TWI605048B - Novel pyrrolopyrimidine compounds or salts thereof, and pharmaceutical compositions containing the same, in particular, prophylactic and / or therapeutic agents for tumors and the like based on the inhibition of NAE - Google Patents

Info

Publication number

TWI605048B

TWI605048B TW104120451A TW104120451A TWI605048B TW I605048 B TWI605048 B TW I605048B TW 104120451 A TW104120451 A TW 104120451A TW 104120451 A TW104120451 A TW 104120451A TW I605048 B TWI605048 B TW I605048B

Authority

TW

Taiwan

Prior art keywords

group

ethynyl

methyl

amino

compound

Prior art date

2014-06-24

Links

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• 150000003839 salts Chemical class 0.000 title claims description 53
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
• 206010028980 Neoplasm Diseases 0.000 title description 40
• 230000005764 inhibitory process Effects 0.000 title description 14
• 239000003814 drug Substances 0.000 title description 8
• 150000004944 pyrrolopyrimidines Chemical class 0.000 title description 3
• 229940124597 therapeutic agent Drugs 0.000 title description 2
• 230000000069 prophylactic effect Effects 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 493
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 211
• -1 amine sulfonate Chemical class 0.000 claims description 196
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 177
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 167
• JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 claims description 130
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 121
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 84
• 229910052757 nitrogen Inorganic materials 0.000 claims description 72
• 229910052717 sulfur Inorganic materials 0.000 claims description 70
• 229910052760 oxygen Inorganic materials 0.000 claims description 67
• 125000005842 heteroatom Chemical group 0.000 claims description 66
• 125000001424 substituent group Chemical group 0.000 claims description 66
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 60
• 125000002950 monocyclic group Chemical group 0.000 claims description 60
• 125000002619 bicyclic group Chemical group 0.000 claims description 59
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 47
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 41
• 150000002367 halogens Chemical class 0.000 claims description 41
• 125000003277 amino group Chemical group 0.000 claims description 35
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 33
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 24
• 102000038427 NEDD8-activating enzyme E1 Human genes 0.000 claims description 23
• 108091007790 NEDD8-activating enzyme E1 Proteins 0.000 claims description 23
• 239000001257 hydrogen Substances 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 22
• 239000011737 fluorine Substances 0.000 claims description 22
• 229910052731 fluorine Inorganic materials 0.000 claims description 22
• 150000001412 amines Chemical class 0.000 claims description 21
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 18
• 150000002431 hydrogen Chemical class 0.000 claims description 16
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 14
• 125000004076 pyridyl group Chemical group 0.000 claims description 13
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 11
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 10
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
• MNLVCBKWEVXHGE-UHFFFAOYSA-N [CH]1[CH]CC[CH]1 Chemical group [CH]1[CH]CC[CH]1 MNLVCBKWEVXHGE-UHFFFAOYSA-N 0.000 claims description 9
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 125000001624 naphthyl group Chemical group 0.000 claims description 7
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 6
• 239000000460 chlorine Substances 0.000 claims description 6
• 229910052801 chlorine Inorganic materials 0.000 claims description 6
• 125000003386 piperidinyl group Chemical group 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 5
• 239000003112 inhibitor Substances 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
• 239000002246 antineoplastic agent Substances 0.000 claims description 4
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• 125000004429 atom Chemical group 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
• 239000004480 active ingredient Substances 0.000 claims 1
• 125000001207 fluorophenyl group Chemical group 0.000 claims 1
• 239000012535 impurity Substances 0.000 claims 1
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical group O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims 1
• 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 1
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
• 229940124530 sulfonamide Drugs 0.000 claims 1
• 238000005160 1H NMR spectroscopy Methods 0.000 description 277
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 248
• 238000003786 synthesis reaction Methods 0.000 description 221
• 230000015572 biosynthetic process Effects 0.000 description 216
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 190
• 238000000034 method Methods 0.000 description 141
• BIFLARAADMSAQE-UHFFFAOYSA-N 2-ethynyl-1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1C#C BIFLARAADMSAQE-UHFFFAOYSA-N 0.000 description 89
• 238000006243 chemical reaction Methods 0.000 description 86
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
• 239000000243 solution Substances 0.000 description 82
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 73
• 239000002904 solvent Substances 0.000 description 73
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
• 235000019439 ethyl acetate Nutrition 0.000 description 68
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
• 235000002639 sodium chloride Nutrition 0.000 description 52
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
• 150000004032 porphyrins Chemical class 0.000 description 44
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
• 210000004027 cell Anatomy 0.000 description 37
• 239000000203 mixture Substances 0.000 description 37
• MCZUXEWWARACSP-UHFFFAOYSA-N 1-ethynylnaphthalene Chemical compound C1=CC=C2C(C#C)=CC=CC2=C1 MCZUXEWWARACSP-UHFFFAOYSA-N 0.000 description 34
• 239000012044 organic layer Substances 0.000 description 34
• 230000002401 inhibitory effect Effects 0.000 description 30
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 28
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
• 239000002585 base Substances 0.000 description 27
• 238000003756 stirring Methods 0.000 description 27
• 238000012360 testing method Methods 0.000 description 26
• UIOAYOIJMYMOEU-UHFFFAOYSA-N 2-fluoro-6-methoxybenzaldehyde Chemical compound COC1=CC=CC(F)=C1C=O UIOAYOIJMYMOEU-UHFFFAOYSA-N 0.000 description 24
• 238000004519 manufacturing process Methods 0.000 description 23
• 239000010410 layer Substances 0.000 description 22
• 238000010898 silica gel chromatography Methods 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
• 229920006395 saturated elastomer Polymers 0.000 description 21
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
• 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 20
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
• 150000001335 aliphatic alkanes Chemical class 0.000 description 18
• 238000001816 cooling Methods 0.000 description 18
• 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 18
• 125000006239 protecting group Chemical group 0.000 description 17
• 229910052938 sodium sulfate Inorganic materials 0.000 description 17
• 235000011152 sodium sulphate Nutrition 0.000 description 17
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 16
• 108090000623 proteins and genes Proteins 0.000 description 16
• 230000035484 reaction time Effects 0.000 description 15
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
• 101710167917 Carbonic anhydrase 2 Proteins 0.000 description 14
• 102100024633 Carbonic anhydrase 2 Human genes 0.000 description 14
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 239000011541 reaction mixture Substances 0.000 description 14
• 125000004149 thio group Chemical group *S* 0.000 description 14
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• 102000004169 proteins and genes Human genes 0.000 description 13
• 230000002829 reductive effect Effects 0.000 description 13
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
• 125000000217 alkyl group Chemical group 0.000 description 12
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• 238000009835 boiling Methods 0.000 description 12
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
• WTCQOVMJLJMLCQ-UHFFFAOYSA-N 2-bromo-5-phenylmethoxypyrimidine Chemical compound C1=NC(Br)=NC=C1OCC1=CC=CC=C1 WTCQOVMJLJMLCQ-UHFFFAOYSA-N 0.000 description 11
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
• 239000012267 brine Substances 0.000 description 11
• 230000000052 comparative effect Effects 0.000 description 11
• 238000002360 preparation method Methods 0.000 description 11
• 239000000126 substance Substances 0.000 description 11
• BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 11
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
• 102100031911 NEDD8 Human genes 0.000 description 10
• 101150107958 NEDD8 gene Proteins 0.000 description 10
• GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 9
• 150000001413 amino acids Chemical class 0.000 description 9
• 230000037396 body weight Effects 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 239000003153 chemical reaction reagent Substances 0.000 description 9
• 230000035755 proliferation Effects 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• 235000017557 sodium bicarbonate Nutrition 0.000 description 9
• 239000007787 solid Substances 0.000 description 9
• DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 8
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 201000011510 cancer Diseases 0.000 description 8
• 238000004440 column chromatography Methods 0.000 description 8
• 210000000056 organ Anatomy 0.000 description 8
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
• 102000004190 Enzymes Human genes 0.000 description 7
• 108090000790 Enzymes Proteins 0.000 description 7
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
• 239000007864 aqueous solution Substances 0.000 description 7
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 230000004663 cell proliferation Effects 0.000 description 7
• 238000005859 coupling reaction Methods 0.000 description 7
• 229940088598 enzyme Drugs 0.000 description 7
• QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• 239000002994 raw material Substances 0.000 description 7
• 239000011780 sodium chloride Substances 0.000 description 7
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
• 230000004614 tumor growth Effects 0.000 description 7
• 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 6
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
• NOPWUXRFETZTQG-UHFFFAOYSA-N 2-ethynyl-1,3,5-trifluorobenzene Chemical compound FC1=CC(F)=C(C#C)C(F)=C1 NOPWUXRFETZTQG-UHFFFAOYSA-N 0.000 description 6
• HGAIPYBAKIPQNV-UHFFFAOYSA-N 3-[(4-iodophenoxy)methyl]pyridine Chemical compound C1=CC(I)=CC=C1OCC1=CC=CN=C1 HGAIPYBAKIPQNV-UHFFFAOYSA-N 0.000 description 6
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
• UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 6
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
• 206010025323 Lymphomas Diseases 0.000 description 6
• 206010039491 Sarcoma Diseases 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 6
• HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 6
• BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
• 239000013078 crystal Substances 0.000 description 6
• DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 6
• 238000010511 deprotection reaction Methods 0.000 description 6
• 230000003394 haemopoietic effect Effects 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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