CA3228310A1 - Composes heterocycliques et procedes d'utilisation - Google Patents
Composes heterocycliques et procedes d'utilisation Download PDFInfo
- Publication number
- CA3228310A1 CA3228310A1 CA3228310A CA3228310A CA3228310A1 CA 3228310 A1 CA3228310 A1 CA 3228310A1 CA 3228310 A CA3228310 A CA 3228310A CA 3228310 A CA3228310 A CA 3228310A CA 3228310 A1 CA3228310 A1 CA 3228310A1
- Authority
- CA
- Canada
- Prior art keywords
- fluoro
- methoxy
- pyrido
- pyrrolizin
- fluorotetrahydro
- Prior art date
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 139
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 990
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- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 101
- WHQDPSGUFIHZTE-UHFFFAOYSA-N naphthalen-2-ol Chemical compound C1=CC=CC2=CC(O)=CC=C21.C1=CC=CC2=CC(O)=CC=C21 WHQDPSGUFIHZTE-UHFFFAOYSA-N 0.000 claims description 89
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 77
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
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- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 239000011737 fluorine Chemical group 0.000 claims description 26
- HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 claims description 26
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- 238000002360 preparation method Methods 0.000 claims description 5
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- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- ZGNXATVKGIJQGC-UHFFFAOYSA-N piperidine-3-carbonitrile Chemical compound N#CC1CCCNC1 ZGNXATVKGIJQGC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 4
- 125000000565 sulfonamide group Chemical group 0.000 claims description 4
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
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- 208000011825 carcinoma of the ampulla of vater Diseases 0.000 claims description 3
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
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- HWZXQNQIPMKXJY-UHFFFAOYSA-N azetidine-3-sulfonamide Chemical compound N1CC(C1)S(=O)(=O)N HWZXQNQIPMKXJY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- IOKHVMNITOWKOY-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1.OC1CCCNC1 IOKHVMNITOWKOY-UHFFFAOYSA-N 0.000 claims 10
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- VALZSZJVEFACEZ-UHFFFAOYSA-N azetidine-3-carboxamide Chemical compound NC(=O)C1CNC1 VALZSZJVEFACEZ-UHFFFAOYSA-N 0.000 claims 2
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- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 229950007231 ravoxertinib Drugs 0.000 description 1
- 229950008933 refametinib Drugs 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 229950003687 ribociclib Drugs 0.000 description 1
- BUROJSBIWGDYCN-QHPXJTPRSA-N ridaforolimus Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)\C(C)=C\C=C\C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-QHPXJTPRSA-N 0.000 description 1
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- 229950009216 sapanisertib Drugs 0.000 description 1
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 1
- 229950010746 selumetinib Drugs 0.000 description 1
- 229950008344 serabelisib Drugs 0.000 description 1
- BLGWHBSBBJNKJO-UHFFFAOYSA-N serabelisib Chemical compound C=1C=C2OC(N)=NC2=CC=1C(=CN12)C=CC1=NC=C2C(=O)N1CCOCC1 BLGWHBSBBJNKJO-UHFFFAOYSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229950007865 sonolisib Drugs 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229950001269 taselisib Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- PRAAPINBUWJLGA-UHFFFAOYSA-N telaglenastat Chemical compound FC(F)(F)OC1=CC=CC(CC(=O)NC=2N=NC(CCCCC=3SC(NC(=O)CC=4N=CC=CC=4)=NN=3)=CC=2)=C1 PRAAPINBUWJLGA-UHFFFAOYSA-N 0.000 description 1
- 229940121507 telaglenastat Drugs 0.000 description 1
- 229950008214 tenalisib Drugs 0.000 description 1
- XUNAYZIHVQJKGX-UHFFFAOYSA-N tert-butyl 2,3,6,7-tetrahydroazepine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=CCC1 XUNAYZIHVQJKGX-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- SCSMCZJZQYDACU-SNVBAGLBSA-N tert-butyl-dimethyl-[[(2r)-pyrrolidin-2-yl]methoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1 SCSMCZJZQYDACU-SNVBAGLBSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 229950007123 tislelizumab Drugs 0.000 description 1
- AKCRNFFTGXBONI-UHFFFAOYSA-N torin 1 Chemical compound C1CN(C(=O)CC)CCN1C1=CC=C(N2C(C=CC3=C2C2=CC(=CC=C2N=C3)C=2C=C3C=CC=CC3=NC=2)=O)C=C1C(F)(F)F AKCRNFFTGXBONI-UHFFFAOYSA-N 0.000 description 1
- 229940121514 toripalimab Drugs 0.000 description 1
- 229950000185 tozasertib Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 229950007127 trilaciclib Drugs 0.000 description 1
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229950008878 ulixertinib Drugs 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 229940121344 umbralisib Drugs 0.000 description 1
- 229950005787 uprosertib Drugs 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 201000003701 uterine corpus endometrial carcinoma Diseases 0.000 description 1
- 229950006605 varlitinib Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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- 229950001576 voxtalisib Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
- KIZNQHOVHYLYHY-UHFFFAOYSA-M zinc;prop-1-ene;bromide Chemical compound [Zn+2].[Br-].[CH2-]C=C KIZNQHOVHYLYHY-UHFFFAOYSA-M 0.000 description 1
- CGTADGCBEXYWNE-GTTQIJKGSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](\C(C)=C\C=C\C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-GTTQIJKGSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
La présente invention concerne des composés utiles pour l'inhibition de KRAS G12D. Les composés ont une formule générale (I), les variables de la formule I étant définies dans la description. L'invention concerne également des compositions pharmaceutiques comprenant les composés, des utilisations des composés et des compositions pour traiter par exemple le cancer.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202163231543P | 2021-08-10 | 2021-08-10 | |
| US63/231,543 | 2021-08-10 | ||
| US202163289579P | 2021-12-14 | 2021-12-14 | |
| US63/289,579 | 2021-12-14 | ||
| PCT/US2022/039971 WO2023018812A1 (fr) | 2021-08-10 | 2022-08-10 | Composés hétérocycliques et procédés d'utilisation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3228310A1 true CA3228310A1 (fr) | 2023-02-16 |
Family
ID=85201014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3228310A Pending CA3228310A1 (fr) | 2021-08-10 | 2022-08-10 | Composes heterocycliques et procedes d'utilisation |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU2022325771A1 (fr) |
| CA (1) | CA3228310A1 (fr) |
| TW (1) | TW202330529A (fr) |
| WO (1) | WO2023018812A1 (fr) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023172940A1 (fr) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Méthodes de traitement du cancer du poumon réfractaire immunitaire |
| WO2023213269A1 (fr) * | 2022-05-06 | 2023-11-09 | Zai Lab (Shanghai) Co., Ltd. | Composés hétérocycliques à substitution amide utilisés en tant que modulateurs de kras g12d et leurs utilisations |
| WO2023240263A1 (fr) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Inhibiteurs de ras macrocycliques |
| WO2023244600A1 (fr) * | 2022-06-15 | 2023-12-21 | Mirati Therapeutics, Inc. | Promédicaments d'inhibiteurs pan-kras |
| WO2024002373A1 (fr) * | 2022-07-01 | 2024-01-04 | 苏州泽璟生物制药股份有限公司 | Inhibiteur de cycle fusionné de pyrimidine substitué, son procédé de préparation et son utilisation |
| WO2024008068A1 (fr) * | 2022-07-04 | 2024-01-11 | Jacobio Pharmaceuticals Co., Ltd. | Inhibiteurs de protéine mutante k-ras |
| WO2024012519A1 (fr) * | 2022-07-13 | 2024-01-18 | 北京华森英诺生物科技有限公司 | Inhibiteur de pan-kras |
| CN117624170A (zh) * | 2022-08-24 | 2024-03-01 | 泰励生物科技（上海）有限公司 | 具有抗kras突变肿瘤活性的化合物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588792B (zh) * | 2013-03-04 | 2016-03-23 | 中国科学院上海药物研究所 | 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途 |
| EP3908283A4 (fr) * | 2019-01-10 | 2022-10-12 | Mirati Therapeutics, Inc. | Inhibiteurs de kras g12c |
| US11453683B1 (en) * | 2019-08-29 | 2022-09-27 | Mirati Therapeutics, Inc. | KRas G12D inhibitors |
-
2022
- 2022-08-10 AU AU2022325771A patent/AU2022325771A1/en active Pending
- 2022-08-10 TW TW111130111A patent/TW202330529A/zh unknown
- 2022-08-10 CA CA3228310A patent/CA3228310A1/fr active Pending
- 2022-08-10 WO PCT/US2022/039971 patent/WO2023018812A1/fr active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023018812A1 (fr) | 2023-02-16 |
| AU2022325771A1 (en) | 2024-02-15 |
| TW202330529A (zh) | 2023-08-01 |
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