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CN-121990971-A - N-phenyl-1H-indole-5-amino compound and preparation method and application thereof

CN121990971ACN 121990971 ACN121990971 ACN 121990971ACN-121990971-A

Abstract

The invention belongs to the technical field of medicines, and relates to an N-phenyl-1H-indole-5-amino compound, a preparation method thereof and application thereof as a therapeutic agent, in particular to a TRK inhibitor. N-phenyl-1H-indole-5-amino compounds, wherein the N-phenyl-1H-indole-5-amino compounds are compounds shown in a formula (I), prodrugs and pharmaceutically active metabolites thereof and pharmaceutically acceptable salts thereof, The compounds related to the invention are not reported in the literature, and have a certain novelty in structure. The preparation process related by the invention is explored and optimized for a long time, and a one-pot method is used for coupling-removing Boc reaction, 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, and can treat tumors caused by NTRK gene fusion.

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 (7)

  1. 1. The N-phenyl-1H-indole-5-amino compound is characterized in that the N-phenyl-1H-indole-5-amino compound is a compound shown in a formula (I), a prodrug and a pharmaceutically active metabolite thereof and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from-CN, -CONH 2 、-C(O)H、-COOH、-CONH 2 (CH 2 ) n CH 3 , C 3 -C 7 ring containing at least one heteroatom; n is 0,1, 2 or 3; R 2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy; m is 1,2, 3 or 4, R 2 may be the same or different when m is an integer of 2 to 4; R 3 is selected from-C (O) NH-Ar, -NHC (O) NH-Ar, -C (O) O-Ar, ar is selected from unsubstituted or 1-4 identical or different R a substituted benzene rings and C 1 -C 6 alkoxy; R a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 nitrogen-containing alkyl, C 3 -C 7 ring containing at least one heteroatom, and when R a is greater than 1, two R a form a C 4 -C 10 ring with adjacent carbons on Ar, a C 4 -C 10 ring containing at least one heteroatom.
  2. 2. The N-phenyl-1H-indol-5-amino compound according to claim 1, wherein the N-phenyl-1H-indol-5-amino compound is a compound represented by formula (I), a prodrug and a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt thereof, In the formula, R 1 is selected from-CN, -CONH 2 、-C(O)H、-COOH、-CONH 2 (CH 2 ) n CH 3 , C 3 -C 6 ring containing 1-2 hetero atoms; n is 0 or 1; R 2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy; m is an integer of 1 to 2, R 2 may be the same or different when m is 2; R 3 is selected from-C (O) NH-Ar, -NHC (O) NH-Ar, -C (O) O-Ar, ar is selected from unsubstituted or 1-4 identical or different R a substituted benzene rings and C 1 -C 6 alkoxy; r a is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 nitrogen-containing alkyl, C 3 -C 6 ring containing at least one heteroatom, and when R a is greater than 1, two adjacent R a groups form a C 4 -C 10 ring with adjacent carbons on Ar, C 4 -C 10 ring containing at least one heteroatom.
  3. 3. The N-phenyl-1H-indol-5-amino compound according to claim 2, wherein the N-phenyl-1H-indol-5-amino compound is a compound represented by formula (I), a prodrug and a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt thereof, In the formula, R 1 is selected from-CN, -CONH 2 、-C(O)H、-COOH、-CONH 2 (CH 2 ) n CH 3 , C 3 -C 6 ring containing 1-2 hetero atoms; n is 0 or 1; R 2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, methyl, methoxy, trifluoromethoxy; m is an integer of 1 to 2, R 2 may be the same or different when m is 2; R 3 is selected from-C (O) NH-Ar, -NHC (O) NH-Ar, -C (O) O-Ar, ar is selected from unsubstituted or 1-4 identical or different R a substituted benzene rings and C 1 -C 6 alkoxy; R a is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, methyl, methoxy, trifluoromethoxy, and when R a is greater than 1, two adjacent R a form a C 4 -C 8 ring with adjacent carbons on Ar, a C 4 -C 8 ring containing at least one heteroatom.
  4. 4. The N-phenyl-1H-indol-5-amino compound according to claim 3, wherein the N-phenyl-1H-indol-5-amino compound is a compound represented by formula (I), a prodrug and a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt thereof, In the formula, R 1 is selected from-CN, -CONH 2 ; R 2 is selected from hydrogen and amino, m is an integer of 1-2, and R 2 can be the same or different when m is 2; R 3 is selected from-C (O) NH-Ar, -NHC (O) NH-Ar, ar is selected from unsubstituted or 1-3 benzene rings substituted by R a , C 1 -C 4 alkoxy, R a is selected from hydrogen, halogen, methyl, methoxy, trifluoromethoxy and dimethylamino, and when R a is greater than 1, two adjacent R a and adjacent carbon on Ar form a ring of C 4 -C 8 containing at least one heteroatom.
  5. 5. The N-phenyl-1H-indol-5-amino compound according to any one of claims 1-4, wherein the pharmaceutically acceptable salt of the compound is a salt with an acid selected from the group consisting of 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 and aspartic acid.
  6. 6. The use of the N-phenyl-1H-indol-5-amino compound of claim 1, wherein the compound of formula (I), prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, are useful in the preparation of TRK therapeutics.
  7. 7. The use of the N-phenyl-1H-indol-5-amino compound according to claim 6, wherein the use of the compound of formula (I), a prodrug and a pharmaceutically active metabolite thereof, and a pharmaceutically acceptable salt thereof, for the preparation of a TRK inhibitor.

Description

N-phenyl-1H-indole-5-amino compound and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and relates to an N-phenyl-1H-indole-5-amino compound, a preparation method thereof and application thereof as a therapeutic agent, in particular to a TRK inhibitor. Background Tumor development and progression are often closely related to genetic variation, abnormalities in signal pathways, and imbalance in cell cycle regulation. Among these oncogenic factors, driving gene mutations, such as EGFR, ALK, ROS a 1, have become effective targets for the treatment of certain cancers. In recent years, NTRK (neurotrophic receptor tyrosine kinase) gene fusion has been found in a variety of tumors, becoming a new oncogenic driving mechanism. The NTRK gene encodes three receptors of the TRK family, TRKA (NTRK 1), TRKB (NTRK 2) and TRKC (NTRK 3), which play a key role in the development of the nervous system. However, when fusion mutations occur in the NTRK gene, fusion proteins are produced that autonomously activate tyrosine kinase activity, driving downstream signaling pathways (e.g., MAPK, PI3K-AKT, etc.), leading to proliferation and survival of cancer cells. NTRK gene fusion was originally found in some rare tumors, such as congenital fibrosarcoma and secretory breast cancer. However, with the application of high throughput sequencing technology, researchers have found NTRK gene fusions in a variety of solid tumors, including lung cancer, thyroid cancer, colorectal cancer, breast cancer, neuroblastoma, and the like. These fusion mutations are often associated with high tumor dependence and treatment difficulties, and thus small molecule inhibitors targeting these fusion proteins are an important advance in anti-tumor therapy. Existing TRK inhibitors, such as Larotrectinib and Entrectinib, show better efficacy in clinical trials on tumors that fuse positive with multiple NTRK genes. However, resistance problems remain and common resistance mechanisms include mutations in the TRK kinase domain, leading to drug failure. 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 N-phenyl-1H-indole-5-amino 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: N-phenyl-1H-indole-5-amino compounds, wherein the N-phenyl-1H-indole-5-amino compounds are compounds shown in a formula (I), prodrugs and pharmaceutically active metabolites thereof and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from-CN, -CONH 2、-C(O)H、-COOH、-CONH2(CH2)nCH3, C 3-C7 ring containing at least one heteroatom; n is 0,1, 2 or 3; R 2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C 1-C4 alkyl, C 1-C4 alkoxy, C 1-C4 haloalkoxy; m is 1,2, 3 or 4, R 2 may be the same or different when m is an integer of 2 to 4; R 3 is selected from-C (O) NH-Ar, -NHC (O) NH-Ar, -C (O) O-Ar, ar is selected from unsubstituted or 1-4 identical or different R a substituted benzene rings, C 1-C6 alkoxy, R a is selected from hydrogen, halogen, C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 haloalkoxy, C 1-C6 nitrogen-containing alkyl, C 3-C7 ring containing at least one heteroatom, and when R a is greater than 1, two adjacent R a forms a C 4-C10 ring with adjacent carbons on Ar, a C 4-C10 ring containing at least one heteroatom. Preferably, the N-phenyl-1H-indole-5-amino compounds are compounds shown in the formula (I), prodrugs and pharmaceutically active metabolites thereof and pharmaceutically acceptable salts thereof, In the formula, R 1 is selected from-CN, -CONH 2、-C(O)H、-COOH、-CONH2(CH2)nCH3, C 3-C6 ring containing 1-2 hetero atoms; n is 0 or 1; R 2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C 1-C4 alkyl, C 1-C4 alkoxy, C 1-C4 haloalkoxy; m is an integer of 1 to 2, R 2 may be the same or different when m is 2; R 3 is selected from-C (O) NH-Ar, -NHC (O) NH-Ar, -C (O) O-Ar, ar is selected from unsubstituted or 1-4 identical or different R a substituted benzene rings and C 1-C6 alkoxy; r a is selected from the group consisting of hydrogen, halogen, C 1-C4 alkyl, C 1-C4 alkoxy, C 1-C4 haloalkoxy, C 1-C4 nitrogen-containing alkyl, C 3-C6 ring containing at least one heteroatom, and when R a is greater than 1, two adjacent R a groups form a C 4-C10 ring with adjacent carbons on Ar, C 4-C10 ring containing at least one heteroatom. Still more preferably, the N-phenyl-1H-indol-5-amino 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-CN,