WO2023284881A1 - Composés hétérocycliques utiles en tant qu'inhibiteurs du g12d de kras - Google Patents

Composés hétérocycliques utiles en tant qu'inhibiteurs du g12d de kras Download PDF

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Publication number
WO2023284881A1
WO2023284881A1 PCT/CN2022/106215 CN2022106215W WO2023284881A1 WO 2023284881 A1 WO2023284881 A1 WO 2023284881A1 CN 2022106215 W CN2022106215 W CN 2022106215W WO 2023284881 A1 WO2023284881 A1 WO 2023284881A1
Authority
WO
WIPO (PCT)
Prior art keywords
diazabicyclo
octan
methyl
pyrimidin
fluoro
Prior art date
Application number
PCT/CN2022/106215
Other languages
English (en)
Inventor
Haiquan Fang
Xiaolei Liu
Hui Yang
Original Assignee
Silexon Ai Technology Co., Ltd.
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
Priority claimed from PCT/CN2021/106767 external-priority patent/WO2023283933A1/fr
Application filed by Silexon Ai Technology Co., Ltd. filed Critical Silexon Ai Technology Co., Ltd.
Publication of WO2023284881A1 publication Critical patent/WO2023284881A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the compound is represented by the Formula (I 0 -2) :
  • X 2 or X 4 is independently N or CR 2 .
  • the compound is represented by the Formula (I 0 -3) :
  • each of R 2x is independently selected from OH, F, Cl, NH 2 , methyl, ethyl, vinyl, ethynyl, deuterated ethynyl, methoxy, 3-membered cycloalkyl, 4-membered cycloalkyl, or 3-membered saturated heterocycle.
  • the KRAS G12D-associated cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, lei
  • the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of at least one of compound of Formular (I 0 ) , Formular (I 0 -1) , Formular (I 0 -2) , Formular (I 0 -2) , Formular (I) , Formula (II-1) , Formula (II-2) , Formula (III-1) , Formula (III-2) , or Table A, or the pharmaceutically acceptable salt, prodrug, PROTAC, racemate enantiomers, solvate, hydrate, tautomer, and diastereoisomers thereof.
  • a KRAS Gl2D mutation e.g., a KRAS Gl2D-associated cancer
  • the administering is done via an oral.
  • substituted alkyl refers to an alkyl group having one or more substituents that include hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • compositions of the present invention comprise a compound represented by Formular (I 0 ) , Formular (I 0 -1) , Formular (I 0 -2) , Formular (I 0 -2) , Formula (I) , (II-1) , (II-2) , (III-1) , and (III-2) , (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, or 1500mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • inhibitor refers to a decrease in the baseline activity of a biological activity or process.
  • “Inhibition of activity of KRAS G12D” or “KRAS G12D ” thereof refers to a decrease in KRAS G12D activity as compared to the activity of that enzyme in the absence of the compound of the present disclosure.
  • subject , “individual “ or “patient” is used interchangeably, and refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans.
  • patient is a human.
  • subject has been accredited or has been diagnosed as having a KRAS G12D mutation positive cancer (e.g., the cancer is determined by measuring method ratified by management organizations, such as Food and Drug Administration (FDA) ) .
  • FDA Food and Drug Administration
  • the subject is suspected of having a KRAS G12D gene-associated cancer.
  • disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
  • the subject matter disclosed herein can be utilized to inhibit, block, reduce or decrease KRAS G12D activation for the reduction of tumor growth and/or tumor metastasis, wherein the method comprises administering to said subject an effective amount of a compound of Formula I or la or a pharmaceutical composition described herein.
  • Step 1 tert-Butyl 5- (7-chloro-8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate
  • Example III KRAS-CRAF interaction assays: inhibition of KRAS G12D mutant versus wild-type (WT) KRAS binding to CRAF

Abstract

L'invention concerne des composés représentés par la formule (I0) ou la formule (I), ou un sel de ceux-ci, des méthodes d'utilisation de tels composés pour moduler ou inhiber l'activité de la protéine mutante G12D de KRAS, et des compositions pharmaceutiques comprenant de tels composés. Ces composés sont utiles dans le traitement de diverses maladies ou affections, telles que les cancers.
PCT/CN2022/106215 2021-07-16 2022-07-18 Composés hétérocycliques utiles en tant qu'inhibiteurs du g12d de kras WO2023284881A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CNPCT/CN2021/106767 2021-07-16
PCT/CN2021/106767 WO2023283933A1 (fr) 2021-07-16 2021-07-16 Composés utiles en tant qu'inhibiteurs de kras g12d
CNPCT/CN2022/093010 2022-05-16
CN2022093010 2022-05-16

Publications (1)

Publication Number Publication Date
WO2023284881A1 true WO2023284881A1 (fr) 2023-01-19

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WO (1) WO2023284881A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
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
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024040131A1 (fr) 2022-08-17 2024-02-22 Treeline Biosciences, Inc. Inhibiteurs de pyridopyrimidine kras
WO2024054647A1 (fr) * 2022-09-09 2024-03-14 Ranok Therapeutics (Hangzhou) Co. Ltd. Dérivés de 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-naphthalene-pyrido[4,3-d]pyrimidine en tant qu'inhibuteurs de l'oncoprotéine mutante kras(g12d) pour le traitement du cancer inhibiteurs de kras (g12d)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021106231A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
WO2022015375A1 (fr) * 2020-07-16 2022-01-20 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022042630A1 (fr) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Composés hétéroaryle, leurs procédés de préparation et leurs utilisations
WO2022061251A1 (fr) * 2020-09-18 2022-03-24 Plexxikon Inc. Composés et procédés pour la modulation de kras et leurs indications
WO2022066646A1 (fr) * 2020-09-22 2022-03-31 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022068921A1 (fr) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Composé quinazoline et son application
WO2022098625A1 (fr) * 2020-11-03 2022-05-12 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022148421A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022161443A1 (fr) * 2021-02-01 2022-08-04 南京明德新药研发有限公司 Composé pyrimidopyrane
WO2022173870A1 (fr) * 2021-02-09 2022-08-18 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2022170999A1 (fr) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Composé de pyridine[4,3-d]pyrimidine
WO2022171143A1 (fr) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Composé de 5,6,7,8-tétrahydropyridine[3,4-d]pyrimidine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021106231A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
WO2022015375A1 (fr) * 2020-07-16 2022-01-20 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022042630A1 (fr) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Composés hétéroaryle, leurs procédés de préparation et leurs utilisations
WO2022061251A1 (fr) * 2020-09-18 2022-03-24 Plexxikon Inc. Composés et procédés pour la modulation de kras et leurs indications
WO2022066646A1 (fr) * 2020-09-22 2022-03-31 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022068921A1 (fr) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Composé quinazoline et son application
WO2022098625A1 (fr) * 2020-11-03 2022-05-12 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022148421A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022161443A1 (fr) * 2021-02-01 2022-08-04 南京明德新药研发有限公司 Composé pyrimidopyrane
WO2022173870A1 (fr) * 2021-02-09 2022-08-18 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2022170999A1 (fr) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Composé de pyridine[4,3-d]pyrimidine
WO2022171143A1 (fr) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Composé de 5,6,7,8-tétrahydropyridine[3,4-d]pyrimidine

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Title
DATABASE REGISTRY 25 April 2022 (2022-04-25), ANONYMOUS : "3,8-Diazabicyclo[3.2.1]octane-6-carbonitrile, 3-[7-(8-chloro-1-naphthalenyl)-5,6,7,8-tetrahydro-2-[[(2S)-1-methyl-2- pyrrolidinyl]methoxy]pyrido[3,4-d]pyrimidin-4-yl]-, (1R,5S,6S)- (CA INDEX NAME)", XP093024876, retrieved from STN Database accession no. 2766210-67-5 *
WANG XIAOLUN, ALLEN SHELLEY, BLAKE JAMES F., BOWCUT VICKIE, BRIERE DAVID M., CALINISAN ANDREW, DAHLKE JOSHUA R., FELL JAY B., FISC: "Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 65, no. 4, 24 February 2022 (2022-02-24), US , pages 3123 - 3133, XP055952002, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c01688 *

Cited By (4)

* Cited by examiner, † Cited by third party
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
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024040131A1 (fr) 2022-08-17 2024-02-22 Treeline Biosciences, Inc. Inhibiteurs de pyridopyrimidine kras
WO2024054647A1 (fr) * 2022-09-09 2024-03-14 Ranok Therapeutics (Hangzhou) Co. Ltd. Dérivés de 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-naphthalene-pyrido[4,3-d]pyrimidine en tant qu'inhibuteurs de l'oncoprotéine mutante kras(g12d) pour le traitement du cancer inhibiteurs de kras (g12d)

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