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CN-121021505-B - Preparation method and application of pyrazole substituted naphthyridine compound

CN121021505BCN 121021505 BCN121021505 BCN 121021505BCN-121021505-B

Abstract

The invention discloses a preparation method and application of a pyrazole substituted naphthyridine compound, and relates to the field of pharmaceutical chemistry, wherein the pyrazole substituted naphthyridine compound is shown in the general formula (I): The preparation method and the application of the pyrazole substituted naphthyridine compound obviously overcome the drug resistance of the existing drug caused by RET kinase gate site and solvent front mutation through brand new framework design, can be applied to the preparation of transmembrane receptor tyrosine kinase RET inhibitors, treat diseases mediated by RET abnormal expression, and have the convenience of oral administration patent medicine and the prospect of rapid clinical transformation.

Inventors

  • WU JUNBO
  • ZHUO LINSHENG
  • ZHOU HUIFANG
  • ZOU HONGYUN

Assignees

  • 衡阳市中心医院

Dates

Publication Date
20260505
Application Date
20250908

Claims (14)

  1. 1. Pyrazole-substituted naphthyridine compounds are characterized in that the compounds are represented by a general formula (I): (I); Wherein R in formula (I) is selected from 、 、 、 、 Or (b) -Representing the connection location; The said Selected from the group consisting of 、 、 Or (b) The following steps Wherein R 1 is-OCH 3 or H, R 2 is halogen atom, H or-CN, said Wherein R 4 is halogen atom, H or-CH 3 ,R 5 is H or-OCH 3 , the said Selected from the group consisting of 、 Or (b) The following steps Wherein R 6 is H or-OCH 3 , the said Wherein R 8 is-NH 2 , H or-CH 3 ,R 9 is halogen atom or H, R 10 is halogen atom, H, -OCH 3 or-CH 3 , the said Wherein R 11 is a halogen atom.
  2. 2. A pyrazole-substituted naphthyridine compound according to claim 1, wherein, R is 、 、 、 Or (b) Pyrazole-substituted naphthyridines have the following chemical formula in sequence: 、 、 、 Or (b) 。
  3. 3. The pyrazole-substituted naphthyridine compound according to claim 1, wherein R is 、 Or (b) Pyrazole-substituted naphthyridines have the following chemical formula in sequence: 、 Or (b) 。
  4. 4.A pyrazole-substituted naphthyridine compound according to claim 1, wherein, R is Or (b) Pyrazole-substituted naphthyridines have the following chemical formula: Or (b) 。
  5. 5. A pyrazole-substituted naphthyridine compound according to claim 1, wherein, R is 、 、 、 、 、 、 、 、 、 Or (b) Pyrazole-substituted naphthyridines have the following chemical formula in sequence: 、 、 、 、 、 、 、 、 Or (b) 。
  6. 6. A pyrazole-substituted naphthyridine compound according to claim 1, wherein, R is 、 Or (b) Pyrazole-substituted naphthyridines have the following chemical formula in sequence: 、 Or (b) 。
  7. 7. A pyrazole-substituted naphthyridine compound according to claim 1, wherein, R is 、 、 Or (b) Pyrazole-substituted naphthyridines have the following chemical formula in sequence: 、 、 Or (b) 。
  8. 8. The preparation method of the pyrazole substituted naphthyridine compound is characterized by comprising the following steps of: 。
  9. 9. The preparation method of the pyrazole substituted naphthyridine compound is characterized by comprising the following steps of: 。
  10. 10. The preparation method of the pyrazole substituted naphthyridine compound is characterized by comprising the following steps of: 。
  11. 11. The preparation method of the pyrazole substituted naphthyridine compound is characterized by comprising the following steps of: 。
  12. 12. The preparation method of the pyrazole substituted naphthyridine compound is characterized by comprising the following steps of: 。
  13. 13. The preparation method of the pyrazole substituted naphthyridine compound is characterized by comprising the following steps of: 。
  14. 14. Use of a pyrazole-substituted naphthyridine compound according to any one of claims 1 to 7 for the preparation of transmembrane receptor tyrosine kinase RET inhibitors and antitumor drugs.

Description

Preparation method and application of pyrazole substituted naphthyridine compound Technical Field The invention relates to a pharmaceutical chemistry technology, in particular to a preparation method and application of a pyrazole substituted naphthyridine compound. Background The RET gene is a proto-oncogene that encodes the transmembrane receptor tyrosine kinase RET. When subjected to sustained oncogenic activation, RET triggers an aberrant RET-related signaling cascade, leading to cell hyperproliferation, ultimately triggering tumor initiation and progression. RET mutation and RET rearrangement are two major mechanisms leading to RET oncogenic activation and driving malignancy, and inhibition of RET kinase is therefore considered a promising therapeutic approach for the treatment of a variety of cancers. Currently, there are two main categories of research aimed at RET inhibitors. The first is a multi-target kinase inhibitor, called first generation RET inhibitor, however, amino acid mutations occurring at the gatekeeper site (V804L/M) and catalytic loop (M918T) of the ATP binding domain of RET result in the first generation RET inhibitor producing acquired resistance with severely limited clinical efficacy. Subsequently, the second generation selective RET inhibitor, saprolitinib, can overcome the first generation RET inhibitor resistance for use in treating RET fusion-positive non-small cell lung cancer patients and RET mutated medullary thyroid cancer patients. However, the secondary mutation of G810R/S/C that occurs in the solvent front region of RET gives rise to acquired resistance to both saprolidine and platinib. Therefore, based on the defects and problems of the existing targeted RET inhibitors, the development of novel selective RET small molecule inhibitors which have higher activity and better safety and can overcome drug resistance has become an unmet new clinical need. Disclosure of Invention The invention aims to provide a preparation method and application of a pyrazole substituted naphthyridine compound, which are used for solving the problem of drug resistance of the existing RET inhibitor caused by RET kinase gate site and solvent front mutation. In order to achieve the purpose, the invention provides the following technical scheme that the pyrazole substituted naphthyridine compound is shown in the general formula (I): Wherein R in formula (I) is selected from The saidWherein R 1 is-OCH 3 or H, R 2 is halogen atom, H or-CN, R 3 is-CH 2-、-CH2CONH-、-CH2 NHCO-or-CH=CH-CO-, the catalyst is a compound of formula IWherein R 4 is halogen atom, H or-CH 3,R5 is H or-OCH 3, the saidWherein R 6 is H or-OCH 3,R7 is-CH 2-、-CH2 CONH-or-CH 2 NHCO-, which are describedWherein R 8 is-NH 2, H or-CH 3,R9 is halogen atom or H, R 10 is halogen atom, H, -OCH 3 or-CH 3, the saidWherein R 11 is a halogen atom. R isPyrazole-substituted naphthyridines have the following chemical formula in sequence: R is Pyrazole-substituted naphthyridines have the following chemical formula in sequence: R is Pyrazole-substituted naphthyridines have the following chemical formula: R is Pyrazole-substituted naphthyridines have the following chemical formula in sequence: R is Pyrazole-substituted naphthyridines have the following chemical formula in sequence: R is Pyrazole-substituted naphthyridines have the following chemical formula in sequence: a process for the preparation of pyrazole-substituted naphthyridines, which is useful for the preparation of said pyrazole-substituted naphthyridines, comprising the steps of: S1, reacting a compound shown in a formula (II) with N-Boc-4-ethynyl piperidine to obtain a compound shown in a formula (III); s2, obtaining a compound of formula (IV) by mixing the compound of formula (III) with 1-methylpyrazole-4-boric acid pinacol ester; S3, removing the compound of the formula (IV) to obtain a compound of the formula (V); S4, reacting the compound shown in the formula (V) with an aromatic aldehyde compound to obtain a pyrazole substituted naphthyridine compound; a process for the preparation of pyrazole-substituted naphthyridines, which is useful for the preparation of said pyrazole-substituted naphthyridines, comprising the steps of: s1, reacting methoxy substituted aromatic amine with bromoacetyl bromide to obtain a compound shown in a formula (VI); s2, reacting a compound shown in a formula (VI) with a compound shown in a formula (VII) to obtain a pyrazole substituted naphthyridine compound; a process for the preparation of pyrazole-substituted naphthyridines, which is useful for the preparation of said pyrazole-substituted naphthyridines, comprising the steps of: S1, reacting a compound shown in a formula (VIII) with a compound shown in a formula (IX) to obtain a compound shown in a formula (X); s2, reacting a compound shown in the formula (X) with methoxy substituted aryl benzylamine to obtain pyrazole substituted naphthyridine compounds; A preparation method of a pyrazole substituted na