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CN-121991023-A - Phenyl thiophene compound and preparation method and application thereof

CN121991023ACN 121991023 ACN121991023 ACN 121991023ACN-121991023-A

Abstract

The invention belongs to the technical field of medicines, and relates to a phenyl thiophene compound, a preparation method thereof and application thereof as a therapeutic agent, in particular to a TRK inhibitor. A phenyl thiophene compound, which is a compound 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 Knoevenagel/Gewald reaction one-pot method is used for synthesizing the aminothiophene ring, so that the reaction time is shortened, and the operability of the preparation process of the compound is enhanced. 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 phenyl thiophene compound 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, In the formula, R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, unsubstituted or substituted with at least one of the same or different substituents, the substituents being C 1 -C 6 alkyl; -NH-Ar, -O-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 6 haloalkoxy, C 1 -C 6 nitrogen-containing alkyl, C 3 -C 7 ring containing at least one heteroatom, unsubstituted or substituted by at least one identical or different C 1 -C 6 alkyl; -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 3 -C 7 cycloalkyl; x is selected from-CH 2 -、-C(O)-、-S(O 2 ) -, -C (O) NH-, -C (O) O-; R 2 is selected from hydrogen, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy; n is 1, 2, 3 or 4.
  2. 2. The phenylthiophene compound according to claim 1, wherein the compound is a compound represented by formula (I), a prodrug and a pharmaceutically active metabolite thereof, and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, unsubstituted or substituted with at least one of the same or different substituents, the substituents being C 1 -C 6 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 haloalkoxy, C 1 -C 4 nitrogen-containing alkyl, C 3 -C 6 ring containing 1-2 heteroatoms, which is unsubstituted or substituted by at least one identical or different C 1 -C 6 alkyl group; -NH-R b ,R b is selected from C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -, -C (O) NH-; R 2 is selected from hydrogen, halogen, nitro, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkyl or C 1 -C 5 haloalkoxy; n is 1, 2, 3 or 4.
  3. 3. The phenylthiophene compound according to claim 2, wherein the compound is a compound represented by formula (I), a prodrug and a pharmaceutically active metabolite thereof, and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, unsubstituted or substituted with at least one of the same or different substituents, the substituents being C 1 -C 6 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 haloalkoxy, C 1 -C 4 nitrogen-containing alkyl, C 3 -C 6 ring containing 1-2 heteroatoms, which is unsubstituted or substituted by at least one identical or different C 1 -C 6 alkyl group; -NH-R b ,R b is selected from C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -, -C (O) NH-; R 2 is selected from hydrogen, halogen, nitro, cyano; n is 1, 2, 3 or 4.
  4. 4. The phenylthiophene compound according to claim 3, wherein the compound is a compound represented by formula (I), a prodrug and a pharmaceutically active metabolite thereof, and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from methyl, ethyl, isopropyl, vinyl, isopropenyl, 2-methylpropenyl, cyclopropyl; -NH-Ar, ar being selected from unsubstituted or 1-2 identical or different R a substituted benzene rings, R a being selected from hydrogen, fluoro, trifluoromethoxy, dimethylamino, piperidinyl, N-methylpiperazinyl, morpholinyl; -NH-R b ,R b is selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl, cyclopentyl; X is selected from-CH 2 -、-C(O)-、-S(O 2 ) -; r 2 is selected from hydrogen, halogen; n is 1, 2, 3 or 4.
  5. 5. The phenylthiophene compound according to claim 1, wherein the salt of the compound represented by formula (I) is formed by a compound represented by 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 phenylthiophene compounds according to claim 1, wherein the compounds shown in formula (I), prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, are used for preparing TRK therapeutic agents.
  7. 7. The use of the phenylthiophenes according to claim 6, wherein the use of the compounds of formula (I), prodrugs and pharmaceutically active metabolites thereof and pharmaceutically acceptable salts thereof for the preparation of TRK inhibitors.
  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 thiophene compound and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and relates to a phenyl thiophene compound, a preparation method thereof and application thereof as a therapeutic agent, in particular to a TRK inhibitor. Background Tumors are one of the most common causes of mortality, and their treatment modalities are complex and diverse, common treatments including surgery, chemotherapy, and radiation therapy. However, these conventional therapies often place a significant physical burden on the patient. In order to improve the efficacy and reduce the side effects, more and more comprehensive treatment schemes are applied to clinic, such as immunotherapy, traditional Chinese medicine therapy, microwave therapy and the like. These regimens can combine the physical condition, tumor type and pathological features of the patient, promote cure rate and improve the quality of life of the patient. Therefore, in order to provide more accurate and less side-effect treatment for cancer patients, the development of highly efficient, selective and low-toxicity targeted antitumor drugs has become an important direction of current drug research. Tropomyosin receptor kinases (tropomyosin receptor kinase, TRKs) belong to the family of receptor tyrosine kinases (receptor tyrosine kinase, RTKs), and activation of TRKs plays a critical role in neuronal differentiation, growth and survival, particularly in synaptic plasticity in the mammalian central and peripheral nervous systems. The primary biological function of the TRK family is to regulate cell differentiation, proliferation and survival, and when TRK is dysfunctional, it leads to excessive activation of downstream signaling pathways, thereby inducing the occurrence of cancer. The TRK family comprises three different types of receptor kinases, TRKA, TRKB and TRKC, encoded by neurotrophic factor receptor tyrosine kinase 1, 2, 3 (neurotrophin receptor kinase, NTRK 1/2/3) genes, respectively, and NTRK gene fusion is closely related to the occurrence and development of cancer. Since the gene fusion product is the major oncogene observed, other targeting strategies (such as antibody therapy) will be ineffective because transmembrane tyrosine kinase fusion typically lacks an extracellular domain. In this case, the fusion protein is only sensitive to small molecule inhibitors. Therefore, attempts to find new agents for the treatment of tumors caused by NTRK gene fusion have great practical and economic value. Disclosure of Invention The invention aims to provide a class of phenyl thiophene compounds, a preparation method thereof and application thereof as a therapeutic agent, particularly a TRK inhibitor. In order to achieve the above purpose, the invention adopts the following technical scheme: a phenyl thiophene compound, which is a compound shown as a formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 3-C7 cycloalkyl, unsubstituted or substituted with at least one of the same or different substituents, the substituents being C 1-C6 alkyl; -NH-Ar, -O-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-C6 haloalkoxy, C 1-C6 nitrogen-containing alkyl, C 3-C7 ring containing at least one heteroatom, unsubstituted or substituted by at least one identical or different C 1-C6 alkyl; -NH-R b、-O-Rb,Rb is selected from C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 3-C7 cycloalkyl; x is selected from-CH 2-、-C(O)-、-S(O2) -, -C (O) NH-, -C (O) O-; R 2 is selected from hydrogen, halogen, nitro, cyano, C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 haloalkyl or C 1-C6 haloalkoxy; n is 1, 2, 3 or 4. Preferably, the compounds are compounds of formula (I), prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, C 3-C5 cycloalkyl, unsubstituted or substituted with at least one of the same or different substituents, the substituents being C 1-C6 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 haloalkoxy, C 1-C4 nitrogen-containing alkyl, C 3-C6 ring containing 1-2 heteroatoms, which is unsubstituted or substituted by at least one identical or different C 1-C6 alkyl group; -NH-R b,Rb is selected from C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, C 3-C7 cycloalkyl; X is selected from-CH 2-、-C(O)-、-S(O2) -, -C (O) NH-; R 2 is selected from hydrogen, halogen, nitro, cyano, C 1-C5 alkyl, C 1-C5 alkoxy, C 1-C5 haloalkyl or C 1-C5 haloalkoxy; n is 1, 2, 3 or 4. Further preferred are compounds of formula (I), prodrugs and pharmaceutically a