WO2023284837A1 - 芳氨基衍生物雌激素受体调节剂及其用途 - Google Patents
芳氨基衍生物雌激素受体调节剂及其用途 Download PDFInfo
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- WO2023284837A1 WO2023284837A1 PCT/CN2022/105788 CN2022105788W WO2023284837A1 WO 2023284837 A1 WO2023284837 A1 WO 2023284837A1 CN 2022105788 W CN2022105788 W CN 2022105788W WO 2023284837 A1 WO2023284837 A1 WO 2023284837A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- cycloalkyl
- heteroatoms
- halogen
- group
- Prior art date
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- 125000001769 aryl amino group Chemical group 0.000 title description 2
- 239000002834 estrogen receptor modulator Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 307
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 238000002360 preparation method Methods 0.000 claims abstract description 49
- 239000012453 solvate Substances 0.000 claims abstract description 49
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 444
- 229910052757 nitrogen Inorganic materials 0.000 claims description 313
- -1 alkenes Alkyl Chemical group 0.000 claims description 286
- 125000005842 heteroatom Chemical group 0.000 claims description 279
- 229910052717 sulfur Inorganic materials 0.000 claims description 273
- 229910052760 oxygen Inorganic materials 0.000 claims description 259
- 150000002367 halogens Chemical class 0.000 claims description 208
- 229910052736 halogen Inorganic materials 0.000 claims description 200
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 172
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 165
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 112
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 95
- 125000001072 heteroaryl group Chemical group 0.000 claims description 72
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 238000006467 substitution reaction Methods 0.000 claims description 49
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 47
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 47
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 229910052805 deuterium Inorganic materials 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000000304 alkynyl group Chemical group 0.000 claims description 28
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 28
- 125000003342 alkenyl group Chemical group 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 25
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 9
- 150000001924 cycloalkanes Chemical class 0.000 claims description 8
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 8
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000003566 oxetanyl group Chemical group 0.000 claims description 7
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
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- 239000000969 carrier Substances 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000013598 vector Substances 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 248
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 217
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 133
- 239000012071 phase Substances 0.000 description 108
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 106
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 98
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 96
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 84
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
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- 239000012074 organic phase Substances 0.000 description 56
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
- 238000010828 elution Methods 0.000 description 54
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- 238000005481 NMR spectroscopy Methods 0.000 description 51
- 239000012141 concentrate Substances 0.000 description 51
- 239000000523 sample Substances 0.000 description 49
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 47
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000000460 chlorine Substances 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 230000014759 maintenance of location Effects 0.000 description 34
- 229960000583 acetic acid Drugs 0.000 description 33
- 239000004698 Polyethylene Substances 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- 239000003643 water by type Substances 0.000 description 29
- 239000002585 base Substances 0.000 description 28
- 125000004432 carbon atom Chemical group C* 0.000 description 28
- 239000000543 intermediate Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 28
- 239000007788 liquid Substances 0.000 description 27
- 102000015694 estrogen receptors Human genes 0.000 description 26
- 108010038795 estrogen receptors Proteins 0.000 description 26
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 25
- 239000005695 Ammonium acetate Substances 0.000 description 25
- 229940043376 ammonium acetate Drugs 0.000 description 25
- 235000019257 ammonium acetate Nutrition 0.000 description 25
- 239000007791 liquid phase Substances 0.000 description 25
- 239000007858 starting material Substances 0.000 description 25
- 241000394635 Acetomicrobium mobile Species 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 20
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 19
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 125000002619 bicyclic group Chemical group 0.000 description 17
- RSOJSFYJLQADDM-UHFFFAOYSA-N ethanesulfonamide Chemical compound [CH2]CS(N)(=O)=O RSOJSFYJLQADDM-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 125000003003 spiro group Chemical group 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 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 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229910052794 bromium Inorganic materials 0.000 description 15
- 125000003367 polycyclic group Chemical group 0.000 description 15
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- 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 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 229910052740 iodine Inorganic materials 0.000 description 13
- 125000004193 piperazinyl group Chemical group 0.000 description 13
- 125000003386 piperidinyl group Chemical group 0.000 description 13
- 238000002953 preparative HPLC Methods 0.000 description 13
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 12
- 239000005909 Kieselgur Substances 0.000 description 12
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 12
- 229940045803 cuprous chloride Drugs 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 12
- FVNLZNMDHCZWDD-SNVBAGLBSA-N C[C@H](CC1=CNC2=CC=C(C)C=C12)NCC(F)(F)F Chemical compound C[C@H](CC1=CNC2=CC=C(C)C=C12)NCC(F)(F)F FVNLZNMDHCZWDD-SNVBAGLBSA-N 0.000 description 11
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
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- YIVPUJBLDOGYKF-CRYYWNKWSA-N CCS(NC1=CC=C([C@@H](C(C(F)=CC(NC2CN(CCCF)C2)=C2)=C2F)N(CC(C)(C)F)[C@H](C)C2)C2=C1F)(=O)=O Chemical compound CCS(NC1=CC=C([C@@H](C(C(F)=CC(NC2CN(CCCF)C2)=C2)=C2F)N(CC(C)(C)F)[C@H](C)C2)C2=C1F)(=O)=O YIVPUJBLDOGYKF-CRYYWNKWSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 8
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 125000002541 furyl group Chemical group 0.000 description 8
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- 125000002883 imidazolyl group Chemical group 0.000 description 8
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 8
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- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
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- ZHZAILNAMXZESV-JOCHJYFZSA-N [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OCC(CN[C@@H](CC1=CNC2=CC=C(C=C12)F)C)(F)F Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OCC(CN[C@@H](CC1=CNC2=CC=C(C=C12)F)C)(F)F ZHZAILNAMXZESV-JOCHJYFZSA-N 0.000 description 6
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 6
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Images
Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the invention relates to an arylamino derivative estrogen receptor modulator and its use in the preparation of medicines for treating/preventing ER-related diseases.
- Estrogen includes estrone, estradiol, etc., which are mainly secreted by the ovary, and a small amount is secreted by the liver, adrenal cortex and breast.
- Estrogen Receptor As the main sex hormone of female animals, estrogen promotes the maturation of female accessory sex organs and the emergence of secondary sexual characteristics, and maintains normal sexual desire and reproductive function. Its role is mainly to diffuse into the nucleus and form a complex with estrogen receptor (Estrogen Receptor, ER).
- Estrogen Receptor ER
- Enhancers include Estrogen Response Elements (ERE) and other binding elements, and recruit other transcription factors to form a transcription initiation complex to induce transcription.
- activated estrogen receptors can also recruit transcriptional co-factors and bind to activating protein 1 (Activating Protein 1, AP-1) located in the promoter region of target genes, thereby regulating gene transcriptional activity.
- the estrogen receptor (ER) is a transcriptional regulatory protein that mediates ligand activation induced by a variety of biological effects through its interaction with endogenous estrogens.
- ER consists of two subtypes: ER ⁇ and ER ⁇ , each encoded by a different gene.
- ER ⁇ and ER ⁇ show a high degree of similarity at the amino acid level, with 97% similarity in the DNA-binding domain and 56% similarity in the ligand-binding domain. However, there is only 24% similarity in the N-terminus. low homology.
- ER contains 6 structural domains (AF), which consist of 4 main functional regions.
- the functional region of the N-terminal A/B domain has a ligand-independent transcriptional activation functional region AF-1, and AF-1 has constitutive activation activity. Activate the transcription of target genes by interacting with basic transcription factors, resurrection factors and other transcription factors. There are multiple phosphorylation sites in this region. It has been reported in the literature that the effect of AF-1 depends on protein phosphorylation.
- the DNA-binding domain (DBD) composed of the C domain is highly conserved and contains two zinc finger domains, which can specifically bind to the target DNA, and this domain plays an important role in the dimerization of the receptor .
- the D domain is the hinge region, linking the DBD and the ligand domain (LBD), with low conservation (the homology between the two subtypes is only 30%).
- the C-terminal E domain constitutes the ligand-binding domain (LBD), which determines the interaction between ER and ligands such as estrogen, SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor down-regulator), etc. specific binding.
- LBD has a ligand-dependent transcriptional activation functional domain AF-2, which cooperates with AF-1 to play the function of ER receptors to activate the transcription of target genes.
- AF-2 ligand-dependent transcriptional activation functional domain
- LBD has a strong dimerization interface and can still function without ligand. Therefore, LBD is the key site for receptor dimerization.
- ER ⁇ is mainly distributed in the uterus, ovary, testis, pituitary, kidney, epididymis and adrenal gland, while ER ⁇ is mainly distributed in the prostate, ovary, lung, bladder, brain and blood vessels. Due to the serious side effects of full agonists or full antagonists, the study of selective estrogen receptor modulator SERM came into being. Its "selectivity" means that SERM acts as an agonist in certain tissues such as bone, liver, and cardiovascular system ER ⁇ concentration areas, while it acts as an antagonist in other tissues such as breast. It can be either an agonist or an antagonist in the uterus (where ER alpha is more prominent).
- SERMs currently on the market include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc., but studies have found that SERMs currently on the market still have severe For example, long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps, and endometrial cancer, while common side effects of raloxifene include hot flashes, leg pain, breast tenderness, and venous Embolism, etc. Therefore, the research and development of new compounds is still an urgent problem to be solved.
- SESDs Selective Estrogen Receptor Degraders
- E3 ubiquitin ligases by binding to estrogen receptors and inducing their conformational changes, resulting in the exposure of hydrophobic residues to the molecular surface.
- Ubiquitin ligases modify estrogen receptor ubiquitination and ultimately direct it to the proteasome for degradation.
- SERD can also degrade mutated estrogen receptors, thereby avoiding the emergence of drug resistance.
- Fulvestrant is currently the only SERD drug approved for clinical use in the treatment of ER+ breast cancer, but it has poor druggability, rapid metabolism and must be administered by monthly intramuscular injections, unlike those seen in in vitro studies This limits the effective degradation of ER compared to complete ER degradation (-50% ER degradation in clinical samples).
- Selective estrogen receptor down-regulators have shown certain therapeutic advantages, but more orally available SERDs still need to be developed, so that candidate drugs have more excellent properties, such as better efficacy, lower side effects, and better pharmacokinetic properties , longer dosing intervals, etc., so as to be better used for the prevention or treatment of estrogen receptor-related diseases. But so far, there are still no effective oral ER degraders on the market, so oral ER degraders with high inhibitory activity and low toxicity still represent an unmet clinical need.
- the object of the present invention is to provide a selective estrogen receptor down-regulator compound, its stereoisomer, solvate, deuterium or pharmaceutically acceptable salt, and its medical application.
- the compound has good curative effect, It has the advantages of low toxic and side effects, good safety, high selectivity, good pharmacokinetics, high bioavailability, and no inhibition of CYP enzymes.
- Ring A is selected from I-a or I-b;
- ring A is selected from II-a or II-b:
- X is N or CRx; in some embodiments, X is N, CH or CF;
- a is 0, 1, 2 or 3; in some embodiments, a is 0, 1 or 2; in some embodiments, a is 1 or 2;
- b is 1 or 2; in some embodiments, a is 1; in some embodiments, a is 2;
- Y is NR 8 or CHR 8 ;
- R 1 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and said R 1 is optionally replaced by 1-3 members selected from halogen, OH, NH 2 , -OC 1-4 Alkyl, -NHC 1-4 alkyl, C 3-6 cycloalkyl, and a 4-7-membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms, wherein, Said cycloalkyl and heterocycloalkyl are optionally further substituted by 1-3 groups selected from halogen, OH, C 1-4 alkyl and -OC 1-4 alkyl; in some embodiments, R 1 is C 1-4 alkyl, said R 1 is optionally replaced by 1-3 members selected from halogen, OH, NH 2 , -OC 1-4 alkyl, -NHC 1-4 alkyl, C 3-6 Cycloalkyl and substituted by a group containing 1-3 4-7 membered heterocycloalky
- Each R x is independently H, NH 2 , OH, halogen, C 1-4 alkyl, haloC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NHC 1-4 alkane or -OC 1-4 alkyl; in some embodiments, each R x is independently H or halogen; in some embodiments, each R x is independently H, F, Cl, Br, or I;
- R 2 , R 5 , R 6 , R 2 ′, R 5 ′, and R 6 ′ are independently H, CN, OH, NH 2 , SH, or halogen; in some embodiments, R 2 , R 5 , R 6 , R 2 ', R 5 'and R 6 ' are independently H, CN, OH, NH 2 , SH, F, Cl, Br or I;
- R a is H or R b ;
- R b is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected
- a 4-7 membered heterocycloalkyl group selected from N, S, O heteroatoms said alkyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and 1-3 substituted by a 4-7 membered heterocycloalkyl group selected from N, S, O heteroatoms; in some embodiments, R b is methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, tert-butyl, cyclopropyl,
- R 3 ' and R 4 ' are independently H, -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, halogen, SF 5 , CN, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O or 4-membered heteroaryl containing 1-3 heteroatoms selected from N, S, O -7-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl optionally replaced by 1-3 members selected from halogen, CN, NH , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and 1-3 heteroaryls selected from N, S, O heteroatoms
- one R 3 ' and one R 4 ' together with the atoms to which they are attached form a C 4-6 cycloalkyl, which is optionally replaced by 1-3 members selected from the group consisting of halogen, OH, C 1-4 alkyl group substitution; in some specific embodiments, one R 3 ' and one R 4 ' form cyclobutyl, cyclopentyl, cyclohexyl together with the atoms they are connected to, and the cyclobutyl ,
- R 3 ' and R 4 ' are not simultaneously selected from H;
- R c is H, C 1-4 alkyl or C 3-6 cycloalkyl; In some embodiments, R c is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl;
- R c ' is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -COR e , -OH, -OC 1-4 alkyl or -SO 2 Re; in some embodiments In, R c ' is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OH or -OC 1-4 alkyl; in some specific embodiments, R c ' is ethyl propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, -COR e , -OH, methoxy, ethoxy , propoxy, isopropyloxy or -SO 2 Re;
- Re is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, -C 1-4 alkyl C 3-6 cycloalkyl, containing 1-3 A 5-6 membered heteroaryl group selected from N, S, O heteroatoms or a 4-7 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms, said alkyl, alkenyl , alkynyl, cycloalkyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl
- Re is ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propyne Cyclobutyl,
- R d is a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or a heteroaryl group containing 1-3 heteroatoms selected from N, S, O 4-7 membered heterocycloalkyl substituted C 1-4 alkyl, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl , the cycloalkyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl Group substitution; further, R d is C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or 1-3 heteroaryls selected from N, C 1-4 alkyl substituted by 4-7 membered heterocycloal
- R 7 and R 7 ' are H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, SH, C 1 -4 alkyl and C 3-6 cycloalkyl group substitution; in some embodiments, R 7 and R 7 ' are H or C 1-4 alkyl; in some embodiments, R 7 and R 7 'is H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said R 7 and R 7 'are optionally replaced by 1 -3 groups selected from F, Cl, Br, I, OH, SH, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl replace;
- R 8 and R 8 ' are independently C 1-6 alkyl, -OR f , -SR f , -NHR f , C 3-6 cycloalkyl or contain 1-3 heteroatoms selected from N, S, O 4-7 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, - C 1-4 alkyl-OH, C 3-6 cycloalkyl and substituted by a group containing 1-3 4-7 membered heterocycloalkyl selected from N, S, O heteroatoms; in some specific embodiments
- R 8 and R 8 ' are independently C 1-4 alkyl, -OR f , -NHR f , C 3-6 cycloalkyl or 5 containing 1-3 heteroatoms selected from N, S, O -6 membered heterocycloalkyl, said alky
- R f is H, C 1-4 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, ring Alkyl and heterocycloalkyl are optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contain 1-3 selected from N, S, O heteroatoms are substituted by 4-7 membered heterocycloalkyl groups; in some specific embodiments, R f is C 1-4 alkyl, C 3-6 cycloalkyl or contains 1-3 selected A 5-6 membered heterocycloalkyl group selected from N, S, O heteroatoms, said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and substituted
- the compound needs to satisfy:
- R 3 is -NR a SO 2 R b , -SO 2 NR a , CN or halogen; or
- R B is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected A 4-7 membered heterocycloalkyl group from N, S, O heteroatoms; when R B is the alkyl group, it is further selected from halogen, CN, C 3-6 cycloalkyl, containing 1-3 3 5-6 membered heteroaryl groups selected from N, S, O heteroatoms and substituted by a group containing 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms; when R When B is said cycloalkyl, phenyl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH and C 1-4 alkyl; or
- R is CN or halogen ;
- R 8 is -OR f , -SR f , -NHR f , C 1-6 alkyl, C 3-6 cycloalkyl or 4- containing 1-3 heteroatoms selected from N, S, O
- a 7 -membered heterocycloalkyl group when R is the alkyl group, it is further replaced by a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or containing 1-3 4-7 membered heterocycloalkyls selected from N, S, O heteroatoms are substituted; when R is said cycloalkyl or heterocycloalkyl, optionally 1-3 are selected from halogen , OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O ;or
- At least one of R 3 ' and R 4 ' is -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, containing 1-3 selected from N, S, A 5-6 membered heteroaryl group with O heteroatom or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S and O, the alkenyl, alkynyl, heteroaryl and heterocycle Alkyl is optionally replaced by 1-3 heteroatoms selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, containing 1-3 heteroatoms selected from N, S, O
- the 5-6 membered heteroaryl group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O
- R c ' is C 2-6 alkyl, C 2 -6 alkenyl, C 2-6 alkyn
- one R 3 ' and one R 4 ' together with the atoms they are connected to form a C 3-8 cycloalkyl group, or a 4-12 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 groups selected from halogen, OH, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl; or
- R 8 ' is -OR f
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and Substitution with 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms;
- the compound needs to meet:
- R 3 is -NR a SO 2 R b , -SO 2 NR a , CN or halogen; or
- R B is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected A 5-6 membered heterocycloalkyl group from N, S, O heteroatoms; when R B is the alkyl group, it is further selected from 1-3 halogen, CN, C 3-6 cycloalkyl, containing 1- 3 5-6 membered heteroaryl groups selected from N, S, O heteroatoms and substituted by a group containing 1-3 5-6 membered heterocycloalkyl groups selected from N, S, O heteroatoms; when R When B is said cycloalkyl, phenyl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH and C 1-4 alkyl; or
- R is CN or halogen ;
- R 8 is -OR f , -NHR f , C 1-4 alkyl, C 3-6 cycloalkyl or a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl group, when R 8 is said alkyl group, it is further replaced by C 3-6 cycloalkyl group, 5-6 membered heteroaryl group containing 1-3 selected from N, S, O heteroatoms or containing 1-3 A 5-6 membered heterocycloalkyl group selected from N, S, and O heteroatoms; when R is the cycloalkyl or heterocycloalkyl group, it is optionally 1-3 selected from halogen, OH, CN , NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl, and a 5-6 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms; or
- At least one of R 3 ' and R 4 ' is -NHR c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, containing 1-3 selected from N, S, O hetero Atomic 5-membered heteroaryl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkenyl, alkynyl, heteroaryl and heterocycloalkyl are optionally Ground is covered with 1-3 selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 containing 1-3 heteroatoms selected from N, S, O Substituted by a heteroaryl group and a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, R c ' is C 2-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, -OC
- one R 3 ' and one R 4 ' together with the atoms they are connected to form a C 3-8 cycloalkyl group, or a 4-12 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 groups selected from halogen, OH, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl; or
- R 8 ' is -OR f , C 3-6 cycloalkyl, said cycloalkyl is optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkyl and a 4-7 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms;
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl And heterocycloalkyl is optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contains 1-3 selected from N, S, A 5-6 membered heterocycloalkyl group of O heteroatom is substituted.
- X is N or CR x ;
- a 0, 1, 2 or 3;
- b is 1 or 2;
- Y is NR 8 or CHR 8 ;
- R 1 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and said R 1 is optionally replaced by 1-3 members selected from halogen, OH, NH 2 , -OC 1-4 Alkyl, -NHC 1-4 alkyl, C 3-6 cycloalkyl, and a 4-7-membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms, wherein, Said cycloalkyl and heterocycloalkyl are optionally further substituted by 1-3 groups selected from halogen, OH, C 1-4 alkyl and -OC 1-4 alkyl;
- Each R x is independently H, NH 2 , OH, halogen, C 1-4 alkyl, haloC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NHC 1-4 alkane Group or -OC 1-4 alkyl;
- R2, R5 , R6 , R2 ', R5 ' and R6' are independently H, CN , OH, NH2 , SH or halogen ;
- R a is H or R b ;
- R b is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected
- a 4-7 membered heterocycloalkyl group selected from N, S, O heteroatoms said alkyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and 1-3 Substitution of 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms;
- R 3 ' and R 4 ' are independently H, -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, halogen, SF 5 , CN, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or 1-3 heteroatoms selected from N, S, O 4-7 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, CN, NH 2.
- one R 3 ' and one R 4 ' together with the atoms they are connected to form a C 3-8 cycloalkyl group, or a 4-12 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 groups selected from halogen, OH, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl;
- R c is H, C 1-4 alkyl or C 3-6 cycloalkyl
- R c ' is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -COR e , -OH, -OC 1-4 alkyl or -SO 2 Re;
- Re is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, -C 1-4 alkyl C 3-6 cycloalkyl, containing 1-3
- R d is a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or a heteroaryl group containing 1-3 heteroatoms selected from N, S, O 4-7 membered heterocycloalkyl substituted C 1-4 alkyl, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, or halogenated C 1-4 alkane
- the cycloalkyl, heteroaryl and heterocycloalkyl groups are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl group substitution;
- R 7 and R 7 ' are H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, SH, C 1 -4 alkyl and C 3-6 cycloalkyl group substitution;
- R 8 and R 8 ' are independently C 1-6 alkyl, -OR f , -SR f , -NHR f , C 3-6 cycloalkyl or contain 1-3 heteroatoms selected from N, S, O 4-7 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, - C 1-4 alkyl-OH, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl groups containing 1-3 selected from N, S, O heteroatoms;
- R f is H, C 1-4 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, ring Alkyl and heterocycloalkyl are optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contain 1-3 selected from N, 4-7 membered heterocycloalkyl groups of S, O heteroatoms are substituted.
- X is N or CR x ;
- a 0, 1, 2 or 3;
- b is 1 or 2;
- Y is NR 8 or CHR 8 ;
- R 1 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and said R 1 is optionally replaced by 1-3 members selected from halogen, OH, NH 2 , -OC 1-4 Alkyl, -NHC 1-4 alkyl, C 3-6 cycloalkyl, and a 4-7-membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms, wherein, Said cycloalkyl and heterocycloalkyl are optionally further substituted by 1-3 groups selected from halogen, OH, C 1-4 alkyl and -OC 1-4 alkyl;
- Each R x is independently H, NH 2 , OH, halogen, C 1-4 alkyl, haloC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NHC 1-4 alkane Group or -OC 1-4 alkyl;
- R2, R5 , R6 , R2 ', R5 ' and R6' are independently H, CN , OH, NH2 , SH or halogen ;
- R a is H or R b ;
- R b is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected
- a 4-7 membered heterocycloalkyl group selected from N, S, O heteroatoms said alkyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and 1-3 Substitution of 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms;
- R 3 ' and R 4 ' are independently H, -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, halogen, SF 5 , CN, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O or 4-membered heteroaryl containing 1-3 heteroatoms selected from N, S, O -7-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl optionally replaced by 1-3 members selected from halogen, CN, NH , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and 1-3 heteroaryls selected from N, S, O heteroatom 4
- R c is H, C 1-4 alkyl or C 3-6 cycloalkyl
- R c ' is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -COR e , -OH, -OC 1-4 alkyl or -SO 2 Re;
- Re is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, -C 1-4 alkyl C 3-6 cycloalkyl, containing 1-3
- R d is a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or a heteroaryl group containing 1-3 heteroatoms selected from N, S, O C 1-4 alkyl substituted by 4-7 membered heterocycloalkyl, said cycloalkyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl are substituted; or R d is C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, or Halogenated C 1-4 alkyl;
- R 7 and R 7 ' are H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, SH, C 1 -4 alkyl and C 3-6 cycloalkyl group substitution;
- R 8 and R 8 ' are independently C 1-6 alkyl, -OR f , -SR f , -NHR f , C 3-6 cycloalkyl or contain 1-3 heteroatoms selected from N, S, O 4-7 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl groups are substituted with 4-7 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, S, O;
- R f is H, C 1-4 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, ring Alkyl and heterocycloalkyl are optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contain 1-3 selected from N, 4-7 membered heterocycloalkyl groups of S, O heteroatoms are substituted.
- R 3 is -NR a SO 2 R b , -SO 2 NR a , CN or halogen; or
- R B is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected A 4-7 membered heterocycloalkyl group from N, S, O heteroatoms; when R B is the alkyl group, it is further selected from halogen, CN, C 3-6 cycloalkyl, containing 1-3 3 5-6 membered heteroaryl groups selected from N, S, O heteroatoms and substituted by a group containing 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms; when R When B is said cycloalkyl, phenyl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH and C 1-4 alkyl; or
- R is CN or halogen ;
- R 8 is -OR f , -SR f , -NHR f , C 1-6 alkyl, C 3-6 cycloalkyl or 4- containing 1-3 heteroatoms selected from N, S, O
- a 7 -membered heterocycloalkyl group when R is the alkyl group, it is further replaced by a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or containing 1-3 4-7 membered heterocycloalkyls selected from N, S, O heteroatoms are substituted; when R is said cycloalkyl or heterocycloalkyl, optionally 1-3 are selected from halogen , OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O ;or
- At least one of R 3 ' and R 4 ' is -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, containing 1-3 selected from N, S, A 5-6 membered heteroaryl group with O heteroatom or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S and O, the alkenyl, alkynyl, heteroaryl and heterocycle Alkyl is optionally replaced by 1-3 heteroatoms selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, containing 1-3 heteroatoms selected from N, S, O
- the 5-6 membered heteroaryl group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O
- R c ' is C 2-6 alkyl, C 2 -6 alkenyl, C 2-6 alkyn
- one R 3 ' and one R 4 ' together with the atoms they are connected to form a C 3-8 cycloalkyl group, or a 4-12 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 groups selected from halogen, OH, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl; or
- R 8 ' is -OR f , C 3-6 cycloalkyl, said cycloalkyl is optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkyl and a 4-7 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms;
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl And heterocycloalkyl is optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contains 1-3 selected from N, S, 4-7 membered heterocycloalkyl groups of O heteroatoms are substituted;
- R 3 is -NR a SO 2 R b , -SO 2 NR a , CN or halogen; or
- R B is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected A 4-7 membered heterocycloalkyl group from N, S, O heteroatoms; when R B is the alkyl group, it is further selected from halogen, CN, C 3-6 cycloalkyl, containing 1-3 3 5-6 membered heteroaryl groups selected from N, S, O heteroatoms and substituted by a group containing 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms; when R When B is said cycloalkyl, phenyl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH and C 1-4 alkyl; or
- R is CN or halogen ;
- R 8 is -OR f , -SR f , -NHR f , C 1-6 alkyl, C 3-6 cycloalkyl or 4- containing 1-3 heteroatoms selected from N, S, O
- a 7 -membered heterocycloalkyl group when R is the alkyl group, it is further replaced by a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or containing 1-3 4-7 membered heterocycloalkyls selected from N, S, O heteroatoms are substituted; when R is said cycloalkyl or heterocycloalkyl, optionally 1-3 are selected from halogen , OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O ;or
- At least one of R 3 ' and R 4 ' is -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, containing 1-3 selected from N, S, A 5-6 membered heteroaryl group with O heteroatom or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S and O, the alkenyl, alkynyl, heteroaryl and heterocycle Alkyl is optionally replaced by 1-3 heteroatoms selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, containing 1-3 heteroatoms selected from N, S, O
- the 5-6 membered heteroaryl group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O
- R c ' is C 2-6 alkyl, C 2 -6 alkenyl, C 2-6 alkyn
- R 8 ' is -OR f
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and Substitution with 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms;
- Ring A is selected from II-a or II-b:
- X is N or CR x ;
- Y is NR 8 or CHR 8 ;
- each R x is independently H or halogen
- R 3 ' and R 4 ' are independently H, -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, halogen, SF 5 , CN, C 1-4 alkane group, C 3-6 cycloalkyl group, 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or 5-6-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O Heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, CN, NH 2 , OH, C 1- 4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and heteroaryl containing 1-3 heteroatoms selected from N, S, O 5-6 member
- one R 3 ' and one R 4 ' together with the atoms to which they are attached form a C 4-6 cycloalkyl, which is optionally replaced by 1-3 members selected from halogen, OH, C 1- 4 alkyl group substitutions;
- R c is H, C 1-4 alkyl or C 3-6 cycloalkyl
- R c ' is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OH or -OC 1-4 alkyl;
- R d is a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or a heteroaryl group containing 1-3 heteroatoms selected from N, S, O 5-6 membered heterocycloalkyl substituted C 1-4 alkyl, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, or halogenated C 1-4 alkane
- the cycloalkyl group, heteroaryl group and heterocycloalkyl group are optionally substituted by 1-3 groups selected from halogen, OH, C 1-4 alkyl and halogenated C 1-4 alkyl;
- R is independently H, CN, OH or halogen
- R 7 is H or C 1-4 alkyl
- R 8 and R 8 ' are independently C 1-4 alkyl, -OR f , -NHR f , C 3-6 cycloalkyl or 5-6 containing 1-3 heteroatoms selected from N, S, O Membered heterocycloalkyl, the alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 Alkyl-OH, C 3-6 cycloalkyl, and a 5-6 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms;
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl And heterocycloalkyl is optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contains 1-3 selected from N, S, 5-6 membered heterocycloalkyl groups of O heteroatoms are substituted;
- R 3 is -NR a SO 2 R b , -SO 2 NR a , CN or halogen; or
- R B is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected A 5-6 membered heterocycloalkyl group from N, S, O heteroatoms; when R B is the alkyl group, it is further selected from 1-3 halogen, CN, C 3-6 cycloalkyl, containing 1- 3 5-6 membered heteroaryl groups selected from N, S, O heteroatoms and substituted by a group containing 1-3 5-6 membered heterocycloalkyl groups selected from N, S, O heteroatoms; when R When B is said cycloalkyl, phenyl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH and C 1-4 alkyl; or
- R is CN or halogen ;
- R 8 is -OR f , -NHR f , C 1-4 alkyl, C 3-6 cycloalkyl or a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl group, when R 8 is said alkyl group, it is further replaced by C 3-6 cycloalkyl group, 5-6 membered heteroaryl group containing 1-3 selected from N, S, O heteroatoms or containing 1-3 A 5-6 membered heterocycloalkyl group selected from N, S, and O heteroatoms; when R is the cycloalkyl or heterocycloalkyl group, it is optionally 1-3 selected from halogen, OH, CN , NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl, and a 5-6 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms; or
- At least one of R 3 ' and R 4 ' is -NHR c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, containing 1-3 selected from N, S, O hetero Atomic 5-membered heteroaryl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkenyl, alkynyl, heteroaryl and heterocycloalkyl are optionally Ground is covered with 1-3 selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 containing 1-3 heteroatoms selected from N, S, O Substituted by a heteroaryl group and a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, R c ' is C 2-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, -OC
- one R 3 ' and one R 4 ' together with the atoms they are connected to form a C 3-8 cycloalkyl group, or a 4-12 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl, said cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 groups selected from halogen, OH, NH 2 , C 1-4 alkyl and halogenated C 1-4 alkyl; or
- R 8 ' is -OR f , C 3-6 cycloalkyl, said cycloalkyl is optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkyl and a 4-7 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms;
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl And heterocycloalkyl is optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contains 1-3 selected from N, S, 5-6 membered heterocycloalkyl groups of O heteroatoms are substituted;
- R 3 ' and R 4 ' are independently H, -NR c R c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, halogen, SF 5 , CN, C 1-4 alkane group, C 3-6 cycloalkyl group, 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or 5-6-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O Heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, CN, NH 2 , OH, C 1- 4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O and heteroaryl containing 1-3 heteroatoms selected from N, S, O 5-6 member
- R c is H, C 1-4 alkyl or C 3-6 cycloalkyl
- R c ' is C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OH or -OC 1-4 alkyl;
- R d is a C 3-6 cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, O, or a heteroaryl group containing 1-3 heteroatoms selected from N, S, O C 1-4 alkyl substituted by 5-6 membered heterocycloalkyl, said cycloalkyl, heteroaryl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, C 1-4 alkane or, R d is C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, or halogenated C 1 -4 alkyl;
- R is independently H, CN, OH or halogen
- R 7 is H or C 1-4 alkyl
- R 8 and R 8 ' are independently C 1-4 alkyl, -OR f , -NHR f , C 3-6 cycloalkyl or 5-6 containing 1-3 heteroatoms selected from N, S, O Membered heterocycloalkyl, the alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 ring Alkyl is substituted with a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O;
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl And heterocycloalkyl is optionally replaced by 1-3 selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and contains 1-3 selected from N, S, 5-6 membered heterocycloalkyl groups of O heteroatoms are substituted;
- R 3 is -NR a SO 2 R b , -SO 2 NR a , CN or halogen; or
- R B is C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 selected from N, S, O heteroatoms or containing 1-3 selected A 5-6 membered heterocycloalkyl group from N, S, O heteroatoms; when R B is the alkyl group, it is further selected from 1-3 halogen, CN, C 3-6 cycloalkyl, containing 1- 3 5-6 membered heteroaryl groups selected from N, S, O heteroatoms and substituted by a group containing 1-3 5-6 membered heterocycloalkyl groups selected from N, S, O heteroatoms; when R When B is said cycloalkyl, phenyl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH and C 1-4 alkyl; or
- R is CN or halogen ;
- R 8 is -OR f , -NHR f , C 1-4 alkyl, C 3-6 cycloalkyl or a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl group, when R 8 is said alkyl group, it is further replaced by C 3-6 cycloalkyl group, 5-6 membered heteroaryl group containing 1-3 selected from N, S, O heteroatoms or containing 1-3 A 5-6 membered heterocycloalkyl group selected from N, S, and O heteroatoms; when R is the cycloalkyl or heterocycloalkyl group, it is optionally 1-3 selected from halogen, OH, CN , NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl, and a 5-6 membered heterocycloalkyl group containing 1-3 selected from N, S, O heteroatoms; or
- At least one of R 3 ' and R 4 ' is -NHR c ', OR d , C 2-6 alkenyl, C 2-6 alkynyl, containing 1-3 selected from N, S, O hetero Atomic 5-membered heteroaryl or 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, the alkenyl, alkynyl, heteroaryl and heterocycloalkyl are optionally Ground is covered with 1-3 selected from halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 containing 1-3 heteroatoms selected from N, S, O Substituted by a heteroaryl group and a 5-6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, R c ' is C 2-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, -OC
- R 8 ' is -OR f
- R f is C 1-4 alkyl, C 3-6 cycloalkyl or a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, O Alkyl
- said alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl and Substituted by 1-3 5-6 membered heterocycloalkyl groups selected from N, S, O heteroatoms;
- Ring A is selected from II-a or II-b:
- X is N or CR x ;
- Y is NR 8 or CHR 8 ;
- each R x is independently H or halogen
- each Rx is independently H or halogen
- R 3 ' and R 4 ' are independently H, C 1-6 alkyl, C 1-6 alkoxy, -O-CH 2 -C 3-6 cycloalkyl, containing 1-3 selected from N, 5-6 membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl of S, O heteroatoms, or, R 3 ' and R 4 ' form 4-membered cycloalkyl, 5-membered cycloalkyl;
- R 8 ' is independently C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, Cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkane The group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;
- each Rx is independently H or halogen
- R 3 ' and R 4 ' are independently H, C 2-6 alkenyl, C 2-6 alkynyl, provided that R 3 ' and R 4 ' are not selected from H at the same time;
- R 8 ' is independently C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, Cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkane The group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O.
- each Rx is independently H, F, or Cl; in certain embodiments, each Rx is independently F, Cl; in certain embodiments, each Rx is independently F;
- R 3 ' and R 4 ' are independently H, C 1-4 alkyl, C 1-4 alkoxy, -O-CH 2 -C 3-6 cycloalkyl, containing 1-3 selected from N, 5-6 membered heteroaryl, C 2-4 alkenyl, C 2-4 alkynyl of S, O heteroatoms; in certain embodiments, R 3 ' and R 4 ' are independently H, C 2- 4 alkenyl, C 2-4 alkynyl; in certain embodiments, R 3 ' and R 4 ' are independently H, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl ; Provided that R 3 ' and R 4 ' are not simultaneously selected from H;
- R 8 ' is independently C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, Cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkane and substituted by a group containing 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms;
- R 8 ' is independently C 1-4 alkyl, C 3-4 cycloalkyl or 4, 5, 6 membered heterocycloalkyl containing 1, 2, 3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl and heterocycloalkyl are any Optionally 1, 2, 3 selected from halogen, OH, CN, NH 2 , C 1-2 alkyl
- R 8 ' is independently methyl, ethyl, propyl , isopropyl, butyl, isobutyl, and optionally 1, 2, 3 selected from halogen, OH, CN, NH 2 , C 1-2 alkyl, -C 1-2 alkyl-OH , C 3-4 cycloalkyl and substituted by a group containing 1, 2, 3 4, 5, 6 membered heterocycloalkyls selected from N, S, O heteroatoms; in certain embodiments, R 8 'independently C 1-4 alkyl group, said alkyl group is selected from F, Cl, OH, CN, NH 2 , methyl, hydroxymethyl, cyclopropyl, azetidine by 1, 2 or 3 group, oxetanyl group substitution.
- R 8 ' is independently -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 CH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 , -CH 2 CH 2 CH 3 , - CH 2 CF 2 CH 3 , -CH 2 CF 2 CH 2 OH, -CH 2 CF 2 CH 2 F, -CH 2 CF 2 CHF 2 , -CH 2 CF 2 CF 3 , -CF 2 CF 2 CH 2 OH, -CH (F) CF2CH2OH , -CH ( F ) CH ( F ) CH2OH , -CH2CCl2CH3 , -CH2CCl2CH
- each Rx is independently H or halogen
- R 3 ' and R 4 ' are independently H, halogenated C 1-4 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen; or
- R 3 ' and R 4 ' together form a cyclobutyl group
- R 8 ' is independently C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, Cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkane The group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;
- each Rx is independently H or halogen
- R 3 ' and R 4 ' are independently H, C 2-6 alkenyl, C 2-6 alkynyl, halogen;
- R 8 ' is independently C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, Cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkane The group is substituted with a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O;
- R3 ' and R4' are not selected from H at the same time .
- each Rx is independently H, F, or Cl; in certain embodiments, each Rx is independently F, Cl; in certain embodiments, each Rx is independently F;
- R 3 ' and R 4 ' are independently H, C 2-4 alkenyl, C 2-4 alkynyl, halogen; in certain embodiments, R 3 ' and R 4 ' are independently H, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, F, Cl; with the proviso that R3 ' and R4' are not simultaneously selected from H ;
- R 8 ' is independently C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, Cycloalkyl and heterocycloalkyl are optionally replaced by 1-3 members selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, -C 1-4 alkyl-OH, C 3-6 cycloalkane and substituted by a group containing 1-3 4-7 membered heterocycloalkyl groups selected from N, S, O heteroatoms; in certain embodiments, R 8 ' is independently C 1-4 alkyl, C 3-4 cycloalkyl or 4, 5, 6 membered heterocycloalkyl containing 1, 2, 3 heteroatoms selected from N, S, O, the alkyl, cycloalkyl and heterocycloalkyl are any Optionally 1, 2, 3 selected from halogen, OH, CN, NH 2 , C 1-2 al
- R 8 ' is independently methyl, ethyl, propyl , isopropyl, butyl, isobutyl, and optionally 1, 2, 3 selected from halogen, OH, CN, NH 2 , C 1-2 alkyl, -C 1-2 alkyl-OH , C 3-4 cycloalkyl and substituted by a group containing 1, 2, 3 4, 5, 6 membered heterocycloalkyls selected from N, S, O heteroatoms; in certain embodiments, R 8 'independently C 1-4 alkyl group, said alkyl group is selected from F, Cl, OH, CN, NH 2 , methyl, hydroxymethyl, cyclopropyl, azetidine by 1, 2 or 3 In some embodiments, R 8 ' is independently -CH 3 , -CH 2 F, -CHF 2
- each Rx is independently F
- R 3 ' and R 4 ' are independently H, difluoromethyl, trifluoromethyl, vinyl, propenyl, ethynyl, propynyl, F or
- R 3 ' and R 4 ' are independently H, vinyl, propenyl, ethynyl, propynyl, F
- R 8 ' is independently methyl, ethyl, and propyl, and the methyl, ethyl, and propyl groups are replaced by 1, 2, or 3 members selected from F, Cl, OH, CN, NH 2 , methyl, and hydroxymethyl Substitution of radical, cyclopropyl, azetidinyl, oxetanyl;
- R3 ' and R4' are not selected from H at the same time .
- the present invention also provides a pharmaceutical composition, which contains the compound described in any one of the aforementioned first to fifteenth technical schemes, its stereoisomers, solvates, deuteriums or pharmaceutically acceptable salts thereof, and Pharmaceutically acceptable excipients and/or carriers.
- the pharmaceutical composition comprises 1-600 mg of the compound described in any of the aforementioned technical schemes, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary materials and/or vectors.
- the present invention also provides the compound described in any one of the preceding embodiments, its stereoisomer, solvate, deuterated compound or pharmaceutically acceptable salt or pharmaceutical composition in the preparation of ER-mediated disease medicine the use of.
- ER-mediated diseases include but not limited to breast cancer, ovarian cancer, uterine cancer or cervical cancer.
- the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, solvate, deuterium or pharmaceutically acceptable salt, and pharmaceutically acceptable adjuvants and/or carriers.
- the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
- the present invention also provides a method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any one of the aforementioned technical schemes, its stereoisomers, deuteriums, solvents compound, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable adjuvant and/or carrier, the therapeutically effective dose is preferably 1-600mg; the disease is preferably an ER-mediated disease, and the disease is more preferably breast cancer, Ovarian, uterine, or cervical cancer.
- the present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, pharmaceutically acceptable Accepted salts or pharmaceutical compositions.
- the mammals of the present invention include humans.
- Effective amount or “therapeutically effective amount” as used in the present application refers to the administration of a sufficient amount of the compound disclosed in the present application, which will alleviate to some extent one or more of the diseases or conditions (such as cancer) to be treated. symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired alteration of a biological system.
- an "effective amount” for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
- therapeutically effective amounts include, but are not limited to, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40 -600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg , 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90 -500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg,
- the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound described in the present invention or its stereoisomer, deuterated product, solvate, pharmaceutically acceptable Salt and Excipients and/or Carriers.
- the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
- the pharmaceutical composition includes, but is not limited to: 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80mg, 90mg, 100mg, 120mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, 500mg, 600mg of the compound of the present invention or its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt.
- a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, pharmaceutically acceptable salt, a therapeutically effective amount Preferably 1-600mg, the said disease is preferably breast cancer, ovarian cancer, uterine cancer or cervical cancer.
- a method for treating diseases in mammals comprises: administering the compound of the present invention or its stereoisomer, deuterated product, solvate, and pharmaceutically acceptable salt at a daily dose of 1-600 mg/day
- the daily dose may be a single dose or divided doses.
- the daily dose includes but is not limited to: 1-600 mg/day, 1-500 mg/day, 1-400 mg/day, 1-300 mg /day, 1-250mg/day, 1-200mg/day, 1-150mg/day, 1-125mg/day, 1-100mg/day, 1-80mg/day, 1-60mg/day, 1-40mg/day , 1-20mg/day, 5-600mg/day, 5-500mg/day, 5-400mg/day, 5-300mg/day, 5-250mg/day, 5-200mg/day, 5-150mg/day, 5 -125mg/day, 5-100mg/day, 5-80mg/day, 5-60mg/day, 5-40mg/day, 5-20mg/day, 5-90mg/day, 5-70mg/day, 5-50mg /day, 5-30mg/day, 10-600mg/day, 10-500mg/day, 10-400mg/day, 10-300mg/day, 10-
- daily doses include, but are not limited to: 1 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, 12.5 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day , 35mg/day, 40mg/day, 45mg/day, 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 120mg/day, 150mg/day, 200mg/day, 250mg /day, 300mg/day, 400mg/day, 500mg/day, 600mg/day.
- the present invention relates to a kit, which may include a single-dose or multi-dose composition, the kit comprising the compound of the present invention or its stereoisomer, deuterated product, solvate, pharmaceutically acceptable salt,
- the amount of the compound of the present invention or its stereoisomer, deuterium, solvate, and pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.
- Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
- references books and monographs in the field detail the synthesis of reactants useful in the preparation of the compounds described herein, or are provided by reference to articles describing such preparations. These reference books and monographs include: “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S.R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions", 2nd Ed., W.A.Benjamin, Inc.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (deuterium, also known as deuterium ), tritium (T, also known as tritium), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, the isotope of fluorine is 19 F, the isotope of chlorine includes 35 Cl and 37 Cl, and the isotope of bromine includes 79 Br and 81 Br.
- isotopes of carbon include 12 C, 13 C and 14 C
- Halogen herein refers to F, Cl, Br, I, or isotopes thereof.
- Halo or halogen substitution refers to being substituted by more than one selected from F, Cl, Br, I, or their isotopes, and the upper limit of the number of halogen substituents is equal to the sum of the hydrogen numbers that can be substituted by the substituted groups, Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution. It usually includes 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.
- Deuterium refers to deuterium, an isotope of hydrogen (H).
- Deuterated or “deuterated” means that the hydrogen atoms on the groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl are replaced by at least In the case of a deuterium atom being substituted, the upper limit of the number of deuteriums is equal to the sum of the number of hydrogens that can be substituted by the substituted group.
- the number of deuteriums is any integer between 1 and the upper limit, for example, 1- 20 deuterium atom substitutions, 1-10 deuterium atom substitutions, 1-6 deuterium atom substitutions, 1-3 deuterium atom substitutions, 1-2 deuterium atom substitutions or 1 deuterium atom substitution.
- C xy group refers to a group containing x to y carbon atoms, such as "C 1-6 alkyl” refers to an alkyl group containing 1-6 carbon atoms.
- Alkyl refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Usually, it is an alkyl group of 1 to 20 carbon atoms, or an alkyl group of 1 to 8 carbon atoms, or an alkyl group of 1 to 6 carbon atoms, or an alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl etc., the alkyl group may be further substituted by a substituent.
- Haloalkyl refers to the situation in which one or more hydrogens in the alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine or its isotopes), and the upper limit of the number of halogen substituents is equal to that in the alkyl group.
- the sum of the hydrogen numbers that can be substituted, unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit.
- the alkyl group is substituted by 1-5 halogens, or 1-3 halogens, or 1-2 halogens or 1 halogen; when the number of halogen substituents is greater than 1, it can be substituted by the same or different halogens; Specific examples include, but are not limited to, -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CCl 2 , CF 3 and the like.
- Alkoxy or "alkyloxy” means -O-alkyl.
- -OC 1-8 alkyl for example -OC 1-8 alkyl, -OC 1-6 alkyl, -OC 1-4 alkyl or -OC 1-2 alkyl.
- Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, Cyclopropoxy, cyclobutoxy, etc.; said alkoxy may be optionally substituted by a substituent.
- Haloalkoxy means -O-haloalkyl.
- -O-halogenated C 1-8 alkyl -O-halogenated C 1-6 alkyl, -O-halogenated C 1-4 alkyl or -O-halogenated C 1-2 alkyl; halogen
- the upper limit of the number of substituents is equal to the sum of the hydrogen numbers that can be substituted by the substituted group.
- the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, 1 halogen substitution; when the number of halogen substituents is greater than 1, they can be substituted by the same or different halogens; non-limiting examples include monofluoromethoxy, di Fluoromethoxy, trifluoromethoxy, difluoroethyloxy and the like.
- Alkynyl means a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond (C ⁇ C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, further comprising 2 to 4 carbon atoms, examples of which include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl Base, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2- Heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, etc.; said alkynyl may be optionally substituted by a substituent.
- Cycloalkyl refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic, bicyclic or polycyclic can be parallel ring, spiro ring, bridged ring or a combination thereof, bicyclic or polycyclic can include one or more aromatic rings, but the ring system as a whole Non-aromatic, the linking site can be on the aromatic ring or on the non-aromatic ring.
- cycloalkyl contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and further contains 3-6 carbon atoms; when it is a monocyclic cycloalkyl group, it contains 3-15 carbon atoms, or 3 - 10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl group, it contains 5-12 carbon atoms, or contains 5-11 carbon atoms, or contain 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, etc., cycloalkyl groups may be optionally substituted with substituents.
- Aryl means an aromatic carbocyclic ring without heteroatoms, including single-ring aryl and condensed-ring aryl. Typically 6 to 13 carbon atoms, further 6 to 9 carbon atoms, further phenyl, non-limiting examples include phenyl, naphthyl, anthracenyl, phenanthrenyl, aryl may optionally be substituted by replace.
- Carbocycle or “carbocyclyl” means a saturated, partially unsaturated, or aromatic carbocycle, and its meaning includes aryl and cycloalkyl.
- Carbocycles can be monocyclic, bicyclic or polycyclic, and bicyclic or polycyclic include bridged rings, amalgamated rings and spiro rings and combinations thereof.
- Carbocycles typically have 3 to 12 carbon atoms, alternatively 3-10 carbon atoms, alternatively 3-6 carbon atoms.
- monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc.
- bicyclic bridged rings include Etc.
- the double ring union includes etc.
- bicyclic spirocycles include etc.
- carbocycles may be optionally substituted with substituents.
- Heterocycloalkyl refers to a saturated or partially unsaturated non-aromatic carbocycle containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O.
- Heterocycloalkyl can be monocyclic, bicyclic or polycyclic, bicyclic or polycyclic can be bridged ring, parallel ring, spiro ring or a combination thereof, and bicyclic or polycyclic can include one or more aromatic rings or heteroaryl rings , but the ring system as a whole is not aromatic, and the connection site can be on an aromatic ring or a non-aromatic ring.
- the heterocycloalkyl group is a 3- to 20-membered ring, and when it is a monocyclic heterocycloalkyl group, it is usually a 3- to 15-membered ring, or a 3-10-membered ring, or a 3-8-membered ring, or a 3-6-membered ring ; When it is a bicyclic or polycyclic ring heterocycloalkyl group, it is usually a 5-12-membered ring, or a 5-11-membered ring, or a 6-9-membered ring.
- the heteroatoms N and S include their oxidation states.
- heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azepine group, azacyclohexenyl, oxolyl, oxenyl, etc., and the heterocycloalkyl group may be optionally substituted by a substituent.
- heteroaryl ring refers to an aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and its oxidation state, which can be monocyclic or bicyclic Or polycyclic, bicyclic or polycyclic can be bridging ring, double ring, spiro ring and their combinations; when it is bicyclic or polycyclic, it can be heteroaryl and aryl fused, or heteroaryl and Fusions of heteroaryls, where either the heteroaryl or the aryl can be the point of attachment.
- Non-limiting examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, etc.; said heteroaryl can be optionally substituted by substituents.
- aromatic ring or “aromatic ring” includes aryl and heteroaryl groups, said aromatic ring may be optionally substituted by substituents.
- Heterocycle or “heterocyclyl” means a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, and its meaning includes hetero Aryl and heterocycloalkyl.
- Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiroheterocycles, or combinations thereof. Typically, it is a 3- to 12-membered heterocycle, or a 5- to 12-membered heterocycle, or a 5- to 7-membered heterocycle.
- the heterocyclic group can be attached to a heteroatom or a carbon atom, non-limiting examples include oxiranyl, aziridyl, oxetanyl, azetidinyl, 1,3-dioxolane Base, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrole Base, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiyl, dihydrofuranyl , dihydropyranyl, dithiapentyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl
- Heterocyclylene refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include Wait.
- Spiro ring refers to a polycyclic group that shares one carbon atom (called a spiro atom) between rings and rings, which may contain 0 or more than 1 double bond or triple bond, and may contain 0 to 5 atoms selected from N, O, S, P, Si and heteroatoms in their oxidation states.
- spiro rings are 6 to 14 membered rings, alternatively 6 to 12 membered rings, alternatively 6 to 10 membered rings.
- the spiro ring is trispiro three (representing a three-membered ring and a three-membered ring), three spiro four, three spiro five, three spiro six, four four spiro four, four four spiro five, four four spiro six, five five spiro five or five five spiro six.
- spirocycles include
- the spiro ring can be optionally substituted by a substituent.
- “Bound ring” refers to a polycyclic group in which the ring shares two adjacent ring atoms and a chemical bond with the ring, and may contain one or more double bonds or triple bonds, and the ring may contain 0 to 5 members selected from N, S, O, P, Si and heteroatoms in their oxidation states.
- the ring is a 5 to 20 membered ring, or a 5 to 14 membered ring, or a 5 to 12 membered ring, or a 5 to 10 membered ring.
- the combined ring is a three-membered ring and a four-membered ring (representing a combined ring formed by a three-membered ring and a four-membered ring. According to the IUPC naming rules, it may be a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same below Li), three and five rings, three and six rings, four and four rings, four and five rings, four and six rings, five and five rings, five and six rings, six and six rings.
- Non-limiting examples of azocyclics include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene,
- the said ring can be optionally substituted by a substituent.
- Bridged ring means that two non-adjacent ring atoms are shared between two rings, which may contain one or more double bonds or triple bonds.
- the bridging ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and oxidation states thereof.
- the bridged ring has 5 to 20 ring atoms, alternatively 5 to 14, alternatively 5 to 12, alternatively 5 to 10 ring atoms.
- Non-limiting examples of bridged rings include adamantane,
- substitution refers to arbitrary substitution at positions allowed by chemical theory, and the number of substituents conforms to the rules of chemical bonds, unless otherwise specified.
- substituents include, but are not limited to: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 heteroalkyl, C 5-12 aryl, 5-12 membered Heteroaryl, hydroxyl, C 1-6 alkoxy, C 5-12 aryloxy, thiol, C 1-6 alkylthio, cyano, halogen, C 1-6 alkylthiocarbonyl, C 1 -6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, amino , Phosphonic acid, -CO 2 (C 1-6 alkyl)
- Alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
- “Pharmaceutically acceptable salt” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is mixed with a non-toxic inorganic base or organic base, and the free base is mixed with a non-toxic inorganic base or organic base.
- Non-toxic salts obtained by reacting inorganic or organic acids.
- “Pharmaceutical composition” means a mixture of one or more compounds described herein, or stereoisomers, solvates, deuterated pharmaceutically acceptable salts or cocrystals thereof, with other constituents, wherein the other constituents comprise physiologically / pharmaceutically acceptable carrier and / excipient.
- Carrier refers to: does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the body and its distribution in the body, controls the release rate of the drug and releases the drug.
- Non-limiting examples of systems for delivery to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.
- Excipient means: not itself a therapeutic agent, used as a diluent, adjuvant, binder and/or vehicle, added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate The compound or pharmaceutical composition is presented in unit dosage form for administration.
- pharmaceutical excipients can serve various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrating agents, absorbing agents, preservatives , surfactants, coloring agents, flavoring agents and sweeteners.
- Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (such as croscarmellose sodium) (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as oil (13) a
- Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- the compounds of the present invention also include their tautomers.
- the present invention describes the left side compound whose pyrimidine ring is substituted by OH
- the right side tautomeric compound is also included.
- Solvate means a compound of the present invention or a salt thereof formed with a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces.
- the solvent is water, it is a hydrate.
- Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF are both solid, and there is a fixed stoichiometric ratio between the components.
- a co-crystal is a multi-component crystal, including both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.
- Figure 1 shows the change of intracranial fluorescence signal in the mouse brain orthotopic MCF-7 model.
- Figure 2 shows the change rate of mouse body weight in the mouse brain orthotopic MCF-7 model.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- HPLC HPLC-based high pressure liquid chromatography
- the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. -0.5mm;
- PE petroleum ether
- DIPEA N,N-Diisopropylethylamine
- BINAP binaphthyldiphenylphosphine
- the third step 6-(diethoxy)-N-(1-(3-fluoropropyl)pyrrolyl-3-yl)pyridin-3-amine (3-E)
- Example 1 1-cyclopropyl-N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3- Base) amino) phenyl) -2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methanesulfonamide (compound 1)
- the sixth step N-((1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl- 1,2,3,4-Tetrahydroisoquinolin-6-yl)-1-cyclopropylmethanesulfonamide (1L)
- the seventh step 1-cyclopropyl-N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3- Base) amino) phenyl) -2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methanesulfonamide (compound 1)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.12min.
- the fifth step N-(2-(bicyclo[1.1.1]pentane-1-yl)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,2, 3,4-Tetrahydroisoquinolin-6-yl)ethanesulfonamide (2H)
- the sixth step N-(2-(bicyclo[1.1.1]pentan-1-yl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azacyclic Butyl-3-yl)amino)phenyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (Compound 2)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 13.12min.
- the second step ((1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1, 2,3,4-Tetrahydroisoquinolin-6-yl)phosphonium dimethyl (3D)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.80min.
- Example 4 N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene Base)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 4)
- the seventh step N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene Base)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 4)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.38min.
- the starting material 5B (3.0g, 7.5mmol) was added to dichloromethane (20mL), then trifluoroacetic acid (5mL), stirred at room temperature for 1 hour, and the filtrate was concentrated to give the title compound 5C (5g, yield 90%).
- the fifth step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-6-iodo-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1- Alcohol (Compound 5F)
- the sixth step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl)phenyl)-3-methanol Base-6-((trimethylsilyl)ethynyl)-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-di Fluoropropan-1-ol (Compound 5G)
- the seventh step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-6-ethynyl-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1 -alcohol (compound 5)
- Example 7 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-3,7-Dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropyl-1 -alcohol (compound 7)
- the fifth step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-3,7-Dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropyl-1 -alcohol (compound 7)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.60min.
- Example 8 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)benzene Base)-3,7-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropyl- 1-alcohol (Compound 8)
- the first step 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)benzene Base)-3,7-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropyl- 1-alcohol (Compound 8)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 11.20min.
- the second step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene base)-3,6-dimethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1- Alcohol (Compound 9)
- the fifth step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-6-methoxy-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropane Ethyl-1-ol (Compound 10)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in methanol, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 30%-65%; c. flow rate 15mL/min. d. elution time 15min; retention time: 8.40min.
- Example 11 3-((1R,3R)-7-(cyclopropylmethyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl -3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2hydro-pyrido[3,4]indol-2-yl)-2,2-di Fluoropropan-1-ol (Compound 11)
- the seventh step 3-((1R,3R)-7-(cyclopropylmethyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl) -3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2hydro-pyrido[3,4]indol-2-yl)-2,2-di Fluoropropan-1-ol (Compound 11)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.38min.
- Example 12 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl) -3-Methyl-7-(1H-pyrazol-4-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4]indol-2-yl)-2 ,2-Difluoropropan-1-ol (compound 12)
- Step 6 (R)-N-(1-(6-(1H-pyrazol-4-yl)-1H-indol-3-yl)prop-2-yl)-3-((tert-butyl Diphenylsilyl)oxy)-2,2-difluoropropan-1-amine (12J)
- the seventh step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl) -3-methyl 7-(1hydro-pyrazol-4-yl)-1,3,4,9-tetrahydro-2hydro-pyrido[3,4]indol-2-yl)-2, 2-Difluoropropan-1-ol (Compound 12)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.38min.
- Example 13 ((1R,2R)-2-((1R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl )amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)cyclopropyl)methanol (compound 13)
- the fourth step ((1R,2R)-2-((1R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl )amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)cyclopropyl)methanol (compound 13)
- composition of mobile phase A and B mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate).
- the preparation was concentrated and lyophilized to obtain the target compound 13 (39 mg, 19.08%).
- Example 14 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-7-ethynyl-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1 -alcohol (compound 14)
- the starting material 14B (2g) was added to dichloromethane (20mL), then trifluoroformic acid (5mL) was added, stirred at room temperature for 1 hour, and the reaction solution was directly concentrated to obtain the title compound 14C (2g, yield 100%).
- the fifth step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene Base)-7-iodo-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1 -alcohol (compound 14F)
- the starting material 14F (300mg, 0.46mmol), trimethylsilylacetylene (182mg, 1.86mmol), cuprous iodide (9.0mg, 0.05mmol), triethylamine (10mg, 0.1mmol) were added to N,N- In dimethylformamide solution (5ml), the nitrogen gas was replaced 3 times, and the catalyst bis(triphenylphosphine)palladium dichloride (60mg, 0.1mmol) was added, followed by reaction at 75°C for 16 hours.
- Example 15 3-((1R,3R)-1-(2,6-difluoro-4-((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)phenyl )-5-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1- Alcohol (compound 15)
- the fifth step 3-((1R,3R)-1-(2,6-difluoro-4-((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)phenyl )-5-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropane-1- Alcohol (compound 15)
- Example 16 6-((1S,3R)-3,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)pyridin-3-amine (compound 16)
- the fourth step 6-((1S,3R)-3,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine (compound 16)
- Example 17 (S)-N-(4-((1R,3R)-3,7-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 -tetrahydro-1H-pyridin[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)pyrrolyl-3-amine (compound 17 )
- Example 18 (S)-N-(3,5-difluoro-4-((1R,3R)-6-fluoro-3-methyl-2-(2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolyl-3-amine (compound 18)
- the first step 6-((1S,3R)-6-fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridin[3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)pyridin-3-amine (Compound 19)
- Example 20 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl )-3-methyl-1,3,4,6,7,9-hexahydro-2H-cyclobutane[f]pyrido[3,4-b]indol-2-yl)-2,2- Difluoropropan-1-ol and
- Step 4 Ethyl (E)-4-((4-iodobicyclo[4.2.0]octa-1,3,5-trien-3-yl)amino)croton-2-ester (20E)
- the ninth step 3-((1-(5,6-dihydro-1H-cyclobutane[f]indol-3-yl)propyl-2-yl)amino)-2,2-difluoropropane Ethyl-1-ol (20J)
- Step 10 3-(1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)phenyl)-3-methyl -1,3,4,6,7,9-Hexahydro-2H-cyclobutane[f]pyrido[3,4-b]indol-2-yl)-2,2-difluoropropane-1- Alcohol (20K)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 12.0min.
- the eleventh step 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene base)-3-methyl-1,3,4,6,7,9-hexahydro-2H-cyclobutane[f]pyrido[3,4-b]indol-2-yl)-2,2 -difluoropropan-1-ol and
- the first step 2,2-difluoro-3-(1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl- 1,3,4,6,7,9-Hexahydro-2H-cyclobutane[f]pyrido[3,4-b]indol-2-yl)propan-1-ol (21A)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 11.2min.
- the second step 2,2-difluoro-3-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)pyridine- 2-yl)-3-methyl-1,3,4,6,7,9-hexahydro-2H-cyclobutane[f]pyrido[3,4-b]indol-2-yl)propane- 1-alcohol and
- Mobile phase A: carbon dioxide and B: methanol + acetonitrile (0.1% ammonia water); isocratic elution: 50% mobile phase B; flow rate: 100mL/min; back pressure: 100bar; column temperature: 35°C; wavelength: 220nm; Elution time: 6min.
- Example 22 N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,6 ,7,9-Hexahydro-1H-cyclobutane[f]pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl- 3-amine and
- the first step 1-(5,6-dihydro-1H-cyclobutane[f]indol-3-yl)-N-(2,2,2-trifluoroethyl)propyl-2-amine ( 22A)
- the second step N-(3,5-difluoro-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,6,7,9-hexa Hydrogen-1H-cyclobutane[f]pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl-3-amine (22B)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 11.6min.
- the third step N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,6 ,7,9-Hexahydro-1H-cyclobutane[f]pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl- 3-amine and
- Example 23 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)benzene base)-3-methyl-6-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2 -Difluoropropan-1-ol (compound 23)
- the first step (R)-(1-(5-(trifluoromethyl)-1H-indol-3-yl)propyl-2-yl)tert-butyl carbonate (23B)
- the third step (R)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoro-N-(1-(5-(trifluoromethyl)-1H- Indol-3-yl)propyl-2-yl)propyl-1-amine (23D)
- the fifth step 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)benzene base)-3-methyl-6-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2 -Difluoropropan-1-ol (compound 23)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 45%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.1min.
- Example 24 6-((1S,3R)-3,7-Dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)pyridin-3-amine (compound 24)
- the second step 6-((1S,3R)-3,7-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)pyridin-3-amine (compound 24)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 11.5min.
- Example 25 N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene base)-5-fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 25)
- the fifth step N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene base)-5-fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 25)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.5min.
- Example 26 N-((1S,3R)-5-fluoro-1-(5-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)pyridine-2- Base)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 26)
- the third step N-((1S,3R)-5-fluoro-1-(5-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)pyridine-2- Base)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 26)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 11.2min.
- Example 27 N-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidinyl-3-yl)amino)benzene Base)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 27)
- the first step (R)-(1-(3-bromo-2-fluorophenyl)prop-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2- Difluoropropyl-1-amine (27B)
- the third step (R)-3-((1-(3-amino-2-fluorophenyl) propyl-2-yl) amino)-2,2-difluoropropyl-1-alcohol ( 27D)
- the fourth step 3-((1S,3R)-6-amine-1-(4-bromo-2,6-difluorophenyl)-5-fluoro-3-methyl-3,4-tetrahydroiso Quinoline-2(1hydrogen)-yl-2,2-difluoropropyl-1-aminoalcohol (27E)
- the sixth step N-((1S,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoro Propyl)azetidinyl-3-yl)amino)phenyl)-5-fluoro-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 27)
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 40%-80%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.38min.
- Example 28 N-((1S,3R)-2-(2,2-difluoro-3-hydroxypropyl)-5-fluoro-1-(5-((1-(3-fluoropropyl) Azetidinyl-3-yl)amino)pyridin-2-yl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 28 )
- the first step 3-((1S,3R)-6-amine-1-(5-bromopyridin-2-yl)-5-fluoro-3-methyl-3,4-tetrahydroisoquinoline-2 (1H)-yl-2,2-difluoropropyl-1-amino alcohol (28A)
- the seventh step N-((1S,3R)-2-(2,2-difluoro-3-hydroxypropyl)-5-fluoro-1-(5-((1-(3-fluoropropyl) Azetidinyl-3-yl)amino)pyridin-2-yl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethanesulfonamide (compound 28 )
- Preparation method Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm; the sample is dissolved in DMF, filtered with a 0.45 ⁇ m filter head to make a sample liquid; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); b. gradient elution, mobile phase A content from 20%-70%; c. flow rate 15mL/min. d. elution time 20min; retention time: 10.38min.
- Example 29 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolyl-3-yl)amino)benzene Base)-3-methyl-7-trifluoromethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-di Fluoropropyl-1-ol (Compound 29)
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Abstract
Description
化合物 | 测试的最高浓度抑制率 | IC 50(μM) |
WO2021228210化合物4 | 97.65±1.26%@10μM | 0.7021 |
化合物32 | 100.20±0.74%@40μM | 4.14 |
化合物18 | 99.98±1.79%@40μM | 2.82 |
化合物43 | 98.28±0.93%@40μM | 12.3 |
Claims (17)
- 一种式(I)所示的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中,环A选自I-a或I-b:X为N或CR x;a为0、1、2或3;b为1或2;Y为NR 8或CHR 8;R 1为C 1-6烷基、C 2-6烯基或C 2-6炔基,所述R 1任选地被1-3个选自卤素、OH、NH 2、-OC 1-4烷基、-NHC 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代,其中,所述环烷基和杂环烷基任选进一步被1-3个选自卤素、OH、C 1-4烷基和-OC 1-4烷基的基团取代;每个R x独立地为H、NH 2、OH、卤素、C 1-4烷基、卤代C 1-4烷基、-N(C 1-4烷基) 2、-NHC 1-4烷基或-OC 1-4烷基;R 2、R 5、R 6、R 2’、R 5’和R 6’独立地为H、CN、OH、NH 2、SH或卤素;R 3、R 4独立地为H、卤素、SF 5、CN、-NR aSO 2R b、-SO 2NHR a、-P(=O)(R b) 2、-NR aP(=O)(R b) 2;R a为H或R b;R b为C 1-4烷基、C 3-6环烷基、苯基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、环烷基、苯基、杂芳基和杂环烷基任选地被1-3个选自卤素、CN、NH 2、OH、C 1-4烷基、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;R 3’和R 4’独立地为H、-NR cR c’、OR d、C 2-6烯基、C 2-6炔基、卤素、SF 5、CN、C 1-4烷基、 C 3-6环烷基、苯基、含有1-3个选自N、S、O杂原子的5-6元杂芳基,或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、烯基、炔基、环烷基、苯基、杂芳基和杂环烷基任选地被1-3个选自卤素、CN、NH 2、OH、C 1-4烷基、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;可选地,一个R 3’和一个R 4’与它们连接的原子一起形成C 3-8环烷基、或含有1-3个选自N、S、O杂原子的4-12元杂环烷基,所述环烷基或杂环烷基任选地被1-3个选自卤素、OH、NH 2、C 1-4烷基和卤代C 1-4烷基的基团取代;条件是,当b选自2时,R 3’和R 4’不同时选自H;R c为H、C 1-4烷基或C 3-6环烷基;R c’为C 2-6烷基、C 2-6烯基、C 2-6炔基、-COR e、-OH、-OC 1-4烷基或-SO 2R e;R e为C 2-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、-C 1-4烷基C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、烯基、炔基、环烷基、杂芳基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基和卤代C 1-4烷基的基团取代;R d为被C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基取代的C 1-4烷基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、或卤代C 1-4烷基,所述环烷基、杂芳基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基和卤代C 1-4烷基的基团取代;R 7和R 7’为H、C 1-4烷基或C 3-6环烷基,所述烷基和环烷基任选地被1-3个选自卤素、OH、SH、C 1-4烷基和C 3-6环烷基的基团取代;R 8和R 8’独立地为C 1-6烷基、-OR f、-SR f、-NHR f、C 3-6环烷基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、-C 1-4烷基-OH、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;R f为H、C 1-4烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代。
- 根据权利要求1所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中,(i)R 3为-NR aSO 2R b、-SO 2NR a、CN或卤素;或者(ii)R 4为SF 5、-NR aSO 2R B、-SO 2NR a、-P(=O)(R b) 2或-NR aP(=O)(R b) 2,其中,R B为C 1-4烷基、C 3-6环烷基、苯基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基;当R B为所述烷基时进一步被1-3个选自卤素、CN、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;当R B为所述环烷基、苯基、杂芳基或杂环烷基时任选地被1-3个选自卤素、CN、NH 2、OH和C 1-4烷基的基团取代;或者(iii)R 5为CN或卤素;或者(iv)R 8为-OR f、-SR f、-NHR f、C 1-6烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,当R 8为所述烷基时进一步被C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基取代;当R 8为所述环烷基或杂环烷基时任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;或者(v)R 3’和R 4’中的至少一个为-NR cR c’、OR d、C 2-6烯基、C 2-6炔基、含有1-3个选自N、S、O杂原子的5-6元杂芳基,或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烯基、炔基、杂芳基和杂环烷基任选地被1-3个选自卤素、CN、NH 2、OH、C 1-4烷基、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代,R c’为C 2-6烷基、C 2-6烯基、C 2-6炔基、-OC 1-4烷基或OH;可选地,一个R 3’和一个R 4’与它们连接的原子一起形成C 3-8环烷基、或含有1-3个选自N、S、O杂原子的4-12元杂环烷基,所述环烷基或杂环烷基任选地被1-3个选自卤素、OH、NH 2、C 1-4烷基和卤代C 1-4烷基的基团取代;或者(vi)R 8’为-OR f或C 3-6环烷基,所述环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、-C 1-4烷基-OH、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;R f为C 1-4烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代。
- 根据权利要求3所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中,R 3’和R 4’独立地为H、-NR cR c’、OR d、C 2-6烯基、C 2-6炔基、卤素、SF 5、CN、C 1-4烷基、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5元杂芳基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基,所述烷基、烯基、炔基、环烷基、杂芳基和杂环烷基任选地被1-3个选自卤素、CN、NH 2、OH、C 1-4烷基、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代;可选地,一个R 3’和一个R 4’与它们连接的原子一起形成C 4-6环烷基,所述环烷基任选地被1-3个选自卤素、OH、C 1-4烷基的基团取代;R c为H、C 1-4烷基或C 3-6环烷基;R c’为C 2-6烷基、C 2-6烯基、C 2-6炔基、-OH或-OC 1-4烷基;R d为被C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基取代的C 1-4烷基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、或卤代C 1-4烷基,所述环烷基、杂芳基和杂环烷基任选地被1-3个选自卤素、OH、C 1-4烷基和卤代C 1-4烷基的基团取代;R 5独立地为H、CN、OH或卤素;R 7为H或C 1-4烷基;R 8和R 8’独立地为C 1-4烷基、-OR f、-NHR f、C 3-6环烷基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、-C 1-4烷基-OH、C 3-6环烷基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代;R f为C 1-4烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代;条件是所述化合物满足:(i)R 3为-NR aSO 2R b、-SO 2NR a、CN或卤素;或者(ii)R 4为SF 5、-NR aSO 2R B、-SO 2NR a、-P(=O)(R b) 2或-NR aP(=O)(R b) 2,其中,R B为C 1-4烷基、C 3-6环烷基、苯基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基;当R B为所述烷基时进一步被1-3个选自卤素、CN、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代;当R B为所述环烷基、苯基、杂芳基或杂环烷基时任选地被1-3个选自卤素、CN、NH 2、OH和C 1-4烷基的基团取代;或者(iii)R 5为CN或卤素;或者(iv)R 8为-OR f、-NHR f、C 1-4烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基,当R 8为所述烷基时进一步被C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基取代;当R 8为所述环烷基或杂环烷基时任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代;或者(v)R 3’和R 4’中的至少一个为-NHR c’、OR d、C 2-6烯基、C 2-6炔基、含有1-3个选自N、S、O杂原子的5元杂芳基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基,所述烯基、炔基、杂芳基和杂环烷基任选地被1-3个选自卤素、CN、NH 2、OH、C 1-4烷基、C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代,R c’为C 2-6烷基、C 2-6烯基、C 2-6炔基、-OC 1-4烷基或OH;可选地,一个R 3’和一个R 4’与它们连接的原子一起形成C 3-8环烷基、或含有1-3个选自N、S、O杂原子的4-12元杂环烷基,所述环烷基或杂环烷基任选地被1-3个选自卤素、OH、NH 2、C 1-4烷基和卤代C 1-4烷基的基团取代;或者(vi)R 8’为-OR f、C 3-6环烷基,所述环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、-C 1-4烷基-OH、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;R f为C 1-4烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的5-6元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、C 3-6环烷基和含有1-3个选自N、S、O杂原子的5-6元杂环烷基的基团取代。
- 根据权利要求1所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中,所述化合物具有式(II’-a)、式(II’-a-1)的结构,每个Rx独立地为H或卤素;R 3’和R 4’独立地为H、C 1-6烷基、C 1-6烷氧基、-O-CH 2-C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基、C 2-6烯基、C 2-6炔基,或者,R 3’和R 4’形成4元环烷基、5元环烷基;条件是,R 3’和R 4’不同时选自H;R 8’独立地为C 1-6烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、-C 1-4烷基-OH、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代。
- 根据权利要求6所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中,每个Rx独立地为H或F;R 3’和R 4’独立地为H、C 1-4烷基、C 1-4烷氧基、-O-CH 2-C 3-6环烷基、含有1-3个选自N、S、O杂原子的5-6元杂芳基、C 2-4烯基、C 2-4炔基,条件是,R 3’和R 4’不同时选自H;R 8’独立地为C 1-4烷基,所述烷基被1、2或3个选自F、Cl、OH、CN、NH 2、甲基、羟基甲基、环丙基、氮杂环丁基、氧杂环丁基的基团取代。
- 根据权利要求1所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中,所述化合物具有式(II’-1a)、式(II’-1a-1)的结构,每个Rx独立地为H或卤素;R 3’和R 4’独立地为H、卤代C 1-4烷基、C 1-6烷基、C 2-6烯基、C 2-6炔基或卤素;或者R 3’和R 4’一起形成环丁基;R 8’独立地为C 1-6烷基、C 3-6环烷基或含有1-3个选自N、S、O杂原子的4-7元杂环烷基,所述烷基、环烷基和杂环烷基任选地被1-3个选自卤素、OH、CN、NH 2、C 1-4烷基、-C 1-4烷基-OH、C 3-6环烷基和含有1-3个选自N、S、O杂原子的4-7元杂环烷基的基团取代;条件是,R 3’和R 4’不同时选自H。
- 根据权利要求1所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中每个Rx独立地为F;R 3’和R 4’独立地为H、二氟甲基、三氟甲基、乙烯基、丙烯基、乙炔基、丙炔基、F或Cl;R 8’独立地为甲基、乙基或丙基,所述甲基、乙基或丙基被1、2或3个选自F、Cl、OH、CN、NH 2、甲基、羟基甲基、环丙基、氮杂环丁基或氧杂环丁基的基团取代;条件是,R 3’和R 4’不同时选自H。
- 根据权利要求1所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,其中每个Rx独立地为H或F;R 3’和R 4’独立地为H、C 2-4烯基、C 2-4炔基、F或Cl;R 8’独立地为C 1-4烷基,所述烷基被1、2或3个选自F、Cl、OH、CN、NH 2、甲基、羟基甲基、环丙基、氮杂环丁基或氧杂环丁基的基团取代;条件是,R 3’和R 4’不同时选自H。
- 一种药物组合物,其特征在于,含有权利要求1-12任意一项所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,以及药学上可接受的辅料和/或载体。
- 权利要求1-12任意一项所述的化合物,其立体异构体、溶剂化物、氘代物或药学上可接受的盐,或者权利要求13所述的药物组合物在制备治疗/预防ER介导的疾病的药物中的用途。
- 根据权利要求14所述的用途,其中ER介导的疾病选自乳腺癌、卵巢癌、子宫癌或宫颈癌。
- 一种药物组合物或药物制剂,所述的药物组合物或药物制剂包含选1-600mg的权利要求1-12任意一项所述的化合物或者其立体异构体、溶剂化物、氘代物或药学上可接受的盐,以及药学上可接受的辅料和/或载体。
- 一种用于治疗哺乳动物的疾病的方法,所述方法包括给予受试者治疗有效量的权利要求1-12任意一项所述的化合物或者其立体异构体、溶剂化物、氘代物或药学上可接受的盐,治疗有效量优选1-600mg,所述的疾病优选乳腺癌、卵巢癌、子宫癌或宫颈癌。
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- 2022-07-14 EP EP22841470.2A patent/EP4371977A1/en active Pending
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