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

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

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
fluoro
membered heterocycloalkyl
pyrido
pyrrolizin
Prior art date
Application number
PCT/US2023/064041
Other languages
English (en)
Inventor
Jingrong Jean Cui
Evan W. ROGERS
Eugene Yuanjin Rui
Dayong Zhai
Nancy Ji LING
Ping Jiang
Anindya SARKAR
Original Assignee
Blossomhill Therapeutics, Inc.
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 Blossomhill Therapeutics, Inc. filed Critical Blossomhill Therapeutics, Inc.
Publication of WO2023173016A1 publication Critical patent/WO2023173016A1/fr

Links

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
    • 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.

Landscapes

  • 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)
  • 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 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 WO2023173016A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
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

Publications (1)

Publication Number Publication Date
WO2023173016A1 true WO2023173016A1 (fr) 2023-09-14

Family

ID=87935998

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/064041 WO2023173016A1 (fr) 2022-03-09 2023-03-09 Inhibiteurs de kras pour le traitement d'une maladie

Country Status (1)

Country Link
WO (1) WO2023173016A1 (fr)

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

Similar Documents

Publication Publication Date Title
EP4053118A1 (fr) Composé cyclique condensé hétérocyclique substitué, son procédé de préparation et son utilisation pharmaceutique
AU2019279951B2 (en) Diaryl macrocycles as modulators of protein kinases
CN112166110B (zh) Shp2磷酸酶抑制剂及其使用方法
CN113767106B (zh) 氧杂氮杂喹唑啉-7(8h)-酮类化合物,其制法与医药上的用途
CN111511738B (zh) 杂芳类衍生物调节剂、其制备方法和应用
CN105732636B (zh) 杂芳化合物及其在药物中的应用
TW202122396A (zh) ＫＲａｓ Ｇ１２Ｄ抑制劑
JP5654715B1 (ja) テトラヒドロイミダゾ［１，５−ｄ］［１，４］オキサゼピン誘導体（ＴＥＴＲＡＨＹＤＲＯＩＭＩＤＡＺＯ［１，５−ｄ］［１，４］ＯＸＡＺＥＰＩＮＥＤＥＲＩＶＡＴＩＶＥ）
JP2022523981A (ja) 抗癌剤として有用な縮合三環式化合物
EP4332105A1 (fr) Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale
CN106749233B (zh) 一类磺酰胺衍生物及其应用
EP3670506A1 (fr) Thiazolecarboxamides et composés de pyridinecarboxamide utiles en tant qu'inhibiteurs de kinase pim
EA032839B1 (ru) Конденсированные пентациклические производные имидазола
KR20240013776A (ko) Kras 돌연변이 단백질을 억제할 수 있는 피리도[4,3-d]피리미딘 화합물
EP4365176A1 (fr) Inhibiteur de kras g12d et son utilisation
CN114302886B (zh) 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途
WO2023173017A1 (fr) Inhibiteurs de kras pour le traitement d'une maladie
TW202321242A (zh) 雜環化合物及使用方法
AU2021401741A1 (en) Macrocycles and their use
WO2023041049A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de sos1 et ses utilisations
WO2023173016A1 (fr) Inhibiteurs de kras pour le traitement d'une maladie
CN117881683A (zh) PI3Kα抑制剂及其使用方法
TWI841200B (zh) 雜環類化合物、藥物組成物及其應用
WO2024015262A1 (fr) Inhibiteurs de kras à cycles fusionnés pour le traitement d'une maladie
WO2023173014A1 (fr) Inhibiteurs de kras et leur utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23767697

Country of ref document: EP

Kind code of ref document: A1