WO2023143494A1 - Nouveau composé protac - Google Patents

Nouveau composé protac Download PDF

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Publication number
WO2023143494A1
WO2023143494A1 PCT/CN2023/073524 CN2023073524W WO2023143494A1 WO 2023143494 A1 WO2023143494 A1 WO 2023143494A1 CN 2023073524 W CN2023073524 W CN 2023073524W WO 2023143494 A1 WO2023143494 A1 WO 2023143494A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heteroaryl
aryl
cycloalkyl
heterocyclyl
Prior art date
Application number
PCT/CN2023/073524
Other languages
English (en)
Chinese (zh)
Inventor
钱昱瑧
李珂
陈伟
张一宁
韩福庆
张亚超
高鑫
叶靓雯
Original Assignee
甘李药业股份有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 甘李药业股份有限公司 filed Critical 甘李药业股份有限公司
Publication of WO2023143494A1 publication Critical patent/WO2023143494A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a bifunctional compound comprising a target protein binding part and an E3 ubiquitin ligase binding part, its pharmaceutical composition, and the medical use of the compound and the pharmaceutical composition.
  • PROTACs Compared with traditional small-molecule drugs, PROTACs only need to bind to the target protein transiently to complete the process of ubiquitin transfer to achieve irreversible degradation of the target protein, making PROTACs have stronger degradation effects and longer-lasting drug effects.
  • the target protein has higher selectivity and can overcome the drug resistance of traditional small molecule inhibitors due to the mutation of the target protein.
  • c-MYC is one of the most common changes in human cancer cells, and it is a key gene for malignant transformation of cells. Therefore, the development of c-MYC inhibitors is one of the most attractive potential anticancer strategies. Unfortunately, c-MYC is currently considered “undruggable” due to the difficulty of targeting transcription factors with small molecules. Therefore, there is an urgent need to develop small molecule inhibitors targeting c-MYC and PROTAC molecules targeting c-MYC.
  • PTM is the target protein binding moiety
  • G 1 and G 2 are each independently selected from CR'R", C ⁇ O, SO 2 , NR' and cycloalkylene,
  • formula (II) is selected from the following structures:
  • W is selected from O, S(O) 0-2 and CH 2 , preferably O, S or CH 2 , more preferably O;
  • R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, deuterium atom, NO 2 , CN, NH 2 , CF 3 , halogen, OR 7 , C(O)-R 7.
  • R is selected from C 0-6 alkylene, C 1-6 heteroalkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, optionally the C 0-6 alkylene Alkyl, C 1-6 heteroalkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene can be further replaced by halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, halo Heteroalkyl, Haloalkoxy, Hydroxy, Hydroxyalkyl, Cyano, Amino, Nitro, Cycloalkyl, Heterocyclyl, Aryl, Heteroaryl, Halocycloalkyl, Haloheterocyclyl, One or more substituents in halogenated aryl and halogenated heteroaryl are substituted; preferably, R is selected from C 0-6 alkylene, C 1-6 heteroalkylene, C 3-11 ring Alkyl, C 3-11 heterocyclylene, C 6-10
  • L, BL and q are as defined in the first aspect of the invention.
  • the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, the compound described in the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, or the third aspect of the present invention A pharmaceutical composition according to one aspect, which is used for treating or preventing a condition treated by binding to cerebellar protein in vivo.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • spirocycloalkyl refers to a polycyclic group with 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more A double bond in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • isomer means that the compounds of the present invention may exist as asymmetric centers and as racemates, racemic mixtures and individual diastereomers, all of which, including stereoisomers, geometric isomers Constructs are included in the present invention.
  • a compound or a salt thereof exists in a stereoisomeric form (for example, it contains one or more asymmetric carbon atoms)
  • individual stereoisomers (enantiomers and diastereoisomers) body) and mixtures thereof are included within the scope of the present invention.
  • the invention also includes individual isomers of the compounds or salts, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • Step 4 N1-(4-fluorobenzyl)-N1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)ethane-1,2-diamine synthesis
  • Step 3-6 N-(2-cyclopropyl-4-fluorophenyl)-2-(4-((4-fluoro-1,3-dioxoisoindol-2-yl)methyl) Synthesis of piperidin-1-yl)-N-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)acetamide
  • Membrane washing Place the PVDF membrane in PBST, shake and wash 3 times, 10min each time.
  • Membrane washing Place the PVDF membrane in PBST, shake and wash 3 times, 10min each time.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé PROTAC bifonctionnel ayant une structure telle que représentée par la formule (I) ou la formule (IV), CLM-L-PTM (I), ou ULM-L-PTM (IV) ou un sel pharmaceutiquement acceptable de celui-ci, et son procédé de préparation et son utilisation dans le traitement de cancers et d'autres maladies.
PCT/CN2023/073524 2022-01-28 2023-01-28 Nouveau composé protac WO2023143494A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210109487 2022-01-28
CN202210109487.1 2022-01-28

Publications (1)

Publication Number Publication Date
WO2023143494A1 true WO2023143494A1 (fr) 2023-08-03

Family

ID=87470643

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/073524 WO2023143494A1 (fr) 2022-01-28 2023-01-28 Nouveau composé protac

Country Status (1)

Country Link
WO (1) WO2023143494A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180179183A1 (en) * 2016-12-23 2018-06-28 Arvinas, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2019148055A1 (fr) * 2018-01-26 2019-08-01 Yale University Modulateurs de protéolyse à base d'imide et procédés d'utilisation associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180179183A1 (en) * 2016-12-23 2018-06-28 Arvinas, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2019148055A1 (fr) * 2018-01-26 2019-08-01 Yale University Modulateurs de protéolyse à base d'imide et procédés d'utilisation associés

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