Androgen Receptor Degrading Compounds and Their Pharmaceutical Uses

Abstract

This disclosure provides compounds or pharmaceutically acceptable salts thereof having a specific chemical structure that exhibits excellent androgen receptor (AR) degradation activity and superior pharmacokinetic and pharmacodynamic properties. This disclosure also provides compositions comprising such compounds or pharmaceutically acceptable salts thereof. Furthermore, this disclosure provides pharmaceutical applications of the compounds, salts thereof, and compositions comprising these for the treatment or prevention of AR-related diseases. Finally, this disclosure provides a method for the treatment or prevention of AR-related diseases, comprising administering an effective amount of the compounds, salts thereof, or compositions comprising these to an individual in need of treatment.

Description

[Technical Field]

[0001] This application claims priority based on Korean Patent Application No. 10-2023-0116263 filed on September 1, 2023, and all contents disclosed in the specification and drawings of the said application are incorporated into this application.

[0002] The present disclosure relates to a specific compound that has excellent androgen receptor degrading activity and excellent pharmacokinetic and pharmacodynamic properties. The present disclosure also relates to a pharmaceutical composition comprising such a compound. The present disclosure also relates to a useful method for treating androgen receptor-related diseases using such a compound. That is, the present disclosure relates to the pharmaceutical use of the compound according to the present disclosure for treating or preventing androgen receptor-related diseases. [Background Art]

[0003] Androgen hormone receptor (AR) is a transcription factor belonging to the nuclear hormone receptor (NR) superfamily. In the absence of androgens, AR binds to Heat shock protein 90 (Hsp90) in the cytosol. Hsp90 dissociates from AR, and androgen binds to AR. When AR binds to the hormone dihydrotestosterone (DHT), the resulting complex translocates to the nucleus and activates transcription of target genes through a series of processes.

[0004] AR contributes to the development of masculinity, and it is also a well-known oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). Currently, there are two main approaches to treating androgen-related prostate cancer. The first approach is to regulate androgen levels by removing androgens or preventing their translocation into the nucleus by interfering with the binding of their ligand, DHT. The second approach aims to suppress AR function by targeting AR (Nature Reviews Drug Discovery, 2013, 12, 823-824). In other words, alternative approaches to treating prostate cancer include removing the AR protein. AR is a key driver of tumorigenesis in many forms of prostate cancer.

[0005] Furthermore, AR can be a major target in the treatment of acne, alopecia (especially androgenetic alopecia), cutaneous wounds, and hirsutism (Arch Dermatol Res. 2012 September;304(7):499-510, Biomedicine & Pharmacotherapy 137(2021)111247). AR expression and activation are also known to play an important role in breast cancer (especially androgen receptor-positive triple-negative breast cancer (AR+TNBC)) (npj Breast Cancer (2020) 6:47).

[0006] Representative anti-androgen receptor drugs include enzalutamide and bicalutamide, and apalutamide was recently approved. However, approximately 15-25% of prostate cancer patients do not respond to anti-androgen drugs, and while approved drugs show excellent anti-cancer effects in the initial stages of treatment, drug resistance with continued use makes them unusable, thus urgently necessitating the development of new therapeutic agents.

[0007] PROTAC (Proteolysis Targeting Chimera) technology is a technique that induces the degradation of target proteins using the intracellular protein degradation system (Ubiquitin-Proteasome System). PROTAC compounds consist of a ligand that binds to the target protein, a ligand that binds to an E3 ligase protein, and a linker that connects the two ligands. Through the formation of a target protein-PROTAC compound-E3 ligase complex, it ubiquitinates the target protein and guides it to the proteasome. By degrading and removing the target protein, PROTAC technology is expected to have superior therapeutic efficacy compared to conventional inhibitors and can overcome the problems of toxicity at high doses and the development of tolerance with long-term administration, which are disadvantages of inhibitors.

[0008] Therefore, AR-degrading drugs offer a viable alternative to overcome the limitations of conventional prostate cancer treatments. However, PROTAC-degrading drugs are bifunctional compounds that simultaneously interact with target proteins and E3 ligase proteins to exhibit degradation activity. Since their degradation activity is influenced by various factors such as the structure of each ligand, the structure of the linker, and the binding method to each protein, finding a PROTAC compound with superior degradation activity is extremely difficult. Furthermore, PROTAC-degrading drugs generally have large molecular weights, low solubility, and poor oral absorption. Therefore, various studies are being conducted to derive PROTAC compounds that possess both good pharmacokinetic and pharmacodynamic properties as well as superior degradation activity. [Overview of the project]

[0009] Therefore, the problem that the present invention aims to solve is to provide compounds that exhibit excellent androgen receptor (AR) degradation activity and have excellent pharmacokinetic and pharmacodynamic characteristics, pharmaceutical compositions containing these as active ingredients, and pharmaceutical uses for the treatment or prevention of AR-related diseases.

[0010] Another problem that the present invention aims to solve is to provide a method for treating or improving AR-related diseases, which involves administering a compound according to the present invention, characterized by decomposing AR and consequently reducing AR activity, to patients who require treatment, improvement, or prevention of AR-related diseases.

[0011] <Inventive compound> To solve the above problems, one aspect of the present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0012] [ka]

[0013] In chemical formula 1, R1 is H, halogen (preferably Cl), C 1-3 Alkyl, C 1-3 Alkoxy (preferably -OCH3), or C 1-3 It is a haloalkyl (preferably -CF3), R2 is H, halogen (preferably F), or C 1-3 It is a haloalkyl, X1, X2, and X3 are each independently either CH or N. R3 is H, halogen (preferably F or Cl), C 1-3 Alkyl, or C 1-3 It is a haloalkyl (preferably -CF3), n is 0, 1, or 2.

[0014] The compounds of the present invention exhibit extremely high AR degradation activity by effectively inducing interaction between AR proteins and E3 ligase proteins through a specific structure of AR-binding ligand, an E3 ligase-binding ligand, and a linker that connects these ligands. The compounds of the present invention exhibit remarkably superior AR degradation activity and, upon administration, produce remarkably excellent pharmacological effects, such as anticancer effects. Furthermore, the compounds of the present invention have an excellent pharmacokinetic profile, which contributes to their remarkably superior pharmacodynamic efficacy. Moreover, upon administration, the ratio of plasma concentration to cancer tissue is very high, which is highly advantageous for achieving excellent anticancer effects.

[0015] On the other hand, the compounds of the present invention exhibit excellent decomposition capabilities against AR mutants (such as T878A, M896V, F877L, H875Y, L702H, and W742C). Since resistance to conventional anti-androgen receptor drugs can arise from AR mutations, the excellent AR mutant decomposition capabilities of the compounds of the present invention may help overcome resistance to conventional drugs. [Modes for carrying out the invention]

[0016] In this specification, the terms "substituent," "radical," "group," "moiety," and "fragment" may be used interchangeably.

[0017] If a substituent is described as "arbitrarily substituted" or "selectively substituted," then the substituent may (1) remain unsubstituted or (2) be substituted with one or more of the defined substituents. If the substituted position is unsubstituted, the default substituent is a hydride radical.

[0018] As used herein, the term "alkyl" means a saturated linear or branched acyclic hydrocarbon having 1 to 10 carbon atoms (unless otherwise specified). "Lower alkyl" means a linear or branched alkyl having 1 to 4 carbon atoms. In one embodiment of the present invention, alkyl is a linear or branched alkyl having 1 to 3 carbon atoms. Typical saturated linear alkyls include -methyl, -ethyl, and -n-propyl, and saturated branched alkyls include -isopropyl.

[0019] As used herein, the term "alkoxy" means -O-(alkyl), including -OCH3, -OCH2CH3, -O(CH2)2CH3, and similar groups, where alkyl is defined as described above.

[0020] In this specification, "C 1-6 When written as "C1-6" or "C1-C6", it means that the number of carbon atoms is between 1 and 6. For example, C 1-3 Alkyl refers to alkyl groups with 1 to 3 carbon atoms.

[0021] As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine, or iodine. In one preferred embodiment of the present invention, the halogen is chlorine or fluorine.

[0022] As used herein, the term "haloalkyl" means an alkyl group in which one or more hydrogen atoms are substituted with halogen atoms. For example, haloalkyls include -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and similar groups. In one preferred embodiment of the present invention, the haloalkyl is -CF3, where alkyl and halogen are as defined above.

[0023] In this specification, * or [ka] This means that it is connected to other parts.

[0024] In terms of various aspects such as AR degradation activity, (metabolic) stability, pharmacokinetic properties, and pharmacodynamic properties, one preferred embodiment of the present invention is in the above chemical formula 1, R1 is H, Cl, -CH3, -OCH3, or -CF3. R2 is either H or F. X1, X2, and X3 are each independently either CH or N. R3 is H, F, Cl, -CH3, or -CF3. n is 0, 1, or 2. The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0025] In terms of various aspects such as AR degradation activity, (metabolic) stability, pharmacokinetic properties, and pharmacodynamic properties, one preferred embodiment of the present invention is in the above chemical formula 1, R1 is Cl, -OCH3, or -CF3. R2 is either H or F. X1, X2, and X3 are each independently either CH or N. R3 is F, Cl, or -CF3. n is either 0 or 1. The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0026] In terms of various aspects such as AR degradation activity, (metabolic) stability, pharmacokinetic properties, and pharmacodynamic properties, a more preferred embodiment of the present invention is in the above chemical formula 1, R1 is Cl, -OCH3, or -CF3. R2 is either H or F. X1 and X2 are CH, and X3 is either CH or N. R3 is F or Cl (more preferably, [ka] n is 1. The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0027] In particular, the structure of the E3 ligase-binding ligand, such as the position where the linker is attached to the benzene ring and the position where R3 is attached to the benzene ring, is important for the AR degradation activity of the compound of the present invention.

[0028] Furthermore, a preferred embodiment of the present invention is: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 1), (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 2), (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 3), 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1'-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)-[1,4'-bipiperidine]-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 4), 1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 5), 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperazine-1-carboxamide (Example 6), 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (Example 7), 1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 8), (S)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 9), (R)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 10), 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 11), 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 12), 1-(4-cyano-3-methoxyphenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 13), 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (Example 14), 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (Example 15), 1-(4-cyano-3-methoxyphenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (Example 16), N-(5-((1-((1-(2-chloro-4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (Example 17), or This is 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide (Example 18). The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0029] In the present invention, “pharmaceutically acceptable salts” include salts of active compounds prepared with relatively non-toxic acids and bases, depending on specific substitutions found in the compounds referred herein. When the compounds of the present invention have relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base and a pure or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amino or magnesium, or similar salts. When the compounds of the present invention have relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid and a pure or suitable inert solvent. Examples of pharmaceutically acceptable acidic addition salts include not only salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and their analogues, but also hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydrogen iodide, or phosphorous acid and their analogues. The invention also includes salts of amino acids such as arginate and its analogues, and analogues of organic acids such as glucuronic acid or galactunoric acid and its analogues. Some specific compounds of the present invention possess both basic and acidic functionality, which allows them to be converted into basic or acidic addition salts. Other examples of salts are well known through literature known in the art to which the present invention belongs.

[0030] In this specification, the term “compound of the present invention” includes not only each compound of Chemical Formula 1, but also their clathrates, hydrates, solvates, polymorphs, or isotopically labeled analogs. Furthermore, the term “compound of the present invention” also includes pharmaceutically acceptable salts of the compounds of the present invention unless otherwise specified. In one embodiment, the compounds of the present invention may exist as stereoisomerically pure compounds (e.g., compounds with substantially no other stereoisomers (e.g., 85% ee or higher, 90% ee or higher, 95% ee or higher, 97% ee or higher, or 99% ee or higher)). That is, if a compound of Chemical Formula 1 or a salt thereof according to the present invention is a tautomer and / or stereoisomer (e.g., a geometrical isomer and a conformational isomer), then each of their separated isomers and mixtures is also included in the category of compounds of the present invention. If a compound or salt thereof of the present invention has an asymmetric carbon in its structure, optically active compounds and racemic mixtures thereof are also included in the category of compounds of the present invention. In this specification, the term “solvent compound” means a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent forces. Preferred solvents are volatile and non-toxic and can be administered to humans in very small amounts.

[0031] In this specification, the term "hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent forces.

[0032] In this specification, the term "clathrate" means a crystalline lattice compound or salt thereof of the present invention that includes spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0033] As used herein, the term "isotope-labeled analog" refers to a compound in which one or more atoms of the compound of the present invention are replaced with an atom (isotopologue) having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of isotopes that can be incorporated into the compounds described herein are each 2 H ("D"), 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine. For example, a compound described herein may have one or more H atoms replaced with deuterium. Unless otherwise specified, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure described herein are included within the scope of the present disclosure except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by 13 C- or 14 C-enriched carbon. In some embodiments, 3 H and 14 certain isotope-labeled compounds such as those labeled with C may be useful for analysis of compound and / or substrate tissue distribution. Tritiated ( 3 H) and carbon-14 ( 14C) Isotopes are particularly preferred due to their ease of preparation and detection. Substitution with heavier isotopes, such as deuterium, is also preferred in some situations because it can provide specific therapeutic advantages through greater metabolic stability, such as an increased in vivo half-life or a reduced dosage requirement. Isotope-labeled compounds can generally be prepared by substituting non-isotope-labeled reagents with isotope-labeled reagents, using procedures similar to those described herein, for example, in the Examples section.

[0034] In this specification, the term "purified" means that, upon separation, the separated product is 90% or more pure, in one embodiment 95% or more pure, in another embodiment 99% or more pure, and in yet another embodiment 99.9% or more pure.

[0035] <Method for producing the compound of the present invention> One embodiment of the present invention provides a method for producing the compound of chemical formula 1 according to the present invention.

[0036] The compound of chemical formula J used to synthesize the compound of the present invention can be produced by the method of reaction 1 or 2 below.

[0037] [ka]

[0038] In reaction equation 1, Hal is a halogen, R is an alkyl group, P is a protecting group, X2 is CH, and the remaining definitions are as defined in chemical formula 1 above.

[0039] A compound of chemical formula D can be produced by reacting a compound of chemical formula A with a compound of chemical formula B at high temperature or with a metal catalyst, followed by a hydrolysis reaction, or by reacting a compound of chemical formula A with piperidine-4-carboxylic acid at high temperature.

[0040] The compound of chemical formula G can be produced by a reduction reaction between the compound of chemical formula E and the compound of chemical formula F, which is produced by reacting the compound of chemical formula E with a piperidine-4-ol that has a protected amine group, or by an amination reaction between the compound of chemical formula H and the compound of chemical formula I, which is produced by reacting the compound of chemical formula H with a piperidine-4-ol that has a protected amine group.

[0041] A compound of chemical formula J can be produced by reacting a compound of chemical formula D with a compound of chemical formula G at room temperature using a suitable coupling reagent.

[0042] [ka]

[0043] In reaction equation 2, Hal is a halogen, P is a protecting group, X2 is nitrogen, and the remaining definitions are the same as those in chemical formula 1 above.

[0044] Compound K can be produced by reacting compound A with piperazine at high temperature. Compound L can be produced by reacting compound G with phenyl chloroformate at room temperature. Compound J can be produced by reacting compound K and compound L at high temperature.

[0045] The compounds of the present invention can be produced by the method of reaction formula 3 or 4 below.

[0046] [ka]

[0047] In reaction equation 3, Hal is a halogen, P is a protecting group, n is 1 or 2, m is 0 or 1, and the remaining definitions are as defined in chemical formula 1 above.

[0048] A compound of chemical formula T can be produced by sequentially performing oxidation, acetal protection, reduction, and alkylation reactions on a compound of chemical formula P, which is produced by reacting a compound of chemical formula O with a piperidine substituted with a hydroxyalkyl group. A compound of chemical formula 1 can be produced by reductive amination at room temperature of a compound of chemical formula N, which is produced by deprotecting a compound of chemical formula T, and a compound of chemical formula M, which is produced by deprotecting a compound of chemical formula J. A stereoselective compound of chemical formula T can be obtained through stereoselective separation methods such as SFC (Supercritical Fluid Chromatography).

[0049] [ka]

[0050] In reaction equation 4, Hal is a halogen, n is 0, and the remaining definitions are as defined in chemical formula 1 above.

[0051] Compound Z can be produced by sequentially performing an acetal protection reaction, a reduction reaction, and an alkylation reaction on the compound W prepared by reacting the compound V with 4-piperidone. Compound U, prepared by deprotecting the compound Z, can be produced by reductive amination of the compound U and the compound M at room temperature. Compound Z, which exhibits stereoselectivity, can be obtained through stereoselective separation methods such as SFC.

[0052] The reaction conditions for the above reaction can be modified, as is well known in this industry.

[0053] The manufacturing methods for reaction equations 1 to 4 described above will be further elaborated in the examples described later.

[0054] <Pharmaceutical uses and therapeutic methods of the compound of the present invention> The present invention further provides a method for treating the following diseases or conditions in individuals who have or are prone to having the following diseases or conditions by administering a therapeutically effective amount of one or more of the above compounds to an individual. In one embodiment, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In yet another embodiment, the treatment is a restorative treatment.

[0055] 1. Disease or condition The AR-degrading compounds of the present invention are useful for a variety of therapeutic or preventive applications (e.g., cancer, prostate cancer, Kennedy's disease; spinal and bulbar muscular atrophy). Such compounds are used to degrade AR and reduce AR activity, and may further be used for the treatment of AR-related diseases or to prevent the exacerbation of such diseases. Accordingly, the present invention provides a method for degrading intracellular AR. In such a method, the cells come into contact with an effective amount of the compound of the present invention. In one embodiment, the cells are present within an organism. The method of the present invention involves administering a pharmaceutical composition containing a therapeutically or preventively effective amount of the compound according to the present invention to an organism in need of treatment or prevention.

[0056] In one embodiment, the present invention provides a method for degrading AR within cells of individuals with AR-related diseases. For example, the present invention may be used to degrade AR within cells of individuals having AR-related diseases, as described below, thereby reducing AR activity. In another embodiment of the present invention, the present invention may be used to degrade AR within cells of cancer, particularly prostate cancer cells.

[0057] In another embodiment, the present invention provides a method for treating AR-related diseases, comprising the step of administering a therapeutically effective amount of the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual. Such a method comprises the step of administering to an individual in need of treatment an amount sufficient to break down AR, i.e., a therapeutically effective amount of the compound of the present invention. In such a method, the compound of the present invention may be administered to the individual in the form of a pharmaceutical composition described herein.

[0058] In this invention, AR-related diseases are not limited to these, but include asthma, multiple sclerosis, cancer (especially prostate cancer, breast cancer (especially androgen receptor-positive triple-negative breast cancer (AR+TNBC))), Kennedy's disease, acne, alopecia (especially androgenic alopecia), cutaneous wound, hirsutism, ciliopathy, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, and cystic fibrosis. These include fibrosis, Duchenne muscular dystrophy, hemochromatosis, haemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome, sickle-cell disease, Tay-Sachs disease, and Turner syndrome. In a preferred embodiment of the present invention, the AR-related disease is cancer, more preferably prostate cancer.

[0059] In other words, the present invention provides pharmaceutical uses of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for treating or preventing the aforementioned disease.

[0060] 2. Subjects The preferred subjects to be treated by the present invention include mammals. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, and intrauterine mammals.

[0061] In one embodiment, the preferred subject to be treated by the present invention is human.

[0062] 3. Administration and Dosing The compounds of the present invention are generally administered in therapeutically effective amounts.

[0063] As used herein, “effective amount” means an amount of the compound of the present invention sufficient to delay or minimize the progression of AR-related disease, or to provide therapeutic benefits in the treatment or management of AR-related disease. “Effective amount” also means an amount sufficient to suppress or reduce AR activity, either in vitro or in vivo.

[0064] The compounds of the present invention can be administered by any preferred route, in the form of a pharmaceutical composition appropriate to such route, and in an effective dose for the intended treatment. The effective dose is generally about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg / day, in single or divided doses. Depending on age, species, and the disease or condition being treated, dose levels below the lower limit of this range may be appropriate. In other cases, even higher doses may be used without adverse side effects. Higher doses may be divided into several smaller doses for administration throughout the day.

[0065] <Pharmaceutical composition of the inventive compound> In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive. In one embodiment of the present invention, the pharmaceutical composition is used for the treatment or prevention of AR-related diseases, preferably prostate cancer, as described later.

[0066] The term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation, generally considered safe for such use, officially approved for such use by a national regulatory body, or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0067] <Pharmaceutical composition, dosage form, and route of administration> To treat the diseases or conditions described herein, the compounds or pharmaceutically acceptable salts thereof may be administered as follows:

[0068] Oral administration The compounds of the present invention may be administered orally, and the oral cavity is a concept that includes swallowing. By oral administration, the compounds of the present invention may enter the gastrointestinal tract, or they may be absorbed directly into the bloodstream from the oral cavity, for example, by buccal or sublingual administration.

[0069] A suitable composition for oral administration may be solid, liquid, gel, or powder, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0070] Compositions for oral administration may be selectively enteric-coated, and the enteric coating may embody delayed or sustained release. That is, compositions for oral administration according to the present invention may be dosage forms having immediate release or modified release patterns.

[0071] Liquid dosage forms may include solutions, syrups, and suspensions, and such liquid compositions may be in the form of being filled into soft or rigid capsules. Such dosage forms may contain a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose, or oil. The dosage forms may also contain one or more emulsifiers and / or suspending agents.

[0072] In tablet formulations, disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof. Lubricants for manufacturing tablets include talc, silicon dioxide, stearic acid, calcium stearate, zinc stearate, magnesium stearate, and sodium stearyl fumarate, but the present invention is not limited by the type of such additive. Binders for manufacturing tablets may include gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Suitable diluents for manufacturing tablets may include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, and microcrystalline cellulose, but the present invention is not limited by the type of such additive.

[0073] Solubilizers that can be selectively incorporated into tablets include, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, gelucire TM ), caprylic / capric acid mono / diglyceride, sorbitan fatty acid ester, solutol TMExamples include HS, but the present invention is not limited to such specific types of solubilizing agents.

[0074] Parenteral administration The compounds of the present invention can be administered directly into the bloodstream, muscles, or internal organs. Preferred methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, and intracranial injections. Preferred apparatus for parenteral administration includes syringes (including needles and needleless syringes) and injection methods.

[0075] Compositions for parenteral administration may be in dosage forms having an immediate or modified release pattern, the modified release pattern may be a delayed release pattern or a sustained release pattern.

[0076] Most parenteral dosage forms are liquid compositions, and such liquid compositions are aqueous solutions containing the pharmaceutically active ingredient, salt, buffer, isotonic agent, etc., according to the present invention.

[0077] Furthermore, parenteral dosage forms may be manufactured in a dry form (e.g., lyophilized) or as a sterile non-aqueous solution. These dosage forms may be used with a suitable vehicle, such as sterile water. Solubility enhancers may also be used in the manufacture of parenteral solutions.

[0078] Topical administration The compounds of the present invention can be administered topically via the skin or transderm. Dosage forms for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration dosage forms may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.

[0079] Compositions for topical administration may be in dosage forms having an immediate or modified release pattern, the modified release pattern may be a delayed-release pattern or a sustained-release pattern.

[0080] Effects of the invention The present invention provides compounds with excellent AR degradation activity and superior pharmacokinetic and pharmacodynamic properties, pharmaceutical compositions containing these as active ingredients, pharmaceutical uses thereof (particularly for prostate cancer), and therapeutic methods comprising administering these to individuals in need of treatment or prevention. The compounds according to the present invention or pharmaceutically acceptable salts thereof are excellent in various aspects such as activity, (metabolic) stability, and pharmacodynamic properties. [Examples]

[0081] The present invention will be described in detail below, including examples, to aid in understanding the present invention. However, the examples of the present invention can be modified into a variety of other forms, and the scope of the present invention should not be construed as being limited to the examples described below. The examples of the present invention are provided to give a more complete explanation of the present invention to a person with average knowledge of the art to which the present invention belongs.

[0082] The synthesized compounds were analyzed as follows: Nuclear magnetic resonance (NMR) spectroscopy was performed using a 400 MHz spectrometer from JEOL, and chemical shift was analyzed in ppm. LC-MS was performed using a Waters ACQUITY UPLC H-Class PLUS. MPLC was performed using a Biotage Isolera instrument and Sfδr Silica column, and chiral separation was performed using a Waters 150 Prep-SFC instrument and a Daicel chiral cell column. The starting materials were synthesized according to the literature using known compounds or obtained commercially.

[0083] <Production of the compound of the present invention> The synthesis process of some of the compounds of the present invention is described below. Compounds not described below can be produced by similar methods by substituting the starting materials, intermediates, and / or reactants.

[0084] Intermediate 1-1,1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid [ka]

[0085] 4-Fluoro-2-(trifluoromethyl)benzonitrile (5.00 g, 26.4 mmol), piperidine-4-carboxylic acid (3.41 g, 15.9 mmol), and DIPEA (11.0 ml, 79.2 mmol) were suspended in DMSO (20.0 ml) and stirred at 90°C for 16 hours. 100 ml of 1 M aqueous HCl was added to the reaction mixture, and the mixture was extracted with SiO2 (50 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (SiO2) to obtain 5.98 g (76%) of a beige solid. m / z 299.06 [M+H] + .

[0086] Intermediate 1-2,1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)piperidine-4-carboxylic acid [ka]

[0087] Step 1: Synthesis of ethyl 1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)piperidine-4-carboxylate 5-Bromo-3-(trifluoromethyl)-2-pyridinecarbonitrate (500 mg, 1.99 mmol), ethylpiperidine-4-carboxylate (344 mg, 2.19 mmol), CuI (38 mg, 0.199 mmol), and K2CO3 (550 mg, 3.98 mmol) were suspended in DMF (3.0 ml) and stirred with a microwave at 150°C for 1 hour. Distilled water (10 ml) was added to the reaction mixture and extracted with EtOAC (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (30% Â / hexane) to obtain 449 mg (69%) of a white solid. m / z 328.09 [M+H] + .

[0088] Step 2: Synthesis of 1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)piperidine-4-carboxylic acid Ethyl 1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)piperidine-4-carboxylate (449 mg, 1.37 mmol) was suspended in THF (10.0 ml) and distilled water (5.0 ml), then LiOH monohydrate (230 mg, 5.49 mmol) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, 15 ml of 1 M aqueous HCl solution was added and the mixture was extracted with RINKAN (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 327 mg (81%) of a white solid. m / z 300.05 [M+H] + .

[0089] Intermediate 1-3,4-(piperazin-1-yl)-2-(trifluoromethyl)benzonitrile [ka]

[0090] 4-Fluoro-2-(trifluoromethyl)benzonitrile (1.00 g, 5.29 mmol) and piperazine (683 mg, 7.93 mmol) were suspended in DMF (10.0 ml) and stirred at 85°C for 16 hours. Distilled water (20 ml) was added to the reaction mixture and extracted with siRNA (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH / DCM) to obtain 868 mg (64%) of a white solid. m / z 256.13 [M+H] + .

[0091] Intermediate 1-4,1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid [ka]

[0092] Intermediate 1-4 was synthesized using 2-chloro-4-fluorobenzonitrile instead of 4-fluoro-2-(trifluoromethyl)benzonitrile, in the same manner as intermediate 1-1.

[0093] Intermediate 1-5,1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid [ka]

[0094] Step 1: Synthesis of 3,4-difluoro-2-(trifluoromethyl)benzonitrile 1-Bromo-3,4-difluoro-2-(trifluoromethyl)benzene (300 mg, 1.15 mmol) and CuCN (113 mg, 1.27 mmol) were suspended in NMP (3.0 ml) and stirred at 150°C for 3 hours. Distilled water (10 ml) was added to the reaction mixture and extracted with EtOAC (10 ml x 2). The organic layer was washed with saturated NaCl aqueous solution and 50% NH4Cl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 232 mg of brown oil (mixture).

[0095] Step 2: Synthesis of ethyl 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylate 3,4-Difluoro-2-(trifluoromethyl)benzonitrile (232 mg, mixture), ethylpiperidine-4-carboxylate (163 mg, 1.27 mmol), and DIPEA (0.40 mL, 2.30 mmol) were suspended in ACN (2.0 ml) and stirred at 90°C for 16 hours. Distilled water (10 ml) was added to the reaction mixture and extracted with EtOAC (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was subjected to MPLC (15% siRNA / hexane) to obtain 130 mg of a white solid (33%, two-step yield). m / z 345.29 [M+H] + .

[0096] Step 3: Synthesis of 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid Ethyl 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylate (130 mg, 0.378 mmol) was suspended in a mixed solvent of THF (3.0 ml), MeOH (1.0 ml), and distilled water (1.0 ml). LiOH monohydrate (30 mg, 0.756 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then 15 ml of 1 M aqueous HCl solution was added and extracted with RINKAN (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 84 mg (70%) of a white solid. m / z 317.25 [M+H]+ .

[0097] Intermediate 1-6,1-(3-chloro-4-cyano-2-fluorophenyl)piperidine-4-carboxylic acid [ka]

[0098] Intermediate 1-6 was synthesized using 2-chloro-3,4-difluorobenzonitrile instead of 4-fluoro-2-(trifluoromethyl)benzonitrile, in the same manner as intermediate 1-1.

[0099] Intermediate 1-7,1-(4-cyano-3-methoxyphenyl)piperidine-4-carboxylic acid [ka]

[0100] Intermediate 1-7 was synthesized using 4-fluoro-2-methoxybenzonitrile instead of 4-fluoro-2-(trifluoromethyl)benzonitrile, in the same manner as intermediate 1-1.

[0101] Intermediate 2-1,1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde [ka]

[0102] Step 1: Synthesis of (1-(2-fluoro-4-nitrophenyl)piperidine-4-yl)methanol 1,2-Difluoro-4-nitrobenzene (10.0 g, 62.8 mmol), 4-piperidine methanol (7.96 g, 69.1 mmol), and DIPEA (13.0 ml, 75.4 mmol) were suspended in ACN (30.0 ml) and stirred at 90°C for 2 hours. Distilled water (100 ml) was added to the reaction mixture, and it was extracted with SiO2 (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (SiO2 / hexane) to obtain 15.7 g (98%) of a yellow solid. m / z 255.21 [M+H] + .

[0103] Step 2: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidine-4-carbaldehyde (1-(2-fluoro-4-nitrophenyl)piperidine-4-yl)methanol (8.00 g, 31.5 mmol) was suspended in DCM (35.0 ml), then DMP (16.0 g, 37.8 mmol) was added and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of Na2S2O3 (50 ml) was added to the reaction mixture and extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was subjected to MPLC (50% siRNA / hexane) to obtain 5.69 g (72%) of a yellow solid. m / z 253.22[M+H] + .

[0104] Step 3: Synthesis of 4-(1,3-dioxolan-2-yl)-1-(2-fluoro-4-nitrophenyl)piperidine 1-(2-fluoro-4-nitrophenyl)piperidine-4-carbaldehyde (5.69 g, 22.6 mmol) was suspended in toluene (100.0 ml), then pyridinium p-toluenesulfonate (568 mg, 2.26 mmol) and ethylene glycol (2.53 ml, 45.2 mmol) were added, and the mixture was stirred at 110°C for 2 hours. A saturated aqueous solution of NaHCO3 (50 ml) was added to the reaction mixture, and the mixture was extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was recrystallized (siRNA / hexane) to yield 6.44 g (96%) of a yellow solid. m / z 297.19[M+H] + .

[0105] Step 4: Synthesis of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluoroaniline 4-(1,3-dioxolan-2-yl)-1-(2-fluoro-4-nitrophenyl)piperidine (6.44 g, 21.7 mmol) was dissolved in a mixture of EtOH (60.0 ml) and DCM (60.0 ml). Pd / C (10 wt% Pd, 665 mg) was added, and the mixture was stirred at room temperature under a hydrogen stream for 24 hours. The reaction mixture was filtered and concentrated to obtain 5.36 g (93%) of a beige solid. m / z 267.27 [M+H] + .

[0106] Step 5: Synthesis of 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluoroaniline (5.91 g, 22.2 mmol), 3-bromopiperidine-2,6-dione (5.96 g, 31.1 mmol), and NaHCO3 (4.09 g, 48.8 mmol) were suspended in DMF (110.0 ml) and stirred at 60°C for 16 hours. Distilled water (200 ml) was added to the reaction mixture and extracted with siRNA (150 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was subjected to MPLC (50% siRNA / hexane) and 5.80 g (66%) of a green solid was obtained. m / z 378.54 [M+H] + .

[0107] Step 6: Synthesis of 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (200 mg, 0.530 mmol) was suspended in THF (1.86 ml), and then 2 M aqueous HCl (1.86 ml) was added and the mixture was stirred at 50°C for 3 hours. After concentrating the reaction mixture under reduced pressure, saturated aqueous NaHCO3 (30 ml) was added and extracted with DCM (30 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was recrystallized (Âxate / hexane) to obtain 107 mg (61%) of a beige solid. m / z 334.23 [M+H] + .

[0108] Intermediate 2-2.(S)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde [ka]

[0109] Step 1: Synthesis of (S)-3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (step 5 of intermediate 2-1, 8.60 g, 22.8 mmol) was separated using SFC (Waters 150 Prep-SFC, Daicel chiral cell IG column, mobile phase A: CO2, mobile phase B: IPA / ACN, 65% phase B gradient, flow rate: 100 mL / min) to obtain 3.89 g (45.2%) of a green solid.

[0110] Analytical SFC (Shimadzu LC-30ADSF, IG 50×4.6mm I.D., 3.0μm particle size, mobile phase A: CO2, mobile phase B: 0.05% DEA in IPA / ACN, 60% phase B gradient, flow rate: 3mL / min): retention time 0.661 min, >99% ee.

[0111] Step 2: Synthesis of (S)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (S)-3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (3.00 g, 7.95 mmol) was suspended in THF (60.0 ml), and then 2 M aqueous HCl (60.0 ml) was added and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous NaHCO3 (350 ml) was added and extracted with DCM (150 ml x 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was recrystallized (siRNA / hexane) to obtain 2.40 g (89%) of a beige solid. m / z 334.26 [M+H] + .

[0112] Intermediate 2-3.(R)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde [ka]

[0113] Step 1: Synthesis of (R)-3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (step 5 of intermediate 2-1, 8.60 g, 22.8 mmol) was separated using SFC (Waters 150 Prep-SFC, Daicel chiral cell IG column, mobile phase A: CO2, mobile phase B: IPA / ACN, 65% phase B gradient, flow rate: 100 mL / min) to obtain 3.94 g (45.8%) of a green solid.

[0114] Analytical SFC (Shimadzu LC-30ADSF, IG 50×4.6mm I.D., 3.0μm particle size, mobile phase A: CO2, mobile phase B: 0.05% DEA in IPA / ACN, 60% phase B gradient, flow rate: 3mL / min): retention time 1.101 min, >99% ee.

[0115] Step 2: Synthesis of (R)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (R)-3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (250 mg, 0.662 mmol) was suspended in THF (2.32 ml), and then 2 M aqueous HCl (2.32 ml) was added and the mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous NaHCO3 (60 ml) was added and extracted with DCM (20 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was recrystallized (siRNA / hexane) to obtain 172 mg (78%) of a beige solid. m / z 334.32[M+H] + .

[0116] Intermediate 2-4,3-((3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka]

[0117] Step 1: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidine-4-one 1,2-Difluoro-4-nitrobenzene (300 mg, 1.89 mmol), 4-piperidone monohydrate hydrochloride (348 mg, 1.95 mmol), and DIPEA (0.66 ml, 3.78 mmol) were suspended in DMF (4.0 ml) and stirred at 90°C for 2 hours. Distilled water (20 ml) was added to the reaction mixture and extracted with siRNA (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was subjected to MPLC (80% siRNA / hexane) to obtain 390 mg (87%) of a yellow solid. m / z 239.22 [M+H] + .

[0118] Step 2: Synthesis of 8-(2-fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane 1-(2-fluoro-4-nitrophenyl)piperidine-4-one (150 mg, 0.630 mmol) was suspended in toluene (2.0 ml), then pyridinium p-toluenesulfonate (16 mg, 0.063 mmol) and ethylene glycol (0.07 ml, 0.84 mmol) were added, and the mixture was stirred at 110°C for 2 hours. A saturated aqueous solution of NaHCO3 (20 ml) was added to the reaction mixture, and the mixture was extracted with DCM (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was recrystallized (siRNA) to yield 147 mg (83%) of a yellow solid. m / z 283.16 [M+H] + .

[0119] Step 3: Synthesis of 3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline 8-(2-fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (136 mg, 0.481 mmol) was dissolved in a mixture of DCM (1.0 ml) and MeOH (3.0 ml). Pd / C (10 wt% Pd, 15 mg) was added, and the mixture was stirred at room temperature under a hydrogen stream for 16 hours. The reaction mixture was filtered and concentrated to obtain 120 mg (99%) of a pink solid. m / z 253.26 [M+H] + .

[0120] Step 4: Synthesis of 3-((3-fluoro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione 3-Fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (60 mg, 0.238 mmol), 3-bromopiperidine-2,6-dione (68 mg, 0.357 mmol), and NaHCO3 (44 mg, 0.52 mmol) were suspended in DMF (1.5 ml) and stirred at 80°C for 12 hours. Distilled water (15 ml) was added to the reaction mixture and extracted with siRNA (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% siRNA / hexane) to obtain 54 mg (62%) of a green solid. m / z 364.24 [M+H] + .

[0121] Step 5: Synthesis of 3-((3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione 3-((3-fluoro-4-(1,4-dioxa-8-azaspiro[4,5]decane-8-yl)phenyl)amino)piperidine-2,6-dione (54 mg, 0.15 mmol) was suspended in THF (0.75 ml), and then 2 M aqueous HCl (0.75 ml, 1.5 mmol) was added and the mixture was stirred at 60°C for 16 hours. After concentrating the reaction mixture under reduced pressure, saturated aqueous NaHCO3 (20 ml) was added and the mixture was extracted with DCM (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35 mg (73%) of a blue solid. m / z 320.21 [M+H] + .

[0122] Intermediate 2-5.1-(2-chloro-4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-carbaldehyde [ka]

[0123] Intermediate 2-5 was synthesized using 2-chloro-1-fluoro-4-nitrobenzene instead of 1,2-difluoro-4-nitrobenzene, in a similar manner to intermediate 2-1.

[0124] Intermediate 2-6.1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-carbaldehyde [ka]

[0125] Intermediate 2-6 was synthesized using 1-fluoro-4-nitro-2-(trifluoromethyl)benzene instead of 1,2-difluoro-4-nitrobenzene, in the same manner as intermediate 2-1.

[0126] Example 1. 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0127] Step 1: Synthesis of tert-butyl 4-((6-nitropyridine-3-yl)oxy)piperidine-1-carboxylate 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (8.50 g, 42.2 mmol) was suspended in THF (180 ml), and 60% NaH (1.69 g, 42.2 mmol) was added at 0°C. The mixture was stirred at room temperature for 30 minutes. 5-fluoro-2-nitropyridine (5.00 g, 35.2 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Distilled water (200 ml) was added to the reaction mixture, and the mixture was extracted with ELISA (150 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (ELISA) to obtain 7.20 g (63%) of a beige solid. m / z 324.15 [M+H] + .

[0128] Step 2: Synthesis of tert-butyl 4-((6-aminopyridine-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-nitropyridine-3-yl)oxy)piperidine-1-carboxylate (7.20 g, 22.3 mmol) was dissolved in a mixture of DCM (50 ml) and MeOH (60 ml). Pd / C (10 wt% Pd, 25 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen stream. The reaction mixture was filtered and concentrated to obtain a black solid (6.54 g, quant.). m / z 294.20 [M+H] + .

[0129] Step 3: Synthesis of tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxyamide)pyridine-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-aminopyridine-3-yl)oxy)piperidine-1-carboxylate (6.54 g, 22.3 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 6.65 g, 22.3 mmol), HATU (10.2 g, 26.8 mmol), and DIPEA (7.77 ml, 44.6 mmol) were suspended in DMF (45.0 ml) and stirred at room temperature for 16 hours. Distilled water (15 ml) was added to the reaction mixture and extracted with SiO (150 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (SiO), yielding 9.23 g (72%) of a beige solid. m / z 574.30 [M+H] + .

[0130] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidine-4-yloxy)pyridine-2-yl)piperidine-4-carboxamide Tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide)pyridine-3-yl)oxy)piperidine-1-carboxylate (9.23 g, 16.1 mmol) was suspended in DCM (41.0 ml), and TFA (16.4 ml, 214.0 mmol) was added and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction mixture under reduced pressure, 150 ml of 2 M NaOH aqueous solution was added and extracted with DCM (100 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7.52 g (99%) of a beige solid. m / z 474.22 [M+H] + .

[0131] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidine-4-yloxy)pyridine-2-yl)piperidine-4-carboxamide (3.41 g, 7.20 mmol) and 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-1, 2.40 g, 7.20 mmol) were suspended in a mixture of DCM (50.0 ml) and MeOH (5.0 ml). Then, sodium triacetoxyborohydride (3.82 g, 18.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. Saturated aqueous solution of NaHCO3 (70 ml) was added to the reaction mixture and extracted with DCM (70 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (10% MeOH / DCM), and 4.56 g (80%) of a beige solid was obtained.

[0132] Example 2. (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0133] Example 2 was synthesized in the same manner as in Example 1, using (S)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-2) instead of 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-1).

[0134] Example 3. (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0135] Example 3 was synthesized in the same manner as in Example 1, using (R)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-3) instead of 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-1).

[0136] Example 4.1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1'-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)-[1,4'-bipiperidine]-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0137] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidine-4-yloxy)pyridine-2-yl)piperidine-4-carboxamide (Step 4 of Example 1, 43 mg, 0.091 mmol) and 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-4, 35 mg, 0.11 mmol) were suspended in a mixture of MeOH (1.0 ml) and AcOH (0.1 ml), and then 2-methylpyridineborane complex (29 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 16 hours. 1.0 ml of 1 M KOH aqueous solution was added to the reaction mixture and extracted with DCM (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (10% MeOH / DCM), and 13 mg (18%) of a light blue solid was obtained.

[0138] Example 5.1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0139] Example 5 was synthesized in the same manner as in Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0140] Example 6. 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperazine-1-carboxamide [ka]

[0141] Step 1: Synthesis of tert-butyl 4-((6-((phenoxycarbonylamino)pyridine-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-aminopyridine-3-yl)oxy)piperidine-1-carboxylate (Step 2 of Example 1, 100 mg, 0.341 mmol) was suspended in THF (2.0 ml), then phenyl chloroformate (0.05 mg, 0.375 mmol) and pyridine (0.03 ml, 0.375 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. After adding distilled water (15 ml) to the reaction mixture, the precipitated solid was filtered and vacuum-dried to obtain 105 mg (74%) of a white solid. m / z 414.16 [M+H] + .

[0142] Step 2: Synthesis of tert-butyl 4-((6-(4-(4-cyano-3-(trifluoromethyl)phenyl)piperazine-1-carboxyamide)pyridine-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-((phenoxycarbonyl)amino)pyridine-3-yl)oxy)piperidine-1-carboxylate (105 mg, 0.254 mmol), 4-(piperazine-1-yl)-2-(trifluoromethyl)benzonitrile (intermediate 1-3, 65 mg, 0.254 mmol), and DMAP (30 mg, 0.127 mmol) were suspended in DMF (1.0 ml) and stirred at 80°C for 3 hours. Distilled water (15 ml) was added to the reaction mixture and extracted with ELISA (25 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH / DCM) to obtain 126 mg (86%) of a white solid. m / z 575.29 [M+H] + .

[0143] Step 3: Synthesis of 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidine-4-yloxy)pyridine-2-yl)piperazine-1-carboxamide Tert-butyl 4-((6-(4-(4-cyano-3-(trifluoromethyl)phenyl)piperazine-1-carboxamide)pyridine-3-yl)oxy)piperidine-1-carboxylate (126 mg, 0.219 mmol) was suspended in DCM (1.0 ml), and then 4 M HCl in dioxane (0.27 ml, 1.10 mmol) was added and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, saturated aqueous solution of NaHCO3 (15 ml) was added and extracted with DCM (25 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 100 mg (82%) of a white solid. m / z 475.24 [M+H] + .

[0144] Step 4: Synthesis of 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperazine-1-carboxamide 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidine-4-yloxy)pyridine-2-yl)piperazine-1-carboxamide (20 mg, 0.042 mmol) and 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-1, 14 mg, 0.042 mmol) were suspended in a mixture of DCM (1.0 ml) and MeOH (0.25 ml), and then sodium triacetoxyborohydride (22 mg, 0.11 mmol) was added and the mixture was stirred at room temperature for 16 hours. Saturated aqueous solution of NaHCO3 (15 ml) was added to the reaction mixture and extracted with DCM (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (10% MeOH / DCM), and 16 mg (48%) of a beige solid was obtained.

[0145] Example 7.1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide [ka]

[0146] Step 1: Synthesis of tert-butyl 4-((6-chloropyridazine-3-yl)oxy)piperidine-1-carboxylate 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (7.08 g, 35.2 mmol) was suspended in THF (350 ml), then 60% NaH (2.11 g, 52.8 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. 3,6-dichloropyridazine (5.00 g, 35.2 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Distilled water (300 ml) was added to the reaction mixture, and the mixture was extracted with RINKAN (150 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (RINKAN), yielding 8.42 g (76%) of a white solid. m / z 336.36 [M+Na] + .

[0147] Step 2: Synthesis of tert-butyl 4-((6-((diphenylmethylene)amino)pyridazin-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-chloropyridazine-3-yl)oxy)piperidine-1-carboxylate (8.42 g, 26.8 mmol), benzophenone imine (5.35 g, 29.5 mmol), and Cs2CO3 (26.2 g, 80.4 mmol) were suspended in toluene (150.0 ml). Then, Pd2(dba)3 (1.54 g, 2.68 mmol) and BINAP (3.34 g, 5.36 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered and concentrated, and the resulting residue was subjected to MPLC (30% siRNA / hexane) to obtain 9.42 g (76%) of a white solid. m / z 459.31[M+H] + .

[0148] Step 3: Synthesis of tert-butyl 4-((6-aminopyridazine-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-((diphenylmethylene)amino)pyridazin-3-yl)oxy)piperidine-1-carboxylate (9.42 g, 20.5 mmol) was dissolved in MeOH (100.0 ml), then hydroxylamine hydrochloride (1.57 g, 22.6 mmol) and NaOAc (4.20 g, 51.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added to MPLC (10% MeOH / DCM) to obtain 4.66 g (77%) of a white solid. m / z 295.23 [M+H] + .

[0149] Step 4: Synthesis of tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxyamide)pyridazine-3-yl)oxy)piperidine-1-carboxylate Tert-butyl 4-((6-aminopyridazine-3-yl)oxy)piperidine-1-carboxylate (14.3 g, 48.6 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 14.5 g, 48.6 mmol), HATU (22.2 g, 58.3 mmol), and DIPEA (16.9 ml, 97.2 mmol) were suspended in DMF (100.0 ml) and stirred at room temperature for 16 hours. Distilled water (150 ml) was added to the reaction mixture and extracted with SiO2 (200 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was recrystallized (SiO2) to obtain 23.3 g (83%) of a beige solid. m / z 597.28 [M+Na] + .

[0150] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(piperidine-4-yloxy)pyridazin-3-yl)piperidine-4-carboxamide Tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide)pyridazin-3-yl)oxy)piperidine-1-carboxylate (21.0 g, 36.5 mmol) was suspended in DCM (280.0 ml), and then TFA (42.0 ml, 548 mmol) was added and the mixture was stirred at room temperature for 20 hours. After concentrating the reaction mixture under reduced pressure, 150 ml of saturated 2 M NaOH solution was added and the mixture was extracted with DCM (200 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 16.8 g (97%) of a beige solid. m / z 475.23 [M+H] + .

[0151] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(piperidine-4-yloxy)pyridazin-3-yl)piperidine-4-carboxamide (30 mg, 0.0063 mmol) and 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-1, 21 mg, 0.063 mmol) were suspended in a mixture of DCM (1.0 ml) and MeOH (0.25 ml), and then sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added and the mixture was stirred at room temperature for 16 hours. Saturated aqueous solution of NaHCO3 (15 ml) was added to the reaction mixture and extracted with DCM (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (10% MeOH / DCM), and 17 mg (34%) of a beige solid was obtained.

[0152] Example 8.1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0153] Example 8 was synthesized in the same manner as in Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-4) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0154] Example 9. (S)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0155] Example 9 was synthesized in the same manner as in Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-4) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1), and (S)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-2) instead of 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-2).

[0156] Example 10. (R)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0157] Example 10 was synthesized in the same manner as in Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-4) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1), and (R)-1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-3) instead of 1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (intermediate 2-3).

[0158] Example 11. 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0159] Example 11 was synthesized in the same manner as in Example 1, using 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-5) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0160] Example 12. 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0161] Example 12 was synthesized in the same manner as in Example 1, using 1-(3-chloro-4-cyano-2-fluorophenyl)piperidine-4-carboxylic acid (intermediate 1-6) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0162] Example 13. 1-(4-cyano-3-methoxyphenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0163] Example 13 was synthesized in the same manner as in Example 1, using 1-(4-cyano-3-methoxyphenyl)piperidine-4-carboxylic acid (intermediate 1-7) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0164] Example 14. 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide [ka]

[0165] Example 14 was synthesized in the same manner as in Example 7, using 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-5) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0166] Example 15. 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide [ka]

[0167] Example 15 was synthesized in the same manner as in Example 7, using 1-(3-chloro-4-cyano-2-fluorophenyl)piperidine-4-carboxylic acid (intermediate 1-6) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0168] Example 16. 1-(4-cyano-3-methoxyphenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide [ka]

[0169] Example 16 was synthesized in the same manner as in Example 7, using 1-(4-cyano-3-methoxyphenyl)piperidine-4-carboxylic acid (intermediate 1-7) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0170] Example 17. N-(5-((1-((1-(2-chloro-4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide [ka]

[0171] Example 17 was synthesized in the same manner as in Example 1, using 1-(2-chloro-4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-carbaldehyde (intermediate 2-5) instead of 1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-carbaldehyde (intermediate 2-1).

[0172] Example 18. 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide [ka]

[0173] Example 18 was synthesized in the same manner as in Example 1, except that 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-carbaldehyde (Intermediate 2-6) was used in place of 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1).

[0174] The NMR and / or LC / MS measurement results of the compounds synthesized as described above are summarized in the table below.

[0175]

Table 1

[0176] Experimental Example 1: Measurement of androgen receptor (AR) protein degradation ability After treating the compounds of the synthesized examples with LNCaP cells or VCaP cells, the amount of AR protein present in the cells was measured. The amount of AR protein was measured using Western Blotting detection. The protocol of the experiment carried out using LNCaP cells or VCaP cells is as follows.

[0177] [Culture] LNCaP cells were resuspended in RPMI-1640 MEDIUM + HEPES (Hyclone, SH30255.01), 10% FBS (Hyclone, SV30207.02) and 1% penicillin-streptomycin (Welgene, LS202-02), 3×10 5 cells / mL were seeded at 1 mL per well in a 12-well plate, then cultured for 3 days. VCaP cells were resuspended in IMDM MEDIUM (Hyclone, SH30228.01), 20% FBS (Hyclone, SV30207.02) and 1% penicillin-streptomycin (Welgene, LS202-02), 9×10 5 cells / mL were seeded at 1 mL per well in a 12-well plate, then cultured for 3 days.

[0178] [Compound Treatment] 10 μL of a 100× stock (e.g., 0.1, 1, 10 μM) compound solution corresponding to the final compound treatment concentration (e.g., 0.001, 0.01, 0.1 μM) was added to 1 mL of medium in each well, and cells were harvested after 20 hours. DC 50 For measurement, a 100× stock (0.01, 0.1, 1, 10, 100, 1000 μM) compound solution corresponding to the final compound treatment concentration (0.0001, 0.001, 0.01, 0.1, 1, 10 μM) was used.

[0179] [Cell Lysis] After resuspending cell pellets in 1% SDS lysis buffer (50 mM Tris, 1 mM EDTA, 1% SDS, pH 8.0, 0.5 mM PMSF, 1× protease / phosphatase inhibitor cocktail (Cell Signaling Technology, 5872S)), sonication was performed (70% AMP, 10 cycles (30 sec on / 59 sec off)). After centrifugation at 20000×g for 20 minutes at 4°C, cell lysate was obtained and transferred to a new tube.

[0180] [Protein Quantification] BCA protein assay using a 96-well microplate (SMART TM BCA Protein Assay Kit, iNtRON Biotechnology, 21071) was performed. After adding 5 μL of cell lysate and 5 μL of 1% SDS lysis buffer to each well of a 96-well plate, 200 μL of BCA reagent (reagent A : reagent B = 50:1) was further added. After incubation at 37°C for 30 minutes, the plate was cooled at room temperature for 10 minutes. Thereafter, after shaking for 10 seconds, absorbance was measured at a wavelength of 562 nm. Unknown protein concentration was determined using a BSA standard curve (0, 0.125, 0.25, 0.5, 1, 2 mg / mL). Cell lysate, 1% SDS lysis buffer, 4× NuPAGE TM LDS Sample Buffer (Invitrogen, NP0008), and 10× NuPAGE TMThe sample reduction reagent (Invitrogen, NP0009) was mixed and boiled at 70°C for 10 minutes to prepare the Western blotting sample.

[0181] [Electrophoresis] NuPAGE TM After loading 10 μg of protein sample into each well of a 4-12%, Bis-Tris, 1.0 mm mini protein gel, 15-well, 17-well, or 26-well (Invitrogen, NP0323BOX, NP0329BOX, or WG1403BOX), perform NuPAGE. TM Electrophoresis was performed for 40 minutes at 200V (constant voltage) using MES SDS running buffer (Invitrogen, NP0002).

[0182] [Transfer] Trans-blot of the gel after electrophoresis. TM Transfer was performed for 15 or 18 minutes under conditions of 1.3A (constant current) and 25V (limiting voltage) using a transfer starter system (Bio-RAD, #17001918, mini-nitrocellulose). To confirm protein transfer, the samples were stained with 15 mL of Ponceau-S solution (Sigma, P7170-1L) for 1 minute, washed, and the degree of transfer was checked.

[0183] [Blocking] Membranes for AR and GAPDH detection were blocked for 45 minutes with 5% skim milk / 0.2% TBST (Skim milk: BD, 232100 / 20X TBS: Biosesang, TR2008-100-00 / 10% Twin 20 solution: Bio-RAD, #161-0781).

[0184] [Antibodies and Detection] Primary AR antibody (androgen receptor: CST, 5153S) was mixed with 5% skim milk / 0.2% TBST in a ratio of 1:1000 and reacted at room temperature for 3 hours or overnight at 4°C. Primary GAPDH antibody (CST, 2118S) was mixed with 5% skim milk / 0.2% TBST in a ratio of 1:2000 and reacted at room temperature for 3 hours or overnight at 4°C. Subsequently, the mixture was washed three times every 5 minutes using TBST (0.2% Twin 20). As a secondary antibody against the AR antibody, HRP-labeled anti-rabbit IgG antibody (Anti-rabbit IgG HRP-linked Antibody, CST, 7074S) was mixed with 5% skim milk / 0.2% TBST in a ratio of 1:5000 and reacted at room temperature for 45 minutes. As a secondary antibody against GAPDH antibody, IRDye® 800CW Goat anti-Rabbit IgG Secondary Antibody was mixed in a 1:10000 ratio with 5% skim milk / 0.2% TBST and reacted at room temperature for 45 minutes. After 45 minutes, the mixture was washed five times every 5 minutes using TBST (0.2% Twin 20). SuperSignal TM The West Pico Plus chemiluminescent substrate (Thermo Scientific, 34580) was used to react with the membrane, and then the samples were detected using the Odyssey® Fc imaging system (LI-COR, 2800).

[0185] [Quantification of numerical values] The amount of AR protein is measured using a program built into the Odyssey® Fc imaging system (LI-COR, 2800), and the amount is normalized by the measured amount of GAPDH protein to obtain the degradation % and D max , and DC 50 This was quantified.

[0186] The evaluation results are shown in the table below.

[0187] [Table 2]

[0188] [Table 3]

[0189] [Table 4]

[0190] As shown in the table above, the compounds according to the present invention exhibit excellent activity in the degradation of androgen receptors.

[0191] Experimental Example 2: Measurement of Pharmacodynamic Efficacy The protocol for constructing a xenograft model using VCaP cells and conducting pharmacodynamic experiments is as follows:

[0192] [Cell Culture] VCaP cells were cultured in a mixture of DMEM MEDIUM (Hyclone, SH30243.01), 10% FBS (Hyclone, SV30207.02), 1% penicillin-streptomycin (Welgene, LS202-02), and 1x non-essential amino acid solution (100x) (Sigma, M7145-100mL) in 4x10 cells. 5 The cells were resuspended to a concentration of cells / mL. Then, the CellBIND cell culture flask (150 cm³) was used. 2 50 mL of each seed was sown in Corning (3291) and cultured for 5 days.

[0193] [Xenotransplantation] The culture medium was removed from the flask of cultured VCaP cells and washed with 10 mL of PBS (Welgene, LB001-02). After removing the PBS, 2 mL of 1 x 0.05% trypsin-EDTA (Welgene, LS015-01) was added and the cells were treated in a cell incubator for 3 minutes. Then, 10 mL of culture medium was added and pipetting was performed, and the contents were transferred to a 50 mL tube. The pellet was collected by centrifugation at 500 g for 5 minutes. The collected pellet was washed once more with 20 mL of PBS. The washed pellet was collected by centrifugation at 500 g for 5 minutes. The PBS was removed, 500 μL of HBSS (Gibco, 14025092) was added, and pipetting was performed. After diluting 100-fold with HBSS and counting the cells, 3 × 10⁶ cells were collected. 6 The cells were diluted with HBSS at a rate of 50 μL / mouse and stored in an ice bucket. The same amount of Matrigel (R&D system, 3432-005-01) was added to the stored cells, homogenized by pipetting, and then 100 μL per mouse was inoculated subcutaneously into the right flank of CB17 / SCID mice.

[0194] [Cancer Size Measurement and Grouping] Two to three weeks after inoculation of cancer cells, once the transplanted cancer cells had grown, their size was measured using calipers. The measured cancer size was [long axis × short axis]. 2 The calculation was performed using [×0.5]. The size of the cancer was approximately 200 mm. 2 Based on the above criteria, experimental animals were divided into groups according to the average size of the tumors and the concentration of the administered drug. Each group always included a vehicle containing only the solvent and no drug.

[0195] [Drug Preparation and Administration] The drug was dissolved in a solvent and orally administered in a volume of 200 μL per experimental animal (approximately 8 mL / kg). The solvent composition consisted of 3% DMSO (Sigma, D8418), 10% Cremophor EL (Sigma, C5135), 20% PEG400 (Sigma, 06855-1KG), and 67% distilled water. The preparation method is as follows. The drug was weighed out separately according to the target drug concentration (e.g., 10 or 30 mg / kg), and dissolved in DMSO corresponding to 3% of the total solvent volume. 10% Cremophor EL and 20% PEG400 were added to the drug dissolved in DMSO, followed by vortexing; finally, 67% of DW was added and vortexed again. The prepared drug was orally administered to experimental animals according to their group allocation.

[0196] [Extraction of Cancer Tissue] The prepared drug was orally administered once a day at the same time for 3 consecutive days. Changes in cancer size were measured within the set administration period, and the animals were sacrificed 6 hours after the last administration. After sacrifice, cancer tissues were collected, washed with PBS, and stored at -80°C.

[0197] [Tissue Homogenization and Cell Lysis] After thawing the cancer tissue stored at -80°C on ice, the tissue was cut into equal-sized pieces of 0.5 cm × 0.5 cm × 0.5 cm (width × length × height). One 2.8 mm ceramic bead (Omni international Inc., 19-646-3) and seven 1.4 mm ceramic beads (Omni international Inc., 19-645-3) were placed into an E-tube, the cut cancer tissue was added together with 1% SDS lysis buffer (50 mM Tris, 1 mM EDTA, 1% SDS, pH 8.0, 0.5 mM PMSF, 1× protease / phosphatase inhibitor cocktail (Cell Signaling Technology, 5872S)), and homogenized using a bead homogenizer (Omni international Inc., #19-040E). Subsequently, sonication was performed (70% AMP, 10 cycles (10 sec on / 30 sec off)), followed by centrifugation at 20000 g at 4°C for 15 minutes, and cell lysate was obtained as the supernatant.

[0198] [Western blotting sample preparation] Cell lysate, 1% SDS-Lysis Buffer, 4x NuPAGE TM LDS sample buffer (Invitrogen, NP0008) and 10x NuPAGE TM The sample reduction reagent (Invitrogen, NP0009) was mixed and boiled at 70°C for 10 minutes to prepare the Western blotting sample.

[0199] [Electrophoresis] NuPAGE TM After loading 10 μL of the prepared sample into each well of a 4-12%, Bis-Tris, 1.0 mm mini protein gel, 15-well or 17-well (Invitrogen, NP0323BOX or NP0329BOX), NuPAGE... TM Electrophoresis was performed for 40 minutes at 200V (constant voltage) using MES SDS running buffer (Invitrogen, NP0002).

[0200] [Transfer] Trans-blot of the gel after electrophoresis. TM Transfer was performed for 15 minutes using a transfer starter system (Bio-RAD, #17001918, mini-nitrocellulose) under conditions of 1.3A (constant current) and 25V (limiting voltage). To confirm protein transfer, the samples were stained with 15 mL of Ponceau-S solution (Sigma, P7170-1L) for 1 minute, washed, and the degree of transfer was checked.

[0201] [Blocking] Membranes for AR and GAPDH detection were blocked for 45 minutes with 5% skim milk / 0.2% TBST (Skim milk: BD, 232100 / 20X TBS: Biosesang, TR2008-100-00 / 10% Twin 20 solution: Bio-RAD, #161-0781).

[0202] [Antibodies and Detection] Primary AR antibody (androgen receptor: CST, 5153S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:1000 and reacted overnight at 4°C. Primary GAPDH antibody (CST, 2118S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:1000 and reacted overnight at 4°C. Afterwards, the mixture was washed three times at 5-minute intervals using TBST (0.2% Twin 20). As a secondary antibody against the AR antibody and GAPDH antibody, HRP-labeled anti-rabbit IgG antibody (Anti-rabbit IgG HRP-linked Antibody, CST, 7074S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:5000 and reacted at room temperature for 45 minutes. After 45 minutes, the mixture was washed five times at 5-minute intervals using TBST (0.2% Twin 20). SuperSignal TM The West Pico Plus chemiluminescent substrate (Thermo Scientific, 34580) was used to react with the membrane, and then the samples were detected using the Odyssey® Fc imaging system (LI-COR, 2800).

[0203] [Quantification of numerical values] The amount of AR protein was measured using a program built into the Odyssey® Fc imaging system (LI-COR, 2800), and the AR degradation percentage was calculated by normalizing it with the amount of GAPDH protein measured.

[0204] The results of this pharmacodynamic evaluation are shown in the table below.

[0205] [Table 5]

[0206] As shown in the table, the compounds according to the present invention were found to exhibit excellent AR degradation activity after oral administration and to possess extremely excellent pharmacodynamic properties.

[0207] Experimental Example 3: Concentration Analysis in Plasma and Cancer Tissue After Oral Administration The concentrations of orally administered drugs in plasma and cancer tissue of a xenograft model using VCaP cells were analyzed as follows:

[0208] [Blood Collection and Tissue Extraction] The compounded drug was administered orally at a dose of 10 mg / kg once daily at the same time for 3 days. Sacrificial deaths were performed 2 hours, 6 hours, and 24 hours after the last dose. Blood collection and tissue extraction were performed immediately after each sacrificial death. Blood collected from the heart was left in a K2EDTA tube for 30 minutes, then centrifuged at 15,000 rpm at 4°C for 10 minutes. The supernatant plasma was separated, stored at -20°C, and then used for analysis. The extracted tissue was washed with PBS, cut into pieces approximately 10 mg in size, stored at -80°C, and then used for analysis.

[0209] [Sample Preparation] Cancer tissue was homogenized once for 20 seconds at 5500 rpm using a tissue lithograph (Precellys Evolution, Bertin Technology) after adding 9 times its weight in distilled water. For cancer tissue, 20 μL of the homogenized material was mixed with 20 μL of blank plasma sample, 20 μL of internal standard (carbamazepine, 30 ng / mL in acetonitrile), and 140 μL of acetonitrile. For plasma, 20 μL of plasma sample was mixed with 20 μL of liver tissue blank sample, 20 μL of internal standard, and 140 μL of acetonitrile. The mixed samples were then suspended for 10 minutes using a vortex mixer, centrifuged at room temperature at 13500 rpm for 10 minutes, and 140 μL of the supernatant was taken and transferred to an analysis vessel.

[0210] [Sample Analysis] The concentrations of drugs in cancer tissue and plasma samples were quantified using an HPLC / MS / MS system. 5 μL of the sample prepared in the analysis vessel was injected into the HPLC / MS / MS system for analysis. For elution of the drugs, a combination of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile was used as the mobile phase, and a C18 column was used as the reversed phase for chromatogram confirmation using isocratic elution. Ion detection proceeded in ESI-positive MRM mode, and the integration of detection peaks was performed using Analyst SoftBank version 1.6.4 (Applied Biosystems / MDS SCIEX). The concentration of the drug in cancer tissue was calculated by multiplying the concentration obtained from the analysis of the cancer tissue homogenized material by a dilution factor of 10.

[0211] The results of the analysis of drug concentrations in plasma and cancer tissue are shown in the table below.

[0212] [Table 6]

[0213] As shown in the table, the compounds according to the present invention were confirmed to have remarkably excellent pharmacodynamic properties, as they exhibited a very good plasma concentration ratio to cancer tissue after oral administration.

Claims

1. The compound of the following chemical formula 1, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In chemical formula 1, R １ H, halogen, C １－３ Alkyl, C １－３ Alkoxy, or C １－３ It is a haloalkyl, R ２ is H, halogen, or C １－３ It is a haloalkyl, X １ , X ２ , and X ３ are each independently CH or N, R ３ H, halogen, C １－３ Alkyl, or C １－３ It is a haloalkyl, n is 0, 1, or 2.

2. In the aforementioned chemical formula 1, R １ H, Cl, -CH ３ , -OCH ３ , or -CF ３ And, R ２ is H or F, X １ , X ２ , and X ３ Each is independently CH or N, R ３ H, F, Cl, -CH ３ , or -CF ３ And, n is 0, 1, or 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. In the aforementioned chemical formula 1, R １ is Cl, -OCH ３ , or -CF ３ And, R ２ is H or F, X １ , X ２ , and X ３ Each is independently CH or N, R ３ is F, Cl, or -CF ３ And, n is either 0 or 1. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. In the aforementioned chemical formula 1, R １ is Cl, -OCH ３ , or -CF ３ And, R ２ is H or F, X １ and X ２ CH is X ３ is CH or N, R ３ is F or Cl, n is 1. The compound according to claim 3 or a pharmaceutically acceptable salt thereof.

5. In the aforementioned chemical formula 1, 【Chemistry 2】 The compound according to claim 4 or a pharmaceutically acceptable salt thereof.

6. The aforementioned compound, 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1'-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)-[1,4'-bipiperidine]-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 1-(6-cyano-5-(trifluoromethyl)pyridine-3-yl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperazine-1-carboxamide, 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide, 1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, (S)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, (R)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 1-(4-cyano-3-methoxyphenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazine-3-yl)piperidine-4-carboxamide, 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazine-3-yl)piperidine-4-carboxamide, 1-(4-cyano-3-methoxyphenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridazine-3-yl)piperidine-4-carboxamide, N-(5-((1-((1-(2-chloro-4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide, or It is 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)oxy)pyridine-2-yl)piperidine-4-carboxamide, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. A composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition for inhibiting or degrading androgen receptors (ARs), comprising as an active ingredient a compound described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for the treatment or prevention of cancer, Kennedy disease, acne, alopecia, skin wounds, or hirsutism.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is for the treatment or prevention of prostate cancer or breast cancer.

11. A method for treating or preventing an androgen receptor-related disease, comprising the step of administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 6 to an individual in need thereof.

12. The treatment or prevention method according to claim 11, wherein the androgen receptor-related disorder is cancer, Kennedy disease, acne, alopecia, skin wound, or hirsutism.

13. The treatment or prevention method according to claim 12, wherein the androgen receptor-related disease is prostate cancer or breast cancer.

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