WO2020063636A1 - 吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用 - Google Patents
吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用 Download PDFInfo
- Publication number
- WO2020063636A1 WO2020063636A1 PCT/CN2019/107734 CN2019107734W WO2020063636A1 WO 2020063636 A1 WO2020063636 A1 WO 2020063636A1 CN 2019107734 W CN2019107734 W CN 2019107734W WO 2020063636 A1 WO2020063636 A1 WO 2020063636A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- cancer
- pharmaceutically acceptable
- general formula
- Prior art date
Links
- -1 Pyrazolopyrimidine compound Chemical class 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000002246 antineoplastic agent Substances 0.000 title description 2
- 229940041181 antineoplastic drug Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 68
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000012453 solvate Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims description 13
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 12
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 11
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 206010006187 Breast cancer Diseases 0.000 claims description 10
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 108091007960 PI3Ks Proteins 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 2
- RKHQZMOCQHXUBC-UHFFFAOYSA-N phenol;potassium Chemical compound [K].OC1=CC=CC=C1 RKHQZMOCQHXUBC-UHFFFAOYSA-N 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 101100520033 Dictyostelium discoideum pikC gene Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 27
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 239000007787 solid Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000011535 reaction buffer Substances 0.000 description 12
- 101150037263 PIP2 gene Proteins 0.000 description 11
- 101100262439 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UBA2 gene Proteins 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 239000004202 carbamide Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000012224 working solution Substances 0.000 description 10
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 6
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 5
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 5
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 5
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 4
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 4
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- QRMNEDFMHQCLKC-UHFFFAOYSA-N 1-[4-(4-cyano-5-fluoro-6-morpholin-4-ylpyrimidin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea Chemical group C(#N)C1=NC(=NC(=C1F)N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)CO QRMNEDFMHQCLKC-UHFFFAOYSA-N 0.000 description 4
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 4
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 4
- 239000012828 PI3K inhibitor Substances 0.000 description 4
- 101710093328 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 4
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000003149 assay kit Methods 0.000 description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 229940125810 compound 20 Drugs 0.000 description 4
- 229940126086 compound 21 Drugs 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 229940125846 compound 25 Drugs 0.000 description 4
- 229940125851 compound 27 Drugs 0.000 description 4
- 229940127204 compound 29 Drugs 0.000 description 4
- 229940125877 compound 31 Drugs 0.000 description 4
- 229940125878 compound 36 Drugs 0.000 description 4
- 229940125807 compound 37 Drugs 0.000 description 4
- 229940127573 compound 38 Drugs 0.000 description 4
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- LHUFLXGLSKTRPX-UHFFFAOYSA-N 2-(4-aminophenyl)-n-methylsulfonylacetamide Chemical group CS(=O)(=O)NC(=O)CC1=CC=C(N)C=C1 LHUFLXGLSKTRPX-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 Cc1ccc(**)cc1 Chemical compound Cc1ccc(**)cc1 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108030003815 Inositol 3-kinases Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229940124607 PI3Kα inhibitor Drugs 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- HSFFHODYXGPJOW-UHFFFAOYSA-N 1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethyl)phenyl]-3-[4-(4-cyano-5-fluoro-6-morpholin-4-ylpyrimidin-2-yl)phenyl]urea Chemical group [Si](C)(C)(C(C)(C)C)OCC1=C(C=C(C=C1)NC(=O)NC1=CC=C(C=C1)C1=NC(=C(C(=N1)C#N)F)N1CCOCC1)C(F)(F)F HSFFHODYXGPJOW-UHFFFAOYSA-N 0.000 description 2
- WGHVHAMMEOJGMS-UHFFFAOYSA-N 2-(2-cyanopropan-2-yl)benzonitrile Chemical group N#CC(C)(C)C1=CC=CC=C1C#N WGHVHAMMEOJGMS-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- NLBLQQGXBNAMEX-UHFFFAOYSA-N 2-chloro-5-fluoro-6-morpholin-4-ylpyrimidine-4-carboxamide Chemical group ClC1=NC(=C(C(=N1)C(=O)N)F)N1CCOCC1 NLBLQQGXBNAMEX-UHFFFAOYSA-N 0.000 description 2
- IJRTYXJAHMLEJN-UHFFFAOYSA-N 4,4-dimethyl-7-nitroisoquinoline-1,3-dione Chemical group [O-][N+](=O)C1=CC=C2C(C)(C)C(=O)NC(=O)C2=C1 IJRTYXJAHMLEJN-UHFFFAOYSA-N 0.000 description 2
- VSRVOIDBBCKMTM-UHFFFAOYSA-N 4,4-dimethylisoquinoline-1,3-dione Chemical group C1=CC=C2C(C)(C)C(=O)NC(=O)C2=C1 VSRVOIDBBCKMTM-UHFFFAOYSA-N 0.000 description 2
- ZFWRTOGKYLEMAB-UHFFFAOYSA-N 4-(2-phenylmethoxyethyl)morpholine Chemical group C=1C=CC=CC=1COCCN1CCOCC1 ZFWRTOGKYLEMAB-UHFFFAOYSA-N 0.000 description 2
- QAGWEQLDROBYHE-UHFFFAOYSA-N 4-[2-[(4-nitrophenyl)methoxy]ethyl]morpholine Chemical group [N+](=O)([O-])C1=CC=C(COCCN2CCOCC2)C=C1 QAGWEQLDROBYHE-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101100297694 Arabidopsis thaliana PIP2-7 gene Proteins 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- DQJOBBWEMAVHSW-UHFFFAOYSA-N COC(=O)c1nc(Cl)nc(Cl)c1F Chemical group COC(=O)c1nc(Cl)nc(Cl)c1F DQJOBBWEMAVHSW-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 2
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 101150063858 Pik3ca gene Proteins 0.000 description 2
- 101100456541 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) MEC3 gene Proteins 0.000 description 2
- 101100483663 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UFD1 gene Proteins 0.000 description 2
- PHXSMIURLXWUMB-UHFFFAOYSA-N [4-nitro-2-(trifluoromethyl)phenyl]methanol Chemical group OCC1=CC=C([N+]([O-])=O)C=C1C(F)(F)F PHXSMIURLXWUMB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229950002550 copanlisib Drugs 0.000 description 2
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009261 endocrine therapy Methods 0.000 description 2
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HVRPGESTLCRKKH-UHFFFAOYSA-N methyl 5-fluoro-2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical group COC(=O)C=1NC(=O)NC(=O)C=1F HVRPGESTLCRKKH-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229940124654 piqray Drugs 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- 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 1
- FKIDDBFGGYCRLK-UHFFFAOYSA-N 1-(3,3-dimethyl-2-oxo-1H-indol-6-yl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound CC1(C(NC2=CC(=CC=C12)NC(=O)NC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O)C FKIDDBFGGYCRLK-UHFFFAOYSA-N 0.000 description 1
- NWIGQSKIKVGILP-UHFFFAOYSA-N 1-[4-(2-hydroxypropan-2-yl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound OC(C)(C)C1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C NWIGQSKIKVGILP-UHFFFAOYSA-N 0.000 description 1
- KFLSUQUDSNRWGZ-UHFFFAOYSA-N 1-[4-(2-morpholin-4-ylethoxymethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound O1CCN(CC1)CCOCC1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C KFLSUQUDSNRWGZ-UHFFFAOYSA-N 0.000 description 1
- ROWNMOAJTUDHLF-UHFFFAOYSA-N 1-[4-(3-amino-7-morpholin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-3-(3,3-dimethyl-2-oxo-1H-indol-6-yl)urea Chemical compound NC1=NNC2=C1N=C(N=C2N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC=C2C(C(NC2=C1)=O)(C)C ROWNMOAJTUDHLF-UHFFFAOYSA-N 0.000 description 1
- GIEVAVKLOLSQRV-UHFFFAOYSA-N 1-[4-(3-amino-7-morpholin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-3-[4-(2-hydroxypropan-2-yl)phenyl]urea Chemical compound NC1=NNC2=C1N=C(N=C2N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)C(C)(C)O GIEVAVKLOLSQRV-UHFFFAOYSA-N 0.000 description 1
- NZHMYSMTGNUODD-UHFFFAOYSA-N 1-[4-(3-amino-7-morpholin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-3-[4-(2-morpholin-4-ylethoxymethyl)phenyl]urea Chemical compound NC1=NNC2=C1N=C(N=C2N2CCOCC2)C2=CC=C(C=C2)NC(=O)NC2=CC=C(C=C2)COCCN2CCOCC2 NZHMYSMTGNUODD-UHFFFAOYSA-N 0.000 description 1
- TXUCAQIALZEPJJ-UHFFFAOYSA-N 1-[4-(3-amino-7-morpholin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-3-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NNC2=C1N=C(N=C2N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC(=C(C=C1)CO)C(F)(F)F TXUCAQIALZEPJJ-UHFFFAOYSA-N 0.000 description 1
- ARDFMJMCBXIDAI-UHFFFAOYSA-N 1-[4-(3-amino-7-morpholin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea Chemical compound NC1=NNC2=C1N=C(N=C2N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)CO ARDFMJMCBXIDAI-UHFFFAOYSA-N 0.000 description 1
- CPGXTTJSDOAZNQ-UHFFFAOYSA-N 1-[4-(3-amino-7-morpholin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-3-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NNC2=C1N=C(N=C2N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC(=C(C=C1)CO[Si](C)(C)C(C)(C)C)C(F)(F)F CPGXTTJSDOAZNQ-UHFFFAOYSA-N 0.000 description 1
- NQEXUAFDKKKGGI-UHFFFAOYSA-N 1-[4-(4-cyano-5-fluoro-6-morpholin-4-ylpyrimidin-2-yl)phenyl]-3-[4-(2-hydroxypropan-2-yl)phenyl]urea Chemical compound C(#N)C1=NC(=NC(=C1F)N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)C(C)(C)O NQEXUAFDKKKGGI-UHFFFAOYSA-N 0.000 description 1
- CVHYBTCVFUWSQC-UHFFFAOYSA-N 1-[4-(4-cyano-5-fluoro-6-morpholin-4-ylpyrimidin-2-yl)phenyl]-3-[4-(2-morpholin-4-ylethoxymethyl)phenyl]urea Chemical compound C(#N)C1=NC(=NC(=C1F)N1CCOCC1)C1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)COCCN1CCOCC1 CVHYBTCVFUWSQC-UHFFFAOYSA-N 0.000 description 1
- FIXSEFLQIQLWNC-UHFFFAOYSA-N 1-[4-(hydroxymethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound O1C(C)(C)C(C)(C)OB1C(C=C1)=CC=C1NC(=O)NC1=CC=C(CO)C=C1 FIXSEFLQIQLWNC-UHFFFAOYSA-N 0.000 description 1
- CUXPBHBBCDZSFD-UHFFFAOYSA-N 1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound [Si](C)(C)(C(C)(C)C)OCC1=C(C=C(C=C1)NC(=O)NC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)C(F)(F)F CUXPBHBBCDZSFD-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- RHKRIDVZGAXYQE-UHFFFAOYSA-N 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical group O1C(C)(C)C(C)(C)OB1C1=CC=C(N=C=O)C=C1 RHKRIDVZGAXYQE-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- YDQJGZWAYLEMFS-UHFFFAOYSA-N 2-chloro-5-fluoro-6-morpholin-4-ylpyrimidine-4-carbonitrile Chemical group ClC1=NC(=C(C(=N1)C#N)F)N1CCOCC1 YDQJGZWAYLEMFS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- BINZMXLWBWSDNW-UHFFFAOYSA-N 4-(2-morpholin-4-ylethoxymethyl)aniline Chemical compound C1=CC(N)=CC=C1COCCN1CCOCC1 BINZMXLWBWSDNW-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- SEHFUALWMUWDKS-UHFFFAOYSA-N 5-fluoroorotic acid Chemical compound OC(=O)C=1NC(=O)NC(=O)C=1F SEHFUALWMUWDKS-UHFFFAOYSA-N 0.000 description 1
- IWARVYFPBLDOAK-UHFFFAOYSA-N 6-amino-3,3-dimethyl-1h-indol-2-one Chemical compound NC1=CC=C2C(C)(C)C(=O)NC2=C1 IWARVYFPBLDOAK-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- AQFYFLSOEOSBGQ-UHFFFAOYSA-N CS(NC([N+]([O-])=O)=O)(=O)=O Chemical compound CS(NC([N+]([O-])=O)=O)(=O)=O AQFYFLSOEOSBGQ-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 1
- 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 1
- 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 1
- 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 108050005377 Phosphatidylinositol kinases Proteins 0.000 description 1
- 102000017343 Phosphatidylinositol kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229950010482 alpelisib Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000008995 epigenetic change Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical group O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- WNDRRULPOPULST-UHFFFAOYSA-N methyl 2-chloro-5-fluoro-6-morpholin-4-ylpyrimidine-4-carboxylate Chemical group COC(=O)C1=NC(=NC(=C1F)N1CCOCC1)Cl WNDRRULPOPULST-UHFFFAOYSA-N 0.000 description 1
- GXZQHMHLHHUHAM-UHFFFAOYSA-N methyl pyrimidine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=N1 GXZQHMHLHHUHAM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000092 prognostic biomarker Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZIEWSZYVEDTXGH-UHFFFAOYSA-N pyrimidine-4-carbonitrile Chemical compound N#CC1=CC=NC=N1 ZIEWSZYVEDTXGH-UHFFFAOYSA-N 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- RPLTZITZFYXWOP-UHFFFAOYSA-N tert-butyl-dimethyl-[[4-nitro-2-(trifluoromethyl)phenyl]methoxy]silane Chemical group C(C)(C)(C)[Si](OCC1=C(C=C(C=C1)[N+](=O)[O-])C(F)(F)F)(C)C RPLTZITZFYXWOP-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
- 239000012085 test solution Substances 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Definitions
- the invention belongs to the field of medicinal chemistry, and particularly relates to a class of pyrazolopyrimidine compounds and a preparation method thereof.
- the pyrazolopyrimidine compounds have a phosphoinositide-3-kinase (PI3K) inhibitory activity and can be used for preparing drugs for preventing and treating tumor .
- PI3K phosphoinositide-3-kinase
- PI3K is an intracellular phosphatidylinositol kinase.
- Lewis C. Cantley a professor of cancer biomedicine at Weill Cornell Medical College, has discovered the phosphoinositide-3-kinase (PI3K) signaling pathway and clarified its key role in tumor development.
- the PI3K signaling pathway is usually activated by receptors on the cell surface, such as receptor tyrosine kinases, GPCRs, and some oncogenes, such as RAS.
- the activated p110 subunit catalyzes the conversion of PIP2 to PIP3 and activates Akt activity.
- Akt will further transmit signals to downstream molecules, such as mTORC1, GSK3, and BCL-2, to regulate different cellular physiological processes.
- mTORC2 activates the Akt molecule through phosphorylation of Ser at position 473.
- PTEN is able to dephosphorylate PIP3 to PIP2.
- the downstream signal pathway of PI3K molecule is more complex, including some feedback loops.
- Each of the four catalytic isomers of class I PI3K preferentially regulates specific signal transduction and tumor cell survival, depending on the type of malignancy and the genetic or epigenetic changes that occur.
- p110 ⁇ is essential for tumor cell growth driven by PIK3CA mutations or oncogenes RAS and receptor tyrosine kinases; p110 ⁇ mediates PTEN-deficient tumorigenesis; and p110 ⁇ is highly expressed in leukocytes, making It becomes an ideal target for the treatment of hematological malignancies.
- PI3 kinase was discovered to be an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al. (1988) Nature, 332664).
- PI3K was originally thought to be a single enzyme, but it has been clarified that there are multiple subtypes in PI3K, PI3K ⁇ is one of them.
- PI3K ⁇ has high-frequency activation mutations in breast cancer, which is closely related to breast cancer development and resistance, and has become an important target for breast cancer treatment.
- Copanlisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, which has a good inhibitory activity against PI3K- ⁇ and PI3K- ⁇ subtypes expressed in malignant B cells.
- PI3K phosphatidylinositol-3-kinase
- Piqray is an oral small molecule alpha-specific PI3K inhibitor developed by Novartis, which is a PI3K alpha inhibitor.
- Novartis is a PI3K alpha inhibitor.
- the present invention also uses PI3K ⁇ as a starting point for the research of new drugs. Especially, no PI3K ⁇ inhibitor invented by China has been used in the treatment of malignant tumors. The innovative research structure of the present invention will fill this gap in China. Such as the final listing will have significant social and economic benefits.
- the technical problem to be solved by the present invention is to provide a class of pyrazolopyrimidine compounds having PI3K inhibitory activity.
- the invention also provides an intermediate for preparing the pyrazolopyrimidine compound.
- the invention also provides a method for preparing the pyrazolopyrimidine compound.
- the present invention adopts the following technical solution:
- a pyrazolopyrimidine compound or an isomer thereof, a pharmaceutically acceptable salt, a solvate, or a crystal having the formula (I) (sometimes collectively referred to herein as "the compound of the present invention"):
- A is -OH, -NH 2 , -SH, B is -C n H 2n , n is 1, 2, 3, or 4; where A is When one end is connected to the B and the other end is connected to a carbon atom on the benzene ring to which the B is connected;
- Z is hydrogen, hydroxy, C 1-3 alkyl, fluorine, chlorine or bromine, or C 1-3 alkyl substituted with one or more selected from fluorine, chlorine and bromine;
- M is H,- CH 3 or -CH 2 CH 3 .
- Z is preferably hydrogen, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, or pentafluoroethyl.
- the structure of the pyrazolopyrimidine compound is represented by the following formula (I-a):
- Z 1 is hydrogen, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, or pentafluoroethyl.
- the B may be linear or branched, and is not particularly limited.
- the B is -CH 2- , -CH 2 CH 2- , -CH 2 CH 2 CH 2- , -CH (CH 3 )-, -CH (CH 3 ) CH 2- , -C (CH 3 ) 2 -or -CH 2 C (CH 3 ) 2 .
- the B is -CH 2 -or -C (CH 3 ) 2- .
- N is connected to a carbon atom on a benzene ring to which B is connected, and A and B together with the carbon atom to which they are connected form a 5- to 7-membered ring.
- the carbon atom to which the N atom constituting A and the carbon atom to which B is attached are located adjacent to the benzene ring.
- B is -C (CH 3 ) 2- .
- B is -CH 2-
- A is -OH
- B is -C (CH 3 ) 2 -and A is -OH or
- the pyrazolopyrimidine compound is selected from compounds represented by the following structures:
- the present invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising one or more of the pyrazolopyrimidine compounds provided above, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
- the composition further comprises a pharmaceutically acceptable carrier.
- the present invention provides the aforementioned pyrazolopyrimidine compounds or isomers thereof, pharmaceutically acceptable salts, hydrates, solvates, crystals or pharmaceutical compositions containing the pyrazolopyrimidine compounds in the preparation of treatment and / or Application in medicine for preventing diseases mediated by phosphatidylinositol-3-kinase.
- Cancers include but are not limited to kidney cancer, liver cancer, colon cancer, gastrointestinal stromal tumors, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, leukemia and prostate cancer, etc. .
- the invention also provides the application of the pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer, and a method for treating or preventing cancer by using the pharmaceutical composition.
- a pharmaceutical composition according to the invention wherein the compound of the invention is preferably present in a therapeutically effective amount.
- the pharmaceutically acceptable carrier in the above pharmaceutical composition may be, for example, a pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, absorption enhancer, surfactant, lubricant, flavor Agents, sweeteners, etc.
- the medicine prepared by using the compound of the present invention as an active ingredient may be in various forms such as tablets, powders, capsules, granules, oral liquids, and injection preparations.
- the dosage form of the pharmaceutical composition is preferably a tablet, capsule or injection.
- the above-mentioned pharmaceuticals in various dosage forms can be prepared according to conventional methods in the pharmaceutical field.
- the present invention also provides an intermediate for preparing a pyrazolopyrimidine compound represented by the general formula (I) of the present invention, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystalline intermediate thereof.
- the intermediate has the formula (II) ) Structure shown:
- a 1 is t-butyldimethylsiloxy (TBSO) or A 1 is the same as A;
- the stereoisomers, pharmaceutically acceptable salts, solvates, or crystalline intermediates of the pyrazolopyrimidine compounds described above for preparing the present invention include the following compounds:
- the present invention further provides a method for preparing a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a crystal of the pyrazolopyrimidine compound represented by the above general formula (I) according to the present invention, which comprises the following formula (II): The steps of reacting the intermediate with hydrazine hydrate are shown.
- the reaction of the intermediate represented by formula (II) with hydrazine hydrate is performed at 20-100 ° C, preferably 30-95 ° C, and more preferably 40-90 ° C. It is more preferably carried out at 55-80 ° C, and still more preferably carried out at 60-75 ° C. According to some preferred and specific aspects of the present invention, the reaction of the intermediate represented by formula (II) with hydrazine hydrate is performed at 65-70 ° C.
- the reaction in the process of preparing the intermediate represented by formula (II), is performed under alkaline conditions, at a temperature of 30-120 ° C, and optionally under an inert atmosphere. . More preferably, in the process of preparing the intermediate represented by formula (II), the reaction is performed at a temperature of 40-110 ° C, further preferably at a temperature of 50-105 ° C, and even more preferably at a temperature of 60- It is carried out at 100 ° C, and still more preferably at a temperature of 70-95 ° C. According to some specific aspects of the present invention, in the process of preparing the intermediate represented by formula (II), the reaction is performed at a temperature of 85-90 ° C.
- the inert atmosphere is a nitrogen atmosphere.
- the basic condition is formed by adding a basic substance selected from potassium acetate, potassium carbonate, potassium phenol, potassium phosphate, potassium tert-butoxide, sodium carbonate, hydrogen carbonate
- a basic substance selected from potassium acetate, potassium carbonate, potassium phenol, potassium phosphate, potassium tert-butoxide, sodium carbonate, hydrogen carbonate
- the alkaline substance is sodium bicarbonate.
- the present invention has the following advantages compared with the prior art:
- the invention provides a novel pyrazolopyrimidine compound, which has excellent PI3K inhibitory activity, and can be applied to treat diseases mediated by phospholipid inositol-3-kinase (PI3K), and provide cancer treatment More and better drug options.
- PI3K phospholipid inositol-3-kinase
- the pyrazolopyrimidine compound of the present invention has a simple structure and relatively low preparation cost.
- FIG. 1 shows the relationship between the inhibition rate of PI3K ⁇ by compounds I-1 to I-6 and the positive control compound GDC-0941.
- isomer refers to an isomer produced by the different arrangement of atoms in a molecule in space. Including cis-trans isomers, enantiomers and conformers. All stereoisomers are within the scope of the invention.
- the compounds of the invention may be individual stereoisomers or a mixture of other isomers such as a racemate, or a mixture of all other stereoisomers.
- salt refers to a pharmaceutically acceptable salt formed by the compound according to the present invention with an acid.
- the acid may be an organic acid or an inorganic acid, and may specifically be selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluenesulfonic, malic, methanesulfonic, or the like.
- solvate refers to the form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the invention, the solvate is preferably a hydrate.
- crystalline refers to various solid forms, including crystalline forms and amorphous forms, formed by the compounds of the present invention.
- DBU 1,8-diazabicycloundec-7-ene
- DMF N, N-dimethylformamide
- THF tetrahydrofuran
- Pd (dppf) Cl 2 [1,1'-bis ( Diphenylphosphino) ferrocene] palladium dichloride
- DTT dithiothreitol
- ATP adenosine triphosphate
- TK tyrosine kinase
- HEPES 4-hydroxyethylpiperazineethanesulfonic acid.
- Compound 2 Chinese name is 5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid methyl ester; English name is methyl5-fluoro-2,6-dioxo-1 , 2,3,6-tetrahydropyrimidine-4-carboxylate;
- Compound 3 Chinese name is 2,6-dichloro-5-fluoropyrimidine-4-carboxylic acid methyl ester; English name is methyl2,6-dichloro-5-fluoropyrimidine-4-carboxylate;
- Compound 4 Chinese name is 2-chloro-5-fluoro-6-morpholine pyrimidine-4-carboxylic acid methyl ester; English name is methyl2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxylate;
- Compound 5 Chinese name is 2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxamide; English name is 2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxamide;
- Compound 8 Chinese name is 2- (4-isocyanatephenyl) -4,4,5,5-tetramethyl-1,3,2-dioxolane; English name is 2- (4-isocyanatophenyl ) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane;
- Compound I-1 Chinese name is 1- (4- (3-amino-7-morpholine-1H-pyrazoline [4,3-d] pyrimidin-5-yl) phenyl) -3- (4- Hydroxymethyl) phenyl) urea; the English name is:
- Compound I-2 Chinese name is 1- (4- (3-amino-7-morpholine-1H-pyrazoline [4,3-d] pyrimidin-5-yl) phenyl) -3- (4- (2-hydroxypropyl-2-yl) phenyl) urea; the English name is:
- Dissolve compound 13 (6.0 g, 0.033 mol) in dichloromethane (100 mL), add CDI (10.7 g, 0.066 mol, N, N'-carbonyldiimidazole), stir at room temperature for 1 h, and add methylsulfonamide (3.45 g, 0.036 mol).
- the reaction solution was stirred at room temperature overnight, DBU (10.0 g, 0.066 mol) was added, and then stirred at room temperature overnight.
- Compound 21 Chinese name is 4,4-dimethyl-7-nitroisoquinoline-1,3 (2H, 4H) -dione; English name is 4,4-dimethyl-7-nitroisoquinoline-1, 3 (2H, 4H) -dione;
- Compound 22 Chinese name is 3,3-dimethyl-6-nitroindolin-2-one 3,3-dimethyl-6-nitroindolin-2-one
- Compound 23 Chinese name is 6-amino-3,3-dimethylindololin-2-one; English name is:
- Compound 24 Chinese name is 1- (3,3-dimethyl-2-oxindole-6-yl) -3- (4,4,5,5-tetramethyl-1,3,2-di Oxalol-2-yl) phenyl) urea; the English name is:
- Compound 25 Chinese name is 1- (4- (4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl) phenyl) -3- (4- (hydroxymethyl) phenyl) urea; English name is:
- Compound I-4 Chinese name is 1- (4- (3-amino-7-morpholine-1H-pyrazole [4,3-d] pyrimidin-5-yl) phenyl) -3- (3,3 -Dimethyl-2-oxindolin-6-yl) urea; the English name is:
- Compound 28 Chinese name is tert-butyldimethyl (4-nitro-2- (trifluoromethyl) benzyl) oxy) silane; English name is tert-butyldimethyl ((4-nitro-2- (trifluoromethyl ) benzyl) oxy) silane;
- Compound 29 Chinese name is 4-((tert-butyldimethylsilyl) oxy) methyl) -3- (trifluoromethyl) aniline; English name is 4-((tert-butyldimethylsilyl) oxy) methyl ) -3- (trifluoromethyl) aniline;
- Compound 32 Chinese name is 1- (4- (3-amino-7-morpholine-1H-pyrazole [4,3-D] pyrimidin-5-yl) phenyl) -3- (4-((tert Butyldimethylsilyl) oxy) methyl) -3- (trifluoromethyl) phenyl) urea; the English name is:
- Compound 37 Chinese name is 1- (4-((2-morpholinyloxy) methyl) phenyl) -3- (4- (4,4,5,5-tetramethyl-1,3,2 -Dioxol-2-yl) phenyl) urea; the English name is:
- Compound 38 Chinese name is 1- (4- (4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl) phenyl) -3- (4-((2-morpholinyloxy) methyl Yl) phenyl) urea; the English name is:
- Compound I-6 Chinese name is 1- (4- (3-amino-7-morpholine-1H-pyrazoline [4,3-D] pyrimidin-5-yl) phenyl) -3- (4- ((2-morpholinyloxy) methyl) phenyl) urine;
- the English name is: 1- (4- (3-amino-7-morpholino-1H-pyrazolo [4,3-d] pyrimidin-5-yl) phenyl) -3- (4-((2-morpholinoethoxy) methyl) phenyl) urea;
- Example 7 Biological activity test of the compound of Example
- the six compounds I-1, I-2, I-3, I of the examples were applied using the PI3-Kinase (human) HTRF TM Assay kit test (the method of the PI3-Kinase (human) HTRF TM Assay kit test is an internationally accepted method).
- -4, I-5, I-6 (in the following experiments, codenames RMP-D09, RMP-D01, RMP-D02, RMP-D03, RMP-D04, RMP-D05) were used to halve the PI3K alpha enzyme inhibitory concentration ( IC 50 assay), compound GDC-0941 was used as a positive control.
- PI3-Kinase human
- HTRFTM Assay Kit Cat. 33-016, Millipore
- Stop A (Cat. 33-006, Millipore); Stop B (Cat. 33-008, Millipore); DM A (Cat. 33-010, Millipore); DM B (Cat. 33-012, Millipore); DM C (Cat.33-014, Millipore); PI3k alpha (Cat. 14-602, Millipore); ATP 10mM (cat PV3227, Invitrogen); DTT 1M (cat D5545, Sigma)
- Test compounds I-1, I-2, I-3, I-4, I-5, I-6 in the following experiments, the codes RMP-D09, RMP-D01, RMP-D02, RMP-D03 were RMP-D04, RMP-D05), and GDC-0941.
- 4 ⁇ Reaction Buffer was diluted to 1 ⁇ with ddH 2 O, and 1M DTT was added to a final concentration of 5 mM.
- 1M DTT was added to a final concentration of 5 mM.
- prepare 10mL of 1 ⁇ Reaction Buffer add 2.5mL of 4 ⁇ Reaction Buffer, 50 ⁇ L 1M DTT, ddH 2 O 7.45mL.
- freshly prepared 1 ⁇ Reaction Buffer was used to prepare ATP working solution, substrate and enzyme mixed working solution, etc.
- test compound was dissolved in DMSO to 1 mM as a storage solution, and then diluted 4 times with DMSO for a total of 10 concentration points. Take 1 ⁇ L each and add it to 24 ⁇ L 1 ⁇ Reaction Buffer. 5 ⁇ L of each diluted solution was added to a 384-well plate and contained 1% DMSO.
- the kinase was diluted with 2 ⁇ PIP2 working solution to a concentration of 10 ng / well.
- 10 mM ATP was diluted to 40 ⁇ M with a 1 ⁇ reaction buffer.
- concentration of ATP was 10 ⁇ M.
- 2ml of ATP working solution is prepared, and 8 ⁇ L of 10 mM ATP is added to 1992 ⁇ L of 1 ⁇ reaction buffer.
- Stop A and Stop B are mixed in a ratio of 3: 1, and they can be used after being left at room temperature for at least 2 hours.
- the stop solution can be stable at room temperature for 12 hours.
- DM C, DM A, and DM B are mixed at a ratio of 18: 1: 1, and can be used after being left at room temperature for at least 2 hours.
- the detection solution can be stable at room temperature for 12 hours.
- Emission Ratio (ER) 665nM Emission signature / 620nm Emission signature
- the inhibition rate is calculated using the following formula:
- Inhibition rate (ER sample -ER 0% ) / (ER 100% -ER 0% ) x 100% [(ER positive-ER sample) / (ER positive-ER negative) * 100%]
- PI3-Kinase human HTRFTM Assay kit was used to detect the inhibitory rate of PI3K-alpha enzyme at different concentrations of 6 compounds.
- the DMSO concentration was controlled to 1%, and each concentration was duplicated.
- the measurement results are shown in Fig. 1. According to the detection result, each concentration of the compounds to inhibit the enzyme PI3K-alpha half (IC 50) are summarized in Table 1 below.
- novel pyrazolopyrimidine compounds of the present invention demonstrate the inhibitory effect of the novel pyrazolopyrimidine compounds of the present invention on phospholipid inositol-3-kinase (PI3K), indicating that the novel pyrazolopyrimidine compounds (including pharmaceutically acceptable salts thereof) of the present invention are a kind of New PI3K inhibitor. Therefore, it can be used to treat diseases mediated by phospholipid inositol-3-kinase (PI3K).
- the malignant tumors that can be treated include, but are not limited to, kidney cancer, liver cancer, colon cancer, gastrointestinal stromal tumor, and non-small cell lung cancer , Breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, leukemia and prostate cancer.
- the other compounds of the present invention have substantially the same structure as the compounds I-1 to I-6, and they can be expected to have excellent activities equivalent to those of the compounds I-1 to I-6.
- This type of compound is the first new type of compound in the world, and has shown obvious strong activity. It will be used for further new drug research, invented domestic innovative drugs, and is used in market anti-cancer drugs with strong effects, small side effects and low cost. .
Abstract
本发明提供了式(I)所示的一类吡唑并嘧啶化合物或其药学可接受的盐及其制备方法和在制备治疗或预防癌症的药物中的应用。该类化合物是新型的PI3K抑制剂,具有优异的抑制活性,有望用于多种恶性肿瘤的治疗。
Description
本发明属于医药化学领域,尤其涉及一类吡唑并嘧啶化合物及其制备方法,该吡唑并嘧啶化合物具有磷酸肌醇-3-激酶(PI3K)抑制活性,可用于制备预防和***的药物。
PI3K是一种胞内磷脂酰肌醇激酶。威尔康乃尔医学院癌症生物医学教授Lewis C.Cantley发现了磷酸肌醇-3-激酶(PI3K)信号通路,同时阐明了其在肿瘤发展过程中所扮演的关键角色。PI3K信号通路通常会被细胞表面的受体所激活,如受体酪氨酸激酶、GPCR以及一些癌基因,如RAS等。活化后的p110亚基催化PIP2向PIP3转化,并激活Akt活性。Akt则会进一步将信号传递至下游分子,如mTORC1、GSK3以及BCL-2等来调节不同的细胞生理学过程。mTORC2则通过473位Ser的磷酸化来活化Akt分子。与此相反,PTEN则能够将PIP3去磷酸化成为PIP2。PI3K分子下游信号通路传递较为复杂,包含了一些反馈循环。I类PI3K的四种催化异构体中的每一种都优先调节特定的信号转导及肿瘤细胞的存活,这取决于恶性肿瘤的类型及其所发生的基因或表观遗传学改变。例如,p110α对于PIK3CA突变或癌基因RAS及受体酪氨酸激酶所驱动的肿瘤细胞的生长至关重要;p110β则会介导PTEN缺失型的肿瘤发生;而p110δ则在白细胞中高表达,从而使其成为治疗血液***恶性肿瘤的理想靶点。
在二十世纪八十年代后期,发现PI3激酶(PI3K)是将磷脂酰肌醇的肌醇环的3-位磷酸化的酶(D.Whitman等人(1988)Nature,332664)。最初认为PI3K是一种单一酶,但现已澄清,PI3K中存在多个亚型,PI3Kα是其中的一种。PI3Kα在乳腺癌中发生高频激活突变,与乳腺癌发生发展以及耐药密切相关,已成为治疗乳腺癌的重要靶标。
Copanlisib是磷脂酰肌醇-3-激酶(PI3K)抑制剂,主要针对恶性B细胞中表达的PI3K-α和PI3K-δ两种亚型有很好的抑制活性。
现有PI3Kα抑制剂的种类有限且在临床试验中疗效个体差异大,亟需发现新的PI3Kα抑制剂以及疗效预测生物标志物。
2019年上半年,美国FDA宣布,批准诺华公司(NVS.US)开发的Piqray(alpelisib)上市,与内分泌疗法氟维司群(fulvestrant)联用,治疗携带PIK3CA基因突变的HR+/HER2-晚期或转移性乳腺癌患者。这些患者在接受内分泌疗法之后疾病继续恶化。这是FDA批准的第一款用于治疗乳腺癌的PI3K抑制剂。转移性乳腺癌患者的肿瘤已经扩散到身体的其它部分,最常见的转移器官包括骨骼、肺部、肝脏和大脑。在HR+/HER2-晚期乳腺癌中,PI3K通路的改变是肿瘤恶化,疾病进展和产生治疗耐药性的最常见原因。大约40%的HR+/HER2-晚期乳腺癌患者携带PIK3CA基因突变。Piqray是诺华公司开发的一款口服小分子α特异性PI3K抑制剂,即PI3Kα抑制剂。在携带PIK3CA基因突变的乳腺癌细胞系中,它已显示出抑制PI3K通路的潜力,并具有抑制细胞增殖的作用。本发明也将PI3Kα作为靶点研究新药的起点,尤其是国内还未见有中国发明的PI3Kα抑制剂用于治疗恶性肿瘤。本发明的创新性研究结构将填补国内这一空白。如最终上市将具有重大的社会效益和经济效益。
发明内容
本发明所要解决的技术问题是提供一类具有PI3K抑制活性的吡唑并嘧啶化合物。
本发明同时还提供了一种制备上述吡唑并嘧啶化合物的中间体。
本发明同时还提供了一种制备上述吡唑并嘧啶化合物的方法。
为解决以上技术问题,本发明采取如下一种技术方案:
一种具有式(I)所示的吡唑并嘧啶化合物或其异构体、可药用盐、溶剂化物或结晶(在本文中有时统称为“本发明化合物”):
Z为氢、羟基、C
1-3烷基、氟、氯或溴,或为被选自氟、氯和溴中的一个或多个所取代的C
1-3烷基;M为H、-CH
3或-CH
2CH
3。
进一步地,Z优选为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基等。
根据本发明的一些优选且具体的方面,所述吡唑并嘧啶化合物的结构如下式(I-a)所示:
其中,A、B和M的定义分别同前,Z
1的定义同Z。进一步地,Z
1为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基等。
根据本发明的进一步实施方案,所述B可以是直链或支链,没有特别限制。
根据本发明的一些优选方面,所述B为-CH
2-、-CH
2CH
2-、-CH
2CH
2CH
2-、-CH(CH
3)-、-CH(CH
3)CH
2-、-C(CH
3)
2-或-CH
2C(CH
3)
2。尤其优选地,所述B为-CH
2-或者为-C(CH
3)
2-。
根据本发明的一些优选方面,当A为
时,其中C连接所述B,N与所 述B所连接的苯环上的碳原子连接,且A、B与它们所连接的碳原子一起构成5至7元环。在一些具体实施方式中,组成A的N原子所连接的碳原子、B所连接的碳原子处于苯环的相邻位置。进一步优选地,其中B为-C(CH
3)
2-。
根据本发明的一些优选且具体的方面,所述吡唑并嘧啶化合物选自如下结构所示化合物:
本发明还进一步提供包含一种或多种上述提供的吡唑并嘧啶化合物、其异构体、其药物可接受的盐或其溶剂化物的药物组合物。在一些实施实例中,该组合物还包括药物可接受的载体。
本发明提供了上述所述的吡唑并嘧啶化合物或其异构体、可药用盐、水合物、溶 剂化物、结晶或含有所述吡唑并嘧啶化合物的药物组合物在制备治疗和/或预防由磷脂酰肌醇-3-激酶介导的疾病的药物中的应用。
由磷脂酰肌醇-3-激酶介导的疾病通常包括癌症。癌症包括但不限于肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌,纤维肉瘤、卵巢癌、白血病和***癌等。
本发明同时还提供所述药物组合物在制备用于治疗和/或预防癌症药物中的应用以及采用所述药物组合物治疗或预防癌症的方法。
根据本发明的药物组合物,其中本发明化合物优选以治疗有效量存在。
上述药物组合物中药学上可接受的载体,可以是例如药学上可接受的稀释剂、赋型剂、填充剂、粘合剂、崩解剂、吸收促进剂、表面活性剂、润滑剂、香味剂、甜味剂等。
以本发明化合物为活性成分制备的药物可以是片剂、粉剂、胶囊、粒剂、口服液以及注射制剂等多种形式。药物组合物的剂型优选为片剂、胶囊或针剂。
上述各种剂型的药物均可以按药学领域的常规方法制备。
本发明同时还提供制备本发明上述通式(I)所示的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶的中间体,该中间体具有如式(II)所示结构:
式(II)中,A
1为叔丁基二甲基硅氧基(TBSO)或者A
1与A相同;
B、Z则对应与通式(I)中的B、Z相同。
根据本发明的一些具体方面,所述制备本发明上述所述的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶的中间体包括如下一些化合物:
本发明还进一步提供本发明上述通式(I)所示的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶的制备方法,其包括使上述式(II)所示中间体与水合肼进行反应的步骤。
在本发明的一些实施方式中,所述式(II)所示中间体与水合肼的反应在20-100℃下进行,优选在30-95℃下进行,更优选在40-90℃下进行,进一步优选在55-80℃下进行,再进一步优选在60-75℃下进行。根据本发明的一些优选且具体的方面,所述式(II)所示中间体与水合肼的反应在65-70℃下进行。
根据本发明的一些优选方面,制备所述的式(II)所示中间体的过程中,所述反应在碱性条件下、温度30-120℃下进行,还选择性地在惰性气氛下进行。更优选地,制备所述的式(II)所示中间体的过程中,所述反应在温度40-110℃下进行,进一步优选在温度50-105℃下进行,更进一步优选在温度60-100℃下进行,再进一步优选在温度70-95℃下进行。根据本发明的一些具体方面,制备所述的式(II)所示中间体的 过程中,所述反应在温度85-90℃下进行。
根据本发明的一些实施方案,所述惰性气氛为氮气气氛。
根据本发明的一些实施方案,所述碱性条件通过添加碱性物质形成,所述碱性物质为选自乙酸钾、碳酸钾、苯酚钾、磷酸钾、叔丁醇钾、碳酸钠、碳酸氢钠、叔丁醇钠、甲醇钠、乙醇钠、三乙基胺、三正丁基胺和二异丙基乙基胺中的一种或多种的组合。根据本发明的一个优选且具体的方面,所述碱性物质为碳酸氢钠。
由于以上技术方案的实施,本发明与现有技术相比存在如下优势:
本发明提供了新型的吡唑并嘧啶化合物,该类吡唑并嘧啶化合物具有优异的PI3K抑制活性,可以应用于治疗由磷脂肌醇-3-激酶(PI3K)介导的疾病,为癌症治疗提供更多更优的药物选择。此外,相比已有PI3K抑制剂,本发明的吡唑并嘧啶化合物结构简单,制备成本相对较低。
图1显示了化合物I-1至化合物I-6以及阳性对照化合物GDC-0941对PI3Kα的抑制率的关系曲线。
术语定义
除非另外定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物可以为单独立体异构体或其它异构体的混合例如外消旋体,或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐,所述的酸可以是有机酸或无机酸,具体可选自:磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂化物的特殊形式,其中与水发生配位。在本发明范围内,溶剂化物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态,包括晶型、无定形。
以下实施例可以使本专业技术人员更全面地理解本发明,但不以任何方式限制本发明。所有化合物的结构均经1H NMR或MS所确定。
实施例中用到的化合物名称缩写如下:
DBU:1,8-二氮杂二环十一碳-7-烯;DMF:N,N-二甲基甲酰胺;THF:四氢呋喃;Pd(dppf)Cl
2:[1,1'-双(二苯基膦基)二茂铁]二氯化钯;DTT:二硫苏糖醇;ATP:三磷酸腺苷;TK:酪氨酸激酶;HEPES:4-羟乙基哌嗪乙磺酸。
实施例1化合物I-1的制备
采取以下路线合成化合物I-1:
1.1.化合物2的合成
化合物2:中文名称为5-氟-2,6-二氧-1,2,3,6-四氢嘧啶-4-羧酸甲酯;英文名称为methyl5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate;
将5-氟乳清酸(化合物1)(40g,0.23mol)溶于N,N-二甲基甲酰胺(500mL)中,缓慢滴加DBU(35.0g,0.23mol),室温下搅拌1h,再缓慢滴加碘甲烷(32.0g,0.23mol),在60度下搅拌4h。反应结束后,搅拌下加入100mL的冰水,析出固体,过滤,滤饼用水洗涤(100mL x 3),真空干燥,得到化合物2(30g,产率=70%)。测得:
1H NMR(CDCl
3,400MHz):δ11.85(s,1H),10.84(s,1H),3.88(s,3H).
1.2.化合物3的合成
化合物3:中文名称为2,6-二氯-5-氟嘧啶-4-羧酸甲酯;英文名称为methyl2,6-dichloro-5-fluoropyrimidine-4-carboxylate;
在三氯氧磷(700mL)中依次加入化合物2(46.0g,0.24mol),N,N-二甲基甲酰胺(0.5mL),1,4-二氧六环(20mL),在110度下搅拌7天。LCMS检测反应结束后,减压浓缩,将所得残余物缓慢滴加到碳酸氢钠水溶液中,并用乙酸乙酯萃取(500mL x 3),有机相用硫酸钠干燥浓缩后得到化合物3(53.7g,产率>90%)。测得:ESI-MS m/z=225[M+1]
+.
1H NMR(CDCl
3,400MHz):3.94(s,3H).
1.3.化合物4的合成
化合物4:中文名称为2-氯-5-氟-6-吗啉嘧啶-4-羧酸甲酯;英文名称为methyl2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxylate;
将化合物3(53.7g,12.9mmol)溶在乙酸乙酯(1.5L)中,反应液冷却到零度,然后分次加入吗啉(44.6g,0.5mol)。在此温度下反应1h,LCMS检测反应结束后,加入100mL的水,有机相用硫酸钠干燥后浓缩,得到化合物4(60.0g,产率=90%)。测得:ESI-MS m/z=276[M+1]
+.
1H NMR(CDCl
3,400MHz):δ3.97(s,3H),3.90-3.86(m,4H),3.82-3.79(m,4H).
1.4.化合物5的合成
化合物5:中文名称为2-氯-5-氟-6-吗啉嘧啶-4-甲酰胺;英文名称为2-chloro-5-fluoro-6-morpholinopyrimidine-4-carboxamide;
将化合物4(55.0g,0.2mol)溶于甲醇(250mL)、四氢呋喃(750mL)和水(250mL)中,分次加入氢氧化锂(12.6g,1.5mol)。反应液在0度下反应1h,LCMS检测反应结束后,加入盐酸水溶液(1M)调至pH=5,减压浓缩得到粗品(50.0g,产率>90%).将该粗品(50g,0.19mol)溶于氯化亚砜(200mL)中,在室温搅拌4h。LCMS检测反应结束后,减压浓缩干后,加入1,4-二氧六环(1L)配成溶液,然后不断通入氨气,反应液在0度下搅拌4h。LCMS检测反应结束后,将反应液浓缩后,加入乙酸乙酯(500mL),滤掉固体,滤液旋干,用柱层析纯化(石油醚/乙酸乙酯=1:1),得到化合物5(36.5g,产率=71%)。测得:ESI-MS m/z=261[M+1]
+.
1H NMR(DMSO-d6,400MHz):δ8.01(s,1H)δ7.85(s,1H),3.76-3.71(m,4H),3.70-3.68(m,4H).
1.5.化合物6的合成
化合物6:中文名称为2-氯-5-氟-6-吗啉嘧啶-4-碳腈;英文名称为2-chloro-5-fluoro-6-morpholinopyrimidine-4-carbonitrile;
将化合物5(36.5g,0.138mol)溶在二氯甲烷(1.5L)中,反应液冷却到零度,分别加入三乙胺(140g,1.38mol),三氟乙酸酐(82g,0.69mol)。室温下反应过夜,LCMS检测反应结束后,将反应液浓缩后,加入乙酸乙酯,有机相用碳酸氢钠水洗,饱和盐水洗,用硫酸钠干燥后浓缩,用柱层析纯化(石油醚/乙酸乙酯=10:1),得到化合物6(25.0g,产率=73%)。测得:ESI-MS m/z=243[M+1]
+.
1H NMR(CDCl
3,400MHz):δ3.90-3.88(m,4H),3.84-3.80(m,4H).
1.6.化合物8的合成
化合物8:中文名称为2-(4-异氰酸酯苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊烷;英文名称为2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane;
在300mL的二氯甲烷中分别加入4-氨基苯硼酸频哪醇酯化合物7(10g,45.6mmol),三乙胺(13.8g,136.8mmol),冷却到零度,在零度分批缓慢加入三光气(8.1g,27.4mmol),之后在零度下搅拌50分钟得到化合物8的溶液,直接用于下一步。
1.7.化合物9的合成
化合物9:中文名称为1-(4-(羟甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二恶英-2-基)苯基)脲;英文名称为:
1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea;
在零度向上述化合物8的溶液加入对氨基苯甲醇(8.4g,68mmol),之后在零度下搅拌15分钟,升温至室温,在室温下再搅拌3h。LC-MS检测反应结束后,将反应液浓缩旋干,用二氯甲烷萃取,有机相用碳酸氢钠饱和溶液和氯化钠饱和溶液洗涤,无水硫酸钠干燥,过滤,滤液旋干,经柱层析纯化(二氯甲烷/甲醇=40:1),得到黄色固体化合物9(11g,产率=60%)。
测得:ESI-MS m/z=369[M+1]
+.
1H NMR(DMSO-d6,400MHz):δ9.02(s,1H),8.89(s,1H),7.60-7.58(d,J=8Hz,2H),7.49-7.47(d,J=8.4Hz,2H),7.42-7.40(d,J=8Hz,2H),7.24-7.21(d,J=8.4Hz,2H),5.06(m,1H),4.44-4.42(d,J=5.6Hz,2H),1.28(s,12H).
1.8.化合物10的合成
化合物10:中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-(羟甲基)苯基)尿素;英文名称为:
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-(hydroxymethyl)phenyl) urea;
将化合物(9)(3.5g,9.5mmol)溶于二氧六环(100mL)和水(5mL)中,再加入化合物(6)(2.9g,12mmol),碳酸氢钠(2.4g,28.5mmol),XPhos(400mg)和Pd
2(dba)
3(180mg),氮气置换3次。在氮气保护下在85度搅拌2天。反应液减压浓缩,加入乙酸乙酯(20mL)和水(30mL),室温下搅拌0.5小时,过滤,滤饼用水洗,乙酸乙酯洗涤。滤饼加入乙酸乙酯(15mL)再搅拌0.5小时,过滤,真空干燥得到化合物(10)(1.9g,产率=44.7%)。测得:ESI-MS m/z=449[M+1]
+.
1H NMR(DMSO-d6,400MHz):δ8.98(s,1H),8.72(s,1H),8.17-8.15(d,J=8.4Hz,2H),7.58-7.56(d,J=9.2Hz,2H),7.43-7.41(d,J=8Hz,2H),7.24-7.22(d,J=8Hz,2H),5.08-5.05(t,J=6Hz,1H),4.44-4.42(d,J=5.6Hz,2H),3.87-3.86(m,4H),3.77-3.75(m,4H).
1.9.化合物I-1的合成
化合物I-1:中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑啉[4,3-d]嘧啶-5-基)苯基)-3-(4-羟甲基)苯基)脲;英文名称为:
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(hydroxymethyl)phenyl)urea;
将化合物10(0.9g,2.5mmol)混悬于1,4-二氧六环(80mL)中,加入水合肼(20mL,85%),在65度下搅拌20h,LCMS检测反应结束后,加入20mL的水,浓缩,析出固体,过滤,滤饼用水洗(10mL×2),经柱层析纯化(二氯甲烷/甲醇=20:1~5:1),得到化合物I-1(0.55g,产率=59.7%)。测得:
1H NMR(DMSO-d6+D
2O,400MHz):δ8.29(m,2H),7.54-7.52(m,2H),7.44-7.41(m,2H),7.26-7.214(m,2H),4.44(s,2H), 4.28-3.79(m,8H).LCMS[mobile phase:from 85%water(0.02%NH
4Ac)and 15%CH
3CN to 40%water(0.02%NH
4Ac)and 60%CH
3CN in 15min,finally under these conditions for 0.5min.]purity is>96%,Rt=9.205min;MS Calcd.:460;MS Found:461[M+H]
+.
实施例2化合物I-2的制备
采取以下路线合成化合物I-2:
2.1.化合物11的合成
化合物11:中文名称为1-(4-(2-羟丙基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素;英文名称为:
1-(4-(2-hydroxypropan-2-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea;
在零度向化合物8的溶液(100mL,来自4.34g的化合物7,19.8mmol)加入胺(
2.0g,13.2mmol)。反应液在零度下搅拌15分钟,自然升至室温,在室温下再搅拌4h。LC-MS检测反应结束后,氯化钠饱和溶液洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,残余物加入***(10mL),过滤,真空干燥得到白色固体化合物11(5.0g,产率=96%)。测得:ESI-MS m/z=397[M+1]
+
2.2.化合物12的合成
化合物12:中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-(2-羟丙基-2-基)苯基)尿素;英文名称为:
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;
将化合物11(2.0g,5mmol)溶于二氧六环(40mL)和水(4mL)中,再加入化合物6(1.5g,6mmol),碳酸氢钠(1.3g,15mmol),XPhos(400mg)和Pd
2(dba)
3(180mg),氮气置换3次。在氮气保护下在90度搅拌16小时。反应液减压浓缩,加入乙酸乙酯(20mL)和水(30mL),室温下搅拌0.5小时,过滤,滤饼用水洗,乙酸乙酯洗涤。滤饼加入乙酸乙酯(10mL)再搅拌0.5小时,过滤,真空干燥得到化合物12(1.2g,产率=50%)。测得:ESI-MS m/z=477[M+1]
+。
2.3.化合物I-2的合成
化合物I-2:中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑啉[4,3-d]嘧啶-5-基)苯基)-3-(4-(2-羟丙基-2-基)苯基)尿素;英文名称为:
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;
将化合物12(2.0g,4.2mmol)混悬于二氧六环(50mL)中,加入水合肼(10mL,85%),在70度下搅拌16h,LCMS检测反应结束后,加入20mL的水,浓缩,析出固体,过滤,得到滤饼,并以水洗(10mL×2),经柱层析纯化(二氯甲烷/甲醇=20:1~5:1),得到化合物I-2(1.0g,产率=48.8%)。测得:
1H NMR(DMSO-d6,400MHz):δ11.86(1H), 8.79(s,1H),8.62(s,1H),8.31-8.29(d,J=8.4Hz,2H),7.57-7.53(d,J=8.8Hz,2H),7.37(s,4H),5.43-5.40(m,1.5H),4.90(s,H),3.97(s,3H),3.78(m,8H),1.41(s,6H).LCMS[mobile phase:from 80%water(0.02%NH
4Ac)and 20%CH
3CN to 50%water(0.02%NH
4Ac)and 50%CH
3CN in 6.5min,finally under these conditions for 0.5min.]purityis>95%,Rt=3.198min;MS Calcd.:488;MS Found:489[M+H]
+.
实施例3化合物I-3的制备
采取以下路线合成化合物I-3:
3.1.化合物14的合成
化合物14:中文名称为N-(甲磺酰基)-2-(4-硝基苯基)乙酰胺;英文名称为:
N-(methylsulfonyl)-2-(4-nitrophenyl)acetamide;
将化合物13(6.0g,0.033mol)溶解于二氯甲烷(100mL)中,加入CDI(10.7g,0.066mol,N,N'-羰基二咪唑),在室温下搅拌1h,加入甲基磺酰胺(3.45g,0.036mol)。反应液在室温下搅拌过夜,加入DBU(10.0g,0.066mol),然后室温搅拌过夜。反应液用盐酸(4N) 调pH=1,有机相用水洗涤,无水硫酸钠干燥,过滤。滤液减压浓缩,过滤,用二氯甲烷洗滤饼。滤饼真空干燥得到黄色固体化合物14(4.4g,产率=59.7%)。测得:ESI-MS m/z=257[M-1]
+.
1H NMR(DMSO-d6,400MHz):δ12.07(s,1H),8.22-8.20(d,J=8.8Hz,2H),7.57-7.55(d,J=8.4Hz,2H),3.83(s,2H),3.25(s,3H).
3.2.化合物15的合成
化合物15:中文名称为2-(4-氨基苯基)-N-(甲磺酰)乙酰胺;英文名称为:
2-(4-aminophenyl)-N-(methylsulfonyl)acetamide;
将化合物14)(4.4g,0.017mol)溶于乙醇(100mL)中,加入浓盐酸(1.6mL),钯碳(10%,0.4g),氢气置换3次。反应液在氢气球下室温搅拌过夜。LCMS监控反应完全后,减压浓缩。残余物加入水(50mL),滤掉钯碳。滤液经减压旋蒸至干,得到白色固体化合物15(4.1g,产率=91.7%)。测得:ESI-MS m/z=229[M+1]
+.
1H NMR(DMSO-d6,300MHz):δ7.38-7.33(m,4H),3.70(s,2H),3.26(s,3H).
3.3.化合物16的合成
化合物16:中文名称为N-(甲磺酰基)-2-(4-(3-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)脲基)苯基)乙酰胺;英文名称为:
N-(methylsulfonyl)-2-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)phenyl)acetamide;
将化合物15(6.3g,0.026mol)溶解于二氯甲烷(60mL)中,加入三乙胺(5.9mL,0.044mol),在冰水浴冷却下加入化合物8的溶液(100mL,来自4.7g的化合物7,17mmol),缓慢升至室温,搅拌过夜,用水(30mL*3)萃取,水相用盐酸(2N)酸化使pH=6,过滤,真空干燥得到白色固体粗品化合物16(6.1g,产率>76.2%).测得:ESI-MS m/z=474[M+1]
+
3.4.化合物17的合成
化合物17:中文名称为2-(4-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)脲基)苯基)-N-(甲磺酰基)乙酰胺;英文名称为:
2-(4-(3-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)ureido)phenyl)-N-(methylsulfonyl)acetamide;
将化合物16(5.0g,10.6mmol)溶于1,4-二氧六环(100mL)和水(5mL)中,再加入化合物6(2.6g,10.6mmol),碳酸氢钠(2.7g,31.8mmol),XPhos(400mg)和Pd
2(dba)
3(180mg),氮气置换3次。在氮气保护下85度搅拌2天。反应液减压浓缩,加入乙酸乙酯(50mL)和水(200mL),室温下搅拌0.5小时,过滤,滤饼用水洗,乙酸乙酯洗涤。水相用盐酸(2N)酸化使pH=6,过滤,滤饼在乙酸乙酯(15mL)中搅拌0.5h,过滤真空干燥得到灰色固体化合物17(2.8g,产率>47.8%).测得:ESI-MS m/z=554[M+1]
+
3.5.化合物I-3的合成
化合物I-3:中文名称为2-(4-(3-(3-氨基-7-吗啉-1H-吡唑啉[4,3-D]嘧啶-5-基)苯基)脲基)苯基)-N-(甲磺酰基)乙酰胺;英文名称为:
2-(4-(3-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)ureido)phenyl)-N-(methylsulfonyl)acetamide;
将化合物8(2.0g,3.6mmol)混悬于二氧六环(50mL)中,加入水合肼(20mL,85%),在65度下搅拌15min,在冰水冷却下用盐酸(2N)酸化使pH=7,过滤,滤饼经硅胶柱纯化(DCM:MeOH=30:1~5:1),得到黄色固体,再进一步用HPLC制备,得到化合物I-3(125mg,产率=6.25%)。测得:
1H NMR(DMSO-d6,400MHz):δ11.90(bs,1H),8.82(s,1H),8.69(s,1H),8.31-8.28(d,J=8.4Hz,2H),7.53-7.51(d,J=8.4Hz,2H),7.42-7.40(d,J= 8.4Hz,2H),7.19-7.17(d,J=8.8Hz,2H),5.42(bs,2H),3.97(m,4H),3.79(m,4H),3.49(s,2H),3.14(s,3H).LCMS[mobile phase:from 90%water(0.02%NH
4Ac)and 10%CH
3CN to 50%water(0.02%NH
4Ac)and 50%CH
3CN in 6.5min,finally under these conditions for 0.5min.]purity is>95%,Rt=2.992min;MS Calcd.:565;MS Found:566[M+H]
+.
实施例4化合物I-4的制备
采取以下路线合成化合物I-4:
4.1.化合物19的合成
化合物19:中文名称为2-(2-氰基丙烷-2-基)苯甲腈;英文名称为:
2-(2-cyanopropan-2-yl)benzonitrile;
将氢化钠(60%,12.0g,0.3mol)加入到四氢呋喃(150mL),冰水浴冷却至0度,滴加化 合物18(14.2g,0.1mol)的四氢呋喃(50mL)溶液,加完后在室温搅拌1小时。将反应液再冷却到0度,滴加CH
3I(57.0g,0.4mol),室温搅拌过夜,倒入冰水(200mL)淬灭,乙酸乙酯萃取(50mL x 2),有机相用硫酸钠干燥浓缩,加入甲基叔丁基醚(20mL)和石油醚(50mL),搅拌过滤,真空干燥得到黄色固体化合物19(13.8g,产率18.1%)。测得:
1H NMR(CDCl
3,400MHz):δ7.79-7.76(m,2H),7.67-7.62(m,1H),7.48-7.44(m,1H),1.97(s,6H).
4.2.化合物20的合成
化合物20:中文名称为4,4-二甲基异喹啉-1,3(2H,4H)-二酮;英文名称为:
4,4-dimethylisoquinoline-1,3(2H,4H)-dione;
在冰水浴冷却下将化合物19(13.8g,0.081mol)加入到H
2SO
4(90%,44mL)中,室温下搅拌2天,再60度搅拌过夜。反应液冷却到室温再倒入搅拌的冰水中,过滤,水洗,真空干燥得到类白色固体化合物20(14.9g,产率97.3%)。测得:ESI-MS m/z=188[M-1]
-.
1H NMR(CDCl
3,400MHz):8.41(bs,1H),8.24-8.22(m,1H),7.70-7.66(m,1H),7.51-7.44(m,2H),1.66(s,6H).
4.3.化合物21的合成
化合物21:中文名称为4,4-二甲基-7-硝基异喹啉-1,3(2H,4H)-二酮;英文名称为:4,4-dimethyl-7-nitroisoquinoline-1,3(2H,4H)-dione;
将发烟硝酸(60mL)冷却到0度,缓慢加入浓硫酸(60mL),再分次加入化合物20(14.0g,0.074mol),得到黄色的溶液,0~5度搅拌2小时后倒入搅拌的冰水(400mL)中,过滤,水洗,真空干燥得到类白色固体化合物21(17g,产率98.2%)。测得:ESI-MS m/z=233[M-1]
-.
1H NMR(acetone-d6,400MHz):δ10.44(bs,1H),8.89-8.86(d,J=2.8Hz,1H),8.58-8.55(m,1H),8.10-8.08(d,J=8.4Hz,1H),1.76(s,6H).
4.4.化合物22的合成
化合物22:中文名称为3,3-二甲基-6-硝基吲哚啉-2-酮3,3-dimethyl-6-nitroindolin-2-one
将NaOH(19.6g,0.49mol)溶于水(300mL)中,在冰水浴冷却至5度以下,分次加入Br
2(20.7g,0.13mol),搅拌10分钟后加入化合物21(19.0g,0.081mol),室温搅拌过夜。在反应液中加入NaOH(10.0g,0.25mol)和水(40mL)。将反应液在80度搅拌0.5小时,再冷却至室温,在冰水浴冷却下,用浓盐酸调pH=1,过滤,水洗,真空干燥得到黄色固体化合物22(10.0g,产率59.9%)。测得:ESI-MS m/z=205[M-1]
-.
1H NMR(CDCl
3,400MHz):δ9.00(s,1H),8.00-7.97(m,1H),7.79-7.78(d,J=2.4Hz,1H),7.35-7.33(d,J=7.6Hz,1H),1.45(s,6H).
4.5.化合物23的合成
化合物23:中文名称为6-氨基-3,3-二甲基吲哚啉-2-酮;英文名称为:
6-amino-3,3-dimethylindolin-2-one;
将化合物22(10.0g,0.19mol)溶于乙醇(700mL)和二氯甲烷(150mL)中,加入浓盐酸(10mL),钯碳(10%,400mg),氢气球置换3次,室温搅拌过夜。过滤掉钯碳,滤液减压浓缩,剩余物加入甲基叔丁基醚,过滤,真空干燥得到黄色固体化合物23(9.0g,产率87.3%)。测得:ESI-MS m/z=177[M+1]
+.
1H NMR(CDCl
3,400MHz):δ10.48(s,1H),7.31-7.29(d,J=7.6Hz,1H),6.83-6.79(m,2H),1.22(s,6H).
4.6.化合物24的合成
化合物24:中文名称为1-(3,3-二甲基-2-氧吲哚-6-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素;英文名称为:
1-(3,3-dimethyl-2-oxoindolin-6-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea;
在0~5度向化合物8的溶液(100mL,来自5.3g的化合物7,23.7mmol)滴加化合物23(4.0g,18.8mmol)和三乙胺(2.6mL,18.8mmol)的二氯甲烷溶液。反应液在室温搅拌过夜,用碳酸氢钠水溶液洗涤,水洗,有机相减压浓缩,过滤,少量二氯甲烷洗滤饼,真空干燥得到类白色固体化合物24(5.2g,产率65.7%)。测得:ESI-MS m/z=295[M+1]
+
4.7.化合物25的合成
化合物25:中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-(羟甲基)苯基)尿素;英文名称为:
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-(hydroxymethyl)phenyl)urea;
将化合物24(2.0g,4.7mmol)溶于1,4-二氧六环(25mL)和水(1.25mL)中,再加入化合物6(1.1g,4.7mmol),碳酸氢钠(1.2g,14.2mmol),XPhos(600mg)和Pd
2(dba)
3(300mg)。反应液在90度下搅拌过夜,LCMS检测反应结束后,加入10mL的水,并用乙酸乙酯萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩,经柱层析纯化(二氯甲烷/甲醇=20:1),得到化合物25(500mg,产率=20%)。测得:ESI-MS m/z=502[M+1]
+.
1H NMR(DMSO-d6,400MHz):δ10.28(s,1H),8.92(s,1H),8.74(s,1H),8.17-8.15(d,J=7.2Hz,1H),7.58-7.56(d,J=8Hz,2H),7.27(s,1H),7.17-7.15(d,J=8Hz,1H),6.88-6.84(m,1H).
4.8.化合物I-4的合成
化合物I-4:中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑[4,3-d]嘧啶-5-基)苯基)-3- (3,3-二甲基-2-氧吲哚啉-6-基)尿素;英文名称为:
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(3,3-dimethyl-2-oxoindolin-6-yl)urea;
将化合物25(1.26g,2.5mmol)溶于1,4-二氧六环(80mL)中,再加入水合肼(25mL,85%),在70度下搅拌20h,LCMS检测反应结束后,加入10mL的水,浓缩,析出固体,过滤,滤饼用水洗(10mL x 2),经柱层析纯化(二氯甲烷/甲醇=20:1),得到化合物I-4(0.86g,产率=47%)。测得:
1H NMR(DMSO-d6,400MHz):δ12.84(s,0.3H),11.85(s,0.6H),10.28(s,1H),8.88-8.70(m,2H),8.301(s,2H),7.53-7.51(d,J=8Hz,2H),7.30(s,1H),7.16-7.14(d,J=8Hz,1H),6.86-6.83(d,J=8Hz,1H),5.70(s,0.6H),5.28(s,1H),4.34-4.16(m,1H),4.10-3.78(m,7H),3.18-3.17(d,J=4Hz,1H),1.23(s,6H).LCMS[mobile phase:from 80%water(0.02%NH
4Ac)and 20%CH
3CN to 30%water(0.02%NH
4Ac)and 70%CH
3CN in 6.5min,finally under these conditions for 0.5min.]purityis>96%,Rt=2.888min;MS Calcd.:513;MS Found:514[M+H]
+.
实施例5化合物I-5的制备
采取以下路线合成化合物I-5:
5.1.化合物27的合成
化合物27:中文名称为(4-硝基-2-(三氟甲基)苯基)甲醇;英文名称为:
(4-nitro-2-(trifluoromethyl)phenyl)methanol;
将化合物26(25.0g,106.4mmol)溶于四氢呋喃(100mL)中,冰浴下缓慢加入硼氢化钠(11.5g,319.1mmol),再缓慢滴加三氟化硼***(20mL),之后室温搅拌过夜。TLC显示反应结束后,加入100mL的盐水,使用乙酸乙酯(300mL x 3)萃取,有机相用硫酸钠干燥浓缩后,得到化合物27(14.5g,产率=61%).测得:ESI-MS m/z=222[M+1]
+
5.2.化合物28的合成
化合物28:中文名称为叔丁基二甲基(4-硝基-2-(三氟甲基)苄基)氧基)硅烷;英文名称为tert-butyldimethyl((4-nitro-2-(trifluoromethyl)benzyl)oxy)silane;
冰浴下在二氯甲烷(120mL)中分别加入化合物27(14.0g,63.64mmol),叔丁基二甲基氯硅烷(19.2g,127.27mmol),三乙胺(16.1g,159.1mmol),对二甲胺基吡啶(0.78g,6.36mmol),然后反应液在室温搅拌2h。TLC检测反应结束后,加入100mL的盐水,并用二氯甲烷(200mL x 3)萃取,有机相用硫酸钠干燥浓缩后,用柱层析纯化(石油醚/乙酸乙酯=100:1-50:1),得到化合物28(15.0g,产率=70%),直接用于下一步反应。
5.3.化合物29的合成
化合物29:中文名称为4-((叔丁基二甲基硅)氧基)甲基)-3-(三氟甲基)苯胺;英文名称为4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)aniline;
将化合物28(15.0g,44.78mmol)溶在乙醇/水(200mL/80mL)中,加入氯化铵(15.0g,268.68mmol),温度升到80度,再次加入铁粉(11.0g,201.49mmol),反应在此温度下反应1h,LCMS检测反应结束后,加入盐水(100mL)过滤,滤液使用乙酸乙酯(200mL x 3)萃取,有机相用硫酸钠干燥后浓缩,得到化合物29(11.0g,产率=80%)。测得:ESI-MS m/z=306[M+1]
+.
1H NMR(CDCl
3,400MHz):δ7.49(d,J=8.0Hz,1H),6.90(s,1H),6.83(d,J=8.0Hz,1H),4.78(s,2H),0.94(s,9H),0.09(s,6H).
5.4.化合物30的合成
化合物30:中文名称为1-(4-((叔丁基二甲基硅基)氧基)甲基)-3-(三氟甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素;英文名称为:
1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea;
将化合物29(6.0g,19.68mol)溶于四氢呋喃(90mL)中,加入化合物8(12.0g,49.19mmol)。室温反应过夜,LCMS检测反应结束后,减压浓缩,用柱层析纯化(石油醚/乙酸乙酯=10:1-5:1),得到化合物30(5.5g,产率50%)。测得:ESI-MS m/z=551.6[M+1]
+
5.5.化合物31的合成
化合物31:中文名称为1-(4-((叔丁基二甲基硅氧基)甲基)-3-(三氟甲基)苯基)-3-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)尿素;英文名称为:
1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)urea;
将化合物30(6.5g,11.82mmol)溶于二氧六环(50mL)\水(5mL)中,再加入化合物6(3.2g,13.00mmol),碳酸氢钠(3.0g,35.46mmol),XPhos(563mg,1.19mmol)和Pd
2(dba)
3(220mg,0.24mmol)。反应在85度下反应过夜,LCMS检测反应结束后,加入35mL的盐水,并用乙酸乙酯萃取,有机相用硫酸钠干燥后浓缩,用柱层析纯化(石油醚/乙酸乙酯=3:1-1:2),得到化合物31(3.0g,产率=40%)。测得:ESI-MS m/z=629.7[M-1]
-.
5.6.化合物32的合成
化合物32:中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑[4,3-D]嘧啶-5-基)苯基)-3-(4-((叔丁基二甲基硅基)氧基)甲基)-3-(三氟甲基)苯基)尿素;英文名称为:
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)urea;
将化合物31(2.8g,4.45mmol)溶于1,4-二氧六环(50mL)中,再加入水合肼(12mL,85%)。反应在70度下反应2天,LCMS检测反应结束后,加入35mL的盐水,并用乙酸乙酯萃取,有机相用硫酸钠干燥后浓缩,用硅胶柱层析纯化(二氯甲烷/甲醇=100:1-10:1),再使用反相柱纯化得到化合物32(1.30g,产率=45%)。测得:ESI-MS m/z=643.7[M+1]
+.
1H NMR(DMSO-d6,400MHz):δ9.02(s,1H),8.89(s,1H),8.21(d,J=8.0Hz,2H),7.92(s,1H),7.52(brs,2H),7.44(d,J=8.0Hz,2H),4.69(s,2H),3.78– 3.50(m,8H),0.81(s,9H),0.00(s,6H).
5.7.化合物I-5的合成
化合物I-5:中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑[4,3-D]嘧啶-5-基)苯基)-3-(4-(羟甲基)-3-(三氟甲基)苯基)脲;英文名称为:
1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)urea;
将化合物32(1.3g,2.02mmol)溶解在0.5M的1,4-二氧六环(20mL)溶液里,再加入水(3mL).室温下搅拌2h,LCMS检测反应结束后,过滤。得到的不溶物分别使用乙腈,乙酸乙酯和甲基叔丁醚打浆,干燥得到化合物I-5(0.85g,产率80%)。测得:
1H NMR(DMSO-d6,400MHz):δ9.67(s,1H),9.57(s,1H),8.37(d,J=8.4Hz,2H),7.95(s,1H),7.69-7.62(m,4H),4.61(s,2H),4.45-4.15(m,4H),3.84-3.78(m,4H).
1H NMR(DMSO-d6+D
2O,400MHz):δ9.60(s,0.3H),9.48(s,0.3H),8.33(d,J=8.4Hz,2H),7.97(s,1H),7.72-7.64(m,4H),4.64(s,2H),4.46-4.24(m,4H),3.87(brs,4H).LCMS[mobile phase:from 80%water(0.02%NH
4Ac)and 20%CH
3CN to 30%water(0.02%NH
4Ac)and 70%CH
3CN in 6.5min,finally under these conditions for 0.5min.]purity is>95%,Rt=2.974min;MS Calcd.:528;MS Found:529[M+H]
+.
实施例6化合物I-6的制备
采取以下路线合成化合物I-6:
6.1.化合物34的合成
化合物34:中文名称为4-(2-(苄氧基)乙基)吗啉;英文名称为:
4-(2-(benzyloxy)ethyl)morpholine;
将化合物33(32.8g,0.25mol)溶于DMF(200mL)中,在冰水浴冷却下分次加入NaH(10g,0.25mol),在室温搅拌1.5小时,滴加溴化苄(39.3g,0.23mol)。反应液在室温搅拌16小时,减压浓缩,加入乙酸乙酯(100mL),用水洗涤,饱和食盐水洗涤。有机相减压浓缩,经硅胶柱纯化(DCM:MeOH=10:1),得到无色的油化合物34(40g,产率78%)。测得:ESI-MS m/z=222[M+1]
+
6.2.化合物35的合成
化合物35:中文名称为4-(2-((4-硝基苄基)氧基)乙基)吗啉;英文名称为:
4-(2-((4-nitrobenzyl)oxy)ethyl)morpholine;
将化合物34(40.0g,0.18mol)溶于乙酸酐(200mL)中,在冰水浴冷却至5度,滴加发烟硝酸(60mL),在5度搅拌4小时。反应液缓慢倒入碳酸钠水溶液中,使得pH>8,用乙酸乙酯萃取。有机相用水洗涤,饱和食盐水洗涤,减压浓缩,经硅胶柱纯化(DCM:MeOH=10:1),得到无色的油化合物35(30.1g,产率62%)。测得:ESI-MS m/z=267[M+1]
+
6.3.化合物36的合成
化合物36:中文名称为4-((2-吗啉氧基)甲基)苯胺;英文名称为:
4-((2-morpholinoethoxy)methyl)aniline;
将化合物35(5.0g,0.018mol)溶于乙酸乙酯(200mL)中,加入10%的钯碳(1.0g),氢气置换3次,在氢气球下室温搅拌16小时。反应液过滤,滤液减压浓缩至干,得到红色粗品化合物36(4.5g),直接用于下一步。测得:ESI-MS m/z=237[M+1]
+
6.4.化合物37的合成
化合物37:中文名称为1-(4-((2-吗啉氧基)甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素;英文名称为:
1-(4-((2-morpholinoethoxy)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea;
冰浴下向化合物8的二氯甲烷溶液(100mL,来自6.6g的化合物7,30mmol),滴加化合物36(5.9g,25mmol)的二氯甲烷(30mL)溶液。反应液在室温搅拌过夜,用碳酸氢钠水溶液洗涤,水洗,有机相减压浓缩,经硅胶柱纯化(DCM:MeOH=10:1),得到 黄色固体化合物37(8.7g,产率72.3%)。测得:ESI-MS m/z=482[M+1]
+
6.5.化合物38的合成
化合物38:中文名称为1-(4-(4-氰基-5-氟-6-吗啉嘧啶-2-基)苯基)-3-(4-((2-吗啉氧基)甲基)苯基)尿素;英文名称为:
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea;
将化合物37(4.0g,8.3mmol)溶于1,4-二氧六环(100mL)和水(10mL)中,再加入化合物6(3.0g,12mmol),碳酸氢钠(2.5g,29.7mmol),XPhos(600mg)和Pd
2(dba)
3(300mg)。反应液在85度下搅拌过夜,LCMS检测反应结束后,加入20mL的水,并用乙酸乙酯萃取,有机相用无水硫酸钠干燥后过滤,滤液减压浓缩,得到红色固体化合物38(6.0g,粗品),直接用于下一步。测得:ESI-MS m/z=562[M+1]
+
6.6.化合物I-6的合成
化合物I-6:中文名称为1-(4-(3-氨基-7-吗啉-1H-吡唑啉[4,3-D]嘧啶-5-基)苯基)-3-(4-((2-吗啉氧基)甲基)苯基)尿;
英文名称为:1-(4-(3-amino-7-morpholino-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea;
将化合物38(5.5g,粗品)溶于1,4-二氧六环(100mL)中,再加入水合肼(15mL,85%),在70度下搅拌16h,LCMS检测反应结束后,加入10mL的水,浓缩,析出固体,过滤,滤饼用水洗(10mL x 2),经柱层析纯化(二氯甲烷/甲醇=20:1),得到化合物I-6(900mg,19%)。测得:
1H NMR(DMSO-d6,400MHz):δ11.76(s,1H),8.81(s,1H),8.71(s,1H),8.31-8.29(m,2H),7.54-7.52(m,2H),7.46-7.44(m,2H),7.25-7.23(m,2H),5.36 (bs,2H),4.40(s,2H),3.96(bs,3H),3.76(s,4H),3.55-3.52(m,6H),2.40(s,4H).LCMS[mobile phase:from 80%water(0.02%NH
4Ac)and 20%CH
3CN to 30%water(0.02%NH
4Ac)and 70%CH
3CN in 6.5min,finally under these conditions for 0.5min.]purity is>95%,Rt=2.823min;MS Calcd.:573;MS Found:574[M+H]
+.
实施例7实施例化合物的生物活性实验
应用PI3-Kinase(human)HTRF
TM Assay kit检测(PI3-Kinase(human)HTRF
TM Assay kit检测的方法为国际通用方法)实施例的六个化合物I-1,I-2,I-3,I-4,I-5,I-6(以下实验中分别给予代号RMP-D09,RMP-D01,RMP-D02,RMP-D03,RMP-D04,RMP-D05)对PI3K alpha酶的半数抑制浓度(IC
50测定),采用化合物GDC-0941作为阳性对照。阳性对照品:GDC0941(Pictilisib)
7.1材料和仪器
384 well opaque balck plate(Cat.6007270,PerkinElmer);
PI3-Kinase(human)HTRFTM Assay kit(Cat.33-016,Millipore);
4×Reaction Buffer(Cat.33-002,Millipore);PIP2 1mM(Cat.33-004,Millipore);
Stop A(Cat.33-006,Millipore);Stop B(Cat.33-008,Millipore);DM A(Cat.33-010,Millipore);DM B(Cat.33-012,Millipore);DM C(Cat.33-014,Millipore);PI3k alpha(Cat.14-602,Millipore);ATP 10mM(cat PV3227,Invitrogen);DTT 1M(cat D5545,Sigma);
待测化化合物I-1,I-2,I-3,I-4,I-5,I-6(以下实验中分别给予代号RMP-D09,RMP-D01,RMP-D02,RMP-D03,RMP-D04,RMP-D05),以及GDC-0941。
7.2试剂配制
1×Reaction Buffer
4×Reaction Buffer用ddH
2O稀释至1×,并加入1M DTT使其终浓度为5mM。每次使用前新鲜配制。例如配制10mL 1×Reaction Buffer,加入2.5mL 4×Reaction Buffer,50μL 1M DTT,ddH
2O 7.45mL。整个实验中,用新鲜配制的1×Reaction Buffer配制ATP工作液,底物和酶混合工作液等。
4×化合物工作液
待测化合物用DMSO溶解至1mM作为储存液,然后用DMSO4倍倍比稀释,共10个浓度点。各取1μL加入24μL 1×Reaction Buffer中。每个稀释溶液各取5μL加入384孔板中,并含有1%DMSO。
2×PIP2工作液
用1×reaction buffer配制2×PIP2工作液,使其终浓度为20μM,PIP2的反应终浓度为10μM,例如配制1ml 1x reaction buffer/PIP2工作液,取20μL PIP2加入到980μL 1×reaction buffer中。这个工作液要多配0.1-0.2ml,以满足对照使用和死体积。
2×PIP2/激酶工作液
用2×PIP2工作液稀释激酶,激酶工作液的浓度为10ng/well。
无激酶对照(可视为100%抑制)
即2×PIP2工作液。
4×ATP工作液
10mM的ATP用1×reaction buffer稀释至40μM。在20μL激酶反应体系中,ATP的浓度为10μM。例如配制2ml ATP工作液,取8μL10mM ATP加入到1992μL 1×reaction buffer中。
终止液
Stop A和Stop B按3:1的比例混合,室温放置至少2小时后才可用,终止液可在室温下稳定12个小时。
检测液
DM C,DM A和DM B按照18:1:1的比例混合,室温放置至少2小时后才可用,检测液可在室温下稳定12个小时。
7.3实验流程
数据分析
计算各孔的Emission Ratio(ER)
Emission Ratio(ER)=665nM Emission signal/620nm Emission signal
100%抑制对照的平均发射强度比(Emission Ratio)记为:ER
100%
0%抑制对照的平均Emission Ratio记为:ER
0%
计算抑制率
抑制率用以下公式计算:
抑制率=(ER
sample-ER
0%)/(ER
100%-ER
0%)×100%【(ER阳性―ER样品)/(ER阳性―ER阴性)*100%】
7.4实验结果
应用PI3-Kinase(human)HTRFTM Assay kit检测6个化合物不同浓度下对PI3K-alpha酶的抑制率,控制DMSO浓度为1%,每个浓度为复孔,并选取GDC-0941作为阳性参照物进行测定,结果如图1所示。根据检测结果,各化合物对PI3K-alpha酶的半数抑制浓度(IC
50)总结如下表1所示。
表1、待测化合物对PI3K-alpha的半数抑制浓度(IC
50)
化合物名称 | IC 50(nM) |
I-1(RMP-D09) | 10.7 |
I-2(RMP-D01) | 89.6 |
I-3(RMP-D02) | 89.07 |
I-4(RMP-D03) | 108.4 |
I-5(RMP-D04) | 228.4 |
I-6(RMP-D05) | 40.9 |
GDC0941(Pictilisib) | 31.28 |
以上实验证明了本发明的新型吡唑并嘧啶化合物对磷脂肌醇-3-激酶(PI3K)的抑制作用,表明本发明的新型吡唑并嘧啶化合物(包括其可药用盐等)是一种新型PI3K抑制剂。因此,可以应用于治疗由磷脂肌醇-3-激酶(PI3K)介导的疾病,可治疗的恶性肿瘤包括但不限于肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌,纤维肉瘤、卵巢癌,白血病和***癌等。
本发明的其他化合物与化合物I-1至化合物I-6具有基本相同的结构,可以预期他们具有与化合物I-1至化合物I-6相当的优异活性。该类化合物是世界上首创的新型化合物,已经显示了明显的强活性,将用于进一步的新药研究,发明出国产的创新药物,用于市场急需的作用强,副作用小而且便宜的抗癌药。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (17)
- 根据权利要求1或2所述的通式(I)所示的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶,其特征在于:所述B为-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、 -CH(CH 3)-、-CH(CH 3)CH 2-、-C(CH 3) 2-或-CH 2C(CH 3) 2-。
- 如权利要求1至6中任一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶在制备预防和/或治疗由磷脂酰肌醇-3-激酶(PI3K)介导的疾病的药物中的应用。
- 根据权利要求7所述的应用,其特征在于:所述由磷脂酰肌醇-3-激酶(PI3K)介导的疾病包括癌症,所述癌症包括肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌,纤维肉瘤、卵巢癌、白血病和***癌。
- 一种药物组合物,其特征在于:包括一种或多种如权利要求1至6中任一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶,以及药学可接受的载体。
- 根据权利要求9所述的药物组合物,其特征在于:所述药物组合物为治疗癌症的组合物。
- 一种如权利要求1至6中任意一项权利要求所述的通式(I)所示的吡唑并嘧啶化合物,其立体异构体、可药用盐、溶剂化物或结晶的制备方法,其特征在于:所述制备方法包括使权利要求11或12所述的式(II)所示中间体与水合肼进行反应的步骤。
- 根据权利要求13的制备方法,其特征在于:所述式(II)所示中间体与水合肼的反应在20-100℃下进行,优选在30-95℃下进行,更优选在40-90℃下进行,进一步优选在55-80℃下进行,再进一步优选在60-75℃下进行。
- 根据权利要求15所述的制备方法,其特征在于:制备所述的式(II)所示中间体的过程中,所述反应在碱性条件下、温度30-120℃下进行,还选择性地在惰性气氛下进行。
- 根据权利要求16所述的制备方法,其特征在于:所述碱性条件通过添加碱性物质形成,所述碱性物质为选自乙酸钾、碳酸钾、苯酚钾、磷酸钾、叔丁醇钾、碳酸钠、碳酸氢钠、叔丁醇钠、甲醇钠、乙醇钠、三乙基胺、三正丁基胺和二异丙基乙基胺中的一种或多种的组合。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/280,245 US20220106316A2 (en) | 2018-09-27 | 2019-09-25 | Pyrazolopyrimidine compound and preparation method therefor and use thereof in preparation of anti-cancer drug |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811146369 | 2018-09-27 | ||
CN201811146369.8 | 2018-09-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020063636A1 true WO2020063636A1 (zh) | 2020-04-02 |
Family
ID=69949577
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/107734 WO2020063636A1 (zh) | 2018-09-27 | 2019-09-25 | 吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用 |
Country Status (3)
Country | Link |
---|---|
US (1) | US20220106316A2 (zh) |
CN (1) | CN110950868B (zh) |
WO (1) | WO2020063636A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001083456A1 (fr) * | 2000-04-27 | 2001-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'heteroaryle condenses |
WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
CN105143209A (zh) * | 2013-03-14 | 2015-12-09 | 诺华股份有限公司 | 作为激酶抑制剂的联芳基酰胺化合物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0609802A2 (pt) * | 2005-05-20 | 2017-05-02 | Alantos Pharmaceuticals Holding Inc | composto, composição farmacêutica e uso de um composto |
CN102014914A (zh) * | 2008-01-15 | 2011-04-13 | 惠氏有限责任公司 | 3h-[1,2,3]***并[4,5-d]嘧啶化合物、其作为mtor激酶和pi3激酶抑制剂的用途、以及它们的合成 |
WO2009097446A1 (en) * | 2008-01-30 | 2009-08-06 | Genentech, Inc. | Pyrazolopyrimidine pi3k inhibitor compounds and methods of use |
US20090192176A1 (en) * | 2008-01-30 | 2009-07-30 | Wyeth | 1H-PYRAZOLO[3,4-D]PYRIMIDINE, PURINE, 7H-PURIN-8(9H)-ONE, 3H-[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE, AND THIENO[3,2-D]PYRIMIDINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES |
RU2515541C2 (ru) * | 2009-11-12 | 2014-05-10 | Ф.Хоффманн-Ля Рош Аг | N-7 замещенные пурины и пиразолопиримидины, их композиции и способы применения |
-
2019
- 2019-09-25 US US17/280,245 patent/US20220106316A2/en active Pending
- 2019-09-25 CN CN201910908739.5A patent/CN110950868B/zh active Active
- 2019-09-25 WO PCT/CN2019/107734 patent/WO2020063636A1/zh active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001083456A1 (fr) * | 2000-04-27 | 2001-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'heteroaryle condenses |
WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
CN105143209A (zh) * | 2013-03-14 | 2015-12-09 | 诺华股份有限公司 | 作为激酶抑制剂的联芳基酰胺化合物 |
Also Published As
Publication number | Publication date |
---|---|
US20220106316A2 (en) | 2022-04-07 |
CN110950868B (zh) | 2022-05-13 |
US20210340146A1 (en) | 2021-11-04 |
CN110950868A (zh) | 2020-04-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2021169990A1 (zh) | 用于癌症治疗的kras抑制剂 | |
WO2021088945A1 (zh) | 作为shp2抑制剂的化合物及其应用 | |
JP6771491B2 (ja) | Ebna1阻害剤およびその使用方法 | |
WO2013134252A1 (en) | 2-amino, 6 - phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as raf kinase inhibitors | |
JP2010523638A (ja) | Pi3k阻害剤としての2−モルホリン−4−イル−ピリミジン | |
WO2014135028A1 (zh) | 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途 | |
JP2010502650A (ja) | Raf阻害化合物およびその使用法 | |
BR112015017963B1 (pt) | Composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto | |
JP2016501251A (ja) | がんの治療のための新規二環フェニル−ピリジン/ピラジン | |
CN111566100A (zh) | 嘧啶类化合物、其制备方法及其医药用途 | |
WO2022135590A1 (zh) | 一类嘧啶并杂环类化合物、制备方法和用途 | |
JP2021501215A (ja) | アミノ置換窒素含有縮合環化合物、その調製方法及び使用 | |
EP3389662B1 (en) | Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer | |
WO2020221209A1 (zh) | 一种cd73抑制剂,其制备方法和应用 | |
WO2023178928A1 (zh) | 2-氨基-4-吲哚基嘧啶类化合物及其制备方法与应用 | |
CN111825719A (zh) | 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 | |
WO2019223777A1 (zh) | 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 | |
WO2015014283A1 (zh) | 蛋白酪氨酸激酶抑制剂及其应用 | |
WO2020063636A1 (zh) | 吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用 | |
CN113072550B (zh) | 一种高选择性成纤维细胞生长因子受体抑制剂和应用 | |
WO2021078141A1 (zh) | 新型嘌呤衍生物及其中间体与制备抗癌症药物的应用 | |
CN114555597A (zh) | 异柠檬酸脱氢酶(idh)抑制剂 | |
CN112209933B (zh) | 含有4-氮杂螺庚烷的btk抑制剂 | |
CN112851679B (zh) | 2,4,7-三取代嘧啶并吲哚化合物抗肿瘤作用 | |
CN109422739B (zh) | 氘代的吲哚胺2,3-双加氧酶抑制剂及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19867442 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19867442 Country of ref document: EP Kind code of ref document: A1 |