物及其制备方法和用途 |
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| EP3953345B1 (en) | 2019-04-11 | 2023-04-05 | Janssen Pharmaceutica NV | Pyridine rings containing derivatives as malt1 inhibitors |
| TW202106684A (zh) | 2019-05-03 | 2021-02-16 | 美商奇奈特生物製藥公司 | Raf激酶抑制劑 |
| CN112125885B (zh) * | 2019-06-25 | 2026-03-17 | 中国药科大学 | 苯并吲哚类双功能分子衍生物及其应用 |
| CN116723839A (zh) | 2020-10-14 | 2023-09-08 | C4医药公司 | 用于降解靶蛋白质的三环杂双官能化合物 |
| CA3194351A1 (en) | 2020-10-14 | 2022-04-21 | Christopher G. Nasveschuk | Tricyclic compounds to degrade neosubstrates for medical therapy |
| WO2022089406A1 (zh) | 2020-10-26 | 2022-05-05 | 上海青煜医药科技有限公司 | 含氮稠杂环类化合物及其制备方法和应用 |
| CN114907358A (zh) * | 2021-02-09 | 2022-08-16 | 上海翰森生物医药科技有限公司 | 含吡啶多环类衍生物调节剂、其制备方法和应用 |
| BR112023017689A2 (pt) * | 2021-03-03 | 2023-11-14 | Janssen Pharmaceutica Nv | Método de tratamento de uma condição com o uso de uma dose terapeuticamente eficaz do inibidor de malt1 jnj-67856633 (1-(1-oxo-1,2-di-hidroisoquinolin-5-il)-5-(trifluorometil)-n(2-(trifluorometil)piridin-4-il)-1h-pirazol-4-carboxamida) |
| TW202317537A (zh) * | 2021-06-18 | 2023-05-01 | 大陸商上海拓界生物醫藥科技有限公司 | 一種malt 1抑制劑及其製備方法和用途 |
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| TW202333682A (zh) | 2023-09-01 |
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