CA3096732A1 - Dual atm and dna-pk inhibitors for use in anti-tumor therapy - Google Patents

Info

Publication number

CA3096732A1

CA3096732A1 CA3096732A CA3096732A CA3096732A1 CA 3096732 A1 CA3096732 A1 CA 3096732A1 CA 3096732 A CA3096732 A CA 3096732A CA 3096732 A CA3096732 A CA 3096732A CA 3096732 A1 CA3096732 A1 CA 3096732A1

Authority

CA

Canada

Prior art keywords

optionally substituted

pyrrolo

methy1

oxo

pyridin

Prior art date

2018-04-20

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

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 230000000259 anti-tumor effect Effects 0.000 title claims description 4
• 230000009977 dual effect Effects 0.000 title description 6
• 239000003112 inhibitor Substances 0.000 title description 5
• 238000002560 therapeutic procedure Methods 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 232
• 150000003839 salts Chemical class 0.000 claims abstract description 38
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
• 201000010099 disease Diseases 0.000 claims abstract description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 513
• 125000003003 spiro group Chemical group 0.000 claims description 411
• 239000000203 mixture Substances 0.000 claims description 201
• -1 dimethylsulfamoyl Chemical group 0.000 claims description 168
• 125000001072 heteroaryl group Chemical group 0.000 claims description 105
• 125000000623 heterocyclic group Chemical group 0.000 claims description 100
• 238000000034 method Methods 0.000 claims description 62
• 125000003118 aryl group Chemical group 0.000 claims description 60
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 60
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 56
• 125000005843 halogen group Chemical group 0.000 claims description 54
• 229910052739 hydrogen Inorganic materials 0.000 claims description 54
• 239000001257 hydrogen Substances 0.000 claims description 54
• 125000001188 haloalkyl group Chemical group 0.000 claims description 49
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 48
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 42
• 125000000217 alkyl group Chemical group 0.000 claims description 42
• 229910052757 nitrogen Inorganic materials 0.000 claims description 42
• 125000003107 substituted aryl group Chemical group 0.000 claims description 39
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 36
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 36
• 125000002947 alkylene group Chemical group 0.000 claims description 30
• 238000001959 radiotherapy Methods 0.000 claims description 24
• 229910052720 vanadium Inorganic materials 0.000 claims description 24
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
• 125000004450 alkenylene group Chemical group 0.000 claims description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 17
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 17
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 125000004419 alkynylene group Chemical group 0.000 claims description 14
• 239000012453 solvate Substances 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 125000000262 haloalkenyl group Chemical group 0.000 claims description 13
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
• 239000002246 antineoplastic agent Substances 0.000 claims description 12
• 125000004429 atom Chemical group 0.000 claims description 11
• 201000011510 cancer Diseases 0.000 claims description 11
• OWCDMRFUFMERMZ-UHFFFAOYSA-N benzenesulfonamide;hydrochloride Chemical compound Cl.NS(=O)(=O)C1=CC=CC=C1 OWCDMRFUFMERMZ-UHFFFAOYSA-N 0.000 claims description 9
• 241001465754 Metazoa Species 0.000 claims description 8
• 125000002950 monocyclic group Chemical group 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 7
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 208000035475 disorder Diseases 0.000 claims description 5
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
• AYVGBNGTBQLJBG-UHFFFAOYSA-N [3-(hydroxymethyl)cyclopentyl]methanol Chemical compound OCC1CCC(CO)C1 AYVGBNGTBQLJBG-UHFFFAOYSA-N 0.000 claims description 4
• 125000005717 substituted cycloalkylene group Chemical group 0.000 claims description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 3
• XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 3
• XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 3
• 239000012661 PARP inhibitor Substances 0.000 claims description 3
• 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 3
• VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
• HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 3
• 229930195731 calicheamicin Natural products 0.000 claims description 3
• 229960004562 carboplatin Drugs 0.000 claims description 3
• DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
• 229960004316 cisplatin Drugs 0.000 claims description 3
• 229960000908 idarubicin Drugs 0.000 claims description 3
• 238000009169 immunotherapy Methods 0.000 claims description 3
• 229960001756 oxaliplatin Drugs 0.000 claims description 3
• DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 3
• ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 3
• 229960000653 valrubicin Drugs 0.000 claims description 3
• OTBFUMSMIVYLAK-UHFFFAOYSA-N 1,3-thiazole-5-sulfonamide Chemical compound NS(=O)(=O)C1=CN=CS1 OTBFUMSMIVYLAK-UHFFFAOYSA-N 0.000 claims description 2
• 238000002725 brachytherapy Methods 0.000 claims description 2
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims 7
• WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 claims 5
• GMRVKINFAYTSJF-UHFFFAOYSA-N cyclopropanesulfonamide hydrochloride Chemical compound Cl.C1(CC1)S(=O)(=O)N GMRVKINFAYTSJF-UHFFFAOYSA-N 0.000 claims 3
• QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 claims 2
• DWXLVZSMXXCSMJ-UHFFFAOYSA-N piperazine-1-sulfonamide Chemical compound NS(=O)(=O)N1CCNCC1 DWXLVZSMXXCSMJ-UHFFFAOYSA-N 0.000 claims 2
• STIUWSWFXIBBKI-UHFFFAOYSA-N azetidine-1-sulfonamide Chemical compound NS(=O)(=O)N1CCC1 STIUWSWFXIBBKI-UHFFFAOYSA-N 0.000 claims 1
• 239000003124 biologic agent Substances 0.000 claims 1
• RSOJSFYJLQADDM-UHFFFAOYSA-N ethanesulfonamide Chemical compound [CH2]CS(N)(=O)=O RSOJSFYJLQADDM-UHFFFAOYSA-N 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• UMRKNFYJEVIMLC-UHFFFAOYSA-N oxetane-3-sulfonamide Chemical compound NS(=O)(=O)C1COC1 UMRKNFYJEVIMLC-UHFFFAOYSA-N 0.000 claims 1
• LPPOVVJDAVMOET-UHFFFAOYSA-N pyrrolidine-1-sulfonamide Chemical compound NS(=O)(=O)N1CCCC1 LPPOVVJDAVMOET-UHFFFAOYSA-N 0.000 claims 1
• 230000009885 systemic effect Effects 0.000 claims 1
• BWJZHYWAXLWLTB-UHFFFAOYSA-N thiophene-3-sulfonamide Chemical compound NS(=O)(=O)C=1C=CSC=1 BWJZHYWAXLWLTB-UHFFFAOYSA-N 0.000 claims 1
• 230000000771 oncological effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 273
• 229940124530 sulfonamide Drugs 0.000 description 255
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 243
• 230000002829 reductive effect Effects 0.000 description 191
• 150000003456 sulfonamides Chemical class 0.000 description 183
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 179
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
• 238000005160 1H NMR spectroscopy Methods 0.000 description 145
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 128
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 119
• 239000007787 solid Substances 0.000 description 109
• 239000000243 solution Substances 0.000 description 103
• PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 89
• 101150041968 CDC13 gene Proteins 0.000 description 88
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 88
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 74
• 238000010898 silica gel chromatography Methods 0.000 description 72
• 239000000706 filtrate Substances 0.000 description 70
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 68
• 239000012044 organic layer Substances 0.000 description 65
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 63
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 59
• 238000001914 filtration Methods 0.000 description 58
• 238000003756 stirring Methods 0.000 description 58
• 229920006395 saturated elastomer Polymers 0.000 description 57
• 239000012267 brine Substances 0.000 description 56
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
• 238000006243 chemical reaction Methods 0.000 description 54
• 239000000543 intermediate Substances 0.000 description 47
• 229910000104 sodium hydride Inorganic materials 0.000 description 47
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 42
• 239000012299 nitrogen atmosphere Substances 0.000 description 42
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
• 125000000753 cycloalkyl group Chemical group 0.000 description 40
• BPSUJSDZHLTNJR-UHFFFAOYSA-N sulfamide;hydrochloride Chemical compound Cl.NS(N)(=O)=O BPSUJSDZHLTNJR-UHFFFAOYSA-N 0.000 description 40
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 40
• 238000007792 addition Methods 0.000 description 39
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 239000003208 petroleum Substances 0.000 description 35
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
• 235000019270 ammonium chloride Nutrition 0.000 description 34
• 239000012071 phase Substances 0.000 description 29
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 28
• 238000005481 NMR spectroscopy Methods 0.000 description 26
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 24
• 239000012312 sodium hydride Substances 0.000 description 24
• 239000002480 mineral oil Substances 0.000 description 23
• 235000010446 mineral oil Nutrition 0.000 description 23
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 22
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 22
• 125000004432 carbon atom Chemical group C* 0.000 description 22
• 125000001309 chloro group Chemical group Cl* 0.000 description 21
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 125000004093 cyano group Chemical group *C#N 0.000 description 19
• 239000000047 product Substances 0.000 description 18
• 125000001424 substituent group Chemical group 0.000 description 18
• 241000124008 Mammalia Species 0.000 description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• 125000001246 bromo group Chemical group Br* 0.000 description 15
• 239000003921 oil Substances 0.000 description 15
• 235000019198 oils Nutrition 0.000 description 15
• 239000002904 solvent Substances 0.000 description 15
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
• FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 14
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 13
• 229910004373 HOAc Inorganic materials 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 125000002015 acyclic group Chemical group 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 125000003342 alkenyl group Chemical group 0.000 description 11
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 11
• 125000004043 oxo group Chemical group O=* 0.000 description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• CQTCMODFSOZVLY-UHFFFAOYSA-N C(C1)CC11C(C(C=CC=C2)=C2N=C2)=C2N=C1 Chemical compound C(C1)CC11C(C(C=CC=C2)=C2N=C2)=C2N=C1 CQTCMODFSOZVLY-UHFFFAOYSA-N 0.000 description 10
• 108010006124 DNA-Activated Protein Kinase Proteins 0.000 description 10
• 102000005768 DNA-Activated Protein Kinase Human genes 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 10
• 238000001816 cooling Methods 0.000 description 10
• 229910052731 fluorine Inorganic materials 0.000 description 10
• 229910000027 potassium carbonate Inorganic materials 0.000 description 10
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
• 239000004215 Carbon black (E152) Substances 0.000 description 9
• 238000006069 Suzuki reaction reaction Methods 0.000 description 9
• 150000001412 amines Chemical class 0.000 description 9
• 125000003710 aryl alkyl group Chemical group 0.000 description 9
• 229930195733 hydrocarbon Natural products 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• 239000011541 reaction mixture Substances 0.000 description 9
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 8
• BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
• 239000002585 base Substances 0.000 description 8
• 229910052796 boron Inorganic materials 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 238000002648 combination therapy Methods 0.000 description 8
• OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 238000003818 flash chromatography Methods 0.000 description 8
• 239000010410 layer Substances 0.000 description 8
• NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 8
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
• 239000012258 stirred mixture Substances 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
• 235000012538 ammonium bicarbonate Nutrition 0.000 description 7
• 150000002430 hydrocarbons Chemical group 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
• 230000002285 radioactive effect Effects 0.000 description 7
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 7
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
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