WO2018220149A1 - Composés - Google Patents

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Publication number
WO2018220149A1
WO2018220149A1 PCT/EP2018/064399 EP2018064399W WO2018220149A1 WO 2018220149 A1 WO2018220149 A1 WO 2018220149A1 EP 2018064399 W EP2018064399 W EP 2018064399W WO 2018220149 A1 WO2018220149 A1 WO 2018220149A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
oxo
isoindolin
thiazol
acetamide
Prior art date
Application number
PCT/EP2018/064399
Other languages
English (en)
Inventor
Georg Jaeschke
Antonio Ricci
Daniel Rueher
Sandra Steiner
Martin Duplessis
Yvonne Alice Nagel
Bernd Kuhn
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
C4 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
Priority to JP2019566634A priority Critical patent/JP7191045B2/ja
Priority to PL18728875.8T priority patent/PL3630754T3/pl
Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc., C4 Therapeutics, Inc. filed Critical F. Hoffmann-La Roche Ag
Priority to PE2019002464A priority patent/PE20200718A1/es
Priority to ES18728875T priority patent/ES2927480T3/es
Priority to EP18728875.8A priority patent/EP3630754B8/fr
Priority to MYPI2019007060A priority patent/MY201976A/en
Priority to RU2019143647A priority patent/RU2774952C2/ru
Priority to CA3065874A priority patent/CA3065874A1/fr
Priority to BR112019025370-0A priority patent/BR112019025370A2/pt
Priority to CN201880036589.7A priority patent/CN110753691B/zh
Priority to CR20190542A priority patent/CR20190542A/es
Priority to AU2018276441A priority patent/AU2018276441B2/en
Priority to MX2019014332A priority patent/MX2019014332A/es
Priority to KR1020197038496A priority patent/KR20200015595A/ko
Priority to UAA202000003A priority patent/UA126452C2/uk
Publication of WO2018220149A1 publication Critical patent/WO2018220149A1/fr
Priority to PH12019502662A priority patent/PH12019502662A1/en
Priority to IL271013A priority patent/IL271013B2/en
Priority to CONC2019/0013557A priority patent/CO2019013557A2/es
Priority to US16/700,900 priority patent/US11117890B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides a compound of formula I and their pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the therapeutic and/or prophylactic treatment of cancer, in particular non- small-cell lung cancer.
  • 5-membered heteroaryl refers to a single 5- membered aromatic ring, containing 1 or 2 heteroatoms selected from N, O and S, in particular one N and one S, for example thiazolyl.
  • a specific group is thiazol-2-yl.
  • 6-membered heteroaryl refers to a single 6-membered aromatic ring, containing 1 or 2 heteroatoms selected from N, O and S, in particular one N, for example pyridinyl.
  • a specific group is 2-pyridyl.
  • pharmaceutically acceptable denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.
  • a pharmaceutically acceptable salt refers to a salt that is suitable for use in contact with the tissues of humans and animals.
  • aromatic denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).
  • pharmaceutically acceptable excipient denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.
  • R 4 is each independently selected from the group consisting of
  • R 4 and R 5 form together with the N they are attached to a heterocyclyl, which heterocyclyl is optionally be substituted by R 6 .
  • a certain embodiment of the invention relates to the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein
  • R 4 and R 5 form together with the N they are attached to a heterocyclyl
  • n 0, 1, 2 or 3;
  • a certain embodiment of the invention relates to the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is -NH 2 .
  • a certain embodiment of the invention relates to the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is -NH 2 .
  • a certain embodiment of the invention relates to the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, n is 1, R 2 is -NH 2 , B is phenyl, m is 0 and C is thiazolyl.
  • a certain embodiment of the invention relates to the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
  • a certain embodiment of the invention relates to a method for the therapeutic and/or prophylactic treatment of cancer, in particular non-small-cell lung cancer by administering the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, to a patient.
  • the sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases.
  • the corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a suitable solvent such as e.g. dioxane or tetrahydrofuran and adding an appropriate amount of the corresponding acid.
  • the products can usually be isolated by filtration or by chromatography.
  • the conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base.
  • One possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as e.g.
  • the compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine.
  • the mixture is returned to the mixer; the talc is added thereto and mixed thoroughly.
  • the mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.
  • Example E Sachets of the following composition are manufactured:
  • (2RS)-2-(tert-Butoxycarbonylamino)-2-phenyl-acetic acid (9.5 g, 37.8 mmol) was dissolved in 75 ml of ethyl acetate and 10 ml of DMF.
  • Thiazol-2-amine (3.79 g, 37.8 mmol, 1 equiv.)
  • Hunig's base (14.7 g, 19.8 ml, 113 mmol, 3 equiv.)
  • Propylphosphonic anhydride solution (50% in ethyl acetate) (36.1 g, 33.8 ml, 56.7 mmol, 1.5 equiv.) were added drop wise at room temperature. The mixture was stirred at room temperature for 30 minutes.
  • Step 4 (2RS -2-r6-r2-(6-Amino-3-pyridyl ethvnyll-l-oxo-isoindolin-2-yll-2-(2,5- difluorophenyl)-N-thiazol-2-yl-acetamide
  • Step 3 (2RS)-2-(6-Bromo- l-oxo-isoindolin-2-yl)-2-ri-(2-trimethylsilylethoxymethyl)-5,6- dihvdro-4H-cvclopentarclpyrazol-3-yll acetic acid
  • Step 5 ( 2RSV2- ⁇ 6- ⁇ 2- 6- Amino-3-pyridyl ethvnyll - 1 -oxo-isoindolin-2-yll -N-thiazol-2- yl-2- ⁇ 1 -
  • Step 3 (2RS)-2-(6-Bromo- l-oxo-isoindolin-2-yl)-2-(5-fluoro-2-methoxy-phenyl)-N-thiazol-2- yl-acetamide
  • Step 2 (2RS)-2-r6-r2-(6-Amino-3-pyridyl)ethvnyll-7-methyl-l-oxo-isoindolin-2-yll-2-(5-fluoro- 2-methox v-phen yl) -N- (2-pyridyl) acetamide
  • Step 3 (2RS)-2-r6-r2-(6-Amino-3-pyridyl)ethynyll-7-methyl-l-oxo-isoindolin-2-yll-2-(5-fluoro- 2-hydroxy-phenyl) -N- (2-pyridyl) acetamide
  • Step 5 (2RS)-2-r6-r2-(6-Amino-3-pyridyl)ethvnyll-l-oxo-isoindolin-2-yll-2-(5-chloro-2- methoxy-phenyl)-N-thiazol-2-yl-acetamide
  • step 1 (190 mg, 0.523 mmol) was dissolved in 2 ml of dichloromethane and HC1 (4N in dioxane) (1.31 ml, 5.23 mmol, 10 equiv.) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness and used directly in the next step.
  • Step 1 (2RS)-2-(6-Bromo- l-oxo-isoindolin-2-yl)-2-(3-methoxy-2-pyridyl)acetonitrile
  • Step 3 (2RS)-2-(5-Fluoro-2-hvdroxy-phenyl)-2-r7-fluoro-l-oxo-6-r2-(3- pyridyl)ethvnyllisoindolin-2-yll-N-thiazol-2-yl-acetamide
  • Step 1 (2RS)-2-(5-Fluoro-2-methoxy-phenyl)-2-r6-r2-(4-formylphenyl)ethynyll-l-oxo- isoindolin-2-yll-N-thiazol-2-yl-acetamide
  • Step 2 (2RS -2-(5-Fluoro-2-hvdroxy-phenyl -2-r6-r2-r4-r(4-hydroxy-l- piperidyl)methyllphenyllethvnyll-l-oxo-isoindolin-2-yll-N-thiazol-2-yl-acetamide

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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)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés qui sont des inhibiteurs allostériques sélectifs de TMLR, TMLRCS, LR, LRCS contenant des mutants de l'EGFR, leur fabrication, des compositions pharmaceutiques les contenant et leur utilisation en tant que substances thérapeutiquement actives.
PCT/EP2018/064399 2017-06-02 2018-06-01 Composés WO2018220149A1 (fr)

Priority Applications (19)

Application Number Priority Date Filing Date Title
CR20190542A CR20190542A (es) 2017-06-02 2018-06-01 Compuestos
CN201880036589.7A CN110753691B (zh) 2017-06-02 2018-06-01 用于治疗性和/或预防性治疗癌症的化合物
AU2018276441A AU2018276441B2 (en) 2017-06-02 2018-06-01 Compounds
PL18728875.8T PL3630754T3 (pl) 2017-06-02 2018-06-01 Związki izoindolinoacetylenowe do leczenia nowotworu
EP18728875.8A EP3630754B8 (fr) 2017-06-02 2018-06-01 Composes d'isoindoline-acetylene pour le traitement du cancer
MYPI2019007060A MY201976A (en) 2017-06-02 2018-06-01 Compounds
RU2019143647A RU2774952C2 (ru) 2017-06-02 2018-06-01 Соединения
CA3065874A CA3065874A1 (fr) 2017-06-02 2018-06-01 Composes
BR112019025370-0A BR112019025370A2 (pt) 2017-06-02 2018-06-01 Compostos de fórmula i, composição farmacêutica e método para o tratamento terapêutico e/ ou profilático de câncer
JP2019566634A JP7191045B2 (ja) 2017-06-02 2018-06-01 化合物
ES18728875T ES2927480T3 (es) 2017-06-02 2018-06-01 Compuestos de isoindolina-acetileno para el tratamiento del cáncer
PE2019002464A PE20200718A1 (es) 2017-06-02 2018-06-01 Compuestos
MX2019014332A MX2019014332A (es) 2017-06-02 2018-06-01 Compuestos.
KR1020197038496A KR20200015595A (ko) 2017-06-02 2018-06-01 화합물
UAA202000003A UA126452C2 (uk) 2017-06-02 2018-06-01 Похідні ізоіндолу
PH12019502662A PH12019502662A1 (en) 2017-06-02 2019-11-25 Compounds
IL271013A IL271013B2 (en) 2017-06-02 2019-11-28 Allosteric egfr inhibitors with a modified isoindole, pharmaceutical preparations containing them and their use in medical treatment and/or preventive treatment of cancer
CONC2019/0013557A CO2019013557A2 (es) 2017-06-02 2019-11-29 Compuestos
US16/700,900 US11117890B2 (en) 2017-06-02 2019-12-02 Substituted isoindole allosteric EGFR inhibitors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201762514244P 2017-06-02 2017-06-02
EP17174334.7 2017-06-02
US62/514,244 2017-06-02
EP17174334 2017-06-02
US201762543438P 2017-08-10 2017-08-10
US62/543,438 2017-08-10

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/700,900 Continuation US11117890B2 (en) 2017-06-02 2019-12-02 Substituted isoindole allosteric EGFR inhibitors

Publications (1)

Publication Number Publication Date
WO2018220149A1 true WO2018220149A1 (fr) 2018-12-06

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/064399 WO2018220149A1 (fr) 2017-06-02 2018-06-01 Composés

Country Status (2)

Country Link
AR (1) AR113299A1 (fr)
WO (1) WO2018220149A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020002487A1 (fr) * 2018-06-29 2020-01-02 F. Hoffmann-La Roche Ag Composés
WO2020181232A1 (fr) 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
US10870636B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Pyrimidines as EGFR inhibitors and methods of treating disorders
WO2020254547A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs d'egfr
WO2020254562A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Inhibiteur d'egfr pour le traitement du cancer
WO2020257607A1 (fr) * 2019-06-21 2020-12-24 Dana-Farber Cancer Institute, Inc. Inhibiteurs allostériques d'egfr et leurs procédés d'utilisation
WO2020254544A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs d'egfr
WO2021123087A1 (fr) * 2019-12-20 2021-06-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr
WO2021127561A1 (fr) 2019-12-20 2021-06-24 C4 Therapeutics, Inc. Composés d'isoindolinone et d'indazole pour la dégradation de l'egfr
WO2021123084A1 (fr) * 2019-12-20 2021-06-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr
WO2023283130A1 (fr) 2021-07-04 2023-01-12 Newave Pharmaceutical Inc. Dérivés d'isoquinoléine en tant que modulateurs d'egfr mutants et leurs utilisations
US11584746B2 (en) 2018-02-20 2023-02-21 Dana-Farber Cancer Institute, Inc. Inhibitors of EGFR and methods of use thereof
RU2818677C2 (ru) * 2019-06-21 2024-05-03 Ф. Хоффманн-Ля Рош Аг Ингибитор egfr для лечения рака

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WO2011128279A1 (fr) 2010-04-13 2011-10-20 F. Hoffmann-La Roche Ag Dérivés d'aryléthynyle
WO2016183534A1 (fr) 2015-05-14 2016-11-17 The Wistar Institute Of Anatomy And Biology Inhibiteurs d'ebna1 et méthodes les utilisant

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10870636B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Pyrimidines as EGFR inhibitors and methods of treating disorders
US11673882B2 (en) 2014-12-23 2023-06-13 Dana-Farber Cancer Institute, Inc. Pyrimidines as EGFR inhibitors and methods of treating disorders
US11584746B2 (en) 2018-02-20 2023-02-21 Dana-Farber Cancer Institute, Inc. Inhibitors of EGFR and methods of use thereof
WO2020002487A1 (fr) * 2018-06-29 2020-01-02 F. Hoffmann-La Roche Ag Composés
WO2020181232A1 (fr) 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
CN113966335A (zh) * 2019-06-21 2022-01-21 豪夫迈·罗氏有限公司 用于治疗癌症的egfr抑制剂
WO2020254547A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs d'egfr
WO2020254572A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr pour le traitement du cancer
WO2020254565A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr pour le traitement du cancer
WO2020254568A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr pour le traitement du cancer
WO2020254544A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs d'egfr
JP7530391B2 (ja) 2019-06-21 2024-08-07 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト がんの治療のためのｅｇｆｒ阻害剤
JP7530390B2 (ja) 2019-06-21 2024-08-07 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト 新規ｅｇｆｒ阻害剤
CN113993873B (zh) * 2019-06-21 2024-08-02 豪夫迈·罗氏有限公司 用于治疗癌症的egfr抑制剂
WO2020254562A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Inhibiteur d'egfr pour le traitement du cancer
CN113993590A (zh) * 2019-06-21 2022-01-28 豪夫迈·罗氏有限公司 新型egfr抑制剂
CN113993872A (zh) * 2019-06-21 2022-01-28 豪夫迈·罗氏有限公司 用于治疗癌症的egfr抑制剂
CN113993873A (zh) * 2019-06-21 2022-01-28 豪夫迈·罗氏有限公司 用于治疗癌症的egfr抑制剂
CN114008049A (zh) * 2019-06-21 2022-02-01 豪夫迈·罗氏有限公司 用于癌症治疗的egfr抑制剂
RU2818677C2 (ru) * 2019-06-21 2024-05-03 Ф. Хоффманн-Ля Рош Аг Ингибитор egfr для лечения рака
WO2020257607A1 (fr) * 2019-06-21 2020-12-24 Dana-Farber Cancer Institute, Inc. Inhibiteurs allostériques d'egfr et leurs procédés d'utilisation
WO2020254546A1 (fr) * 2019-06-21 2020-12-24 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs d'egfr
US11673902B2 (en) 2019-12-20 2023-06-13 C4 Therapeutics, Inc. Isoindolinone and indazole compounds for the degradation of EGFR
CN114901277A (zh) * 2019-12-20 2022-08-12 C4医药公司 用于egfr降解的异吲哚啉酮和吲唑化合物
CN114867531B (zh) * 2019-12-20 2024-03-22 豪夫迈·罗氏有限公司 Egfr抑制剂
CN114867531A (zh) * 2019-12-20 2022-08-05 豪夫迈·罗氏有限公司 Egfr抑制剂
CN114901277B (zh) * 2019-12-20 2024-05-17 C4医药公司 用于egfr降解的异吲哚啉酮和吲唑化合物
WO2021123084A1 (fr) * 2019-12-20 2021-06-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr
WO2021127561A1 (fr) 2019-12-20 2021-06-24 C4 Therapeutics, Inc. Composés d'isoindolinone et d'indazole pour la dégradation de l'egfr
WO2021123087A1 (fr) * 2019-12-20 2021-06-24 F. Hoffmann-La Roche Ag Inhibiteurs d'egfr
WO2023283130A1 (fr) 2021-07-04 2023-01-12 Newave Pharmaceutical Inc. Dérivés d'isoquinoléine en tant que modulateurs d'egfr mutants et leurs utilisations

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