US20190142811A1 - Estrogen receptor modulators - Google Patents
Estrogen receptor modulators Download PDFInfo
- Publication number
- US20190142811A1 US20190142811A1 US16/086,434 US201716086434A US2019142811A1 US 20190142811 A1 US20190142811 A1 US 20190142811A1 US 201716086434 A US201716086434 A US 201716086434A US 2019142811 A1 US2019142811 A1 US 2019142811A1
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- United States
- Prior art keywords
- optionally substituted
- mmol
- compound
- methyl
- indol
- Prior art date
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- 239000002834 estrogen receptor modulator Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 170
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 102100038595 Estrogen receptor Human genes 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 108010007005 Estrogen Receptor alpha Proteins 0.000 claims abstract description 19
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 18
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 18
- 230000001419 dependent effect Effects 0.000 claims abstract description 17
- 230000001404 mediated effect Effects 0.000 claims abstract description 15
- -1 X1 is NH Inorganic materials 0.000 claims description 79
- 125000000623 heterocyclic group Chemical group 0.000 claims description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 63
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 51
- 125000001072 heteroaryl group Chemical group 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 37
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 34
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 32
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- GDGULTXZDPTNNZ-NSCUHMNNSA-N methyl (E)-3-(3,5-difluoro-4-formylphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\c1cc(F)c(C=O)c(F)c1 GDGULTXZDPTNNZ-NSCUHMNNSA-N 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- MAWOHFOSAIXURX-UHFFFAOYSA-N cyclopentylcyclopentane Chemical group C1CCCC1C1CCCC1 MAWOHFOSAIXURX-UHFFFAOYSA-N 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010014733 Endometrial cancer Diseases 0.000 claims description 4
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- ZTXSPLGEGCABFL-UHFFFAOYSA-N 1.1.1-propellane Chemical compound C1C23CC31C2 ZTXSPLGEGCABFL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
- 238000007918 intramuscular administration Methods 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 238000011200 topical administration Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 167
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 392
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 258
- 239000000243 solution Substances 0.000 description 191
- 235000019439 ethyl acetate Nutrition 0.000 description 160
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 151
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 137
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 111
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 111
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 103
- 125000000217 alkyl group Chemical group 0.000 description 103
- 229910052938 sodium sulfate Inorganic materials 0.000 description 103
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 101
- 239000011541 reaction mixture Substances 0.000 description 97
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 96
- 239000012044 organic layer Substances 0.000 description 93
- 239000007787 solid Substances 0.000 description 78
- 239000000377 silicon dioxide Substances 0.000 description 71
- 235000011152 sodium sulphate Nutrition 0.000 description 71
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
- 229910052681 coesite Inorganic materials 0.000 description 70
- 229910052906 cristobalite Inorganic materials 0.000 description 70
- 229910052682 stishovite Inorganic materials 0.000 description 70
- 229910052905 tridymite Inorganic materials 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 125000003118 aryl group Chemical group 0.000 description 44
- 238000003818 flash chromatography Methods 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 125000000753 cycloalkyl group Chemical group 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 0 CC(Cc1c(C2c3c(*)cc(C=C**)cc3I)[n]c3c1cccc3)N2C1(C2)CC2(C)C1 Chemical compound CC(Cc1c(C2c3c(*)cc(C=C**)cc3I)[n]c3c1cccc3)N2C1(C2)CC2(C)C1 0.000 description 35
- 239000007832 Na2SO4 Substances 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 239000007864 aqueous solution Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 30
- 229960000583 acetic acid Drugs 0.000 description 29
- 125000004429 atom Chemical group 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 28
- 150000002431 hydrogen Chemical class 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- 108010038795 estrogen receptors Proteins 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 22
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 17
- 125000000304 alkynyl group Chemical group 0.000 description 17
- 239000007788 liquid Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- QSQQQURBVYWZKJ-MRVPVSSYSA-N (2r)-1-(1h-indol-3-yl)propan-2-amine Chemical compound C1=CC=C2C(C[C@H](N)C)=CNC2=C1 QSQQQURBVYWZKJ-MRVPVSSYSA-N 0.000 description 16
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 235000019253 formic acid Nutrition 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000012267 brine Substances 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 239000006184 cosolvent Substances 0.000 description 11
- ZHJBZIANKVWBRP-ONEGZZNKSA-N ethyl (E)-3-(3,5-difluoro-4-formylphenyl)prop-2-enoate Chemical compound FC=1C=C(C=C(C=1C=O)F)/C=C/C(=O)OCC ZHJBZIANKVWBRP-ONEGZZNKSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 10
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- 239000012279 sodium borohydride Substances 0.000 description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- VKLJLIUSOUUEQR-LYIQJEATSA-N (E)-3-[3-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-1-bicyclo[1.1.1]pentanyl]prop-2-enoic acid Chemical compound FC(CN1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1C)C12CC(C1)(C2)/C=C/C(=O)O)(C)C VKLJLIUSOUUEQR-LYIQJEATSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- DXFUTQQRVOKTCV-UPEJEEEKSA-N methyl (E)-3-[4-[(1R,3R)-2-(1-bicyclo[1.1.1]pentanyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)N1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1C)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F DXFUTQQRVOKTCV-UPEJEEEKSA-N 0.000 description 9
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- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 8
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 8
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- XZSQKRWMNNBJPA-PYHKZKJUSA-N (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C[C@@H]1Cc2c([nH]c3ccc(O)cc23)[C@H](N1CC(C)(C)F)c1c(F)cc(\C=C\C(O)=O)cc1F XZSQKRWMNNBJPA-PYHKZKJUSA-N 0.000 description 5
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- LIHRMMKQEVVBOR-OECKFSCXSA-N ethyl (E)-3-[3-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-1-bicyclo[1.1.1]pentanyl]prop-2-enoate Chemical compound FC(CN1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1C)C12CC(C1)(C2)/C=C/C(=O)OCC)(C)C LIHRMMKQEVVBOR-OECKFSCXSA-N 0.000 description 3
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- OYDMPSNPZBSMRU-COHABYCKSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-3-methyl-2-[(3R)-oxolan-3-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)[C@H]1COCC1)F)/C=C/C(=O)OC OYDMPSNPZBSMRU-COHABYCKSA-N 0.000 description 3
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- DXFUTQQRVOKTCV-AODNEYDMSA-N methyl (E)-3-[4-[(1R,3R)-2-(1-bicyclo[1.1.1]pentanyl)-1-deuterio-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)N1[C@](C=2NC3=CC=CC=C3C=2C[C@H]1C)([2H])C1=C(C=C(C=C1F)/C=C/C(=O)OC)F DXFUTQQRVOKTCV-AODNEYDMSA-N 0.000 description 3
- CQACBVZOOIDEJM-HBOWPIQTSA-N methyl (E)-3-[4-[(1R,3R)-2-(3,3-difluorocyclobutyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound FC1(CC(C1)N1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1C)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F)F CQACBVZOOIDEJM-HBOWPIQTSA-N 0.000 description 3
- DXFUTQQRVOKTCV-WBDNCGLUSA-N methyl (E)-3-[4-[(1S,3S)-2-(1-bicyclo[1.1.1]pentanyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)N1[C@H](C=2NC3=CC=CC=C3C=2C[C@@H]1C)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F DXFUTQQRVOKTCV-WBDNCGLUSA-N 0.000 description 3
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- APBRLLHHQIXIGF-UHFFFAOYSA-N N-[1-(1H-indol-3-ylmethyl)cyclopropyl]bicyclo[1.1.1]pentane-1-carboxamide Chemical compound N1C=C(C2=CC=CC=C12)CC1(CC1)NC(=O)C12CC(C1)C2 APBRLLHHQIXIGF-UHFFFAOYSA-N 0.000 description 2
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- 239000002253 acid Substances 0.000 description 2
- TXUZVZSFRXZGTL-QPLCGJKRSA-N afimoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=C(O)C=C1 TXUZVZSFRXZGTL-QPLCGJKRSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
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- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- LUYGYUGZSGMKOX-INIZCTEOSA-N benzyl n-[(2s)-1-hydroxy-3-(1h-indol-3-yl)propan-2-yl]carbamate Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)CO)C(=O)OCC1=CC=CC=C1 LUYGYUGZSGMKOX-INIZCTEOSA-N 0.000 description 2
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 239000008004 cell lysis buffer Substances 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229940009976 deoxycholate Drugs 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- SABGKUGSMBFIQM-KTVBDLDWSA-N ethyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=C(C=C21)O)C)CC(C)(C)F)F)/C=C/C(=O)OCC SABGKUGSMBFIQM-KTVBDLDWSA-N 0.000 description 2
- YFUDPNAQTHTVAH-GBPLQENWSA-N ethyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-[(3-fluorooxetan-3-yl)methyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC1(COC1)F)F)/C=C/C(=O)OCC YFUDPNAQTHTVAH-GBPLQENWSA-N 0.000 description 2
- CTQKDCGYOZFGOW-VYGGMCTJSA-N ethyl (E)-3-[3,5-difluoro-4-[(1R,3R)-3-methyl-2-(oxetan-3-ylmethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC1COC1)F)/C=C/C(=O)OCC CTQKDCGYOZFGOW-VYGGMCTJSA-N 0.000 description 2
- MABMSEOHDXVQQZ-SAEWTEAUSA-N ethyl (E)-3-[3,5-difluoro-4-[(1R,3R)-3-methyl-2-[(3-methyloxetan-3-yl)methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC1(COC1)C)F)/C=C/C(=O)OCC MABMSEOHDXVQQZ-SAEWTEAUSA-N 0.000 description 2
- XSGXVWNYRDAPDR-AGJHBYALSA-N ethyl (E)-3-[3,5-difluoro-4-[(1R,3S)-3-(hydroxymethyl)-2-(oxolan-3-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)CO)C1COCC1)F)/C=C/C(=O)OCC XSGXVWNYRDAPDR-AGJHBYALSA-N 0.000 description 2
- TZEJQTWXPWGARX-BQYQJAHWSA-N ethyl (E)-3-[3,5-difluoro-4-[2-(oxolan-3-yl)spiro[4,9-dihydro-1H-pyrido[3,4-b]indole-3,1'-cyclopropane]-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1C1N(C2(CC3=C1NC1=CC=CC=C31)CC2)C1COCC1)F)/C=C/C(=O)OCC TZEJQTWXPWGARX-BQYQJAHWSA-N 0.000 description 2
- RQWVXIGLDUEKLK-ONEGZZNKSA-N ethyl (E)-3-[3-(hydroxymethyl)-1-bicyclo[1.1.1]pentanyl]prop-2-enoate Chemical compound OCC12CC(C1)(C2)/C=C/C(=O)OCC RQWVXIGLDUEKLK-ONEGZZNKSA-N 0.000 description 2
- LIHRMMKQEVVBOR-CUWRDKRYSA-N ethyl (E)-3-[3-[(3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-1-bicyclo[1.1.1]pentanyl]prop-2-enoate Chemical compound FC(CN1C(C=2NC3=CC=CC=C3C=2C[C@H]1C)C12CC(C1)(C2)/C=C/C(=O)OCC)(C)C LIHRMMKQEVVBOR-CUWRDKRYSA-N 0.000 description 2
- NMZBTJSAZAVIQC-ZDXWXINFSA-N ethyl (E)-3-[3-[(3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-1-bicyclo[1.1.1]pentanyl]prop-2-enoate Chemical compound C[C@@H]1CC2=C(NC3=CC=CC=C23)C(N1)C12CC(C1)(C2)/C=C/C(=O)OCC NMZBTJSAZAVIQC-ZDXWXINFSA-N 0.000 description 2
- ADCKHXMMUQYJLW-CMDGGOBGSA-N ethyl (E)-3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-bicyclo[1.1.1]pentanyl]prop-2-enoate Chemical compound [Si](C)(C)(C(C)(C)C)OCC12CC(C1)(C2)/C=C/C(=O)OCC ADCKHXMMUQYJLW-CMDGGOBGSA-N 0.000 description 2
- FHCNYMOGPIWNRA-OGVHOKRMSA-N ethyl (E)-3-[4-[(1R,3R)-3-ethyl-2-(oxolan-3-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C(C)[C@@H]1CC2=C(NC3=CC=CC=C23)[C@H](N1C1COCC1)C1=C(C=C(C=C1F)/C=C/C(=O)OCC)F FHCNYMOGPIWNRA-OGVHOKRMSA-N 0.000 description 2
- PVGBPCVXBLDYLH-LOWFCHKKSA-N ethyl (E)-3-[4-[(1R,3S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-(oxolan-3-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OC[C@@H]1CC2=C(NC3=CC=CC=C23)[C@H](N1C1COCC1)C1=C(C=C(C=C1F)/C=C/C(=O)OCC)F PVGBPCVXBLDYLH-LOWFCHKKSA-N 0.000 description 2
- SYBJWKJJFRFVBQ-PETVGNNHSA-N ethyl (E)-3-[4-[(3S)-3-(difluoromethyl)-2-(oxolan-3-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound FC([C@@H]1CC2=C(NC3=CC=CC=C23)C(N1C1COCC1)C1=C(C=C(C=C1F)/C=C/C(=O)OCC)F)F SYBJWKJJFRFVBQ-PETVGNNHSA-N 0.000 description 2
- SEYSLXNYMUVIAY-MDZDMXLPSA-N ethyl (E)-3-[4-[2-(1-bicyclo[1.1.1]pentanylmethyl)-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)CN1C(C=2NC3=CC=CC=C3C=2CC1(C)C)C1=C(C=C(C=C1F)/C=C/C(=O)OCC)F SEYSLXNYMUVIAY-MDZDMXLPSA-N 0.000 description 2
- BXOYLTHIVUYZAY-MDZDMXLPSA-N ethyl (E)-3-[4-[2-(1-bicyclo[1.1.1]pentanylmethyl)-3-ethyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)CN1C(C=2NC3=CC=CC=C3C=2CC1CC)C1=C(C=C(C=C1F)/C=C/C(=O)OCC)F BXOYLTHIVUYZAY-MDZDMXLPSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- KCWXQKUDEGLRHE-JTXSWIJISA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-[(4-methoxyphenyl)methyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC1=CC=C(C=C1)OC)F)/C=C/C(=O)OC KCWXQKUDEGLRHE-JTXSWIJISA-N 0.000 description 2
- QYJUDQDZYHYTMH-SQVINRLWSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-3-methyl-2-(oxan-4-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)C1CCOCC1)F)/C=C/C(=O)OC QYJUDQDZYHYTMH-SQVINRLWSA-N 0.000 description 2
- JLDNEVCSILKHIG-HBOWPIQTSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-3-methyl-2-(oxetan-3-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)C1COC1)F)/C=C/C(=O)OC JLDNEVCSILKHIG-HBOWPIQTSA-N 0.000 description 2
- GSDPXOCXMVSIBF-VIRWDPDXSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-3-methyl-2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC12CC(C1)(C2)C(F)(F)F)F)/C=C/C(=O)OC GSDPXOCXMVSIBF-VIRWDPDXSA-N 0.000 description 2
- DHVVEZHLQYHDNB-AKWFWPGUSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-6-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C1NC1=CC=C(C=C21)F)C)CC(C)(C)F)F)/C=C/C(=O)OC DHVVEZHLQYHDNB-AKWFWPGUSA-N 0.000 description 2
- XCKVTDPRJMJWBJ-FXJVEYLQSA-N methyl (E)-3-[3,5-difluoro-4-[(1S,3S)-3-methyl-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound FC=1C=C(C=C(C=1[C@@H]1N([C@H](CC2=C1NC1=CC=CC=C21)C)C12CC(C1)(C2)C(F)(F)F)F)/C=C/C(=O)OC XCKVTDPRJMJWBJ-FXJVEYLQSA-N 0.000 description 2
- OMDXGLSVSPKMNG-MHVLFRNWSA-N methyl (E)-3-[4-[(1R,3R)-2-(1-bicyclo[1.1.1]pentanyl)-3,9-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)N1[C@@H](C=2N(C3=CC=CC=C3C=2C[C@H]1C)C)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F OMDXGLSVSPKMNG-MHVLFRNWSA-N 0.000 description 2
- VQUXDBPGXUPZKL-MMWQXONGSA-N methyl (E)-3-[4-[(1R,3R)-2-(1-bicyclo[1.1.1]pentanyl)-3-ethyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)N1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1CC)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F VQUXDBPGXUPZKL-MMWQXONGSA-N 0.000 description 2
- FFGXZUFVSSNGBR-HWPZAJRLSA-N methyl (E)-3-[4-[(1R,3R)-2-(1-bicyclo[1.1.1]pentanylmethyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound C12(CC(C1)C2)CN1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1C)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F FFGXZUFVSSNGBR-HWPZAJRLSA-N 0.000 description 2
- MJVXBXDFBDLJDQ-UNZADJOKSA-N methyl (E)-3-[4-[(1R,3R)-2-[(3,3-difluorocyclobutyl)methyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound FC1(CC(C1)CN1[C@@H](C=2NC3=CC=CC=C3C=2C[C@H]1C)C1=C(C=C(C=C1F)/C=C/C(=O)OC)F)F MJVXBXDFBDLJDQ-UNZADJOKSA-N 0.000 description 2
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Images
Classifications
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- 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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- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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- 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
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C2603/56—Ring systems containing bridged rings
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- C07C2603/62—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing three- or four-membered rings
Definitions
- the present application relates to compounds that are estrogen receptor alpha modulators and methods of using them to treat conditions characterized by excessive cellular proliferation, such as cancer.
- ERs estrogen receptors
- SERMs selective estrogen receptor modulators
- fulvestrant is a drug that is used for the treatment of metastatic breast cancer. It has antagonistic effects on ER-alpha and is considered a selective estrogen receptor alpha degrader (SERD).
- SESD selective estrogen receptor alpha degrader
- RAD1901 A compound known as RAD1901 has also been reported to be a SERD. See Garner, F. et al., “RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models” Anti-Cancer Drugs 26(9), 948-956 (2015). RAD1901 has the following chemical structure:
- SERDs include the compounds known as AZD9496 and GDC-0810.
- AZD9496 Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist”, J. Med. Chem. 58, 8128-8140 (2015) (“De Savi”) and Lai, A.
- GDC-0810 ARN-810
- SESD Selective Estrogen Receptor Degrader
- SERDs include those disclosed in WO 2008/002490; WO 2011/156518; WO 2013/090829; WO 2013/090836; WO 2013/142266; WO 2014/151899; WO 2014/191726; WO 2015/082990; and US 2014/00235660.
- An embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure below.
- X 1 , Y 1 and Z 1 are each independently C or N, with the first proviso that at least one of X 1 , Y 1 and Z 1 is N; with the second proviso that each of X 1 , Y 1 and Z 1 is uncharged; with third proviso that two of the dotted lines indicate double bonds; and with the fourth proviso that the valencies of X 1 , Y 1 and Z 1 can be each independently satisfied by attachment to a substituent selected from H and R 12 .
- a 1 is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl.
- X 2 is O, NH or S.
- R 1 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted cycloalkenyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl).
- R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl; or R 2 and R 3 together with the carbon to which R 2 and R 3 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl; or R 4 and R 5 together with the carbon to which R 4 and R 5 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl.
- R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted haloalkyl, an optionally substituted mono-substituted amine, and an optionally substituted di-substituted amine.
- R 10 is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl.
- R 11 is hydrogen or an optionally substituted C 1-6 alkyl.
- R 12 is hydrogen, halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 1-3 haloalkyl or an optionally substituted C 1-3 alkoxy.
- R 11 when R 11 is hydrogen or methyl, X 1 is NH, Y 1 and Z 1 are each C, X 2 is O, A 1 is a phenyl, 2-fluorophenyl, or 2,6-difluorophenyl, both R 2 and R 3 are methyl or one of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is methyl, and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each hydrogen, then R 1 cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.
- any one or more of each of R 2 , R 3 , R 4 , R 5 , R 6 , R, R 8 , R 9 and R 10 is hydrogen.
- An embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
- An embodiment provides a method of treatment, comprising identifying a subject that is in need of treatment for a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated; and administering to said subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).
- the disease or condition is selected from the group consisting of a breast cancer and a gynecological cancer.
- the disease or condition is selected from the group consisting of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer.
- An embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), for use in the treatment of a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated.
- FIG. 1 illustrates General Scheme 1 for preparing compounds of the Formula (I).
- FIG. 2 illustrates a method of making Compound 11A.
- the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl,
- C a to C b in which “a” and “b” are integers refer to the number of carbon atoms in a group.
- the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
- a “C 1 to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 —, CH 3 CH 2 —, CH 3 CH 2 CH 2 —, (CH 3 ) 2 CH—, CH 3 CH 2 CH 2 CH 2 —, CH 3 CH 2 CH(CH 3 )— and (CH 3 ) 3 C—. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
- R groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle.
- R a and R b of an NR a R b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:
- alkyl refers to a fully saturated aliphatic hydrocarbon group.
- the alkyl moiety may be branched or straight chain.
- branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
- straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
- the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
- the alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms.
- the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
- An alkyl group may be substituted or unsubstituted.
- alkenyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
- An alkenyl group may be unsubstituted or substituted.
- alkynyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like.
- An alkynyl group may be unsubstituted or substituted.
- cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge.
- Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
- a cycloalkyl group may be unsubstituted or substituted.
- Typical mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.
- cycloalkenyl refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.
- cycloalkynyl refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. Cycloalkynyl groups can contain 6 to 10 atoms in the ring(s) or 6 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. A cycloalkynyl group may be unsubstituted or substituted.
- aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
- the number of carbon atoms in an aryl group can vary.
- the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
- An aryl group may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
- the number of atoms in the ring(s) of a heteroaryl group can vary.
- the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine
- heterocyclyl or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
- the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
- a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
- oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
- the rings When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
- the term “fused” refers to two rings which have two atoms and one bond in common.
- bridged heterocyclyl or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms.
- spiro refers to two rings which have one atom in common and the two rings are not linked by a bridge.
- Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
- heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
- heterocyclyl or heteroalicyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil,
- spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
- aralkyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.
- heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
- heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).
- lower alkylene groups are straight-chained —CH 2 -tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —) and butylene (—CH 2 CH 2 CH 2 CH 2 —).
- a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a cycloalkyl group (e.g.,
- hydroxy refers to a —OH group.
- alkoxy refers to the Formula —OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
- R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
- a non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy,
- acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
- a “cyano” group refers to a “—CN” group.
- halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
- a “thiocarbonyl” group refers to a “—C( ⁇ S)R” group in which R can be the same as defined with respect to O-carboxy.
- a thiocarbonyl may be substituted or unsubstituted.
- An “O-carbamyl” group refers to a “—OC( ⁇ O)N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An O-carbamyl may be substituted or unsubstituted.
- N-carbamyl refers to an “ROC( ⁇ O)N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-carbamyl may be substituted or unsubstituted.
- An “O-thiocarbamyl” group refers to a “—OC( ⁇ S)—N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An O-thiocarbamyl may be substituted or unsubstituted.
- N-thiocarbamyl refers to an “ROC( ⁇ S)N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-thiocarbamyl may be substituted or unsubstituted.
- a “C-amido” group refers to a “—C( ⁇ O)N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- a C-amido may be substituted or unsubstituted.
- N-amido refers to a “RC( ⁇ O)N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-amido may be substituted or unsubstituted.
- S-sulfonamido refers to a “—SO 2 N(R A R B )” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An S-sulfonamido may be substituted or unsubstituted.
- N-sulfonamido refers to a “RSO 2 N(R A )—” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- An N-sulfonamido may be substituted or unsubstituted.
- An “O-carboxy” group refers to a “RC( ⁇ O)O—” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- An O-carboxy may be substituted or unsubstituted.
- esters and C-carboxy refer to a “—C( ⁇ O)OR” group in which R can be the same as defined with respect to O-carboxy.
- An ester and C-carboxy may be substituted or unsubstituted.
- a “nitro” group refers to an “—NO 2 ” group.
- a “sulfenyl” group refers to an “—SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
- a sulfenyl may be substituted or unsubstituted.
- a “sulfinyl” group refers to an “—S( ⁇ O)—R” group in which R can be the same as defined with respect to sulfenyl.
- a sulfinyl may be substituted or unsubstituted.
- a “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to sulfenyl.
- a sulfonyl may be substituted or unsubstituted.
- haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl).
- a halogen e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl.
- groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl.
- a haloalkyl may be substituted or unsubstituted.
- haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy).
- a halogen e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy.
- groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
- a haloalkoxy may be substituted or unsubstituted.
- amino refers to a —NH 2 group.
- a “mono-substituted amino” group refers to a “—NHR” group in which R can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- a mono-substituted amino may be substituted or unsubstituted. Examples of mono-substituted amino groups include, but are not limited to, —NH(methyl), —NH(phenyl) and the like.
- a “di-substituted amino” group refers to a “—NR A R B ” group in which R A and R B can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
- a di-substituted amino may be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, —N(methyl) 2 , —N(phenyl)(methyl), —N(ethyl)(methyl) and the like.
- substituents there may be one or more substituents present.
- haloalkyl may include one or more of the same or different halogens.
- C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
- a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
- a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
- the term “radical” can be used interchangeably with the term “group.”
- linking groups are chemical groups that are indicated as having multiple open valencies for connecting to two or more other groups.
- lower alkylene groups of the general formula —(CH 2 ) n — where n is in the range of 1 to 10 are examples of linking groups that are described elsewhere herein as connecting molecular fragments via their terminal carbon atoms.
- Other examples of linking groups include —(CH 2 ) n O—, —(CH 2 ) n NH—, —(CH 2 ) n N(C 1 -C 6 alkyl)-, and —(CH 2 ) n S—, wherein each n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- n can be zero for some linking groups such as —(CH 2 ) n O—, in which case the linking group is simply —O—.
- reference herein to an asymmetrical linking group will be understood as a reference to all orientations of that group (unless stated otherwise).
- reference herein to —(CH 2 ) n O— will be understood as a reference to both —(CH 2 ) n O— and —O—(CH 2 ) n —.
- pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- the salt is an acid addition salt of the compound.
- Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate).
- Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic, or naphthalenesulfonic acid.
- an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
- Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
- a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such
- a salt is formed by protonation of a nitrogen-based group (for example, NH 2 )
- the nitrogen-based group can be associated with a positive charge (for example, NH 2 can become NH 3 + ) and the positive charge can be balanced by a negatively charged counterion (such as Cl ⁇ ).
- each center may independently be of R-configuration or S-configuration or a mixture thereof.
- the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
- each double bond may independently be E or Z a mixture thereof.
- all tautomeric forms are also intended to be included.
- valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
- each chemical element as represented in a compound structure may include any isotope of said element.
- a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
- the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).
- reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
- the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
- the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
- the compounds described herein exist in unsolvated form.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
- the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
- the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
- a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless the context indicates otherwise.
- a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless the context indicates otherwise.
- Some embodiments disclosed herein relate to compounds of the Formula (I), or pharmaceutically acceptable salts thereof.
- compounds of Formula (I) are useful for ameliorating, treating and/or diagnosing a disease or condition that is estrogen receptor dependent and/or estrogen receptor mediated.
- the disease is cancer.
- the cancer is breast cancer.
- compounds of Formula (I) are selective estrogen receptor modulators (SERMs).
- compounds of Formula (I) are selective estrogen receptor degraders (SERDs). Additional details regarding various uses and methods of treatment are described elsewhere herein.
- variables X 1 , Y 1 and Z 1 in Formula (I) are each independently C or N, with the first proviso that at least one of X 1 , Y 1 and Z 1 is N; with the second proviso that each of X 1 , Y 1 and Z 1 is uncharged; with third proviso that two of the dotted lines indicate double bonds; and with the fourth proviso that the valencies of X 1 , Y 1 and Z 1 can be each independently satisfied by attachment to a substituent selected from H and R 12 .
- the variable X 2 in Formula (I) is O, NH or S.
- X 2 is O.
- R 12 is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 1-3 haloalkyl and an optionally substituted C 1-3 alkoxy. In an embodiment, R 12 is hydrogen. In another embodiment, R 12 is not hydrogen.
- variable A 1 in Formula (I) is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl.
- a 1 is an optionally substituted aryl.
- a 1 is an optionally substituted phenyl.
- a 1 is a substituted phenyl or an unsubstituted phenyl.
- a 1 is an optionally substituted cycloalkyl.
- a 1 is an optionally substituted bicyclopentyl.
- a 1 is a substituted bicyclopentyl or an unsubstituted bicyclopentyl.
- variable R 1 in Formula (I) is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted cycloalkenyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl).
- R 1 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted heterocyclyl and an optionally substituted heterocyclyl(C 1-6 alkyl).
- R 1 in Formula (I) is a substituted cycloalkyl.
- R 1 is substituted cycloalkyl that is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, an optionally substituted alkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine.
- R 1 is an optionally substituted cycloalkyl selected from the group consisting of unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl.
- R 1 is an optionally substituted cycloalkyl(C 1-6 alkyl) selected from the group consisting of unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, and unsubstituted trifluoromethylcyclopropylmethyl.
- C 1-6 alkyl selected from the group consisting of unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, and unsubstituted trifluoromethylcyclopropylmethyl.
- R 1 is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.
- R 1 is an optionally substituted heterocyclyl(C 1-6 alkyl) is selected from the group consisting of unsubstituted oxetanylmethyl and unsubstituted fluorooxetanylmethyl
- R 1 in Formula (I) is a substituted alkyl.
- R 1 is a substituted alkyl that is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine.
- R 1 is a substituted alkyl that is a haloalkyl.
- R 1 is an optionally substituted C 1-6 alkyl selected from the group consisting of C 4 alkyl, fluoro(C 4 alkyl), and trifluoro(C 2 alkyl).
- variables R 2 and R 3 in Formula (I) are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl.
- R 2 and R 3 together with the carbon to which R 2 and R 3 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl.
- R 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl and difluoromethyl.
- variables R 4 and R 5 in Formula (I) are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl.
- R 4 and R 5 together with the carbon to which R 4 and R 5 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl.
- variables R 6 , R 7 , R 8 and R 9 in Formula (I) are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted haloalkyl, an optionally substituted mono-substituted amine, and an optionally substituted di-substituted amine.
- R 7 is selected from the group consisting of halogen, hydroxy, and unsubstituted alkoxy.
- R 7 is selected from the group consisting of fluoro and methoxy.
- variable R 10 in Formula (I) is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl.
- variable R 11 in Formula (I) is hydrogen or an optionally substituted C 1-6 alkyl.
- R 11 is an unsubstituted C 1-6 alkyl.
- R 11 is methyl, ethyl or propyl (e.g., isopropyl or n-propyl).
- R 11 when R 11 is hydrogen or methyl, X 1 is NH, Y 1 and Z 1 are each C, X 2 is O, A 1 is a phenyl, 2-fluorophenyl, or 2,6-difluorophenyl, both R 2 and R 3 are methyl or one of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is methyl, and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each hydrogen, then R 1 cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.
- R 10 when R 10 is hydrogen, R 11 is hydrogen or methyl, X 1 is NH, Y 1 and Z 1 are each C, X 2 is O, A 1 is an optionally substituted phenyl, one of R 2 and R 3 is hydrogen or an optionally substituted C 1-6 alkyl and the other of R 2 and R 3 is an optionally substituted C 1-6 alkyl, then R 1 cannot be a substituted C 1-6 alkyl substituted with one or more substituents selected from the group consisting of halogen and hydroxy.
- the variables R 1 , R 6 , R 7 , R 8 and R 10 for the compounds of Formulae (Ia), (Ib), (Ic) and (Id) are the same as described elsewhere herein.
- variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substituted C 1-6 alkyl selected from the group consisting of C 4 alkyl, fluoro(C 4 alkyl), and trifluoro(C 2 alkyl).
- the variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substituted cycloalkyl selected from the group consisting of unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl.
- variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substituted cycloalkyl(C 1-6 alkyl) selected from the group consisting of unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, and unsubstituted trifluoromethylcyclopropylmethyl.
- variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.
- variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.
- variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substituted heterocyclyl(C 1-6 alkyl) selected from the group consisting of unsubstituted oxetanylmethyl and unsubstituted fluorooxetanylmethyl.
- the variables R 6 , R 7 and R 8 are hydrogen
- the variable R 1 in Formulae (Ia), (Ib), (Ic) and (Id) cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.
- the variables R 6 , R 7 and R 8 in Formulae (Ia), (Ib), (Ic) and (Id) are each independently selected from the group consisting of halogen e.g., fluoro, chloro or bromo), hydroxy, and unsubstituted alkoxy (e.g., methoxy, ethoxy or propoxy).
- the variables R 6 and R 8 in Formulae (Ia), (Ib), (Ic) and (Id) are both hydrogen.
- the variables R 6 and R 7 in Formulae (Ia), (Ib), (Ic) and (Id) are both hydrogen.
- the variables R 7 and R 8 in Formulae (Ia), (Ib), (Ic) and (Id) are both hydrogen.
- variable R 10 in Formulae (Ia), (Ib), (Ic) and (Id) is hydrogen or a C 1-6 alkyl. In an embodiment, the variable R 10 in Formulae (Ia), (Ib), (Ic) and (Id) is not hydrogen.
- variables R 1 , R 7 , and R 10 for the compounds of Formulae (Ie), (If), (Ig) and (Ih) are the same as described elsewhere herein.
- variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substituted C 1-6 alkyl selected from the group consisting of C 4 alkyl, fluoro(C 4 alkyl), and trifluoro(C 2 alkyl).
- the variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substituted cycloalkyl selected from the group consisting of unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl.
- variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substituted cycloalkyl(C 1-6 alkyl) selected from the group consisting of unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, and unsubstituted trifluoromethylcyclopropylmethyl.
- variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.
- variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.
- variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substituted heterocyclyl(C 1-6 alkyl) selected from the group consisting of unsubstituted oxetanylmethyl and unsubstituted fluorooxetanylmethyl.
- variable R 7 when the variable R 7 is hydrogen, the variable R 1 in Formulae (Ie), (If), (Ig) and (Ih) cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.
- variable R 7 in Formulae (Ie), (If), (Ig) and (Ih) is selected from the group consisting of halogen (e.g., fluoro, chloro or bromo), hydroxy, and unsubstituted alkoxy (e.g., methoxy, ethoxy or propoxy).
- the variable R 10 in Formulae (Ie), (If), (Ig) and (Ih) is hydrogen or a C 1-6 alkyl.
- the variable R 10 in Formulae (Ie), (If), (Ig) and (Ih) is not hydrogen.
- any intermediate reaction products formed as a result of the reaction between compounds of the general formulae (A) and (B) can be readily converted to compounds of the Formula (I) by those skilled in the art in view of the detailed teaching provided herein, e.g., by appropriate adjustment of the reagents and conditions described in Example 1A for the preparation of Compound 1A from intermediate ethyl (E)-3-(3-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylate.
- one or more compounds of Formula (I), or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described herein can be used to inhibit the growth of a cell.
- the cell is identified as having an estrogen receptor that mediates a growth characteristic of the cell. Growth of a cell can be inhibited by contacting the cell with an effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described elsewhere herein.
- Such contacting of the one or more compounds, or pharmaceutically acceptable salts thereof can take place in various ways and locations, including without limitation away from a living subject (e.g., in a laboratory, diagnostic and/or analytical setting) or in proximity to a living subject (e.g., within or on an exterior portion of an animal, e.g., a human).
- a living subject e.g., in a laboratory, diagnostic and/or analytical setting
- a living subject e.g., within or on an exterior portion of an animal, e.g., a human.
- an embodiment provides a method of treating a subject, comprising identifying a subject that is in need of treatment for a disease or condition that is estrogen receptor dependent and/or estrogen receptor mediated and administering to said subject an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described elsewhere herein.
- Another embodiment provides a use of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition (as described elsewhere herein), in the manufacture of a medicament for the treatment of a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated.
- Non-limiting examples of diseases or conditions that are estrogen receptor alpha dependent and/or estrogen alpha receptor mediated and thus suitable for treatment using the compounds, compositions and methods described herein include breast cancers and gynecological cancers.
- diseases or conditions may include one or more of the following: breast cancer, endometrial cancer, ovarian cancer and cervical cancer.
- An embodiment provides a use of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition (as described elsewhere herein), in the manufacture of a medicament for the treatment of breast cancers and gynecological cancers, including for example one or more of the following: breast cancer, endometrial cancer, ovarian cancer and cervical cancer.
- compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described elsewhere herein can be administered to such subjects by a variety of methods.
- administration can be by various routes known to those skilled in the art, including without limitation oral, intravenous, intramuscular, topical, subcutaneous, systemic, and/or intraperitoneal administration to a subject in need thereof.
- the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.
- a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition, or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
- the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration.
- the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
- the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
- dosages may be calculated as the free base.
- a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg.
- a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day.
- the compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg or 5 to 50 mg of active ingredient per unit dosage form.
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
- the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
- the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
- the determination of effective dosage levels can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies.
- useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as fulvestrant.
- Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
- MEC minimal effective concentration
- the MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
- Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
- the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
- the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition to be treated and to the route of administration. The severity of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
- the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
- a cell line such as a mammalian, and preferably human, cell line.
- the results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
- the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
- the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
- compositions that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
- composition refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers.
- the pharmaceutical composition facilitates administration of the compound to an organism.
- Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
- Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
- physiologically acceptable defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.
- a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
- DMSO dimethyl sulfoxide
- a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
- a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
- a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
- an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
- stabilizers such as anti-oxidants and metal-chelating agents are excipients.
- the pharmaceutical composition comprises an anti-oxidant and/or a metal-chelating agent.
- a “diluent” is a type of excipient.
- compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
- compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
- a compound, salt and/or composition include, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
- the liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.
- compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
- the pack may for example comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device may be accompanied by instructions for administration.
- the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
- Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
- the compounds of Formula (I) illustrated in Table 1 can be prepared in various ways, using techniques known to those skilled in the art as guided by the detailed teachings provided herein.
- the compounds of Formula (I) illustrated in Table 1 can be prepared in accordance with General Scheme 1 as described in the Examples below.
- the compounds of Formula (I) illustrated in Table 2 can be readily prepared in accordance with General Scheme 1 in view of the detailed teachings set forth in the Examples below.
- p-Toluenesulfonyl chloride (21.2 g, 111 mmol) was added to a solution of benzyl (S)-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)carbamate (34 g, 105 mmol) and TEA (20.7 g, 204 mmol) in dry DCM (350 mL) at 0° C. After addition, the cooling bath was removed and the resulting reaction mixture was stirred at room temperature for 16 h. Solvent was evaporated under reduced pressure.
- the obtained residue was acidified with 1N HCl at at 0° C., extracted with ethyl acetate (3 ⁇ 50 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the obtained residue was purified by SFC (Column/dimensions: Chiralcel OJ-H (250 ⁇ 4.6 mm), 5 m; % CO 2 : 60.0; % Co-solvent: 40.0 (100% Methanol); Total Flow: 70.0 g/min; Back Pressure: 100.0 bar; UV: 228 nm; Stack time: 6.5 min; Load/Inj: 11 mg; Solubility: Methanol; Total No of injections: 25; Instrument details: Make/Model: Thar SFC-80) to afford 42 mg (18% yield) of (E)-3-(3-((1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[
- 1,1-Dibromo-2,2-bis(chloromethyl)cyclopropane 25 g, 84 mmol was dissolved in anhydrous n-Bu 2 O (30 mL) at room temperature. The resulting solution was cooled to ⁇ 78° C. (dry ice/acetone cooling bath) and PhLi (100 ml, 168 mmol, 1.7M solution in n-Bu 2 O) was added dropwise. The reaction mixture was stirred at ⁇ 78° C. for 5 minutes and then warmed to 0° C. for 2 h. The white-yellow suspension of tricyclo[1.1.1.0 1,3 ]pentane 11-3 in n-Bu 2 O was allowed to warm to room temperature and stirred for a few minutes.
- the reaction mixture was vigorously stirred at 60° C. for 16 hours.
- the heterogeneous solution was poured into a saturated aqueous solution of NH 4 Cl (200 mL) at 0° C.
- the sealed tube was washed carefully with ethyl acetate and water.
- the mixture was transferred to a separatory funnel and the layers were separated.
- the aqueous layers were washed with ethyl acetate (2 ⁇ 250 mL). All of the organic layers were combined, dried over sodium sulfate and concentrated under vacuum.
- the resultant material was dissolved in toluene (1 mL) which was pre-heated to 90° C. Hexane, pre-heated to 70° C., was slowly added. The mixture was cooled to rt and then stored at 4° C. for 12 h.
- the residue was treated with an aqueous solution of hydrogen chloride (1N) at 0° C. to adjust pH to 6.
- the aqueous layer was extracted with diethyl ether (2 ⁇ 10 mL) and the combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated.
- the crude product was further purified by SFC [Column/dimensions: Chiralcel OD-H (250 ⁇ 30 mm), 5 m silica; % CO 2 : 70.0%; % Co-solvent (MeOH): 30.0%; Total Flow: 100.0 g/min; Back Pressure: 100.0 bar; UV: 212 nm; Stack time: 5.80 min; Load/Inj 5.2 mg; Solubility: Methanol; Total No of injections: 130; Instrument details (Make/Model): Thar SFC-200-005]; to afford (E)-3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (220 mg, 0.47 mmol, 37% yield) as an off white solid
- Ethylmagnesium bromide (44 mL, 134.5 mmol, 3.0M solution in Et 2 O) was added dropwise at 0° C. to a solution of 6-(benzyloxy)-1H-indole (10 g, 44.8 mmol) over a period of 1 h in DCM (100 mL) under an atmosphere of argon.
- the resultant reaction mixture was warmed to room temperature and stirred for an additional 1 h.
- the above reaction mixture was cooled to 0° C.
- the resulting residue was acidified with a aqueous solution of citric acid (1M) at 0° C. to carefully adjust pH to 5.
- the precipitate that formed was dissolved in EtOAc.
- the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated.
- the resulting solid was dissolved in DMSO (1 mL) and purified by reversed-phase HPLC, using 10-60% acetonitrile (contains 0.1% formic acid) in water (contains 0.1% formic acid).
- Ethylmagnesium bromide (30.5 mL, 91.7 mmol, 3.0M solution in Et 2 O) was added dropwise to a solution of 5-fluoro-1H-indole (4.13 g, 44.8 mmol) in DCM (100 mL) at 0° C. over a period of 0.5 h under an atmosphere of argon. After being stirred at rt for 1 h, the reaction mixture was cooled to 0° C. and treated with a solution of (9H-fluoren-9-yl)methyl 1-chloro-1-oxopropan-2-ylcarbamate (15 g, 45.59 mmol) in DCM (100 mL) under an atmosphere of argon.
- MCF7 was expanded and maintained in the medium (Phenol red free DMEM/F12 (Hyclone SH30272.01) NEAA (Gibco11140-050) Na-pyruvate (Gibco 11360-070) and Re-stripped Charcoal stripped FBS (Gemini 100-119)).
- the cells were adjusted to a concentration of 3,000 cells per mL in the above media, and the cells were incubated (37° C., 5% CO 2 ). The following day a 10 point, serial dilution of compounds was added to the cells at a final concentration ranging from 10-0.000005 ⁇ M for test compounds (17-estradiol was used as a control).
- MCF-7 cells are plated at 0.3 million cells/mL (3 mL/well) in 6-well plates in experiment media and incubated at 37° C., 5% CO2 for 48 hours. Next day, 10 ⁇ solution of compounds are made in DMSO and added the solution to the cells to achieve a final concentration of 10 ⁇ M.
- a DMSO control is included to enable a determination of the relative efficacy of test compounds. Fulvestrant is used as a positive control for ER-alpha degradation, and 4-OH tamoxifen as a control for receptor stabilization.
- cell lysates are prepared (2 ⁇ Cell lysis buffer: 100 mM Tris, pH 8, 300 mM NaCl, 2% NP40, 1% Na deoxycholate, 0.04% SDS, 2 mM EDTA) and mixed thoroughly and incubated on ice. The protein concentration is quantified using BCA kit. Protein was separated on 4%-20% NuPAGE Novex 4-12% Bis-Tris Protein Gels using 1 ⁇ MES running buffer. The gel was then transferred onto a nitrocellulose membrane. The blots were probed with antibodies against ESR1 protein (Santa Cruz, sc-8005). GAPDH protein was used as an internal control.
- MCF-7 cells are plated at 0.3 million cells/mL (3 mL/well) in 6-well plates in experiment media and incubated at 37° C., 5% CO2 for 48 hours. Next day, 10 mM solution of compounds are made in DMSO and added the solution to the cells to achieve a final concentration of 10 ⁇ M. For EC 50 determination, MCF-7 cells were incubated with 3 ⁇ or 5 ⁇ serial dilutions of 10 mM compounds, final concentration of the compounds was from 10 ⁇ M to designed concentrations based on the potency of the compounds. A DMSO control is included to enable a determination of the relative efficacy of test compounds.
- Fulvestrant is used as a positive control for ER-alpha degradation, and 4-OH tamoxifen as a control for receptor stabilization.
- cell lysates are prepared (2 ⁇ Cell lysis buffer: 100 mM Tris, pH 8, 300 mM NaCl, 2% NP40, 1% Na deoxycholate, 0.04% SDS, 2 mM EDTA) and mixed thoroughly and incubated on ice.
- the protein concentration is quantified using BCA kit. Protein was separated on 4%-20% NuPAGE Novex 4-12% Bis-Tris Protein Gels using 1 ⁇ MES running buffer. The gel was then transferred onto a nitrocellulose membrane.
- the blots were probed with antibodies against ESR1 protein (Santa Cruz, sc-8005). GAPDH protein was used as an internal control.
- the blots were imaged on Azure C600 Imager and Band density of the western blots was quantified with Azurespot software. EC 50 is calculated with GraphpadPrism.
- the formulation for IV groups is DMSO/PEG400/150 mM glycine (pH 9) (5/10/85) and the formulation for PO groups is PEG400/PVP/Tween 80/0.5% CMC in water (9/0.5/0.5/90).
- blood samples of intravenous injection group were collected at time points of predose, 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h; blood samples of oral group were collected at time points of predose, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h.
- Standard curve was plotted based on concentrations of the samples in a suitable range, the concentrations of test compounds in plasma samples were determined by using LC-MS/MS.
- Pharmacokinetic parameters were calculated according to drug concentration-time curve using a noncompartmental method by WinNonLin (PhoenixTM, version 6.1) or other similar software.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US20230042653A1 (en) * | 2019-12-20 | 2023-02-09 | Recurium Ip Holdings, Llc | Combinations |
BR112022012266A2 (pt) * | 2019-12-20 | 2022-08-30 | Recurium Ip Holdings Llc | Combinações |
WO2021127042A1 (en) * | 2019-12-20 | 2021-06-24 | Recurium Ip Holdings, Llc | Combinations |
CA3165479A1 (en) * | 2019-12-20 | 2021-06-24 | Recurium Ip Holdings, Llc | Combinations |
CA3179331A1 (en) * | 2020-04-22 | 2021-10-28 | Recurium Ip Holdings, Llc | Preparation of an selective estrogen receptor degrader |
WO2021253380A1 (en) * | 2020-06-19 | 2021-12-23 | InventisBio Co., Ltd. | Oral formulations and uses thereof |
WO2022061242A1 (en) * | 2020-09-20 | 2022-03-24 | Tactogen Inc | Advantageous tryptamine compositions for mental disorders or enhancement |
WO2022133446A1 (en) * | 2020-12-16 | 2022-06-23 | Recurium Ip Holdings, Llc | Combinations |
JP2024502270A (ja) | 2020-12-23 | 2024-01-18 | リキュリウム アイピー ホールディングス リミテッド ライアビリティー カンパニー | エストロゲン受容体調節薬 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017136688A1 (en) * | 2016-02-05 | 2017-08-10 | Inventisbio Inc. | Selective estrogen receptor degraders and uses thereof |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0749313A4 (en) | 1994-03-11 | 2001-10-24 | Lilly Co Eli | METHOD OF TREATING CONDITIONS ASSOCIATED WITH THE 5HT 2B RECEPTOR |
GB9604996D0 (en) | 1996-03-08 | 1996-05-08 | Black James Foundation | Benzodiazonine derivatives |
EP1113007A1 (en) * | 1999-12-24 | 2001-07-04 | Pfizer Inc. | Tetrahydroisoquinoline compounds as estrogen agonists/antagonists |
ATE348828T1 (de) | 2001-10-19 | 2007-01-15 | Transtech Pharma Inc | Beta-carbolin-derivate als ptp-inhibitoren |
US8076352B2 (en) * | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
US20080103164A1 (en) | 2004-08-02 | 2008-05-01 | Kristjan Gudmundsson | Useful compounds for hpv infection |
WO2007002051A1 (en) | 2005-06-22 | 2007-01-04 | Smithkline Beecham Corporation | Carboline derivatives and their use as inhibitors of flaviviridae infections |
CA2656067C (en) | 2006-06-23 | 2014-08-12 | Radius Health, Inc. | Treatment of vasomotor symptoms with selective estrogen receptor modulators |
WO2008127714A1 (en) | 2007-04-13 | 2008-10-23 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
DE102007028515A1 (de) | 2007-06-21 | 2008-12-24 | Merck Patent Gmbh | 6-(Pyrrolopyridinyl)-pyrimidinyl-2-amin-derivate |
TW201028414A (en) * | 2009-01-16 | 2010-08-01 | Merck Sharp & Dohme | Oxadiazole beta carboline derivatives as antidiabetic compounds |
US20120135089A1 (en) | 2009-03-17 | 2012-05-31 | Stockwell Brent R | E3 ligase inhibitors |
US20120202801A1 (en) * | 2009-05-27 | 2012-08-09 | Liangxian Cao | Methods for treating breast cancer |
PT2434891T (pt) * | 2009-05-27 | 2020-10-23 | Ptc Therapeutics Inc | Métodos para tratamento de cancro e afeções não neoplásicas |
PL2460801T3 (pl) * | 2009-07-28 | 2014-11-28 | Ono Pharmaceutical Co | Związek bicykliczny i jego zastosowanie do celów medycznych |
WO2011088025A1 (en) | 2010-01-15 | 2011-07-21 | Merck Sharp & Dohme Corp. | Oxadiazole beta carboline derivatives as antidiabetic compounds |
TWI577665B (zh) * | 2010-02-11 | 2017-04-11 | 必治妥美雅史谷比公司 | 作為因子xia抑制劑之巨環類 |
US20130172320A1 (en) | 2010-02-18 | 2013-07-04 | Sarvajit Chakravarty | Pyrido [4,3-b] indole and pyrido [3,4-b] indole derivatives and methods of use |
CA2800673A1 (en) | 2010-06-10 | 2011-12-15 | Aragon Pharmaceuticals, Inc. | Estrogen receptor modulators and uses thereof |
JP5835236B2 (ja) * | 2011-01-27 | 2015-12-24 | 小野薬品工業株式会社 | 二環式化合物およびその医薬用途 |
CN102432608B (zh) | 2011-11-01 | 2013-04-17 | 浙江大学 | 手性螺环磷酸催化合成光学活性四氢-β-咔啉衍生物的方法 |
WO2013090836A1 (en) | 2011-12-14 | 2013-06-20 | Aragon Pharmaceuticals, Inc. | Fluorinated estrogen receptor modulators and uses thereof |
RS56616B1 (sr) * | 2011-12-31 | 2018-02-28 | Beigene Ltd | Kondenzovani tetra ili penta-ciklični dihidrodiazepinokarbazoloni kao parp inhibitori |
BR112014019426A8 (pt) * | 2012-02-07 | 2017-07-11 | Eolas Therapeutics Inc | Prolinas/ piperidinas substituídas como antagonistas do receptor de orexina |
EA201491530A1 (ru) | 2012-03-20 | 2015-07-30 | Серагон Фармасьютикалс, Инк. | Модуляторы рецепторов эстрогенов и их применение |
PT2872482T (pt) | 2012-07-13 | 2020-09-22 | Oncternal Therapeutics Inc | Método de tratamento de cancro de mama com modulador seletivo do recetor de andrógeno (sarm) |
CA2899030C (en) | 2013-02-19 | 2021-03-09 | Novartis Ag | Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders |
CA2899969A1 (en) | 2013-03-14 | 2014-09-25 | Seragon Pharmaceuticals, Inc. | Polycyclic estrogen receptor modulators and uses thereof |
CN105229004B (zh) * | 2013-05-28 | 2017-05-03 | 阿斯利康(瑞典)有限公司 | 化合物 |
CA2932106A1 (en) | 2013-12-06 | 2015-06-11 | F. Hoffmann-La Roche Ag | Estrogen receptor modulator for the treatment of locally advanced or metastatic estrogen receptor positive breast cancer |
CN104693211A (zh) | 2013-12-10 | 2015-06-10 | 南京明德新药研发股份有限公司 | 作为抗病毒剂的咪唑衍生物及其制药用途 |
TW201613891A (en) * | 2014-02-12 | 2016-04-16 | Eolas Therapeutics Inc | Substituted prolines / piperidines as orexin receptor antagonists |
US9695166B2 (en) * | 2014-05-05 | 2017-07-04 | Global Blood Therapeutics, Inc. | Pyrazolopyridine pyrazolopyrimidine and related compounds |
JP2017515906A (ja) | 2014-05-16 | 2017-06-15 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | 抗菌性キナゾロン−4(3h)−オン誘導体 |
AU2015279047B2 (en) | 2014-06-27 | 2020-01-02 | Nogra Pharma Limited | Aryl receptor modulators and methods of making and using the same |
MX2017004655A (es) | 2014-10-09 | 2018-03-27 | Guangdong Zhongsheng Pharmaceutical Co Ltd | Compuestos de hidroxil purinas y aplicaciones de estos. |
US10654809B2 (en) | 2016-06-10 | 2020-05-19 | University Of Tennessee Research Foundation | Selective androgen receptor degrader (SARD) ligands and methods of use thereof |
WO2016172358A1 (en) | 2015-04-21 | 2016-10-27 | Gtx, Inc. | Selective androgen receptor degrader (sard) ligands and methods of use thereof |
CN107406457B (zh) * | 2015-06-16 | 2019-02-01 | 江苏恒瑞医药股份有限公司 | 哌啶类衍生物、其制备方法及其在医药上的应用 |
WO2017080338A1 (zh) | 2015-11-12 | 2017-05-18 | 浙江海正药业股份有限公司 | 丙烯酸类衍生物、其制备方法及其在医药上的用途 |
WO2017172957A1 (en) | 2016-04-01 | 2017-10-05 | Kalyra Pharmaceuticals, Inc. | Estrogen receptor modulators |
BR112018075347A2 (pt) | 2016-06-10 | 2019-03-19 | University Of Tennessee Research Foundation | ligantes de degradadores de receptor androgênico seletivos (sard) e métodos de uso dos mesmos |
WO2018001232A1 (zh) * | 2016-06-29 | 2018-01-04 | 浙江海正药业股份有限公司 | 丙烯酸类衍生物及其制备方法和其在医药上的用途 |
WO2018065501A1 (en) * | 2016-10-05 | 2018-04-12 | F. Hoffmann-La Roche Ag | Methods for preparing antibody drug conjugates |
WO2018130124A1 (zh) | 2017-01-11 | 2018-07-19 | 南京圣和药业股份有限公司 | 作为选择性雌激素受体下调剂的三环类化合物及其应用 |
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WO2023283329A1 (en) * | 2021-07-08 | 2023-01-12 | Olema Pharmaceuticals, Inc. | Methods of treating estrogen receptor-associated diseases |
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