CN-111825657-B - Bifunctional chimeric heterocyclic compound for targeting and degrading androgen receptor and application thereof

Abstract

The invention relates to a bifunctional chimeric heterocyclic compound for targeting and degrading androgen receptor and application thereof, and in particular provides a compound shown in a formula (I), or an isotopic compound, or an optical isomer, or a tautomer thereof, or a pharmaceutically acceptable salt, or a prodrug thereof, or a solvate thereof, wherein ARB is an androgen receptor recognition/binding part, L is a linking part, U is ubiquitin protease recognition/binding part, and the three parts are connected through chemical bonds. The compound provided by the invention can target and degrade androgen receptor in prostate cancer cells, inhibit proliferation of the prostate cancer cells, and simultaneously show good metabolic stability and pharmacokinetic properties. The compound has good application prospect in preparing protein degradation targeting chimera of androgen receptor and preparing medicaments for treating related diseases (including prostate cancer, breast cancer and kennedy disease) regulated by androgen receptor.

Inventors

• DU WU
• AI CHAOWU
• TU ZHILIN
• CHEN YUANWEI
• LI XINGHAI
• LI HAIBO
• WEN KUN
• FU YIWEI
• LV HAIBIN
• HE JINYUN
• QIN DEKUN
• LI YU
• DUAN JINGYI
• LI YONG

Assignees

• 成都海创药业有限公司

Dates

Publication Date

20260505

Application Date

20200416

Priority Date

20190418

Claims (9)

1. 1. A compound of formula (I), or an isotopic compound thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof: (I) wherein ARB is androgen receptor recognition/binding part, L is linking part, U is ubiquitin protease recognition/binding part, and the three parts are connected by chemical bond; The ARB is selected from the structures of the formula: the L is selected from the structures shown below: ; The U is selected from the structures of the following formula (X-B-1): X-B-1 Wherein R g3 is selected from H and halogen.
2. 2. The compound of claim 1, or an isotopic compound thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: the halogen is chlorine or bromine.
3. 3. The compound of claim 1, or an isotopic compound thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein U is selected from the group consisting of: 。
4. 4. Use of a compound according to any one of claims 1-3, or an isotopic compound thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a protein degradation targeting chimera of an androgen receptor.
5. 5. The method according to claim 4, wherein the protein degradation targeting chimeric is capable of targeting recognition and/or binding to androgen receptor.
6. 6. The method according to claim 4, wherein the protein degradation targeting chimeric is capable of degrading and/or down-regulating androgen receptor.
7. 7. The method according to claim 4 to 6, wherein the protein degradation targeting chimera is an active ingredient of a drug for treating a related disorder modulated by androgen receptor.
8. 8. The method according to claim 7, wherein the disease is selected from the group consisting of prostate cancer, breast cancer, and Kennedy's disease.
9. 9. A medicament for treating related diseases regulated by androgen receptors is characterized in that the medicament is a preparation prepared from the compound, or an isotopic compound, or a tautomer thereof, or pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable auxiliary materials as claimed in any one of claims 1 to 3.

Description

Bifunctional chimeric heterocyclic compound for targeting and degrading androgen receptor and application thereof Technical Field The invention belongs to the field of medicines, and particularly relates to a bifunctional chimeric heterocyclic compound for targeting and degrading androgen receptor and application thereof. Background With the ever-increasing and aging global population, prostate cancer incidence continues to increase, and the primary treatment is androgen deprivation therapy. Androgen receptor (androgen receptor, AR) belongs to the nuclear receptor family and is a ligand-dependent transcription factor. Abnormal regulation of the AR signaling pathway plays an important role in the development and progression of prostate cancer, and studies have shown that castration-resistant prostate cancer (castration-RESISTANT PROSTATE CANCER, CRPC) is still dependent on the role of AR. The androgen receptor comprises 918 amino acids, has a similar structure and function to other nuclear receptors, and consists of three important domains, namely a DNA binding domain (DNA binding domain, DBD), a ligand binding domain (ligand binding domain, LBD) and a nitrogen terminal binding domain (NTD), wherein the DBD and the LBD are connected through a Hinge region (Hinge). The LBD present at the carbon end of AR is the site where AR binds to the ligand, determining the specificity of ligand binding to AR, ligand binding to LBD and thus activating AR. Two transcriptional activation domains have been identified in AR, namely activation domain 1 in the NTD domain (activation function, AF 1) and the highly conserved hydrophobic pocket activation domain 2 in the LBD domain (AF 2). Docetaxel-based chemotherapy was the only treatment that extended survival of metastatic CRPC patients before 2010. Protein degradation targeting chimeras (PROTACs) have received great attention as small molecules capable of inducing degradation of target proteins. PROTACs as bifunctional molecules comprising a small molecule compound capable of binding to a target protein (protein of interest, POI), introducing a linking group at a suitable position thereof, and linking to a small molecule compound capable of binding to ubiquitin-proteinase. The obtained small molecular probe can be combined with target protein and ubiquitin protease at the same time, so that target protein ubiquitination is promoted, and the protein subjected to multiple ubiquitination can be recognized and degraded by a proteasome. By utilizing PROTACs strategy, the protein degradation targeting chimeric body capable of targeting and recognizing/combining the androgen receptor is prepared, the level of the androgen receptor can be regulated and controlled through an intracellular ubiquitin-proteasome degradation system, and the androgen receptor degradation is induced, so that the effect of treating related diseases such as prostate cancer and the like regulated and controlled by the androgen receptor is achieved. Therefore, a bifunctional chimeric molecule capable of targeting and combining with an androgen receptor and effectively reducing Jie Xiong hormone receptor is developed, and has good application prospect in treating related diseases regulated by the androgen receptor. Disclosure of Invention The invention aims to provide a protein degradation targeting chimeric body which has stronger targeting binding capacity with androgen receptor and higher activity of Jie Xiong hormone receptor. The present invention provides a compound represented by formula (I), or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof: wherein ARB is androgen receptor recognition/binding part, L is linking part, U is ubiquitin protease recognition/binding part, and the three parts are connected by chemical bond; wherein the ARB is selected from the structures represented by the formula (I-A): Wherein W 1 is selected from substituted or unsubstituted aryl or heteroaryl, the substituents on W 1 are each independently selected from halogen, hydroxy, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF 3, heterocyclyl, C 1-6 alkyl or its halo or its deuterated, C 3-6 cycloalkyl, C 1-6 alkoxy or its halo or its deuterated, C 1-6 alkylamino, C 2-6 alkenyl or C 2-6 alkynyl; Each Y 1,Y2,Y3,Y4 is independently selected from a bond, O, S, NR 1,CR2R3, C=O, C=S, SO or SO 2, each R 1,R2,R3 is independently selected from H, C 1-6 alkyl or a halo or deutero thereof, a 3-8 membered cycloalkyl or heterocyclyl containing 0-2 heteroatoms, or R 2 and R 3 are linked to form a 3-8 membered ring containing 0-2 heteroatoms; Q is selected from saturated cycloalkyl, saturated heterocyclic group substituted by 0-6R q, or aryl or heteroaryl containing 0-4 hetero atoms, R q is independently selected from H, D, OH, halogen, C 1-6 alkyl or halogeno, C 1-6 alkoxy or halogeno, or 2 substituents are connect