ES2607064T3 - Indoles - Google Patents
Indoles Download PDFInfo
- Publication number
- ES2607064T3 ES2607064T3 ES11844228.4T ES11844228T ES2607064T3 ES 2607064 T3 ES2607064 T3 ES 2607064T3 ES 11844228 T ES11844228 T ES 11844228T ES 2607064 T3 ES2607064 T3 ES 2607064T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- methyl
- substituted
- pyridinyl
- unsubstituted
- 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.)
- Active
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- 150000002475 indoles Chemical class 0.000 title description 5
- -1 C1-C3-alkoxycarbonyl Chemical group 0.000 claims abstract description 249
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 229910003827 NRaRb Inorganic materials 0.000 claims abstract description 118
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 89
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 83
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 81
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 64
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 61
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 56
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 54
- 125000005843 halogen group Chemical group 0.000 claims abstract description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
- 239000001257 hydrogen Substances 0.000 claims abstract description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 43
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 42
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 39
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 34
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 28
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 27
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 26
- 229910052717 sulfur Chemical group 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 22
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims abstract description 21
- 150000001602 bicycloalkyls Chemical group 0.000 claims abstract description 18
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 13
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000001301 oxygen Substances 0.000 claims abstract description 11
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 125000004429 atom Chemical group 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- 229910006074 SO2NH2 Inorganic materials 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000011593 sulfur Chemical group 0.000 claims abstract description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 6
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- IYPZRUYMFDWKSS-UHFFFAOYSA-N piperazin-1-amine Chemical compound NN1CCNCC1 IYPZRUYMFDWKSS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 55
- 238000011282 treatment Methods 0.000 claims description 53
- 206010028980 Neoplasm Diseases 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 40
- 201000011510 cancer Diseases 0.000 claims description 30
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 5
- 229930192474 thiophene Natural products 0.000 claims description 5
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 4
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 4
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 claims description 4
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 2
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 2
- 125000002950 monocyclic group Chemical group 0.000 abstract 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract 1
- 125000006413 ring segment Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- 239000000203 mixture Substances 0.000 description 116
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 107
- 238000006243 chemical reaction Methods 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- 239000007787 solid Substances 0.000 description 95
- 239000000243 solution Substances 0.000 description 84
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 66
- 229910001868 water Inorganic materials 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 58
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 239000000047 product Substances 0.000 description 42
- 230000000694 effects Effects 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000725 suspension Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 28
- 239000012071 phase Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 26
- 239000003795 chemical substances by application Substances 0.000 description 25
- 239000002246 antineoplastic agent Substances 0.000 description 23
- 238000004458 analytical method Methods 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 20
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 19
- 150000003857 carboxamides Chemical class 0.000 description 19
- 108020004414 DNA Proteins 0.000 description 18
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- 206010065553 Bone marrow failure Diseases 0.000 description 15
- 206010025323 Lymphomas Diseases 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 201000009030 Carcinoma Diseases 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 12
- 229940102223 injectable solution Drugs 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 11
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 229940127089 cytotoxic agent Drugs 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 230000000670 limiting effect Effects 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Veterinary Medicine (AREA)
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- Public Health (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
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| US41847010P | 2010-12-01 | 2010-12-01 | |
| US418470P | 2010-12-01 | ||
| PCT/US2011/062537 WO2012075080A1 (en) | 2010-12-01 | 2011-11-30 | Indoles |
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| ES2607064T3 true ES2607064T3 (es) | 2017-03-29 |
Family
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| EP (1) | EP2646020B1 (OSRAM) |
| JP (1) | JP5908493B2 (OSRAM) |
| ES (1) | ES2607064T3 (OSRAM) |
| WO (1) | WO2012075080A1 (OSRAM) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130102477A1 (en) | 2010-06-23 | 2013-04-25 | Ryan D. Morin | Biomarkers for non-hodgkin lymphomas and uses thereof |
| RU2618475C2 (ru) | 2010-09-10 | 2017-05-03 | Эпизайм, Инк. | Ингибиторы ezh2 человека и способы их применения |
| US9175331B2 (en) | 2010-09-10 | 2015-11-03 | Epizyme, Inc. | Inhibitors of human EZH2, and methods of use thereof |
| JP2014511389A (ja) | 2011-02-28 | 2014-05-15 | エピザイム インコーポレイテッド | 置換６，５−縮合二環式ヘテロアリール化合物 |
| JO3438B1 (ar) | 2011-04-13 | 2019-10-20 | Epizyme Inc | مركبات بنزين مستبدلة بأريل أو أريل غير متجانس |
| TW201733984A (zh) | 2011-04-13 | 2017-10-01 | 雅酶股份有限公司 | 經取代之苯化合物 |
| US9730925B2 (en) | 2011-09-30 | 2017-08-15 | Glaxomithkline Llc | Methods of treating cancer |
| EP2780013A4 (en) | 2011-11-18 | 2015-07-01 | Constellation Pharmaceuticals Inc | MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF |
| WO2013075083A1 (en) | 2011-11-18 | 2013-05-23 | Constellation Pharmaceuticals | Modulators of methyl modifying enzymes, compositions and uses thereof |
| JP5989805B2 (ja) * | 2012-02-10 | 2016-09-07 | コンステレーション・ファーマシューティカルズ・インコーポレイテッドＣｏｎｓｔｅｌｌａｔｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | メチル基変更酵素の調節物質、組成物及びその使用 |
| LT2836491T (lt) | 2012-04-13 | 2017-03-27 | Epizyme, Inc. | Žmogaus histono metiltransferazės ezh2 slopiklio druskos forma |
| US9562041B2 (en) | 2012-05-16 | 2017-02-07 | Glaxosmithkline Llc | Enhancer of zeste homolog 2 inhibitors |
| CN105102431B (zh) | 2012-10-15 | 2018-03-02 | Epizyme股份有限公司 | 经取代的苯化合物 |
| BR112015008447A2 (pt) * | 2012-10-15 | 2017-07-04 | Epizyme Inc | métodos para tratar câncer |
| US9701666B2 (en) | 2012-12-21 | 2017-07-11 | Epizyme, Inc. | 1,4-pyridone bicyclic heteroaryl compounds |
| WO2014100646A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | 1,4-pyridone compounds |
| US9045455B2 (en) | 2013-03-14 | 2015-06-02 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US8952026B2 (en) | 2013-03-14 | 2015-02-10 | Epizyme, Inc. | PRMT1 inhibitors and uses thereof |
| US20160031839A1 (en) | 2013-03-14 | 2016-02-04 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US9120757B2 (en) | 2013-03-14 | 2015-09-01 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US9765035B2 (en) | 2013-03-14 | 2017-09-19 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| SI2970132T1 (sl) | 2013-03-14 | 2021-02-26 | Epizyme, Inc. | Inhibitorji argininmetiltransferaze in njihove uporabe |
| EP2970135B1 (en) | 2013-03-14 | 2018-07-18 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
| WO2014153214A1 (en) | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Arginine methyl transferase inhibtors and uses thereof |
| WO2014178954A1 (en) | 2013-03-14 | 2014-11-06 | Epizyme, Inc. | Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof |
| US9447079B2 (en) | 2013-03-14 | 2016-09-20 | Epizyme, Inc. | PRMT1 inhibitors and uses thereof |
| US9745305B2 (en) | 2013-03-15 | 2017-08-29 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| BR112015027527A2 (pt) | 2013-04-30 | 2017-07-25 | Glaxosmithkline Ip No 2 Ltd | intensificador de inibidores do homólogo zeste 2 |
| CN105452246A (zh) * | 2013-06-06 | 2016-03-30 | 葛兰素史密斯克莱知识产权（第2号）有限公司 | Zeste增强子同源物2的抑制剂 |
| WO2015004618A1 (en) | 2013-07-10 | 2015-01-15 | Glaxosmithkline Intellectual Property (No.2) Limited | Enhancer of zeste homolog 2 inhibitors |
| WO2015023915A1 (en) | 2013-08-15 | 2015-02-19 | Constellation Pharmaceuticals, Inc. | Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof |
| CA2925889C (en) | 2013-10-16 | 2020-09-29 | Epizyme, Inc. | Hydrochloride salt form for ezh2 inhibition |
| WO2015077194A1 (en) * | 2013-11-22 | 2015-05-28 | Bristol-Myers Squibb Company | Inhibitors of lysine methyl transferase |
| US20160361309A1 (en) | 2014-02-26 | 2016-12-15 | Glaxosmithkline Intellectual Property (No.2) Limited | Methods of treating cancer patients responding to ezh2 inhibitor gsk126 |
| TW201636344A (zh) | 2014-12-05 | 2016-10-16 | 美國禮來大藥廠 | Ｅｚｈ２抑制劑 |
| WO2016102493A1 (en) * | 2014-12-22 | 2016-06-30 | Bayer Pharma Aktiengesellschaft | Imidazopyridine ezh2 inhibitors |
| WO2016101956A2 (en) | 2014-12-23 | 2016-06-30 | University Of Copenhagen | Treatment of cancer by inhibiting ezh2 activity |
| KR20180042356A (ko) | 2015-08-24 | 2018-04-25 | 에피자임, 인코포레이티드 | 암 치료 방법 |
| TW201718598A (zh) | 2015-08-27 | 2017-06-01 | 美國禮來大藥廠 | Ｅｚｈ２抑制劑 |
| US10577350B2 (en) | 2015-08-28 | 2020-03-03 | Constellation Pharmaceuticals, Inc. | Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide |
| CN105801463A (zh) * | 2016-03-31 | 2016-07-27 | 常州大学 | 一种2-甲酸-3-丙氧基-5-甲基吡咯的合成方法 |
| CN107573327B (zh) * | 2016-07-05 | 2020-03-31 | 四川大学 | 吲唑-甲酰胺-吡啶酮衍生物及其制备方法和用途 |
| CN109790160B (zh) * | 2016-09-07 | 2022-11-15 | 上海海和药物研究开发股份有限公司 | 吡啶并五元芳香环类化合物、其制备方法及用途 |
| CA3039059A1 (en) | 2016-10-19 | 2018-04-26 | Constellation Pharmaceuticals, Inc. | Synthesis of inhibitors of ezh2 |
| US10793549B2 (en) | 2016-11-11 | 2020-10-06 | Shanghai Haiyan Pharmaceutical Technology Co., Ltd. | Sulfuryl-substituted benzoheterocyclic derivative, preparation method and medical use thereof |
| CN110191879A (zh) * | 2017-01-25 | 2019-08-30 | 恩瑞生物医药科技（上海）有限公司 | 一种组蛋白甲基转移酶ezh2抑制剂、其制备方法及其医药用途 |
| JP2021531340A (ja) | 2018-07-09 | 2021-11-18 | フォンダシヨン、アジール、デ、アブグルスFondation Asile Des Aveugles | 眼障害を治療するためのｐｒｃ２サブユニットの阻害 |
| US11535621B2 (en) | 2019-07-31 | 2022-12-27 | Ribon Therapeutics, Inc. | Heterobicyclic amides as inhibitors of CD38 |
| CN113666920B (zh) * | 2020-04-14 | 2025-10-03 | 浙江华海药业股份有限公司 | 苯并恶唑类化合物制备方法及其在医药领域的应用 |
| EP4271374A4 (en) * | 2020-12-29 | 2025-03-05 | Revolution Medicines, Inc. | SOS1 INHIBITORS AND USES THEREOF |
| PE20232047A1 (es) | 2021-01-29 | 2023-12-27 | Boehringer Ingelheim Int | Quinolinas y azaquinolinas como inhibidores de cd38 |
| EP4392034A1 (en) | 2021-08-25 | 2024-07-03 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Use of ezh2 inhibitors for the treatment of aortic valve stenosis |
Family Cites Families (9)
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| US5330986A (en) | 1992-11-24 | 1994-07-19 | Hoechst-Roussel Pharmaceuticals Inc. | Indole-7-carboxamide derivatives |
| DE10022925A1 (de) * | 2000-05-11 | 2001-11-15 | Basf Ag | Substituierte Indole als PARP-Inhibitoren |
| GB0400895D0 (en) * | 2004-01-15 | 2004-02-18 | Smithkline Beecham Corp | Chemical compounds |
| US20090012031A1 (en) * | 2007-07-03 | 2009-01-08 | The Regents Of The University Of Michigan | EZH2 Cancer Markers |
| CN102369204A (zh) * | 2008-09-26 | 2012-03-07 | 新加坡科技研究局 | 3-脱氮瓶菌素衍生物 |
| EP2566479B1 (en) | 2010-05-07 | 2014-12-24 | GlaxoSmithKline LLC | Azaindazoles |
| WO2011140325A1 (en) * | 2010-05-07 | 2011-11-10 | Glaxosmithkline Llc | Indazoles |
| SG185431A1 (en) | 2010-05-07 | 2012-12-28 | Glaxosmithkline Llc | Indoles |
| JP2014511389A (ja) | 2011-02-28 | 2014-05-15 | エピザイム インコーポレイテッド | 置換６，５−縮合二環式ヘテロアリール化合物 |
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| WO2012075080A1 (en) | 2012-06-07 |
| US8765792B2 (en) | 2014-07-01 |
| EP2646020A1 (en) | 2013-10-09 |
| EP2646020B1 (en) | 2016-09-21 |
| JP5908493B2 (ja) | 2016-04-26 |
| JP2013544840A (ja) | 2013-12-19 |
| US20130245016A1 (en) | 2013-09-19 |
| EP2646020A4 (en) | 2014-04-23 |
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