JP2020506914A5 - - Google Patents

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Publication number

JP2020506914A5

JP2020506914A5 JP2019540457A JP2019540457A JP2020506914A5 JP 2020506914 A5 JP2020506914 A5 JP 2020506914A5 JP 2019540457 A JP2019540457 A JP 2019540457A JP 2019540457 A JP2019540457 A JP 2019540457A JP 2020506914 A5 JP2020506914 A5 JP 2020506914A5

Authority

JP

Japan

Prior art keywords

alkyl

optionally substituted

group

substituted

ulm

Prior art date

2018-01-26

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Granted

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• 125000000217 alkyl group Chemical group 0.000 claims description 318
• 150000001875 compounds Chemical class 0.000 claims description 229
• 125000003118 aryl group Chemical group 0.000 claims description 215
• 125000001072 heteroaryl group Chemical group 0.000 claims description 213
• 125000005647 linker group Chemical group 0.000 claims description 175
• 229910052739 hydrogen Inorganic materials 0.000 claims description 166
• 125000005843 halogen group Chemical group 0.000 claims description 155
• -1 substituted Chemical class 0.000 claims description 153
• 229910052799 carbon Inorganic materials 0.000 claims description 129
• 125000000623 heterocyclic group Chemical group 0.000 claims description 124
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 124
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 106
• 229910052736 halogen Inorganic materials 0.000 claims description 106
• 230000027455 binding Effects 0.000 claims description 104
• 150000002367 halogens Chemical class 0.000 claims description 100
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 100
• 229910052760 oxygen Inorganic materials 0.000 claims description 94
• 125000001424 substituent group Chemical group 0.000 claims description 88
• 239000000126 substance Substances 0.000 claims description 85
• 229910052731 fluorine Inorganic materials 0.000 claims description 80
• 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 claims description 79
• 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims description 79
• 229910052717 sulfur Inorganic materials 0.000 claims description 79
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 71
• 229910052757 nitrogen Inorganic materials 0.000 claims description 69
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
• 230000001588 bifunctional effect Effects 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 61
• 125000003107 substituted aryl group Chemical group 0.000 claims description 59
• 125000003545 alkoxy group Chemical group 0.000 claims description 50
• 125000005842 heteroatom Chemical group 0.000 claims description 48
• 239000001257 hydrogen Substances 0.000 claims description 48
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 48
• 108010038795 estrogen receptors Proteins 0.000 claims description 46
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 45
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 40
• 125000004429 atom Chemical group 0.000 claims description 39
• 239000000203 mixture Substances 0.000 claims description 39
• 150000003839 salts Chemical class 0.000 claims description 39
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
• 125000001188 haloalkyl group Chemical group 0.000 claims description 35
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 34
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 33
• 230000004481 post-translational protein modification Effects 0.000 claims description 31
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 30
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 26
• 201000010099 disease Diseases 0.000 claims description 24
• 238000000034 method Methods 0.000 claims description 24
• 125000004122 cyclic group Chemical group 0.000 claims description 21
• 125000004432 carbon atom Chemical group C* 0.000 claims description 20
• PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 19
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 18
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 17
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• 150000001413 amino acids Chemical group 0.000 claims description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
• 239000011737 fluorine Substances 0.000 claims description 17
• 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
• 101000941994 Homo sapiens Protein cereblon Proteins 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
• 125000002619 bicyclic group Chemical group 0.000 claims description 13
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
• 239000012453 solvate Substances 0.000 claims description 13
• 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
• 208000035475 disorder Diseases 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
• 206010028980 Neoplasm Diseases 0.000 claims description 10
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
• 229910052794 bromium Inorganic materials 0.000 claims description 10
• 125000000524 functional group Chemical group 0.000 claims description 10
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• 208000026310 Breast neoplasm Diseases 0.000 claims description 9
• 229940024606 amino acid Drugs 0.000 claims description 9
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• 239000012634 fragment Substances 0.000 claims description 9
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• 230000000707 stereoselective effect Effects 0.000 claims description 8
• 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 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
• 229910052740 iodine Inorganic materials 0.000 claims description 7
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 7
• 229960003433 thalidomide Drugs 0.000 claims description 7
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 102000015694 estrogen receptors Human genes 0.000 claims description 6
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
• 125000002768 hydroxyalkyl group Chemical group 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
• 208000024891 symptom Diseases 0.000 claims description 6
• 150000001345 alkine derivatives Chemical class 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
• 239000012867 bioactive agent Substances 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
• 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 5
• 229960000688 pomalidomide Drugs 0.000 claims description 5
• 150000003235 pyrrolidines Chemical class 0.000 claims description 5
• GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical class C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 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
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
• 201000009273 Endometriosis Diseases 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
• 150000001204 N-oxides Chemical class 0.000 claims description 3
• ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
• 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
• KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 3
• 230000002776 aggregation Effects 0.000 claims description 3
• 238000004220 aggregation Methods 0.000 claims description 3
• 235000004279 alanine Nutrition 0.000 claims description 3
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
• AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 3
• GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 3
• 229960004942 lenalidomide Drugs 0.000 claims description 3
• VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical class O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 3
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• 125000002723 alicyclic group Chemical group 0.000 claims description 2
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• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
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• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 51
• 229920006395 saturated elastomer Polymers 0.000 description 51
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 48
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