JP2020504089A5

JP2020504089A5 -

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Publication number: JP2020504089A5
Authority: JP; Japan
Prior art keywords: optionally substituted; alkyl; group; substituted; formula
Prior art date: 2017-12-01
Legal status : Granted

Application number

JP2019529568A

Other languages

English (en)

Japanese (ja)

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JP2020504089A (ja

JP6957620B2 (ja

Filing date

2017-12-01

Publication date

2020-08-27

2017-12-01 Application filed filed Critical

2017-12-01 Priority claimed from PCT/US2017/064283 external-priority patent/WO2018102725A1/en

2020-02-06 Publication of JP2020504089A publication Critical patent/JP2020504089A/ja

2020-02-28 Priority to JP2020033150A priority Critical patent/JP6972211B2/ja

2020-08-27 Publication of JP2020504089A5 publication Critical patent/JP2020504089A5/ja

2021-11-02 Application granted granted Critical

2021-11-02 Publication of JP6957620B2 publication Critical patent/JP6957620B2/ja

Status Active legal-status Critical Current

2037-12-01 Anticipated expiration legal-status Critical

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125000000217 alkyl group Chemical group 0.000 claims description 308
-1 methoxy, ethoxy Chemical group 0.000 claims description 228
150000001875 compounds Chemical class 0.000 claims description 221
125000003118 aryl group Chemical group 0.000 claims description 220
125000001072 heteroaryl group Chemical group 0.000 claims description 212
125000005647 linker group Chemical group 0.000 claims description 188
125000005843 halogen group Chemical group 0.000 claims description 160
229910052739 hydrogen Inorganic materials 0.000 claims description 137
229910005965 SO 2 Inorganic materials 0.000 claims description 135
125000000623 heterocyclic group Chemical group 0.000 claims description 126
125000000547 substituted alkyl group Chemical group 0.000 claims description 123
229910052799 carbon Inorganic materials 0.000 claims description 117
125000000753 cycloalkyl group Chemical group 0.000 claims description 109
229910052736 halogen Inorganic materials 0.000 claims description 109
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 101
150000002367 halogens Chemical class 0.000 claims description 96
229910052760 oxygen Inorganic materials 0.000 claims description 87
125000001424 substituent group Chemical group 0.000 claims description 86
239000000126 substance Substances 0.000 claims description 85
102000006275 Ubiquitin-Protein Ligases Human genes 0.000 claims description 80
108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims description 80
230000027455 binding Effects 0.000 claims description 80
229910052731 fluorine Inorganic materials 0.000 claims description 79
229910052717 sulfur Inorganic materials 0.000 claims description 75
229910052757 nitrogen Inorganic materials 0.000 claims description 70
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 66
229910052801 chlorine Inorganic materials 0.000 claims description 63
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 60
125000003107 substituted aryl group Chemical group 0.000 claims description 58
230000001588 bifunctional effect Effects 0.000 claims description 55
125000003545 alkoxy group Chemical group 0.000 claims description 53
239000001257 hydrogen Substances 0.000 claims description 49
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 47
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 46
125000005842 heteroatom Chemical group 0.000 claims description 46
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
239000000203 mixture Substances 0.000 claims description 43
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 42
125000004093 cyano group Chemical group *C#N 0.000 claims description 41
125000004429 atom Chemical group 0.000 claims description 38
102000015694 estrogen receptors Human genes 0.000 claims description 37
108010038795 estrogen receptors Proteins 0.000 claims description 37
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 34
125000003710 aryl alkyl group Chemical group 0.000 claims description 34
125000001188 haloalkyl group Chemical group 0.000 claims description 34
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 32
201000010099 disease Diseases 0.000 claims description 32
230000004481 post-translational protein modification Effects 0.000 claims description 31
102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 30
229910020008 S(O) Inorganic materials 0.000 claims description 30
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
150000003839 salts Chemical class 0.000 claims description 28
238000000034 method Methods 0.000 claims description 27
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 26
150000003384 small molecules Chemical class 0.000 claims description 26
238000006467 substitution reaction Methods 0.000 claims description 25
125000004122 cyclic group Chemical group 0.000 claims description 22
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 19
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 17
150000001413 amino acids Chemical group 0.000 claims description 16
125000004432 carbon atom Chemical group C* 0.000 claims description 16
125000005415 substituted alkoxy group Chemical group 0.000 claims description 16
125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 15
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
125000002619 bicyclic group Chemical group 0.000 claims description 14
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
239000011737 fluorine Substances 0.000 claims description 14
239000012453 solvate Substances 0.000 claims description 14
125000004438 haloalkoxy group Chemical group 0.000 claims description 13
206010028980 Neoplasm Diseases 0.000 claims description 12
208000035475 disorder Diseases 0.000 claims description 12
229910052794 bromium Inorganic materials 0.000 claims description 11
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
206010006187 Breast cancer Diseases 0.000 claims description 10
208000026310 Breast neoplasm Diseases 0.000 claims description 10
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
201000011510 cancer Diseases 0.000 claims description 10
150000001721 carbon Chemical group 0.000 claims description 10
229940024606 amino acid Drugs 0.000 claims description 9
235000001014 amino acid Nutrition 0.000 claims description 9
239000012634 fragment Substances 0.000 claims description 9
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
239000003937 drug carrier Substances 0.000 claims description 8
125000000524 functional group Chemical group 0.000 claims description 8
229910052740 iodine Inorganic materials 0.000 claims description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
230000018883 protein targeting Effects 0.000 claims description 8
230000000707 stereoselective effect Effects 0.000 claims description 8
239000012867 bioactive agent Substances 0.000 claims description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
230000014509 gene expression Effects 0.000 claims description 7
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125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
229940002612 prodrug Drugs 0.000 claims description 6
239000000651 prodrug Substances 0.000 claims description 6
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 5
150000001204 N-oxides Chemical class 0.000 claims description 5
208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 5
125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
125000001309 chloro group Chemical group Cl* 0.000 claims description 5
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 5
150000003235 pyrrolidines Chemical class 0.000 claims description 5
208000024891 symptom Diseases 0.000 claims description 5
206010046766 uterine cancer Diseases 0.000 claims description 5
UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 4
OPYRETPBRCRXQU-UHFFFAOYSA-N 4,6-dihydro-1h-pyrrolo[3,2-b]pyrrol-5-one Chemical class N1C=CC2=C1CC(=O)N2 OPYRETPBRCRXQU-UHFFFAOYSA-N 0.000 claims description 4
GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical class C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 4
150000002462 imidazolines Chemical class 0.000 claims description 4
229960000310 isoleucine Drugs 0.000 claims description 4
VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 4
229960004942 lenalidomide Drugs 0.000 claims description 4
GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 4
229960000688 pomalidomide Drugs 0.000 claims description 4
UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 4
150000004944 pyrrolopyrimidines Chemical class 0.000 claims description 4
229960003433 thalidomide Drugs 0.000 claims description 4
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 3
KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 3
101150051118 PTM1 gene Proteins 0.000 claims description 3
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
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235000004279 alanine Nutrition 0.000 claims description 3
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
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239000002246 antineoplastic agent Substances 0.000 claims description 2
229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
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238000009825 accumulation Methods 0.000 claims 2
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JP2019529568A 2016-12-01 2017-12-01 エストロゲン受容体分解物質としてのテトラヒドロナフタレン誘導体およびテトラヒドロイソキノリン誘導体 Active JP6957620B2 (ja)