WO2024109660A1 - Inhibiteurs de cdk - Google Patents
Inhibiteurs de cdk Download PDFInfo
- Publication number
- WO2024109660A1 WO2024109660A1 PCT/CN2023/132400 CN2023132400W WO2024109660A1 WO 2024109660 A1 WO2024109660 A1 WO 2024109660A1 CN 2023132400 W CN2023132400 W CN 2023132400W WO 2024109660 A1 WO2024109660 A1 WO 2024109660A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mmol
- pharmaceutically acceptable
- phenyl
- pyrazol
- compound
- Prior art date
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- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 claims abstract description 28
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 claims abstract description 28
- 102100033145 Cyclin-dependent kinase 19 Human genes 0.000 claims abstract description 17
- 101000944345 Homo sapiens Cyclin-dependent kinase 19 Proteins 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 51
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 35
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 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 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
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- 239000003814 drug Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
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- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 6
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- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
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- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
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- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
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- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- DYFFAVRFJWYYQO-UHFFFAOYSA-N n-methyl-n-phenylaniline Chemical compound C=1C=CC=CC=1N(C)C1=CC=CC=C1 DYFFAVRFJWYYQO-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- LZCVVMQABORALM-UHFFFAOYSA-N spiro[2.5]octyl Chemical group [CH]1CC11CCCCC1 LZCVVMQABORALM-UHFFFAOYSA-N 0.000 description 1
- GAJDDVONBAWAGB-UHFFFAOYSA-N spiro[2.6]nonyl Chemical group [CH]1CC11CCCCCC1 GAJDDVONBAWAGB-UHFFFAOYSA-N 0.000 description 1
- LMUMMJCCZMWLEN-UHFFFAOYSA-N spiro[3.3]heptyl Chemical group [CH]1CCC11CCC1 LMUMMJCCZMWLEN-UHFFFAOYSA-N 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une nouvelle classe de composés qui agissent en tant qu'inhibiteurs sélectifs de CDK8/CDK19, des compositions pharmaceutiques comprenant les composés, des intermédiaires utiles pour la préparation des composés, et des méthodes de traitement de maladies prolifératives cellulaires, telles que le cancer, à l'aide des composés de la présente invention. Les composés ont des structures telles que représentées dans la formule (I).
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211453864 | 2022-11-21 | ||
CN202211453864.X | 2022-11-21 | ||
CN202310553978 | 2023-05-16 | ||
CN202310553978.X | 2023-05-16 | ||
CN202310802087.3 | 2023-06-30 | ||
CN202310802087 | 2023-06-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024109660A1 true WO2024109660A1 (fr) | 2024-05-30 |
Family
ID=91195179
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/132400 WO2024109660A1 (fr) | 2022-11-21 | 2023-11-17 | Inhibiteurs de cdk |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024109660A1 (fr) |
-
2023
- 2023-11-17 WO PCT/CN2023/132400 patent/WO2024109660A1/fr unknown
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