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CN-116917280-B - Tetrahydronaphthalene compound, preparation method thereof and application thereof in medicine

CN116917280BCN 116917280 BCN116917280 BCN 116917280BCN-116917280-B

Abstract

The present disclosure relates to tetrahydronaphthalene compounds, methods for their preparation and their use in medicine. In particular, the present disclosure relates to tetrahydronaphthalene compounds of general formula (I), a process for their preparation and pharmaceutical compositions containing them and their use as therapeutic agents, in particular as estrogen receptor degrading agents, in the manufacture of a medicament for the treatment and/or prophylaxis of estrogen receptor mediated or dependent diseases or conditions and in the manufacture of a medicament for the treatment and/or prophylaxis of diseases or conditions by degradation of a target protein.

Inventors

  • YANG FANGLONG
  • YU NAN
  • LIU ZHIWEI
  • HE FENG
  • TAO WEIKANG

Assignees

  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20220329
Priority Date
20210329

Claims (20)

  1. 1. A compound of formula (II) or a pharmaceutically acceptable salt thereof: Wherein: R 3a is C 1-6 alkyl or 5 or 6 membered heterocyclyl; R 3b is a hydrogen atom; X is an oxygen atom or CH 2 ; r 1 is a hydrogen atom; Each of G 1 、G 2 、G 3 and G 4 is independently CR 7 ; Z 1 、Z 3 and Z 4 are CR 8 , or Z 1 is nitrogen atom, Z 3 and Z 4 are CR 8 ; L is J is an integer from 0 to 10; R 4a and R 4b are hydrogen atoms; R 5a and R 5b are both hydrogen atoms, or R 5a and R 5b together form an oxo group; each R 7 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group; each R 8 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group.
  2. 2. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is And j is 0.
  3. 3. The compound represented by the general formula (II) according to claim 1, wherein R 5a and R 5b are each a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  4. 4. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III): Wherein: j is 0; x, G 1 to G 4 、Z 1 、Z 3 、Z 4 、R 1 、R 3a 、R 3b 、R 4a and R 4b are as defined in claim 1.
  5. 5. The compound represented by the general formula (II) according to claim 1, wherein R 3a is a C 1-6 alkyl group and R 3b is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  6. 6. The compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, wherein G 1 、G 2 、G 3 and G 4 are each the same or different from CR 7 ;R 7 and are each independently a hydrogen atom or a halogen.
  7. 7. A compound of the general formula (II) according to claim 1, wherein Z 1 、Z 3 and Z 4 are both CH, or Z 1 is a nitrogen atom, and Z 3 and Z 4 are CH, or a pharmaceutically acceptable salt thereof.
  8. 8. The compound of formula (II) according to claim 1, wherein Z 1 、Z 3 and Z 4 are both CH, or a pharmaceutically acceptable salt thereof.
  9. 9. The compound of formula (II) according to claim 1, wherein X is CH 2 , or a pharmaceutically acceptable salt thereof.
  10. 10. A compound or a pharmaceutically acceptable salt thereof selected from the following compounds:
  11. 11. a process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising: Subjecting a compound shown in the general formula (IIIa) and a compound shown in the general formula (VI) or a salt thereof to reductive amination reaction to obtain a compound shown in the general formula (III) or a pharmaceutically acceptable salt thereof; Wherein: x, G 1 to G 4 、Z 1 、Z 3 、Z 4 、R 1 、R 3a 、R 3b 、R 4a 、R 4b and j are as defined in claim 4.
  12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  13. 13. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder by degradation of a target protein.
  14. 14. The use according to claim 13, wherein the disease or condition is selected from abnormal cell proliferation, tumors, immune disorders, diabetes, cardiovascular disorders, infectious disorders and inflammatory disorders.
  15. 15. The use according to claim 13, wherein the disease or condition is a tumour or an infectious disease.
  16. 16. The use of claim 14, wherein the tumor is cancer.
  17. 17. The use of claim 14, wherein the tumor is selected from the group consisting of breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, leukemia, skin cancer, squamous cell cancer, basal cell cancer, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral nerve epithelial tumor, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal tumor, meningioma, neurofibroma, schwannoma, thyroid cancer, wilms' tumor, and teratocarcinoma.
  18. 18. The use according to claim 14, wherein the tumor is selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumors.
  19. 19. The use according to claim 14, wherein the infectious disease is selected from the group consisting of viral pneumonia, influenza, avian influenza, meningitis, gonorrhea or a disease of infection HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, trace virus, rotavirus, coronavirus, EBV, drug resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, gram negative bacteria, gram positive bacteria, atypical bacteria, staphylococci, streptococcus, escherichia coli, salmonella, helicobacter pylori, chlamydiaceae, mycoplasma, fungi, protozoa, enterozoon, helminths, prions or parasites.
  20. 20. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the treatment and/or prophylaxis of an estrogen receptor mediated or dependent disease or condition.

Description

Tetrahydronaphthalene compound, preparation method thereof and application thereof in medicine Technical Field The present disclosure relates to a tetrahydronaphthalene compound, a preparation method thereof and application thereof in medicine, which belongs to the field of medicine. In particular, the present disclosure relates to tetrahydronaphthalene compounds of general formula (I), a process for their preparation and pharmaceutical compositions containing them and their use as therapeutic agents, in particular as estrogen receptor degrading agents, in the manufacture of a medicament for the treatment and/or prophylaxis of estrogen receptor mediated or dependent diseases or conditions and in the manufacture of a medicament for the treatment and/or prophylaxis of diseases or conditions by degradation of a target protein. Background According to the global latest cancer burden report issued by the international cancer research Institute (IARC) of the world health organization in 2020, the number of female breast cancer incidences exceeds lung cancer for the first time, and becomes the most common cancer worldwide. Over 226 ten thousand women worldwide have breast cancer, accounting for about 11.7% of all newly diagnosed cancer patients, accounting for 24.5% of the newly diagnosed cancer patients, and are the first to enter the female cancer patients. Of the newly diagnosed patients, 1 per 8 were breast cancer patients. Meanwhile, more than 68 ten thousand people die from breast cancer, accounting for about 6.9% of all cancer deaths, accounting for 15.5% of all global female cancer deaths, and also being the most global female cancer deaths. About 70% of breast cancer patients are estrogen receptor (estrogen receptor, ER) positive breast cancers. Endocrine therapy plays an important role in the treatment of these breast cancer patients. Endocrine therapy is mainly classified into three types, namely, aromatase inhibitors (aromatase inhibitor, AI) capable of inhibiting the conversion of androgens to estrogens and reducing the level of estrogens in the body, selective estrogen receptor modulators (SELECTIVE ESTROGEN RECEPTOR MODULATOR, SERM) capable of antagonizing the activity of estrogen receptors, and selective estrogen receptor degradants (SELECTIVE ESTROGEN RECEPTOR DEGRADER, SERD) capable of antagonizing not only the activity of estrogen receptors but also promoting the degradation of receptors (J.biol. Chem.2006,14, 9607-9615). The only marketed medicine which can exert the drug effect through degrading the estrogen receptor mechanism is Fulvestrant (Fulvestrant), and the clinical application dosage of the Fulvestrant is increased from 250mg to 500mg, so that better clinical curative effect can be obtained. In a study in which the levels of estrogen receptor degradation in a patient's tumor were observed with isotopically labeled estrogen, it was found that the levels of estrogen receptor degradation correlated with the clinical benefit of the patient. While incomplete degradation of estrogen receptors may be associated with early disease progression. However, due to poor water solubility of fulvestrant, low bioavailability, intramuscular administration is difficult to further increase the dose. Therefore, development of a drug having a better effect than fulvestrant on estrogen receptor degradation is necessary. The proteolytic targeting chimera (protein proteolysis-TARGETING CHIMERA, PROTAC) is a hybrid bifunctional small molecule compound. The structure of the kit contains two different ligands, namely an E3 ubiquitin ligase ligand and a ligand combined with target protein, wherein the two ligands are connected by a connecting arm. PROTAC by bringing together the target protein of interest and intracellular E3 ubiquitin ligase, a target protein-PROTAC-E3 ternary complex is formed, then E3 ubiquitin ligase labels the target protein with a ubiquitinated protein tag, a powerful ubiquitination hydrolysis process in the cell is started, and the target protein is specifically degraded by using the ubiquitin-proteasome pathway. Compared with the traditional small molecule inhibitor, PROTAC shows unique advantages that 1) PROTAC does not need to be combined with target protein for a long time and with high strength, and the process of degrading the target protein is similar to catalytic reaction, can circularly combine and degrade the target protein, thereby reducing the system exposure of medicaments and reducing the occurrence of toxic and side effects, 2) the target protein needs to be synthesized again after being degraded to restore functions, so that the degraded target protein shows more efficient and durable anti-tumor effect than inhibiting the activity of the target protein, and does not generate drug resistance caused by mutation of the target protein, and 3) PROTAC has therapeutic potential on targets which are considered to be non-patent at present, such as transcription factors, scaffold prot