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CN-121990999-A - Phenyl isoxazole-containing compound and application thereof

CN121990999ACN 121990999 ACN121990999 ACN 121990999ACN-121990999-A

Abstract

The invention belongs to the technical field of medicines, and relates to a compound containing phenyl isoxazoles and application of the compound as a TRK therapeutic agent, in particular to a TRK inhibitor. A compound containing phenyl isoxazole, which is shown as a formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof, The compounds related by the invention are not reported in the literature, and the structure type is novel. The preparation process related by the invention is explored and optimized for a long time, and the preparation method is simple and feasible and is easy to operate. The compound has good inhibition effect on TRK kinase, can treat tumors caused by NTRK gene fusion, and has good application value and development and application prospect.

Inventors

  • ZHANG MEIHUI
  • XU SHAOSHAN
  • JIANG XIAOSHENG
  • XU MENGDI
  • ZHAO GUANYI
  • Ai Chengjian
  • JIANG TAO
  • DONG JINHUA

Assignees

  • 沈阳药科大学

Dates

Publication Date
20260508
Application Date
20241105

Claims (9)

  1. 1. A compound containing phenyl isoxazoles is characterized in that the compound is shown as a formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof, Wherein R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, unsubstituted or substituted with at least one of the same or different substituents as described below, wherein the substituents are C 1 -C 6 alkyl; NH-Ar, -O-Ar, ar is selected from unsubstituted or 1 to 2 benzene rings substituted with R a which are the same or different, R a is selected from hydrogen, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 sulfonyl, C 1 -C 6 nitrogen-containing alkyl, C 3 -C 7 ring containing at least one heteroatom which is unsubstituted or substituted with at least one C 1 -C 6 alkyl which is the same or different, and when R a is two, two R a form a C 4 -C 10 ring containing at least one heteroatom with adjacent carbon; -NH-R b 、-O-R b ,R b is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl; R 2 is selected from-CN, -C (O) NH 2 、-COO(CH 2 )nCH 3 , n is 0, 1, 2 or 3; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -, -C (O) NH-, -C (O) O-; R 3 is selected from hydrogen, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and m is 1,2, 3, or 4.
  2. 2. The compound containing phenyl isoxazoles according to claim 1, wherein the compound is represented by the formula (I), a prodrug and a pharmaceutically active metabolite thereof, and pharmaceutically acceptable salts thereof, Wherein R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, unsubstituted or substituted with at least one of the same or different substituents as described below, wherein the substituents are C 1 -C 4 alkyl; -NH-Ar, ar being selected from unsubstituted or 1-2 identical or different R a substituted benzene rings, R a being selected from hydrogen, halogen, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 nitrogen-containing alkyl, C 3 -C 6 ring of 1-2 heteroatoms, which is unsubstituted or substituted by at least one identical or different C 1 -C 4 alkyl, and, when R a is two, two R a form with adjacent carbon a C 4 -C 10 ring of at least one heteroatom; -NH-R b ,R b is selected from C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl; R 2 is selected from-CN, -C (O) NH 2 、-COO(CH 2 )nCH 3 , n is 0, 1; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -, -C (O) NH-; R 3 is selected from hydrogen, halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, and m is 1,2, or 3.
  3. 3. The compound containing phenyl isoxazoles according to claim 2, wherein the compound is represented by the formula (I), a prodrug and a pharmaceutically active metabolite thereof, and pharmaceutically acceptable salts thereof, Wherein R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, unsubstituted or substituted with at least one of the same or different substituents as described below, wherein the substituents are C 1 -C 4 alkyl; -NH-Ar, ar being selected from unsubstituted or 1-2 identical or different R a substituted benzene rings, R a being selected from hydrogen, halogen, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 nitrogen-containing alkyl, C 3 -C 6 ring of 1-2 heteroatoms, which is unsubstituted or substituted by at least one identical or different C 1 -C 4 alkyl, and, when R a is two, two R a form with adjacent carbon a C 4 -C 8 ring of at least one heteroatom; -NH-R b ,R b is selected from C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl; R 2 is selected from-CN, -C (O) NH 2 、-COO(CH 2 )nCH 3 , n is 0, 1; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -, -C (O) NH-; R 3 is selected from hydrogen, halogen, nitro, cyano, m is 1, 2 or 3.
  4. 4. The compound containing phenyl isoxazole according to claim 3, wherein the compound is represented by the formula (I), a prodrug and a pharmaceutically active metabolite thereof, and a pharmaceutically acceptable salt thereof, Wherein R 1 is selected from methyl, ethyl, isopropyl, vinyl, isopropenyl, 2-methylpropenyl; -NH-Ar, ar being selected from hydrogen, fluoro, chloro, bromo, methoxy, trifluoromethoxy, dimethylamino, piperidinyl, morpholinyl, N-methylpiperazinyl, when R a is two, two R a form a C 4 -C 8 ring of at least one heteroatom with adjacent carbons; -NH-R b ,R b is selected from methyl, ethyl, allyl, propargyl, isopropyl, cyclopropyl, isobutyl, methoxyethyl, n-butyl, methoxypropyl, cyclopentyl; R 2 is selected from-CN, -C (O) NH 2 ; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -; R 3 is selected from hydrogen and halogen, and m is 1 or 2.
  5. 5. The compound containing phenyl isoxazole according to claim 1, wherein the salt of the compound represented by the general formula (I) is formed by the compound represented by the general formula (I) and an acid selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.
  6. 6. The use of the compound containing phenylisoxazoles according to claim 1, wherein the compound shown in the formula (I), the prodrug and the pharmaceutically active metabolite thereof and the pharmaceutically acceptable salt thereof are used for preparing TRK therapeutic agents.
  7. 7. The application of the compound containing the phenyl isoxazole as claimed in claim 6, wherein the application of the compound shown in the formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof in preparing TRK inhibitors is disclosed.
  8. 8. A pharmaceutical composition is characterized in that the composition contains a compound shown as a formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof.
  9. 9. The method of claim 1, wherein the composition is used in the preparation of a TRK therapeutic agent.

Description

Phenyl isoxazole-containing compound and application thereof Technical Field The invention belongs to the technical field of medicines, and relates to a compound containing phenyl isoxazoles and application of the compound as a TRK therapeutic agent, in particular to a TRK inhibitor. Background The Tropomyosin Receptor Kinase (TRK) family is a class of transmembrane Receptor Tyrosine Kinases (RTKs) that regulate synaptic strength and plasticity in the mammalian nervous system. The major biological functions of the TRK family are the regulation of cell differentiation, proliferation, survival. There are three members of the TRK family, TRKA (encoded by the NTRK1 gene), TRKB (NTRK 2) and TRKC (NTRK 3), which are all involved in the development and progression of malignant tumors. NTRK rearrangement and fusion gene products are observed in a variety of tumor types, and the incidence of NTRK fusion genes in each particular tumor type is generally rare, which presents great difficulty in patient identification and adequate recruitment for clinical trials. The main method for targeting TRK oncogenes is to use small molecule kinase inhibitors, and at present, two small molecule TRK inhibitors (Larotrectinib and Entrectinib) are available on the market, so that hope is brought to patients. However, during the course of treatment, the problem of acquired drug resistance inevitably arises due to secondary mutations in the TRK kinase domain. Therefore, an attempt to find a new chemical structural framework and a high-efficiency TRK inhibitor for treating tumors caused by NTRK gene fusion has great practical significance and economic value. Disclosure of Invention The invention aims to provide a compound containing phenyl isoxazole and application of the compound as a therapeutic agent, particularly a TRK inhibitor. In order to achieve the above purpose, the invention adopts the technical scheme that: A compound containing phenyl isoxazole, which is shown as a formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof, Wherein R 1 is selected from the group consisting of C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, unsubstituted or substituted with at least one of the same or different substituents as described below, wherein the substituents are C 1-C6 alkyl; NH-Ar, -O-Ar, ar is selected from unsubstituted or 1 to 2 benzene rings substituted with R a which are the same or different, R a is selected from hydrogen, halogen, C 1-C6 alkoxy, C 1-C6 haloalkoxy, C 1-C6 sulfonyl, C 1-C6 nitrogen-containing alkyl, C 3-C7 ring containing at least one heteroatom which is unsubstituted or substituted with at least one C 1-C6 alkyl which is the same or different, and when R a is two, two R a form a C 4-C10 ring containing at least one heteroatom with adjacent carbon; -NH-R b、-O-Rb,Rb is selected from C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl; R 2 is selected from-CN, -C (O) NH 2、-COO(CH2)nCH3, n is 0, 1, 2 or 3; X is selected from-CH 2-、-C(O)-、-S(O2) -, -C (O) NH-, -C (O) O-; R 3 is selected from hydrogen, halogen, nitro, cyano, C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 haloalkyl, C 1-C6 haloalkoxy, and m is 1,2, 3, or 4. Preferably, the compounds are those of formula (I), prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, Wherein R 1 is selected from the group consisting of C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, unsubstituted or substituted with at least one of the same or different substituents as described below, wherein the substituents are C 1-C4 alkyl; -NH-Ar, ar being selected from unsubstituted or 1-2 identical or different R a substituted benzene rings, R a being selected from hydrogen, halogen, C 1-C4 alkoxy, C 1-C4 haloalkoxy, C 1-C4 sulfonyl, C 1-C4 nitrogen-containing alkyl, C 3-C6 ring of 1-2 heteroatoms, which is unsubstituted or substituted by at least one identical or different C 1-C4 alkyl, and, when R a is two, two R a form with adjacent carbon a C 4-C10 ring of at least one heteroatom; -NH-R b,Rb is selected from C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, C 1-C5 alkoxy, C 3-C6 cycloalkyl; R 2 is selected from-CN, -C (O) NH 2、-COO(CH2)nCH3, n is 0, 1; X is selected from-CH 2-、-C(O)-、-S(O2) -, -C (O) NH-; R 3 is selected from hydrogen, halogen, nitro, cyano, C 1-C4 alkyl, C 1-C4 alkoxy, C 1-C4 haloalkyl, C 1-C4 haloalkoxy, and m is 1,2, or 3. Further preferably, the compounds are those of formula (I), prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, Wherein R 1 is selected from the group consisting of C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, unsubstituted or substituted with at least one of the same or different substituents as described below, wherein the substituents are C 1-C4 alkyl; -NH-Ar, ar being selected from unsubstituted or 1-2 identical or different R a substituted benzene rings, R a being