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WO2023173016A1 - Inhibiteurs de kras pour le traitement d'une maladie - Google Patents

Inhibiteurs de kras pour le traitement d'une maladie Download PDF

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Publication number
WO2023173016A1
WO2023173016A1 PCT/US2023/064041 US2023064041W WO2023173016A1 WO 2023173016 A1 WO2023173016 A1 WO 2023173016A1 US 2023064041 W US2023064041 W US 2023064041W WO 2023173016 A1 WO2023173016 A1 WO 2023173016A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
fluoro
membered heterocycloalkyl
pyrido
pyrrolizin
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.)
Ceased
Application number
PCT/US2023/064041
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English (en)
Inventor
Jingrong Jean Cui
Evan W. ROGERS
Eugene Yuanjin Rui
Dayong Zhai
Nancy Ji LING
Ping Jiang
Anindya SARKAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Blossomhill Therapeutics Inc
Original Assignee
Blossomhill Therapeutics Inc
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Filing date
Publication date
Application filed by Blossomhill Therapeutics Inc filed Critical Blossomhill Therapeutics Inc
Publication of WO2023173016A1 publication Critical patent/WO2023173016A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

  • Ras is a GTP-binding protein and regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc.
  • H-Ras, K-Ras, and N- Ras are the main members of Ras superfamily, which are tightly regulated by factors that switch on/off the GTPase activity.
  • Somatic mutations at codons 12, 13 and 61 in the RAS genes are associated with about 16% of all human cancers and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-related cancers (Prior I. A. et al, A comprehensive survey of Ras mutations in cancer. Cancer Res.
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [0183] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0184] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, [0195] wherein R 1 , R 2 , R 3 , R 10 , R a , R b , B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , n, p, and q are as described herein. [0196] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, XV [0203] wherein R, R, R , R , R , R, R, A, X, Z, Z, Z, Z, Z, m, n, p, and q are as described herein.
  • the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XXa), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XXa), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.
  • ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl, wherein each of mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl is unsubstituted or substituted with one or more of R 11 ; or a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membere
  • alkynyl refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C2-C20 alkynyl, C2-C12 alkynyl, or C2-C6 alkynyl. Examples of alkynyl groups include acetylenyl (- C ⁇ CH) and propargyl (-CH2C ⁇ CH), but-3-yn-1,4-diyl (-C ⁇ C-CH2CH2-), and the like.
  • alkynyl group can be unsubstituted or substituted as described herein.
  • An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • the term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms.
  • Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems.
  • heterocycloalkyl refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. .
  • heteroaryl refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle.
  • Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5- naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H- pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula .
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • substituted means that the specified group or moiety bears one, two, or three substituents.
  • substituted means that the specified group or moiety bears one or two substituents.
  • substituted means the specified group or moiety bears one substituent.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXa), and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XXa) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med.
  • the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof, XVI [0548] wherein R 2 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and q are as described herein. [0549] In some embodiments, the disclosure provides a compound of the formula XVIa, or a pharmaceutically acceptable salt thereof,
  • Y is -S(O) 2 - or –C(O)NR 10 -. In some embodiments, Y is -S(O) 2 - . In some embodiments, Y is –C(O)NR 10 -. In some embodiments, Y is -S(O) 2 - or –C(O)NR 10 - , and R 1 is ring A. In some embodiments, Y is -S(O) 2 -, and R 1 is ring A.
  • Ring A is [0592] wherein * is a point of covalent attachment to [0593] In some embodiments, Ring A is not of the formula [0594] wherein * is a point of covalent attachment to [0595] In some embodiments, Ring A is an unsubstituted C 6 -C 10 aryl or a C 6 -C 10 aryl substituted with one or more of R 11 .
  • Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R 11 , or naphthyl substituted with one or more of R 11 .
  • Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R 11 , or naphthyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • Ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with one or more of R 11 .
  • Ring A is an unsubstituted C 3 -C 8 cycloalkyl or a C 3 -C 8 cycloalkyl substituted with one or more of R 11 . In some embodiments, Ring A is an unsubstituted C 3 -C 8 cycloalkyl or a C 3 -C 8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • R 12 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e ,
  • R 3 is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C 1 -C 6 alkyl-(4- to 10- membered heterocycloalkyl), -OR e , -OC(O)R e
  • any of the possible combinations of Z 1 -Z 7 can be combined as embodiemnts.
  • Z 6 is N or C(R 14 ).
  • Z 7 is N or C(R 15 ).
  • Z 1 is N, and Z 2 is N.
  • Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is N, and Z 5 is C(R 9 ).
  • Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is C(R 8 ), and Z 5 is C(R 9 ).
  • the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • Step 3 A solution of the product of I-1-2-4 (1.0 eq.) in NH3/H2O (25-28%, 0.8 M) is stirred for 12 h at 120 °C in a sealed tube. The mixture is concentrated to provide I-1-2-5.
  • Step 4 A mixture of I-1-2-5 (1.0 eq.) in phenylphosphonic dichloride (0.6 M) is stirred for 16 h at 130 °C. The mixture is poured slowly into ice water, and the pH of the solution is adjusted pH>7 with NaHCO3 (solid). The mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give I- 1-2.
  • Step 3 To a solution of oxalyl chloride (10 eq.) and 3 ⁇ MS in DCM (0.2 M) at -78 °C under N 2 is added dropwise a solution of DMSO (20 eq.) in DCM. After 15 min a solution of II-1-18-3 in DCM is slowly added dropwise. After 30 min, Et3N (30 eq.) is added dropwise. The reaction is stirred 30 min at -78 °C then slowly allowed to warm to rt and stirred for 1 h.
  • IV-2-1 is prepared following Step 2 and 3 in General Method A. [01077] To a solution of IV-2-1 (1.0 eq.) in MeOH (0.2 M) is added LiOH (3 eq.) in H 2 O (1 M). The mixture is stirred at 60 °C until the hydrolysis reaction is completed. The solution is cooled to ambient temperature, concentrated to remove methanol, acidified by aqueous HCl (1 N) until pH ⁇ 4-5, and then extracted with CH2Cl2. The combined extracts are dried over Na2SO4, concentrated, and dried under vacuum to provide IV-3-1.
  • KRAS mutant cells were plated in clear bottom 96 well plates at a density of 50,000-120,000 cells per well. Cells were allowed to attach overnight and then treated with compounds for 3 hours. After treatment, cells were fixed with 10% buffered formalin for 20 minutes at room temperature, washed with PBS, and then permeabilized with ice cold 100% methanol for 10 minutes to overnight at -20°C. Odyssey Blocking Buffer (LiCOR Biosciences: 927-60001) was added to each well for 1 hour at room temperature prior to incubation with primary antibodies overnight at 4°C.
  • Ex.1 was administered to female BALB/c mice via oral gavage at the dose level of 50 mg/kg. Mouse plasma was collected before the dose and at 15 min, 1 h, 2 h, 4 h, and 8 h after the dose.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des composés diaryle ciblant KRAS, des compositions pharmaceutiques contenant les composés, ainsi que des méthodes d'utilisation de tels composés pour traiter une maladie, telle que le cancer.
PCT/US2023/064041 2022-03-09 2023-03-09 Inhibiteurs de kras pour le traitement d'une maladie Ceased WO2023173016A1 (fr)

Applications Claiming Priority (4)

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US202263318352P 2022-03-09 2022-03-09
US63/318,352 2022-03-09
US202263359804P 2022-07-09 2022-07-09
US63/359,804 2022-07-09

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
WO2024119277A1 (fr) * 2022-12-08 2024-06-13 Risen (Suzhou) Pharma Tech Co., Ltd. Inhibiteurs de kras et leurs utilisations pharmaceutiques
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025076044A1 (fr) 2023-10-03 2025-04-10 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12404285B2 (en) 2022-05-06 2025-09-02 PAQ Therapeutics Inc. KRAS G12D proteolysis targeting chimeras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055866A1 (fr) * 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation Composes derives de quinazoline et de quinoline servant d'inhibiteurs de prolylpeptidase, d'inducteurs d'apoptose et d'agents therapeutiques anticancereux
US20120136014A1 (en) * 2010-06-02 2012-05-31 Trius Therapeutics, Inc. Dihydrofolate reductase inhibitors
WO2018218070A2 (fr) * 2017-05-25 2018-11-29 Araxes Pharma Llc Inhibiteurs covalents de kras
WO2020146613A1 (fr) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055866A1 (fr) * 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation Composes derives de quinazoline et de quinoline servant d'inhibiteurs de prolylpeptidase, d'inducteurs d'apoptose et d'agents therapeutiques anticancereux
US20120136014A1 (en) * 2010-06-02 2012-05-31 Trius Therapeutics, Inc. Dihydrofolate reductase inhibitors
WO2018218070A2 (fr) * 2017-05-25 2018-11-29 Araxes Pharma Llc Inhibiteurs covalents de kras
WO2020146613A1 (fr) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12404285B2 (en) 2022-05-06 2025-09-02 PAQ Therapeutics Inc. KRAS G12D proteolysis targeting chimeras
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
WO2024119277A1 (fr) * 2022-12-08 2024-06-13 Risen (Suzhou) Pharma Tech Co., Ltd. Inhibiteurs de kras et leurs utilisations pharmaceutiques
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025076044A1 (fr) 2023-10-03 2025-04-10 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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