ES2980254T3 - Compuesto con actividad antineoplásica - Google Patents

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Publication number

ES2980254T3

ES2980254T3 ES19774768T ES19774768T ES2980254T3 ES 2980254 T3 ES2980254 T3 ES 2980254T3 ES 19774768 T ES19774768 T ES 19774768T ES 19774768 T ES19774768 T ES 19774768T ES 2980254 T3 ES2980254 T3 ES 2980254T3

Authority

ES

Spain

Prior art keywords

compound

formula

group represented

manufactured

manufacturing

Prior art date

2018-03-30

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 1507
• 230000000118 anti-neoplastic effect Effects 0.000 title description 5
• 150000003839 salts Chemical class 0.000 claims abstract description 156
• -1 tetrahydro-1H-azepinyl Chemical group 0.000 claims description 373
• 125000000217 alkyl group Chemical group 0.000 claims description 151
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 133
• 125000004432 carbon atom Chemical group C* 0.000 claims description 106
• 230000027455 binding Effects 0.000 claims description 58
• 229910052736 halogen Inorganic materials 0.000 claims description 45
• 150000002367 halogens Chemical class 0.000 claims description 45
• 206010028980 Neoplasm Diseases 0.000 claims description 37
• 201000011510 cancer Diseases 0.000 claims description 21
• 230000002265 prevention Effects 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 239000001257 hydrogen Substances 0.000 claims description 16
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
• 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 claims description 15
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 11
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000001153 fluoro group Chemical group F* 0.000 claims description 7
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
• 101710148027 Ribulose bisphosphate carboxylase/oxygenase activase 1, chloroplastic Proteins 0.000 claims description 5
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 4
• 125000002252 acyl group Chemical group 0.000 claims 1
• 230000001093 anti-cancer Effects 0.000 abstract 1
• 238000004519 manufacturing process Methods 0.000 description 362
• 238000000034 method Methods 0.000 description 249
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
• 239000002904 solvent Substances 0.000 description 178
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
• 239000000203 mixture Substances 0.000 description 159
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 150
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 147
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 134
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 118
• 239000000047 product Substances 0.000 description 110
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 90
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 84
• 239000000243 solution Substances 0.000 description 84
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 76
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 71
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 68
• 239000002585 base Substances 0.000 description 65
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 64
• 239000011541 reaction mixture Substances 0.000 description 64
• 230000002829 reductive effect Effects 0.000 description 59
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 59
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 58
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 58
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
• 238000009835 boiling Methods 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
• 238000005160 1H NMR spectroscopy Methods 0.000 description 50
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 47
• AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 40
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 39
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 37
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 35
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 34
• 239000003054 catalyst Substances 0.000 description 34
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 33
• 125000006242 amine protecting group Chemical group 0.000 description 33
• 239000012044 organic layer Substances 0.000 description 33
• 239000012043 crude product Substances 0.000 description 32
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 31
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
• 229910002092 carbon dioxide Inorganic materials 0.000 description 29
• 229910000027 potassium carbonate Inorganic materials 0.000 description 29
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 27
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
• 229910052763 palladium Inorganic materials 0.000 description 26
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 24
• 210000004027 cell Anatomy 0.000 description 24
• 238000012360 testing method Methods 0.000 description 24
• 239000000126 substance Substances 0.000 description 23
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
• 238000004440 column chromatography Methods 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
• 239000002253 acid Substances 0.000 description 21
• 238000003786 synthesis reaction Methods 0.000 description 21
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 20
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 20
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 20
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
• 125000001424 substituent group Chemical group 0.000 description 20
• 239000003208 petroleum Substances 0.000 description 19
• 238000004808 supercritical fluid chromatography Methods 0.000 description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
• 239000003446 ligand Substances 0.000 description 17
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
• IGOFBBKBMHSAMW-SUMWQHHRSA-N 4-[[(2S,4R)-2-methyl-1-propanoyl-3,4-dihydro-2H-quinolin-4-yl]amino]benzoic acid Chemical compound C[C@@H]1N(C2=CC=CC=C2[C@@H](C1)NC1=CC=C(C(=O)O)C=C1)C(CC)=O IGOFBBKBMHSAMW-SUMWQHHRSA-N 0.000 description 15
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 15
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
• 230000014509 gene expression Effects 0.000 description 15
• 239000000741 silica gel Substances 0.000 description 15
• 229910002027 silica gel Inorganic materials 0.000 description 15
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 14
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 14
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
• 229910052698 phosphorus Inorganic materials 0.000 description 14
• 239000011574 phosphorus Substances 0.000 description 14
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 14
• 239000012298 atmosphere Substances 0.000 description 13
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 13
• 230000002401 inhibitory effect Effects 0.000 description 13
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
• 239000005711 Benzoic acid Substances 0.000 description 12
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 11
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 11
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• 239000007800 oxidant agent Substances 0.000 description 11
• 229960005235 piperonyl butoxide Drugs 0.000 description 11
• 239000011591 potassium Substances 0.000 description 11
• 229910052700 potassium Inorganic materials 0.000 description 11
• 229910000029 sodium carbonate Inorganic materials 0.000 description 11
• 239000012312 sodium hydride Substances 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
• 235000010233 benzoic acid Nutrition 0.000 description 10
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 10
• GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 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
• 238000010898 silica gel chromatography Methods 0.000 description 10
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 9
• LJDJBCHZQUGODP-KRWDZBQOSA-N 4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]benzoic acid Chemical compound C(C)(C)(C)OC(C[C@H]1C=2N(C3=C(C(=N1)C1=CC=C(C(=O)O)C=C1)C(=C(S3)C)C)C(=NN=2)C)=O LJDJBCHZQUGODP-KRWDZBQOSA-N 0.000 description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• 125000001589 carboacyl group Chemical group 0.000 description 9
• 238000006243 chemical reaction Methods 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 9
• 239000012046 mixed solvent Substances 0.000 description 9
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 9
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
• XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
• 229910000024 caesium carbonate Inorganic materials 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 230000000052 comparative effect Effects 0.000 description 8
• UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 8
• 239000007789 gas Substances 0.000 description 8
• RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 8
• NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 8
• 229910000105 potassium hydride Inorganic materials 0.000 description 8
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
• 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 8
• DTCJPIHJKGYDOQ-NRFANRHFSA-N 2-[(9S)-4,5,13-trimethyl-7-(4-phenylmethoxycarbonylphenyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid Chemical compound C(C1=CC=CC=C1)OC(=O)C1=CC=C(C=C1)C1=N[C@H](C=2N(C3=C1C(=C(S3)C)C)C(=NN=2)C)CC(=O)O DTCJPIHJKGYDOQ-NRFANRHFSA-N 0.000 description 7
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
• 235000011054 acetic acid Nutrition 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
• 239000001569 carbon dioxide Substances 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
• 229910052805 deuterium Inorganic materials 0.000 description 7
• 235000019253 formic acid Nutrition 0.000 description 7
• 125000002541 furyl group Chemical group 0.000 description 7
• 125000002883 imidazolyl group Chemical group 0.000 description 7
• 239000010410 layer Substances 0.000 description 7
• 125000001715 oxadiazolyl group Chemical group 0.000 description 7
• 125000002971 oxazolyl group Chemical group 0.000 description 7
• 125000003373 pyrazinyl group Chemical group 0.000 description 7
• 125000003226 pyrazolyl group Chemical group 0.000 description 7
• 125000002098 pyridazinyl group Chemical group 0.000 description 7
• 125000004076 pyridyl group Chemical group 0.000 description 7
• 125000000714 pyrimidinyl group Chemical group 0.000 description 7
• 125000000168 pyrrolyl group Chemical group 0.000 description 7
• 238000004007 reversed phase HPLC Methods 0.000 description 7
• 125000003831 tetrazolyl group Chemical group 0.000 description 7
• 125000000335 thiazolyl group Chemical group 0.000 description 7
• 125000001544 thienyl group Chemical group 0.000 description 7
• 125000001425 triazolyl group Chemical group 0.000 description 7
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
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• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• GNPXKHTZVDUNOY-UHFFFAOYSA-N oxomethylidenerhodium Chemical compound O=C=[Rh] GNPXKHTZVDUNOY-UHFFFAOYSA-N 0.000 description 1
• GCWIQUVXWZWCLE-INIZCTEOSA-N pelabresib Chemical compound N([C@@H](CC(N)=O)C=1ON=C(C=1C1=CC=CC=C11)C)=C1C1=CC=C(Cl)C=C1 GCWIQUVXWZWCLE-INIZCTEOSA-N 0.000 description 1
• 229940049954 penicillin Drugs 0.000 description 1
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
• COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
• 235000008729 phenylalanine Nutrition 0.000 description 1
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
• 239000010452 phosphate Substances 0.000 description 1
• 150000003014 phosphoric acid esters Chemical class 0.000 description 1
• 230000004962 physiological condition Effects 0.000 description 1
• 229910052697 platinum Inorganic materials 0.000 description 1
• XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
• RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
• UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
• 238000003753 real-time PCR Methods 0.000 description 1
• 238000011084 recovery Methods 0.000 description 1
• 238000001953 recrystallisation Methods 0.000 description 1
• 229910052707 ruthenium Inorganic materials 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
• 235000017557 sodium bicarbonate Nutrition 0.000 description 1
• 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
• 229960001922 sodium perborate Drugs 0.000 description 1
• 159000000000 sodium salts Chemical class 0.000 description 1
• 229910052938 sodium sulfate Inorganic materials 0.000 description 1
• 235000011152 sodium sulphate Nutrition 0.000 description 1
• PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
• 239000011755 sodium-L-ascorbate Substances 0.000 description 1
• 235000019187 sodium-L-ascorbate Nutrition 0.000 description 1
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
• YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
• 238000001228 spectrum Methods 0.000 description 1
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• 238000007920 subcutaneous administration Methods 0.000 description 1
• 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
• 229910052717 sulfur Inorganic materials 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 239000000725 suspension Substances 0.000 description 1
• 229950009390 symclosene Drugs 0.000 description 1
• ABANSZWIBIWCIC-IBGZPJMESA-N tert-butyl 2-[(9S)-7-[4-(2-aminoethylcarbamoyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate Chemical compound NCCNC(=O)C1=CC=C(C=C1)C1=N[C@H](C=2N(C3=C1C(=C(S3)C)C)C(=NN=2)C)CC(=O)OC(C)(C)C ABANSZWIBIWCIC-IBGZPJMESA-N 0.000 description 1
• BAKFOMLJJXOWFU-UHFFFAOYSA-N tert-butyl 2-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1N BAKFOMLJJXOWFU-UHFFFAOYSA-N 0.000 description 1
• VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
• GSIBTIUXYYFCPU-UHFFFAOYSA-N tert-butyl 4-(bromomethyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(CBr)C=C1 GSIBTIUXYYFCPU-UHFFFAOYSA-N 0.000 description 1
• JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
• ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
• ANJZWACAZSXSNR-OWUIVRORSA-N tert-butyl 5-[4-[[(2S,4R)-2-methyl-1-propanoyl-3,4-dihydro-2H-quinolin-4-yl]amino]benzoyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C[C@@H]1N(C2=CC=CC=C2[C@@H](C1)NC1=CC=C(C(=O)N2C3CN(C(C2)C3)C(=O)OC(C)(C)C)C=C1)C(CC)=O ANJZWACAZSXSNR-OWUIVRORSA-N 0.000 description 1
• QDIPSXASGUPBDB-HTAPYJJXSA-N tert-butyl N-(4-formylphenyl)-N-[(2S,4R)-2-methyl-1-propanoyl-3,4-dihydro-2H-quinolin-4-yl]carbamate Chemical compound C(=O)C1=CC=C(C=C1)N(C(OC(C)(C)C)=O)[C@@H]1C[C@@H](N(C2=CC=CC=C12)C(CC)=O)C QDIPSXASGUPBDB-HTAPYJJXSA-N 0.000 description 1
• AAHLVBMONRTGGP-UHFFFAOYSA-N tert-butyl N-[1-[4-(4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl)benzoyl]piperidin-4-yl]carbamate Chemical compound CC1=C(C=2C(=NCC=3N(C=2S1)C(=NN=3)C)C1=CC=C(C(=O)N2CCC(CC2)NC(OC(C)(C)C)=O)C=C1)C AAHLVBMONRTGGP-UHFFFAOYSA-N 0.000 description 1
• FVONWUQPLKHQCM-UHFFFAOYSA-N tert-butyl N-[1-[[3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-hydroxyphenyl]methyl]piperidin-4-yl]carbamate Chemical compound CC1=NOC(=C1C=1C=C(CN2CCC(CC2)NC(OC(C)(C)C)=O)C=C(C=1)O)C FVONWUQPLKHQCM-UHFFFAOYSA-N 0.000 description 1
• DBTARAPTSFMKHI-HTAPYJJXSA-N tert-butyl N-[4-(hydroxymethyl)phenyl]-N-[(2S,4R)-2-methyl-1-propanoyl-3,4-dihydro-2H-quinolin-4-yl]carbamate Chemical compound OCC1=CC=C(C=C1)N(C(OC(C)(C)C)=O)[C@@H]1C[C@@H](N(C2=CC=CC=C12)C(CC)=O)C DBTARAPTSFMKHI-HTAPYJJXSA-N 0.000 description 1
• GPRGCPMNVNGOPX-UHFFFAOYSA-N tert-butyl N-[4-[(2-ethyl-4-oxo-6,7-dihydro-5H-indol-1-yl)methyl]phenyl]carbamate Chemical compound C(C)C=1N(C=2CCCC(C=2C=1)=O)CC1=CC=C(C=C1)NC(OC(C)(C)C)=O GPRGCPMNVNGOPX-UHFFFAOYSA-N 0.000 description 1
• OPDOEOOBYOABCJ-UHFFFAOYSA-N tert-butyl n-(3-aminocyclobutyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CC(N)C1 OPDOEOOBYOABCJ-UHFFFAOYSA-N 0.000 description 1
• POHWAQLZBIMPRN-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCN POHWAQLZBIMPRN-UHFFFAOYSA-N 0.000 description 1
• FNHPTFKSPUTESA-UHFFFAOYSA-N tert-butyl n-(3-oxocyclobutyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CC(=O)C1 FNHPTFKSPUTESA-UHFFFAOYSA-N 0.000 description 1
• WYVFPGFWUKBXPZ-UHFFFAOYSA-N tert-butyl n-(4-oxocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)CC1 WYVFPGFWUKBXPZ-UHFFFAOYSA-N 0.000 description 1
• URXUHALBOWYXJZ-UHFFFAOYSA-N tert-butyl n-[4-(aminomethyl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CN)C=C1 URXUHALBOWYXJZ-UHFFFAOYSA-N 0.000 description 1
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 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
• QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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• 230000001225 therapeutic effect Effects 0.000 description 1
• 238000004809 thin layer chromatography Methods 0.000 description 1
• ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• 238000000844 transformation Methods 0.000 description 1
• 150000003852 triazoles Chemical group 0.000 description 1
• TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
• PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 description 1
• 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
• 235000019798 tripotassium phosphate Nutrition 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 230000003442 weekly effect Effects 0.000 description 1
• 230000004580 weight loss Effects 0.000 description 1
• 150000003751 zinc Chemical class 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1