JP2020505327A5

JP2020505327A5 -

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Publication number: JP2020505327A5
Authority: JP; Japan
Prior art keywords: alkyl; substituted; optionally substituted; group; formula
Prior art date: 2017-12-22
Legal status : Pending

Application number

JP2019534368A

Other languages

English (en)

Japanese (ja)

Other versions

JP2020505327A (ja

Filing date

2017-12-22

Publication date

2021-02-04

2017-12-22 Application filed filed Critical

2017-12-22 Priority claimed from PCT/US2017/068308 external-priority patent/WO2018119441A1/en

2020-02-20 Publication of JP2020505327A publication Critical patent/JP2020505327A/ja

2021-02-04 Publication of JP2020505327A5 publication Critical patent/JP2020505327A5/ja

Status Pending legal-status Critical Current

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125000000217 alkyl group Chemical group 0.000 claims description 296
125000003118 aryl group Chemical group 0.000 claims description 251
125000001072 heteroaryl group Chemical group 0.000 claims description 246
125000005647 linker group Chemical group 0.000 claims description 188
150000001875 compounds Chemical class 0.000 claims description 187
229910052739 hydrogen Inorganic materials 0.000 claims description 169
-1 -C (= O) R Chemical group 0.000 claims description 158
125000000623 heterocyclic group Chemical group 0.000 claims description 125
229910052799 carbon Inorganic materials 0.000 claims description 121
125000000753 cycloalkyl group Chemical group 0.000 claims description 114
125000000547 substituted alkyl group Chemical group 0.000 claims description 111
229910052760 oxygen Inorganic materials 0.000 claims description 106
229910052717 sulfur Inorganic materials 0.000 claims description 97
229910052757 nitrogen Inorganic materials 0.000 claims description 94
239000000126 substance Substances 0.000 claims description 90
229910052731 fluorine Inorganic materials 0.000 claims description 82
229910052801 chlorine Inorganic materials 0.000 claims description 69
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
125000000524 functional group Chemical group 0.000 claims description 10
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
230000000707 stereoselective effect Effects 0.000 claims description 8
150000001204 N-oxides Chemical class 0.000 claims description 3
125000005843 halogen group Chemical group 0.000 description 140
229910052736 halogen Inorganic materials 0.000 description 123
150000002367 halogens Chemical class 0.000 description 118
108090000623 proteins and genes Proteins 0.000 description 118
102000004169 proteins and genes Human genes 0.000 description 117
125000001424 substituent group Chemical group 0.000 description 112
125000002887 hydroxy group Chemical group [H]O* 0.000 description 106
230000027455 binding Effects 0.000 description 99
235000018102 proteins Nutrition 0.000 description 76
125000005842 heteroatom Chemical group 0.000 description 72
239000000460 chlorine Substances 0.000 description 71
102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 70
108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 70
108091007065 BIRCs Proteins 0.000 description 66
102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 description 66
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 65
125000003545 alkoxy group Chemical group 0.000 description 64
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 63
108020005497 Nuclear hormone receptor Proteins 0.000 description 62
125000001188 haloalkyl group Chemical group 0.000 description 61
125000004093 cyano group Chemical group *C#N 0.000 description 60
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 60
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 59
210000004027 cell Anatomy 0.000 description 55
125000003107 substituted aryl group Chemical group 0.000 description 54
102000001301 EGF receptor Human genes 0.000 description 52
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 52
239000001257 hydrogen Substances 0.000 description 52
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 51
125000000592 heterocycloalkyl group Chemical group 0.000 description 51
229920006395 saturated elastomer Polymers 0.000 description 51
108060006698 EGF receptor Proteins 0.000 description 50
239000003446 ligand Substances 0.000 description 47
125000005346 substituted cycloalkyl group Chemical group 0.000 description 47
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 43
102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 43
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 43
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 43
125000003710 aryl alkyl group Chemical group 0.000 description 41
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
125000004435 hydrogen atom Chemical group [H]* 0.000 description 40
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 39
230000015556 catabolic process Effects 0.000 description 38
238000006731 degradation reaction Methods 0.000 description 38
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 37
UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 36
125000004429 atom Chemical group 0.000 description 35
125000004169 (C1-C6) alkyl group Chemical group 0.000 description 34
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 34
210000005261 ventrolateral medulla Anatomy 0.000 description 32
125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 31
230000001588 bifunctional effect Effects 0.000 description 30
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 29
102000027426 receptor tyrosine kinases Human genes 0.000 description 29
108091008598 receptor tyrosine kinases Proteins 0.000 description 29
125000006273 (C1-C3) alkyl group Chemical group 0.000 description 28
239000000203 mixture Substances 0.000 description 27
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 26
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 25
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 25
238000006467 substitution reaction Methods 0.000 description 25
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 24
150000003384 small molecules Chemical class 0.000 description 24
VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 23
238000000034 method Methods 0.000 description 23
230000003278 mimic effect Effects 0.000 description 23
150000003839 salts Chemical group 0.000 description 23
238000011282 treatment Methods 0.000 description 20
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 19
125000004446 heteroarylalkyl group Chemical group 0.000 description 19
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 17
125000000304 alkynyl group Chemical group 0.000 description 17
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
125000001153 fluoro group Chemical group F* 0.000 description 17
PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 description 16
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
150000001412 amines Chemical class 0.000 description 16
125000004122 cyclic group Chemical group 0.000 description 16
125000001316 cycloalkyl alkyl group Chemical group 0.000 description 16
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
235000019000 fluorine Nutrition 0.000 description 16
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 15
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 15
102000044159 Ubiquitin Human genes 0.000 description 15
108090000848 Ubiquitin Proteins 0.000 description 15
125000003282 alkyl amino group Chemical group 0.000 description 15
150000001408 amides Chemical class 0.000 description 15
125000004432 carbon atom Chemical group C* 0.000 description 15
230000000694 effects Effects 0.000 description 15
239000011737 fluorine Substances 0.000 description 15
125000001624 naphthyl group Chemical group 0.000 description 15
125000004433 nitrogen atom Chemical group N* 0.000 description 15
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 15
102100023102 Solute carrier family 22 member 18 Human genes 0.000 description 14
125000003342 alkenyl group Chemical group 0.000 description 14
125000002947 alkylene group Chemical group 0.000 description 14
125000004663 dialkyl amino group Chemical group 0.000 description 14
108090000765 processed proteins & peptides Proteins 0.000 description 14
125000005415 substituted alkoxy group Chemical group 0.000 description 14
230000034512 ubiquitination Effects 0.000 description 14
238000010798 ubiquitination Methods 0.000 description 14
239000002136 L01XE07 - Lapatinib Substances 0.000 description 13
206010028980 Neoplasm Diseases 0.000 description 13
102100032783 Protein cereblon Human genes 0.000 description 13
150000001413 amino acids Chemical class 0.000 description 13
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 13
ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 13
CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 13
229960004891 lapatinib Drugs 0.000 description 13
125000002950 monocyclic group Chemical group 0.000 description 13
102000004196 processed proteins & peptides Human genes 0.000 description 13
125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 12
125000006747 (C2-C10) heterocycloalkyl group Chemical group 0.000 description 12
229940083346 IAP antagonist Drugs 0.000 description 12
125000002619 bicyclic group Chemical group 0.000 description 12
150000001721 carbon Chemical group 0.000 description 12
YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 12
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 12
201000010099 disease Diseases 0.000 description 12
239000012453 solvate Substances 0.000 description 12
239000000758 substrate Substances 0.000 description 12
150000003852 triazoles Chemical class 0.000 description 12
102000003745 Hepatocyte Growth Factor Human genes 0.000 description 11
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125000002768 hydroxyalkyl group Chemical group 0.000 description 11
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125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
150000002916 oxazoles Chemical class 0.000 description 11
229920001184 polypeptide Polymers 0.000 description 11
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 10
230000004913 activation Effects 0.000 description 10
RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 10
201000011510 cancer Diseases 0.000 description 10
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 10
238000002474 experimental method Methods 0.000 description 10
238000003119 immunoblot Methods 0.000 description 10
125000000468 ketone group Chemical group 0.000 description 10
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
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JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 9
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101000941994 Homo sapiens Protein cereblon Proteins 0.000 description 9
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229910052794 bromium Inorganic materials 0.000 description 9
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CSKSDAVTCKIENY-UHFFFAOYSA-N hydron;pyrrolidine-2-carboxamide;chloride Chemical compound Cl.NC(=O)C1CCCN1 CSKSDAVTCKIENY-UHFFFAOYSA-N 0.000 description 8
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125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 description 7
LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 7
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QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
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PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 7
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YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
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NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
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125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 4
BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 4
HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical class C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 4
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JP2019534368A 2016-12-23 2017-12-22 Ｅｇｆｒタンパク質分解標的化キメラ分子およびその関連する使用方法 Pending JP2020505327A (ja)