WO2022033430A1 - 一种杂三环类化合物及其制备方法和应用 - Google Patents
一种杂三环类化合物及其制备方法和应用 Download PDFInfo
- Publication number
- WO2022033430A1 WO2022033430A1 PCT/CN2021/111513 CN2021111513W WO2022033430A1 WO 2022033430 A1 WO2022033430 A1 WO 2022033430A1 CN 2021111513 W CN2021111513 W CN 2021111513W WO 2022033430 A1 WO2022033430 A1 WO 2022033430A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- alkoxy
- amino
- heterocycle
- pyrrolo
- Prior art date
Links
- -1 Heterotricyclic compound Chemical class 0.000 title claims abstract description 375
- 238000002360 preparation method Methods 0.000 title claims abstract description 89
- 150000001875 compounds Chemical class 0.000 claims abstract description 201
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 55
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 55
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 230000002159 abnormal effect Effects 0.000 claims abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 230000004952 protein activity Effects 0.000 claims abstract description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 172
- 229910052805 deuterium Inorganic materials 0.000 claims description 172
- 229910052736 halogen Inorganic materials 0.000 claims description 167
- 150000002367 halogens Chemical class 0.000 claims description 167
- 125000000623 heterocyclic group Chemical group 0.000 claims description 148
- 229910052739 hydrogen Inorganic materials 0.000 claims description 132
- 239000001257 hydrogen Substances 0.000 claims description 132
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 128
- 150000002431 hydrogen Chemical class 0.000 claims description 127
- 125000004585 polycyclic heterocycle group Chemical group 0.000 claims description 125
- 125000003118 aryl group Chemical group 0.000 claims description 106
- 125000001072 heteroaryl group Chemical group 0.000 claims description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 95
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 80
- 238000000034 method Methods 0.000 claims description 66
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 43
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 40
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 39
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 37
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 35
- 238000006467 substitution reaction Methods 0.000 claims description 34
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 33
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
- 125000003367 polycyclic group Chemical group 0.000 claims description 32
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 31
- 125000002950 monocyclic group Chemical group 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 19
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 15
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 15
- 125000003277 amino group Chemical class 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- 150000003457 sulfones Chemical class 0.000 claims description 12
- 239000002207 metabolite Substances 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 239000002243 precursor Substances 0.000 claims description 11
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 10
- 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 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 9
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical group OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- 150000001204 N-oxides Chemical class 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 238000005576 amination reaction Methods 0.000 claims description 8
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001174 sulfone group Chemical group 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 claims description 5
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 4
- VHIBOFWCGOAFJE-UHFFFAOYSA-N C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.Cl.Cl.[Fe+2] Chemical compound C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.Cl.Cl.[Fe+2] VHIBOFWCGOAFJE-UHFFFAOYSA-N 0.000 claims description 4
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 4
- 239000001099 ammonium carbonate Substances 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- APTKLZSJBQFHPM-OAQYLSRUSA-N (1S)-1'-[12-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine Chemical compound N[C@@H](C(C1)(CC2)CCN2C2=NC(NC=C3SC4=CC=CN=C4C(F)(F)F)=C3C3=NC=CN23)C2=C1C=CC=C2 APTKLZSJBQFHPM-OAQYLSRUSA-N 0.000 claims description 3
- ODRATRMSROBZTH-GAJHUEQPSA-N (3S,4S)-3-methyl-8-(12-naphthalen-1-yl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3C4=C(C=CC=C5)C5=CC=C4)=C3C3=NC=CN23)[C@@H]1N ODRATRMSROBZTH-GAJHUEQPSA-N 0.000 claims description 3
- OYBARCVILCWIDN-HNAYVOBHSA-N (3S,4S)-3-methyl-8-(12-phenyl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3C4=CC=CC=C4)=C3C3=NC=CN23)[C@@H]1N OYBARCVILCWIDN-HNAYVOBHSA-N 0.000 claims description 3
- ICPIXXFXJRXKKX-KSFYIVLOSA-N (3S,4S)-3-methyl-8-(12-quinolin-5-yl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3C4=C(C=CC=N5)C5=CC=C4)=C3C3=NC=CN23)[C@@H]1N ICPIXXFXJRXKKX-KSFYIVLOSA-N 0.000 claims description 3
- ORFZLYMFNCQEEE-ORAYPTAESA-N (3S,4S)-8-[12-(2,3-dichlorophenyl)sulfanyl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3SC(C=CC=C4Cl)=C4Cl)=C3C3=NC=CN23)[C@@H]1N ORFZLYMFNCQEEE-ORAYPTAESA-N 0.000 claims description 3
- XHNOBGJPJUQBTL-LHSJRXKWSA-N (3S,4S)-8-[12-(4-chloro-2-methylindazol-5-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3C(C=CC4=NN(C)C=C44)=C4Cl)=C3C3=NC=CN23)[C@@H]1N XHNOBGJPJUQBTL-LHSJRXKWSA-N 0.000 claims description 3
- 238000005885 boration reaction Methods 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- DULZFHOAFWRMLZ-JOCHJYFZSA-N (1S)-1'-(12-pyridin-4-yl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl)spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine Chemical compound N[C@@H](C(C1)(CC2)CCN2C2=NC(NC=C3C4=CC=NC=C4)=C3C3=NC=CN23)C2=C1C=CC=C2 DULZFHOAFWRMLZ-JOCHJYFZSA-N 0.000 claims description 2
- AUOXSPXQSDPVEF-AREMUKBSSA-N (1S)-1'-(12-quinolin-4-yl-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl)spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine Chemical compound N[C@@H](C(C1)(CC2)CCN2C2=NC(NC=C3C4=C(C=CC=C5)C5=NC=C4)=C3C3=NC=CN23)C2=C1C=CC=C2 AUOXSPXQSDPVEF-AREMUKBSSA-N 0.000 claims description 2
- DKINOFNIUBXSIP-JOCHJYFZSA-N (1S)-1'-[12-(3-chloropyridin-4-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine Chemical compound N[C@@H](C(C1)(CC2)CCN2C2=NC(NC=C3C(C=CN=C4)=C4Cl)=C3C3=NC=CN23)C2=C1C=CC=C2 DKINOFNIUBXSIP-JOCHJYFZSA-N 0.000 claims description 2
- YSUAARLNSNYSAL-IFXJQAMLSA-N (3S,4S)-8-[12-(2-chlorophenyl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3C(C=CC=C4)=C4Cl)=C3C3=NC=CN23)[C@@H]1N YSUAARLNSNYSAL-IFXJQAMLSA-N 0.000 claims description 2
- OYCLZDDODPTWAO-LHSJRXKWSA-N (3S,4S)-8-[12-(5-chloroquinoxalin-6-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC(CC2)(CCN2C2=NC(NC=C3C(C=CC4=C5N=CC=N4)=C5Cl)=C3C3=NC=CN23)[C@@H]1N OYCLZDDODPTWAO-LHSJRXKWSA-N 0.000 claims description 2
- GJDZZMNKODDVFI-HHHXNRCGSA-N 4-[7-[(1S)-1-aminospiro[1,3-dihydroindene-2,4'-piperidine]-1'-yl]-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-12-yl]naphthalen-1-ol Chemical compound N[C@@H](C(C1)(CC2)CCN2C2=NC(NC=C3C(C=C4)=C(C=CC=C5)C5=C4O)=C3C3=NC=CN23)C2=C1C=CC=C2 GJDZZMNKODDVFI-HHHXNRCGSA-N 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- PFXVKGGZWQQTSE-UHFFFAOYSA-N sulfuryl dicyanide Chemical compound N#CS(=O)(=O)C#N PFXVKGGZWQQTSE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims 2
- AHXROKUZDXRXMT-OAQYLSRUSA-N (3R)-1'-[12-(3-chloropyridin-4-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]spiro[3H-1-benzofuran-2,4'-piperidine]-3-amine Chemical compound N[C@@H]1C(C=CC=C2)=C2OC1(CC1)CCN1C1=NC(NC=C2C(C=CN=C3)=C3Cl)=C2C2=NC=CN12 AHXROKUZDXRXMT-OAQYLSRUSA-N 0.000 claims 1
- AQDMIIYOUCXGMR-LJQANCHMSA-N (4R)-8-[12-(4-chloro-2-methylindazol-5-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-8-azaspiro[4.5]decan-4-amine Chemical compound CN1N=C(C=CC(C2=CNC3=C2C2=NC=CN2C(N(CC2)CCC2(CCC2)[C@@H]2N)=N3)=C2Cl)C2=C1 AQDMIIYOUCXGMR-LJQANCHMSA-N 0.000 claims 1
- HSVIYQFAAWYXBL-GOSISDBHSA-N (4S)-8-[12-(4-chloro-2-methylindazol-5-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound CN1N=C(C=CC(C2=CNC3=C2C2=NC=CN2C(N(CC2)CCC2(COC2)[C@@H]2N)=N3)=C2Cl)C2=C1 HSVIYQFAAWYXBL-GOSISDBHSA-N 0.000 claims 1
- 125000006802 (C2-C6) alkynylamino group Chemical group 0.000 claims 1
- JAYWEHSMQZTEAW-UHFFFAOYSA-N 1-[12-(4-chloro-2-methylindazol-5-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-7-yl]-4-methylpiperidin-4-amine Chemical compound CC(CC1)(CCN1C1=NC(NC=C2C(C=CC3=NN(C)C=C33)=C3Cl)=C2C2=NC=CN12)N JAYWEHSMQZTEAW-UHFFFAOYSA-N 0.000 claims 1
- CWVKBTNAEMWPHW-UHFFFAOYSA-N 12-(4-chloro-2-methylindazol-5-yl)-7-(1,4-diazepan-1-yl)-3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaene Chemical compound CN1N=C(C=CC(C2=CNC3=C2C2=NC=CN2C(N2CCNCCC2)=N3)=C2Cl)C2=C1 CWVKBTNAEMWPHW-UHFFFAOYSA-N 0.000 claims 1
- YXPUNWKYPJPPFC-UHFFFAOYSA-N COC1=C(C(=CC=C1)OC)C1=CC=CC=C1.P Chemical group COC1=C(C(=CC=C1)OC)C1=CC=CC=C1.P YXPUNWKYPJPPFC-UHFFFAOYSA-N 0.000 claims 1
- 150000005840 aryl radicals Chemical class 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
- 125000000565 sulfonamide group Chemical group 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 13
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 description 199
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 183
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 85
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 76
- 239000007787 solid Substances 0.000 description 56
- 239000000243 solution Substances 0.000 description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
- 239000012043 crude product Substances 0.000 description 34
- 0 C*=C(*)C1=C(C)*=C(*(*)C*)*2C=*(C3)[C@@]3*C12 Chemical compound C*=C(*)C1=C(C)*=C(*(*)C*)*2C=*(C3)[C@@]3*C12 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 31
- 230000005764 inhibitory process Effects 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 16
- 230000002401 inhibitory effect Effects 0.000 description 16
- 235000011181 potassium carbonates Nutrition 0.000 description 16
- 239000003921 oil Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 229910021529 ammonia Inorganic materials 0.000 description 13
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 101150003085 Pdcl gene Proteins 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- 239000000758 substrate Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 9
- 230000006044 T cell activation Effects 0.000 description 9
- 230000002255 enzymatic effect Effects 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 6
- 108700008625 Reporter Genes Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000011535 reaction buffer Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 101800001401 Activation peptide Proteins 0.000 description 5
- 102400000069 Activation peptide Human genes 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 125000003003 spiro group Chemical group 0.000 description 5
- 108010009202 Growth Factor Receptors Proteins 0.000 description 4
- 102000009465 Growth Factor Receptors Human genes 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000001917 fluorescence detection Methods 0.000 description 4
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 3
- DZANYXOTJVLAEE-UHFFFAOYSA-N 6,8-difluoro-4-methylumbelliferyl phosphate Chemical compound FC1=C(OP(O)(O)=O)C(F)=CC2=C1OC(=O)C=C2C DZANYXOTJVLAEE-UHFFFAOYSA-N 0.000 description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 description 3
- 108010074708 B7-H1 Antigen Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 3
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 3
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 229910001947 lithium oxide Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VUYVXCJTTQJVKJ-UHFFFAOYSA-L palladium(2+);tricyclohexylphosphane;dichloride Chemical compound Cl[Pd]Cl.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 VUYVXCJTTQJVKJ-UHFFFAOYSA-L 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 3
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- LFILDSDQMSCNBV-LURJTMIESA-N propane-2-sulfinamide Chemical compound CC(C)[S@@](N)=O LFILDSDQMSCNBV-LURJTMIESA-N 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- DVBFPMDYIJYYKK-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-3-thiol Chemical compound SC=1C(=NC=CC1)C(F)(F)F DVBFPMDYIJYYKK-UHFFFAOYSA-N 0.000 description 2
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 2
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 2
- LJFSIDNUMPTTAF-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC2=CC=CC=C12 LJFSIDNUMPTTAF-UHFFFAOYSA-N 0.000 description 2
- PEHVGBZKEYRQSX-UHFFFAOYSA-N 7-deaza-adenine Chemical compound NC1=NC=NC2=C1C=CN2 PEHVGBZKEYRQSX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 2
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- XZRUNZCMOCXTDJ-UHFFFAOYSA-N P.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P.CC1(C)c2ccccc2Oc2ccccc12 XZRUNZCMOCXTDJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 102000018120 Recombinases Human genes 0.000 description 2
- 108010091086 Recombinases Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 2
- 230000003281 allosteric effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- YOMWYEITAAOYEC-UHFFFAOYSA-N butane-2-sulfinamide Chemical compound CCC(C)S(N)=O YOMWYEITAAOYEC-UHFFFAOYSA-N 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 102000048776 human CD274 Human genes 0.000 description 2
- 102000048362 human PDCD1 Human genes 0.000 description 2
- 102000044858 human PTPN11 Human genes 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229940126546 immune checkpoint molecule Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- ONOKMILZEVKNEA-UHFFFAOYSA-N spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine Chemical compound N1CCC2(CC1)C(C1=CC=CC=C1C2)N ONOKMILZEVKNEA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- TYIKXPOMOYDGCS-UHFFFAOYSA-N (2,3-dichlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1Cl TYIKXPOMOYDGCS-UHFFFAOYSA-N 0.000 description 1
- XBFYDECHVMPQHV-UHFFFAOYSA-N (2-bromo-3-chloropyridin-4-yl)boronic acid Chemical compound OB(O)C1=CC=NC(Br)=C1Cl XBFYDECHVMPQHV-UHFFFAOYSA-N 0.000 description 1
- UCJZOKGUEJUNIO-IINYFYTJSA-N (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC2(CCN(CC2)C2=CN=C(SC3=C(Cl)C(N)=NC=C3)C(N)=N2)[C@@H]1N UCJZOKGUEJUNIO-IINYFYTJSA-N 0.000 description 1
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 1
- HGYTYZKWKUXRKA-MRXNPFEDSA-N 1-[4-[3-amino-5-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-3,3-difluoro-2H-indol-1-yl]ethanone Chemical compound NC=1C(=NC=C(N=1)N1CCC2([C@@H](COC2)N)CC1)SC1=C2C(CN(C2=CC=C1)C(C)=O)(F)F HGYTYZKWKUXRKA-MRXNPFEDSA-N 0.000 description 1
- NFVJBEHBWDPHCF-UHFFFAOYSA-N 1-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound CC1OCC(C11CCNCC1)N NFVJBEHBWDPHCF-UHFFFAOYSA-N 0.000 description 1
- WGBFZRUMPWHPRJ-UHFFFAOYSA-N 1-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound O1CCC(C11CCNCC1)N WGBFZRUMPWHPRJ-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- QGRKONUHHGBHRB-UHFFFAOYSA-N 2,3-dichlorobenzenethiol Chemical compound SC1=CC=CC(Cl)=C1Cl QGRKONUHHGBHRB-UHFFFAOYSA-N 0.000 description 1
- GVVNJCCBLOXETG-UHFFFAOYSA-N 2-(1,3-benzodioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC2=C1OCO2 GVVNJCCBLOXETG-UHFFFAOYSA-N 0.000 description 1
- ZHZARBYBLJOTCS-UHFFFAOYSA-N 2-[(2,4-dichloro-5-pyridin-4-ylpyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethylsilane Chemical compound C12=C(Cl)N=C(Cl)N=C2N(COCC[Si](C)(C)C)C=C1C1=CC=NC=C1 ZHZARBYBLJOTCS-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- CGXKWAJDTOSBHZ-UHFFFAOYSA-N 2-amino-3-chloro-1H-pyridine-4-thione Chemical compound NC1=NC=CC(=C1Cl)S CGXKWAJDTOSBHZ-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- WRFPVMFCRNYQNR-UHFFFAOYSA-N 2-hydroxyphenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1O WRFPVMFCRNYQNR-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- WJMSINQARSIDBW-RBFZIWAESA-N 2-methyl-N-[(1S)-spiro[1,3-dihydroindene-2,4'-piperidine]-1-yl]propane-2-sulfinamide Chemical compound N1CCC2(CC1)[C@@H](C1=CC=CC=C1C2)NS(=O)C(C)(C)C WJMSINQARSIDBW-RBFZIWAESA-N 0.000 description 1
- MRSZSPVVWPUESC-UHFFFAOYSA-N 3,6,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,3,7,9,11-pentaene Chemical compound N1=CCN2C=NC=3C(=C21)C=CN=3 MRSZSPVVWPUESC-UHFFFAOYSA-N 0.000 description 1
- MROVZCRMXJZHCN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-hydroxyethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCO)C=CC=1 MROVZCRMXJZHCN-UHFFFAOYSA-N 0.000 description 1
- ZMCQQCBOZIGNRV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(1,2,4-triazol-1-yl)ethyl]benzamide Chemical compound NCC1=CC(OC2=CC=CC(=C2)C(=O)NCCN2C=NC=N2)=NC(=C1)C(F)(F)F ZMCQQCBOZIGNRV-UHFFFAOYSA-N 0.000 description 1
- AJZDHLHTTJRNQJ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(tetrazol-1-yl)ethyl]benzamide Chemical compound N1(N=NN=C1)CCNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O AJZDHLHTTJRNQJ-UHFFFAOYSA-N 0.000 description 1
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-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
- VUWRRLUCWJCPMF-UHFFFAOYSA-N 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC=C1Cl VUWRRLUCWJCPMF-UHFFFAOYSA-N 0.000 description 1
- YGUFCDOEKKVKJK-UHFFFAOYSA-N 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine Chemical compound NC1(CCN(CC1)C1=CN=C(C(=N1)N)C1=C(C(=CC=C1)Cl)Cl)C YGUFCDOEKKVKJK-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- ZERCTXGMBRAWQP-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octan-3-amine Chemical compound C1C(N)CC2CCC1N2 ZERCTXGMBRAWQP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZZHWFUDVZGOQSF-ULUSZKPHSA-N C(C1)[C@H]2NC1CNCC2 Chemical compound C(C1)[C@H]2NC1CNCC2 ZZHWFUDVZGOQSF-ULUSZKPHSA-N 0.000 description 1
- ISGOOAZVDIZEMN-UHFFFAOYSA-N C1C2NCC1CNC2 Chemical compound C1C2NCC1CNC2 ISGOOAZVDIZEMN-UHFFFAOYSA-N 0.000 description 1
- XVXBRZPKYXNDAC-UHFFFAOYSA-N CC(C)C1=CCC2NN=NC2=C1 Chemical compound CC(C)C1=CCC2NN=NC2=C1 XVXBRZPKYXNDAC-UHFFFAOYSA-N 0.000 description 1
- HFYWOOUKPVJGBA-UHFFFAOYSA-N CC(C)c1ccnc2c1cccc2 Chemical compound CC(C)c1ccnc2c1cccc2 HFYWOOUKPVJGBA-UHFFFAOYSA-N 0.000 description 1
- BXOFMBYDOREPNM-UHFFFAOYSA-N CC1=CC2SC=NC2C=C1 Chemical compound CC1=CC2SC=NC2C=C1 BXOFMBYDOREPNM-UHFFFAOYSA-N 0.000 description 1
- YTGIWZVLLCQQPW-UHFFFAOYSA-N CCc(cc1)cc2c1[nH]nc2 Chemical compound CCc(cc1)cc2c1[nH]nc2 YTGIWZVLLCQQPW-UHFFFAOYSA-N 0.000 description 1
- BZZCGYHKQRWOCM-UHFFFAOYSA-N CN(CC1)CCC1(C1)Oc2c1cccc2 Chemical compound CN(CC1)CCC1(C1)Oc2c1cccc2 BZZCGYHKQRWOCM-UHFFFAOYSA-N 0.000 description 1
- AFXMWPJJZSIUHD-UHFFFAOYSA-N CN(CC1)CCC11OCCC1 Chemical compound CN(CC1)CCC11OCCC1 AFXMWPJJZSIUHD-UHFFFAOYSA-N 0.000 description 1
- TYVLSEQHFRQJPZ-UHFFFAOYSA-N CN(CCC12)CC1NC2C1[N](C)(C)CC2(CNC2)C1 Chemical compound CN(CCC12)CC1NC2C1[N](C)(C)CC2(CNC2)C1 TYVLSEQHFRQJPZ-UHFFFAOYSA-N 0.000 description 1
- JOWAQVQRALBJGS-UHFFFAOYSA-N CN1C2CNCC1C2 Chemical compound CN1C2CNCC1C2 JOWAQVQRALBJGS-UHFFFAOYSA-N 0.000 description 1
- WTDREKHEHGDYAC-UHFFFAOYSA-N CN1CCC(C2)(Cc3c2cccc3)CC1 Chemical compound CN1CCC(C2)(Cc3c2cccc3)CC1 WTDREKHEHGDYAC-UHFFFAOYSA-N 0.000 description 1
- NTMYZTCUNFLGFE-UHFFFAOYSA-N CN1CCC(C2)(Cc3c2cccn3)CC1 Chemical compound CN1CCC(C2)(Cc3c2cccn3)CC1 NTMYZTCUNFLGFE-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N CN1CCCCC1 Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- YFDRYBUJCGOYCQ-WDSKDSINSA-N CN1[C@@H](C2)CN[C@@H]2C1 Chemical compound CN1[C@@H](C2)CN[C@@H]2C1 YFDRYBUJCGOYCQ-WDSKDSINSA-N 0.000 description 1
- TXQDHQBSNAJSHQ-ZBHICJROSA-N C[C@@H]1NC(C)C=C1 Chemical compound C[C@@H]1NC(C)C=C1 TXQDHQBSNAJSHQ-ZBHICJROSA-N 0.000 description 1
- AKOLDLJOFHJDDT-UHFFFAOYSA-N C[ClH]CCNCC[ClH]C Chemical compound C[ClH]CCNCC[ClH]C AKOLDLJOFHJDDT-UHFFFAOYSA-N 0.000 description 1
- HNQGJCZTRDEZPY-UHFFFAOYSA-N C[N]1(CCC2(CNC2)CC1)[IH]C Chemical compound C[N]1(CCC2(CNC2)CC1)[IH]C HNQGJCZTRDEZPY-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 101150039808 Egfr gene Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 1
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 1
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- NHPPIJMARIVBGU-UHFFFAOYSA-N Ic1cccc2c1cccc2 Chemical compound Ic1cccc2c1cccc2 NHPPIJMARIVBGU-UHFFFAOYSA-N 0.000 description 1
- XDELKSRGBLWMBA-UHFFFAOYSA-N Ic1cnccc1 Chemical compound Ic1cnccc1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- FHTVMTXPCSHMQY-UHFFFAOYSA-N Nc1cc(CC(CC2)=O)c2cc1 Chemical compound Nc1cc(CC(CC2)=O)c2cc1 FHTVMTXPCSHMQY-UHFFFAOYSA-N 0.000 description 1
- HZPNYRFNYKDKRM-UHFFFAOYSA-N O=C(c1ccccc1)ON(CC1)CCC1(Cc1ccccc11)C1=O Chemical compound O=C(c1ccccc1)ON(CC1)CCC1(Cc1ccccc11)C1=O HZPNYRFNYKDKRM-UHFFFAOYSA-N 0.000 description 1
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 1
- 101150048674 PTPN11 gene Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940126002 RMC-4630 Drugs 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- 229940125811 TNO155 Drugs 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- LJHFUFVRZNYVMK-ZDUSSCGKSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3S)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@H](CC1)O LJHFUFVRZNYVMK-ZDUSSCGKSA-N 0.000 description 1
- HISJAYUQVHMWTA-BLLLJJGKSA-N [6-(2-amino-3-chloropyridin-4-yl)sulfanyl-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl]methanol Chemical compound NC1=NC=CC(=C1Cl)SC1=C(N=C(C(=N1)CO)N1CCC2([C@@H]([C@@H](OC2)C)N)CC1)C HISJAYUQVHMWTA-BLLLJJGKSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229940125528 allosteric inhibitor Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000001908 autoinhibitory effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- XRVDKIQEFCJTBZ-UHFFFAOYSA-N c1nc(ccnc2)c2[o]1 Chemical compound c1nc(ccnc2)c2[o]1 XRVDKIQEFCJTBZ-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 108700021358 erbB-1 Genes Proteins 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000006166 lysate Substances 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- PPPQGEJKMPGMLM-CQSZACIVSA-N tert-butyl N-[(3R)-spiro[3H-1-benzofuran-2,4'-piperidine]-3-yl]carbamate Chemical compound N1CCC2(CC1)OC1=C([C@H]2NC(OC(C)(C)C)=O)C=CC=C1 PPPQGEJKMPGMLM-CQSZACIVSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the technical field of medicine, and in particular relates to a brand-new heterotricyclic compound of SHP2 inhibitor and a preparation method and application thereof.
- SHP2 is a subtype of the Src homology 2 domain (SH2) protein tyrosine phosphatase (PTP) family, a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene.
- SH2 Src homology 2 domain
- PTP protein tyrosine phosphatase
- the N-SH2 domain of the SHP2 protein binds to the PTP domain to block the entry of the substrate into the catalytic site, thereby making the SHP2 activity self-inhibited.
- the SH2 domain destroys the autoinhibitory state of SHP2 by binding to a specific phosphotyrosine motif, and SHP2 is activated to perform the function of substrate dephosphorylation.
- SHP2 can regulate cell growth, differentiation and apoptosis by activating the RAS-ERK signaling pathway.
- SHP2 is also a key mediator in receptor tyrosine kinase (RTK) signaling that regulates cell proliferation.
- RTK receptor tyrosine kinase
- recent studies have shown that SHP2 is an important protein in the process of Kras-driven tumor cell growth, and SHP2 can also bind to the phosphotyrosine motif of PD1 through the N-SH2 domain, which not only inhibits T cell activation but also may Disable T cells.
- SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade. Acta Pharm Sin B. 2019, 9(2):304-315.). Therefore, the development of novel small-molecule SHP2 inhibitors will provide new therapeutic opportunities for cancer patients.
- the SHP2 inhibitors reported so far can be divided into two categories, including the first category of catalytic site inhibitors, such as those containing sulfonic acid groups, salicylic acid groups, and those derived from Inhibitors of natural products, in order to have a strong inhibitory effect, these structures usually use the phosphate group in the mimic substrate tyrosine phosphate, which leads to their poor oral bioavailability, which affects druggability;
- the second class of allosteric inhibitors was first reported by the Novartis research team in 2016, and the site of action is at the interface of the N-SH2, C-SH2 and PTP domains of SHP2.
- SHP2 inhibitors including SHP099, TNO155, RMC4630, JAB-3068, JAB-3312 and other SHP2 inhibitors in clinical research, but no approved drugs are on the market.
- One aspect of the present invention relates to heterotricyclic compounds capable of inhibiting the activity of SHP2 protein, as well as isomers, pharmaceutically acceptable salts, precursors, metabolites and N-oxides thereof.
- Another aspect of the present invention pertains to methods of making the compounds described herein.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the present invention as an active ingredient, and a drug for treating and/or preventing a disease associated with abnormal SHP2 protein activity by the compound or the pharmaceutical composition of the present invention; for the treatment of tumors or cancer.
- the present invention relates to compounds represented by formula (I), or isomers, pharmaceutically acceptable salts, precursors, metabolites, N oxides thereof,
- Ring A is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently a 5- to 12-membered monocyclic or polycyclic ring ;
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- X 1 is selected from CH or N;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3-15 membered mono-heterocycle or polycyclic heterocycle, wherein said C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3-15 membered mono- or polycyclic heterocycles are each independently optionally selected from one or more halogens , hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy base, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycles include but are not limited to spiro heterocycles, bridged heterocycles, fused
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3-15 membered mono-heterocycle or polycyclic heterocycle, wherein said C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3-15 membered mono- or polycyclic heterocycles are each independently optionally selected from one or more halogens , hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy base, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycles include but are not limited to spiro heterocycles, bridged heterocycles, fused
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, R c SO 2 -NR a COC 2 -C 6 alkenyl, -NR a CONR a , -NR a SONR a , sulfone group, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono C 1 -C 4 alkyl amino, bis C 1 -C 4 alkyl amino
- the polycyclic heterocycles include, but are not limited to, spirocyclic heterocycles, bridged heterocycles, and fused ring heterocycles; alternatively, spirocyclic heterocycles
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- p and q which are the same or different, are each independently selected from 0, 1;
- s and t which are the same or different, are each independently selected from 0, 1, 2, 3, and 4;
- Ring B is cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently a 3-15-membered monocyclic or polycyclic ring;
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, R c SO 2 -, hydroxyl, mercapto, cyano, amino, Nitro group, carboxyl group, wherein said C 1 -C 4 alkyl group, C 2 -C 6 alkenyl group, C 1 -C 4 alkoxy group, mercapto group, amino group, carboxyl group are each independently replaced by one or more deuterium, halogen , sulfone, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substituted;
- R b may be selected from hydrogen, deuterium, C 1 -C 4 alkyl
- R c is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein Said C 1 -C 4 alkyl group, C 2 -C 6 alkenyl group, C 1 -C 4 alkoxy group, mercapto group, amino group and carboxyl group are each independently replaced by one or more deuterium, halogen, sulfone, hydroxyl, Substitution of mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
- R d is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein The C 1 -C 4 alkyl group, C 2 -C 6 alkenyl group, C 1 -C 4 alkoxy group, sulfone group, mercapto group, amino group and carboxyl group are each independently replaced by one or more deuterium, halogen, sulfone groups , hydroxy, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substituted;
- the present invention relates to compounds represented by formula (I), or isomers, pharmaceutically acceptable salts, precursors, metabolites, N oxides thereof, wherein,
- Ring A in R 1 is selected from heterocyclyl, aryl, and heteroaryl, wherein the heterocyclyl, aryl, and heteroaryl are each independently a 5-12-membered monocyclic or polycyclic ring;
- Exemplary rings for Ring A include, but are not limited to:
- n is selected from 0, 1, 2, 3, 4, 5;
- X 1 is selected from CH or N;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, 3-15-membered monoheterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, 3-15 membered mono-heterocycle or polycyclic heterocycle are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 - C4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, mono C 1 -C 4 alkylamino, bis-C 1 - C 4 alkylamino substituted, the polycyclic heterocycles include but are not limited to spirocyclic heterocycles, bridged heterocycles, fused ring heterocycles, or, spirocycl
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, wherein said C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl are each independently optional by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen Substituted C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substitution, the polycyclic heterocycles include but are not limited to spiro heterocycles, bridged heterocycles Ring, fused heterocycle, spiro heterocycle, bridged heterocycle may be fused to an aryl, heteroaryl or cycloalkyl ring; or
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, sulfone, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkyl Oxygen, single C 1 -C 4 alkylamino, double C 1 -C 4 alkyl amino group substitution, the polycyclic heterocycle includes but not limited to spiro heterocycle, bridged heterocycle, fused ring Heterocycle; alternatively, spiro heterocycle, bridged heterocycle can also be fused to aryl, heteroaryl or cycloalkyl ring;
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- p and q which are the same or different, are each independently selected from 0, 1;
- R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxyl, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy; or
- s and t may be the same or different each independently selected from 0, 1, 2, 3, 4;
- R 7 and R 8 may be the same or different independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxyl, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, Hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy; or
- Ring B is an aryl group or a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 3-15-membered monocyclic or polycyclic ring;
- n is selected from 0, 1, 2, 3, 4, 5, 6;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, R c SO 2 -, hydroxyl, mercapto, cyano, amino, Nitro group, carboxyl group, wherein said C 1 -C 4 alkyl group, C 2 -C 6 alkenyl group, C 1 -C 4 alkoxy group, mercapto group, amino group, carboxyl group are each independently replaced by one or more deuterium, halogen , hydroxy, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substituted;
- R b is selected from hydrogen, deuterium, C 1 -C 4 alkyl
- R c is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein The C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, mercapto, amino, and carboxyl groups are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano base, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substituted;
- R d is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein Said C 1 -C 4 alkyl group, C 2 -C 6 alkenyl group, C 1 -C 4 alkoxy group, sulfone group, mercapto group, amino group and carboxyl group are each independently replaced by one or more deuterium, halogen, hydroxyl, Substitution of mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
- the present invention relates to the compound represented by formula (I), or its isomer, pharmaceutically acceptable salt, precursor, metabolite, N-oxide, wherein,
- Ring A is selected from an aryl group and a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 5-12 membered monocyclic or polycyclic ring;
- Exemplary preferred rings for Ring A include, but are not limited to:
- n is selected from 0, 1, 2, 3, 4, 5;
- X 1 is selected from CH or N;
- X 2 , X 3 are the same or different, each independently selected from CR a , N, O;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle
- the cyclic heterocycles are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to A spiro heterocycle, a bridged heterocycle, a fused heterocycle, or, a spiro heterocycle, a bridged heterocycle can also be fused to an ary
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered monoheterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl and 3-15-membered heterocyclic groups are each independently optionally optionally by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy base, halogenated C 1 -C 4 alkoxy, mono C 1 -C 4 alkylamino, bis C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to spiro heterocycle, A bridged heterocycle, a fused heterocycle, or a spiro heterocycle, a bridged heterocycle can also be fused to an aryl, heteroaryl, or cycloalkyl ring; or
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy,
- the group substitution of single C 1 -C 4 alkylamino group and double C 1 -C 4 alkyl amino group, and the polycyclic heterocycles include but are not limited to spirocyclic heterocycles, bridged heterocycles, and fused ring heterocycles; Alternatively, spiro heterocycles, bridged heterocycles can also be fused to aryl, heteroaryl or cycloalkyl rings;
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- p and q which are the same or different, are each independently selected from 0, 1;
- R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, C1- C4alkoxy , halogenated C1 - C4alkoxy ; or
- s and t which are the same or different, are each independently selected from 0, 1, 2, 3, and 4;
- R 7 and R 8 are the same or different and are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, C1- C4alkoxy , halogenated C1 - C4alkoxy ; or
- W is selected from O, NH, or absent
- Ring B is an aryl group or a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 3-15-membered monocyclic or polycyclic ring;
- R 9 which are the same or different are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl , C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy;
- n is selected from 0, 1, 2, 3, 4;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- R b is selected from hydrogen, deuterium, methyl, ethyl, isopropyl
- R c is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- R d is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- the present invention relates to the compound represented by formula (I), or its isomer, pharmaceutically acceptable salt, precursor, metabolite, N-oxide, wherein,
- Ring A is selected from an aryl group and a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 5-12 membered monocyclic or polycyclic ring;
- Exemplary preferred rings for Ring A include, but are not limited to:
- R 2 is independently selected from the same or different hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino, R d CO-, C 1 - described therein C 4 alkyl, C 1 -C 4 alkoxy, amino are each independently replaced by one or more of deuterium, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, halogenated C 1 - C 4 alkoxy, cyano, amino, nitro, carboxyl, C 1 -C 4 alkylcarbonylamino, mono C 1 -C 4 alkylaminocarbonyl, bis C 1 -C 4 alkylaminocarbonyl substituted;
- n is selected from 0, 1, 2, 3, 4, 5;
- X 1 is selected from CH or N;
- X 2 , X 3 are the same or different, each independently selected from CR a , N, O;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle
- the cyclic heterocycles are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to A spiro heterocycle, a bridged heterocycle, a fused heterocycle, or, a spiro heterocycle, a bridged heterocycle can also be fused to an ary
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15 membered mono-heterocycle or polycyclic heterocycle wherein said C 1 -C 4 alkyl, 3-15 membered mono-heterocycle or polycyclic
- the heterocycles are each independently optionally replaced by one or more selected from halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 - C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted
- the polycyclic heterocycle includes but is not limited to spiro A cyclic heterocycle, bridged heterocycle, fused heterocycle, alternatively, a spiro heterocycle, bridged heterocycle can also be fused to an aryl, heteroaryl or cycloalkyl ring
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono C 1 -C 4 alkylamino, bis C 1 -C 4 alkyl
- the amino group is substituted, and the polycyclic heterocycles include but are not limited to spirocyclic heterocycles, bridged heterocycles, and fused ring heterocycles; or, spirocyclic heterocycles and bridged heterocycles can also be fused to an aryl group , heteroaryl or cycloalkyl ring;
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, C1- C4alkoxy , halogenated C1 - C4alkoxy ; or
- s and t which are the same or different, are each independently selected from 0, 1, and 2;
- R 7 and R 8 are the same or different and are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, C1- C4alkoxy , halogenated C1 - C4alkoxy ; or
- W is selected from O, NH, or absent
- Ring B is an aryl group or a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 3-15-membered monocyclic or polycyclic ring;
- R 9 is each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 - C 4 alkoxy, halogenated C 1 -C 4 alkoxy;
- n is selected from 0, 1, 2;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- R b is selected from hydrogen, deuterium, methyl, ethyl, isopropyl
- R d is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- the present invention relates to the compound represented by formula (I), or its isomer, pharmaceutically acceptable salt, precursor, metabolite, N oxide, wherein,
- Ring A is selected from an aryl group and a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 5-12 membered monocyclic or polycyclic ring;
- Exemplary preferred rings for Ring A include, but are not limited to:
- R 2 is independently selected from the same or different hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino, C 1 -C 4 alkyl described therein, C 1 -C 4 alkoxy, amino are each independently replaced by one or more of deuterium, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy , cyano, amino, C 1 -C 4 alkylcarbonylamino, single C 1 -C 4 alkylaminocarbonyl, double C 1 -C 4 alkylaminocarbonyl substitution;
- n 0, 1, 2, 3;
- X 1 is selected from CH or N;
- X 2 and X 3 are the same or different, each independently selected from CR a , N;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle, wherein said C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle
- the cyclic heterocycles are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to A spiro, bridged, or fused heterocycle, which may be fused to an aryl, heteroaryl, or cycloalkyl ring; or
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono C 1 -C 4 alkylamino, bis C 1 -C 4 alkyl
- the amino group is substituted, and the polycyclic heterocycles include but are not limited to spirocyclic heterocycles, bridged heterocycles, and fused ring heterocycles; or, spirocyclic heterocycles and bridged heterocycles can also be fused to an aryl group , heteroaryl or cycloalkyl ring;
- exemplary 3-15 membered monoheterocycles or polycyclic heterocycles formed by R3 and R4 together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, C1- C4alkoxy , halogenated C1 - C4alkoxy ; or
- s and t which are the same or different are independently selected from 0 and 1;
- R 7 and R 8 are the same or different and are independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, C1- C4alkoxy , halogenated C1 - C4alkoxy ; or
- W is selected from O, NH, or absent
- Ring B is an aryl group or a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 3-15-membered monocyclic or polycyclic ring;
- R 9 which are the same or different are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl , C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy;
- n is selected from 0, 1, 2;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- R b is selected from hydrogen, deuterium, methyl, ethyl, isopropyl
- the present invention relates to a compound represented by formula (I), or its isomer, pharmaceutically acceptable salt, precursor, metabolite, N-oxide, wherein,
- Ring A is selected from an aryl group and a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 5-12 membered monocyclic or polycyclic ring;
- Exemplary preferred rings for Ring A include, but are not limited to:
- R 2 is independently selected from the same or different hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, wherein said C 1 -C 4 alkyl, C 1 - C 4 alkoxy, amino are each independently replaced by one or more of deuterium, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, cyano , amino substitution;
- n 0, 1, 2, 3;
- X 1 is selected from CH or N;
- X 2 and X 3 are the same or different, each independently selected from CR a , N;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle
- the cyclic heterocycles are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to A spiro heterocycle, a bridged heterocycle, a fused heterocycle, or, a spiro heterocycle, a bridged heterocycle can also be fused to an ary
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono C 1 -C 4 alkylamino, bis C 1 -C 4 alkyl
- the amino group is substituted, and the polycyclic heterocycles include but are not limited to spirocyclic heterocycles, bridged heterocycles, and fused ring heterocycles; or, spirocyclic heterocycles and bridged heterocycles can also be fused to an aryl group , heteroaryl or cycloalkyl ring;
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- R 5 and R 6 are independently selected from hydrogen, deuterium, amino, hydroxy, haloC 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo Substituted C 1 -C 4 alkoxy;
- s and t which are the same or different are independently selected from 0 and 1;
- R 7 and R 8 may be the same or different independently selected from hydrogen, deuterium, amino, hydroxy, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 - C4alkoxy , halogenated C1 - C4alkoxy ; or
- W is selected from O, NH, or absent
- Ring B is an aryl group or a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 3-15-membered monocyclic or polycyclic ring;
- R 9 which are the same or different are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl , C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy;
- n is selected from 0, 1, 2;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 alkoxy, mercapto, amino, carboxyl are each independently replaced by one or more deuterium, halogen, hydroxyl, mercapto, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy substitution;
- R b is selected from hydrogen, deuterium, methyl, ethyl
- the present invention relates to a compound represented by formula (I), or an isomer or a pharmaceutically acceptable salt thereof, wherein,
- Ring A is selected from an aryl group and a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 5-12 membered monocyclic or polycyclic ring;
- Exemplary preferred rings for Ring A include, but are not limited to:
- R 2 is independently selected from the same or different hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, said C 1 -C 4 alkyl, C 1 - C 4 alkoxy, amino are each independently replaced by one or more of deuterium, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, cyano , amino substitution;
- n 0, 1, 2, 3;
- X 1 is selected from CH or N;
- X 2 , X 3 can be the same or different and independently selected from CR a , N;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle
- the cyclic heterocycles are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to A spiro heterocycle, a bridged heterocycle, a fused heterocycle, or, a spiro heterocycle, a bridged heterocycle can also be fused to an ary
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, cyano, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono C 1 -C 4 alkylamino, bis C 1 -C 4 alkyl
- the amino group is substituted, and the polycyclic heterocycles include but are not limited to spirocyclic heterocycles, bridged heterocycles, and fused ring heterocycles; or, spirocyclic heterocycles and bridged heterocycles can also be fused to an aryl group , heteroaryl or cycloalkyl ring;
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- R 5 and R 6 are the same or different and are independently selected from hydrogen, deuterium, amino, hydroxyl;
- s and t which are the same or different are independently selected from 0 and 1;
- R 7 and R 8 are the same or different and are independently selected from hydrogen, deuterium, amino, hydroxy, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy; or
- W is selected from O, NH, or absent
- Ring B is an aryl group or a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 3-15-membered monocyclic or polycyclic ring;
- R 9 which are the same or different are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl , C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy;
- n is selected from 0, 1, 2;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, cyano, amino, wherein said C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino are each independently substituted by one or more deuterium, halogen, hydroxyl, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
- R b is selected from hydrogen, deuterium, methyl, ethyl
- the present invention relates to a compound represented by formula (I), or an isomer or a pharmaceutically acceptable salt thereof, wherein,
- Ring A is selected from an aryl group and a heteroaryl group, wherein the aryl group and the heteroaryl group are each independently a 5-12 membered monocyclic or polycyclic ring;
- Exemplary preferred rings for Ring A include, but are not limited to:
- R 2 is one or more substituents independently selected from the same or different hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, C 1 - C 4 alkyl, C 1 -C 4 alkoxy, amino are each independently replaced by one or more of deuterium, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, halogenated C 1 - C 4 alkoxy, cyano, amino substituted;
- n 0, 1, 2, 3;
- X 1 is selected from CH;
- X 2 and X 3 are the same or different, each independently selected from CR a , N;
- R 3 is selected from hydrogen, deuterium, C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle, wherein the C 1 -C 4 alkyl, 3-15-membered mono-heterocycle or polycyclic heterocycle
- the cyclic heterocycles are each independently optionally replaced by one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, single C 1 -C 4 alkylamino, double C 1 -C 4 alkylamino substituted, the polycyclic heterocycle includes but is not limited to A spiro heterocycle, a bridged heterocycle, a fused heterocycle, or, a spiro heterocycle, a bridged heterocycle can also be fused to an ary
- R 4 is selected from hydrogen, deuterium, C 1 -C 4 alkyl
- R 3 and R 4 together with the nitrogen atom to which they are commonly attached form a 3-15 membered mono- or polycyclic heterocycle, wherein said mono- or polycyclic heterocycle is optionally substituted by one or more selected from halogen, Amino, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, the polycyclic heterocycles include but are not limited to spiro heterocycles, bridged heterocycles, Fused ring heterocycle; alternatively, spiro heterocycle, bridged heterocycle can also be fused to aryl, heteroaryl or cycloalkyl ring;
- Exemplary 3-15 membered mono- or polycyclic heterocycles formed by R and R together with the nitrogen atom to which they are commonly attached include, but are not limited to:
- R3 and R4 are formed together with the nitrogen atom to which they are commonly attached
- R 5 and R 6 are the same or different and are independently selected from hydrogen, deuterium, amino, hydroxyl;
- s and t which are the same or different are independently selected from 0 and 1;
- R 7 and R 8 are the same or different and are independently selected from hydrogen, deuterium, amino, hydroxy, hydroxy C 1 -C 4 alkyl;
- W is selected from O, NH, or absent
- Ring B is phenyl, pyridyl
- R 9 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxy;
- n is selected from 0, 1, 2;
- R a is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, cyano, amino, wherein said C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino are each independently substituted with one or more hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
- R b is selected from hydrogen, deuterium, methyl, ethyl
- the compounds represented by the formula (I) involved in the present invention include but are not limited to:
- halogen in the present invention is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- alkyl group in the present invention includes straight-chain or branched-chain alkyl groups.
- the C 1 -C 4 alkyl group in the present invention refers to an alkyl group with 1-4 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
- the alkyl groups in the compounds of the present invention may be optionally substituted or unsubstituted, and the substituted substituents may include alkyl groups, halogens, alkoxy groups, haloalkyl groups, cyano groups, hydroxyl groups, and the like.
- Examples of alkyl groups of the present invention include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.
- alkoxy group in the present invention refers to a group formed by connecting the above-mentioned alkyl group with an oxygen atom, wherein the oxygen atom has the ability to form bonds freely.
- alkoxy group in the present invention include methoxy, ethoxy group, n-propoxy, n-butoxy, isopropoxy, tert-butoxy, cyclopropoxy and the like.
- alkylamino group in the present invention refers to the group formed by connecting the above-mentioned alkyl group with an amino group, such as methylamino, ethylamino, dimethylamino and the like.
- halogenated C 1 -C 4 alkyl group means that one or more hydrogen atoms of said alkyl, alkenyl, alkynyl and alkoxy groups are replaced by halogen atoms, especially fluorine or chlorine atoms.
- fluoro eg, CF3 , CHF2 , CH2F , CH2CH2F , CH2CHF2 , CH2CF3 , OCF3 , OCHF2 , OCH2F , OCH2CH
- fluoro eg, CF3 , CHF2 , CH2F , CH2CH2F , CH2CHF2 , CH2CF3 , OCF3 , OCHF2 , OCH2F , OCH2CH
- 2F OCH2CHF2 or OCH2CF3 .
- cycloalkyl in the present invention includes 3-8 membered cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- Cycloalkyl groups in the compounds of the present invention may be optionally substituted or unsubstituted, and the substituents may include alkyl groups, halogens, alkoxy groups, hydrocarbyl groups, hydroxyl groups, and the like.
- the "spiro ring” in the present invention refers to a polycyclic hydrocarbon with one carbon atom (spiro atom) shared between 3-15-membered monocyclic rings, which may contain one or more double bonds, but none of the rings has a conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups. According to the present invention, single spirocycloalkyl groups and double spirocycloalkyl groups are preferred. base.
- the "bridged ring" in the present invention refers to a 3- to 15-membered monocyclic polycyclic hydrocarbon that shares two or more carbon atoms, which may contain one or more double bonds, but none of the rings has a conjugated ⁇ electronic system. According to the number of constituent rings, it is divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.
- heterocyclyl used in the present invention refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms, that is, partially unsaturated or fully saturated ring systems.
- Preferred heteroatoms according to the present invention include N, O and S.
- Monocyclic heterocycles include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydroimidazolyl, dihydrofuranyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
- Polycyclic heterocyclic groups include spiro, bridged, and fused-ring heterocyclic groups, and the heterocyclic groups may be fused to aryl, heteroaryl or cycloalkyl rings.
- aryl in the present invention refers to a monocyclic or polycyclic aromatic ring system, such as a benzene ring, a naphthalene ring, and the like.
- Aryl groups can be substituted or unsubstituted.
- Heteroaryl refers to an aromatic ring system containing at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused spiro or bridged rings.
- substituted means that one or more hydrogen atoms in a group are capable of being independently replaced with the corresponding number of substituents. Those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitution positions without undue effort.
- substituents referred to by the "substituted” refer to, including but not limited to: deuterium, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy base, halogenated C 1 -C 4 alkyl C 2 -C 6 alkenyl, halogenated C 1 -C 4 alkoxy C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, amino, Nitro, carboxyl, -CONH 2 , sulfonamido, C 1 -C 4 alkylcarbonylamino, mono C 1 -C 4 alkylaminocarbonyl, bis C 1 -C 4 alkylaminocarbonyl, C 2 -C 6 Alkenylcarbonylamino , C2 - C6alkynylcarbonylamino , C2 - C6alkenylaminocarbon
- the chemical name when the chemical name is specifically designated as the (R)- or (S)-isomer, it should be understood that the predominant configuration is the (R)-isomer or the (S)-isomer, respectively body.
- Any asymmetric carbon atom may exist in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
- the compounds described herein may therefore exist as a mixture of isomers, or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
- the "pharmaceutically acceptable salt” in the present invention refers to an acid addition salt obtained by reacting the compound of the present invention with a pharmaceutically acceptable acid, or a salt formed by the reaction of a compound with an acidic group and a basic compound.
- the acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.), and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or Benzoic acid, etc.);
- the basic compound is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium bicarbonate and the like.
- the above-mentioned pharmaceutically acceptable salts are easy to separate, and can be purified by conventional separation methods, such as solvent extraction, dilution, recrystallization, column chromatography and preparative thin layer chromatography.
- Another aspect of the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) above, or an isomer, pharmaceutically acceptable salt, precursor, metabolite, N-oxide thereof, as activity Element.
- the compounds described in the present invention can optionally be used in combination with one or more other active ingredients, and their respective dosages and ratios can be adjusted by those skilled in the art according to specific conditions and specific conditions of patients and clinical needs.
- the compounds of the general formula (I) of the present invention can be prepared by those skilled in the art (experience or references) .
- Another aspect of the present invention also provides a process for the preparation of the above-mentioned compounds according to the present invention.
- the following synthetic route describes the preparation method of the compound of formula (I) of the present invention.
- the raw materials, reagents, catalysts, solvents, etc. used in the following synthetic schematic diagram can be prepared by methods well known to those of ordinary skill in the field of organic chemistry or can be obtained commercially.
- All final derivatives of the present invention can be prepared by the methods described in the schematic diagrams or analogs thereof, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these diagrams are as defined in context.
- the compounds of the general formula (I) and the related intermediates can be purified by common separation methods, such as extraction, recrystallization and silica gel column chromatography separation.
- the 200-300 mesh silica gel and thin-layer chromatography silica gel plates used were produced by Qingdao Ocean Chemical Factory.
- the chemical reagents used are commercial products of analytical or chemical purity of general reagents, and are used without further purification.
- the present invention provides a kind of preparation method of compound shown in general formula (I), comprises the following steps:
- the compound represented by the formula (I-a) is subjected to Miyaura Boration reaction under appropriate basic conditions and a solvent under a catalyst to obtain the compound represented by the formula (I-b).
- the catalysts include but are not limited to palladium acetate (Pd(OAc) 2 ), palladium dichloride (PdCl 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), [1,1' - Bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl 2 (dppf)), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (PdCl 2 (dppf) ⁇ CH 2 Cl 2 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), bis(tricyclohexylphosphine) palladium dichloride (PdCl 2 (P(Cy) 3 ) 2 ), 2-dicyclohexylphosphine-2',6'-dimethoxybi
- the catalysts include but are not limited to palladium acetate (Pd(OAc) 2 ), palladium dichloride (PdCl 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), [1,1' - Bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl 2 (dppf)), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (PdCl 2 (dppf) ⁇ CH 2 Cl 2 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), bis(tricyclohexylphosphine) palladium dichloride (PdCl 2 (P(Cy) 3 ) 2 ), 2-dicyclohexylphosphine-2',6'-dimethoxybi
- the catalyst includes but is not limited to tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), cuprous iodide (CuI);
- the ligand includes but is not limited to 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (Xantphos), 1,10-phenoline;
- reagents for the alkaline conditions include organic bases and inorganic bases, including but not limited to triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), potassium carbonate (K 2 CO 3 ), lithium hydroxide (LiOH);
- the solvents include but are not limited to dioxane, tetrahydrofuran (THF) , acetonitrile (CH 3 CN), N,N'-dimethylformamide (DMF), and mixed solvents formed by these solvents and water in different proportions.
- the compound represented by the formula (I-d) is subjected to an amination reaction to obtain the compound represented by the formula (I-e) under the condition of an aminating agent, and the aminating agent includes but is not limited to ammonia water, ammonia gas, liquid ammonia, and ammonium bicarbonate.
- the compound represented by the formula (I-e) is subjected to a cyclization reaction to obtain the compound represented by the formula (I-f).
- the compound represented by the formula (If) and the compound represented by the formula (Ig) are subjected to nucleophilic substitution reaction to obtain the compound represented by the formula (Ih), followed by one or more steps of deprotection to obtain the compound of the general formula (I) of the present invention. .
- the boronic acid ester includes but is not limited to 4,4,5,5-tetramethyl-1,3,2-dioxolaborane, diboronic acid neopentyl glycol Esters, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane), B( OBu-n) 3 , B(OPr-i) 3 ;
- Y is selected from CH 2 R a , NH 2 , OH, SH;
- R 10 is selected from halogen, methanesulfonyl, p-toluenesulfonyl;
- P 1 is a protecting group selected from ((2-trimethylsilyl)ethoxy)methyl (SEM), tetrahydro-2H-pyran-2-yl (THP), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenemethoxycarbonyl), Cbz (N-benzyloxycarbonyl), methanesulfonyl, p-toluenesulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl;
- P 2 is a protecting group selected from hydroxymethylene, Fmoc (9-fluorenemethoxycarbonyl), Cbz (N-benzyloxycarbonyl), methanesulfonyl, p-toluenesulfonyl, acetyl, methoxycarbonyl, ethoxy carbonyl;
- the present invention also provides another preparation method of the compound shown in general formula (I), comprising the following steps:
- the compound shown in formula (Ic) obtains the compound shown in formula (I1-d) through amination reaction under the condition of aminating agent, and the aminating agent includes but is not limited to ammonia water, ammonia gas, liquid ammonia, ammonium bicarbonate ;
- the compound represented by the formula (I1-d) is subjected to a ring-forming reaction to obtain the compound represented by the formula (I1-e);
- the compound represented by the formula (I1-e) and the compound represented by the formula (I-g) are subjected to nucleophilic substitution reaction to obtain the compound represented by the formula (I1-f);
- the catalysts include but are not limited to palladium acetate (Pd(OAc) 2 ), palladium dichloride (PdCl 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), [1,1' - Bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl 2 (dppf)), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (PdCl 2 (dppf) ⁇ CH 2 Cl 2 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), bis(tricyclohexylphosphine) palladium dichloride (PdCl 2 (P(Cy) 3 ) 2 ), 2-dicyclohexylphosphine-2',6'-dimethoxybi
- the catalyst includes but is not limited to tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), cuprous iodide (CuI);
- the ligand includes but is not limited to 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (Xantphos), 1,10-phenoline;
- reagents for the alkaline conditions include organic bases and inorganic bases, including but not limited to triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), potassium carbonate (K 2 CO 3 ), lithium hydroxide (LiOH);
- the solvents include but are not limited to dioxane, tetrahydrofuran (THF) , acetonitrile (CH 3 CN), N,N'-dimethylformamide (DMF), and mixed solvents formed by these solvents and water in different proportions.
- the compound represented by the formula (I1-g) is then subjected to one or more steps of deprotection to obtain the compound of the general formula (I) described in the present invention.
- the boronic acid ester includes but is not limited to 4,4,5,5-tetramethyl-1,3,2-dioxolaborane, diboronic acid neopentyl glycol Esters, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane), B( OBu-n) 3 , B(OPr-i) 3 ;
- Y is selected from CH 2 R a , NH 2 , OH, SH;
- R 10 is selected from halogen, methanesulfonyl, p-toluenesulfonyl;
- P 1 is a protecting group selected from ((2-trimethylsilyl)ethoxy)methyl (SEM), tetrahydro-2H-pyran-2-yl (THP), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenemethoxycarbonyl), Cbz (N-benzyloxycarbonyl), methanesulfonyl, p-toluenesulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl;
- P 2 is a protecting group selected from hydroxymethylene, Fmoc (9-fluorenemethoxycarbonyl), Cbz (N-benzyloxycarbonyl), methanesulfonyl, p-toluenesulfonyl, acetyl, methoxycarbonyl, ethoxy carbonyl;
- the present invention provides a novel heterotricyclic SHP2 inhibitor for treating or preventing tumors or cancers related to the target.
- these compounds or pharmaceutical compositions containing them as active ingredients can maximize the clinical efficacy on these diseases within a safe therapeutic window.
- the present invention has prepared representative compounds, and the present invention is further described below with reference to the examples, but these examples do not limit the scope of the present invention.
- I-1a (1.50 g, 6.11 mmol) was dissolved in 1,4-dioxane (20 mL), pinacol biboronate (2.02 g, 7.94 mmol), KOAc (1.80 g, 18.33 mmol) were added mmol), PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.23 g, 0.31 mmol), replaced by N 2 three times, the temperature was raised to 90° C., and the reaction was performed overnight. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated.
- the intermediate I-1f (0.14 g, 0.29 mmol) and commercially available I-1 g (0.13 g, 0.58 mmol) were dissolved in N-methylpyrrolidone (5 mL), and the microwave was raised to 140 °C for 30 min. The temperature was lowered to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phase was washed with saturated brine (20 mL ⁇ 1). It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- I-2b (0.33 g, 2.70 mmol)
- I-1c (1.00 g, 2.26 mmol)
- potassium phosphate (1.40 g, 6.60 mmol)
- PdCl 2 (dppf) CH 2 Cl 2 0.33 g, 0.40 mmol
- 1,4-dioxane 27 mL
- water 3 mL
- N 3 times heated to 100 °C and stirred for 2 h
- the TLC plate monitored the completion of the reaction and lowered to room temperature
- Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, and the layers were separated.
- I-2g-1 (104.00 g, 582.70 mmol) was dissolved in dichloromethane (1000 mL), triethylamine (148.00 g, 1462.59 mmol) was added, cooled to 0 °C in an ice bath, and chloroformic acid was slowly added dropwise Benzyl ester (120.00 g, 703.44 mmol) was added dropwise and reacted at room temperature for 16 h; water (1000 mL) was added to quench, and the layers were separated. The organic phase was washed with saturated brine (500 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated.
- the intermediate I-2f (0.05 g, 0.13 mmol) was dissolved in N-methylpyrrolidone (2 mL), I-2 g (0.08 g, 0.26 mmol) was added, and the temperature was raised to 140°C by microwave for 30 min. The temperature was lowered to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phase was washed with saturated brine (20 mL ⁇ 2). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
- Yellow solid intermediate I1-4g is obtained from intermediate I1-4f (300.00 mg, 0.42 mmol, 1.0 eq), commercially available 2-(2,3-dichlorophenyl)-4,4,5,5-tetra Methyl-1,3,2-dioxaborane I1-4b (137.59 mg, 0.50 mmol, 1.2 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloride Chloromethane complex (34.93 mg, 0.04 mmol, 0.1 eq), potassium carbonate 174.48 mg, 1.26 mmol, 3.0 eq), 1,4-dioxane (10 mL) and water (1 mL) according to Intermediate I-1d prepared by similar steps in . (150.0 mg, yield 48.4%). LC-MS MS-ESI (m/z) 737.3 [M+H] + .
- Yellow oily intermediate I1-5g is obtained from intermediate I1-4f (300.00mg, 0.42mmol, 1.0eq), commercially available 3-chloro-4-pyridineboronic acid pinacol I1-5b (119.76mg, 0.50mmol, 1.2 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (34.93mg, 0.04mmol, 0.1eq), potassium carbonate (174.48mg, 1.26mmol, 3.0 eq), 1,4-dioxane (10 mL) and water (1 mL) were prepared following a similar procedure in Intermediate I-1d (141.0 mg, 47.7% yield). LC-MS MS-ESI (m/z) 704.3 [M+H] + .
- a yellow oil intermediate I1-5h was prepared from intermediate I1-5g (141.0 mg, 0.20 mmol, 1.0 eq) and concentrated hydrochloric acid (3 mL) following a similar procedure as in intermediate I1-4h. (crude product, the yield is 100%). LC-MS MS-ESI (m/z) 600.3 [M+H] + .
- Yellow oily intermediate I1-6g is obtained from intermediate I1-4f (300.00 mg, 0.42 mmol, 1.0 eq), commercially available 4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1-naphthol I1-6b (136.15 mg, 0.50 mmol, 1.2 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium dichloromethane complex (34.93mg, 0.04mmol, 0.1eq), potassium carbonate (174.48mg, 1.26mmol, 3.0eq), 1,4-dioxane (10mL) and water (1mL) as intermediate Prepared by a similar procedure as in I-1b (155.0 mg, 50.2% yield). LC-MS MS-ESI (m/z) 735.3 [M+H] + .
- the yellow oil intermediate I1-6h was prepared from intermediate I1-6g (155.0 mg, 0.21 mmol, 1.0 eq) and concentrated hydrochloric acid (3 mL) according to the similar procedure of intermediate I1-4h (crude product, yield according to 100% count). LC-MS MS-ESI (m/z) 631.3 [M+H] + .
- Yellow oily intermediate I1-7g is composed of intermediate I1-4f (300.00mg, 0.42mmol, 1.0eq), commercially available 4-quinoline boronic acid pinacol ester I1-7b (127.56mg, 0.50mmol, 1.2eq) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (34.93mg, 0.04mmol, 0.1eq), potassium carbonate (174.48mg, 1.26mmol, 3.0eq) ), 1,4-dioxane (10 mL) and water (1 mL) were prepared following a similar procedure in Intermediate I-1d (132.0 mg, 43.6% yield). LC-MS MS-ESI (m/z) 720.3 [M+H] + .
- a yellow oil intermediate I1-7h was prepared from intermediate I1-7g (132.0 mg, 0.18 mmol, 1.0 eq) and concentrated hydrochloric acid (3 mL) following a similar procedure as in intermediate I1-4h. (crude product, the yield is 100%). LC-MS MS-ESI (m/z) 616.3 [M+H] + .
- Intermediate I1-7i as a yellow oil was prepared from intermediate I1-7h (crude, 0.18 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-4i. (crude product, the yield is 100%). LC-MS MS-ESI (m/z) 516.2 [M+H] + .
- the homemade intermediate I1-10h (crude product, 0.40 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), ammonia water (10 mL) was added, and the reaction was carried out at room temperature for 3 h. Ethyl acetate (50 mL) and saturated brine (50 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the yellow solid intermediate I1-11g is composed of intermediate I1-10f (300.00mg, 0.44mmol, 1.0eq), commercially available pinacol ester phenylboronic acid I1-11b (108.12mg, 0.53mmol, 1.2eq), [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (35.93mg, 0.04mmol, 0.1eq), potassium carbonate (183.48mg, 1.32mmol, 3.0eq), 1 , 4-Dioxane (10 mL) and water (1 mL) were prepared following similar procedures as in Intermediate I1-10g. (214.00 mg, 76.8% yield). LC-MS MS-ESI (m/z) 633.4 [M+H] + .
- a yellow oily intermediate I1-11h was prepared from intermediate I1-11 g (214.00 mg, 0.34 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h. (crude product, the yield is 100%). LC-MS MS-ESI (m/z) 433.2 [M+H] + .
- the pale yellow compound I-11 was prepared from intermediate I1-11h (crude, 0.34 mmol, 1.0 eq), tetrahydrofuran (10 mL) and ammonia (10 mL) according to the similar procedure in compound I-10 (96.50 mg, yield 70.5%).
- the yellow solid intermediate I1-12g is composed of intermediate I1-10f (300.00mg, 0.44mmol, 1.0eq), commercially available 4-quinoline boronic acid pinacol ester I1-7b (135.20mg, 0.53mmol, 1.2eq) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (35.93mg, 0.044mmol, 0.1eq), potassium carbonate (183.48mg, 1.32mmol, 3.0eq) ), 1,4-dioxane (10 mL) and water (1 mL) were prepared following a similar procedure to compound I1-10g (243.00 mg, 80.7% yield). LC-MS MS-ESI (m/z) 684.4 [M+H] + .
- a yellow oily intermediate I1-12h was prepared from intermediate I1-12g (243.00 mg, 0.36 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h. (crude product, the yield is 100%).
- the yellow solid intermediate I1-13g is composed of intermediate I1-10f (300.00mg, 0.44mmol, 1.0eq), commercially available 1-naphthalene boronic acid pinacol ester I1-13b (134.67mg, 0.53mmol, 1.2eq), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (35.93mg, 0.04mmol, 0.1eq), potassium carbonate (183.48mg, 1.32mmol, 3.0eq) , 1,4-dioxane (10 mL) and water (1 mL) were prepared following a similar procedure in Intermediate I1-10g (224.00 mg, 74.5% yield). LC-MS MS-ESI (m/z) 683.4 [M+H] + .
- Yellow oily intermediate I1-13h was prepared from intermediate I1-13g (224.00 mg, 0.33 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h (crude, yield according to 100% count).
- the yellow solid intermediate I1-14g is composed of intermediate I1-10f (300.00mg, 0.44mmol, 1.0eq), commercially available 2,3-methylenedioxyphenylboronic acid pinacol ester I1-14b (130.99mg , 0.53mmol, 1.2eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (35.93mg, 0.044mmol, 0.1eq), potassium carbonate (183.48 mg, 1.32 mmol, 3.0 eq), 1,4-dioxane (10 mL) and water (1 mL) were prepared following a similar procedure as in Intermediate I1-10 g (139.00 mg, 46.7% yield). LC-MS MS-ESI (m/z) 677.3 [M+H] + .
- a yellow oily intermediate I1-14h was prepared from intermediate I1-14g (139.00 mg, 0.21 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h. (crude product, the yield is 100%). LC-MS MS-ESI (m/z) 477.2 [M+H] + .
- Yellow solid intermediate I1-15g is prepared from intermediate I1-10f (300.00mg, 0.44mmol, 1.0eq), 4-chloro-2-methyl-5-(4,4,5,5-tetramethyl) -1,3,2dioxaboran-2-yl)-2H-indazole I-1b (155.08mg, 0.53mmol, 1.2eq), [1,1'-bis(diphenylphosphino)diacene Iron] palladium dichloride dichloromethane complex (35.93mg, 0.04mmol, 0.1eq), potassium carbonate (183.48mg, 1.32mmol, 3.0eq), 1,4-dioxane (10mL) and water ( 1 mL) was prepared following a similar procedure in Intermediate I1-10g (170.00 mg, 53.6% yield). LC-MS MS-ESI (m/z) 721.3 [M+H] + .
- a yellow oily intermediate I1-15h was prepared from intermediate I1-15g (170.00 mg, 0.24 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h. (crude product, the yield is 100%). LC-MS MS-ESI (m/z) 521.2 [M+H] + .
- the intermediate I1-16g' (326.00mg, 0.44mmol, 1.0eq), commercially available cyclopropylamine (125.62mg, 2.20mmol, 5.0eq), cesium carbonate (430.32mg, 1.32mmol, 3.0eq), three ( Dibenzylideneacetone) dipalladium (40.26mg, 0.04mmol, 0.1eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (41.10mg, 0.07mmol, 0.15eq), toluene (10mL) ) and triethylamine (1 mL) were weighed into a 30 mL microwave tube, purged with nitrogen for 30 s, sealed the microwave tube, heated to 130° C.
- Yellow oily intermediate I1-16h was prepared from intermediate I1-16g (132.00 mg, 0.18 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h (crude, yield according to 100% count). LC-MS MS-ESI (m/z) 523.2 [M+H] + .
- Yellow solid intermediate I1-17g is obtained from intermediate I1-10f (300.00 mg, 0.44 mmol, 1.0 eq), commercially available 5-chloro-6-(4,4,5,5-tetramethyl-1,3 ,2-dioxaboran-2-yl)quinoxaline I1-17b (153.38mg, 0.53mmol, 1.2eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium dichloromethane complex (35.93mg, 0.04mmol, 0.1eq), potassium carbonate (183.48mg, 1.32mmol, 3.0eq), 1,4-dioxane (10mL) and water (1mL) as intermediate Prepared by a similar procedure as in I1-10g (168.00 mg, 53.1% yield). LC-MS MS-ESI (m/z) 719.3 [M+H] + .
- Yellow oily intermediate I1-17h was prepared from intermediate I1-17g (168.00 mg, 0.23 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure for intermediate I1-10h (crude, yield according to 100% count).
- the yellow solid intermediate I1-18g is composed of intermediate I1-16g' (180.00mg, 0.24mmol, 1.0eq), commercially available methylamine hydrochloride (81.00mg, 1.20mmol, 5.0eq), cesium carbonate (234.72mg) , 0.72mmol, 3.0eq), tris(dibenzylideneacetone)dipalladium (21.96mg, 0.02mmol, 0.1eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (22.42mg, 0.04 mmol, 0.15 eq), toluene (10 mL) and triethylamine (1 mL) were prepared following a similar procedure in intermediate I1-16g (94.00 mg, 56.2% yield). LC-MS MS-ESI (m/z) 697.3 [M+H] + .
- a yellow oily intermediate I1-18h was prepared from intermediate I1-18g (94.00 mg, 0.13 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h (crude, yield according to 100% count).
- Yellow oily intermediate I1-19h was prepared from intermediate I1-19g (294.00 mg, 0.40 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure for intermediate I1-10h (crude, yield according to 100% count).
- Off-white solid compound 1-20 was prepared from intermediate I1-20g (130.00 mg, 0.18 mmol, 1.0 eq), trifluoroacetic acid (10 mL), tetrahydrofuran (10 mL) and ammonia (10 mL) following a similar procedure as in compound 1-10 prepared (44.00 mg, 50.3% yield).
- the yellow solid intermediate I1-21g is composed of intermediate I1-10f (300.00mg, 0.44mmol, 1.0eq), commercially available 2,3-dichlorophenylboronic acid I1-21b (101.12mg, 0.53mmol, 1.2eq), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (35.93mg, 0.04mmol, 0.1eq), potassium carbonate (183.48mg, 1.32mmol, 3.0eq) , 1,4-dioxane (10 mL) and water (1 mL) were prepared following a similar procedure for intermediate I1-10g (206.00 mg, 66.7% yield). LC-MS MS-ESI (m/z) 701.3 [M+H] + .
- Yellow oily intermediate I1-21h was prepared from intermediate I1-21g (206.00 mg, 0.29 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) following a similar procedure as in intermediate I1-10h (crude, yield according to 100% count).
- the yellow compound I-21 was prepared from intermediate I1-21h (crude, 0.29 mmol, 1.0 eq), tetrahydrofuran (10 mL) and ammonia (10 mL) according to the similar procedure in compound I-10 (104.00 mg, yield 76.1 %).
- I-22g-2 (39.00g, 162.71mmol, 1.0eq) was added to a mixed solvent of tetrahydrofuran (200mL) and water (200mL), sodium carbonate (25.87g, 244.06mmol, 1.5eq) was added, and the temperature was lowered to 0- 10 °C, benzyl chloroformate (27.76 g, 162.71 mmol, 1.0 eq) was added dropwise, and the temperature was controlled below 10 °C to finish dropping. The temperature was naturally raised to room temperature and 15°C for overnight reaction for 15h. Complete reaction of starting materials was monitored by TLC plate.
- reaction solution was extracted with ethyl acetate (200 mL ⁇ 2), and the organic phase was washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain a white solid I-22g-3 (54.00 g, collected rate 98.4%).
- I-22g-3 (27.00g, 80.03mmol, 1.0eq) was added to tetrahydrofuran (135mL), followed by (R)-(+)-tert-butylsulfinamide (29.10g, 240.10mmol, 3.0eq) ) and tetraethyl titanate (105.88g, 464.18mmol, 5.8eq), then the temperature was raised to 70-80°C for 17h, the liquid phase monitoring of raw materials remaining 17.9%, and the reaction continued for 29h. Liquid phase monitoring raw material remaining 4.8%. The reaction was stopped and the temperature was lowered to room temperature.
- I-22g-4 (27.00g, 61.29mmol, 1.0eq) was dissolved in tetrahydrofuran (70mL), cooled to -20 ⁇ -25°C, and BH 3 /THF (104.19mmol, 1.0M, 104.19mL) was added dropwise , 1.7eq), the temperature is controlled below -20 °C and the dripping is completed, and the temperature is kept stirring for 30min after the dripping. The reaction of the starting material was complete as monitored by TLC. The reaction solution was slowly poured into ice water (150 mL) and extracted once with ethyl acetate (300 mL).
- the organic phase was washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 28.00 g of crude product.
- the crude product was heated to 65 °C with toluene (80 mL) to dissolve, stirred for 30 min, and n-heptane (160 mL) was added dropwise to the system at 65 °C, stirred for 30 min, and then cooled down to room temperature 15 °C and stirred overnight for 15 h. A large amount of solid was precipitated. It was suction filtered, and the filter cake was dried to obtain 18.00 g of white solid.
- Dissolve I-22g-5 (15.25g, 40.68mmol, 1.0eq) in a mixed solvent of tetrahydrofuran (100mL) and water (100mL), add sodium carbonate (8.62g, 81.36mmol, 2.0eq, dropwise below 10°C) Tert-butyl carbonate (9.32g, 42.72mmol, 1.1eq) was added and stirred at 15°C overnight for 15h. TLC monitored the reaction of the raw materials for completeness. Water (100mL) was added to the reaction solution, and ethyl acetate (100mL ⁇ 2) was added to the reaction solution.
- I-22g-6 (15.00g, 34.21mmol, 1.0eq) was dissolved in methanol (150mL), Pd(OH) 2 /C (2.00g, 20% purity) was added, and hydrogen balloon (1 atm) replaced hydrogen for 3 times , and reacted at 15°C for 15h overnight.
- the reaction of the starting material was complete as monitored by TLC.
- the reaction solution was suction filtered, the filter cake was rinsed with methanol (20 mL), and the filtrate was concentrated to dryness to obtain white solid I-22g (7.50 g, yield 72.0%).
- the yellow solid I1-22g is composed of intermediate I1-22f (358.35mg, 0.5mmol, 1.0eq), 3-chloro-4-pyridineboronic acid pinacol ester I1-5b (109.20mg, 0.45mmol, 1.2eq) [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30.80mg, 0.04mmol, 0.1eq), potassium carbonate (157.50mg, 1.1mmol, 3.0eq), 1 , 4-Dioxane (10 mL) and water (1 mL) were prepared following a similar procedure as in Intermediate I1-10g (140.00 mg, 39.8% yield). LC-MS MS-ESI (m/z) 702.3 [M+H] + .
- the detection method is used for the evaluation of the biological activity of the compounds described in the present invention at the molecular and cellular levels in vitro, including the evaluation of the enzymatic inhibitory activity at the recombinant protein level in vitro and the evaluation of the biological function activity in two different cell models.
- This assay is to comprehensively evaluate the characteristics of the allosteric inhibitory activities of different compounds on SHP2 phosphohydrolase and the effects of SHP2-mediated signaling pathways on biological activities in two different cell models, including the downstream activation of tumor cell growth factor receptors. Effects of signaling and effects on immunosuppressive signaling mediated by immune checkpoint molecules in T cells.
- the recombinant human SHP2 full-length protein is in an inactive state due to the binding of its own protein domains to each other; when the synthetic activation peptide is added, the SHP2 full-length protein binds to the activation peptide and undergoes allostery, exposing phosphorolysis.
- Enzyme (PTP) domain which can catalyze the reaction substrate, excite fluorescence, and show enzymatic activity.
- the SHP2 small molecule inhibitor can bind to a specific site of the full-length SHP2 protein, so that the SHP2 protein cannot change the protein conformation and bind to the activation peptide, so it remains in an inactive state and cannot catalyze the reaction substrate.
- the small molecule compound as the allosteric inhibitor could not inhibit the enzymatic activity of the SHP2 protein fragment.
- SHP2 recombinase (Cat#: ab268899) was purchased from Abcam, activating peptide dPEG8 (Cat#: P1958586-2) was purchased from Bioengineering, substrate DiFMUP (Cat#: D6567) was purchased from ThermoFisher; reaction buffer: 50mM HEPES, 150mM NaCl, 1 mM EDTA, 2 mM DTT, adjusted to pH 6.9; 96-well black microtiter plate (Cat#: 3915) was purchased from Corning.
- the fluorescence detection microplate reader is Thermo Labsystems.
- a control group was also set for the detection reaction, including a 0% inhibition control without the addition of the test compound (with an equal volume of reaction buffer) and a 100% inhibition control without the recombinase, and duplicate wells were set for all detections.
- inhibition rate (%) [1-(fluorescence signal value of detection well-100% inhibition control)/(0% inhibition control fluorescence signal value-100% inhibition control )] ⁇ 100%.
- the 50% inhibitory concentration (IC 50 ) was further calculated after the inhibition rates of the test compounds with different concentration gradients were calculated respectively.
- SHP2 participates in and mediates multiple downstream signals of the pathway activated by the binding of growth factor receptors to ligands Phosphorylation of proteins, especially activation of the RAS-MAPK-ERK pathway.
- RAS-MAPK-ERK pathway is in a spontaneous high-level activation state, and is closely related to the malignant proliferation of tumor cells. Therefore, by detecting the phosphorylation (p-ERK1/2) level of ERK1/2, the enzymatic activity of SHP2 in cells and its inhibition can be indirectly reflected.
- HTRF Homogeneous Time-Resolved Fluorescence
- the human esophageal squamous cell carcinoma cell line KYSE-520 was purchased from ATCC, the human recombinant epidermal growth factor (EGF, C610033) was purchased from Shanghai Sangon, and the human p-ERK1/2 protein kit (Cat#: 64ERKPEG) for detecting the cellular level was purchased from Cisbio company, other related reagents such as cell lysate, dilution buffer, detection buffer, etc. were purchased from Cisbio company.
- the fluorescence detection instrument Tecan (Spark 10M) was purchased from Tecan Company, Switzerland.
- KYSE-520 cells collected by trypsinization were resuspended in serum-free medium, the count was adjusted to 4 ⁇ 10 5 cells/mL, and 100 ⁇ L of cell suspension was added to each well of a 96-well plate, 37 Cultivate overnight;
- Table 2 EC 50 of the compounds of the present invention inhibiting p-ERK in KYSE-520 cells
- the compounds of the present invention have good or certain inhibitory activity of intracellular p-ERK, and other compounds of the general formula (I) of the present invention also have the activity of inhibiting p-ERK.
- SHP2 can participate in PD-1 molecule-mediated suppression of T cells by binding to immune checkpoint molecules such as the intracellular segment immunosuppressive motif (ITIM) of PD-1.
- immune checkpoint molecules such as the intracellular segment immunosuppressive motif (ITIM) of PD-1.
- ITIM intracellular segment immunosuppressive motif
- Activated immunosuppressive signaling Therefore, in the model of T cell activation inhibition caused by PD-1/PD-L1 binding at the cellular level, by detecting the level of reporter genes directly related to T cell activation signals, it can indirectly reflect the SHP2 in T cells triggered by immune checkpoint inhibitory signals. Phosphohydrolase activity.
- CHO-PD-L1-CD3L cells stably expressing human PD-L1 molecule and anti-CD3 single-chain antibody (ScFv) and stable Jurkat-PD-1-NFAT cells expressing human PD-1 molecule and NFAT reporter gene.
- ScFv single-chain antibody
- the anti-CD3ScFv on the CHO cell surface bound to the membrane CD3 molecules of Jurkat cells to transmit the activation signal inward, while the PD-L1 on the CHO cell surface bound to the PD-1 molecule on the Jurkat cell surface and inhibited the activation signal.
- the luciferase reporter gene is not expressed.
- SHP2 small molecule inhibitor was added, the inhibitory signal of T cell activation mediated in part by SHP2 was blocked, and the expression of luciferase reporter gene was increased.
- CHO-PD-L1-CD3L cells expressing human PD-L1 molecule and anti-CD3 single-chain antibody (ScFv) and Jurkat-PD-1-NFAT cells stably expressing human PD-1 molecule and NFAT reporter gene were produced by Connoya Dr. Chen Bo of Biomedical Technology (Chengdu) Co., Ltd. independently built and presented it.
- PMA was purchased from Sigma, and the luciferase substrate was purchased from Promega. Fluorescence detection instrument Tecan (Spark 10M) was purchased from Tecan Company, Switzerland.
- test compounds Dilute the test compounds into different concentration gradients and add them to 96-well plates; adjust the Jurkat-PD-1-NFAT cell count to 2 ⁇ 10 5 cells/mL, and add 100ng/mL PMA for Amplify T cell activation signals; add 100 ⁇ L of cells to each well of a 96-well plate;
- a control group is also set for the detection reaction, including a 0% inhibition control without the addition of the test compound and a 100% inhibition control with the highest reporter gene signal value measured in the current experiment. All tests are equipped with duplicate holes;
- inhibition rate (%) (fluorescence signal ratio of detection well - 0% inhibition control) / (100% inhibition control fluorescence signal ratio - 0% inhibition control) ⁇ 100%.
- the 50% inhibitory concentration (EC 50 ) was further calculated after calculating the binding inhibition rate of the test compounds with different concentration gradients.
- the compounds of the present invention have good T cell activation signal inhibitory activity mediated by SHP2, and other compounds of the general formula (I) of the present invention also have T cell activation signal inhibitory activity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
化合物编号 | IC 50(nM) | 化合物编号 | IC 50(nM) | 化合物编号 | IC 50(nM) |
I-1 | 1.40 | I-2 | 1.65 | I-4 | 21.81 |
I-5 | 3.53 | I-8 | 7.80 | I-9 | 10.15 |
I-10 | 7.78 | I-11 | 5.68 | I-12 | 4.54 |
I-13 | 12.9 | I-14 | 9.78 | I-15 | 3.89 |
I-17 | 5.82 | I-18 | 3.28 | I-20 | 6.53 |
I-21 | 7.62 | I-22 | 10.37 |
化合物编号 | EC 50(nM) | 化合物编号 | EC 50(nM) | 化合物编号 | EC 50(nM) |
I-1 | 242.9 | I-2 | 457.8 | I-4 | 90.6 |
I-5 | 34.7 | I-8 | 52.0 | I-9 | 89.7 |
I-10 | 148.7 | I-11 | 109.2 | I-12 | 59.5 |
I-13 | 125.2 | I-14 | 237.9 | I-15 | 93.9 |
I-17 | 124.9 | I-18 | 220.8 | I-20 | 217.1 |
I-21 | 97.2 | I-22 | 62.2 |
化合物编号 | EC 50(nM) | 化合物编号 | EC 50(nM) | 化合物编号 | EC 50(nM) |
I-1 | 51.83 | I-2 | 29.96 | I-4 | 47.62 |
I-5 | 2.41 | I-8 | 3.22 | I-9 | 25.56 |
I-10 | 178.30 | I-11 | 43.83 | I-12 | 9.54 |
I-13 | 32.27 | I-14 | 20.63 | I-15 | 72.69 |
I-17 | 186.09 | I-18 | 58.04 | I-20 | 2.57 |
I-21 | 27.59 | I-22 | 63.02 |
Claims (21)
- 一种式(I)所示的化合物,或其异构体、药学可接受的盐、前体、代谢产物、N-氧化物,其中,环A选自环烷基、杂环基、芳基、杂芳基,其中所述环烷基、杂环基、芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 4烷氧基、R cSO 2、羟基、巯基、氰基、氨基、硝基、羧基、CONH 2、磺酰胺基、胺基磺酰基、R dCO-、氨基羰基氨基、CONHOH、C 3-C 8环烷基、C 4-C 8环烯基、3-15元杂环基、芳基、杂芳基,或者同一个碳原子上的两个R 2在一起表示氧代(=O)、硫代(=S);其中所述的C 1-C 4烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 4烷氧基、巯基、氨基、羧基、CONH 2、磺酰胺基、胺基磺酰基、氨基羰基氨基、CONHOH、C 3-C 8环烷基、C 4-C 8环烯基、3-15元杂环基、芳基和杂芳基各自独立地被一个或多个氘、卤素、羟基、C 3-C 6环烷基、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、卤代C 1-C 4烷基C 2-C 6烯基、卤代C 1-C 4烷氧基C 2-C 6烯基、C 2-C 6炔基、氰基、氨基、硝基、羧基、-CONH 2、磺酰胺基、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基、C 2-C 6烯基羰基氨基、C 2-C 6炔基羰基氨基、C 2-C 6烯基氨基羰基、C 2-C 6炔基氨基羰基、环烷基C 1-C 4烷基、环烷基C 1-C 4烷氧基、杂环烷基C 1-C 4烷基、杂环烷基C 1-C 4烷氧基、芳基C 1-C 4烷基、芳基C 1-C 4烷氧基取代;m选自0、1、2、3、4、5、6;X 1选自CH或N;X 2、X 3相同或不同的各自独立地选自CR a、N、O、S、-S(=O)-、-C(=O)-;R 3选自氢、氘、C 1-C 4烷基、C 2-C 6烯基、C 3-C 8环烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、C 2-C 6烯基、C 3-C 8环烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4 烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基、C 2-C 6烯基、C 3-C 8环烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、C 2-C 6烯基、C 3-C 8环烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;或者,R 3和R 4与它们共同连接的氮原子一起形成3-15元单杂环或者多环杂环,其中所述的单杂环或者多环杂环任选被一个或多个选自卤素、氨基、氰基、R cSO 2、-NR aCOC 2-C 6烯基、-NR aCONR a、-NR aSONR a、砜基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基、C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基的基团取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环;或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R a选自氢、氘、卤素、C 1-C 4烷基、C 2-C 6烯基、C 1-C 4烷氧基、R cSO 2-、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 2-C 6烯基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;R c选自氢、氘、卤素、C 1-C 4烷基、C 2-C 6烯基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 2-C 6烯基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;R d选自氢、氘、卤素、C 1-C 4烷基、C 2-C 6烯基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 2-C 6烯基、C 1-C 4烷氧基、砜基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;
- 根据权利要求1所述的化合物,其中,R 1中的环A选自杂环基、芳基、杂芳基,其中所述杂环基、芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 2-C 6烯基、C 2-C 6 炔基、C 1-C 4烷氧基、R cSO 2-、羟基、巯基、氰基、氨基、硝基、羧基、CONH 2、磺酰胺基、胺基磺酰基、R dCO-、氨基羰基氨基、CONHOH,或者同一个碳原子上的两个R 2在一起表示氧代(=O)、硫代(=S);其中所述的C 1-C 4烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 4烷氧基、巯基、氨基、羧基、CONH 2、磺酰胺基、胺基磺酰基、氨基羰基氨基、CONHOH各自独立地被一个或多个氘、卤素、羟基、C 3-C 6环烷基、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、卤代C 1-C 4烷基C 2-C 6烯基、卤代C 1-C 4烷氧基C 2-C 6烯基、C 2-C 6炔基、氰基、氨基、硝基、羧基、-CONH 2、磺酰胺基、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基、C 2-C 6烯基羰基氨基、C 2-C 6炔基羰基氨基、C 2-C 6烯基氨基羰基、C 2-C 6炔基氨基羰基、环烷基C 1-C 4烷基、环烷基C 1-C 4烷氧基、杂环烷基C 1-C 4烷基、杂环烷基C 1-C 4烷氧基、芳基C 1-C 4烷基、芳基C 1-C 4烷氧基取代;m选自0、1、2、3、4、5;X 2、X 3相同或不同的各自独立地选自CR a、N、O、-C(=O)-;R 3选自氢、氘、C 1-C 4烷基、C 3-C 8环烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、C 3-C 8环烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基、C 3-C 8环烷基,其中所述的C 1-C 4烷基、C 3-C 8环烷基各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代;或者R 3和R 4与它们共同连接的氮原子一起形成3-15元单杂环或者多环杂环,其中所述的单杂环或者多环杂环任选被一个或多个选自卤素、氨基、氰基、砜基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基、C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基的基团取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环;或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环。
- 根据权利要求1所述的化合物,其中,R 1中的环A选自芳基、杂芳基,其中所述芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、R cSO 2-、羟基、巯基、氰基、氨基、硝基、羧基、CONH 2、R dCO-,或者同一个碳原子上 的两个R 2在一起表示氧代(=O)、硫代(=S);其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基、CONH 2各自独立地被一个或多个氘、卤素、羟基、C 3-C 6环烷基、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、氰基、氨基、硝基、羧基、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基、C 2-C 6烯基羰基氨基、C 2-C 6炔基羰基氨基、C 2-C 6烯基氨基羰基、C 2-C 6炔基氨基羰基取代;m选自0、1、2、3、4、5;X 2、X 3相同或不同的各自独立地选自CR a、N、O;R 3选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;或者R 3和R 4与它们共同连接的氮原子一起形成3-15元单杂环或者多环杂环,其中所述的单杂环或者多环杂环任选被一个或多个选自卤素、氨基、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基、C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基的基团取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环;或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R a选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;R c选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;R d选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代。
- 根据权利要求1所述的化合物,其中,R 1中的环A选自芳基、杂芳基,其中所述芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氰基、氨基、R dCO-,或者同一个碳原子上的两个R 2在一起表示氧代(=O);其中所述的C 1-C 4烷基、C 1-C 4烷氧基、氨基各自独立地被一个或多个氘、卤素、羟基、C 3-C 6环烷基、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、氰基、氨基、硝基、羧基、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基取代;m选自0、1、2、3、4、5;X 2、X 3相同或不同的各自独立地选自CR a、N、O;R 3选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;或者R 3和R 4与它们共同连接的氮原子一起形成3-15元单杂环或者多环杂环,其中所述的单杂环或者多环杂环任选被一个或多个选自卤素、氨基、氰基、C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基、C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基的基团取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环;或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R a选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4 烷氧基取代;R d选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代。
- 一种式(I)所示的化合物,或其异构体、药学可接受的盐、前体、代谢产物、N-氧化物,其中,R 1中的环A选自芳基、杂芳基,其中所述芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氰基、氨基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、氨基各自独立地被一个或多个氘、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、氰基、氨基、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基取代;m选自0、1、2、3;X 1选自CH或N;X 2、X 3相同或不同的各自独立地选自CR a、N;R 3选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;或者R 3和R 4与它们共同连接的氮原子一起形成其中p和q相同或不同的各自独立地选自0、1;R 5和R 6相同或不同的独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、羧基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者R 5和R 6与它们共同连接的碳原子一起形成羰基、-C(=S)-、C=NH、C=NOH、3-15元单杂环或者多环杂环、C 3-C 8环烷基;s和t相同或不同的各自独立地选自0、1、2、3、4;R 7和R 8相同或不同的独立地选自氢、氘、卤素、氨基、羟基、氰基、羧基、硝基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者R 7和R 8与它们共同连接的碳原子一起形成羰基、-C(=S)-、C=NR b、3-15元单杂环或者多环杂环、5-10元杂芳基、C 3-C 8环烷基,其中所述3-15元单杂环或者多环杂环、5-10元杂芳基、C 3-C 8环烷基各自独立地被一个或多个氢、氘、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、卤代C 1-C 4烷基C 2-C 6烯基、卤代C 1-C 4烷氧基C 2-C 6烯基、C 2-C 6炔基、氰基、氨基、硝基、羧基、-CONH 2、磺酰胺基、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基、C 2-C 6烯基羰基氨基、C 2-C 6炔基羰基氨基、C 2-C 6烯基氨基羰基、C 2-C 6炔基氨基羰基、环烷基C 1-C 4烷基、环烷基C 1-C 4烷氧基、杂环烷基C 1-C 4烷基、杂环烷基C 1-C 4烷氧基、芳基C 1-C 4烷基、芳基C 1-C 4烷氧基取代;W选自O、S、NH、-C(=O)-、-C(=S)-或者不存在;环B为环烷基、杂环基、芳基、杂芳基,其中所述环烷基、杂环基、芳基、杂芳基各自独立地为3-15元的单环或多环;R 9相同或不同的各自独立地选自氢、氘、卤素、氨基、羟基、氰基、羧基、硝基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者同一个碳原子上的两个R 9在一起表示氧代(=O)、硫代(=S);n选自0、1、2、3、4、5、6;R a选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、 硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、羟基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;R b选自氢、氘、C 1-C 4烷基。
- 根据权利要求5所述的化合物,其中,R 1中的环A选自芳基、杂芳基,其中所述芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氨基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、氨基各自独立地被一个或多个氘、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、氰基、氨基取代;m选自0、1、2、3;X 1选自CH或N;X 2、X 3相同或不同的各自独立地选自CR a、N;R 3选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基;或者R 3和R 4与它们共同连接的氮原子一起形成其中p和q相同或不同的各自独立地选自0、1;R 5和R 6相同或不同的独立地选自氢、氘、卤素、氨基、羟基、氰基、羧基、硝基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;s和t相同或不同的各自独立地选自0、1、2、3、4;R 7和R 8相同或不同的独立地选自氢、氘、卤素、氨基、羟基、氰基、羧基、硝基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者R 7和R 8与它们共同连接的碳原子一起形成C=NR b、3-15元单杂环或者多环杂环、5-10元杂芳基、C 3-C 8环烷基,其中所述3-15元单杂环或者多环杂环、5-10元杂芳基、C 3-C 8环烷基各自独立地被一个或多个氢、氘、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、卤代C 1-C 4烷基C 2-C 6烯基、卤代C 1-C 4烷氧基C 2-C 6烯基、氰基、氨基、-CONH 2、C 1-C 4烷基羰基氨基、单C 1-C 4烷基氨基羰基、双C 1-C 4烷基氨基羰基、C 2-C 6烯基羰基氨基、C 2-C 6炔基羰基氨基、C 2-C 6烯基氨基羰基取代;W选自O、NH、-C(=O)-、或者不存在;环B为芳基、杂芳基,其中所述芳基、杂芳基各自独立地为3-15元的单环或多环;R 9相同或不同的各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C 1-C 4烷基、羧基、硝基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者同一个碳原子上的两个R 9在一起表示氧代(=O)、硫代(=S);n选自0、1、2、3、4、5、6;R a选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、巯基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、巯基、氨基、羧基各自独立地被一个或多个氘、卤素、砜基、羟基、巯基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基取代;R b选自氢、氘、C 1-C 4烷基。
- 根据权利要求5所述的化合物,其中,R 1中的环A选自芳基、杂芳基,其中所述芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氨基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、氨基各自独立地被一个或多个氘、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、氰基、氨基取代;m选自0、1、2、3;X 1选自CH或N;X 2、X 3相同或不同的各自独立地选自CR a、N;R 3选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基;或者R 3和R 4与它们共同连接的氮原子一起形成其中p和q选自1;R 5和R 6相同或不同的独立地选自氢、氘、卤素、氨基、羟基、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者R 5和R 6与它们共同连接的碳原子一起形成C=NH、C=NOH;s和t相同或不同的各自独立地选自0、1、2;R 7和R 8相同或不同的独立地选自氢、氘、卤素、氨基、羟基、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;或者R 7和R 8与它们共同连接的碳原子一起形成C=NR b;W选自O、NH、或者不存在;环B为芳基、杂芳基,其中所述芳基、杂芳基各自独立地为3-15元的单环或多环;R 9相同或不同的各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;n选自0、1、2;R a选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氰基、氨基、硝基、羧基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、羟基、氨基各自独立地被一个或多个选自氘、卤素、羟基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基的基团取代;R b选自氢、氘、甲基、乙基、异丙基。
- 根据权利要求7所述的化合物,其中,R 1中的环A选自芳基、杂芳基,其中所述芳基、杂芳基各自独立地为5-12元的单环或多环;R 2独立地选自相同或不同的氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氨基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、氨基各自独立地被一个或多个氘、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、卤代C 1-C 4烷氧基、氰基、氨基取代;m选自0、1、2、3;X 1选自CH;X 2、X 3相同或不同的各自独立地选自CR a、N;R 3选自氢、氘、C 1-C 4烷基、3-15元单杂环或者多环杂环,其中所述的C 1-C 4烷基、3-15元单杂环或者多环杂环各自独立地任选被一个或多个选自卤素、羟基、氨基、C 1-C 4烷基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、单C 1-C 4烷基氨基、双C 1-C 4烷基氨基取代,所述的多环杂环包括但不限于螺环杂环、桥环杂环、稠环杂环,或者,螺环杂环、桥环杂环还可以稠合于芳基、杂芳基或环烷基环;R 4选自氢、氘、C 1-C 4烷基;或者R 3和R 4与它们共同连接的氮原子一起形成其中p和q选自1;R 5和R 6相同或不同的独立地选自氢、氘、氨基、羟基、卤代C 1-C 4烷基、羟基C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基;s和t相同或不同的各自独立地选自0、1;R 7和R 8相同或不同的独立地选自氢、氘、氨基、羟基、羟基C 1-C 4烷基;或者R 7和R 8与它们共同连接的碳原子一起形成C=NR b;W选自O、NH、或者不存在;环B为苯基、吡啶基;R 9相同或不同的各自独立地选自氢、氘、卤素、氨基、羟基、氰基、甲基、三氟甲基、羟甲基、甲氧基、卤代C 1-C 4烷氧基;n选自0、1、2;R a选自氢、氘、卤素、C 1-C 4烷基、C 1-C 4烷氧基、羟基、氰基、氨基,其中所述的C 1-C 4烷基、C 1-C 4烷氧基、羟基、氨基各自独立地被一个或多个选自氘、卤素、羟基、氰基、氨基、C 1-C 4烷基、C 1-C 4烷氧基的基团取代;R b选自氢、氘、甲基、乙基。
- 根据权利要求1-11任一项所述的化合物,其选自:9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(哌嗪-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;1-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-甲基哌啶-4-胺;1-(9-(3,4-二氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-甲基哌啶-4-胺;1-(9-(4-氟-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-甲基哌啶-4-胺;1-(9-(4-氯-2-乙基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-甲基哌啶-4-胺;1-(5-(5-(4-氨基-4-甲基哌啶-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-9-基)-4-氯-2H-吲唑-2-基)-2-甲基丙基-2-醇;2-(5-(5-(4-氨基-4-甲基哌啶-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-9-基)-4-氯-2H-吲唑-2-基)-N,N-二甲基乙酰胺;(1-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-甲基哌啶-4-基)甲胺;(1-(9-(4-氯-2-甲基-2H-吲唑-5-基)-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-氟哌啶-4-基)甲胺;(R)-9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(3-甲基哌嗪-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;(S)-(4-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)哌嗪-2-基)甲醇;(R)-1-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)吡 咯烷基-3-胺;(3R,4S)-1-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-4-氟吡咯烷基-3-胺;9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(1,4-二氮杂环庚烷-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,8-二氮杂[3.2.1]辛烷-8-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-((1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;(1R,5S,6R)-3-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-氮杂双环[3.1.1]庚烷-6-胺;(1R,3R,5S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3S,5S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(3,4-二氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(4-氟-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(4-氯-2-乙基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(4-氯-1H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(7-氯-2-甲基苯并[d]噁唑-6-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(7-氯-2-甲基苯并[d]噻唑-6-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(7-氯-2-乙基苯并[d]噁唑-6-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(6,7-二氟-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3R,5S)-8-(9-(7-氯-1-甲基-1H-苯并[d][1,2,3]三唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(1S,2R,3R,5R)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-氟-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3S,5S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,3S,5S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-N-甲基-8-氮杂双环[3.2.1]辛烷-3-胺;(1R,2R,4S)-7-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-7-氮杂双环[2.2.1]庚-2-胺;(1R,2R,4S)-7-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-N-甲基-7-氮杂双环[2.2.1]庚烷-2-胺;5-((1R,6R)-3,9-二氮杂双环[4.2.1]壬烷-9-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,6-二氮杂双环[3.2.1]辛烷-3-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,7-二氮杂双环[4.1.1]辛烷-7-基)9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,9-二氮杂双环[3.3.1]壬烷-9-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;7-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷;9-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-氧 杂-9-氮杂双环[3.3.1]壬烷-7-胺;(R)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺;(S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(1R,3R)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-氟-8-氮杂螺[4.5]癸烷-1-胺;(3S,4S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(1,9-二氮杂螺[5.5]十一烷-9-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(1,7-二氮杂螺[3.5]壬烷-7-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(2,7-二氮杂螺[3.5]壬烷-7-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;9-(4-氯-2-甲基-2H-吲唑-5-基)-5-(2,6-二氮杂螺[3.4]辛烷-6-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;5-(3,8-二氮杂双环[4.2.0]辛烷-3-基)-9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶;3-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-氮杂双环[3.1.0]已烷-6-胺;3-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-氮杂双环[3.1.0]已烷-1-胺;(S)-1'-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-1'-(9-(吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(R)-1'-(9-(吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2, 4'-哌啶]-1-胺;(S)-1'-(9-(4-氟苯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-N-(9-(吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-1'-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-5-胺;(S)-1'-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-甲基-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-5-胺;(1R,3R,5S)-8-(9-(吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-8-氮杂双环[3.2.1]辛烷-3-胺;(S)-1'-(9-(2,3-二氯苯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-1'-(9-(3-氯吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-4-(5-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-9-基)-1-萘酚;(S)-1'-(9-(喹啉-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-1'-(9-((2-(三氟甲基)吡啶-3-基)巯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(S)-1'-(9-((2-氨基-3-氯吡啶-4-基)巯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺;(3S,4S)-8-(9-(2-氯苯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-3-甲基-8-(9-苯基-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-3-甲基-8-(9-(喹啉-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-3-甲基-8-(9-(萘-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-(苯并[d][1,3]二氧杂戊环-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-(4-氯-2-甲基-2H-吲唑-5-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-(3-氯-2-(环丙基氨基)吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-(5-氯喹喔啉-6-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-(3-氯-2-(甲氨基)吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-((2,3-二氯苯基)巯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-3-甲基-8-(9-((2-(三氟甲基)吡啶-3-基)巯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(3S,4S)-8-(9-(2,3-二氯苯基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺;(R)-1'-(9-(3-氯吡啶-4-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e]嘧啶-5-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺。
- 一种制备权利要求1-12任一项所述的化合物的方法,其特征在于,包括以下步骤:其中,式(I-a)所示化合物在碱性条件及溶剂下,并在催化剂下经Miyaura Boration反应得到式(I-b)所示化合物;当M为硼酸酯或硼酸时,式(I-b)所示化合物和式(I-c)所示化合物在碱性条件及溶剂下,并在催化剂下经Suzuki反应得到式(I-d)所示化合物;当M为巯基时,式(I-b)所示化合物和式(I-c)所示化合物在碱性条件及溶剂下,并在催化剂和配体作用下形成C-S键,得到式(I-d)所示化合物;式(I-d)所示化合物在胺化剂条件下,经胺化反应得到式(I-e)所示化合物;式(I-e)所示化合物经成环反应得到式(I-f)所示化合物;式(I-f)所示化合物和式(I-g)所示化合物经亲核取代反应得到式(I-h)所示化合物,随后经一步或多步脱保护反应得到通式(I)化合物;其中,当R 1为 时,M为硼酸酯或硼酸,所述硼酸酯包括但不限于4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷、联硼酸新戊二醇酯、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂环戊硼烷)、B(OBu-n) 3、B(OPr-i) 3;Y选自CH 2R a、NH 2、OH、SH;R 10选自卤素、甲磺酰基、对甲苯磺酰基;P 1是保护基,其选自((2-三甲基硅)乙氧)甲基、四氢-2H-吡喃-2-基、叔丁氧羰基、9-芴甲氧羰基、N-苄氧羰基、甲磺酰基、对甲苯磺酰基、乙酰基、甲氧羰基、乙氧羰基;P 2是保护基,其选自羟亚甲基、9-芴甲氧羰基、N-苄氧羰基、甲磺酰基、对甲苯磺酰基、乙酰基、甲氧羰基、乙氧羰基。
- 一种制备权利要求1-12任一项所述的化合物的方法,其特征在于,包括以下步骤:式(I-c)所示化合物在胺化剂条件下,经胺化反应得到式(I1-d)所示化合物,所述的胺化剂包括氨水、氨气、液氨、碳酸氢铵;式(I1-d)所示化合物经成环反应得到式(I1-e)所示化合物;式(I1-e)所示化合物和式(I-g)所示化合物经亲核取代反应得到式(I1-f)所示化合物;当M为硼酸酯或硼酸时,式(I1-f)所示化合物和式(I1-b)所示化合物在碱性条件及溶剂下,并在催化剂下经Suzuki反应得到式(I1-g)所示化合物;当M为巯基时,式(I1-f)所示化合物和式(I1-b)所示化合物在碱性条件及溶剂下,并在催化剂和配体作用下形成C-S键,得到式(I1-g)所示化合物;式(I1-g)所示化合物随后经一步或多步脱保护反应得到本发明所述的通式(I)化合物;当R 1为 时,M为硼酸酯或硼酸,所述硼酸酯包括但不限于4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷、联硼酸新戊二醇酯、4,4,4',4',5,5,5',5'-八甲 基-2,2'-二(1,3,2-二氧杂环戊硼烷)、B(OBu-n) 3、B(OPr-i) 3;Y选自CH 2R a、NH 2、OH、SH;R 10选自卤素、甲磺酰基、对甲苯磺酰基;P 1是保护基,选自((2-三甲基硅)乙氧)甲基、四氢-2H-吡喃-2-基、叔丁氧羰基、9-芴甲氧羰基、N-苄氧羰基、甲磺酰基、对甲苯磺酰基、乙酰基、甲氧羰基、乙氧羰基;P 2是保护基,选自羟亚甲基、9-芴甲氧羰基、N-苄氧羰基、甲磺酰基、对甲苯磺酰基、乙酰基、甲氧羰基、乙氧羰基。
- 根据权利要求13所述的方法,其中,式(I-a)所示化合物在碱性条件及溶剂下,并在催化剂下经Miyaura Boration反应得到式(I-b)所示化合物,以及式(I-b)所示化合物和式(I-c)所示化合物在碱性条件及溶剂下,并在催化剂下经Suzuki反应得到式(I-d)所示化合物中,所述催化剂包括醋酸钯、二氯化钯、三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、四(三苯基膦)钯、双(三环己基膦)二氯化钯、2-二环己基膦-2',6'-二甲氧基联苯;所述碱性条件的试剂包括有机碱和无机碱类,选自三乙胺、N,N-二异丙基乙基胺、正丁基锂、二异丙基氨基锂、双三甲基硅基氨基锂、醋酸钾、叔丁醇钠、叔丁醇钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、氢氧化锂、氢氧化钠;所述溶剂包括二氧六环、四氢呋喃、乙腈、N,N'-二甲基甲酰胺,以及这些溶剂与水以不同比例形成的混合溶剂。
- 根据权利要求14所述的方法,其中,当M为硼酸酯或硼酸时,式(I1-f)所示化合物和式(I1-b)所示化合物在碱性条件及溶剂下,并在催化剂下经Suzuki反应得到式(I1-g)所示化合物中,所述催化剂选自醋酸钯、二氯化钯、三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、四(三苯基膦)钯、双(三环己基膦)二氯化钯、2-二环己基膦-2',6'-二甲氧基联苯;所述碱性条件的试剂包括有机碱和无机碱类,选自三乙胺、N,N-二异丙基乙基胺、正丁基锂、二异丙基氨基锂、双三甲基硅基氨基锂、醋酸钾、叔丁醇钠、叔丁醇钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、氢氧化锂、氢氧化钠;所述溶剂选自二氧六环、四氢呋喃、乙腈、N,N'-二甲基甲酰胺,以及这些溶剂与水以不同比例形成的混合溶剂。
- 根据权利要求14所述的方法,其中,当M为巯基时,式(I1-f)所示化合 物和式(I1-b)所示化合物在碱性条件及溶剂下,并在催化剂和配体作用下,得到式(I1-g)所示化合物中,所述催化剂选自三(二亚苄基丙酮)二钯、碘化亚铜;所述配体包括并不限于4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,10-菲啰林;所述碱性条件的试剂包括有机碱和无机碱类,选自三乙胺、N,N-二异丙基乙基胺、碳酸钾、氢氧化锂;所述溶剂选自二氧六环、四氢呋喃、乙腈、N,N'-二甲基甲酰胺,以及这些溶剂与水以不同比例形成的混合溶剂。
- 根据权利要求13-14所述的方法,其中,式(I-d)所示化合物在胺化剂条件下,经胺化反应得到式(I-e)所示化合物中,以及式(I-c)所示化合物在胺化剂条件下,经胺化反应得到式(I1-d)所示化合物中,所述的胺化剂选自氨水、氨气、液氨、碳酸氢铵。
- 一种药物组合物,其包含权利要求1至12任一项所述的化合物。
- 权利要求1至12任一项所述的化合物或权利要求19所述的药物组合物在制备用于治疗和/或预防与SHP2蛋白活性异常相关的疾病的药物中的应用。
- 根据权利要求20所述的应用,其中,所述与SHP2蛋白活性异常相关的疾病包括肿瘤或癌症。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202180083515.0A CN116724042A (zh) | 2020-08-10 | 2021-08-09 | 一种杂三环类化合物及其制备方法和应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010795930.6 | 2020-08-10 | ||
CN202010795930 | 2020-08-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022033430A1 true WO2022033430A1 (zh) | 2022-02-17 |
Family
ID=80246929
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/111513 WO2022033430A1 (zh) | 2020-08-10 | 2021-08-09 | 一种杂三环类化合物及其制备方法和应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116724042A (zh) |
WO (1) | WO2022033430A1 (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023230205A1 (en) | 2022-05-25 | 2023-11-30 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120330012A1 (en) * | 2011-04-29 | 2012-12-27 | Abbott Laboratories | Novel Tricyclic Compounds |
CN111433205A (zh) * | 2017-12-15 | 2020-07-17 | 锐新医药公司 | 作为变构shp2抑制剂的多环化合物 |
CN111704611A (zh) * | 2019-07-25 | 2020-09-25 | 上海凌达生物医药有限公司 | 一类芳基螺环类shp2抑制剂化合物、制备方法和用途 |
CN113004282A (zh) * | 2019-12-19 | 2021-06-22 | 首药控股(北京)有限公司 | 取代的炔基杂环化合物 |
WO2021121397A1 (zh) * | 2019-12-19 | 2021-06-24 | 首药控股(北京)股份有限公司 | 取代的炔基杂环化合物 |
-
2021
- 2021-08-09 WO PCT/CN2021/111513 patent/WO2022033430A1/zh active Application Filing
- 2021-08-09 CN CN202180083515.0A patent/CN116724042A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120330012A1 (en) * | 2011-04-29 | 2012-12-27 | Abbott Laboratories | Novel Tricyclic Compounds |
CN111433205A (zh) * | 2017-12-15 | 2020-07-17 | 锐新医药公司 | 作为变构shp2抑制剂的多环化合物 |
CN111704611A (zh) * | 2019-07-25 | 2020-09-25 | 上海凌达生物医药有限公司 | 一类芳基螺环类shp2抑制剂化合物、制备方法和用途 |
CN113004282A (zh) * | 2019-12-19 | 2021-06-22 | 首药控股(北京)有限公司 | 取代的炔基杂环化合物 |
WO2021121397A1 (zh) * | 2019-12-19 | 2021-06-24 | 首药控股(北京)股份有限公司 | 取代的炔基杂环化合物 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023230205A1 (en) | 2022-05-25 | 2023-11-30 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
CN116724042A (zh) | 2023-09-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022033430A1 (zh) | 一种杂三环类化合物及其制备方法和应用 | |
AU2022291504B2 (en) | Substituted tricyclic compounds as fgfr inhibitors | |
EP1416935B1 (en) | 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives | |
KR101793807B1 (ko) | 단백질 키나제 억제제로서의 융합된 헤테로시클릭 화합물 | |
TW202144349A (zh) | 作為kras抑制劑的雜環化合物的製備及其應用方法 | |
AU2010271270C1 (en) | Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors | |
TW201726679A (zh) | 作為PI3K-γ抑制劑之雜環化合物 | |
AU2009219175A1 (en) | Bridged, bicyclic heterocyclic or spiro bicyclic heterocyclic derivatives of pyrazolo[1,5-a]pyrimidines, methods for preparation and uses thereof | |
HUE035116T2 (hu) | PI3K inhibitor pirimidinszármazékok és alkalmazásuk | |
TWI829179B (zh) | 用於治療疾病之磷酸肌醇3-激酶(pi3k)異位色烯酮抑制劑 | |
JP2021506979A (ja) | ホスファチジルイノシトールリン酸キナーゼ阻害剤としてのアリール−ビピリジンアミン誘導体 | |
WO2023061294A1 (zh) | 含氮杂环类衍生物调节剂、其制备方法及应用 | |
WO2020259724A2 (zh) | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 | |
TW202400581A (zh) | 驅動蛋白kif18a抑制劑及其應用 | |
TW201446766A (zh) | 3環性吡咯並吡啶化合物及jak阻斷劑 | |
JP7511097B1 (ja) | Her2変異阻害薬 | |
JP2020537672A (ja) | 炎症性障害の治療のための新規化合物及びその医薬組成物 | |
CN117355523A (zh) | 血浆激肽释放酶的多环抑制剂 | |
JP2024518824A (ja) | Enl/af9 yeatsのc結合阻害剤 | |
WO2023069959A1 (en) | Covalent egfr inhibitors and methods of use thereof | |
US7323469B2 (en) | 7H-pyrrolo[2,3-d]pyrimidine derivatives | |
CN112739701B (zh) | 具有表皮生长因子受体突变的抑制效果的融合嘧啶骨架磺酰胺衍生物 | |
TW202212331A (zh) | 作為egfr抑製劑之吲哚啉化合物及衍生物 | |
TWI772370B (zh) | 作為胞內體類鐸(toll-like)受體抑制劑之化合物及組合物 | |
WO2024102952A1 (en) | Sos1 inhibitors |
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: 21855482 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202180083515.0 Country of ref document: CN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
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 10/07/2023) |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21855482 Country of ref document: EP Kind code of ref document: A1 |