Compound for degrading androgen receptor and medical use thereof

Abstract

The present disclosure provides a compound with a specific chemical structure or a pharmaceutically-acceptable salt thereof which exhibits excellent androgen receptor (AR) degradation activity and possesses superior pharmacokinetic and pharmacodynamic properties. The present disclosure also provides a composition comprising the compound or a pharmaceutically acceptable salt thereof. Furthermore, the present disclosure provides medical uses of the compound according to the present disclosure, salt thereof, or the composition containing same for the treatment or prevention of AR-related diseases. Additionally, the present disclosure provides a method for treating or preventing an AR-related disease by administering an effective amount of the compound according to the present disclosure, salt thereof, or composition containing same to a subject in need of treatment.

Description

Androgen receptor degrading compounds and their medicinal uses

[0001] This application claims priority to Korean Patent Application No. 10-2023-0116263, filed September 1, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to specific compounds having excellent androgen receptor degrading activity and excellent pharmacodynamic and pharmacodynamic properties. The present disclosure also relates to pharmaceutical compositions comprising such compounds. The present disclosure also relates to useful methods for treating androgen receptor-associated diseases using such compounds. In other words, the present disclosure relates to the pharmaceutical use of compounds according to the present disclosure for treating or preventing androgen receptor-associated diseases.

[0003] The androgen hormone receptor (AR) is a transcription factor belonging to the nuclear hormone receptor (NR) family. In the absence of androgen, 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), this complex translocates to the nucleus and, through a series of events, activates transcription of target genes.

[0004] While AR contributes to the development of masculinity, it is also a well-known oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). Current treatments for androgen-dependent prostate cancer can be broadly divided into two approaches. The first approach is to modulate androgen levels by removing androgen or interfering with its ligand, dihydrotestosterone (DHT), thereby preventing its translocation into the nucleus. The second strategy targets AR and aims to inhibit its function (Nature Reviews Drug Discovery, 2013, 12, 823-824). Thus, an alternative approach to prostate cancer treatment involves eliminating the AR protein. AR is a key driver of tumorigenesis in many forms of prostate cancer.

[0005] These ARs can also be major targets 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), and AR expression and activation have been shown 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. While approved drugs exhibit excellent anticancer effects initially, continued use leads to drug resistance, making their use difficult. Therefore, the development of new treatments is urgently needed.

[0007] PROTAC (Proteolysis Targeting Chimera) technology utilizes the intracellular protein degradation system (Ubiquitin-Proteasome System) to induce the degradation of target proteins. PROTAC compounds consist of a ligand that binds to the target protein, a ligand that binds to an E3 ligase protein, and a linker connecting the two ligands. The PROTAC complex forms a target protein-PROTAC compound-E3 ligase complex, ubiquitinating the target protein and directing it to the proteasome. PROTAC technology is expected to offer superior therapeutic efficacy compared to existing inhibitors by degrading and removing the target protein, and can overcome the problems of toxicity from high-dose administration and resistance from long-term administration, which are drawbacks of inhibitors.

[0008] Therefore, AR-degrading drugs may be an alternative that can overcome the limitations of existing prostate cancer treatment drugs. However, PROTAC-degrading drugs are bifunctional compounds that exhibit degrading activity only when they simultaneously interact with the target protein and the E3 ligase protein. Since their degrading activity is influenced by various factors such as the structure of each ligand, the structure of the linker, and the binding method with each protein, it is very difficult to find PROTAC compounds with excellent degrading activity. Furthermore, PROTAC-degrading drugs generally have large molecular weights and low solubility, resulting in poor oral absorption. Therefore, much research is being conducted to derive PROTAC compounds that have both good pharmacokinetic and pharmacodynamic characteristics and excellent degrading activity.

[0009] Therefore, the problem to be solved by the present invention is to provide a compound having excellent androgen receptor (AR) decomposition activity and exhibiting excellent pharmacokinetic and pharmacodynamic characteristics, a pharmaceutical composition containing the compound as an active ingredient, and a pharmaceutical use thereof for treating or preventing AR-related diseases.

[0010] Another problem to be solved by the present invention is to provide a method for treating or improving an AR-related disease, characterized in that the compound according to the present invention is characterized in that it decomposes AR and consequently lowers AR activity, and is administered to a patient in need of treatment, improvement, or prevention of an AR-related disease.

[0011] Compound of the present invention

[0012] In order to achieve the above-mentioned problem, in one aspect, the present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0013]

[0014] In the above chemical formula 1,

[0015] R1 is H, halogen (preferably Cl), C 1-3 Alkyl, C 1-3 Alkoxy (preferably, -OCH3), or C 1-3 Haloalkyl (preferably, -CF3),

[0016] R2 is H, halogen (preferably F), or C 1-3 It is haloalkyl,

[0017] X1, X2, and X3 are independently CH or N,

[0018] R3 is H, halogen (preferably F or Cl), C 1-3 Alkyl, or C 1-3 Haloalkyl (preferably, -CF3),

[0019] n is 0, 1, or 2.

[0020]

[0021] The compounds of the present invention exhibit very high AR degradation activity by effectively inducing the interaction between the AR protein and the E3 ligase protein through an AR binding ligand of a specific structure, an E3 ligase binding ligand, and a linker connecting these ligands. The compounds of the present invention exhibit significantly superior AR degradation activity and, upon administration, exhibit significantly superior pharmacological effects, such as anticancer effects. In addition, the compounds of the present invention exhibit excellent pharmacokinetic profiles, and based on this, exhibit significantly superior pharmacodynamic efficacy. Furthermore, the compounds of the present invention exhibit a very high tumor tissue-to-plasma concentration ratio upon administration, which is very advantageous in exhibiting excellent anticancer effects.

[0022] Meanwhile, the compounds of the present invention exhibit excellent degrading activity against AR mutants (T878A, M896V, F877L, H875Y, L702H, W742C, etc.). Since resistance to existing anti-androgen receptor drugs can be caused by AR mutations, the excellent AR mutant degrading activity of the compounds of the present invention can help overcome resistance to existing drugs.

[0023]

[0024] In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

[0025] If a substituent is described as “optionally substituted” or “optionally substituted,” the substituent may be (1) unsubstituted or (2) substituted with one or more of the defined substituents. If a substitutable position is unsubstituted, the default substituent is a hydrido radical.

[0026] The term "alkyl" as used herein (where the number of carbon atoms is not specifically limited) means a saturated straight-chain or branched cyclic hydrocarbon having 1 to 10 carbon atoms. "Lower alkyl" means a straight-chain or branched alkyl having 1 to 4 carbon atoms. In one embodiment of the present invention, the alkyl is a straight-chain or branched alkyl having 1 to 3 carbon atoms. Representative saturated straight-chain alkyls include -methyl, -ethyl, and -n-propyl, while saturated branched alkyls include -isopropyl.

[0027] The term "alkoxy" as used herein means -O-(alkyl), including -OCH3, -OCH2CH3, -O(CH2)2CH3, and the like, wherein alkyl is as defined above.

[0028] In this specification, "C 1-6 ", "C1-6", or "C1-C6", this means that it has 1 to 6 carbon atoms. For example, C 1-3 Alkyl refers to alkyl having 1 to 3 carbon atoms.

[0029] As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine, or iodine. In a preferred embodiment of the present invention, the halogen is chlorine or fluorine.

[0030] The term "haloalkyl" as used herein means alkyl in which one or more hydrogen atoms are each replaced by a halogen atom. For example, haloalkyl includes -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 the like. In a preferred embodiment of the present invention, haloalkyl is -CF3. wherein alkyl and halogen are as defined above.

[0031] In this specification, * or means connected to another moiety.

[0032]

[0033] In terms of AR degradation activity, (metabolic) stability, pharmacodynamic properties, pharmacodynamic properties, etc., a preferred embodiment of the present invention is in the chemical formula 1,

[0034] R1 is H, Cl, -CH3, -OCH3, or -CF3,

[0035] R2 is H or F,

[0036] X1, X2, and X3 are independently CH or N,

[0037] R3 is H, F, Cl, -CH3, or -CF3,

[0038] n is 0, 1, or 2,

[0039] A compound or a pharmaceutically acceptable salt thereof is provided.

[0040]

[0041] In terms of AR degradation activity, (metabolic) stability, pharmacodynamic properties, pharmacodynamic properties, etc., a more preferable embodiment of the present invention is in the chemical formula 1,

[0042] R1 is Cl, -OCH3, or -CF3,

[0043] R2 is H or F,

[0044] X1, X2, and X3 are independently CH or N,

[0045] R3 is F, Cl, or -CF3,

[0046] n is 0 or 1,

[0047] A compound or a pharmaceutically acceptable salt thereof is provided.

[0048]

[0049] In terms of AR degradation activity, (metabolic) stability, pharmacodynamic properties, pharmacodynamic properties, etc., a more preferable aspect of the present invention is in the chemical formula 1,

[0050] R1 is Cl, -OCH3, or -CF3,

[0051] R2 is H or F,

[0052] X1 and X2 are CH, X3 is CH or N,

[0053] R3 is F or Cl (more preferably, Is or ) and,

[0054] n is 1,

[0055] A compound or a pharmaceutically acceptable salt thereof is provided.

[0056] In particular, the structure of the E3 ligase binding ligand, for example, the position at which the linker is connected to the benzene ring, the position at which R3 is connected to the benzene ring, etc., is important in the AR degradation activity of the compound of the present invention.

[0057]

[0058] 본 개시의 바람직한 일 양태는 또한,

[0059] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 1),

[0060] (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 2),

[0061] (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 3),

[0062] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[1,4'-bipiperidin]-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 4),

[0063] 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 5),

[0064] 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (실시예 6),

[0065] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (실시예 7),

[0066] 1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 8),

[0067] (S)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 9), (R)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 10),

[0068] 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 11),

[0069] 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 12),

[0070] 1-(4-cyano-3-methoxyphenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (실시예 13),

[0071] 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (실시예 14),

[0072] 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (실시예 15),

[0073] 1-(4-cyano-3-methoxyphenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide (실시예 16),

[0074] N-(5-((1-((1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (Example 17), or

[0075] A compound, 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (Example 18), or a pharmaceutically acceptable salt thereof is provided.

[0076]

[0077] "Pharmaceutically acceptable salts" in the present invention include salts of the active compounds prepared with relatively non-toxic acids and bases, depending on the specific substituents found in the compounds mentioned herein. When the compounds of the present invention contain relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitably inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or in a suitably inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids, including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like, as well as salts derived from hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide, or phosphorous acids and the like. Also included are salts of amino acids such as arginate and its analogs and analogs of organic acids such as glucuronic or galactunoric acids and their analogs.Certain specific compounds of the present invention possess both basic and acidic functionalities, allowing them to be converted into basic or acidic addition salts. Other examples of salts are well known in the art.

[0078] As used herein, the term "compound of the present invention" is meant to include not only each compound of formula 1, but also clathrates, hydrates, solvates, polymorphs, or isotopically labeled analogs thereof. The term "compound of the present invention" is also meant to include pharmaceutically acceptable salts of the compounds of the present invention, unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, the compounds of the present invention may exist as stereomerically pure compounds (e.g., compounds that are substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee or more)). That is, when the compound of formula 1 according to the present invention or a salt thereof is a tautomer and / or stereoisomer (e.g., geometrical isomer and conformational isomer), each of their separated isomers and mixtures are also included in the scope of the compound of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention. The term "solvent compound" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small amounts.

[0079] The term "hydrate" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0080] The term "clathrate" as used herein means a compound of the present invention or a salt thereof in the form of a crystal lattice that includes spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0081] The term "isotopically labeled analog" as used herein refers to a compound in which one or more atoms of the compounds of the present disclosure 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 disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms constituting such compounds. Examples of isotopes that may be incorporated into the compounds described herein include, respectively: 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 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. For example, the compounds described herein may have one or more H atoms replaced by 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, replacement of hydrogen by deuterium or tritium, or 13 C- or14 Compounds having this structure, except for the replacement of carbon by C-rich carbon, are within the scope of the present disclosure. 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. Tritium ( 3 H) and carbon-14 ( 14 C) Isotopes may be particularly desirable due to their ease of preparation and detection. Furthermore, substituting heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be desirable in some circumstances. Isotopically labeled compounds can generally be prepared by procedures similar to those disclosed herein, e.g., in the Examples section, by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0082] The term "purified" as used herein means that when separated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and in yet another embodiment at least 99.9% pure.

[0083]

[0084] Method for producing the compound of the present invention

[0085] One aspect of the present invention provides a method for preparing a compound of formula 1 according to the present disclosure.

[0086] The compound of chemical formula J used to synthesize the compound of the present invention can be prepared by the method of the following reaction scheme 1 or 2.

[0087] [Reaction Formula 1]

[0088]

[0089] In the above reaction formula 1, Hal is halogen, R is alkyl, P is a protecting group, X2 is CH, and the remaining definitions are the same as those of the preceding chemical formula 1.

[0090] The compound of formula D can be prepared by a method of hydrolyzing the compound of formula A with the compound of formula B at high temperature or using a metal catalyst, or by a method of reacting the compound of formula A with piperidine-4-carboxylic acid at high temperature.

[0091] A compound of formula G can be prepared by a method of reduction reaction of a compound of formula F prepared by reacting a compound of formula E with piperidin-4-ol having a protected amine group, or by a method of amination reaction of a compound of formula I prepared by reacting a compound of formula H with piperidin-4-ol having a protected amine group.

[0092] A compound of chemical formula J can be prepared by reacting a compound of chemical formula D and a compound of chemical formula G at room temperature using an appropriate coupling reagent.

[0093] [Reaction Formula 2]

[0094]

[0095] In the above reaction formula 2, Hal is a halogen, P is a protecting group, X2 is N, and the remaining definitions are the same as those of the above chemical formula 1.

[0096] A compound of chemical formula K can be prepared by reacting a compound of chemical formula A with piperazine at high temperature. A compound of chemical formula L can be prepared by reacting a compound of chemical formula G with phenyl chloroformate at room temperature. A compound of chemical formula J can be prepared by reacting a compound of chemical formula K with a compound of chemical formula L at high temperature.

[0097]

[0098] The compound of the present invention can be prepared by the method of the following reaction scheme 3 or 4.

[0099] [Reaction Formula 3]

[0100]

[0101]

[0102] In the above reaction formula 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 the same as those of the above chemical formula 1.

[0103] A compound of formula T can be prepared by sequentially performing an oxidation reaction, an acetal protection reaction, a reduction reaction, and an alkylation reaction on a compound of formula P, which is prepared by reacting a compound of formula O with a piperidine substituted with hydroxyalkyl. A compound of formula 1 can be prepared by a reductive amination reaction at room temperature on a compound of formula N, which is prepared by a deprotection reaction of a compound of formula T, and a compound of formula M, which is prepared by a deprotection reaction of a compound of formula J. A compound of formula T having stereoselectivity can be obtained through a stereoselective separation method such as SFC (Supercritical fluid chromatography).

[0104] [Reaction Formula 4]

[0105]

[0106] In the above reaction formula 4, Hal is halogen, n is 0, and the remaining definitions are the same as those of the above chemical formula 1.

[0107] A compound of formula Z can be prepared by sequentially performing an acetal protection reaction, a reduction reaction, and an alkylation reaction on a compound of formula W, which is prepared by reacting a compound of formula V with 4-piperidone. A compound of formula 1 can be prepared by a reductive amination reaction at room temperature between a compound of formula U, which is prepared by a deprotection reaction of a compound of formula Z, and a compound of formula M. A compound of formula Z having stereoselectivity can be obtained through a stereoselective separation method such as SFC.

[0108]

[0109] The reaction conditions of the above reactions can be changed as known in the art.

[0110] The manufacturing methods of the above reaction formulas 1 to 4 can be further specified in the examples described below.

[0111]

[0112] Medicinal uses and therapeutic methods of the compounds of the present invention

[0113] The present invention further provides a method for treating the following diseases or conditions in a subject having or susceptible to the following diseases or conditions by administering to the subject a therapeutically effective amount of one or more of the above compounds. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.

[0114] 1. Disease or condition

[0115] The AR-degrading compounds of the present invention are useful for various therapeutic or preventive applications (e.g., cancer, prostate cancer, Kennedy's disease). These compounds can be used to degrade AR and thereby reduce its activity, and can also be used to treat or prevent the worsening of AR-related diseases. Accordingly, the present invention provides a method for degrading AR in a cell. In this method, the cell is contacted with an effective amount of a compound of the present invention. In one embodiment, the cell is present in a subject. The method of the present invention comprises administering to a subject in need of treatment or prevention a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of the present invention.

[0116] In one aspect, the present invention provides a method for degrading AR in cells suffering from an AR-related disease. For example, the present invention can be used to degrade AR in cells of individuals suffering from the AR-related disease described below, thereby reducing AR activity. In another aspect, the present invention can be used to degrade AR in cells of cancer, particularly prostate cancer.

[0117] In another aspect, the present invention provides a method for treating an AR-associated disorder, comprising administering to a subject a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof. The method comprises administering to a subject in need of treatment an amount of the compound of the present invention sufficient to degrade AR, i.e., a therapeutically effective amount. In such a method, the compound of the present invention may be administered to the subject in the form of a pharmaceutical composition as described herein.

[0118] In the present invention, AR-related diseases include, but are not limited to, asthma, multiple sclerosis, cancer (particularly, prostate cancer, breast cancer (particularly, androgen receptor-positive triple-negative breast cancer (AR+ TNBC)), Kennedy's disease, acne, alopecia (particularly, androgenetic 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, Coeliac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, 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.

[0119] That is, the present invention provides a pharmaceutical use of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for treating or preventing the above-described disease.

[0120] 2. Subjects

[0121] Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, and the like, and include mammals in utero.

[0122] In one embodiment, a suitable subject to be treated according to the present invention is a human.

[0123] 3. Administration and Dosing

[0124] The compounds of the present invention are generally administered in a therapeutically effective amount.

[0125] As used herein, "effective amount" refers to an amount of a compound of the present invention sufficient to slow or minimize the progression of an AR-associated disease or provide a therapeutic benefit in the treatment or management of an AR-associated disease. An "effective amount" also refers to an amount sufficient to inhibit or reduce AR activity, either in vitro or in vivo.

[0126] The compounds of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg / kg body weight / day, preferably from about 0.01 to about 50 mg / kg / day, in single or divided doses. Dosage levels below the lower end of this range may be appropriate depending on age, species, and the disease or condition being treated. In other cases, still higher dosages may be used without harmful side effects. A larger dosage may be divided into several smaller doses for administration throughout the day.

[0127]

[0128] Pharmaceutical composition of the compound of the present invention

[0129] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive. In one aspect of the present invention, the pharmaceutical composition is used for the treatment or prevention of AR-related diseases, preferably prostate cancer, as described below.

[0130] The term "pharmaceutically acceptable" means suitable for use in pharmaceutical preparations, generally considered safe for such use, and officially approved by a national regulatory agency for such use or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0131]

[0132] Pharmaceutical compositions, dosage forms and routes of administration

[0133] For the treatment of the disease or condition described above, the compound described herein or a pharmaceutically acceptable salt thereof may be administered as follows.

[0134] Oral administration

[0135] The compounds of the present invention may be administered orally, including by swallowing. Oral administration may result in the compounds of the present invention entering the gastrointestinal tract, or may be absorbed directly into the bloodstream through the mouth, for example, through buccal or sublingual administration.

[0136] Suitable compositions for oral administration may be in the form of solids, liquids, gels, or powders, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0137] Compositions for oral administration may optionally be enteric coated, and may exhibit delayed or sustained release through the enteric coating. That is, the compositions for oral administration according to the present invention may be formulations having an immediate or modified release pattern.

[0138] Liquid formulations may include solutions, syrups, and suspensions, and these liquid compositions may be contained within soft or hard capsules. These formulations may include pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations may also include one or more emulsifying and / or suspending agents.

[0139] In tablet formulations, disintegrants such as lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof may be used, but are not limited thereto. Lubricants for tablet formulations include talc, silicon dioxide, stearic acid, calcium, zinc, or magnesium stearate, sodium stearyl fumarate, and the like, but the present invention is not limited to the types of these additives. Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. can be used as binders for manufacturing into tablets, and mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. can be used as suitable diluents for manufacturing into tablets, but the present invention is not limited to the types of these additives.

[0140] Solubilizing agents that may optionally be included in the tablets include, for example, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR. TM (Nikkol), oleic acid ester, gelucire TM ), caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, solutol HS TM However, the present invention is not limited to specific types of these solubilizing agents.

[0141] Parenteral Administration

[0142] The compounds of the present invention can be administered directly into the bloodstream, muscle, or internal organs. Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, and intracranial injections. Suitable devices for parenteral administration include injectors (including needle and needle-less syringes) and infusion methods.

[0143] Compositions for parenteral administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or sustained release pattern.

[0144] Most parenteral formulations are liquid compositions, which are aqueous solutions containing the active ingredient, salt, buffer, isotonic agent, etc. according to the present invention.

[0145] Parenteral formulations can also be prepared in a dry form (e.g., lyophilized) or as a sterile non-aqueous solution. These formulations can be used with a suitable vehicle, such as sterile water. Solubility-enhancing agents can also be used in the preparation of parenteral solutions.

[0146] Topical Administration

[0147] The compounds of the present invention can be administered topically, either skin-wise or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be accomplished by electroporation, iontophoresis, phonophoresis, and the like.

[0148] Compositions for topical administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or sustained release pattern.

[0149] The present disclosure provides compounds having excellent AR degrading activity and superior pharmacokinetic and pharmacodynamic properties, pharmaceutical compositions comprising these as active ingredients, their medicinal uses (particularly for prostate cancer), and therapeutic methods comprising administering these to a subject in need of treatment or prevention. The compounds according to the present invention or pharmaceutically acceptable salts thereof are excellent in various aspects, including activity, (metabolic) stability, and pharmacodynamic properties.

[0150] Hereinafter, the present invention will be described in detail, using examples and the like, to aid understanding. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0151] The analyses of the compounds prepared below were performed as follows. Nuclear magnetic resonance (NMR) spectroscopy was performed on a Jeol 400 MHz spectrometer, and chemical shifts were analyzed in ppm. LC-MS was performed using an ACQUITY UPLC H-Class PLUS from Waters. MPLC was performed using an Isolera instrument and a Sfδr silica column from Biotage, and chiral separation was performed using a 150 Prep-SFC instrument and a chiralcel column from Daicel from Waters. In addition, each starting material was a known compound, synthesized according to the literature, or purchased commercially.

[0152]

[0153] Preparation of compounds of the present invention

[0154] Hereinafter, the synthetic process of some compounds of the present invention is described, and compounds not mentioned below can be prepared by a similar method by replacing the starting materials, intermediates and / or reactants.

[0155]

[0156] Intermediate 1-1. 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid

[0157]

[0158] 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) was suspended in DMSO (20.0 ml) and stirred at 90°C for 16 hours. 1 M HCl aqueous solution (100 ml) was added to the reaction mixture and extracted with EtOAc (50 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (from EtOAc) to obtain 5.98 g (76%) of an off-white solid. m / z 299.06 [M+H] + .

[0159]

[0160] Intermediate 1-2. 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid

[0161]

[0162] Step 1: Synthesis of ethyl 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate

[0163] 5-Bromo-3-(trifluoromethyl)-2-pyridinecarbonitrile (500 mg, 1.99 mmol), ethyl piperidine-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 in a microwave at 150 °C for 1 h. 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 purified by MPLC (30% EtOAc / Hexane) to obtain 449 mg (69%) of a white solid. m / z 328.09 [M+H] + .

[0164] Step 2: Synthesis of 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid

[0165] Ethyl 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate (449 mg, 1.37 mmol) was suspended in THF (10.0 ml) and distilled water (5.0 ml), LiOH monohydrate (230 mg, 5.49 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, 1 M HCl aqueous solution (15 ml) was added, and the mixture was extracted with EtOAc (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 the title compound as a white solid. m / z 300.05 [M+H] + .

[0166]

[0167] Intermediate 1-3. 4-(piperazin-1-yl)-2-(trifluoromethyl)benzonitrile

[0168]

[0169] 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 h. Distilled water (20 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (10% MeOH / DCM) to obtain 868 mg (64%) of a white solid. m / z 256.13 [M+H] + .

[0170]

[0171] Intermediate 1-4. 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid

[0172]

[0173] Intermediate 1-4 was synthesized in the same manner as intermediate 1-1, using 2-chloro-4-fluorobenzonitrile instead of 4-fluoro-2-(trifluoromethyl)benzonitrile.

[0174]

[0175] Intermediates 1-5. 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid

[0176]

[0177] Step 1: Synthesis of 3,4-difluoro-2-(trifluoromethyl)benzonitrile

[0178] 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 aqueous NaCl solution and 50% aqueous NH4Cl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 232 mg (mixture) of brown oil.

[0179] Step 2: Synthesis of ethyl 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylate

[0180] 3,4-Difluoro-2-(trifluoromethyl)benzonitrile (232 mg, mixture), ethyl piperidine-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 h. Distilled water (10 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by MPLC (15% EtOAc / Hexane) to obtain 130 mg (33%, 2-step yield) of a white solid. m / z 345.29 [M+H] + .

[0181] Step 3: Synthesis of 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid

[0182] 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 h. The reaction solution was concentrated under reduced pressure, 1 M HCl aqueous solution (15 ml) was added, and the mixture was extracted with EtOAc (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 the title compound as a white solid. m / z 317.25 [M+H] + .

[0183]

[0184] Intermediate 1-6. 1-(3-chloro-4-cyano-2-fluorophenyl)piperidine-4-carboxylic acid

[0185]

[0186] Intermediate 1-6 was synthesized in the same manner as intermediate 1-1 using 2-chloro-3,4-difluorobenzonitrile instead of 4-Fluoro-2-(trifluoromethyl)benzonitrile.

[0187]

[0188] Intermediate 1-7. 1-(4-cyano-3-methoxyphenyl)piperidine-4-carboxylic acid

[0189]

[0190] Intermediate 1-7 was synthesized in the same manner as intermediate 1-1, using 4-fluoro-2-methoxybenzonitrile instead of 4-fluoro-2-(trifluoromethyl)benzonitrile.

[0191]

[0192] Intermediate 2-1. 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0193]

[0194] Step 1: Synthesis of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol

[0195] 1,2-Difluoro-4-nitrobenzene (10.0 g, 62.8 mmol), 4-piperidinemethanol (7.96 g, 69.1 mmol), and DIPEA (13.0 ml, 75.4 mmol) was 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 extracted with EtOAc (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (EtOAc / Hexane) to obtain 15.7 g (98%) of a yellow solid. m / z 255.21 [M+H] + .

[0196] Step 2: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidine-4-carbaldehyde

[0197] (1-(2-Fluoro-4-nitrophenyl)piperidin-4-yl)methanol (8.00 g, 31.5 mmol) was suspended in DCM (35.0 ml), DMP (16.0 g, 37.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Saturated Na2S2O3 aqueous solution (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 a residue. The obtained residue was subjected to MPLC (50% EtOAc / Hexane) to obtain 5.69 g (72%) of a yellow solid. m / z 253.22 [M+H] + .

[0198] Step 3: Synthesis of 4-(1,3-dioxolan-2-yl)-1-(2-fluoro-4-nitrophenyl)piperidine

[0199] 1-(2-Fluoro-4-nitrophenyl)piperidine-4-carbaldehyde (5.69 g, 22.6 mmol) was suspended in toluene (100.0 ml), and 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. Saturated NaHCO3 aqueous solution (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 a residue. The obtained residue was recrystallized (EtOAc / Hexane) to obtain 6.44 g (96%) of a yellow solid. m / z 297.19 [M+H] + .

[0200] Step 4: Synthesis of 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-3-fluoroaniline

[0201] 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 for 24 h under a hydrogen stream. The reaction solution was filtered and concentrated to obtain 5.36 g (93%) of an off-white solid. m / z 267.27 [M+H] + .

[0202] Step 5: Synthesis of 3-((4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0203] 4-(4-(1,3-Dioxolan-2-yl)piperidin-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 h. Distilled water (200 ml) was added to the reaction mixture and extracted with EtOAc (150 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by MPLC (50% EtOAc / Hexane) to obtain 5.80 g (66%) of a green solid. m / z 378.54 [M+H] + .

[0204] Step 6: Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0205] 3-((4-(4-(1,3-Dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (200 mg, 0.530 mmol) was suspended in THF (1.86 ml), 2 M HCl aqueous solution (1.86 ml) was added, and the mixture was stirred at 50 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and saturated NaHCO3 aqueous solution (30 ml) was added, followed by extraction with DCM (30 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was recrystallized (EtOAc / Hexane) to obtain 107 mg (61%) of an off-white solid. m / z 334.23 [M+H] + .

[0206]

[0207] Intermediate 2-2. (S)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0208]

[0209] Step 1: Synthesis of (S)-3-((4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0210] 3-((4-(4-(1,3-Dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Intermediate 2-1 Step 5, 8.60 g, 22.8 mmol) was separated via SFC (Waters 150 Prep-SFC, Daicel chiralcel IG column, mobile phase: A for CO2, B for IPA and ACN, 65% phase B gradient, flow rate: 100 mL / min) to obtain 3.89 g (45.2%) of a green solid.

[0211] Analytical SFC (SHIMADZU LC-30AD SF, IG 50

[0212] Step 2: Synthesis of (S)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0213] (S)-3-((4-(4-(1,3-Dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (3.00 g, 7.95 mmol) was suspended in THF (60.0 ml), 2 M HCl aqueous solution (60.0 ml) was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and saturated NaHCO3 aqueous solution (350 ml) was added, followed by extraction with DCM (150 ml x 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was recrystallized (EtOAc / Hexane) to obtain 2.40 g (89%) of an off-white solid. m / z 334.26 [M+H] + .

[0214]

[0215] Intermediate 2-3. (R)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0216]

[0217] Step 1: Synthesis of (R)-3-((4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0218] 3-((4-(4-(1,3-Dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Intermediate 2-1 Step 5, 8.60 g, 22.8 mmol) was separated via SFC (Waters 150 Prep-SFC, Daicel chiralcel IG column, mobile phase: A for CO2, B for IPA and ACN, 65% phase B gradient, flow rate: 100 mL / min) to obtain 3.94 g (45.8%) of a green solid.

[0219] Analytical SFC (SHIMADZU LC-30AD SF, IG 50

[0220] Step 2: Synthesis of (R)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde

[0221] (R)-3-((4-(4-(1,3-Dioxolan-2-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (250 mg, 0.662 mmol) was suspended in THF (2.32 ml), 2 M HCl aqueous solution (2.32 ml) was added, and the mixture was stirred at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure, and saturated NaHCO3 aqueous solution (60 ml) was added, followed by extraction with DCM (20 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was recrystallized (EtOAc / Hexane) to obtain 172 mg (78%) of an off-white solid. m / z 334.32 [M+H] + .

[0222]

[0223] Intermediate 2-4. 3-((3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)amino)piperidine-2,6-dione

[0224]

[0225] Step 1: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one

[0226] 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) was suspended in DMF (4.0 ml) and stirred at 90°C for 2 hours. Distilled water (20 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to MPLC (80% EtOAc / Hexane) to obtain 390 mg (87%) of a yellow solid. m / z 239.22 [M+H] + .

[0227] Step 2: Synthesis of 8-(2-fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

[0228] 1-(2-Fluoro-4-nitrophenyl)piperidin-4-one (150 mg, 0.630 mmol) was suspended in toluene (2.0 ml), and 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. Saturated NaHCO3 aqueous solution (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 a residue. The obtained residue was recrystallized (EtOAc) to obtain 147 mg (83%) of a yellow solid. m / z 283.16 [M+H] + .

[0229] Step 3: Synthesis of 3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline

[0230] 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 for 16 h under a hydrogen stream. The reaction solution was filtered and concentrated to obtain 120 mg (99%) of a pink solid. m / z 253.26 [M+H] + .

[0231] Step 4: Synthesis of 3-((3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)piperidine-2,6-dione

[0232] 3-Fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-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 h. Distilled water (15 ml) was added to the reaction mixture and extracted with EtOAc (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (50% EtOAc / Hexane) to obtain 54 mg (62%) of a green solid. m / z 364.24 [M+H] + .

[0233] Step 5: Synthesis of 3-((3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)amino)piperidine-2,6-dione

[0234] 3-((3-Fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)piperidine-2,6-dione (54 mg, 0.15 mmol) was suspended in THF (0.75 ml), 2 M HCl aqueous solution (0.75 ml, 1.5 mmol) was added, and the mixture was stirred at 60 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure, and saturated NaHCO3 aqueous solution (20 ml) was added, and 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] + .

[0235]

[0236] Intermediate 2-5. 1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-4-carbaldehyde

[0237]

[0238] Intermediate 2-5 was synthesized in the same manner as intermediate 2-1, using 2-chloro-1-fluoro-4-nitrobenzene instead of 1,2-difluoro-4-nitrobenzene.

[0239]

[0240] Intermediate 2-6. 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-carbaldehyde

[0241]

[0242] Intermediate 2-6 was synthesized using the same method as Intermediate 2-1, using 1-fluoro-4-nitro-2-(trifluoromethyl)benzene instead of 1,2-Difluoro-4-nitrobenzene.

[0243]

[0244] Example 1. 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0245]

[0246] Step 1: Synthesis of tert-butyl 4-((6-nitropyridin-3-yl)oxy)piperidine-1-carboxylate

[0247] 1-(Tert-butoxycarbonyl)-4-hydroxypiperidine (8.50 g, 42.2 mmol) was suspended in THF (180 ml), 60% NaH (1.69 g, 42.2 mmol) was added at 0 ℃, and 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 EtOAc (150 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (from EtOAc) to obtain 7.20 g (63%) of an off-white solid. m / z 324.15 [M+H] + .

[0248] Step 2: Synthesis of tert-butyl 4-((6-aminopyridin-3-yl)oxy)piperidine-1-carboxylate

[0249] Tert-butyl 4-((6-nitropyridin-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 for 2 h at room temperature under a hydrogen stream. The reaction solution was filtered and concentrated to obtain a black solid (6.54 g, quant.). m / z 294.20 [M+H] + .

[0250] Step 3: Synthesis of tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamido)pyridin-3-yl)oxy)piperidine-1-carboxylate

[0251] Tert-butyl 4-((6-aminopyridin-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 EtOAc (150 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (EtOAc) to obtain 9.23 g (72%) of an off-white solid. m / z 574.30 [M+H] + .

[0252] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-yloxy)pyridin-2-yl)piperidine-4-carboxamide

[0253] Tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamido)pyridin-3-yl)oxy)piperidine-1-carboxylate (9.23 g, 16.1 mmol) was suspended in DCM (41.0 ml), TFA (16.4 ml, 214.0 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and 2 M NaOH aqueous solution (150 ml) was added, followed by extraction 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 an off-white solid. m / z 474.22 [M+H] + .

[0254] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0255] 1-(4-Cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-yloxy)pyridin-2-yl)piperidine-4-carboxamide (3.41 g, 7.20 mmol) and 1-(4-((2,6-dioxopiperidin-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), sodium triacetoxyborohydride (3.82 g, 18.0 mmol) was added, and the mixture was stirred at room temperature for 16 h. Saturated NaHCO3 aqueous solution (70 ml) was added to the reaction mixture, and the mixture was extracted with DCM (70 ml x 3). 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 4.56 g (80%) of a light-colored solid.

[0256]

[0257] Example 2. (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0258]

[0259] Example 2 was synthesized in the same manner as Example 1, using (S)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-2) instead of 1-(4-((2,6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1).

[0260]

[0261] Example 3. (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0262]

[0263] Example 3 was synthesized in the same manner as Example 1, using (R)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-3) instead of 1-(4-((2,6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1).

[0264]

[0265] Example 4. 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[1,4'-bipiperidin]-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0266]

[0267] 1-(4-Cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-yloxy)pyridin-2-yl)piperidine-4-carboxamide (Example 1 Step 4, 43 mg, 0.091 mmol) and 1-(4-((2,6-dioxopiperidin-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), 2-methylpyridine borane complex (29 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 16 h. 1 M KOH aqueous solution (1.0 ml) was added to the reaction mixture, and the mixture was extracted with DCM (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 (10% MeOH / DCM) to obtain 13 mg (18%) of a sky-blue solid.

[0268]

[0269] Example 5. 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0270]

[0271] Example 5 was synthesized in the same manner as Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (Intermediate 1-2) instead of 1-(4-Cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (Intermediate 1-1).

[0272]

[0273] Example 6. 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide

[0274]

[0275] Step 1: Synthesis of tert-butyl 4-((6-((phenoxycarbonyl)amino)pyridin-3-yl)oxy)piperidine-1-carboxylate

[0276] Tert-butyl 4-((6-aminopyridin-3-yl)oxy)piperidine-1-carboxylate (Example 1 Step 2, 100 mg, 0.341 mmol) was suspended in THF (2.0 ml), and phenyl chloroformate (0.05 mg, 0.375 mmol) and pyridine (0.03 ml, 0.375 mmol) were added at 0 °C and stirred at room temperature for 2 hours. Distilled water (15 ml) was added to the reaction solution, and the precipitated solid was filtered and dried under vacuum to obtain 105 mg (74%) of a white solid. m / z 414.16 [M+H] + .

[0277] Step 2: Synthesis of tert-butyl 4-((6-(4-(4-cyano-3-(trifluoromethyl)phenyl)piperazine-1-carboxamido)pyridin-3-yl)oxy)piperidine-1-carboxylate

[0278] Tert-butyl 4-((6-((phenoxycarbonyl)amino)pyridin-3-yl)oxy)piperidine-1-carboxylate (105 mg, 0.254 mmol), 4-(piperazin-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 h. Distilled water (15 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (25 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (10% MeOH / DCM) to obtain 126 mg (86%) of a white solid. m / z 575.29 [M+H] + .

[0279] Step 3: Synthesis of 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-yloxy)pyridin-2-yl)piperazine-1-carboxamide

[0280] Tert-butyl 4-((6-(4-(4-cyano-3-(trifluoromethyl)phenyl)piperazine-1-carboxamido)pyridin-3-yl)oxy)piperidine-1-carboxylate (126 mg, 0.219 mmol) was suspended in DCM (1.0 ml), 4 M HCl in dioxane (0.27 ml, 1.10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous NaHCO3 solution (15 ml) was added, followed by extraction 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] + .

[0281] Step 4: Synthesis of 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide

[0282] 4-(4-Cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-yloxy)pyridin-2-yl)piperazine-1-carboxamide (20 mg, 0.042 mmol) and 1-(4-((2,6-dioxopiperidin-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), sodium triacetoxyborohydride (22 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 16 h. Saturated NaHCO3 aqueous solution (15 ml) was added to the reaction mixture, and the mixture was extracted with DCM (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 (10% MeOH / DCM) to obtain 16 mg (48%) of a light-colored solid.

[0283]

[0284] Example 7. 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide

[0285]

[0286] Step 1: Synthesis of tert-butyl 4-((6-chloropyridazin-3-yl)oxy)piperidine-1-carboxylate

[0287] 1-(Tert-butoxycarbonyl)-4-hydroxypiperidine (7.08 g, 35.2 mmol) was suspended in THF (350 ml), 60% NaH (2.11 g, 52.8 mmol) was added at 0 ℃, 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 EtOAc (150 ml x 2) was extracted. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (EtOAc) to obtain 8.42 g (76%) of a white solid. m / z 336.36 [M+Na] + .

[0288] Step 2: Synthesis of tert-butyl 4-((6-((diphenylmethylene)amino)pyridazin-3-yl)oxy)piperidine-1-carboxylate

[0289] Tert-butyl 4-((6-chloropyridazin-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), and 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 h. The reaction solution was filtered and concentrated, and the resulting residue was subjected to MPLC (30% EtOAc / Hexane) to obtain 9.42 g (76%) of a white solid. m / z 459.31 [M+H] + .

[0290] Step 3: Synthesis of tert-butyl 4-((6-aminopyridazin-3-yl)oxy)piperidine-1-carboxylate

[0291] 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), and hydroxylamine hydrochloride (1.57 g, 22.6 mmol) and NaOAc (4.20 g, 51.3 mmol) were added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was subjected to MPLC (10% MeOH / DCM) to obtain 4.66 g (77%) of a white solid. m / z 295.23 [M+H] + .

[0292] Step 4: Synthesis of tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamido)pyridazin-3-yl)oxy)piperidine-1-carboxylate

[0293] Tert-butyl 4-((6-aminopyridazin-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 EtOAc (200 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was recrystallized (from EtOAc) to obtain 23.3 g (83%) of an off-white solid. m / z 597.28 [M+Na] + .

[0294] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(piperidin-4-yloxy)pyridazin-3-yl)piperidine-4-carboxamide

[0295] Tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamido)pyridazin-3-yl)oxy)piperidine-1-carboxylate (21.0 g, 36.5 mmol) was suspended in DCM (280.0 ml), TFA (42.0 ml, 548 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and saturated 2M NaOH aqueous solution (150 ml) was added, followed by extraction 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 an off-white solid. m / z 475.23 [M+H] + .

[0296] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide

[0297] 1-(4-Cyano-3-(trifluoromethyl)phenyl)-N-(6-(piperidin-4-yloxy)pyridazin-3-yl)piperidine-4-carboxamide (30 mg, 0.0063 mmol) and 1-(4-((2,6-dioxopiperidin-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), sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 16 h. Saturated NaHCO3 aqueous solution (15 ml) was added to the reaction mixture, and the mixture was extracted with DCM (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 (10% MeOH / DCM) to obtain 17 mg (34%) of an off-white solid.

[0298]

[0299] Example 8. 1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0300]

[0301] Example 8 was synthesized in the same manner as 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).

[0302]

[0303] Example 9. (S)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0304]

[0305] Example 9 was synthesized in the same manner as 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 using (S)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-2) instead of 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1).

[0306]

[0307] Example 10. (R)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0308]

[0309] Example 10 was synthesized in the same manner as 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 using (R)-1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1) instead of 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-3).

[0310]

[0311] Example 11. 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0312]

[0313] Example 11 was synthesized in the same manner as 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).

[0314]

[0315] Example 12. 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0316]

[0317] Example 12 was synthesized in the same manner as 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).

[0318]

[0319] Example 13. 1-(4-cyano-3-methoxyphenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0320]

[0321] Example 13 was synthesized in the same manner as 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).

[0322]

[0323] Example 14. 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide

[0324]

[0325] Example 14 was synthesized in the same manner as 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).

[0326]

[0327] Example 15. 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide

[0328]

[0329] Example 15 was synthesized in the same manner as 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).

[0330]

[0331] Example 16. 1-(4-cyano-3-methoxyphenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide

[0332]

[0333] Example 16 was synthesized in the same manner as 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).

[0334]

[0335] Example 17. N-(5-((1-((1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide

[0336]

[0337] Example 17 was synthesized in the same manner as Example 1, using 1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-4-carbaldehyde (Intermediate 2-5) instead of 1-(4-((2,6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1).

[0338]

[0339] Example 18. 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

[0340]

[0341] Example 18 was synthesized in the same manner as Example 1, using 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidine-4-carbaldehyde (Intermediate 2-6) instead of 1-(4-((2,6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (Intermediate 2-1).

[0342]

[0343] The NMR and / or LC / MS measurement results of the previously synthesized compounds are summarized and presented in the table below.

[0344]

[0345]

[0346]

[0347]

[0348] Experimental Example 1: Measurement of androgen receptor (AR) protein degradation

[0349] After treating LNCaP or VCaP cells with the synthesized compound, the amount of AR protein present in the cells was measured. The amount of AR protein was measured using Western blotting. The protocol for the experiment using LNCaP or VCaP cells was as follows.

[0350] [Culture] LNCaP cells were resuspended in RPMI1640 MEDIUM+HEPES (Hyclone, SH30255.01), 10% FBS (Hyclone, SV30207.02), and 1% Penicillin-streptomycin (Welgene, LS 202-02) and seeded at 3 x 10 5 1 mL of VCaP cells were seeded in 12-well plates at a density of 10 cells / mL and cultured for 3 days. VCaP cells were resuspended in IMDM MEDIUM (Hyclone, SH30228.01), 20% FBS (Hyclone, SV30207.02), and 1% Penicillin-streptomycin (Welgene, LS 202-02) and seeded at 9 x 10 5 1 mL was seeded in each 12-well plate at / mL and cultured for 3 days.

[0351] [Compound treatment] 10 μL of 100x stock (e.g., 0.1, 1, 10 μM) compound solution at the final compound treatment concentration (e.g., 0.001, 0.01, 0.1 μM) was added to each well in 1 mL media, and cells were harvested after 20 hours. DC 50For measurements, 100x stock (0.01, 0.1, 1, 10, 100, 1000 μM) compound solutions were used at final compound treatment concentrations (0.0001, 0.001, 0.01, 0.1, 1, 10 μM).

[0352] [Cell lysis] The cell pellet was suspended using 1% SDS lysis buffer (50 mM Tris, 1 mM EDTA, 1% SDS, pH 8.0, 0.5 mM PMSF, 1x Protease / Phosphatase inhibitor Cocktail (Cell Signaling Technology, 5872S)), and sonication (70% AMP, 10 cycles (30 sec ON / 59 sec OFF)) was performed. After centrifugation at 4℃ and 20,000 g for 20 minutes, the cell lysate was obtained and transferred to a new tube.

[0353] [Protein quantification] BCA protein assay (SMART) using a 96-well microplate TM BCA Protein Assay Kit, iNtRON Biotechnology, 21071) was performed. 5 μL cell lysate and 5 μL 1% SDS lysis buffer were added to each well of a 96-well plate, and 200 μL BCA reagent (Reagent A: Reagent B = 50:1) was additionally added. The plate was incubated at 37°C for 30 min and cooled to room temperature for 10 min. After shaking for 10 s, the absorbance was measured at a wavelength of 562 nm. The unknown protein concentration was measured using a BSA standard curve (0, 0.125, 0.25, 0.5, 1, 2 mg / mL). Cell lysate, 1% SDS lysis buffer, 4x NuPAGE TMLDS Sample buffer (Invitrogen, NP0008) and 10X NuPAGE TM Western blotting samples were prepared by mixing Sample Reducing Agent (Invitrogen, NP0009) and boiling at 70°C for 10 minutes.

[0354] [Electrophoresis] NuPAGE TM 10 μg of protein sample was loaded into each well of 4 to 12%, Bis-Tris, 1.0 mm Mini Protein Gel, 15-well, 17-well, or 26-well (Invitrogen, NP0323BOX, NP0329BOX, or WG1403BOX) and then subjected to NuPAGE. TM Electrophoresis was performed for 40 minutes at 200 V (constant V) using MES SDS Running Buffer (Invitrogen, NP0002).

[0355] [Transfer] Electrophoresis-performed gel and Trans-Blot® Turbo TM Transfer was performed for 15 or 18 minutes using the Transfer Starter System (Bio-RAD, #17001918, Mini Nitrocellulose) at 1.3 A (Constant A), 25 V (Limit V). To confirm protein transfer, 15 mL of Ponceau S solution (Sigma, P7170-1L) was used to stain and wash for 1 minute to check the degree of transfer.

[0356] [Blocking] The membrane for AR and GAPDH detection was blocked with 5% skim milk / 0.2% TBST (Skim milk: BD, 232100 / 20X TBS: Biosesang, TR2008-100-00 / 10% Tween 20 Solution: Bio-RAD, #161-0781) for 45 minutes.

[0357] [Antibodies and Detection] The primary AR antibody (Androgen Receptor: CST, 5153S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:1,000 and reacted at room temperature for 3 hours or at 4℃ overnight. The primary GAPDH antibody (CST, 2118S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:2,000 and reacted at room temperature for 3 hours or at 4℃ overnight. Afterwards, the plates were washed three times every 5 minutes with TBST (0.2% Tween 20). The secondary antibody for AR antibody, Anti-rabbit IgG, HRP-linked Antibody (CST, 7074S), was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:5,000 and reacted at room temperature for 45 minutes. IRDye® 800CW Goat anti-Rabbit IgG secondary antibody against GAPDH antibody was mixed at a ratio of 1:10,000 in 5% skim milk / 0.2% TBST and incubated at room temperature for 45 minutes. After 45 minutes, the plate was washed five times with TBST (0.2% Tween 20) every 5 minutes. SuperSignal TMAfter reacting with the membrane using West Pico Plus Chemiluminescent Substrate (Thermo Scientific, 34580), detection was performed using the Odyssey® Fc Imaging system (LI-COR, 2800).

[0358] [Quantification of numerical values] The amount of AR protein was measured using a program built into the Odyssey® Fc Imaging system (LI-COR, 2800) machine, and normalized to the amount of measured GAPDH protein to obtain % degradation, D max and DC 50 was quantified.

[0359] The results of these evaluations are shown in the tables below.

[0360] Example numberAR degradation in LNCaP cells (%)10 nM100 nM184992869939399476935639768499779938919898696109099128896139199158890169398177799185198

[0361] Example numberAR degradation in VCaP cells (%)10 nM100 nM1899928399372967941008949999499108599118999129498139510014879515981001699100177597

[0362] Example number: AR degradation in VCaP cells 50 (nM)D max (%)20.199990.1099

[0363] As shown in the table above, the compounds according to the present invention showed excellent activity in decomposing androgen receptors.

[0364]

[0365] Experimental Example 2: Measurement of Pharmacodynamic Efficacy

[0366] The protocol for the creation of a xenograft model and pharmacodynamic experiments using VCaP cells was as follows.

[0367] [Cell culture] VCaP cells were cultured at 4 x 10 in a mixture of DMEM MEDIUM (Hyclone, SH30243.01), 10% FBS (Hyclone, SV30207.02), 1% Penicillin-streptomycin (Welgene, LS 202-02), and 1x Non-essential amino acid solution (100x) (Sigma, M7145-100mL). 5 / mL. Then, CELLBIND cell culture flask (150 cm 2 ) (Corning, 3291) were seeded at 50 mL each and cultured for 5 days.

[0368] [Xenotransplantation] The media was removed from the flask of cultured VCaP cells, and 10 mL of PBS (Welgene, LB001-02) was added to wash the flask. After removing the PBS, 2 mL of 1x 0.05% Trypsin-EDTA (Welgene, LS015-01) was added, and the cells were treated in a cell incubator for 3 minutes. 10 mL of media was added, pipetted, and placed in a 50 mL tube. The cells were centrifuged at 500 g for 5 minutes to collect the pellet. The collected pellet was washed once more with 20 mL of PBS. The washed pellet was collected by centrifuging at 500 g for 5 minutes. The PBS was removed, and 500 μL of HBSS (Gibco, 14025092) was added, and pipetted. The cells were diluted 100-fold in HBSS, and the cell count was measured, and 3 x 10 6 / 50 μL / mouse, diluted in HBSS, and stored in an ice bucket. An equal volume of matrigel (R&D system, 3432-005-01) was added to the stored cells, homogenized by pipetting, and 100 μL per mouse was inoculated subcutaneously into the right flank of CB17 / SCID mice.

[0369] [Measurement of cancer size and division into groups] After 2-3 weeks of inoculation with cancer cells, the transplanted cancer cells grew and their size was measured using a caliper. The measured cancer size was calculated as [long axis x short axis]. 2 x 0.5] was calculated. The size of the cancer was approximately 200 mm. 2 If this is the case, experimental animals are divided into groups based on the average tumor size and the concentration of drug administered. A vehicle group containing only the drug was always included in the groups.

[0370] [Drug Preparation and Administration] The drug was dissolved in a solvent and orally administered to each experimental animal in a volume of 200 μL (approximately 8 mL / kg). The solvent composition was 3% DMSO (Sigma, D8418), 10% Cremophor EL (Sigma, C5135), 20% PEG400 (Sigma, 06855-1KG), and 67% distilled water. The preparation method was as follows. Depending on the drug concentration (e.g., 10 or 30 mg / kg), each drug was weighed 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, vortexed, and finally 67% DW was added and vortexed again. The prepared drug was orally administered according to the experimental animal group.

[0371] [Cancer Tissue Extraction] The prepared drug was administered orally once daily at the same time for three days. Changes in tumor size were measured during the prescribed administration period, and the mice were sacrificed 6 hours after the final administration. After sacrifice, tumor tissue was collected, washed in PBS, and stored at -80°C.

[0372] [Tissue homogenization and cell lysis] The cancer tissue stored at -80℃ was thawed on ice and cut into equal sizes of 0.5 cm x 0.5 cm x 0.5 cm (length x width x height). Add 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) to an E.tube and place the cut cancer tissue in 1% SDS lysis buffer (50 mM Tris, 1 mM EDTA, 1% SDS, pH 8.0, 0.5 mM PMSF, 1x Protease / Phosphatase inhibitor Cocktail (Cell Signaling Technology, 5872S)) and homogenize using a bead mill homogenizer (Omni international Inc., #19-040E). Afterwards, sonication (70% AMP, 10 cycles (10 sec ON / 30 sec OFF)) was performed, and after centrifugation at 4℃, 20,000g for 15 minutes, cell lysate was obtained as the supernatant.

[0373] [Western blotting sample preparation] Cell lysate, 1% SDS lysis buffer, 4x NuPAGE TM LDS Sample buffer (Invitrogen, NP0008) and 10x NuPAGE TMWestern blotting samples were prepared by mixing Sample Reducing Agent (Invitrogen, NP0009) and boiling at 70°C for 10 minutes.

[0374] [Electrophoresis] NuPAGE TM 10 μL of the prepared sample was loaded into each well of a 4 to 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 200 V (constant V) using MES SDS Running Buffer (Invitrogen, NP0002).

[0375] [Transfer] Electrophoresis-performed gel and Trans-Blot® Turbo TM Transfer was performed for 15 minutes using the Transfer Starter System (Bio-RAD, #17001918, Mini Nitrocellulose) at 1.3 A (Constant A), 25 V (Limit V). To confirm protein transfer, 15 mL of Ponceau S solution (Sigma, P7170-1L) was used for staining for 1 minute, and then washing to check the degree of transfer.

[0376] [Blocking] The membrane for AR and GAPDH detection was blocked with 5% skim milk / 0.2% TBST (Skim milk: BD, 232100 / 20x TBS: Biosesang, TR2008-100-00 / 10% Tween 20 Solution: Bio-RAD, #161-0781) for 45 minutes.

[0377] [Antibodies and Detection] The primary AR antibody (Androgen Receptor: CST, 5153S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:1,000 and reacted overnight at 4℃. The primary GAPDH antibody (CST, 2118S) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:1,000 and reacted overnight at 4℃. Afterwards, the plate was washed three times every 5 minutes with TBST (0.2% Tween 20). The secondary antibody, Anti-rabbit IgG, HRP-linked Antibody (CST, 7074S) against AR and GAPDH antibodies was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:5,000 and reacted at room temperature for 45 minutes. After 45 minutes, the cells were washed five times with TBST (0.2% Tween 20) every 5 minutes. SuperSignal TM After reacting with the membrane using West Pico Plus Chemiluminescent Substrate (Thermo Scientific, 34580), detection was performed using the Odyssey® Fc Imaging system (LI-COR, 2800).

[0378] [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 was calculated by normalizing it with the amount of measured GAPDH protein.

[0379] The results of these pharmacodynamic evaluations are shown in the table below.

[0380] Example number Administration dose AR degradation in tumor (%) 110 mg / kg 86 210 mg / kg 96 310 mg / kg 89 910 mg / kg 97

[0381] As shown in the table above, it was confirmed that the compounds according to the present invention have excellent pharmacodynamic properties by exhibiting excellent AR decomposition activity after oral administration.

[0382]

[0383] Experimental Example 3: Analysis of concentrations in plasma and cancer tissue after oral administration

[0384] The concentrations of drugs administered orally in plasma and cancer tissues in a xenograft model using VCaP cells were analyzed as follows.

[0385] [Blood collection and tumor tissue extraction] The prepared drug was administered orally at a dose of 10 mg / kg once daily at the same time for 3 days. The mice were sacrificed 2, 6, and 24 hours after the last administration. Blood collection and tumor tissue extraction were performed immediately after sacrifice at each hour. Blood collected from the heart was placed in a K2EDTA tube for 30 minutes and then centrifuged at 15,000 rpm at 4°C for 10 minutes. The supernatant plasma was separated and stored at -20°C for analysis. The extracted tumor tissue was washed in PBS, cut into pieces of approximately 10 mg, and stored at -80°C for analysis.

[0386] [Sample Preparation] After adding 9 times the weight of distilled water to the cancer tissue, the tissue was homogenized once at 5,500 rpm for 20 seconds using a tissue homogenizer (Precellys Evolution, Bertin Technology). For the cancer tissue, 20 μL of the homogenate was mixed with 20 μL of blank plasma sample, 20 μL of the internal standard (carbamazepine, 30 ng / mL in acetonitrile), and 140 μL of acetonitrile. For the plasma, 20 μL of the plasma sample was mixed with 20 μL of the blank liver tissue sample, 20 μL of the internal standard, and 140 μL of acetonitrile. Afterwards, the mixed sample was suspended for 10 minutes using a vortex mixer and centrifuged at 13,500 rpm for 10 minutes at room temperature. 140 μL of the supernatant was collected and transferred to the analysis container.

[0387] [Sample Analysis] Drug concentrations in cancer tissue and plasma samples were quantified using an HPLC / MS / MS system. Five microliters of the sample prepared in the analytical vessel was injected into the HPLC / MS / MS system for analysis. For drug quantification, 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 analytical column as the reverse phase. The chromatogram was confirmed using an isocratic elution method. Ion detection was performed in ESI positive MRM mode, and the integration of the detected peaks was performed using Analyst software version 1.6.4 (Applied Biosystems / MDS SCIEX). The drug concentration in cancer tissue was calculated by multiplying the concentration obtained by analyzing the cancer tissue homogenate by the dilution factor of 10.

[0388] The results of drug concentration analysis in these plasma and cancer tissues are shown in the table below.

[0389] Example Number Time Concentration in Plasma (ng / mL)Concentration in Tumor Tissue (ng / g)Tissue to Plasma Ratio2281655636.786610612710.10245183416.29

[0390] As shown in the above table, it was confirmed that the compound according to the present invention has significantly superior pharmacodynamic properties by showing an excellent tumor tissue to plasma concentration ratio after oral administration.

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof. [Chemical Formula 1] In the above chemical formula 1, R1 is H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, or C 1-3 It is haloalkyl, R2 is H, halogen, or C 1-3 It is haloalkyl X1, X2, and X3 are independently CH or N, R3 is H, halogen, C 1-3 Alkyl, or C 1-3 It is haloalkyl, n is 0, 1, or 2.

2. In the first paragraph, in the chemical formula 1 R1 is H, Cl, -CH3, -OCH3, or -CF3, R2 is H or F, X1, X2, and X3 are independently CH or N, R3 is H, F, Cl, -CH3, or -CF3, A compound wherein n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

3. In the second paragraph, in the chemical formula 1 R1 is Cl, -OCH3, or -CF3, R2 is H or F, X1, X2, and X3 are independently CH or N, R3 is F, Cl, or -CF3, A compound wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

4. In the third paragraph, in the chemical formula 1 R1 is Cl, -OCH3, or -CF3, R2 is H or F, X1 and X2 are CH, X3 is CH or N, R3 is F or Cl, n is a compound or a pharmaceutically acceptable salt thereof.

5. In the fourth paragraph, in the chemical formula 1 Is or A compound of formula (I) or a pharmaceutically acceptable salt thereof.

6. In the first paragraph, the compound 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[1,4'-bipiperidin]-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide, 1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, (S)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, (R)-1-(3-chloro-4-cyanophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 1-(4-cyano-3-methoxyphenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, 1-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide, 1-(3-chloro-4-cyano-2-fluorophenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide, 1-(4-cyano-3-methoxyphenyl)-N-(6-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridazin-3-yl)piperidine-4-carboxamide, N-(5-((1-((1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide, 또는 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide A compound or a pharmaceutically acceptable salt thereof.

7. A composition comprising a compound of 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 decomposing androgen receptor (AR), comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. In the 8th paragraph, the pharmaceutical composition is for the treatment or prevention of cancer, Kennedy's disease, acne, alopecia, cutaneous wound, or hirsutism.

10. In claim 9, 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 administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

12. A method for treating or preventing androgen receptor-related diseases according to claim 11, wherein the androgen receptor-related disease is cancer, Kennedy's disease, acne, alopecia, cutaneous wound, or hirsutism.

13. A method for treating or preventing androgen receptor-related disease according to claim 12, wherein the disease is prostate cancer or breast cancer.

Images