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Preparation method and applications of a class of heterocyclic compounds with immunomodulatory effect

A compound and hydrate technology, applied in the field of small molecule protein inhibitors, can solve the problems of high production cost, easy immunogenicity, poor stability, etc.

Inactive Publication Date: 2020-02-14
SHANGHAI ENNOVABIO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antibody drugs have their own characteristics, such as high production costs, poor stability, need to be administered by injection, and are prone to immunogenicity, etc.

Method used

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  • Preparation method and applications of a class of heterocyclic compounds with immunomodulatory effect
  • Preparation method and applications of a class of heterocyclic compounds with immunomodulatory effect
  • Preparation method and applications of a class of heterocyclic compounds with immunomodulatory effect

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preparation example Construction

[0096] The preparation of formula I compound

[0097] The present invention also provides a method for preparing the compound as described in the first aspect of the present invention, the method comprising step (1) or (2):

[0098]

[0099] Compound 1 is removed from Boc protection under acidic conditions to obtain compound 2, and then compound 3 is reacted with compound 3 under the action of a palladium catalyst in the presence of a base and a phosphine compound to obtain compound 4, compound 4 is reduced to obtain compound 5, and then reductive amination Reaction obtains the compound shown in formula I.

[0100] Pharmaceutical compositions and methods of administration

[0101] Since the compound of the present invention has excellent inhibitory activity against PD-1, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are the main ...

Embodiment 1

[0165] 2-(((2-(2-Chloro-[1,1'-biphenyl]-3-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl)methyl)amino ) Ethan-1-ol

[0166]

[0167] 2-(2-Chloro-[1,1’-biphenyl]-3-yl)-2H-pyrazolo[3,4-b]pyridine-5-carbaldehyde.

[0168]

[0169] To 2-(3-bromo-2-chlorophenyl)-2H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (50mg, 0.15mmol), 1 , to a solution of 4-dioxane (3 mL) and water (0.5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol) and carbonic acid Potassium (62mg, 0.45mmol), under the protection of nitrogen, the reaction solution was heated to 100 degrees and stirred for one hour; TLC showed that the raw material disappeared completely, the reaction solution was filtered, the filter cake was washed twice with methanol, the filtrate was collected, concentrated, and the residue The title compound 2-(2-chloro-[1,1'-biphenyl]-3-yl)-2H-pyrazolo was obtained by normal phase flash separation and purification (petroleum ether:ethyl acetate=50:1) [3,4-b]pyrid...

Embodiment 2

[0177]1-((2-(2-Chloro-[1,1'-biphenyl]-3-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl)methyl)piperidine -2-carboxylic acid

[0178]

[0179] 1-((2-(2-Chloro-[1,1'-biphenyl]-3-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl)methyl)piperidine -2-carboxylic acid

[0180] To Example 1A (25mg, 0.075mmol), piperidine-2-carboxylic acid (19mg, 0.15mmol) in N,N-dimethylformamide (3mL) solution was added catalytic amount of acetic acid (1 drop), the reaction The solution was heated to 60 degrees and stirred for half an hour, then sodium cyanoborohydride (14mg, 0.23mmol) was added, and the stirring was continued overnight; filtered, concentrated, and the residue was purified by preparative high performance liquid chromatography to obtain the target product 1-((2- (2-Chloro-[1,1'-biphenyl]-3-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl)methyl)piperidine-2-carboxylic acid ( 8 mg, 73%) as a white solid.

[0181] MS(ESI):m / z=447.1[M+H] + .

[0182] 1 H NMR (400MHz, DMSO-d 6 )δ8.79 (s, 1H), 8.67 (d, J = 2.2Hz, 1H),...

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Abstract

The invention discloses a preparation method and applications of a class of heterocyclic compounds with immunomodulatory effect, specifically a compound with a structure represented by a formula I, wherein various groups are defined in the specification. The invention further provides applications of the compounds in the fields of immunity regulation and PD-1 / PD-L1 inhibition.

Description

technical field [0001] The present invention relates to the field of small molecule protein inhibitors, in particular, the present invention provides the preparation and application of a heterocyclic compound with immunomodulatory function. Background technique [0002] The immune system has the functions of surveillance, defense and regulation. Cellular immunity is mainly involved in the immune response to intracellular parasitic pathogenic microorganisms and the immune response to tumor cells, in the formation of delayed-type allergic reactions and autoimmune diseases, in transplant rejection and the regulation of humoral immunity. Activation of T lymphocytes by antigen-presenting cells is generally regulated by two distinct signals. The primary signal is transduced by the T cell receptor (TCR) by the presentation of foreign antigen peptides by the major histocompatibility complex (MHC) on APC cells. Secondary signals, also known as costimulatory signals, bind to T cell ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D231/56C07D209/44C07D209/46C07D209/48C07D498/04C07D513/04A61K31/519A61K31/416A61K31/4035A61K31/437A61K31/5025A61K31/5377A61K31/4545A61P35/00A61P31/12A61P37/06A61P31/22A61P31/18A61P31/14A61P31/16A61P33/06A61P31/04
CPCC07D471/04C07D487/04C07D231/56C07D209/44C07D209/46C07D209/48C07D498/04C07D513/04A61K31/519A61P35/00A61P31/12A61P37/06A61P31/22A61P31/18A61P31/14A61P31/16A61P33/06A61P31/04A61P31/00A61P37/00C07D403/06C07D519/00
Inventor 张毅邓建稳江磊路小丽尚珂寿建勇汪兵徐雪莉徐圆
Owner SHANGHAI ENNOVABIO PHARM CO LTD
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