CA3024482A1 - Macrocyclic indole derivatives - Google Patents
Macrocyclic indole derivatives Download PDFInfo
- Publication number
- CA3024482A1 CA3024482A1 CA3024482A CA3024482A CA3024482A1 CA 3024482 A1 CA3024482 A1 CA 3024482A1 CA 3024482 A CA3024482 A CA 3024482A CA 3024482 A CA3024482 A CA 3024482A CA 3024482 A1 CA3024482 A1 CA 3024482A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkylene
- alkyl
- indole
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 5
- 150000002475 indoles Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 570
- 238000000034 method Methods 0.000 claims abstract description 57
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- -1 and a NR21R22 group Chemical group 0.000 claims description 457
- 150000003839 salts Chemical class 0.000 claims description 385
- 150000001204 N-oxides Chemical class 0.000 claims description 337
- 125000001424 substituent group Chemical group 0.000 claims description 295
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 245
- 239000000203 mixture Substances 0.000 claims description 213
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 211
- 125000005843 halogen group Chemical group 0.000 claims description 195
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 189
- JYNZIOFUHBJABQ-UHFFFAOYSA-N allyl-{6-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-hexyl-}-methyl-amin Chemical group C=1OC2=CC(OCCCCCCN(C)CC=C)=CC=C2C=1C1=CC=C(Br)C=C1 JYNZIOFUHBJABQ-UHFFFAOYSA-N 0.000 claims description 182
- 125000004432 carbon atom Chemical group C* 0.000 claims description 177
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 150
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 149
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 142
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 120
- 229910052757 nitrogen Inorganic materials 0.000 claims description 103
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 95
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 86
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 78
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 76
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 74
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 64
- DXGTUUQHTDOFFQ-UHFFFAOYSA-N [N].C1=CC=C2NC=CC2=C1 Chemical group [N].C1=CC=C2NC=CC2=C1 DXGTUUQHTDOFFQ-UHFFFAOYSA-N 0.000 claims description 60
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 60
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000005842 heteroatom Chemical group 0.000 claims description 53
- 125000001041 indolyl group Chemical group 0.000 claims description 52
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 50
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 46
- RPZAVJPSPPSOPS-UHFFFAOYSA-N [C].N1C=CC2=CC=CC=C12 Chemical group [C].N1C=CC2=CC=CC=C12 RPZAVJPSPPSOPS-UHFFFAOYSA-N 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 36
- OKRONUQZNCKGFE-UHFFFAOYSA-N [C].N1N=CC=C1 Chemical group [C].N1N=CC=C1 OKRONUQZNCKGFE-UHFFFAOYSA-N 0.000 claims description 33
- 229920006395 saturated elastomer Polymers 0.000 claims description 33
- 206010028980 Neoplasm Diseases 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- 150000001450 anions Chemical class 0.000 claims description 25
- 210000004027 cell Anatomy 0.000 claims description 25
- 125000004434 sulfur atom Chemical group 0.000 claims description 25
- 125000004429 atom Chemical group 0.000 claims description 24
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 20
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 14
- 125000006643 (C2-C6) haloalkenyl group Chemical group 0.000 claims description 14
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 14
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 11
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000004450 alkenylene group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 8
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 7
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 7
- 150000001733 carboxylic acid esters Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 238000002953 preparative HPLC Methods 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 125000004859 cyclopropyloxymethyl group Chemical group C1(CC1)OC* 0.000 claims description 6
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 230000005526 G1 to G0 transition Effects 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 4
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 206010000830 Acute leukaemia Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims 8
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims 6
- 206010000871 Acute monocytic leukaemia Diseases 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims 2
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 claims 2
- 230000001154 acute effect Effects 0.000 claims 2
- 210000003719 b-lymphocyte Anatomy 0.000 claims 2
- 201000005202 lung cancer Diseases 0.000 claims 2
- 208000020816 lung neoplasm Diseases 0.000 claims 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 230000006882 induction of apoptosis Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000035755 proliferation Effects 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 abstract description 6
- 239000004480 active ingredient Substances 0.000 abstract 1
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 465
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 248
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- 239000000543 intermediate Substances 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 36
- 229910052805 deuterium Inorganic materials 0.000 description 31
- 239000002585 base Substances 0.000 description 28
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 230000000875 corresponding effect Effects 0.000 description 27
- 239000002243 precursor Substances 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 125000004043 oxo group Chemical group O=* 0.000 description 23
- 125000001246 bromo group Chemical group Br* 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 239000003513 alkali Substances 0.000 description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 17
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 16
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 16
- 238000006069 Suzuki reaction reaction Methods 0.000 description 16
- 125000001183 hydrocarbyl group Chemical group 0.000 description 16
- 229910000024 caesium carbonate Inorganic materials 0.000 description 15
- 125000002950 monocyclic group Chemical group 0.000 description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 14
- 239000007858 starting material Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 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 12
- 238000006798 ring closing metathesis reaction Methods 0.000 description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 125000002346 iodo group Chemical group I* 0.000 description 10
- 230000000155 isotopic effect Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- 230000006907 apoptotic process Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 8
- 229910019142 PO4 Inorganic materials 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 239000010452 phosphate Substances 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 8
- 235000021317 phosphate Nutrition 0.000 description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 125000005620 boronic acid group Chemical group 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 230000009466 transformation Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 238000005710 macrocyclization reaction Methods 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 6
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 6
- 238000000844 transformation Methods 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 150000004677 hydrates Chemical class 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 150000001975 deuterium Chemical group 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—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 three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—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 three hetero rings
- C07D498/20—Spiro-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| US201662338942P | 2016-05-19 | 2016-05-19 | |
| US62/338,942 | 2016-05-19 | ||
| EP16172726 | 2016-06-02 | ||
| EP16172726.8 | 2016-06-02 | ||
| PCT/EP2017/000629 WO2017198341A1 (en) | 2016-05-19 | 2017-05-17 | Macrocyclic indole derivatives |
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| CA3024482A1 true CA3024482A1 (en) | 2017-11-23 |
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| UY (1) | UY37250A (zh) |
| WO (1) | WO2017198341A1 (zh) |
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| US10981932B2 (en) | 2016-05-19 | 2021-04-20 | Bayer Aktiengesellschaft | Macrocyclic indole derivatives |
| EP3710456B1 (en) * | 2017-11-17 | 2022-09-21 | The Broad Institute, Inc. | Macrocyclic indole derivatives |
| WO2019096907A1 (en) * | 2017-11-17 | 2019-05-23 | Bayer Aktiengesellschaft | Aryl annulated macrocyclic indole derivatives |
| EP3710451A1 (en) * | 2017-11-17 | 2020-09-23 | Bayer Aktiengesellschaft | Substituted macrocyclic indole derivatives |
| US11286263B2 (en) | 2017-11-17 | 2022-03-29 | The Broad Institute, Inc. | Macrocyclic fluorine substituted indole derivatives |
| EP3710450A1 (en) | 2017-11-17 | 2020-09-23 | Bayer Aktiengesellschaft | Macrocyclic chlorine substituted indole derivatives |
| WO2019096905A1 (en) * | 2017-11-17 | 2019-05-23 | Bayer Aktiengesellschaft | Macrocyclic chlorine substituted indole derivatives |
| WO2020236556A1 (en) * | 2019-05-17 | 2020-11-26 | The Broad Institute, Inc. | Methods of preparing macrocyclic indoles |
| US11964978B2 (en) | 2021-03-18 | 2024-04-23 | Pfizer Inc. | Modulators of STING (stimulator of interferon genes) |
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| JP2001335564A (ja) | 2000-05-26 | 2001-12-04 | Ube Ind Ltd | １−アルキル−５−置換ピラゾール−３−カルボン酸エステルの製造法 |
| JP5496876B2 (ja) | 2007-04-16 | 2014-05-21 | アッヴィ・インコーポレイテッド | ７−置換されていないインドール系Ｍｃｌ−１阻害薬 |
| EP2675440B1 (en) | 2011-02-14 | 2020-03-25 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| WO2015031608A1 (en) * | 2013-08-28 | 2015-03-05 | Vanderbilt University | Substituted indole mcl-1 inhibitors |
| US10533010B2 (en) | 2014-03-27 | 2020-01-14 | Vanderbilt University | Substituted indole Mcl-1 inhibitors |
| US9949965B2 (en) | 2014-10-17 | 2018-04-24 | Vanderbilt University | Tricyclic indole Mcl-1 inhibitors and uses thereof |
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- 2017-05-17 CA CA3024482A patent/CA3024482A1/en active Pending
- 2017-05-19 TW TW106116792A patent/TW201808957A/zh unknown
- 2017-05-19 UY UY0001037250A patent/UY37250A/es not_active Application Discontinuation
Also Published As
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|---|---|
| TW201808957A (zh) | 2018-03-16 |
| UY37250A (es) | 2018-01-02 |
| WO2017198341A1 (en) | 2017-11-23 |
| WO2017198341A8 (en) | 2019-01-03 |
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