WO2022146201A1 - Inhibiteurs du récepteur du facteur de croissance épidermique - Google Patents

Inhibiteurs du récepteur du facteur de croissance épidermique Download PDF

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Publication number
WO2022146201A1
WO2022146201A1 PCT/RU2021/050459 RU2021050459W WO2022146201A1 WO 2022146201 A1 WO2022146201 A1 WO 2022146201A1 RU 2021050459 W RU2021050459 W RU 2021050459W WO 2022146201 A1 WO2022146201 A1 WO 2022146201A1
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WO
WIPO (PCT)
Prior art keywords
unsubstituted
substituted
alkyl
phenyl
several radicals
Prior art date
Application number
PCT/RU2021/050459
Other languages
English (en)
Inventor
Kirill Vadimovich ZAVIALOV
Georgii Viktorovich IAKOBSON
Shamil Dinarovich KADYROV
Adel Ravilevich KHAIDAROV
Daria Dmitrievna BEKETOVA
Daniel Evgenevich POLIANCZYK
Ilia Alexeevich SMETANIN
Ramilia Rinadovna STARODUBTSEVA
Polina Olegovna SUNTSOVA
Dmitry Alekseevich KHALABUDIN
Artsiom Evgenievich SHEKHAUTSOU
Dmitry Valentinovich MOROZOV
Original Assignee
Joint Stock Company "Biocad"
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 RU2021137120A external-priority patent/RU2021137120A/ru
Application filed by Joint Stock Company "Biocad" filed Critical Joint Stock Company "Biocad"
Publication of WO2022146201A1 publication Critical patent/WO2022146201A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators

Definitions

  • Dialkylphosphine oxide or "dialkylphosphoryl” (-P(O)((C 1 -C 6 )alkyl) 2 ) or (-P(O)((C 3- Cio)cycloalkyl) 2 ) means “alkyl” or "cycloalkyl” as defined above, linked to the corresponding fragment of the molecule via a phosphoryl group .
  • dialkylphosphine oxide include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, methylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide, etc.
  • Solvates and/or hydrates preferably exist in crystalline form.
  • protecting group refers to groups that are used to block the reactivity of functional groups, such as an amino group, carboxyl group or hydroxy group.
  • protecting groups include, but are not limited to, tert-butyl oxy carbonyl (Boc), benzyl oxy carbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methyl acetal (SEM), trialkyl silyl, alkyl(diaryl)silyl or alkyl.
  • “Therapeutically effective amount” refers to that amount of the therapeutic agent being administered in the course of treatment which will relieve the severity or eliminate the symptoms of the disease being treated.
  • the present invention relates to a compound of Formula I: or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Li is a chemical bond or -NH-;
  • Hal is a fluorine, bromine, chlorine or iodine atom.
  • the present invention relates to a compound of Formula 1.1 or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Li is a chemical bond or -NH-;
  • each Wi, W 2 , W3, W 4 or W5 is independently -(C 3 -C 6 )cycloalkyl, unsubstituted or substituted by one or several radicals R20; 4-7-membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R20;
  • the present invention relates to a compound of Formula 1.2 or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Li is a chemical bond or -NH-;
  • Xi is -CH-, -N- or -C(Re)-; n is 0, 1, 2, 3 or 4; each Ri is independently -H; -Hal; - C(Hal) 3 ; -CN; -NR 7 R 8 ; -C(0)NR 9 Rio; -C(O)ORu; - C(O)Ri2; -OR13; -(C 1 -C 6 )alkyl, unsubstituted or substituted by one or several radicals R14; -(C3- Ce)cycloalkyl, unsubstituted or substituted by one or several radicals Ri4 a ;
  • the present invention relates to a compound of Formula 1.3
  • R2 is -P(O)((C 1 -C 6 )alkyl) 2 , unsubstituted or substituted by one or several radicals R 15 ; - P(O)((C 3 -C 6 )cycloalkyl) 2 , unsubstituted or substituted by one or several radicals R 15a ; -P(O)((Ci- C 6 )alkyl))((C 3 -C 6 )cycloalkyl), unsubstituted or substituted by one or several radicals R 15 b; - P(O)(O(C 1 -C 6 )alkyl) 2 , unsubstituted or substituted by one or several radicals R 15C ; -P(O)(O(C3- Ce)cycloalkyl) 2 , unsubstituted or substituted by one or several radicals R 15 a; -P(O)(O(Ci- C 6 )alkyl)(
  • Hal is a fluorine, bromine, chlorine or iodine atom.
  • Hal is a fluorine, bromine, chlorine or iodine atom.
  • each R? c , R?d is independently -H, -(C 1 -C 6 )alkyl;
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ.
  • Parenteral administration thus includes, inter alia, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • the present invention relates to the method for treating described above, wherein said disease or disorder is the disease or disorder mediated by the activity of EGFR with a L858R mutation and/or a T790M mutation and/or an exon 19 deletion and/or a C797S mutation.
  • Compound 3o_3 was prepared in a similar manner to Example 3.6, step 2, from 3o_2, yield was 2.3 g (117%).
  • Compound 6b_2 was prepared in a similar manner to Example 7, step 3, from 6a_3 and 3b, yield was 0.89 g (63%).
  • Compound 41 was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3h via 41 1 (table 1). Yield of 41 1 was 0.20 g (55%). Yield of 41 was 0.06 g (55%).
  • Candidate EGFR_58 was prepared in a similar manner to Example 9, from 7d_l, la and 4a (Table 2), yield was 40 mg (18%).
  • Candidate EGFR_656 was prepared in a similar manner to Example 9, from 7a_l, la and 4s (Table 2), yield was 70 mg (55%).
  • Candidate EGFR_862 was prepared in a similar manner to Example 9, from 7b_l, la and 4e (Table 2), yield was 40 mg (28%).
  • Candidate EGFR_348 was prepared in a similar manner to Example 10, from 7d_2 and 4b yield was 30 mg (21%).
  • Candidate EGFR_914 was prepared in a similar manner to Example 10, from 7a_2 andw, yield was 10 mg (18%).
  • Compound 9a_5 was prepared in a similar manner to Example 7, step 4, from 9a_4, yield was 0.14 g (77%).
  • Example 11.2 Method of preparation of candidate EGFR_886.
  • a - solubility value is in the range of >100 pM
  • ** B - IC50 value is in the range of 10-50 nM
  • a - IC50 value is in the range of ⁇ 400 nM
  • the compounds according to the present invention showed antiproliferation activity against Ba/F3 EGFR L858R/T790M/C797S cell line.
  • Example 19 Antiproliferation activity against Ba/F3 EGFR Dell9/T790M/C797S cell line.
  • the compounds according to the present invention showed antiproliferation activity against Ba/F3 EGFR Del 19/T790M/C797S cell line.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de formule I : I ou un sel pharmaceutiquement acceptable, un solvate ou un stéréoisomère de ceux-ci, qui ont des propriétés d'inhibiteur d'EGFR, des compositions pharmaceutiques contenant lesdits composés, des méthodes de traitement de maladies ou de troubles et l'utilisation desdits composés en tant que produits pharmaceutiques pour le traitement de maladies ou de troubles.
PCT/RU2021/050459 2020-12-30 2021-12-30 Inhibiteurs du récepteur du facteur de croissance épidermique WO2022146201A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
RU2020144141 2020-12-30
RU2020144141 2020-12-30
RU2021137120 2021-12-15
RU2021137120A RU2021137120A (ru) 2021-12-15 Ингибиторы рецептора эпидермального фактора роста

Publications (1)

Publication Number Publication Date
WO2022146201A1 true WO2022146201A1 (fr) 2022-07-07

Family

ID=82259596

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2021/050459 WO2022146201A1 (fr) 2020-12-30 2021-12-30 Inhibiteurs du récepteur du facteur de croissance épidermique

Country Status (3)

Country Link
TW (1) TW202241890A (fr)
UY (1) UY39600A (fr)
WO (1) WO2022146201A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110207736A1 (en) * 2009-12-23 2011-08-25 Gatekeeper Pharmaceuticals, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith
WO2011140338A1 (fr) * 2010-05-05 2011-11-10 Gatekeeper Pharmaceuticals, Inc. Composés modulant l'activité des récepteurs egfr et méthodes pour traiter ou prévenir des troubles à l'aide de ceux-ci
EP3181559A1 (fr) * 2014-08-15 2017-06-21 Changzhou Runnor Biological Technology Co., Ltd Dérivé 2-(aniline 2,4,5-substituée)pyrimidine, composition pharmaceutique et leur utilisation
US20190100528A1 (en) * 2014-10-11 2019-04-04 Shanghai Hansoh Biomedical Co., Ltd. Egfr inhibitor, preparation method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110207736A1 (en) * 2009-12-23 2011-08-25 Gatekeeper Pharmaceuticals, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith
WO2011140338A1 (fr) * 2010-05-05 2011-11-10 Gatekeeper Pharmaceuticals, Inc. Composés modulant l'activité des récepteurs egfr et méthodes pour traiter ou prévenir des troubles à l'aide de ceux-ci
EP3181559A1 (fr) * 2014-08-15 2017-06-21 Changzhou Runnor Biological Technology Co., Ltd Dérivé 2-(aniline 2,4,5-substituée)pyrimidine, composition pharmaceutique et leur utilisation
US20190100528A1 (en) * 2014-10-11 2019-04-04 Shanghai Hansoh Biomedical Co., Ltd. Egfr inhibitor, preparation method and use thereof

Also Published As

Publication number Publication date
TW202241890A (zh) 2022-11-01
UY39600A (es) 2022-05-31

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