WO2023280254A1 - Inhibiteur de tead - Google Patents
Inhibiteur de tead Download PDFInfo
- Publication number
- WO2023280254A1 WO2023280254A1 PCT/CN2022/104292 CN2022104292W WO2023280254A1 WO 2023280254 A1 WO2023280254 A1 WO 2023280254A1 CN 2022104292 W CN2022104292 W CN 2022104292W WO 2023280254 A1 WO2023280254 A1 WO 2023280254A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- ring
- compound
- alkyl
- membered
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000000651 prodrug Substances 0.000 claims abstract description 30
- 229940002612 prodrug Drugs 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 239000012453 solvate Substances 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 230000014509 gene expression Effects 0.000 claims abstract description 10
- -1 methoxy, ethoxy, propoxy Chemical group 0.000 claims description 213
- 238000002360 preparation method Methods 0.000 claims description 82
- 229910052757 nitrogen Inorganic materials 0.000 claims description 76
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 125000005842 heteroatom Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 229910052720 vanadium Inorganic materials 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 230000017945 hippo signaling cascade Effects 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 8
- 230000002062 proliferating effect Effects 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 101000653735 Homo sapiens Transcriptional enhancer factor TEF-1 Proteins 0.000 claims description 4
- 101000597045 Homo sapiens Transcriptional enhancer factor TEF-3 Proteins 0.000 claims description 4
- 101000597035 Homo sapiens Transcriptional enhancer factor TEF-4 Proteins 0.000 claims description 4
- 101000597043 Homo sapiens Transcriptional enhancer factor TEF-5 Proteins 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 102100029898 Transcriptional enhancer factor TEF-1 Human genes 0.000 claims description 4
- 102100035148 Transcriptional enhancer factor TEF-3 Human genes 0.000 claims description 4
- 102100035146 Transcriptional enhancer factor TEF-4 Human genes 0.000 claims description 4
- 102100035147 Transcriptional enhancer factor TEF-5 Human genes 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- WSSDGZWSPMAECX-UHFFFAOYSA-N 2-azabicyclo[3.1.0]hexane Chemical group C1CNC2CC21 WSSDGZWSPMAECX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 230000004663 cell proliferation Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 495
- 238000006243 chemical reaction Methods 0.000 description 161
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 157
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 140
- 238000003786 synthesis reaction Methods 0.000 description 124
- 230000015572 biosynthetic process Effects 0.000 description 121
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 116
- 239000012043 crude product Substances 0.000 description 116
- 239000012074 organic phase Substances 0.000 description 115
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 93
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 88
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- 229910052938 sodium sulfate Inorganic materials 0.000 description 81
- 235000011152 sodium sulphate Nutrition 0.000 description 81
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 78
- 239000003208 petroleum Substances 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 51
- 229910002027 silica gel Inorganic materials 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 31
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- RSGVKIIEIXOMPY-UHFFFAOYSA-N 5-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=CC=C(C(F)(F)F)C=N1 RSGVKIIEIXOMPY-UHFFFAOYSA-N 0.000 description 26
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 26
- YBSAGMHWGCRYMW-UHFFFAOYSA-N 4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Chemical compound FC1=C(C=C(C=C1)S(=O)(=O)N(C)CC1=CC=C(C=C1)OC)B1OC(C(O1)(C)C)(C)C YBSAGMHWGCRYMW-UHFFFAOYSA-N 0.000 description 24
- 239000012141 concentrate Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 19
- 239000002585 base Substances 0.000 description 19
- 238000000926 separation method Methods 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- 238000000746 purification Methods 0.000 description 16
- FIXVUVZJPMXIJP-UHFFFAOYSA-N 2-bromo-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine Chemical compound Brc1cn2CCOCc2n1 FIXVUVZJPMXIJP-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 13
- 102100027548 WW domain-containing transcription regulator protein 1 Human genes 0.000 description 13
- 239000012295 chemical reaction liquid Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- XUEIXPYOAOFHGK-UHFFFAOYSA-N 2-(3-oxomorpholin-4-yl)acetamide Chemical compound NC(=O)CN1CCOCC1=O XUEIXPYOAOFHGK-UHFFFAOYSA-N 0.000 description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 11
- OGWGNPOINGXDLB-UHFFFAOYSA-N CN(CC(C=C1)=CC=C1OC)S(C(C=C1)=CC(C2=CN(CCOC3)C3=N2)=C1F)(=O)=O Chemical compound CN(CC(C=C1)=CC=C1OC)S(C(C=C1)=CC(C2=CN(CCOC3)C3=N2)=C1F)(=O)=O OGWGNPOINGXDLB-UHFFFAOYSA-N 0.000 description 11
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 11
- 150000002460 imidazoles Chemical class 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- BXEHPHKSFJRHJB-UHFFFAOYSA-N BrC=1C=C(C=CC=1F)S(=O)(=O)N(C)CC1=CC=C(C=C1)OC Chemical compound BrC=1C=C(C=CC=1F)S(=O)(=O)N(C)CC1=CC=C(C=C1)OC BXEHPHKSFJRHJB-UHFFFAOYSA-N 0.000 description 9
- BJSJMBKHEBSOCN-UHFFFAOYSA-N BrC=1C=C(C=CC=1NC1=NC=C(C=C1)C(F)(F)F)S(=O)(=O)N(C)CC1=CC=C(C=C1)OC Chemical compound BrC=1C=C(C=CC=1NC1=NC=C(C=C1)C(F)(F)F)S(=O)(=O)N(C)CC1=CC=C(C=C1)OC BJSJMBKHEBSOCN-UHFFFAOYSA-N 0.000 description 9
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- ZQTWRNDUFKCLSH-GSVOUGTGSA-N C[C@H](CN12)OC1=NC(Br)=C2Br Chemical compound C[C@H](CN12)OC1=NC(Br)=C2Br ZQTWRNDUFKCLSH-GSVOUGTGSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- WFZFJWWGEDTHMC-UHFFFAOYSA-N methyl 2-(2-methyl-5-oxopyrrolidin-1-yl)acetate Chemical compound COC(=O)CN1C(C)CCC1=O WFZFJWWGEDTHMC-UHFFFAOYSA-N 0.000 description 8
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 8
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 238000001308 synthesis method Methods 0.000 description 8
- KXSKNBFZPZNIBH-UHFFFAOYSA-N CNS(C(C=C1)=CC(C2=CN(CCC3)C3=N2)=C1NC1=NC=C(C(F)(F)F)C=C1)(=O)=O Chemical compound CNS(C(C=C1)=CC(C2=CN(CCC3)C3=N2)=C1NC1=NC=C(C(F)(F)F)C=C1)(=O)=O KXSKNBFZPZNIBH-UHFFFAOYSA-N 0.000 description 7
- XWTABTVCDMGFLR-UHFFFAOYSA-N CNS(C(C=C1)=CC(C2=CN(CCOC3)C3=N2)=C1NC1=NC=C(C(F)(F)F)C=C1)(=O)=O Chemical compound CNS(C(C=C1)=CC(C2=CN(CCOC3)C3=N2)=C1NC1=NC=C(C(F)(F)F)C=C1)(=O)=O XWTABTVCDMGFLR-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- SFZQBHXPXLGKFM-IMJSIDKUSA-N (2S,4S)-4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H](F)CN1N=O SFZQBHXPXLGKFM-IMJSIDKUSA-N 0.000 description 6
- FGBMIGVVEQZDQU-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]-5-oxopyrrolidine-3-carbaldehyde Chemical compound C1=CC(OC)=CC=C1CN1C(=O)CC(C=O)C1 FGBMIGVVEQZDQU-UHFFFAOYSA-N 0.000 description 6
- UVSGSHSBMKNXLM-UHFFFAOYSA-N 2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine Chemical compound C1CCCN2C(Br)=C(Br)N=C21 UVSGSHSBMKNXLM-UHFFFAOYSA-N 0.000 description 6
- AIWRFNIDXKMIDD-UHFFFAOYSA-N 2-(2,4,5-tribromoimidazol-1-yl)ethanol Chemical compound OCCN1C(Br)=NC(Br)=C1Br AIWRFNIDXKMIDD-UHFFFAOYSA-N 0.000 description 6
- WXSIIGNLCUEOLX-UHFFFAOYSA-N 2-(2-methyl-5-oxopyrrolidin-1-yl)acetamide Chemical compound CC1CCC(=O)N1CC(N)=O WXSIIGNLCUEOLX-UHFFFAOYSA-N 0.000 description 6
- KHDDVRGVPOGDPT-UHFFFAOYSA-N 2-(3-methyl-2-oxopyrrolidin-1-yl)acetamide Chemical compound CC1CCN(CC(N)=O)C1=O KHDDVRGVPOGDPT-UHFFFAOYSA-N 0.000 description 6
- ZGDACAYMSJIESS-UHFFFAOYSA-N 2-(4,4-dimethyl-2-oxopyrrolidin-1-yl)acetamide Chemical compound CC1(C)CN(CC(N)=O)C(=O)C1 ZGDACAYMSJIESS-UHFFFAOYSA-N 0.000 description 6
- KSTAACVNVDTPCC-UHFFFAOYSA-N 2-(4-aminopyridin-2-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC(N)=CC=N1 KSTAACVNVDTPCC-UHFFFAOYSA-N 0.000 description 6
- FOHDUJZWVKIJTI-UHFFFAOYSA-N 2-(4-methyl-2-oxopyrrolidin-1-yl)acetamide Chemical compound CC1CN(CC(N)=O)C(=O)C1 FOHDUJZWVKIJTI-UHFFFAOYSA-N 0.000 description 6
- RXGGHFNLSZGCRF-UHFFFAOYSA-N 2-(5-aminopyridin-2-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC=C(N)C=N1 RXGGHFNLSZGCRF-UHFFFAOYSA-N 0.000 description 6
- RDQCATQYMZDJLU-UHFFFAOYSA-N 2-(5-bromopyridin-2-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC=C(Br)C=N1 RDQCATQYMZDJLU-UHFFFAOYSA-N 0.000 description 6
- NLOPAFJRKHHFKE-UHFFFAOYSA-N 2-bromo-6,7-dihydro-5H-imidazo[1,2-a]pyrazin-8-one Chemical compound Brc1cn2CCNC(=O)c2n1 NLOPAFJRKHHFKE-UHFFFAOYSA-N 0.000 description 6
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 6
- OCJFFBJHASDJJJ-UHFFFAOYSA-N 4-(difluoromethyl)pyrrolidin-2-one Chemical compound FC(F)C1CNC(=O)C1 OCJFFBJHASDJJJ-UHFFFAOYSA-N 0.000 description 6
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- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical group C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004654 survival pathway Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- HQYNSFAFYFMRLG-UHFFFAOYSA-N tribromo phosphite Chemical compound BrOP(OBr)OBr HQYNSFAFYFMRLG-UHFFFAOYSA-N 0.000 description 1
- YEMJHNYABQHWHL-UHFFFAOYSA-N tributyl(ethynyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C#C YEMJHNYABQHWHL-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- 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
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
-
- 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
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicine, in particular, the invention relates to a TEAD inhibitor, its preparation method and application.
- the Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, involved in the regulation of physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development.
- NF2 neurofibromatosis type 2, neurofibromin 2
- MST1/2 Mesmalian sterile 20-like kinase 1/2
- LAST1/2 large tumor suppressor kinase 1/2
- phosphorylated YAP/TAZ is localized in the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP/TAZ translocates to the nucleus
- TEADs Transcriptional Enhanced Associate Domains, Transcriptional Enhanced Associate Domains
- TEAD1 TEAD2, TEAD3 and TEAD4. All TEADs subtypes have one N-terminal that binds to DNA
- the TEA domain has a YAP/TAZ binding domain at the C-terminus.
- the DNA binding domain and the YAP/TAZ binding domain are highly conserved in mammals, but the connection between the TEA domain and the transactivation domain Subtypes are very different, the overall homology of the four TEADs subtypes ranged from 61% to 73%.
- the function of TEADs is mediated by their interaction with nuclear coactivators, and YAP is the main nuclear coactivator interacting with TEADs.
- YAP/TAZ-TEADs The activation of YAP/TAZ-TEADs promotes tumor development, and inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors.
- some cancers such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma
- the YAP/TAZ-TEADs complex is frequently overactivated or overexpressed, leading to cancer progression.
- This hyperactivation is usually caused by changes in genes upstream of the Hippo signaling pathway, especially in patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, ⁇ 25% of tumors have MST1 or LAST1/2 mutations or Deletion, 70% of YAP overexpression, and overactivation of YAP/TAZ-TEADs complex contribute to the promotion of tumor cell proliferation, metastasis, epithelial-to-mesenchymal transition (EMT) and maintenance of tumor stem cells.
- EMT epithelial-to-mesenchymal transition
- YAP/TAZ and TEADs interaction inhibitors (VT-01, IK-930) have entered the clinical stage, and YAP/TAZ and TEADs interaction inhibition may be a promising new anti-tumor chemotherapy.
- the invention provides a compound used as a TEAD inhibitor.
- the compound can obviously inhibit the activity of TEADs transcription, and can be used for preventing and/or treating diseases related to increased expression of TEAD.
- W represents CH or N
- R is hydrogen or a substituent selected from the following:
- R 11 , R 12 , and R 13 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl;
- R is hydrogen or a substituent selected from the following: Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
- V 1 , V 2 , V 3 , V 4 each independently represent C, CH or a heteroatom
- the heteroatom is selected from N, O or S;
- V 1 , V 2 , V 3 , V 4 contain 1, 2 or 3 heteroatoms; when there are 2 or 3 heteroatoms, the heteroatoms are the same or different;
- L is O, -NH-Z- or -CH 2 -Z-;
- Z is absent or is C 1 -C 3 alkylene
- Said L is optionally substituted by C 1 -C 3 alkyl
- Ring A is a benzene ring, a 5-6 membered heteroaromatic ring or a 3-8 membered cycloalkyl group;
- Ring B is a 4-8 membered ring
- Ring A is optionally substituted by one or more R3s; when there are multiple substituents R3 , the R3s are the same or different;
- the R 3 is selected from: halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy, -SF 5 , -CF 2 -OR 31 ;
- R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
- R 31 is optionally substituted by a substituent selected from the following: halogen, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy;
- the ring B is optionally substituted by one or more R 4 ; when there are multiple substituent R 4 , the R 4 are the same or different;
- R4 is selected from: halogen, hydroxyl, oxo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, -NH-C(O)-R 41 , -C(O)-NH-R 42 ;
- R 41 and R 42 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, R 41 , R 42 in R 4 are optionally substituted by substituents selected from the following: halogen, hydroxyl , C 1 -C 3 alkoxy.
- W represents C or N
- R is hydrogen or a substituent selected from the following:
- R 11 and R 12 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkane Base, 4-6 membered heterocycloalkyl;
- R is hydrogen or a substituent selected from the following: Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
- V 1 , V 2 , V 3 , V 4 each independently represent C or a heteroatom
- the heteroatom is selected from N, O or S;
- V 1 , V 2 , V 3 , V 4 contain 1, 2 or 3 heteroatoms; when there are 2 or 3 heteroatoms, the heteroatoms are the same or different;
- L is -NH-Z- or -CH 2 -Z-;
- Z is absent or is C 1 -C 3 alkylene
- Said L is optionally substituted by C 1 -C 3 alkyl
- Ring A is a benzene ring or a 5-6 membered heteroaromatic ring
- Ring B is a 4-8 membered ring
- Ring A is optionally substituted by one or more R3s; when there are multiple substituents R3 , the R3s are the same or different;
- the R 3 is selected from: halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy, -SF 5 , -CF 2 -OR 31 ;
- R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
- R 31 is optionally substituted by a substituent selected from the following: halogen, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
- the ring B is optionally substituted by one or more R 4 ; when there are multiple substituent R 4 , the R 4 are the same or different;
- R 4 is selected from: halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, -NH-C(O)-R 41 , -C(O) -NH-R 42 ;
- R 41 and R 42 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, R 41 , R 42 in R 4 are optionally substituted by substituents selected from the following: halogen, hydroxyl , C 1 -C 3 alkoxy.
- the group has structure
- Ring B is a 4-8 membered carbocycle or a 4-8 membered heterocycle; preferably, Ring B is a 5-6 membered carbocycle or a 5-6 membered heterocycle.
- ring B is selected from tetrahydropyrrole ring, morpholine ring, cyclopentane ring, piperazine ring, piperidine ring, oxazolidine ring, 2-azabicyclo[3.1.0] Hexane ring.
- the group has structure
- M represents N, O, S atoms or groups
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are each independently selected from CH, CH 2 , N, O, and S atoms;
- Y 1 , Y 2 and Y 3 are not CH or CH 2 ;
- Y 4 , Y 5 , Y 6 and Y 7 is not CH or CH 2 ;
- Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently selected from CH, CH 2 or groups
- Q 1 and Q 2 are not CH or CH 2 ;
- Q 3 , Q 4 , and Q 5 are not CH or CH 2 ;
- M' represents CH, CH2 , N, O or S.
- each of V 1 , V 2 , V 3 , and V 4 independently represents C, CH, or a heteroatom selected from N, O, and S; and V 1 , V 2 , V 3 , V 4 contains at least one N atom; preferably, V 1 , V 2 , V 3 , and V 4 contain 2 heteroatoms.
- V 1 when V 1 is N, V 2 is C, V 3 is N, and V 4 is CH;
- V 1 When V 1 is N, V 2 is N, V 3 is C, and V 4 is CH;
- V 1 When V 1 is N, V 2 is C, V 3 is C, V 4 is O or S;
- V 1 is CH
- V 2 is N
- V 3 is C
- V 4 is N
- said formula I has the structure Ia:
- the group has structure
- Ring B is a 4-8 membered carbocycle or a 4-8 membered heterocycle; preferably, Ring B is a 5-6 membered carbocycle or a 5-6 membered heterocycle.
- the group has structure Among them, M represents N, O, S atoms or groups
- L is -NH- or -CH 2 -; said -NH- or -CH 2 - is optionally substituted by C 1 -C 3 alkyl; preferably, L is - NH-.
- Ring A is a benzene ring, a 5-6 membered N-containing heteroaryl ring or a 5-8 membered cycloalkyl group; preferably, Ring A is a benzene ring, pyridine, pyrimidine, pyridazine, Pyrazine, pyrrole, pyrazole, imidazole, triazole, cyclohexane, More preferably, ring A is a benzene ring, pyridine or pyrimidine.
- R is hydrogen
- R 11 , R 12 , and R 13 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl;
- R 11 and R 12 are each independently hydrogen, methyl, ethyl, propyl;
- R 11 is hydrogen and R 12 is methyl. Or more preferably, R 13 is vinyl.
- R 2 is hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
- the group has structure wherein, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from CH or N; and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 have at most two Ns.
- ring A is optionally substituted by 1 or 2 R 3 ; when there are 2 substituent R 3 , said R 3 are the same or different;
- the R 3 is selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , -CF 2 -OR 31 ; wherein, R 31 is C 1 -C 6 alkyl, 3- 6-membered cycloalkyl;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy in R 3 , R 31 is optionally substituted by a substituent selected from the following: halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy.
- the R 3 is selected from: -CF 3 , -OCF 3 , -SF 5 ,
- the ring B is optionally substituted by 1 or 2 R 4 ; when there are 2 substituent R 4 , the R 4 are the same or different;
- the R 4 is a substituent selected from the following groups: fluorine, chlorine, hydroxyl, oxo C 1 -C 6 alkyl, -NH-C(O)-R 41 , -C(O)-NH-R 42 ; R 41 and R 42 are each independently C 1 -C 6 alkyl, C 1 - C 6 alkoxy;
- C 1 -C 6 alkyl, R 41 , and R 42 in R 4 are optionally substituted by substituents selected from the group consisting of fluorine, chlorine, hydroxyl, and C 1 -C 3 alkoxy;
- R 4 is a substituent selected from the group consisting of fluorine, chlorine, hydroxyl, oxo Methyl, ethyl, propyl, -NH-C(O)-R 41 , -C(O)-NH-R 42 ; wherein R 41 and R 42 are each independently selected from: methyl, ethyl, propyl group, methoxy, ethoxy, propoxy.
- R 4 is a substituent selected from the following groups: CH 3 , F, OH, oxo -CHF 2 , CF 3 ,
- the compound represented by the formula I includes:
- G is boric acid or borate ester group
- X is a halogen
- Ring A is optionally substituted by one or more R3s; when there are multiple substituents R3 , the R3s are the same or different;
- Ring B is optionally substituted by one or more R 4 ; when there are multiple substituent R 4 , the R 4 are the same or different;
- the method is carried out in an inert solvent.
- the inert solvents include but are not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1, 2-Dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.
- the compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof.
- "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups).
- Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc.
- Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
- Suitable hydroxy protecting groups include benzyl and the like.
- a pharmaceutical composition which includes: the compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug; and a pharmaceutically acceptable carrier.
- the compound represented by formula I as described in the first aspect of the present invention its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or precursor
- the purposes of medicine, or the purposes of pharmaceutical composition as described in the third aspect, described purposes comprises:
- the TEADs include: TEAD1, TEAD2, TEAD3 and TEAD4.
- the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
- the present invention also provides a method for treating diseases, comprising administering to patients a therapeutically effective amount of the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable At least one of a salt, a prodrug, or the pharmaceutical composition.
- the disease is a disease associated with increased expression of TEAD.
- the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
- said patient is a mammal, preferably a human.
- the inventors unexpectedly developed a compound represented by formula I, which can be used as a TEAD inhibitor.
- the compound of the present invention can obviously inhibit the activity of TEADs transcription, can obviously inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826), has a significant effect of inhibiting the growth of NCI-H226 mesothelioma, and shows excellent Pharmacokinetic properties, good druggability.
- the TEAD inhibitor can be used to prepare drugs, pharmaceutical compositions or preparations for preventing and/or treating diseases related to increased expression of TEAD; and/or, to prepare drugs for reducing/inhibiting TEAD expression and increasing TEAD activity Compositions or preparations; and/or, preparation of medicines, pharmaceutical compositions or preparations for reducing/inhibiting Hippo signaling pathway.
- the TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4; the disease is preferably a cell proliferative disorder; the cell proliferative disorder is preferably cancer.
- reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
- the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
- groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
- substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
- R 1 ", “R1” and “R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.
- an unsaturated or partially saturated ring such as an aromatic ring, including carbocyclic or heterocyclic rings.
- an aromatic ring including carbocyclic or heterocyclic rings.
- a benzene ring can be expressed as pyridine
- pyridine can be expressed as
- halogen refers to fluorine, chlorine, bromine, iodine, alone or as part of another substituent.
- amino alone or as part of another substituent means -NH2 .
- hydroxyl alone or as part of another substituent, means -OH.
- alkyl alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups.
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
- An alkyl group can be unsubstituted or substituted with one or more suitable substituents.
- alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
- alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
- alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
- C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
- the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3
- C 1 -C 6 alkoxy alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms Composed of and oxygen atom, or expressed as C 1 -C 6 alkyl-OC 1 -C 6 alkyl definition As described in this specification, the oxygen atom can be attached to a straight or straight chain of C 1 -C 6 alkyl on any carbon atom. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-).
- cycloalkyl refers to a cyclic alkyl group.
- mn-membered cycloalkyl or Cm - Cncycloalkyl is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
- 3-8 membered cycloalkyl refers to a cyclic alkyl group containing 3 to 8 carbon atoms, which may contain 1 to 2 rings.
- the cyclic alkyl group includes monocyclic, bicyclic, spiro or bridged rings.
- unsubstituted cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- Cycloalkyl groups may be substituted with one or more substituents.
- heterocycle or “heterocycloalkyl” or “heterocyclyl” by itself or as part of another substituent means a group in which one or more (in some embodiments 1-3) carbon atoms are Heteroatom substituted cycloalkyl (such as cycloalkyl, cycloalkenyl, cycloalkynyl) such as but not limited to N, O, S and P.
- m-n membered heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms.
- 4-6 membered heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 6 atoms.
- a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group.
- a prefix such as 4-6 membered is used to denote heterocycloalkyl, the number of carbons is also meant to include heteroatoms.
- heterocycles include, but are not limited to, dihydropyridazine, dihydropyrazine, including substituted forms thereof, such as heterocyclyl including, but not limited to, 6-oxo-1,6-dihydropyridazine- 3-yl, 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl, etc.
- heteroaryl/heteroaromatic ring refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl is preferably 5- or 6-membered.
- heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, thia-4H-pyrazolyl, etc.
- benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzo Imidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives , such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
- Haloalkyl or halogen-substituted alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl.
- the term "5-6 membered heteroaromatic ring” is understood to mean an aromatic ring having 5 or 6 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S. ring group.
- the term "5-6 membered heteroaromatic ring” is understood as an aromatic ring group having 5 or 6 ring atoms - and which contains 1 - 3 - heteroatoms independently selected from N, O and S.
- heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.
- salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
- “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
- other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
- stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
- the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
- the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
- Compounds prefixed with (+) or D are dextrorotatory.
- tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
- the compounds of the present invention may exhibit tautomerism.
- Tautomeric compounds can exist in two or more interconvertible species.
- Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
- Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
- the keto form predominates
- the enol form predominates.
- the present invention encompasses all tautomeric forms of the compounds.
- a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
- pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
- solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent force, and when the solvent is water, it is a hydrate.
- prodrug refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
- the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
- Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- excipient means a pharmaceutically acceptable inert ingredient.
- categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
- treatment and other similar synonyms include the following meanings:
- Fig. 1 is a graph showing the inhibition of growth of NCI-H226 mesothelioma by compounds I-39 and I-41.
- the synthetic route is as follows:
- the first step the synthesis of 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A1-2)
- reaction solution was diluted with 100 mL of dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 150 mL), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum ether/ Methyl tert-butyl ether (10/1, v/v) (100mL) was beaten to obtain 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A1- 2) (12g, yield 70.6%).
- A1- 2 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide
- the synthetic route is as follows:
- the first step 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((5-(trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide ( A2-1)
- reaction liquid was slowly dropped into 200 mL of ice-water mixture, the mixture was extracted with ethyl acetate (100 mL x 3), and the organic phase was collected and washed with 200 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- the synthetic route is as follows:
- the first step the synthesis of 3-bromo-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine (A3-2)
- 3-bromo-2-aminopyridine (A3-1) (10g, 57.8mmol), 4-trifluoromethyl iodobenzene (10.48g, 38.5mmol), cuprous iodide (1.47g, 7.7mmol) and tert Potassium butoxide (8.63 g, 77 mmol) was dissolved in anhydrous 1,4-dioxane (100 mL), heated to 100° C. for 24 hours under nitrogen protection, and cooled to room temperature.
- the synthetic route is as follows:
- reaction system was slowly raised to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into a mixed aqueous solution (1000 mL) of potassium ferricyanide (46.8 g, 142 mmol) and potassium hydroxide (15.9 g, 284 mmol) under nitrogen protection and stirred overnight at room temperature.
- potassium ferricyanide 46.8 g, 142 mmol
- potassium hydroxide 15.9 g, 284 mmol
- the second step the synthesis of 5-(chlorotetrafluoro- ⁇ 6 -sulfanyl)-2-fluoropyridine (A4-3)
- the third step the synthesis of 2-fluoro-5-(pentafluoro- ⁇ 6 -sulfanyl)pyridine (A4-4)
- Embodiment 1 the preparation of compound I-1
- the synthetic route is as follows:
- the first step the synthesis of 2-(2-oxopyrrolidone-1-yl)acetamide (B1-2)
- the second step the synthesis of 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B1-3)
- reaction solution was added dropwise to water (30.0 mL), then extracted with ethyl acetate (40.0 mL), the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
- Embodiment 2 the preparation of compound 1-2
- the synthetic route is as follows:
- the first step the synthesis of 2-(3-oxomorpholine) methyl acetate (B2-2)
- Morpholin-3-one (10.0 g, 98.9 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (4.35 g, 109 mmol) was added to the reaction liquid in batches, and the reaction was carried out at 25° C. for 1 hour. Then, methyl bromoacetate (16.6 g, 109 mmol) was added to the reaction liquid, and reacted at 25°C for 9 hours.
- the second step the synthesis of 2-(3-oxomorpholine) acetamide (B2-3)
- the third step the synthesis of 2-bromo-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine (B2-4)
- reaction solution dropwise to 1M hydrochloric acid (100 mL), neutralize with saturated sodium bicarbonate solution, then extract with ethyl acetate (100 mL), wash the organic phase with saturated brine (80.0 mL), dry over sodium sulfate, and concentrate to obtain Crude.
- the sixth step 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-methyl-4-((5-( Trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (I-2)
- reaction liquid to water (40.0 mL), neutralize with saturated sodium bicarbonate solution, then extract with ethyl acetate (40.0 mL), wash the organic phase with saturated brine (80.0 mL), dry over sodium sulfate, and concentrate to obtain Crude.
- Embodiment 3 the preparation of compound 1-3
- the synthetic route is as follows:
- the second step the synthesis of 2-(2-methyl-5-oxopyrrolidin-1-yl)acetamide (B3-3)
- the third step Synthesis of 2-bromo-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B3-4)
- the fourth step 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a] Synthesis of imidazol-2-yl)benzenesulfonamide (B3-5)
- reaction solution was added dropwise to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
- Step 6 Compound N-methyl-3-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-4-((5-( Synthesis of Trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (I-3)
- reaction solution was added to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
- Embodiment 4 the preparation of compound 1-4
- Embodiment 5 the preparation of compound 1-5
- the synthetic route is as follows:
- the second step the synthesis of 2-(4-methyl-2-oxopyrrolidin-1-yl)acetamide (B5-3)
- the third step the synthesis of 2-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B5-4)
- the fourth step 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a] Synthesis of imidazol-2-yl)benzenesulfonamide (B5-5)
- reaction solution was added dropwise to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
- Embodiment 6 the preparation of compound 1-6
- Embodiment 7 the preparation of compound 1-7
- the synthetic route is as follows:
- the third step Synthesis of 2-(tributylstannyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (B7-4)
- Embodiment 8 the preparation of compound 1-8
- Embodiment 9 the preparation of compound I-9
- Embodiment 10 the preparation of compound I-10
- the synthetic route is as follows:
- the first step 3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-(4-methoxybenzyl)-N-methyl-4- Synthesis of ((6-(trifluoromethoxy)pyridin-3-yl)amino)benzenesulfonamide (B10-2)
- Embodiment 11 Preparation of Compound I-11
- the synthetic route is as follows:
- the first step the synthesis of 2-(5-bromopyridin-2-yl)propan-2-ol (B11-2)
- the second step the synthesis of 2-(5-((dibenzylidene)amino)pyridin-2-yl)propan-2-ol (B11-3)
- the third step the synthesis of 2-(5-aminopyridin-2-yl)propan-2-ol (B11-4)
- Embodiment 12 Preparation of compound 1-12
- the synthetic route is as follows:
- the first step the synthesis of 2-(4-aminopyridin-2-yl)propan-2-ol (B12-2)
- reaction solution was quenched with saturated ammonium chloride solution (60.0ml) at 0°C, then extracted with ethyl acetate (90.0mL), the organic phase was washed with saturated brine (60.0mL), dried over sodium sulfate, and concentrated to obtain crude product 2 -(4-aminopyridin-2-yl)propan-2-ol (B12-2) (1.10 g, 54.9% yield).
- the third step 3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-4-((2-(2-hydroxypropane-2-yl)pyridine- Synthesis of 4-yl)amino)-N-methylbenzenesulfonamide (I-12)
- Embodiment 13 Preparation of Compound I-13
- the synthetic route is as follows:
- the third step Synthesis of 2,3-dibromo-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (B13-4)
- reaction solution was quenched by adding saturated aqueous ammonium chloride solution at 0°C, then extracted with ethyl acetate (15.0 mL), washed the organic phase with saturated brine (15.0 mL), dried over sodium sulfate, and concentrated to obtain crude 2-bromo-6 , 7-Dihydroimidazo[1,2-a]pyrazin-8(5H)-one (B13-5) (1.70 g, crude).
- the fifth step 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a Synthesis of ]pyrazin-2-yl)benzenesulfonamide (B13-6)
- the seventh step N-methyl-3-(8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-4-((5- Synthesis of (trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (I-13)
- N-(4-methoxybenzyl)-N-methyl-3-(8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl )-4-((5-(trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (B13-7) (70.0mg, 119 ⁇ mol) was dissolved in trifluoroacetic acid (1.00mL), under nitrogen protection The reaction was stirred at 70°C for 2 hours.
- Embodiment 14 Preparation of Compound I-14
- the synthetic route is as follows:
- the second step the synthesis of (S)-(1-hydroxy-3-methoxypropan-2-yl) tert-butyl carbamate (B14-3)
- Embodiment 15 Preparation of compound 1-15
- Embodiment 16 Preparation of Compound I-16
- Embodiment 17 Preparation of Compound I-17
- Embodiment 18 Preparation of Compound I-18
- Embodiment 19 Preparation of Compound I-19
- the synthetic method of compound I-19 refers to I-1, replaces 5-(trifluoromethyl)pyridine-2-amino with 5-(difluoro(methoxy)methyl)pyridine-2-amino to obtain 4-( (5-(Difluoro(methoxy)methyl)pyridin-2-yl)amino)-3-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)- N-Methylbenzenesulfonamide (I-19); LC-MS, M/Z (ESI): 450.2 [M+H] + .
- Embodiment 20 Preparation of Compound I-20
- the synthetic method of compound I-20 refers to I-1, replaces 5-(trifluoromethyl) pyridine-2-amino with 5-(cyclopropyloxydifluoromethyl) pyridine-2-amino, obtains compound 4-( (5-(cyclopropoxydifluoromethyl)pyridin-2-yl)amino)-3-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-N - Toluenesulfonamide (I-20); LC-MS, M/Z (ESI): 476.2 [M+H] + .
- Embodiment 21 Preparation of Compound I-21
- Embodiment 22 Preparation of Compound I-22
- the synthetic method of compound I-22 refers to I-1, and 5-(trifluoromethyl)pyridine-2-amino is replaced by 5-(pentafluoro- ⁇ 6 -sulfanyl)-2-aminopyridine (A4), to obtain Compound 3-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-N-methyl-4-((5-(pentafluoro- ⁇ 6 -sulfanyl) Pyridin-2-yl)amino)benzenesulfonamide (I-22); LC-MS, M/Z (ESI): 496.1 [M+H] + .
- Embodiment 23 Preparation of Compound I-23
- the synthetic route is as follows:
- the second step Synthesis of 2,3-dibromo-7,7-difluoro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B23-3)
- the third step Synthesis of 2-bromo-7,7-difluoro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B23-4)
- Embodiment 24 Preparation of Compound I-24
- the synthetic route is as follows:
- the first step Synthesis of 2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (B24-2)
- N-(4-methoxybenzyl)-N-methyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)-4-(( 5-(Trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (B24-4) 50 mg, 0.087 mmol was removed from the PMB group in trifluoroacetic acid (1 mL) to give N-methyl- 3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)benzenesulfonate Amide (I-24) (20 mg, yield: 50.6%).
- Embodiment 25 Preparation of Compound I-25
- the synthetic route is as follows:
- the first step Synthesis of 5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (B25-2)
- 2,4,5-Tribromo-1H-imidazole (5g, 16.41mmol) was dissolved in tetrahydrofuran (50mL), cooled to -78°C, and 2.5M n-butyllithium (6.56mL, 16.41mmol) was added dropwise, After stirring for 1 h, 2-methyloxirane (11.48 mL, 164 mmol) was added, gradually warmed to room temperature, and stirred for 12 h. Add saturated ammonium chloride solution (50 mL), extract with ethyl acetate (50 mL x 3), collect the organic phase, and wash with 50 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- the second step Synthesis of 6-bromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (B25-3)
- Embodiment 26 Preparation of Compound I-26
- the synthetic route is as follows:
- the first step Synthesis of 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B26-2)
- the third step (5-(N-(4-methoxybenzyl)-N-methylsulfonamide)-2-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)boronic acid ( Synthesis of B26-4)
- reaction solution was added to water (100mL), then extracted and concentrated with ethyl acetate (100mL) to obtain the crude product (R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl -2,3-Dihydroimidazo[2,1-b]oxazol-6-yl)-6-(4-(trifluoromethyl)phenoxy)pyridine-3-sulfonamide (B26-5) (25.0 mg, 5.70% yield).
- Embodiment 27 Preparation of Compound I-27
- the synthetic route is as follows:
- the first step Synthesis of 2-(3-methyl-2-oxopyrrolidin-1-yl)methyl acetate (B27-2)
- the second step the synthesis of 2-(3-methyl-2-oxopyrrolidin-1-yl)acetamide (B27-3)
- Embodiment 28 Preparation of Compound I-28
- Embodiment 29 Preparation of Compound I-29
- the synthetic route is as follows:
- the second step the synthesis of 2-(4,4-dimethyl-2-oxopyrrolidin-1-yl)acetamide (B29-3)
- the third step Synthesis of 2-bromo-6,6-dimethyl-6,7-dihydro-5H-pyrrole[1,2-a]imidazole (B29-4)
- Embodiment 30 Preparation of Compound I-30
- the synthetic route is as follows:
- the first step Synthesis of 5,6-dibromo-2,2-dimethyl-2,3-dihydroimidazo[2,1-b]oxazole (B30-2)
- 2,4,5-Tribromo-1H-imidazole (5.00g, 16.41mmol) was dissolved in tetrahydrofuran (50.0mL), cooled to -78°C, and n-butyllithium (7.22mL, 18.05 mmol, 2.5M), after stirring at this temperature for 30min, slowly dropwise added methyl propylene oxide (11.83g, 164.06mmol) to it, and slowly raised the temperature to 25°C to react for 16 hours after the addition.
- the second step Synthesis of 6-bromo-2,2-dimethyl-2,3-dihydroimidazo[2,1-b]oxazole (B30-3)
- the compound 6-bromo-2,2-dimethyl-2,3-dihydroimidazo[2,1-b]oxazole (B30-3) (2.00g, 9.21mmol)
- 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)benzenesulfonamide (A5, 4.01g, 9.21mmol) was reacted to give 3-(2,2-dimethyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl) -4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B30-4) (3.18 g, yield 77.5%).
- the synthetic route is as follows:
- Step 1 Synthesis of (S)-5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (B31-2)
- the second step the synthesis of (S)-6-bromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (B31-3)
- the synthetic route is as follows:
- reaction solution was added into water (10ml), extracted with ethyl acetate (10mL x 3), and the organic phase was collected and washed with 10mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Step 1 Synthesis of (R)-5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (B33-2)
- the first step the synthesis of 4-nitrosomorpholine-3-carboxylic acid (B34-2)
- Morpholine-3-carboxylate hydrochloride (8.00g, 47.7mmol) was dissolved in water (100mL), and sodium nitrite (4.94g, 71.6mmol) was added to the reaction solution in batches at 0°C. °C for 3 hours.
- Water (100 mL) was added to the reaction solution, then extracted with ethyl acetate (300 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
- the fifth step 3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-N-(4-methoxybenzyl)- Synthesis of N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide (B34-6)
- the sixth step 3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-N-methyl-4-((4- (Trifluoromethyl)phenyl)amino)benzenesulfonamide (I-34)
- Embodiment 35 Preparation of Compound I-35
- the synthetic route is as follows:
- the first step the synthesis of 2-(2-methyl-5-oxomorpholine) methyl acetate (B35-2)
- the third step the synthesis of 2-bromo-6-methyl-5,6-dihydro-8H-imidazol[2,1-c][1,4]oxazine (B35-4)
- compound B35-4 (359mg, 1.65mmol) was reacted with intermediate A1 (0.6g, 1.38mmol) to obtain compound 4-fluoro-N-(4-methoxybenzyl)-N- Methyl-3-(6-methyl-5,6-dihydro-8H-imidazol[2,1-c][1,4]oxazin-2-yl)benzenesulfonamide (B35-5) (450mg , yield 73.3%).
- Compound B35-6 removes the PMB group in trifluoroacetic acid to give N-methyl-3-(6-methyl-5,6-dihydro-8H-imidazol[2,1-c][1,4 ]oxazin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (I-35) (50 mg, yield: 31.4%)
- Embodiment 36 Preparation of Compound I-36
- the synthetic route is as follows:
- (2S,4S)-4-Fluoropyrrolidine-2-carboxylate hydrochloride (9.00g, 53.1mmol) was dissolved in water (50.0mL), and sodium nitrite (3.66g, 53.1mmol ) were added to the reaction solution in batches, and reacted at 20°C for 4 hours.
- Water (100 mL) was added to the reaction solution, then extracted with ethyl acetate (400 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain crude (2S,4S)-4-fluoro-1- Nitrosopyrrolidine-2-carboxylic acid (B36-2) (8.00 g, yield 93.0%).
- (2S,4S)-4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid (B36-2) (8.00g, 49.3mmol) was dissolved in toluene (100mL), and trifluoroacetic anhydride ( 15.6g, 74.0mmol) was added to the reaction solution and reacted at 20°C for 2 hours. The reaction solution was concentrated to obtain a crude product.
- reaction solution to water (50.0 mL), then adjust the pH to neutral with potassium carbonate, then extract with ethyl acetate (50.0 mL), wash the organic phase with saturated brine (80.0 mL), dry over sodium sulfate, and concentrate get crude.
- the synthetic route is as follows:
- the first step Synthesis of 2,4,5-tribromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H imidazole (B37-2)
- the third step the synthesis of 5,6-dibromo-2,3-dihydroimidazol[2,1-b]oxazole (B37-4)
- compound B37-5 (347mg, 1.84mmol) was reacted with intermediate A1 (0.8g, 1.84mmol) to obtain compound 3-(2,3-dihydroimidazo[2,1-b] Oxazol-6-yl)-4-fluoro-N-(4-methoxybenzyl)-N-toluenesulfonamide (B37-6) (0.2 g, yield: 26.1%).
- the synthetic route is as follows:
- the first step the synthesis of 2-(3-oxomorpholino) methyl acetate (B38-2)
- compound B38-4 (466mg, 2.30mmol) was reacted with intermediate A1 (1.00g, 2.30mmol) to obtain compound 3-(6,8-dihydro-5H-imidazo[2,1 -c][1,4]oxazin-2-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B38-5) (300mg, yield 30.2% ).
- Compound B38-6 (200mg, 349 ⁇ mol) removes the PMB group in trifluoroacetic acid to obtain 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine- 2-yl)-N-methyl-4-((5-(trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (I-38) (53.7 mg, 32.9% yield).
- Embodiment 39 Preparation of Compound I-39
- the synthetic route is as follows:
- Embodiment 40 Preparation of Compound I-40
- the synthetic route is as follows:
- the first step the synthesis of methyl 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate (B40-2)
- the second step the synthesis of 4-(hydroxymethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (B40-3)
- the third step the synthesis of 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carbaldehyde (B40-4)
- the fourth step the synthesis of 4-(difluoromethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (B40-5)
- the fifth step the synthesis of 4-(difluoromethyl)pyrrolidin-2-one (B40-6)
- the sixth step the synthesis of methyl 2-(4-(difluoromethyl)-2-oxopyrrolidin-1-yl)acetate (B40-7)
- Step 8 Synthesis of 2-bromo-6-(difluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B40-9)
- the synthetic route is as follows:
- the synthetic route is as follows:
- the second step the synthesis of 2-(4-trifluoromethyl-2-oxopyrrolidin-1-yl)acetamide (B42-3)
- the third step Synthesis of 2-bromo-6-trifluoromethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (B42-4)
- reaction solution was added to a saturated potassium carbonate aqueous solution, the pH was adjusted to 7-8, and then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain a crude product, which was washed with silica gel
- N-(4-methoxybenzyl)-N-methyl-3-(6-trifluoromethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl )-4-((5-(trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (B42-6) 400 mg, 639 ⁇ mol was removed from the PMB group in trifluoroacetic acid (10.0 mL), N-methyl-3-(6-trifluoromethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-4-((5-(trifluoro Methyl)pyridin-2-yl)amino)benzenesulfonamide (I-42) (28.6 mg, 8.50% yield).
- the synthetic route is as follows:
- Step 1 Synthesis of (R)-6-bromo-2,5-dimethyl-2,3-dihydroimidazo[2,1-b]oxazole (B43-1)
- N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4- ((5-(Trifluoromethyl)pyridin-2-yl)amino)benzenesulfonamide (B43-3) removes the PMB group in trifluoroacetic acid (1ml) to give N-methyl Base-3-(2-methyl-2,3-dihydroimidazol[2,1-b]oxazol-6-yl)-4-((5-(trifluoromethyl)pyridin-2-yl) Amino)benzenesulfonamide (I-43) (50 mg, 90% yield).
- the synthetic route is as follows:
- the first step the synthesis of 2-(3-oxomorpholino)acetamide (B44-2)
- the second step the synthesis of 2-bromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine (B44-3)
- the synthetic route is as follows:
- the synthetic route is as follows:
- the first step the synthesis of N-(2-bromo-4-nitrophenyl)-5-(trifluoromethyl)pyridin-2-amine (B54-2)
- N-(2-bromo-4-nitrophenyl)-5-(trifluoromethyl)pyridin-2-amine (B54-2) (0.5g, 1.38mmol) and (R)-2-methyl -6-(tributylstannyl)-2,3-dihydroimidazo[2,1-b]oxazole (0.54g, 1.31mmol) was dissolved in DMF (10mL), under N 2 protection, added [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (76 mg, 0.11 mmol). The reaction solution was reacted at 130° C. for 12 h under N 2 atmosphere.
- I-59 refers to compound I-58, LC-MS, M/Z (ESI): 431.2[M+H] + .
- the preparation of the reference compound refers to the patent WO2020243415A2, and the structure is as follows:
- Test Example 1 TEADs-mediated transcriptional inhibition IC 50 evaluation test
- HEK293T-TEAD Reporter Assay was used to detect the inhibitory effect of small molecule compounds on TEADs-mediated transcription.
- HEK293T-TEAD-LUC reporter cell line was cultured with DMEM+10%FBS+1%PS+200ug/ml Hygromycin as the complete medium, and the cells in the logarithmic phase were seeded in 384-well plates, 2500cell/well/35ul, Incubate overnight at 37°C with 5% CO 2 , add 5uL of the diluted compound to each well the next day (final concentration of DMSO is 0.1%), and set up a positive control group with only DMSO added, and use 2 ⁇ M Okacid acid signal value as negative Control signal, then incubate at 37°C, 5% CO 2 for 48h, use after incubation luciferase assay system (Promega, E2550) and measure the fluorescence signal value on Envision 2104 Multilabel Reader according to the instructions provided by the supplier.
- the inhibition rate was calculated by the following formula, and then the log value of the concentration of the inhibitor was plotted on the X-axis, and the inhibition rate was
- Inhibition% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
- test compound IC 50 (nM) Control compound 70 I-1 28 I-2 63 I-3 55.5 I-5 39.9 I-7 14 I-10 15.7 I-25 47.6 I-32 50.3 I-33 80.9 I-39 18.6 I-41 36.9 I-42 49.9
- HEK293T-TEAD Reporter Assay show that the compounds of the present invention can significantly inhibit the transcriptional activity of TEADs on HEK293T-TEAD-LUC reporter cell line cells, and show a better inhibitory effect than the control compound.
- Test Example 2 Inhibition of malignant mesothelioma cell proliferation test
- the NCI-H226 cell proliferation assay with NF2 mutation was used to detect the inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells.
- NCI-H226 (ATCC, cat#CRL5826) was cultured with RPMI1640+10%FBS+1%PS as the complete medium, and the cells in the logarithmic phase were seeded in a 96-well plate, 800cell/well/195ul, 37°C, Incubate overnight in 5% CO 2 , add 5uL of the diluted compound (final concentration of DMSO is 0.1%) to each well the next day, and set up a positive control group with only DMSO added, and use 1 ⁇ M Staurosporine signal value as the signal of the negative control group, Then 37 ° C, 5% CO 2 incubation for 6 days, after the incubation, aspirate 100ul medium, use Celltiter Glo assay kit (Promega, G7573) and measure the fluorescence signal value on the Envision 2104 Multilabel Reader according to the instructions provided by the supplier. The inhibition rate was calculated by the following formula, and then the log value of the concentration of the inhibitor was plotted on the X-
- Inhibition% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
- NCI-H226 cell proliferation test show that the compound of the present invention can obviously inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).
- test compound IC 50 (nM) Control compound 66 I-1 twenty two I-2 44 I-5 5.7 I-7 45.4 I-10 10.6 I-23 41.5 I-24 10.4 I-25 50 I-32 76.1 I-33 69.6 I-34 5.4 I-37 25.5 I-39 13 I-41 24.2 I-42 48.3 I-44 7.9 I-45 35
- results of the inhibition test of the compound on the proliferation of malignant mesothelioma cells show that the compound of the present invention can obviously proliferate NCI-H226 cells, and shows a more excellent inhibitory effect than the control compound.
- mice For the mouse pharmacokinetics test, three male ICR mice, 20-25g in weight, were fasted overnight and administered orally (10 mg/kg) by gavage. Blood was collected before administration and 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes to collect plasma and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
- mice pharmacokinetic test results show that the compound of the present invention exhibits excellent pharmacokinetic properties and good druggability.
- mice After one week of adaptive feeding of Nu/Nu nude mice (CRL), resuspend the NCI-H226 cells in logarithmic phase in PBS, and inoculate 5 ⁇ 10 6 NCI-H226 cells on the right rear of the mice at 100 ⁇ L/mouse Subcutaneously, observe the tumor growth regularly. When the tumor grows to an average volume of 80-100mm3 , the mice are randomly divided into the model group and the administration group according to the tumor size and body weight, and the tumor is measured and recorded before and during the administration. Volume and animal weight. After the treatment, the model group was used as the control group, and the growth inhibitory effect of the administration group on the tumor was counted, and TGI was calculated.
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Abstract
L'invention concerne un composé tel que représenté dans la formule (I), un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. La définition de chaque groupe dans la formule (I) est telle que décrite dans la présente invention. Le composé est utilisé comme inhibiteur de TEAD pour prévenir et/ou traiter des maladies associées à une expression accrue de TEAD, telles que des maladies liées à la prolifération cellulaire.
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WO2019113236A1 (fr) * | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Composés benzocarbonyle |
CN111132673A (zh) * | 2017-05-03 | 2020-05-08 | 维瓦斯治疗公司 | 非稠合三环化合物 |
CN111542315A (zh) * | 2017-08-21 | 2020-08-14 | 维瓦斯治疗公司 | 苯并磺酰基化合物 |
WO2020243415A2 (fr) * | 2019-05-31 | 2020-12-03 | Ikena Oncology, Inc. | Inhibiteurs de tead et leurs utilisations |
WO2021018869A1 (fr) * | 2019-07-29 | 2021-02-04 | Basilea Pharmaceutica International AG | Dérivés de la 1,2,4-oxadiazol-5-one pour le traitement du cancer |
WO2022120355A1 (fr) * | 2020-12-02 | 2022-06-09 | Ikena Oncology, Inc. | Agents de dégradation de tead et leurs utilisations |
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CN111132673A (zh) * | 2017-05-03 | 2020-05-08 | 维瓦斯治疗公司 | 非稠合三环化合物 |
CN111542315A (zh) * | 2017-08-21 | 2020-08-14 | 维瓦斯治疗公司 | 苯并磺酰基化合物 |
WO2019113236A1 (fr) * | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Composés benzocarbonyle |
WO2020243415A2 (fr) * | 2019-05-31 | 2020-12-03 | Ikena Oncology, Inc. | Inhibiteurs de tead et leurs utilisations |
WO2021018869A1 (fr) * | 2019-07-29 | 2021-02-04 | Basilea Pharmaceutica International AG | Dérivés de la 1,2,4-oxadiazol-5-one pour le traitement du cancer |
WO2022120355A1 (fr) * | 2020-12-02 | 2022-06-09 | Ikena Oncology, Inc. | Agents de dégradation de tead et leurs utilisations |
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