WO2022048605A1 - 一种杂环化合物、其制备方法、中间体、组合物以及应用 - Google Patents
一种杂环化合物、其制备方法、中间体、组合物以及应用 Download PDFInfo
- Publication number
- WO2022048605A1 WO2022048605A1 PCT/CN2021/116287 CN2021116287W WO2022048605A1 WO 2022048605 A1 WO2022048605 A1 WO 2022048605A1 CN 2021116287 W CN2021116287 W CN 2021116287W WO 2022048605 A1 WO2022048605 A1 WO 2022048605A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ring
- formula
- independently
- alkyl
- hydrogen
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000000203 mixture Substances 0.000 title description 27
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000012453 solvate Substances 0.000 claims abstract description 18
- 229940002612 prodrug Drugs 0.000 claims abstract description 14
- 239000000651 prodrug Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims description 75
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 125000005842 heteroatom Chemical group 0.000 claims description 70
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- 150000002367 halogens Chemical class 0.000 claims description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 31
- 238000006482 condensation reaction Methods 0.000 claims description 24
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 21
- 125000002723 alicyclic group Chemical group 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 239000011593 sulfur Substances 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- -1 methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy Chemical group 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
- 238000010511 deprotection reaction Methods 0.000 claims description 16
- 206010060862 Prostate cancer Diseases 0.000 claims description 14
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 14
- 238000007259 addition reaction Methods 0.000 claims description 14
- 102000001307 androgen receptors Human genes 0.000 claims description 14
- 108010080146 androgen receptors Proteins 0.000 claims description 14
- 239000002207 metabolite Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical group CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-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
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 150000001408 amides Chemical group 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical group CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 230000001394 metastastic effect Effects 0.000 claims description 3
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 230000000593 degrading effect Effects 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 1
- 230000004060 metabolic process Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 230000001419 dependent effect Effects 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 230000002503 metabolic effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 239000000047 product Substances 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 59
- 238000004809 thin layer chromatography Methods 0.000 description 59
- 0 C*(C)C(**1)=CC=C1O Chemical compound C*(C)C(**1)=CC=C1O 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000012265 solid product Substances 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000007821 HATU Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000006285 cell suspension Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000012805 post-processing Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- HBTXAKDVIXNVHZ-UHFFFAOYSA-N 2-chloro-5-fluorobenzonitrile Chemical compound FC1=CC=C(Cl)C(C#N)=C1 HBTXAKDVIXNVHZ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- BDDVAWDNVWLHDQ-UHFFFAOYSA-N 2-chloro-4-hydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C(Cl)=C1 BDDVAWDNVWLHDQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- URWXZLPRVMBAIC-UHFFFAOYSA-N N#Cc(c(Cl)c1)ccc1OC(CC1)CCC1C(O)=O Chemical compound N#Cc(c(Cl)c1)ccc1OC(CC1)CCC1C(O)=O URWXZLPRVMBAIC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 3
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000009167 androgen deprivation therapy Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical compound OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NRGLEJYPIWZORV-PSASIEDQSA-N (1R,3R)-3-(3-chloro-4-cyanophenoxy)cyclopentane-1-carboxylic acid Chemical compound N#CC(C=CC(O[C@H](CC1)C[C@@H]1C(O)=O)=C1)=C1Cl NRGLEJYPIWZORV-PSASIEDQSA-N 0.000 description 2
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 2
- KGPMBYRSXTTZLG-UHFFFAOYSA-N 2-chloro-5-hydroxybenzonitrile Chemical compound OC1=CC=C(Cl)C(C#N)=C1 KGPMBYRSXTTZLG-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 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
- PGKPNNMOFHNZJX-UHFFFAOYSA-N N#Cc(ccc(F)c1)c1Cl Chemical compound N#Cc(ccc(F)c1)c1Cl PGKPNNMOFHNZJX-UHFFFAOYSA-N 0.000 description 2
- DRVQICWBIMDSKN-UHFFFAOYSA-N N#Cc(ncc(OC(CC1)CCC1C(O)=O)c1)c1Cl Chemical compound N#Cc(ncc(OC(CC1)CCC1C(O)=O)c1)c1Cl DRVQICWBIMDSKN-UHFFFAOYSA-N 0.000 description 2
- CLCTZVRHDOAUGJ-UHFFFAOYSA-N N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidin-1-yl]pyridazine-3-carboxamide Chemical compound FC1=CC2=C(C=C1N1CCN(CC3CCN(CC3)C3=CC=C(N=N3)C(=O)NC3CCC(CC3)OC3=CC(Cl)=C(C=C3)C#N)CC1)C(=O)N(C1CCC(=O)NC1=O)C2=O CLCTZVRHDOAUGJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 102000018478 Ubiquitin-Activating Enzymes Human genes 0.000 description 2
- 108010091546 Ubiquitin-Activating Enzymes Proteins 0.000 description 2
- 108010005705 Ubiquitinated Proteins Proteins 0.000 description 2
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 2
- 229960000853 abiraterone Drugs 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000732 arylene group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 2
- 229960004671 enzalutamide Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- MZMNEDXVUJLQAF-YUMQZZPRSA-N 1-o-tert-butyl 2-o-methyl (2s,4s)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C MZMNEDXVUJLQAF-YUMQZZPRSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LJFDXXUKKMEQKE-UHFFFAOYSA-N 2,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(F)=C1 LJFDXXUKKMEQKE-UHFFFAOYSA-N 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- XOZAJNLUAODXSP-UHFFFAOYSA-N 2-fluoro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(F)N=C1 XOZAJNLUAODXSP-UHFFFAOYSA-N 0.000 description 1
- DTXVKPOKPFWSFF-UHFFFAOYSA-N 3(S)-hydroxy-13-cis-eicosenoyl-CoA Chemical compound NC1=CC=C(Cl)N=N1 DTXVKPOKPFWSFF-UHFFFAOYSA-N 0.000 description 1
- WGYGMBYJJOVYNF-UHFFFAOYSA-N 3-aminopiperazine-2,6-dione Chemical compound NC1NCC(=O)NC1=O WGYGMBYJJOVYNF-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
- HCFRWBBJISAZNK-UHFFFAOYSA-N 4-Hydroxycyclohexylcarboxylic acid Chemical compound OC1CCC(C(O)=O)CC1 HCFRWBBJISAZNK-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- POILWHVDKZOXJZ-UHFFFAOYSA-N 4-hydroxypent-3-en-2-one Chemical compound CC(O)=CC(C)=O POILWHVDKZOXJZ-UHFFFAOYSA-N 0.000 description 1
- GMHPKIGFTDRQBP-UHFFFAOYSA-N 5,6-dichloropyridin-3-ol Chemical compound OC1=CN=C(Cl)C(Cl)=C1 GMHPKIGFTDRQBP-UHFFFAOYSA-N 0.000 description 1
- YHKXYWAZCJAGKK-UHFFFAOYSA-N 5-(bromomethyl)-2-chlorobenzonitrile Chemical compound ClC1=CC=C(CBr)C=C1C#N YHKXYWAZCJAGKK-UHFFFAOYSA-N 0.000 description 1
- CGFYNRVHPARGFY-UHFFFAOYSA-N 5-fluoro-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(F)C=N1 CGFYNRVHPARGFY-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- VQDOVIIHBWIQKQ-UHFFFAOYSA-N C=[Br]Cc(cc1)cc(C#N)c1Cl Chemical compound C=[Br]Cc(cc1)cc(C#N)c1Cl VQDOVIIHBWIQKQ-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1O)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1O)=O PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- ZVZJABPYLNPQMI-OLJZXKMSSA-N CC(C)(C)OC(N(C[C@@H](C1)Oc(cc2)cc(Cl)c2C#N)[C@@H]1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)=O Chemical compound CC(C)(C)OC(N(C[C@@H](C1)Oc(cc2)cc(Cl)c2C#N)[C@@H]1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)=O ZVZJABPYLNPQMI-OLJZXKMSSA-N 0.000 description 1
- ZVZJABPYLNPQMI-QBLNDNOCSA-N CC(C)(C)OC(N(C[C@H](C1)Oc(cc2)cc(Cl)c2C#N)[C@H]1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)=O Chemical compound CC(C)(C)OC(N(C[C@H](C1)Oc(cc2)cc(Cl)c2C#N)[C@H]1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)=O ZVZJABPYLNPQMI-QBLNDNOCSA-N 0.000 description 1
- UWYSRQHOWXXYMN-UHFFFAOYSA-N CC(C)(CN)NC Chemical compound CC(C)(CN)NC UWYSRQHOWXXYMN-UHFFFAOYSA-N 0.000 description 1
- XCEXBOISODMPOG-UHFFFAOYSA-N CC(C)c(nc1)ncc1O Chemical compound CC(C)c(nc1)ncc1O XCEXBOISODMPOG-UHFFFAOYSA-N 0.000 description 1
- YABMZAKYRYTCTF-UHFFFAOYSA-N CCc(cc1)cc(Cl)c1C#N Chemical compound CCc(cc1)cc(Cl)c1C#N YABMZAKYRYTCTF-UHFFFAOYSA-N 0.000 description 1
- XISZYIVRTSKCJC-GFCCVEGCSA-N CN(C/C(/C1)=[O]\c(cc2)cc(Cl)c2C#N)[C@H]1C(O)=O Chemical compound CN(C/C(/C1)=[O]\c(cc2)cc(Cl)c2C#N)[C@H]1C(O)=O XISZYIVRTSKCJC-GFCCVEGCSA-N 0.000 description 1
- JOPKTIVRIDNRRJ-NBZXRHOXSA-N CN(C[C@H](C1)Oc(cc2)cc(Cl)c2C#N)[C@H]1C(Nc(cc1)nnc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O Chemical compound CN(C[C@H](C1)Oc(cc2)cc(Cl)c2C#N)[C@H]1C(Nc(cc1)nnc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O JOPKTIVRIDNRRJ-NBZXRHOXSA-N 0.000 description 1
- CUATUBOHNBTTQN-UHFFFAOYSA-N COC(C(CC1)CCC1Oc1cc(Cl)c(C#N)nc1)=O Chemical compound COC(C(CC1)CCC1Oc1cc(Cl)c(C#N)nc1)=O CUATUBOHNBTTQN-UHFFFAOYSA-N 0.000 description 1
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N COC(C1CCCCC1)=O Chemical compound COC(C1CCCCC1)=O ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 1
- ZVTXGFDPDOWQQY-VOMCLLRMSA-N C[C@H](CC(OC(CC1)CCC1C(OC)=O)=C1)CC(Cl)=C1Cl Chemical compound C[C@H](CC(OC(CC1)CCC1C(OC)=O)=C1)CC(Cl)=C1Cl ZVTXGFDPDOWQQY-VOMCLLRMSA-N 0.000 description 1
- LMWSLQQMJDGODG-XAVGPACISA-N C[C@](CC1)(CC[C@H]1Oc(cc1)cc(Cl)c1C#N)C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O Chemical compound C[C@](CC1)(CC[C@H]1Oc(cc1)cc(Cl)c1C#N)C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O LMWSLQQMJDGODG-XAVGPACISA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- HAYDVQXZDFRRJW-UHFFFAOYSA-N Cc(cc(cc1)OC(CC2)CCC2C(O)=O)c1C#N Chemical compound Cc(cc(cc1)OC(CC2)CCC2C(O)=O)c1C#N HAYDVQXZDFRRJW-UHFFFAOYSA-N 0.000 description 1
- NDARWIGJNCQJOB-OLZOCXBDSA-N Cc(cc(cc1)O[C@H](C2)CN(C)[C@@H]2C(O)=O)c1C#N Chemical compound Cc(cc(cc1)O[C@H](C2)CN(C)[C@@H]2C(O)=O)c1C#N NDARWIGJNCQJOB-OLZOCXBDSA-N 0.000 description 1
- YBNWTXGPKZCPJR-UHFFFAOYSA-O Cc(cc1[IH][NH2+]C)ccc1N Chemical compound Cc(cc1[IH][NH2+]C)ccc1N YBNWTXGPKZCPJR-UHFFFAOYSA-O 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ATHOUARZXDYDFG-QYEGHZPBSA-N N#Cc(c(Br)c1)ccc1O[C@H](CC1)CC[C@@H]1C(Nc(cc1)nnc1N1CCC(CN(CC2)CCN2c2cc(C(N(C3)C(CCC(N4)=O)C4=O)=O)c3cc2)CC1)=O Chemical compound N#Cc(c(Br)c1)ccc1O[C@H](CC1)CC[C@@H]1C(Nc(cc1)nnc1N1CCC(CN(CC2)CCN2c2cc(C(N(C3)C(CCC(N4)=O)C4=O)=O)c3cc2)CC1)=O ATHOUARZXDYDFG-QYEGHZPBSA-N 0.000 description 1
- MRBUEFINMBCWAO-UHFFFAOYSA-N N#Cc(c(Cl)c1)ccc1OC(CC1)CCC1C(Nc(nnc(N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)c1)c1F)=O Chemical compound N#Cc(c(Cl)c1)ccc1OC(CC1)CCC1C(Nc(nnc(N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)c1)c1F)=O MRBUEFINMBCWAO-UHFFFAOYSA-N 0.000 description 1
- OLMFZASXNUUKDB-PFKKKLLYSA-N N#Cc(c(Cl)c1)ccc1O[C@@H](CC1)C[C@H]1C(Nc(cc1)ncc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O Chemical compound N#Cc(c(Cl)c1)ccc1O[C@@H](CC1)C[C@H]1C(Nc(cc1)ncc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O OLMFZASXNUUKDB-PFKKKLLYSA-N 0.000 description 1
- NRGLEJYPIWZORV-WPRPVWTQSA-N N#Cc(c(Cl)c1)ccc1O[C@@H](CC1)C[C@H]1C(O)=O Chemical compound N#Cc(c(Cl)c1)ccc1O[C@@H](CC1)C[C@H]1C(O)=O NRGLEJYPIWZORV-WPRPVWTQSA-N 0.000 description 1
- HQQUAEUHPMBRRX-AZEIKPONSA-N N#Cc(c(Cl)c1)ccc1O[C@H](CC1)C[C@@H]1C(Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O Chemical compound N#Cc(c(Cl)c1)ccc1O[C@H](CC1)C[C@@H]1C(Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O HQQUAEUHPMBRRX-AZEIKPONSA-N 0.000 description 1
- NJVUETQNEHQHKB-WAWPNIJLSA-N N#Cc(c(Cl)c1)ccc1O[C@H](CC1)C[C@@H]1C(Nc(cc1)cnc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O Chemical compound N#Cc(c(Cl)c1)ccc1O[C@H](CC1)C[C@@H]1C(Nc(cc1)cnc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O NJVUETQNEHQHKB-WAWPNIJLSA-N 0.000 description 1
- NTVMLCXWDNQYFX-UHFFFAOYSA-N N#Cc(ccc(CN(CC1)CCC1C(Nc(cc1)nnc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl Chemical compound N#Cc(ccc(CN(CC1)CCC1C(Nc(cc1)nnc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl NTVMLCXWDNQYFX-UHFFFAOYSA-N 0.000 description 1
- MNNDREXLRLDWEY-UHFFFAOYSA-N N#Cc(ccc(F)c1)c1Br Chemical compound N#Cc(ccc(F)c1)c1Br MNNDREXLRLDWEY-UHFFFAOYSA-N 0.000 description 1
- MJXMSFCRAVOCEB-UHFFFAOYSA-N N#Cc(ccc(NC(CC1)CCC1C(O)=O)c1)c1Cl Chemical compound N#Cc(ccc(NC(CC1)CCC1C(O)=O)c1)c1Cl MJXMSFCRAVOCEB-UHFFFAOYSA-N 0.000 description 1
- CZXZMFVMKWZMGG-UHFFFAOYSA-N N#Cc(ccc(OC(C1)CC1C(O)=O)c1)c1Cl Chemical compound N#Cc(ccc(OC(C1)CC1C(O)=O)c1)c1Cl CZXZMFVMKWZMGG-UHFFFAOYSA-N 0.000 description 1
- NRGLEJYPIWZORV-UHFFFAOYSA-N N#Cc(ccc(OC(CC1)CC1C(O)=O)c1)c1Cl Chemical compound N#Cc(ccc(OC(CC1)CC1C(O)=O)c1)c1Cl NRGLEJYPIWZORV-UHFFFAOYSA-N 0.000 description 1
- AYKPYGIVOJJRQP-UHFFFAOYSA-N N#Cc(ccc(OC(CC1)CCC1C(Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl Chemical compound N#Cc(ccc(OC(CC1)CCC1C(Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl AYKPYGIVOJJRQP-UHFFFAOYSA-N 0.000 description 1
- KUFXKQJQABIOAH-UHFFFAOYSA-N N#Cc(ccc(OC(CC1)CCC1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)c1)c1Cl Chemical compound N#Cc(ccc(OC(CC1)CCC1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)c1)c1Cl KUFXKQJQABIOAH-UHFFFAOYSA-N 0.000 description 1
- NLBNMPNZXMHVJP-GXSJLCMTSA-N N#Cc(ccc(O[C@@H](C1)CN[C@H]1C(O)=O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@@H](C1)CN[C@H]1C(O)=O)c1)c1Cl NLBNMPNZXMHVJP-GXSJLCMTSA-N 0.000 description 1
- SQZNQGNISWFTOA-AQELMELHSA-N N#Cc(ccc(O[C@@H](CC1)CC1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@@H](CC1)CC1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)c1)c1Cl SQZNQGNISWFTOA-AQELMELHSA-N 0.000 description 1
- PYZRNSKSJKAFQH-SCZZXKLOSA-N N#Cc(ccc(O[C@@H](CC1)C[C@@H]1C(O)O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@@H](CC1)C[C@@H]1C(O)O)c1)c1Cl PYZRNSKSJKAFQH-SCZZXKLOSA-N 0.000 description 1
- HQQUAEUHPMBRRX-YXBGZAQISA-N N#Cc(ccc(O[C@@H](CC1)C[C@H]1C(Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@@H](CC1)C[C@H]1C(Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl HQQUAEUHPMBRRX-YXBGZAQISA-N 0.000 description 1
- SQZNQGNISWFTOA-AWTAWZDRSA-N N#Cc(ccc(O[C@@H](CC1)C[C@H]1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@@H](CC1)C[C@H]1C(Nc1ccc(N2CCC(CN(CC3)CCN3c(cc3)cc(C(N4C(CCC(N5)=O)C5=O)=O)c3C4=O)CC2)nn1)=O)c1)c1Cl SQZNQGNISWFTOA-AWTAWZDRSA-N 0.000 description 1
- OLMFZASXNUUKDB-MNUNMECRSA-N N#Cc(ccc(O[C@H](CC1)CC1C(Nc(cc1)ncc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@H](CC1)CC1C(Nc(cc1)ncc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl OLMFZASXNUUKDB-MNUNMECRSA-N 0.000 description 1
- NFJQJRLICKWNMS-HOMQSWHASA-N N#Cc(ccc(O[C@H](CC1)CC[C@@H]1C(O)=O)c1)c1Br Chemical compound N#Cc(ccc(O[C@H](CC1)CC[C@@H]1C(O)=O)c1)c1Br NFJQJRLICKWNMS-HOMQSWHASA-N 0.000 description 1
- OLMFZASXNUUKDB-WAWPNIJLSA-N N#Cc(ccc(O[C@H](CC1)C[C@@H]1C(Nc(nc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl Chemical compound N#Cc(ccc(O[C@H](CC1)C[C@@H]1C(Nc(nc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O)c1)c1Cl OLMFZASXNUUKDB-WAWPNIJLSA-N 0.000 description 1
- VJKODYJBVLRAIV-BRFYHDHCSA-N N#Cc(ncc(O[C@H](CC1)CC1C(O)=O)c1)c1Cl Chemical compound N#Cc(ncc(O[C@H](CC1)CC1C(O)=O)c1)c1Cl VJKODYJBVLRAIV-BRFYHDHCSA-N 0.000 description 1
- JZZYDIVJSQPPAL-UHFFFAOYSA-N N#Cc1cc(CN(CC2)CCC2C(O)=O)ccc1Cl Chemical compound N#Cc1cc(CN(CC2)CCC2C(O)=O)ccc1Cl JZZYDIVJSQPPAL-UHFFFAOYSA-N 0.000 description 1
- SQGXVRINWRNIBI-UHFFFAOYSA-N N#Cc1cc(NC(CC2)CCC2C(O)=O)ccc1Cl Chemical compound N#Cc1cc(NC(CC2)CCC2C(O)=O)ccc1Cl SQGXVRINWRNIBI-UHFFFAOYSA-N 0.000 description 1
- SQGXVRINWRNIBI-HOMQSWHASA-N N#Cc1cc(N[C@H](CC2)CC[C@@H]2C(O)=O)ccc1Cl Chemical compound N#Cc1cc(N[C@H](CC2)CC[C@@H]2C(O)=O)ccc1Cl SQGXVRINWRNIBI-HOMQSWHASA-N 0.000 description 1
- ZGRYQDZRNCXPBG-UHFFFAOYSA-N N#Cc1cc(OC2CCNCC2)ccc1Cl Chemical compound N#Cc1cc(OC2CCNCC2)ccc1Cl ZGRYQDZRNCXPBG-UHFFFAOYSA-N 0.000 description 1
- ACTKJLMBZUAXJY-UHFFFAOYSA-N Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1 Chemical compound Nc(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1 ACTKJLMBZUAXJY-UHFFFAOYSA-N 0.000 description 1
- 101100016034 Nicotiana tabacum APIC gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- HCFRWBBJISAZNK-IZLXSQMJSA-N O[C@H](CC1)CC[C@@H]1C(O)=O Chemical compound O[C@H](CC1)CC[C@@H]1C(O)=O HCFRWBBJISAZNK-IZLXSQMJSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 108010068086 Polyubiquitin Proteins 0.000 description 1
- 102100037935 Polyubiquitin-C Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 102000003431 Ubiquitin-Conjugating Enzyme Human genes 0.000 description 1
- 108060008747 Ubiquitin-Conjugating Enzyme Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DMCXZVRRTPCCRY-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N(CC1)CCC1C=O)=O Chemical compound [O-][N+](c(cc1)ccc1N(CC1)CCC1C=O)=O DMCXZVRRTPCCRY-UHFFFAOYSA-N 0.000 description 1
- GPMLQLDSXMIGPM-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O Chemical compound [O-][N+](c(cc1)ccc1N1CCC(CN(CC2)CCN2c(cc2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)CC1)=O GPMLQLDSXMIGPM-UHFFFAOYSA-N 0.000 description 1
- DJKPUSPBJFCEMA-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N1CCC(CO)CC1)=O Chemical compound [O-][N+](c(cc1)ccc1N1CCC(CO)CC1)=O DJKPUSPBJFCEMA-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 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
- 231100000517 death Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000001064 degrader Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 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
- 150000002500 ions Chemical class 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- XVJANIDHZGJFDQ-UHFFFAOYSA-N methyl 3-hydroxy-1-methylcyclopentane-1-carboxylate Chemical compound COC(=O)C1(C)CCC(O)C1 XVJANIDHZGJFDQ-UHFFFAOYSA-N 0.000 description 1
- FFKGMXGWLOPOAO-UHFFFAOYSA-N methyl 4-aminocyclohexane-1-carboxylate Chemical compound COC(=O)C1CCC(N)CC1 FFKGMXGWLOPOAO-UHFFFAOYSA-N 0.000 description 1
- HYDYVXROZHFTGB-UHFFFAOYSA-N methyl 4-hydroxycyclohexane-1-carboxylate Chemical compound COC(=O)C1CCC(O)CC1 HYDYVXROZHFTGB-UHFFFAOYSA-N 0.000 description 1
- RZVWBASHHLFBJF-UHFFFAOYSA-N methyl piperidine-4-carboxylate Chemical compound COC(=O)C1CCNCC1 RZVWBASHHLFBJF-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- TUNTZYBQGGWPOO-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate methanol Chemical compound C(=O)(OC(C)(C)C)N1CCCCC1.CO TUNTZYBQGGWPOO-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 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
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a heterocyclic compound, its preparation method, intermediate and application.
- Prostate cancer is a common male malignant tumor, and its incidence worldwide is second only to lung cancer, ranking second in all male malignant tumors.
- the incidence of prostate cancer in China is increasing year by year, and it is expected that by 2020, prostate cancer will become the third leading cause of cancer deaths among men in my country.
- androgen deprivation therapy (ADT) is the main treatment for early-stage prostate cancer, including surgical castration and medical castration.
- ADT cannot cure prostate cancer.
- CRPC castration-resistant prostate cancer
- the proliferation or mutation of the androgen receptor (AR) can make it sensitive to lower levels of androgens in serum, which is the main reason for the deterioration of prostate cancer.
- the representative drugs of androgen receptor inhibitors for the treatment of CRPC include abiraterone, enzalutamide, etc.
- 15-25% of patients do not respond to second-generation hormonal therapy such as abiraterone and enzalutamide, and most patients who do respond eventually develop severe drug resistance, leading to poor prognosis.
- UPS The ubiquitin-proteasome system
- UPS The ubiquitin-proteasome system
- Ub The ubiquitin-proteasome system
- E1 ubiquitin
- E2 ubiquitin-conjugating enzyme
- E3 ubiquitin-protein ligase
- 26S proteasome The ubiquitin-activating enzyme system is responsible for activating ubiquitin and binding it to the protein to be degraded to form a polyubiquitin chain of the target protein, that is, ubiquitination.
- the proteasome system recognizes and degrades ubiquitinated proteins.
- Protein proteolysis-targeting chimeras is a hybrid bifunctional small molecule compound, including a small molecule compound that can bind to the target protein, linking groups at its appropriate position, and then Linked with a small molecule compound capable of binding to E3 ubiquitin ligase.
- PROTACs form a target protein-PROTACs-E3 ternary polymer by bringing the target protein and intracellular E3 closer, and add ubiquitinated protein tag to the target protein through E3 ubiquitin ligase, and utilize ubiquitin-proteasome.
- the ubiquitin-proteasome system specifically degrades target proteins.
- Arvinus disclosed a class of degraders targeting androgen receptors (US 2018/0099940 A1), the representative drug ARV-110, which is currently in clinical phase I for the treatment of CRPC. Phase I data also demonstrated that ARV-110 was safe and effective in patients with metastatic castration-resistant prostate cancer (mCRPC).
- mCRPC metastatic castration-resistant prostate cancer
- the technical problem to be solved by the present invention is to provide a heterocyclic compound, its preparation method, intermediate and application in order to overcome the defect of few types of degradation agents targeting androgen receptor in the prior art.
- the heterocyclic compounds of the present invention have better inhibitory activity on AR-dependent LNCap cells, which can be used for the treatment of prostate cancer.
- the present invention mainly solves the above technical problems through the following technical solutions.
- the present invention provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its prodrug,
- R 2 is hydrogen or
- D is O, NR 6-1 or CR 6-2 R 6-3 ;
- Ring W is a C 6 -C 10 aromatic ring, a C 6 -C 10 aromatic ring substituted by one or more R 8-1 (when there are multiple R 8-1 , R 8-1 is the same or different), 5- 10-membered heteroaromatic ring, or 5-10-membered heteroaromatic ring substituted by one or more R 8-2 (when R 8-2 is more than one, R 8-2 is the same or different); the 5-10
- the heteroatom in the membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5
- the heteroatoms in the 5-10-membered heteroaromatic ring described in the -10-membered heteroaromatic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;
- Ring Z is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
- Ring Y is C 3 -C 10 alicyclic, C 3 -C 10 alicyclic substituted by one or more R 9-1 , 3-10 membered heteroalicyclic, or 3- alicyclic substituted by one or more R 9-2 10-membered heteroalicyclic ring; the heteroatoms in the 3-10-membered heteroalicyclic ring are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3; the described The heteroatoms in the 3-10-membered heteroalicyclic ring in the 3-10-membered heteroalicyclic ring substituted by one or more R 9-2 are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3;
- R 1-1 and R 1-2 are independently hydrogen or C 1 -C 4 alkyl
- R 2-1 is C 1 -C 4 alkyl
- R 6-1 is hydrogen or C 1 -C 4 alkyl
- R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 11-1 and R 11-2 are independently hydrogen, halogen or C 1 -C 4 alkyl;
- R 8-1 and R 8-2 are independently halogen or C 1 -C 4 alkyl
- R 9-1 and R 9-2 are independently halogen, hydroxy or C 1 -C 4 alkyl.
- the halogen eg R 1 , C 1 -C 4 alkyl substituted by one or more halogens, R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R 9-2 , R 11-1 , R 11-2 etc. halogen
- R 1 , C 1 -C 4 alkyl substituted by one or more halogens, R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R 9-2 , R 11-1 , R 11-2 etc. halogen independently is fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine.
- the C 1 -C 4 alkyl (R 1 , one or more halogen-substituted C 1 -C 4 alkyl, R 1-1 , R 1-2 , R 2-1 , R 6-2 , R 6-3 , R 7-1 , R 7-2 , R 8-1 , R 8-2 , R 9-1 , R C 1 -C 4 alkyl in 9-2 , R 11-1 , R 11-2 , etc.) is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, eg methyl.
- the C 1 -C 4 alkoxy group (eg R 1 , one or more halogen-substituted C 1 -C 4 alkoxy groups C 1 -C 4 alkoxy in radicals etc.) is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert- Butoxy.
- the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, preferably a benzene ring.
- the C 6 -C 10 aryl group is a benzene ring or a naphthalene ring, such as benzene ring.
- the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring And the heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2.
- the 5-6 membered heteroaromatic ring is preferably a pyridazine ring, a pyridine ring, a pyrimidine ring or a pyrazine ring.
- the pyridazine ring is preferably The pyridine ring is preferably The pyrimidine ring is preferably Described pyrazine ring is preferably
- the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring;
- the heteroatom in the 5-10-membered heteroaromatic ring and the 5-6-membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1 or 2.
- the 5-6 membered heteroaromatic ring is preferably a pyridazine ring or a pyridine ring.
- the pyridazine ring is preferably The pyridine ring is preferably
- the number of the R 8-2 is one.
- the C 6 -C 10 aromatic ring is a benzene ring or a naphthalene ring, such as a benzene ring.
- the 5-10-membered heteroaromatic ring is a 5-6-membered heteroaromatic ring; the 5-10-membered heteroaromatic ring and the heteroatom in the 5-6 membered heteroaromatic ring is preferably N, and the number of heteroatoms is preferably 1.
- Described 5-10 yuan heteroaromatic ring is preferably pyridine ring, more preferably
- the C 3 -C 10 alicyclic ring is a C 4 -C 7 alicyclic ring, preferably a butane ring, a pentane ring, a hexyl ring , heptyl or spiro[3,3]heptyl.
- the C 3 -C 10 alicyclic ring may be a single ring or a spiro ring, such as a single ring.
- the C 4 -C 10 alicyclic is a C 4 -C 6 alicyclic, Preferably it is butane, pentane or hexyl.
- the C 3 -C 10 alicyclic ring in the one or more R 9-1 substituted C 3 -C 10 alicyclic rings may be monocyclic or spirocyclic, such as monocyclic.
- the number of the R 9-1 is 1, 2 or 4.
- the 3-10 membered heteroalicyclic ring is a 5-6 membered heteroalicyclic ring; the 3-10 membered heteroalicyclic ring and the heteroatom in the 5-6 membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1.
- the 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring. Described tetrahydropyrrole ring is preferably Described piperidine ring is preferably The 3-10 membered heteroalicyclic ring may be a single ring or a spiro ring.
- the 3-10-membered heteroalicyclic ring is a 5-6-membered heteroalicyclic ring;
- the heteroatom in the 3-10-membered heteroalicyclic ring and the 5-6-membered heteroalicyclic ring is preferably N, and the number of heteroatoms is preferably 1.
- the 3-10-membered heteroalicyclic ring is preferably a tetrahydropyrrole ring or a piperidine ring.
- Described tetrahydropyrrole ring is preferably Described piperidine ring is preferably
- the 3-10-membered heteroalicyclic ring in the one or more R 9-2 substituted 3-10-membered heteroalicyclic rings can be a monocyclic ring or a spirocyclic ring.
- the number of the R 9-2 is one.
- R 3-1 and R 3-2 are independently hydrogen, halogen, hydroxy or C 1-4 alkyl
- A is N or CR 4-1 ;
- B is N or CR 4-2 ;
- C is N or CR 4-3 ;
- E is N or CR 4-4 ;
- F is N or CR 4-5 ;
- G is independently NR 5-1 or CR 5-2 R 5-3 ;
- L is independently NR 10-1 or CR 10-2 R 10-3 ;
- R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 5-2 , R 5-3 , R 10-2 , R 10-3 are independently hydrogen, halogen or C 1 -C 4 alkyl;
- R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl
- n and n are independently 0, 1, 2 or 3;
- n1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
- the halogen eg R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 4-1 , 5-2 , R 5-3 , R 10-2 , R 10-3 , etc. halogen
- R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R 4-1 , 5-2 , R 5-3 , R 10-2 , R 10-3 , etc. halogen are independently fluorine, chlorine, bromine or iodine.
- the C 1 -C 4 alkyl group (R 3-1 , R 3-2 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-1 C 1 -C 4 alkyl in 4-5 , R 5-1 , R 5-2 , R 5-3 , R 10-2 , R 10-3 , etc.) is independently methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
- R 1 is halogen or one or more halogen substituted C 1 -C 4 alkyl, eg halogen.
- R2 is hydrogen .
- R 3-1 and R 3-2 are independently hydrogen, hydroxy or C 1-4 alkyl.
- B is CR 4-2 .
- C is CR 4-3 .
- ring W is a C6 - C10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 5-10 membered heteroaromatic ring substituted with one or more R8-2 , such as C6 -C 10 aromatic rings.
- R 4-1 is hydrogen
- R 4-2 is hydrogen
- R 4-3 is hydrogen
- R 4-4 is hydrogen
- R 5-2 and R 5-3 are hydrogen.
- R 6-1 is hydrogen
- R 6-2 and R 6-3 are hydrogen.
- R 7-1 and R 7-2 are hydrogen.
- R 8-2 is independently halogen.
- R 9-2 is independently C 1 -C 4 alkyl.
- R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl.
- R 11-1 and R 11-2 are hydrogen.
- m is 0, 1 or 2.
- n 0, 1 or 2.
- the one or more halogen-substituted C 1 -C 4 alkyl groups are trifluoromethyl groups.
- D is O or NH, eg O.
- R2 is hydrogen .
- ring W is
- n1, m2, n1 and n2 are one.
- R 1 is halogen or C 1 -C 4 alkyl substituted with one or more halogens
- R 2 is hydrogen
- R 3-1 and R 3-2 are independently hydrogen, hydroxyl or C 1-4 alkyl
- A is N or CH
- B is CH
- D is O, NH or CH 2 ;
- E is N or CH
- F is N or CR 4-5 ;
- G is independently NR 5-1 or CH 2 ;
- L is independently NR 10-1 or CR 10-2 R 10-3 ;
- Ring W is a C 6 -C 10 aromatic ring, a 5-10-membered heteroaromatic ring, or a 5-10-membered heteroaromatic ring substituted by one or more R 8-2 ;
- the atom is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 8-2 substituted 5-10-membered heteroaromatic rings
- the heteroatom in the 5-10-membered heteroaromatic ring described in is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;
- R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
- R 8-2 is independently halogen
- R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl
- R 10-2 and R 10-3 are independently hydrogen or C 1 -C 4 alkyl
- n and n are independently 0, 1, 2, or 3;
- n1, m2, n1, and n2 are independently 0, 1, 2, or 3, and m1 and n1 are not both 0, and m2 and n2 are not both 0.
- R 1 is halogen
- R 2 is hydrogen
- R 3-1 and R 3-2 are independently hydrogen
- A is N or CH
- B is CH
- D is O, NH or CH 2 ;
- E is N or CH
- F is N or CR 4-5 ;
- G is independently NR 5-1 or CH 2 ;
- L is independently NR 10-1 or CH 2 ;
- Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
- R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
- R 5-1 and R 10-1 are independently hydrogen or C 1 -C 4 alkyl
- n 0 or 1
- n 1 or 2.
- R 1 is halogen
- R 2 is hydrogen
- R 3-1 and R 3-2 are independently hydrogen
- A is N or CH
- B is CH
- D is O, NH or CH 2 ;
- E is CH
- F is N or CR 4-5 ;
- G is independently NR 5-1 or CH 2 ;
- L is independently NR 10-1 or CH 2 ;
- Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
- R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
- R 5-1 and R 10-1 are independently C 1 -C 4 alkyl
- n 0 or 1
- n 1 or 2.
- R 1 is chlorine
- R 2 is hydrogen
- R 3-1 and R 3-2 are independently hydrogen
- A is CH
- B is CH
- E is CH
- G is independently CH 2 ;
- L is independently CH 2 ;
- Ring W is a C 6 -C 10 aromatic ring or a 5-10-membered heteroaromatic ring; the heteroatom in the 5-10-membered heteroaromatic ring is selected from one or more of nitrogen, oxygen and sulfur, and the heteroatom of the heteroatom is The number is 1, 2, 3 or 4;
- R 4-5 is hydrogen, halogen or C 1 -C 4 alkyl
- R 5-1 and R 10-1 are independently C 1 -C 4 alkyl
- n 0 or 1
- n 2;
- the compound shown in formula I is the compound shown in formula Ia or Ib:
- D is O or NH
- D is attached to a carbon atom on ring Y, The a terminal in the middle is connected to the carbon atom on the ring Y;
- Ring Z, ring Y, ring W, K, M, N, R 1 and R 2 are as defined above;
- (straight dashed key) and (Straight solid line bond) represents that the connecting group connected to it is located on both sides of the plane of the ring Y; in formula Ib, (straight dashed key) and (Straight dashed bond) indicates that the link to which it is attached is on the same side of the Y plane of the ring.
- the compound shown in formula I is the compound shown in formula Ic:
- ring Y is pentane ring or hexyl ring; ring Z, K, M, R 1 and R 2 are as defined above;
- R 1 is halogen (eg fluorine, chlorine or bromine);
- R 2 is H
- the compound shown in the formula I is the compound shown in the formula Id:
- R 1 is halogen (eg chlorine);
- R 2 is H
- Ring Z is a C 6 -C 10 aromatic ring (eg, a benzene ring);
- the compound shown in formula I is any of the following compounds:
- the compound shown in formula I is any of the following compounds,
- the present invention also provides a method for preparing the compound shown in the formula I, which is any of the following methods:
- the first method includes the following steps: in a solvent, under the action of a base and a condensing agent, the compound shown in formula IV and the compound shown in formula V are subjected to the condensation reaction shown below,
- the second method comprises the following steps: in a solvent, the compound shown in formula VI is subjected to the deprotection reaction shown below under the action of an acid,
- the third method includes the following steps: in a solvent, the compound shown in formula VII and the compound shown in formula VIII are subjected to the addition reaction shown below,
- the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an amide solvent, more preferably N,N-dimethylformamide.
- the molar concentration of the compound shown in formula IV in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.0001-0.1 mol/L, More preferably, it is 0.004 to 0.01 mol/L (for example, 0.008 mol/L).
- the base can be a conventional base for this type of reaction in the art, preferably an organic amine, more preferably N,N-diisopropylethylamine.
- the molar ratio of the base to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction.
- the molar ratio is particularly preferably 0.8:1 to 3:1, more preferably 0.9:1 to 1.3:1 (eg 1:1).
- the described condensing agent can be a conventional condensing agent for this type of reaction in the field, and the present invention is particularly preferably 2-(7-azabenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate.
- the molar ratio of the condensing agent to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction, which is particularly preferably 1:1 to 3:1 in the present invention, and further It is preferably 1:1 to 1.5:1 (for example, 1.2:1).
- the molar ratio of the compound represented by the formula V to the compound represented by the formula IV can be the conventional molar ratio of this type of reaction, and the present invention is particularly preferably 0.8:1 ⁇ 3:1, more preferably 0.9:1 to 1.3:1 (for example, 1:1).
- the reaction temperature of the condensation reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
- the reaction progress can be monitored by conventional monitoring methods (such as TLC, HPLC or NMR) in the art, generally to monitor the compound shown in the formula V or the compound shown in the formula IV.
- the disappearance of the indicated compound is the end point of the reaction.
- the reaction time of the condensation reaction is preferably 1 to 3 hours (for example, 2 hours).
- a post-processing step may be further included.
- the post-processing steps may include concentration and purification.
- the purification method can be preparative TLC.
- the eluent used in the preparation of TLC can be dichloromethane and methanol (the volume ratio is preferably 15:1).
- the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an ether solvent, more preferably dioxane.
- the molar concentration of the compound represented by formula VI in the solvent can be the conventional molar concentration of this type of reaction in the field, and the present invention is particularly preferably 0.0001-0.1 mol/L , more preferably 0.002 to 0.004 mol/L (for example, 0.0028 mol/L).
- the acid can be a conventional acid for this type of reaction in the art, preferably an inorganic acid, more preferably hydrochloric acid.
- the reaction temperature of the deprotection reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
- the progress of the reaction can be monitored by conventional monitoring methods in the art (eg TLC, HPLC or NMR), and the end point of the reaction is generally to monitor the disappearance of the compound represented by formula VI.
- the reaction time of the deprotection reaction is preferably 1 to 3 hours (for example, 2 hours).
- a post-processing step may be further included.
- the post-processing steps may include concentration.
- the solvent can be a conventional solvent for this type of reaction in the field, and the present invention is particularly preferably an amide solvent, more preferably N,N-dimethylformamide.
- the molar ratio of the compound represented by the formula VII to the compound represented by the formula VIII can be the conventional molar ratio of this type of reaction, and the present invention is particularly preferably 0.8:1 -3:1, more preferably 0.9:1 - 1.3:1 (for example, 1:1).
- the reaction temperature of the addition reaction can be the conventional reaction temperature of this type of reaction in the art, and is particularly preferably room temperature in the present invention.
- reaction progress can be monitored by conventional monitoring methods (such as TLC, HPLC or NMR) in the art, generally to monitor the compound shown in the formula VII or the compound shown in the formula VII.
- the disappearance of the compound represented by VIII was the end point of the reaction.
- the reaction time of the addition reaction is preferably 1 to 3 hours (for example, 2 hours).
- a post-processing step may be further included.
- the post-processing steps may include concentration and purification.
- the present invention also provides a compound of formula IV or a stereoisomer thereof,
- the compound shown in formula IV is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the stereoisomer of the compound represented by formula IV is
- the present invention also provides a compound of formula VI or a stereoisomer thereof,
- the compound shown in formula VI is the compound shown in formula VI-a or VI-b:
- Ring Z, ring Y', D, K, M, ring W, R 1 and R 2 are as defined above;
- (straight dashed key) and (Straight solid line bond) represents that the connecting group connected to it is located on both sides of the Y plane of the ring; in formula VI-b, (straight dashed key) and (Straight dashed bond) indicates that the link to which it is attached is on the same side of the Y plane of the ring.
- the compound represented by the formula VI is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the stereoisomer of the compound represented by formula VI is
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, Its metabolites or prodrugs thereof, and pharmaceutically acceptable excipients.
- the present invention also provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its precursor
- the invention relates to the application of the medicine, or the pharmaceutical composition, in the preparation of an androgen receptor degrading agent.
- the present invention also provides a compound shown in formula I, its stereoisomer, its tautomer, its solvate, its pharmaceutically acceptable salt, its metabolite or its precursor
- the invention relates to the application of the medicine, or the pharmaceutical composition, in the preparation of a medicine for treating androgen receptor-related diseases.
- the androgen receptor-related disease is prostate cancer, preferably metastatic castration-resistant prostate cancer.
- linking substituents are described.
- the Markush variables listed for that group should be understood to be the linking group.
- the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
- the aryl group represents the linking arylene group.
- plural refers to 2, 3, 4, 5 or 6.
- substituents or hetero atoms may be the same or different.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound of the present invention with a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- stereoisomers includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomer and (L)-isomer.
- tautomer refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert.
- a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
- proton tautomers also referred to as proton tautomers
- proton tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization.
- keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
- Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
- the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
- alicyclic refers to a saturated cyclic structure consisting of carbon atoms.
- heteroalicyclic refers to a saturated cyclic structure composed of carbon atoms and heteroatoms, wherein the heteroatoms are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2 or 3 .
- the room temperature in the present invention is 10-30°C.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive improvement effect of the present invention is that the heterocyclic compound of the present invention has better inhibitory activity on AR-dependent LNCap cells, and has less toxicity to AR-independent PC-3 cells.
- Step 1 Dissolve 5-fluorobenzofuran-1,3-dione (5.0 g, 30.1 mmol, 1 eq) in acetic acid (50 mL), add 3-aminopiperazine-2,6-dione (4.2 g, 33.1 mmol, 1.1 eq) and potassium acetate (5.9 g, 60.2 mmol, 2 eq) and the resulting mixture was stirred at 90°C overnight. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, water (50 mL) was added, a solid was precipitated, suction filtered, the filter cake was washed with water, and dried to obtain 8.05 g of a gray solid.
- Step 2 Dissolve the product obtained in Step 1 (3.0g, 10.9mmol, 1eq) in DMSO (50mL), add N-Boc piperazine (3.0g, 16.3mmol, 1.5eq) and DIEA (2.8g, 21.7mmole) respectively , 2eq), and the resulting mixture was stirred at 130°C for 3h. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, water (50 mL) was added, a solid was precipitated, suction filtration, the filter cake was washed with water, and dried to obtain a yellow solid 3.63g. ESI MS m/z 343[M+H] + .
- Step 4 Dissolve the product obtained in Step 3 (2g, 28.8mmol, 1eq) in tert-butanol (50mL), add Boc anhydride (7.6g, 34.6mmol, 1.2eq), triethylamine (4.4g, 43.2mmol) respectively , 1.2 eq) and DMAP (352 mg, 2.9 mmol, 0.1 eq), and the resulting mixture was stirred at room temperature overnight.
- Boc anhydride 7.6g, 34.6mmol, 1.2eq
- triethylamine 4.4g, 43.2mmol
- DMAP 352 mg, 2.9 mmol, 0.1 eq
- Step 6 Dissolve the product obtained in step 5 (265 mg, 0.77 mmol, 1 eq) in dichloromethane (20 mL), add the product obtained in step 2 (237 mg, 0.77 mmol, 1 eq), stir at room temperature for half an hour, add acetic acid borohydride Sodium (328 mg, 1.55 mmol, 2 eq) and the resulting mixture was stirred at room temperature for 3.5 h.
- Step 8 The trans product (100 mg, 0.34 mmol, 1 eq) obtained in Step 7 was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
- Step 7 of Example 1 respectively obtain a trans-intermediate with a large Rf value and a cis-type intermediate with a small Rf value, and the trans-intermediate according to the synthetic method of Example 1, finally obtain a yellow solid product 3a 11mg .
- Example 3 The cis intermediate in Example 3 was obtained according to the synthetic method of Example 1 to obtain 12 mg of yellow solid product 3b. ESI MS m/z 780[M+H] + .
- Step 1 Dissolve 2-chloro-5-fluorobenzonitrile (500mg, 3.21mmol, 1eq) and methyl trans-4-aminocyclohexanecarboxylate (505mg, 3.21mmol, 1eq) in dioxane (20mL) ), triethylamine (650 mg, 6.43 mmol, 2 eq) was added, and the mixture was stirred at 120°C overnight. After the reaction was detected by TLC, dioxane was removed under reduced pressure, the residue was dissolved in methanol (20 mL), 10% aqueous NaOH solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
- Step 1 Dissolve 2-chloro-5-bromomethylbenzonitrile (500mg, 2.17mmol, 1eq), methyl piperidine-4-carboxylate (372mg, 2.6mmol, 1.2eq) in anhydrous acetonitrile (20mL) To the solution, potassium carbonate (450 mg, 3.25 mmol, 1.5 eq) was added, followed by stirring at room temperature. After the reaction was detected by TLC, acetonitrile was removed under reduced pressure, the residue was dissolved in methanol (20 mL), 10% aqueous NaOH solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
- Step 2 The product obtained in step 1 (100 mg, 0.26 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
- Step 4 Dissolve the product obtained in Step 3 (15 mg, 0.017 mmol, 1 eq) in dioxane (5 mL), slowly drop HCl in dioxane solution (4 M, 1 mL), and stir at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed under reduced pressure to obtain 16 mg of yellow solid product 6.
- Step 1 The product obtained in Step 1 of Example 7 (100 mg, 0.26 mmol, 1 eq) was dissolved in dioxane (10 mL), slowly added dropwise to a solution of HCl in dioxane (5 mL), and stirred at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed under reduced pressure to obtain 73 mg of yellow solid product. ESI MS m/z 281[M+H] + .
- Step 2 The product obtained in step 1 (73mg, 0.26mmol, 1eq) was dissolved in anhydrous acetonitrile (20mL), potassium carbonate (72mg, 0.52mmol, 2eq) and methyl iodide (44mg, 0.31mmol, 1.2eq) were added respectively. Then, stir at room temperature. After the reaction was detected by TLC, acetonitrile was removed under reduced pressure, diluted with ethyl acetate (50 mL), washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to obtain 65 mg of the product. ESI MS m/z 295[M+H] + .
- Step 3 The product obtained in Step 2 (65 mg, 0.22 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
- Example 9 14 mg of yellow solid product 9 was obtained according to the synthetic method of Example 8. ESI MS m/z 780[M+H] + .
- Step 1 Dissolve N-Boc piperidine methanol (776mg, 3.86mmol, 1.2eq) in anhydrous THF, add sodium hydrogen (193mg, 4.82mmol, 60%, 1.5eq) at 0°C, stir under nitrogen for 30min After that, 2-chloro-5-fluorobenzonitrile (500 mg, 3.21 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 4 h.
- Step 1 Mix 5,6-dichloropyridin-3-ol (500mg, 3.05mmol, 1eq), methyl(1R,3R)-3-ethanesulfonyloxy)cyclopentane-1-carboxylate (792mg , 3.35mmol, 1.1eq) was dissolved in DMF (20mL), potassium carbonate (506mg, 3.66mmol, 1.2eq) was added, and stirred at 90°C.
- Step 2 Dissolve the product obtained in step 1 (50mg, 0.17mmol, 1eq) in anhydrous DMF (10mL), add zinc cyanide (12mg, 0.10mmol, 0.6eq) and tetrakistriphenylphosphine palladium (20mg, 0.02 mmol, 0.1 eq), stirred at 120 °C for 2 h under nitrogen.
- Step 3 The product obtained in Step 2 (25 mg, 0.086 mmol, 1 eq) was dissolved in methanol (5 mL), 10% aqueous NaOH solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h.
- Step 1 Dissolve 4-fluoronitrobenzene (500mg, 3.54mmol, 1eq), piperidine-4-methanol (490mg, 4.25mmol, 1.2eq) in dioxane (20mL), add DIEA (696uL, 4.25 mmol, 1.2 eq) and stirred at 120°C overnight. After the reaction was detected by TLC, water (50 mL) was added to dilute, and ethyl acetate (50 mL) was used for extraction. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 250 mg of product by column chromatography. ESI MS m/z 237[M+H] + .
- Step 3 Dissolve the product obtained in Step 2 (180 mg, 0.77 mmol, 1 eq) in dichloromethane (20 mL), add the product of Step 2 in Example 1 (237 mg, 0.77 mmol, 1 eq), and stir at room temperature for half an hour, Sodium borohydride acetate (328 mg, 1.55 mmol, 2 eq) was added and the resulting mixture was stirred at room temperature for 3.5 h.
- Step 4 Dissolve the product obtained in Step 3 (160mg, 0.29mmol, 1eq) in a mixed solvent of methanol and saturated ammonium chloride solution (1:1, 20mL), add iron powder (80mg, 1.43mmol, 1eq), After stirring at 80 degrees for half an hour, dichloromethane (50 mL) was added for extraction, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to obtain 152 mg of crude product.
- ESI MS m/z 531[M+H] + .
- Example 18 Prepared with Example 18 As starting material, following the procedure of Example 17, 10 mg of yellow solid 18 was obtained, ESI MS m/z 779 [M+H] + .
- Example 14 Using methyl 1-methyl-3-hydroxycyclopentanecarboxylate as a raw material, according to the operation of Example 14, a trans intermediate with a large Rf value and a cis intermediate with a small Rf value were obtained, and the trans intermediate was carried out. In the next step, 10 mg of trans product 19 was finally obtained, ESI MS m/z 794 [M+H] + .
- Example 14 Using methyl 1-fluoro-3-hydroxycyclopentanecarboxylate as a raw material, according to the operation of Example 14, a trans intermediate with a large Rf value and a cis intermediate with a small Rf value were obtained, and the trans intermediate was subjected to the following steps. In one step, 20 8 mg of trans-yellow solid was finally obtained, ESI MS m/z 798 [M+H] + .
- Step 1 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolinone-5-yl)piperazine-1-tert-butyl carbonate Ester (1g, 2.26mmol, 1eq) was dissolved in acetic acid, zinc powder (1.48g, 22.6mmol, 10eq) was added, stirred at 60°C for 1h, cooled, suction filtered, the filtrate was concentrated, diluted with 20mL of water, saturated sodium bicarbonate The pH was adjusted to neutral, extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a mixture of 470 mg, ESI MS m/z 445 [M+H] + .
- Step 2 The product obtained in Step 1 (470mg, 1.06mmol, 1eq) was dissolved in dichloromethane, and trifluoroacetic acid (923mg, 9.52mmol, 9eq) and triethylsilane (737mg, 22.6mmol, 6eq) were added dropwise respectively. , after stirring at room temperature for 2 h, the reaction solution was concentrated, prepared and separated to obtain 210 mg of the 3 -position substituted product.
- Step 3 Dissolve the above products (1eq) in THF respectively, add (6-(4-formylpiperidin-1-yl)pyridazin-3-yl)carbamic acid tert-butyl ester (1eq) and stir at room temperature for 30min.
- Step 4 Substitute (1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexane-1-carboxylic acid (30mg, 0.107mmol, 1eq), the 3- and 2-position obtained in step 3
- the product 56mg, 0.107mmol, 1eq
- DIEA 20mg, 0.132mmol, 1.2eq
- HATU 51mg, 0.132mmol, 1.2eq
- reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EA, the organic phases were combined, water was removed with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 100 mg of product, ESI MS m/z 324 [M+H] + .
- PC-3 cells procell, Cat. No. CL-0185.
- LNCaP cells Wuhan Proceeds Life Science and Technology.
- NC negative control
- PC positive control
- NC negative control
- PC positive control
- 158 is the molecule whose compound number is 158 in US 2018/0099940 A1, and the structure is as follows,
- Mass spectrometry conditions LC-MS/MS was used for determination, the ion source was APIC source, positive ionization mode was used for detection, and the scanning mode was selective reaction monitoring (MRM).
- MRM selective reaction monitoring
- mice Male, weighing 180-220g, fasted for 12h, and given the sample solution by oral administration at a dose of 5mg/kg [the vehicle is PEG300:Solutol HS 15:pH 4.65 acetate buffer(10:10:80)], Before administration, blank blood was taken, and about 100 ⁇ L of venous blood was collected at different time points after administration, placed in a test tube with heparin, centrifuged, and about 50 ⁇ L of plasma was collected and stored at -20°C for testing. The blood collection time points were: 18min, 30min, 60min, 120min, 240min, 360min, 480min, 1440min. Take 50 ⁇ L of rat plasma sample, centrifuge at 5500 rpm for 18 minutes, and take 10 ⁇ L for LC-MS/MS determination. The plasma concentration was calculated by the established standard curve.
- PK parameter 2a 158 PO AUC(0-t)(nM.h) 2075 ⁇ 582 6782 ⁇ 735 Cmax(nM) 250 ⁇ 85 453 ⁇ 43 Tmax(h) 2.0 ⁇ 0.0 4.0 ⁇ 0.0 T 1/2 (h) 5.2 ⁇ 1.0 17.9 ⁇ 6.5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
化合物 | LNCap(IC50,μM) | PC-3(IC50,μM) |
2a | 0.052 | >10 |
2b | 1.12 | >10 |
3a | 0.052 | >10 |
3b | 1.20 | >10 |
4 | 0.525 | >10 |
7 | 0.980 | >10 |
9 | 1.12 | >10 |
10 | 2.54 | >10 |
11 | 0.352 | >10 |
12 | 0.588 | >10 |
13 | 0.120 | >10 |
14 | 0.098 | >10 |
15 | 0.251 | >10 |
16 | 0.363 | >10 |
17 | 0.174 | >10 |
18 | 0.525 | >10 |
19 | 0.088 | >10 |
20 | 0.078 | >10 |
21 | 0.251 | >10 |
22 | 0.173 | >10 |
23a | 0.006 | >10 |
23b | 0.030 | >10 |
24a | 0.009 | >10 |
24b | 0.045 | >10 |
26 | 79.4 | >10 |
27 | 612.4 | >10 |
158 | 0.065 | >10 |
PK参数 | 2a | 158 |
PO AUC(0-t)(nM.h) | 2075±582 | 6782±735 |
Cmax(nM) | 250±85 | 453±43 |
Tmax(h) | 2.0±0.0 | 4.0±0.0 |
T 1/2(h) | 5.2±1.0 | 17.9±6.5 |
Claims (15)
- 一种如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,其中,R 1为氢、卤素、羟基、C 1-C 4烷基、一个或多个卤素取代的C 1-C 4烷基、C 1-C 4烷氧基、一个或多个卤素取代的C 1-C 4烷氧基、C 1-C 4烷基-C(=O)-、C 1-C 4烷基-S-或-NR 1-1R 1-2;D为O、NR 6-1或CR 6-2R 6-3;K为-C(=O)-或CR 7-1R 7-2;M为-C(=O)-或CR 11-1R 11-2;环W为C 6-C 10芳环、一个或多个R 8-1取代的C 6-C 10芳环、5-10元杂芳环、或一个或多个R 8-2取代的5-10元杂芳环;所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;所述的一个或多个R 8-2取代的5-10元杂芳环中所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;环Z为C 6-C 10芳环或5-10元杂芳环;所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;环Y为C 3-C 10脂环、一个或多个R 9-1取代的C 3-C 10脂环、3-10元杂脂环、或一个或多个R 9-2取代的3-10元杂脂环;所述的3-10元杂脂环中的杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2或3;所述的一个或多个R 9-2取代的3-10元杂脂环中的3-10元杂脂环中的杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2或3;R 1-1和R 1-2独立地为氢或C 1-C 4烷基;R 2-1为C 1-C 4烷基;R 6-1为氢或C 1-C 4烷基;R 6-2、R 6-3、R 7-1、R 7-2、R 11-1和R 11-2独立地为氢、卤素或C 1-C 4烷基;R 8-1和R 8-2独立地为卤素或C 1-C 4烷基;R 9-1和R 9-2独立地为卤素、羟基或C 1-C 4烷基。
- 如权利要求1所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,其特征在于,所述的卤素独立地为氟、氯、溴或碘,例如氟、氯或溴;和/或,所述的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例甲基;和/或,所述的C 1-C 4烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基;和/或,当环W为C 6-C 10芳环时,所述的C 6-C 10芳基为苯环或萘环,优选为苯环;和/或,当环W为一个或多个R 8-1取代的C 6-C 10芳环时,所述的C 6-C 10芳基为苯环或萘环,例如苯环;和/或,当环W为5-10元杂芳环时,所述的5-10元杂芳环为5-6元杂芳环;所述的5-10元杂芳环和所述的5-6元杂芳环中的杂原子优选为N,杂原子个数优选为1或2;所述的5-6元杂芳环优选为哒嗪环、吡啶环、嘧啶环或吡嗪环;所述的哒嗪环优选为 所述的吡啶环优选为 所述的嘧啶环优选为 所述的吡嗪环优选为和/或,当环W为一个或多个R 8-2取代的5-10元杂芳环时,所述的5-10元杂芳环为5-6元杂芳环;所述的5-10元杂芳环和所述的5-6元杂芳环中的杂原子优选为N,杂原子个数优选为1或2;所述的5-6元杂芳环优选为哒嗪环或吡啶环;所述的哒嗪环优选为 所述的吡啶环优选为和/或,所述的R 8-2的个数为1个;和/或,当环Z为C 6-C 10芳环时,所述的C 6-C 10芳环为苯环或萘环,例如苯环;和/或,当环Z为5-10元杂芳环时,所述的5-10元杂芳环为5-6元杂芳环;所述的5-10元杂芳环和5-6元杂芳环中的杂原子优选为N,杂原子个数优选为1;所述的5-10元杂芳环优选为吡啶环,进一步优选为和/或,当环Y为C 3-C 10脂环时,所述的C 3-C 10脂环为C 4-C 7脂环,优选为丁环、戊环、己环、庚环或螺[3,3]庚环;所述的C 3-C 10脂环可为单环或螺环,例如单环;和/或,当环Y为一个或多个R 9-1取代的C 3-C 10脂环时,所述的C 4-C 10脂环为C 4-C 6脂环,优选为丁环、戊环或己环;所述的一个或多个R 9-1取代的C 3-C 10脂环中的C 3-C 10脂环可为单环或螺环,例如单环;和/或,所述的R 9-1的个数为1、2或4个;和/或,当环Y为3-10元杂脂环时,所述的3-10元杂脂环为5-6元杂脂环;所述的3-10元杂脂环和5-6元杂脂环中的杂原子优选为N,杂原子个数优选为1;所述的3-10元杂脂环优选为四氢吡咯环或哌啶环;所述的四氢吡咯环优选为 所述的哌啶环优选为 所述的3-10元杂脂环可为单环或螺环;和/或,当环Y为一个或多个R 9-2取代的3-10元杂脂环时,所述的3-10元杂脂环为5-6元杂脂环;所述的3-10元杂脂环和5-6元杂脂环中的杂原子优选为N,杂原子个数优选为1;所述的3-10元杂脂环优选为四氢吡咯环或哌啶环;所述的四氢吡咯环优选为 所述的哌啶环优选为 所述的一个或多个R 9-2取代的3-10元杂脂环中的3-10元杂脂环可为单环或螺环;和/或,所述的R 9-2的个数为1个。
- 如权利要求1或2所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,其特征在于,R 3-1和R 3-2独立地为氢、卤素、羟基或C 1-4烷基;A为N或CR 4-1;B为N或CR 4-2;C为N或CR 4-3;E为N或CR 4-4;F为N或CR 4-5;G独立地为NR 5-1或CR 5-2R 5-3;L独立地为NR 10-1或CR 10-2R 10-3;R 4-1、R 4-2、R 4-3、R 4-4、R 4-5、R 5-2、R 5-3、R 10-2、R 10-3独立地为氢、卤素或C 1-C 4烷基;R 5-1和R 10-1独立地为氢或C 1-C 4烷基;m和n独立地为0、1、2或3;m1、m2、n1和n2独立地为0、1、2或3,且m1和n1不同时为0,m2和n2不同时为0。
- 如权利要求3所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,其特征在于,所述的卤素独立地为氟、氯、溴或碘;和/或,所述的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
- 如权利要求3或4所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,其特征在于,R 1为卤素或一个或多个卤素取代的C 1-C 4烷基,例如卤素;和/或,R 2为氢;和/或,R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基;和/或,B为CR 4-2;和/或,C为CR 4-3;和/或,K为-C(=O)-和M为-C(=O)-;或,K为CR 7-1R 7-2和M为-C(=O)-;或,K为-C(=O)-和M为CR 11-1R 11-2;和/或,环W为C 6-C 10芳环、5-10元杂芳环或一个或多个R 8-2取代的5-10元杂芳环,例如C 6-C 10芳环;和/或,R 4-1为氢;和/或,R 4-2为氢;和/或,R 4-3为氢;和/或,R 4-4为氢;和/或,R 5-2和R 5-3为氢;和/或,R 6-1为氢;和/或,R 6-2和R 6-3为氢;和/或,R 7-1和R 7-2为氢;和/或,R 8-2独立地为卤素;和/或,R 9-2独立地为C 1-C 4烷基;和/或,R 10-2和R 10-3独立地为氢或C 1-C 4烷基;和/或,R 11-1和R 11-2为氢;和/或,m为0、1或2;和/或,n为0、1或2。
- 如权利要求3-6任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,其特征在于,所述的化合物为如下任一方案:方案一:R 1为卤素或一个或多个卤素取代的C 1-C 4烷基;R 2为氢;R 3-1和R 3-2独立地为氢、羟基或C 1-4烷基;A为N或CH;B为CH;C为CH;D为O、NH或CH 2;E为N或CH;F为N或CR 4-5;G独立地为NR 5-1或CH 2;L独立地为NR 10-1或CR 10-2R 10-3;K为-C(=O)-或CH 2;M为-C(=O)-;环W为C 6-C 10芳环、5-10元杂芳环、或一个或多个R 8-2取代的5-10元杂芳环;所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;所述的一个或多个R 8-2取代的5-10元杂芳环中所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;R 4-5为氢、卤素或C 1-C 4烷基;R 8-2独立地为卤素;R 5-1和R 10-1独立地为氢或C 1-C 4烷基;R 10-2、R 10-3独立地为氢或C 1-C 4烷基;m和n独立地为0、1、2或3;和m1、m2、n1和n2独立地为0、1、2或3,且m1和n1不同时为0,m2和n2不同时为0;方案二:R 1为卤素;R 2为氢;R 3-1和R 3-2独立地为氢;A为N或CH;B为CH;C为CH;D为O、NH或CH 2;E为N或CH;F为N或CR 4-5;K为-C(=O)-或CH 2;M为-C(=O)-;G独立地为NR 5-1或CH 2;L独立地为NR 10-1或CH 2;环W为C 6-C 10芳环或5-10元杂芳环;所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;R 4-5为氢、卤素或C 1-C 4烷基;R 5-1和R 10-1独立地为氢或C 1-C 4烷基;m为0或1;和n为1或2;方案三:R 1为卤素;R 2为氢;R 3-1和R 3-2独立地为氢;A为N或CH;B为CH;C为CH;D为O、NH或CH 2;E为CH;F为N或CR 4-5;G独立地为NR 5-1或CH 2;L独立地为NR 10-1或CH 2;K为-C(=O)-或CH 2;M为-C(=O)-;环W为C 6-C 10芳环或5-10元杂芳环;所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;R 4-5为氢、卤素或C 1-C 4烷基;R 5-1和R 10-1独立地为C 1-C 4烷基;m为0或1;和n为1或2;方案四:R 1为氯;R 2为氢;R 3-1和R 3-2独立地为氢;A为CH;B为CH;C为CH;D为O;E为CH;F为CH;G独立地为CH 2;L独立地为CH 2;K为-C(=O)-和M为CH 2;或K为CH 2和M为-C(=O)-;环W为C 6-C 10芳环或5-10元杂芳环;所述的5-10元杂芳环中杂原子选自氮、氧和硫中的一种或多种,杂原子的个数为1、2、3或4;R 4-5为氢、卤素或C 1-C 4烷基;R 5-1和R 10-1独立地为C 1-C 4烷基;m为0或1;n为2;
- 如权利要求1-7任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,所述的化合物为如下任一方案:方案a:所述的如式I所示的化合物为如式Ia或Ib所示的化合物:其中,D为O或NH;环Z、环Y、环W、K、M、N、R 1和R 2的定义如权利要求1所述;方案b:所述的如式I所示的化合物为如式Ic所示的化合物:其中,环Y为戊环或己环;环Z、K、M、R 1和R 2的定义如权利要求1所述;优选,所述的如式Ic所示的化合物中:R 1为卤素;R 2为H;方案c:所述的如式I所示的化合物为如式Id所示的化合物:其中,环Z、K、M、R 1和R 2的定义如权利要求1所述;优选,所述的如式Id所示的化合物中,R 1为卤素;R 2为H;环Z为C 6-C 10芳环;
- 一种如权利要求1-9任一项所述的如式I所示化合物的制备方法,其特征在于,其为以下任一方法:方法一包括以下步骤:溶剂中,在碱和缩合剂的作用下,将如式IV所示的化合物和如式V所示的化合物进行如下所示的缩合反应即可,其中,环Z、环Y、D、K、M、环W、R 1和R 2的定义同权利要求1~9任一项所述;方法二包括以下步骤:溶剂中,在酸的作用下将如式VI所示的化合物进行如下所示的脱保护反应即可,方法三包括如下步骤:在溶剂中,将如式VII所示的化合物和如式VIII所示的化合物进行如下所示的加成反应即可,
- 如权利要求10所述的如式I所示化合物的制备方法,其特征在于,所述的缩合反应中,所述的溶剂为酰胺类溶剂,优选为N,N-二甲基甲酰胺;和/或,所述的缩合反应中,所述的如式IV所示的化合物在所述的溶剂中的摩尔浓度为0.0001~0.1mol/L,优选为0.004~0.01mol/L;和/或,所述的缩合反应中,所述的碱为有机胺,优选为N,N-二异丙基乙胺;和/或,所述的缩合反应中,所述的碱与所述的如式IV所示的化合物的摩尔比为0.8:1~3:1,优选为0.9:1~1.3:1;和/或,所述的缩合反应中,所述的缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐;和/或,所述的缩合反应中,所述的缩合剂与所述的如式IV所示的化合物的摩尔比为1:1~3:1,优选为1:1~1.5:1;和/或,所述的缩合反应中,所述的如式V所示的化合物与所述的如式IV所示的化合物的摩尔比为0.8:1~3:1,优选为0.9:1~1.3:1;和/或,所述缩合反应的反应温度为室温;和/或,所述缩合反应的反应时间优选为1~3小时;和/或,所述的脱保护反应中,所述的溶剂为醚类溶剂,优选为二氧六环;和/或,所述的脱保护反应中,所述的如式VI所示的化合物在所述的溶剂中的摩尔浓度为0.0001~0.1mol/L,优选为0.002~0.004mol/L;和/或,所述的脱保护反应中,所述的酸为无机酸,优选为盐酸;和/或,所述脱保护反应的反应温度为室温;和/或,所述脱保护反应的反应时间为1~3小时;和/或,所述的加成反应中,所述的溶剂为酰胺类溶剂,优选为N,N-二甲基甲酰胺;和/或,所述的加成反应中,所述的如式VII所示的化合物与所述的如式VIII所示的化合物的摩尔比为0.8:1~3:1,优选为0.9:1~1.3:1;和/或,所述加成反应的反应温度为室温;和/或,所述加成反应的反应时间优选为1~3小时。
- 一种药物组合物,其包括如权利要求1-9任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药,以及药学上可接受的辅料。
- 一种如权利要求1-9任一项所述的如式I所示的化合物、其立体异构体、其互变异构体、其溶剂合物、其药学上可接受的盐、其代谢产物或其前药、或如权利要求14所述的药物组合物在制备雄激素受体降解剂或治疗与雄激素受体相关疾病的药物中的应用;所述的与雄激素受体相关疾病优选为***癌,进一步优选为转移性去势抵抗***癌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010921464 | 2020-09-04 | ||
CN202010921464.1 | 2020-09-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2022048605A1 true WO2022048605A1 (zh) | 2022-03-10 |
WO2022048605A8 WO2022048605A8 (zh) | 2023-03-30 |
Family
ID=80393920
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/116287 WO2022048605A1 (zh) | 2020-09-04 | 2021-09-02 | 一种杂环化合物、其制备方法、中间体、组合物以及应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114133379B (zh) |
WO (1) | WO2022048605A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11883393B2 (en) | 2019-12-19 | 2024-01-30 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
US12043612B2 (en) | 2020-05-09 | 2024-07-23 | Arvinas Operations, Inc. | Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019199816A1 (en) * | 2018-04-13 | 2019-10-17 | Arvinas Operations, Inc. | Cereblon ligands and bifunctional compounds comprising the same |
CN110506039A (zh) * | 2016-10-11 | 2019-11-26 | 阿尔维纳斯股份有限公司 | 用于雄激素受体靶向降解的化合物和方法 |
CN110612294A (zh) * | 2017-01-31 | 2019-12-24 | 阿尔维纳斯运营股份有限公司 | 人小脑蛋白配体和包含其的双官能化合物 |
WO2021061644A1 (en) * | 2019-09-23 | 2021-04-01 | Accutar Biotechnology Inc. | Novel substituted quinoline-8-carbonitrile derivatives with androgen receptor degradation activity and uses thereof |
WO2021081108A1 (en) * | 2019-10-22 | 2021-04-29 | Arvinas Operations, Inc. | Methods of treating prostate cancer |
-
2021
- 2021-09-02 WO PCT/CN2021/116287 patent/WO2022048605A1/zh active Application Filing
- 2021-09-02 CN CN202111025098.2A patent/CN114133379B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110506039A (zh) * | 2016-10-11 | 2019-11-26 | 阿尔维纳斯股份有限公司 | 用于雄激素受体靶向降解的化合物和方法 |
CN110612294A (zh) * | 2017-01-31 | 2019-12-24 | 阿尔维纳斯运营股份有限公司 | 人小脑蛋白配体和包含其的双官能化合物 |
WO2019199816A1 (en) * | 2018-04-13 | 2019-10-17 | Arvinas Operations, Inc. | Cereblon ligands and bifunctional compounds comprising the same |
WO2021061644A1 (en) * | 2019-09-23 | 2021-04-01 | Accutar Biotechnology Inc. | Novel substituted quinoline-8-carbonitrile derivatives with androgen receptor degradation activity and uses thereof |
WO2021081108A1 (en) * | 2019-10-22 | 2021-04-29 | Arvinas Operations, Inc. | Methods of treating prostate cancer |
Non-Patent Citations (1)
Title |
---|
ACS: "RN 2222114-60-3 etc.", STN REGISTRY, 2 May 2018 (2018-05-02) * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11883393B2 (en) | 2019-12-19 | 2024-01-30 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
US12043612B2 (en) | 2020-05-09 | 2024-07-23 | Arvinas Operations, Inc. | Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same |
Also Published As
Publication number | Publication date |
---|---|
CN114133379A (zh) | 2022-03-04 |
CN114133379B (zh) | 2024-02-13 |
WO2022048605A8 (zh) | 2023-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018304168B2 (en) | Methods of treatment for cystic fibrosis | |
WO2022082876A1 (zh) | 靶向蛋白降解c-Met降解剂及其制备方法与应用 | |
WO2021139678A1 (zh) | 吡啶并嘧啶类kras g12c突变蛋白抑制剂 | |
US20240199573A1 (en) | Polymorphs of n-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and salts thereof | |
KR101473546B1 (ko) | Cf의 치료를 위한 피리딘 및 피라진 유도체 | |
WO2022021841A1 (zh) | 一种新型冠状病毒主蛋白酶的抑制剂及其制备方法和用途 | |
EP4074703A1 (en) | Pyridinyl-(aza)indolsulfonamides | |
WO2022048605A1 (zh) | 一种杂环化合物、其制备方法、中间体、组合物以及应用 | |
CN110092745B (zh) | 一种含芳环的化合物及其应用 | |
EP3789383B1 (en) | Inhibitors of the trpc3 or trpc6 channel | |
CN109705071A (zh) | Hdac抑制剂及其制备方法和用途 | |
ES2516940T3 (es) | 6-(1-metil-1H-pirazol-4-il)-3-(2-metil-2H-indazol-5-iltio)-[1,2,4] triazolo[4,3-b]piridazina como inhibidor de c-Met | |
WO2020108661A1 (zh) | 作为cdk-hdac双通路抑制剂的杂环化合物 | |
TW201704230A (zh) | 化合物 | |
WO2023046149A1 (zh) | 喹喔啉类化合物及其医药用途 | |
JP2009084274A (ja) | 新規1,3,3−トリメチル−7−フェニル−3,4−ジヒドロ−1h−キノキサリン−2−オン誘導体 | |
KR20050102133A (ko) | 허혈 손상 치료용4-[(2,4-디클로로-5-메톡시페닐)아미노]-6-알콕시-3-퀴놀린카보니트릴 | |
WO2019141027A1 (zh) | 吲哚胺2,3-双加氧化酶抑制剂及其制备方法和用途 | |
WO2010029986A1 (ja) | スルホン酸エステル構造を導入したフェニル基を置換基として有する新規1,2,3,4-テトラヒドロキノキサリン誘導体からなるグルココルチコイド受容体アゴニスト | |
JP3287574B2 (ja) | 2,7−置換オクタヒドロ−1h−ピリド[1,2−a]ピラジン誘導体 | |
CN110467616B (zh) | 含杂芳基取代哒嗪酮结构的***并吡嗪类化合物的制备及应用 | |
WO2017206924A1 (zh) | 抑制蛋白激酶活性化合物的晶型及其应用 | |
US20210205348A1 (en) | Methods for the Treatment of Bladder Cancer | |
EP4364739A1 (en) | Pharmaceutical composition for preventing and/or treating kidney injury, and autophagy activator | |
WO2021180023A1 (zh) | 一种弹性蛋白酶抑制剂前药及其用途 |
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: 21863669 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: 21863669 Country of ref document: EP Kind code of ref document: A1 |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 21/09/2023) |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21863669 Country of ref document: EP Kind code of ref document: A1 |