CN106459057B - 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物 - Google Patents
作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物 Download PDFInfo
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- CN106459057B CN106459057B CN201580017657.1A CN201580017657A CN106459057B CN 106459057 B CN106459057 B CN 106459057B CN 201580017657 A CN201580017657 A CN 201580017657A CN 106459057 B CN106459057 B CN 106459057B
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- Prior art keywords
- fluoro
- benzo
- imidazo
- methyl
- formamide
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- -1 benzimidazole compound Chemical class 0.000 title claims abstract description 335
- 239000012661 PARP inhibitor Substances 0.000 title abstract description 6
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 220
- 150000003839 salts Chemical class 0.000 claims abstract description 98
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 377
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 163
- 150000003217 pyrazoles Chemical class 0.000 claims description 124
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 96
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 60
- 229910052731 fluorine Inorganic materials 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 229910052801 chlorine Inorganic materials 0.000 claims description 36
- 229910052794 bromium Inorganic materials 0.000 claims description 34
- 229910052740 iodine Inorganic materials 0.000 claims description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 23
- 150000003053 piperidines Chemical class 0.000 claims description 22
- CSVIUMAJLULMJD-UHFFFAOYSA-N FC=1C=C2N(N=1)C1=C(N2)C=CC=C1 Chemical class FC=1C=C2N(N=1)C1=C(N2)C=CC=C1 CSVIUMAJLULMJD-UHFFFAOYSA-N 0.000 claims description 19
- MREIFUWKYMNYTK-UHFFFAOYSA-N 1H-pyrrole Chemical class C=1C=CNC=1.C=1C=CNC=1 MREIFUWKYMNYTK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 150000001408 amides Chemical class 0.000 claims description 15
- 125000004494 ethyl ester group Chemical group 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 241000790917 Dioxys <bee> Species 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- JUHZIHYGDUXTFJ-UHFFFAOYSA-N 1-ethyl-4-methylpiperidine Chemical compound CCN1CCC(C)CC1 JUHZIHYGDUXTFJ-UHFFFAOYSA-N 0.000 claims description 9
- MFGQIJCMHXZHHP-UHFFFAOYSA-N 5h-imidazo[1,2-b]pyrazole Chemical class N1C=CC2=NC=CN21 MFGQIJCMHXZHHP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 6
- ONQBOTKLCMXPOF-UHFFFAOYSA-N 1-ethylpyrrolidine Chemical compound CCN1CCCC1 ONQBOTKLCMXPOF-UHFFFAOYSA-N 0.000 claims description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- JDAFADIGSWFDNX-UHFFFAOYSA-N 3-ethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1N(CC)CC2CC21 JDAFADIGSWFDNX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003851 azoles Chemical class 0.000 claims description 6
- HGWUUOXXAIISDB-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2CC21 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- OBAXRSXTJUNZRQ-UHFFFAOYSA-N 3-methyl-3-azabicyclo[3.1.0]hexane Chemical compound C1N(C)CC2CC21 OBAXRSXTJUNZRQ-UHFFFAOYSA-N 0.000 claims description 4
- CYMHVSLTDBJXMH-UHFFFAOYSA-N C(C)(C)N1CCC(CC1)(C)C=1C=CC2=C(NC=3N2N=CC3)C1 Chemical class C(C)(C)N1CCC(CC1)(C)C=1C=CC2=C(NC=3N2N=CC3)C1 CYMHVSLTDBJXMH-UHFFFAOYSA-N 0.000 claims description 4
- WPNFCUAYOGKVJU-UHFFFAOYSA-N FC(C=C1)=CC2=C1N1N=CC(C3CCNCC3)=C1N2 Chemical class FC(C=C1)=CC2=C1N1N=CC(C3CCNCC3)=C1N2 WPNFCUAYOGKVJU-UHFFFAOYSA-N 0.000 claims description 4
- RUOFIIKCANAEBW-UHFFFAOYSA-N N-Ethyl-hexahydro-1H-azepine Chemical compound CCN1CCCCCC1 RUOFIIKCANAEBW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 claims description 4
- GIWQSPITLQVMSG-UHFFFAOYSA-N 1,2-dimethylimidazole Chemical class CC1=NC=CN1C GIWQSPITLQVMSG-UHFFFAOYSA-N 0.000 claims description 3
- MDAYDUTUCACRNH-UHFFFAOYSA-N 1,3-dimethylazepine Chemical compound CN1C=CC=CC(C)=C1 MDAYDUTUCACRNH-UHFFFAOYSA-N 0.000 claims description 3
- IGNGFGXAWDQJGP-UHFFFAOYSA-N 1,3-dimethylpyrrolidine Chemical compound CC1CCN(C)C1 IGNGFGXAWDQJGP-UHFFFAOYSA-N 0.000 claims description 3
- IEMFQSPDUIMPAK-UHFFFAOYSA-N 1-(2-methoxyethyl)-4-methylpiperidine Chemical compound COCCN1CCC(C)CC1 IEMFQSPDUIMPAK-UHFFFAOYSA-N 0.000 claims description 3
- JWEAEMQLQIGHSI-UHFFFAOYSA-N 1-(3-methoxypropyl)-4-methylpiperidine Chemical compound COCCCN1CCC(C)CC1 JWEAEMQLQIGHSI-UHFFFAOYSA-N 0.000 claims description 3
- AYCXISJYDYMUIG-UHFFFAOYSA-N 1-[(4-methylpiperidin-1-yl)methyl]cyclobutane-1-carbonitrile Chemical compound CC1CCN(CC2(CCC2)C#N)CC1 AYCXISJYDYMUIG-UHFFFAOYSA-N 0.000 claims description 3
- IPUBFLLIEFJOQC-UHFFFAOYSA-N 1-[(4-methylpiperidin-1-yl)methyl]cyclopropan-1-amine Chemical compound C1CC(C)CCN1CC1(N)CC1 IPUBFLLIEFJOQC-UHFFFAOYSA-N 0.000 claims description 3
- NBQGYJAPPVYUFU-UHFFFAOYSA-N 1-cyclopropyl-4-methylpiperidine Chemical compound C1CC(C)CCN1C1CC1 NBQGYJAPPVYUFU-UHFFFAOYSA-N 0.000 claims description 3
- JUBXTBVKELTJEX-UHFFFAOYSA-N 1-cyclopropylpiperidine Chemical compound C1CC1N1CCCCC1 JUBXTBVKELTJEX-UHFFFAOYSA-N 0.000 claims description 3
- QQUZUWSSLUHHBP-UHFFFAOYSA-N 1-ethoxycarbonylcyclopropane-1-carboxylic acid Chemical compound CCOC(=O)C1(C(O)=O)CC1 QQUZUWSSLUHHBP-UHFFFAOYSA-N 0.000 claims description 3
- YQOPNAOQGQSUHF-UHFFFAOYSA-N 1-propan-2-ylpyrrolidine Chemical compound CC(C)N1CCCC1 YQOPNAOQGQSUHF-UHFFFAOYSA-N 0.000 claims description 3
- KTIJMGLLLNVUDN-UHFFFAOYSA-N 3-(4-methylpiperidin-1-yl)propanenitrile Chemical compound CC1CCN(CCC#N)CC1 KTIJMGLLLNVUDN-UHFFFAOYSA-N 0.000 claims description 3
- KYIOXRSJWUNDPN-UHFFFAOYSA-N 3-methyl-1-propan-2-ylazepine Chemical compound CC(C)N1C=CC=CC(C)=C1 KYIOXRSJWUNDPN-UHFFFAOYSA-N 0.000 claims description 3
- SNCMDWGNPFFORV-UHFFFAOYSA-N 3-propan-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1N(C(C)C)CC2CC21 SNCMDWGNPFFORV-UHFFFAOYSA-N 0.000 claims description 3
- KABYJBJJHQLIES-UHFFFAOYSA-N C(C)N1C=C(C=CC=C1)C Chemical compound C(C)N1C=C(C=CC=C1)C KABYJBJJHQLIES-UHFFFAOYSA-N 0.000 claims description 3
- HEHZBUDMZKAPAC-UHFFFAOYSA-N CC1=NN(C(C=CC=C2)=C2N2)C2=C1F Chemical class CC1=NN(C(C=CC=C2)=C2N2)C2=C1F HEHZBUDMZKAPAC-UHFFFAOYSA-N 0.000 claims description 3
- RINZXDMNRMRWPP-UHFFFAOYSA-N CCN1CCC(C)CC1C Chemical compound CCN1CCC(C)CC1C RINZXDMNRMRWPP-UHFFFAOYSA-N 0.000 claims description 3
- HLHZHYFTTCGUMM-UHFFFAOYSA-N CN(C)CC1C(C1)CN1CCC(CC1)C Chemical compound CN(C)CC1C(C1)CN1CCC(CC1)C HLHZHYFTTCGUMM-UHFFFAOYSA-N 0.000 claims description 3
- LQXMCNHGWFYOTL-UHFFFAOYSA-N N#Cc1cnn2c3ccccc3[nH]c12 Chemical class N#Cc1cnn2c3ccccc3[nH]c12 LQXMCNHGWFYOTL-UHFFFAOYSA-N 0.000 claims description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 3
- 150000002921 oxetanes Chemical class 0.000 claims description 3
- CJNRDUQIOGIUNR-UHFFFAOYSA-N piperazine;pyridine-4-carboxylic acid Chemical compound C1CNCCN1.OC(=O)C1=CC=NC=C1 CJNRDUQIOGIUNR-UHFFFAOYSA-N 0.000 claims description 3
- DHWXHYCQFFUPSD-UHFFFAOYSA-N 1-(2-fluoroethyl)-4-methylpiperidine Chemical compound CC1CCN(CCF)CC1 DHWXHYCQFFUPSD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- UEPULYROJYKFBC-UHFFFAOYSA-N CCN(CC1)CC1(C)C1=C(NC2=C3C=CC=C2)N3N=C1F Chemical class CCN(CC1)CC1(C)C1=C(NC2=C3C=CC=C2)N3N=C1F UEPULYROJYKFBC-UHFFFAOYSA-N 0.000 claims description 2
- BKWVRXAPAPXWDI-UHFFFAOYSA-N N1=CC=C(C=C1)C=1C=CC2=C(NC=3N2N=CC3)C1 Chemical class N1=CC=C(C=C1)C=1C=CC2=C(NC=3N2N=CC3)C1 BKWVRXAPAPXWDI-UHFFFAOYSA-N 0.000 claims description 2
- JBNNTVHZXABFRC-UHFFFAOYSA-N N1C(CCC1)C=1C=CC2=C(NC=3N2N=CC3)C1 Chemical class N1C(CCC1)C=1C=CC2=C(NC=3N2N=CC3)C1 JBNNTVHZXABFRC-UHFFFAOYSA-N 0.000 claims description 2
- ONZAFMWXYPFDTB-UHFFFAOYSA-N N1CCC(CC1)C=1C=CC2=C(NC=3N2N=CC3)C1 Chemical class N1CCC(CC1)C=1C=CC2=C(NC=3N2N=CC3)C1 ONZAFMWXYPFDTB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- TVSMLBGFGKLKOO-UHFFFAOYSA-N 1,4-dimethylpiperidine Chemical compound CC1CCN(C)CC1 TVSMLBGFGKLKOO-UHFFFAOYSA-N 0.000 claims 1
- AKJHDIVKVKLFHQ-UHFFFAOYSA-N 4-ethylpiperidine Chemical compound [CH2]CC1CCNCC1 AKJHDIVKVKLFHQ-UHFFFAOYSA-N 0.000 claims 1
- LJKQRUWNWNNMKM-UHFFFAOYSA-N C1=CC=C2C(=C1)C(C3=CC(=NN23)F)O Chemical class C1=CC=C2C(=C1)C(C3=CC(=NN23)F)O LJKQRUWNWNNMKM-UHFFFAOYSA-N 0.000 claims 1
- SEOYDBHBDMBRNF-UHFFFAOYSA-N C1C2=CC=CC=C2N3C1=CC(=N3)F Chemical class C1C2=CC=CC=C2N3C1=CC(=N3)F SEOYDBHBDMBRNF-UHFFFAOYSA-N 0.000 claims 1
- VSNYAJIXAQVHBM-UHFFFAOYSA-N CN1C2=CC=CC=C2N3C1=CC(=N3)F Chemical class CN1C2=CC=CC=C2N3C1=CC(=N3)F VSNYAJIXAQVHBM-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 description 286
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 210
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 179
- 239000000203 mixture Substances 0.000 description 172
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
- 238000005160 1H NMR spectroscopy Methods 0.000 description 136
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 108
- 238000000034 method Methods 0.000 description 104
- 239000000243 solution Substances 0.000 description 103
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 101
- 238000003756 stirring Methods 0.000 description 89
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 84
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 83
- 238000002360 preparation method Methods 0.000 description 76
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- 239000012044 organic layer Substances 0.000 description 70
- 235000019439 ethyl acetate Nutrition 0.000 description 63
- 238000004440 column chromatography Methods 0.000 description 61
- 239000007787 solid Substances 0.000 description 61
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 59
- 239000010410 layer Substances 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- 230000004224 protection Effects 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 229910052938 sodium sulfate Inorganic materials 0.000 description 47
- 235000011152 sodium sulphate Nutrition 0.000 description 47
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 35
- 238000000605 extraction Methods 0.000 description 34
- 238000005406 washing Methods 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- 125000005842 heteroatom Chemical group 0.000 description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 21
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 20
- 238000002953 preparative HPLC Methods 0.000 description 20
- 229960000583 acetic acid Drugs 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- 235000011181 potassium carbonates Nutrition 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 229910052796 boron Inorganic materials 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 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 14
- 125000004429 atom Chemical group 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
- 150000001721 carbon Chemical group 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 239000011259 mixed solution Substances 0.000 description 13
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 235000019253 formic acid Nutrition 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 150000002475 indoles Chemical class 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 10
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| CN2014101441730 | 2014-04-10 | ||
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| CN201510113090 | 2015-03-13 | ||
| CN201510113090X | 2015-03-13 | ||
| PCT/CN2015/075363 WO2015154630A1 (zh) | 2014-04-10 | 2015-03-30 | 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物 |
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| CN104974161B (zh) * | 2014-04-10 | 2019-11-01 | 湖北生物医药产业技术研究院有限公司 | 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物 |
| CN108137598B (zh) * | 2015-09-30 | 2021-02-12 | 湖北生物医药产业技术研究院有限公司 | 4H-吡唑并[1,5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体 |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| AU2018257582B2 (en) | 2017-04-27 | 2022-06-16 | Bayer Animal Health Gmbh | New bicyclic pyrazole derivatives |
| CN115028641B (zh) * | 2022-07-19 | 2024-05-28 | 湖南大学 | 一种钴催化合成5,8-双官能团取代咪唑并[1,2-a]吡嗪类化合物的方法 |
| CN116969954B (zh) * | 2023-09-21 | 2023-11-28 | 广东省农业科学院农业质量标准与监测技术研究所 | 一类含内酰胺的三环稠合杂环化合物及其应用 |
| CN117534677B (zh) * | 2024-01-09 | 2024-03-12 | 广东省农业科学院农业质量标准与监测技术研究所 | 一类含亚胺的三环稠合杂环化合物及其应用 |
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| US4916051A (en) * | 1987-04-07 | 1990-04-10 | Konica Corporation | Silver halide color photographic light-sensitive material |
| CA2550948A1 (en) * | 2003-12-22 | 2005-07-14 | Sb Pharmco Puerto Rico Inc. | Crf receptor antagonists and methods relating thereto |
| EP1973909A2 (en) * | 2005-12-22 | 2008-10-01 | Biogen Idec MA Inc. | Transforming growth factor modulators |
| WO2007144669A1 (en) * | 2006-06-15 | 2007-12-21 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Pyrazolo[1,5-a]quinazolin-5(4h)-ones as inhibitors of poly(adp-ribose)polymerase (parp) |
| MX2008016339A (es) * | 2006-06-20 | 2009-01-16 | Abbott Lab | Pirazoloquinazolinonas en la forma de inhibidores parp. |
| GB0701273D0 (en) * | 2007-01-24 | 2007-02-28 | Angeletti P Ist Richerche Bio | New compounds |
| ES2535511T3 (es) | 2012-04-26 | 2015-05-12 | Helmut Schickaneder | Ésteres de bendamustina y compuestos relacionados, y uso médico de los mismos |
| CA2872334C (en) | 2012-05-04 | 2020-06-30 | Dieter Dorsch | Pyrrolotriazinone derivatives |
| EP2666775A1 (en) * | 2012-05-21 | 2013-11-27 | Domain Therapeutics | Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors |
| AR091271A1 (es) | 2012-06-07 | 2015-01-21 | Hoffmann La Roche | Pirrolopirimidona y pirrolopiridona, inhibidores de tanquirasa |
| CA2877826C (en) * | 2012-07-09 | 2016-08-16 | Lupin Limited | Tetrahydroquinazolinone derivatives as parp inhibitors |
| CN103570725B (zh) | 2012-08-01 | 2017-03-22 | 中国科学院上海药物研究所 | 哌嗪并三唑类化合物及其制备方法和用途 |
| PL2882714T3 (pl) * | 2012-08-08 | 2020-02-28 | Merck Patent Gmbh | Pochodne (aza-)izochinolinonowe |
| CN104974161B (zh) | 2014-04-10 | 2019-11-01 | 湖北生物医药产业技术研究院有限公司 | 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物 |
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