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WO2023039828A1 - Composés cycliques fusionnés utiles en tant qu'inhibiteurs de tyrosine kinases fgfr4 - Google Patents

Composés cycliques fusionnés utiles en tant qu'inhibiteurs de tyrosine kinases fgfr4 Download PDF

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Publication number
WO2023039828A1
WO2023039828A1 PCT/CN2021/119035 CN2021119035W WO2023039828A1 WO 2023039828 A1 WO2023039828 A1 WO 2023039828A1 CN 2021119035 W CN2021119035 W CN 2021119035W WO 2023039828 A1 WO2023039828 A1 WO 2023039828A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
independently selected
haloalkyl
alkenyl
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/CN2021/119035
Other languages
English (en)
Inventor
Jian Zhang
Jincong Zhou
Shaomin ZHANG
Huihua Cai
Kang HE
Jiajia WU
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.)
Nutshell Biotech Shanghai Co Ltd
Original Assignee
Nutshell Biotech Shanghai 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
Application filed by Nutshell Biotech Shanghai Co Ltd filed Critical Nutshell Biotech Shanghai Co Ltd
Priority to PCT/CN2021/119035 priority Critical patent/WO2023039828A1/fr
Publication of WO2023039828A1 publication Critical patent/WO2023039828A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl group contains 4 to 10 ring-forming atoms, 4 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • the compounds of the present disclosure may exist as rotational isomers. In some embodiments, the compounds of the present disclosure exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds of the present disclosure exist as particular rotational isomers, substantially free of other rotational isomers.
  • R 6 and R 7 are each independently selected from the group consisting of H, D, CN and C 1- 6 alkyl, wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of D, halo, CN, and C (O) NR c R d ;
  • each R e2 is independently selected from the group consisting of H, D, C 1-6 alkyl and CN.
  • A is selected from Cy, wherein Cy is independently selected from the group consisting of 4-10 membered heterocycloalkyl wherein said 4-10 membered heterocycloalkyl are as defined in Formula (I) ; preferably, said 4-10 membered heterocycloalkyl is tetrahydropyrrolyl, tetrahydrofuranyl and tetrahydropyranyl.
  • the compound (s) according to the present disclosure will be administered in effective amount (s) via any of the usual and acceptable modes known in the art, either singly or in combination with additional therapeutic agent (s) .
  • the effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors known to a person skilled in the art.
  • the compound (s) according to the present disclosure may be used in combination with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other apoptosis promoters inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates (ADC) , biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP) -90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins, intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, ma
  • a series of tri-cyclic imidazole derivatives of formula 5-3 can be prepared by the methods outlined in Scheme 5.
  • the tri-cyclic imidazole derivative 5-3 can be obtained reaction of the guanidine derivative 5-1 with alpha-halo acetaldehyde 5-2.
  • Step 4 N- ( (3R, 4S) -4- ( (6- (3, 5-dimethoxyphenyl) -8-ethyl-7-thioxo-5, 6, 7, 8-tetrahydropyrimido [4, 5-d] pyrimidin-2-yl) amino) tetrahydrofuran-3-yl) acrylamide
  • This compound was prepared using procedures analogues those described for Example 9, step 1 using 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-ethyl-3, 4-dihydropyrido [4, 3-d] pyrimidine-2 (1H) -thione to replace 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (1-methyl-1H-pyrazol-4-yl) -3, 4-dihydropyrimido [4, 5-d] pyrimidine-2 (1H) -thione.
  • LCMS calc.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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

L'invention concerne des composés cycliques fusionnés, et des compositions pharmaceutiques les comprenant, des inhibiteurs d'une ou de plusieurs enzymes FGFR et sont utiles dans le traitement de maladies associées au FGFR, en particulier des maladies associées au FGFR4, telles que le cancer.
PCT/CN2021/119035 2021-09-17 2021-09-17 Composés cycliques fusionnés utiles en tant qu'inhibiteurs de tyrosine kinases fgfr4 Ceased WO2023039828A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/119035 WO2023039828A1 (fr) 2021-09-17 2021-09-17 Composés cycliques fusionnés utiles en tant qu'inhibiteurs de tyrosine kinases fgfr4

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/119035 WO2023039828A1 (fr) 2021-09-17 2021-09-17 Composés cycliques fusionnés utiles en tant qu'inhibiteurs de tyrosine kinases fgfr4

Publications (1)

Publication Number Publication Date
WO2023039828A1 true WO2023039828A1 (fr) 2023-03-23

Family

ID=85602289

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/119035 Ceased WO2023039828A1 (fr) 2021-09-17 2021-09-17 Composés cycliques fusionnés utiles en tant qu'inhibiteurs de tyrosine kinases fgfr4

Country Status (1)

Country Link
WO (1) WO2023039828A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025007784A1 (fr) * 2023-07-06 2025-01-09 四川科伦博泰生物医药股份有限公司 Composé cyclique hétéroaromatique, composition pharmaceutique, procédé de préparation s'y rapportant et utilisation associée

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105263931A (zh) * 2013-04-19 2016-01-20 因赛特公司 作为fgfr抑制剂的双环杂环
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
US20160115164A1 (en) * 2014-10-22 2016-04-28 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
CN105263931A (zh) * 2013-04-19 2016-01-20 因赛特公司 作为fgfr抑制剂的双环杂环
US20160115164A1 (en) * 2014-10-22 2016-04-28 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025007784A1 (fr) * 2023-07-06 2025-01-09 四川科伦博泰生物医药股份有限公司 Composé cyclique hétéroaromatique, composition pharmaceutique, procédé de préparation s'y rapportant et utilisation associée

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