WO2017049498A1 - Composé imidazopyridine et utilisations dans la préparation d'un inhibiteur de pi3k - Google Patents

Composé imidazopyridine et utilisations dans la préparation d'un inhibiteur de pi3k Download PDF

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Publication number
WO2017049498A1
WO2017049498A1 PCT/CN2015/090433 CN2015090433W WO2017049498A1 WO 2017049498 A1 WO2017049498 A1 WO 2017049498A1 CN 2015090433 W CN2015090433 W CN 2015090433W WO 2017049498 A1 WO2017049498 A1 WO 2017049498A1
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WIPO (PCT)
Prior art keywords
group
compound
imidazopyridine
compound according
pi3k
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PCT/CN2015/090433
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English (en)
Chinese (zh)
Inventor
刘忠
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前湾医药科技（深圳）有限公司
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Priority to PCT/CN2015/090433 priority Critical patent/WO2017049498A1/fr
Publication of WO2017049498A1 publication Critical patent/WO2017049498A1/fr

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    • 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

Definitions

  • the invention belongs to the field of medicines, and in particular relates to an imidazopyridine compound and application thereof in preparing a PI3K inhibitor.
  • PI3K is a family of lipid kinases. According to their function and sequence homology, PI3K is divided into three types (I, II and III), of which the most comprehensive one is type I PI3K. Based on the difference between signaling pathway and regulatory proteins, type I PI3K can be further divided into IA type and IB type.
  • IA type PI3K includes PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , which exist as heterodimers, each heterodimer consisting of a catalytic subunit (p110 ⁇ , p110 ⁇ , or p110 ⁇ ) and a regulatory subunit, and its signal transduction is usually It is mediated by the receptor tyrosine kinase (RTK).
  • RTK receptor tyrosine kinase
  • the IB type PI3K gamma signal is mediated by a G protein-coupled receptor and consists of a p110 gamma catalytic domain that is linked to a regulatory subunit different from the IA subtype.
  • P13K plays an important role in the regulation of multiple cellular processes including cell cycle regulation, proliferation, survival, apoptosis and migration, and is an important component of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation.
  • I P13K The main P13K isoform in cancer is type I P13K.
  • IA type P13K is activated by RTK or Ras to generate phosphatidylinosnol-3,4,5-triphosphate (PIP3), which acts as a second messenger in the cell to activate the downstream target Akt. It plays an important regulatory role in tumor cell development, proliferation, survival and growth.
  • the two subtypes PI3K ⁇ and PI3K ⁇ are mainly expressed in immune-related cells and participate in the process of inflammatory response, and play a key regulatory role in acquired immunity and innate immune system.
  • P13K ⁇ plays an important role in B cell maturation, T cell activation, and neutrophil migration, and is involved in the activation of leukocytes associated with autoimmune diseases such as macrophages, dendritic cells, and NK T-cells.
  • B cell signaling in P13K ⁇ mutant mice has specific defects that result in B cell developmental disorders and reduced antibody responses following antigen stimulation.
  • P13K ⁇ is involved in the regulation of chemokine signal transduction, and its activity is crucial for T cell activation and differentiation.
  • P13K ⁇ regulates ROS production in neutrophils and regulates the migration of macrophages and neutrophils, which leads to macrophages and neutrophils towards the inflammatory site.
  • Recruitment disorders and T cell activation disorders Based on the close relationship between PI3K and inflammation and autoimmune diseases, PI3K has become a new target for the development of eye-catching anti-inflammatory drugs.
  • Another object of the present invention is to provide a process for producing the above imidazopyridine compounds.
  • a further object of the present invention is to provide the use of the above imidazopyridine compounds for the preparation of PI3K inhibitors.
  • An imidazopyridine compound which is a compound of formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer of said compound of formula I or a pharmaceutically acceptable salt thereof a construct, a tautomer or a mixture thereof in any ratio, including a racemic mixture;
  • Ar is a substituted or unsubstituted aryl or arylhetero group, and the substituted aryl or arylhetero group may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy and cyanogen. base;
  • R 1 is -H, halogen, hydroxy, cyano or C 2 -C 6 alkynyl
  • R 2 is -H or C 1 -C 6 alkyl
  • the aryl group means a carbocyclic hydrocarbon group having 6 to 14 ring carbon atoms and having at least one ring, wherein at least one ring is an aromatic ring, such as a phenyl group;
  • the heteroaryl group means a monocyclic aromatic hydrocarbon group having 6 ring atoms, such as a pyridyl group;
  • halogen or halogen means fluorine, chlorine, bromine or iodine
  • the hydroxyl group refers to an -OH group
  • the cyano group refers to a -CN group
  • the C 2 -C 6 alkynyl group means an alkynyl group having 2 to 6 carbon atoms, and examples of the alkynyl group include, but are not limited to, an ethynyl group, a 2-propynyl group and a 2-butynyl group;
  • the C 1 -C 6 alkyl group means an alkyl group having 1 to 6 carbon atoms, and examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and iso Butyl, sec-butyl and tert-butyl;
  • the imidazopyridine compound is preferably a compound having a structure represented by A, B or C:
  • a pharmaceutically acceptable salt thereof and a solvent compound, enantiomer, diastereomer, or mutual compound of the compound having the structure represented by A, B or C or a pharmaceutically acceptable salt thereof Isomers or mixtures thereof in any ratio, including racemic mixtures;
  • the preparation method of the imidazopyridine compound comprises the following steps:
  • step (3) under alkaline conditions, the product 1 obtained in step (2) is subjected to a hydrolysis reaction to obtain a product 2;
  • step (6) under the action of the reducing agent L-tri-sec-butyl borohydride, the product 5 obtained in step (6) is subjected to a reduction reaction to obtain a product 6;
  • step (9) under basic conditions, the product 7 obtained in step (8) and chloroacetaldehyde cyclization reaction to obtain the product 8;
  • the product 8 obtained in the step (9) is taken off the tert-butylsulfinyl group to obtain the product 9;
  • Step (11) the product obtained is reacted with compound 10 containing a halogen, hydroxyl, cyano or C 2 ⁇ C 6 alkynyl group, to give compound 11, i.e. R 1 is halo, hydroxy, cyano or C 2 to C 6 alkynyl imidazopyridine compounds;
  • the synthetic route of the imidazopyridine compound is as follows:
  • the imidazopyridine compound is used in the preparation of a medicament for treating cancer, diabetes and/or immunoinflammatory;
  • the medicament may contain one or more pharmaceutically acceptable carriers, excipients or diluents;
  • the medicament includes various clinical pharmaceutical dosage forms, such as tablets, injections, liposome nanoparticles, controlled release agents, and the like;
  • a PI3K inhibitor comprising the above imidazopyridine compound
  • a medicament for treating a PI3K mediated disease comprising the above imidazopyridine compound
  • the compound of the present invention is selective for PI3K ⁇ , which is a selective inhibitor of PI3K ⁇ ; said "selective inhibitor of PI3K ⁇ " means that the compound binds or inhibits the affinity or potency of the PI3K ⁇ subtype compared to PI3K other
  • the subtype ie PI3K ⁇ , PI3K ⁇ or PI3K ⁇
  • the compounds of the invention may have a selectivity to PI3K ⁇ of at least about 400 fold, at least about 800 fold, or at least about 1000 fold.
  • the compounds of the invention may inhibit the activity of PI3K and may be useful in the preparation of diseases suitable for the treatment of PI3K activity, including, for example, inflammatory conditions, immunological disorders, cancer, and other diseases.
  • Methyl 2-amino-5-bromo-isonicotinate (10 g, 43.2 mmol) and 2,5-hexanedione (5.4 g, 47.5 mmol) were dissolved in 100 ml of toluene (toluene) and p-toluene was added.
  • step (2) The product obtained in the step (2) (8.4 g, 27.42 mmol) was dissolved in 40 ml of methanol (MeOH) and 10 ml of water, and sodium hydroxide (3.29 g, 82.25 mmol) was added and allowed to react at room temperature for 4 hours.
  • N-chlorosuccinimide (NCS, 24 mg, 0.18 mmol) was added, and the reaction was refluxed overnight and concentrated.
  • Biochemical analysis of PI3K kinase activity was performed using Promega's ADP-Glo technology.
  • the ADP-Glo kinase assay kit and PI3K ⁇ kinase were purchased from Promega, and PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ kinase were purchased from Millipore Corporation. All experiments were performed in 384 well plates at room temperature.
  • the kinase mixture was diluted with kinase buffer including 50 mM HEPES (pH 7.5), 3 mM MgCl 2 , 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS and 2 mM DTT.
  • the ATP/substrate mixture contained 5 ⁇ M PIP2/PS and 25 ⁇ M ATP.
  • Compounds to be tested (A, B and C) were dissolved in 100% DMSO and diluted to a final concentration with ddH 2 O. 2 ⁇ L of the diluted test compound and 4 ⁇ L of ATP/substrate mixture were added to each well of a 384-well assay plate. At the beginning of the reaction, 4 ⁇ L of the kinase mixture was added to each well.
  • the final reaction volume was 10 ⁇ L, the final concentration of PIP2/PS was 2 ⁇ M, and the final concentrations of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ kinase were 0.2, 0.6, 0.25 and 0.4 nM, respectively, and the corresponding ATP final concentrations were 40, 40, 40 and 25 ⁇ M, respectively.
  • Add 10 ⁇ L of kinase ADP-Glo reagent to each well and incubate for 1 h. Then add 20 ⁇ L of kinase assay to each well. After incubation for 30 min, the luminescence readings were measured with Envision plate reader.
  • the inhibition rate of the compound was calculated and the IC 50 was calculated by XLFIT5 software. (50% inhibitory concentration) value.
  • the inhibition data of the measured compounds against PI3K kinase activity are shown in Table 1.
  • the results show that the compounds listed as selective inhibitors of PI3K ⁇ that PI3K ⁇ IC of at least 50 and lower than other subtypes of PI3K (i.e. PI3K ⁇ , PI3K ⁇ or PI3K ⁇ ) 400 times, such as a PI3K inhibitor compound, with For the treatment of diseases associated with PI3K activity, including, for example, inflammatory conditions, immune-based disorders, cancer, and other diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un composé imidazopyridine représenté par la formule (I) ou un sel de qualité pharmaceutique, un composé solvant, un énantiomère, un diastéréoisomère, un tautomère ou un mélange de ces derniers dans une proportion quelconque. Le composé permet d'inhiber l'activité de PI3K, et peut en conséquence être préparé afin de traiter des maladies liées à l'activité de la PI3K, telles que des maladies inflammatoires, des maladies immunitaires et des cancers.
PCT/CN2015/090433 2015-09-23 2015-09-23 Composé imidazopyridine et utilisations dans la préparation d'un inhibiteur de pi3k WO2017049498A1 (fr)

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PCT/CN2015/090433 WO2017049498A1 (fr) 2015-09-23 2015-09-23 Composé imidazopyridine et utilisations dans la préparation d'un inhibiteur de pi3k

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107793394A (zh) * 2017-08-03 2018-03-13 上海厚璞生物科技有限公司 一种生产选择性pi3k抑制剂的系列关键中间体

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710870A (ja) * 1993-06-23 1995-01-13 Asahi Glass Co Ltd 新規アミノピリジン誘導体およびその塩
CN101677569A (zh) * 2007-04-17 2010-03-24 雷诺维思公司 2-氰基苯基稠合杂环化合物及其组合物和用途
US20120035153A1 (en) * 2007-10-12 2012-02-09 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US20130005721A1 (en) * 2009-09-23 2013-01-03 Panmira Pharmaceuticals, Llc Indolizine inhibitors of 5-lipoxygenase
CN105130984A (zh) * 2015-09-23 2015-12-09 前湾医药科技（深圳）有限公司 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710870A (ja) * 1993-06-23 1995-01-13 Asahi Glass Co Ltd 新規アミノピリジン誘導体およびその塩
CN101677569A (zh) * 2007-04-17 2010-03-24 雷诺维思公司 2-氰基苯基稠合杂环化合物及其组合物和用途
US20120035153A1 (en) * 2007-10-12 2012-02-09 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US20130005721A1 (en) * 2009-09-23 2013-01-03 Panmira Pharmaceuticals, Llc Indolizine inhibitors of 5-lipoxygenase
CN105130984A (zh) * 2015-09-23 2015-12-09 前湾医药科技（深圳）有限公司 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107793394A (zh) * 2017-08-03 2018-03-13 上海厚璞生物科技有限公司 一种生产选择性pi3k抑制剂的系列关键中间体

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