Compounds for androgen receptor degradation and pharmaceutical uses thereof

Abstract

The present disclosure provides compounds or pharmaceutically acceptable salts thereof having a specific chemical structure, which have activity in degrading androgen receptor (AR). The present disclosure also provides compositions comprising such compounds or pharmaceutically acceptable salts thereof. The present disclosure also provides medical uses of the compounds according to the present disclosure, salts thereof, and compositions comprising these for treating or preventing AR-related diseases. The present disclosure also provides a method of treating or preventing AR-related diseases, which comprises administering to a subject in need thereof an effective amount of the compounds of the present disclosure, salts thereof, or compositions comprising these.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 10-2020-0089940, filed on July 21, 2020, and all the contents disclosed in the specification of that application are incorporated herein by reference.

[0002] This disclosure relates to a group of compounds having androgen receptor-degrading activity. This disclosure also relates to pharmaceutical compositions comprising such compounds. The invention further relates to useful methods of treating androgen receptor-related diseases using such compounds. In other words, this disclosure relates to the medical use of compounds according to this disclosure for the treatment or prevention of androgen receptor-related diseases. Background Technology

[0003] The androgen receptor (AR) is a transcription factor belonging to the nuclear hormone receptor (NR) family. In the absence of androgens, AR binds to heat shock protein 90 (Hsp90) in the cytoplasm. Hsp90 dissociates from AR, and androgens bind to AR. When AR binds to the hormone dihydrotestosterone (DHT), these complexes are translocated to the nucleus and activate the transcription of target genes through a series of processes.

[0004] AR contributes to masculinity, but it is also a well-known oncogene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). Current treatment options for androgen-associated prostate cancer fall into two main categories. The first approach controls androgen levels by removing androgens or by interfering with the binding of their ligand DHT to prevent their metastasis into the nucleus. The second strategy aims to inhibit AR function by targeting AR (Nature Reviews Drug Discovery, 2013, 12, 823-824). In other words, alternative approaches to treating prostate cancer include deleting the AR protein. AR is a significant driver of tumorigenesis in many forms of prostate cancer.

[0005] This AR can also be a major target for the treatment of acne, hair loss (especially androgenetic alopecia), skin trauma, hirsutism and other conditions (Arch Dermatol Res. 2012 September; 304(7): 499–510, Biomedicine & Pharmacotherapy 137(2021) 111247), and AR expression and activation have also been found 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, with apalutamide recently approved. However, approximately 15% to 25% of prostate cancer patients do not respond to anti-androgen drugs, and while approved drugs show excellent anti-cancer effects in the initial stages of administration, resistance develops with continued use, making them difficult to continue. Therefore, there is an urgent need to develop new therapeutic agents. Summary of the Invention

[0007] Technical issues

[0008] Therefore, the problem to be solved by the present invention is to provide a compound having androgen receptor (AR) degradation activity, a pharmaceutical composition comprising the compound as an active ingredient, and for medical use in treating or preventing AR-related diseases.

[0009] Another problem to be solved by the present invention is to provide a method for treating or alleviating AR-related diseases, characterized in that it degrades AR and thus reduces AR activity, and it comprises administering a compound according to the invention to a patient who needs treatment, improvement or prevention of AR-related diseases.

[0010] Technical solution

[0011] The compounds of the present invention

[0012] To address the above problems, one embodiment of the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0013] [Chemical Formula 1]

[0014]

[0015] In chemical formula 1,

[0016] R1 is H, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy

[0017] R2 is H, C 1-4 Alkyl, halogen or halogenated C 1-4 alkyl,

[0018] X1, X3, X4, and X5 are each independently CH or N.

[0019] X2 is either CR3 or N, where R3 is H or C. 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, C 1-6alkoxy or -OH

[0020] n is 0, 1, or 2.

[0021] m is 0 or 1.

[0022] L is the following chemical formula 2:

[0023] [Chemical Formula 2]

[0024]

[0025] In chemical formula 2,

[0026] A1, A2, and A3 are each independently directly connected to -O-, -N(R4)-, -C(O)-, -CC-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, or -C(O)CH2O-, where R4 is H, C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0027] B1, B2, and B3 are each directly connected independently; C 3-12 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein these optionally have a C-shaped structure. 1-6 Alkyl, halogen, halogenated C 1-6 One or more hydrogen atoms substituted with alkyl or -OH groups.

[0028] q1 to q6 are each an independent integer from 0 to 6.

[0029] E is either chemical formula 3 or chemical formula 4:

[0030] [Chemical Formula 3]

[0031]

[0032] [Chemical Formula 4]

[0033]

[0034] In chemical formulas 3 and 4,

[0035] X6, X7, X8, and X9 are each independently CH or N.

[0036] Y is -C(R6)2-, -C(O)-, -C(R6)2-C(R6')2-, -C(R6)=C(R6')-, -C(R6)=N-, -N=C(R6)-, or -N=N-,

[0037] Z is directly connected to -C(R6)2-, -N(R6)-, -O-, or -C(O)NH-.

[0038] R5 and R5' are independently H and C. 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy

[0039] R6 and R6' are independently H and C. 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkyl group.

[0040] The inventors sought to develop a novel compound with excellent AR degradation activity, (metabolic) stability, and superior physicochemical properties (cLogP value, water solubility, cell membrane permeability) as an active ingredient by combining a CRBN ligand (E in Formula 1) with a specific structure that binds to E3 ubiquitin ligase with an AR-binding moiety (relative to the left side of the linker). For this purpose, various reported AR-binding moieties, such as enzalutamide, were used; however, contrary to expectations, the desired level of activity or physical properties were not achieved. When using the novel AR-binding moiety used only in this invention, compounds with better activity and physical properties were obtained.

[0041] Furthermore, these compounds, in specific combinations, more adequately satisfy several objectives of the present invention. For example, for the AR-binding moiety (AR conjugate), AR degradation activity is relatively reduced when the pyridine ring is converted to a pyrimidine or benzene ring. AR degradation activity tends to decrease when the left-hand benzene ring of Formula 1 is converted to a pyridine ring and F is introduced into the piperidine ring. Furthermore, for the linker (L in Formula 1), linear linkers are less preferred in terms of AR degradation activity and metabolic stability, and AR degradation activity tends to decrease when the linker length is too short. Some linker moietyes are less desirable than others in terms of AR degradation activity or metabolic stability. Additionally, for the CRBN conjugate (E in Formula 1), some CRBN conjugates are less preferred in terms of AR degradation activity, pharmacokinetics (oral absorption rate, etc.), or physicochemical properties (solubility, etc.).

[0042] On the other hand, the compounds of the present invention exhibit excellent degradation activity against AR mutants (T877A, M896V, F876L, H874Y, L702H, W741C, etc.). Since resistance to existing anti-androgen receptor drugs can be caused by AR mutations, the excellent AR mutant degradation activity of the compounds of the present invention can help overcome resistance to existing drugs. For example, the compounds of Examples 6 and 49 of this disclosure showed 73% and 46% degradation activity against the T877AAR mutant, respectively, at a concentration of 100 nM.

[0043] Furthermore, another mechanism of resistance to existing treatments is the expression of AR splice variants (such as AR-V7). The compounds of the present invention exhibit excellent performance in reducing the expression of these variants (e.g., AR-V7), and therefore demonstrate better anti-proliferative activity in AR-V7-positive prostate cancer cells. For example, the compounds of Examples 6 and 169 of this disclosure inhibited AR-V7 expression by 87% and 48%, respectively, at a concentration of 100 nM.

[0044] As used herein, the terms “substituent,” “radical,” “group,” “part,” and “fragment” are used interchangeably.

[0045] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted by one or more defined substituents. If the substituted position is unsubstituted, the default substituent is a hydride group.

[0046] As used herein, unless the context clearly specifies otherwise, the term "alkyl" refers to a saturated straight-chain acyclic hydrocarbon or a saturated branched acyclic hydrocarbon having 1 to 10 carbon atoms. "Lower alkyl" refers to an alkyl group having 1 to 4 carbon atoms. Representative saturated straight-chain alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl, while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylpentyl, 2,2-Dimethylhexyl, 3,3-Dimethylpentyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylpentyl, 3-Ethylpentyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, 2-Methyl-4-Ethylpentyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2-Methyl-4-Ethylhexyl, 2,2-Diethylpentyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, 3,3-Diethylhexyl, etc.

[0047] As used herein, the term "alkoxy" refers to -O-(alkyl), including -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, etc., where alkyl is as defined above.

[0048] As used in this article, if the term "C" is used... 1-6 "C1-6" or "C1-C6" means that the number of carbon atoms is 1 to 6. For example, C 1-6 Alkyl refers to an alkyl group having any integer number of carbon atoms from 1 to 6.

[0049] As used herein, the terms "halogen" and "halogenated" refer to fluorine, chlorine, bromine, or iodine. In a preferred embodiment of the invention, the halogen is chlorine or fluorine.

[0050] As used herein, the terms "haloalkyl," "haloalkoxy," "haloalkenyl," or "haloalkynyl" refer to an alkyl, alkoxy, alkenyl, or alkynyl group in which one or more hydrogen atoms are substituted by a halogen atom. For example, the haloalkyl groups include -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, etc., wherein the alkyl group and the halogen are as described above. In a preferred embodiment of the invention, the haloalkyl group is -CF3.

[0051] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic ring having carbon and hydrogen atoms and without carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7)cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of polycyclic rings include, but are not limited to, fused bicyclic rings, such as octahydropentene and decahydronaphthalene; spirocyclic rings, such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, and spiro[5.5]undecane; and bridged bicyclic rings, such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and bicyclo[2.2.2]octane. The cycloalkyl group may be unsubstituted or optionally substituted.

[0052] The term "heterocycle" or "heterocyclic alkyl" refers to a saturated heterocycle of 5 to 7 members (monocyclic) or 7 to 12 members (bicyclic), containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatomium may optionally be quaternized. Heterocycles include heteroaryl groups as defined above. Representative heterocycles include ethylene oxide, oxetane, tetrahydrofuran, tetrahydropyran, and 1,4-di(ethylene oxide). Alkanes, cyclopropidines, azacyclobutanes, pyrrolidines, piperidines, piperazines, pyrrolidones, hydantoin, valproamides, thiopropanes, thiophenes, tetrahydrothiophenes, tetrahydrothiorans, morpholine, tetrahydropyridine, and tetrahydropyrimidines. Heterocycles include bicyclic rings in which a portion of the heterocycle is fused to a benzene ring or a cyclopentadiene ring. Heterocycles can be linked by any heteroatom or carbon atom. Furthermore, heterocycles include fused bicyclic rings, spirocyclic rings, and bridged bicyclic rings, wherein one or more carbon atoms of the aforementioned polycyclic rings are substituted with nitrogen, oxygen, or sulfur atoms. For example, when the heteroatom is nitrogen, these heterocycles include, but are not limited to, fused heterobicycles such as octahydrocyclopentadieno[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, and decahydro-2,6-naphthidine; spirocycles such as 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, and 2-azaspiro[4.4]... Nonane, 2,7-diazaspiro[4.4]nonane, 8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-diazaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane; and bridging heterobicycles, such as 2-diazabicyclo[2.1.1]hexane, 2-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-diazabicyclo[2.2.2]octane and 2,5-diazabicyclo[2.2.2]octane.

[0053] As used herein, the term "aryl" refers to a carbocyclic aryl group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracel, fluorenyl, indene, and azulel. The carbocyclic aryl group may be unsubstituted or optionally substituted.

[0054] As used herein, the term "heteroaryl" refers to a 5- to 10-membered aromatic heterocycle having at least one heteroatom selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom, including monocyclic and bicyclic cyclic systems. Representative heteroaryl groups include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetraazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, etc. azole, isotonic azole, thiazole, isothiazole diazole, benzofuran, benzothiophene, quinoline, indole, benzo[] Azole, benzimidazole, benzothiazole, cyclophosphine, phthalazine, quinazoline, 1H-aza, etc.

[0055] In several aspects, such as AR degradation activity, (metabolic) stability, physicochemical properties, etc., preferred embodiments of the present invention provide a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein

[0056] R1 is H, C 1-6 Alkyl, halogen or halogenated C 1-6 alkyl,

[0057] R2 is H or C 1-2 alkyl,

[0058] X1, X3, X4, and X5 are each independently CH or N.

[0059] X2 is either CR3 or N, where R3 is H or C. 1-6 Alkyl, halogen or -OH,

[0060] n is 0, 1, or 2.

[0061] m is 0 or 1.

[0062] L is the following chemical formula 2:

[0063] [Chemical Formula 2]

[0064]

[0065] In chemical formula 2,

[0066] A1, A2, and A3 are each independently directly connected to -O-, -N(R4)-, -C(O)-, -CC-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, or -C(O)CH2O- (preferably directly connected to -O-, -N(R4)-, -C(O)-, -CC-, -C(O)NH-, or -C(O)CH2NH-), where R4 is H or C. 1-6 alkyl,

[0067] B1, B2, and B3 are each independently directly connected, or any of the following substituents:

[0068]

[0069] Among them, R4' are independently H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, halogen, or -OH, q1 to q6 are each independently an integer from 0 to 4.

[0070] E is either chemical formula 3 or chemical formula 4:

[0071] [Chemical Formula 3]

[0072]

[0073] [Chemical Formula 4]

[0074]

[0075] In chemical formulas 3 and 4,

[0076] X6, X7, X8, and X9 are each independently CH or N.

[0077] Y is -C(R6)2-, -C(O)-, or -N=N-.

[0078] Z is directly connected, -N(R6)- or -C(O)NH-,

[0079] R5 and R5' are independently H and C. 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl or C 1-4 Alkoxy

[0080] R6 is independently H and C. 1-4 Alkyl or halogenated C 1-4 alkyl.

[0081] A preferred embodiment of the present invention provides a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein

[0082] R1 is a halogen or halogenated C. 1-6 Alkyl group (preferably, R1 is C1 or CF3),

[0083] R2 is H.

[0084] X1 is N or CH (preferably CH),

[0085] X3, X4, and X5 are each independently one of the following combinations: N, CH, and CH; N, N, and CH; or CH, N, and N (preferably, N, CH, and CH; or CH, N, and N).

[0086] X2 is CR3, where R3 is H, F, or CH3 (preferably H).

[0087] n is 1,

[0088] m is 0,

[0089] L is the following chemical formula 2:

[0090] [Chemical Formula 2]

[0091]

[0092] In chemical formula 2,

[0093] A2 is a direct connection, and A1 and A3 are each independently either a direct connection or -O- (preferably, when A3 is -O-, B3 is a direct connection and q6 is 0, and when A1 is -O-, q1 is 0).

[0094] B1, B2, and B3 are each independently directly connected, or any of the following substituents:

[0095]

[0096] In this case, R4' is independently either H or C. 1-4 Alkyl groups (preferably H or CH3),

[0097] q1 to q6 are each an independent integer between 0 and 2.

[0098] (Preferred, (Not directly connected to the ring containing X3, X4, and X5)

[0099] E is the following chemical formula 3:

[0100] [Chemical Formula 3]

[0101]

[0102] In chemical formula 3,

[0103] X6 is CH or N (preferably CH).

[0104] Y is -C(O)- or -CH2- (preferably -C(O)-),

[0105] R5 is H or a halogen (preferably H or F).

[0106] In one embodiment of the invention, the chemical formula 1 (linked to *-LE) other than -LE can be any of the following structures:

[0107]

[0108] In a preferred embodiment of the invention, the chemical formula 1 (linked to *-LE) can be any of the following structures, except for -LE:

[0109]

[0110] In one embodiment of the present invention, E in Formula 1 can be any of the following structures:

[0111]

[0112] In a preferred embodiment of the present invention, E in Formula 1 can be any of the following structures:

[0113]

[0114] In one embodiment of the present invention, L in chemical formula 1 can be any of the following structures:

[0115]

[0116]

[0117]

[0118] In this specification, * or This indicates a connection to another part.

[0119] Non-limiting examples of compounds of Formula 1 according to this disclosure are compounds prepared in the examples below. Each example number corresponds to a compound number. For example, the final compound prepared in Example 150 is designated as compound 150.

[0120] Among these compounds, those listed in Table 1 below are particularly preferred in several aspects, such as AR degradation activity, cytotoxicity to cancer cell lines, (metabolic) stability, and physicochemical properties.

[0121] [Table 1]

[0122]

[0123]

[0124]

[0125] More specifically, the inventors have demonstrated the following through multiple experiments.

[0126] - For the purposes of this invention, AR conjugates with specific structures are more desirable. For example, in Formula 1, it is preferred in many combinations when the ring containing X3 is a pyridine ring, while it is less preferred when it is a pyrimidine ring or a benzene ring. Furthermore, when using a pyridine ring, AR degradation activity decreases when the N of the pyridine moves to position 3 based on the amide instead of position 2.

[0127] While specific linkers (including 4-ethynylpiperidine, piperazine ethanol, and 1-methylpiperidine) exhibit some efficacy, they are less than ideal for the purposes of this invention (e.g., metabolic stability and AR degradation activity). The 2,7-diazaspiro[3.5]nonane linker (where the 6-membered ring is initially attached to the AR conjugate) is also less preferred in terms of AR degradation activity. Furthermore, AR degradation activity is relatively reduced when the linker length is short, and the attachment position of the E portion changes from position 5 to position 4.

[0128] - As the E structure of Formula 1, the structure of Formula 3 is more suitable for the AR conjugate structure disclosed herein than the structure of Formula 4. Furthermore, even within the E structure of Formula 3, the specific structure is more preferred in terms of oral absorption rate, solubility, AR degradation activity, etc.

[0129] As used herein, the term "one or more pharmaceutically acceptable salts" refers to a salt prepared from an active compound according to this disclosure with a relatively non-toxic acid or base, depending on the specific substituents of those compounds. When the compound has a relatively acidic group, a base addition salt can be obtained by contacting a neutral compound with a sufficient amount of the desired base and a pure or inert solvent. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, organic amino, and magnesium salts. When the compound has a relatively basic group, an acid addition salt can be obtained by contacting a neutral compound with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include salts derived from non-toxic organic acids and non-toxic inorganic acids, wherein the organic acids include, but are not limited to, acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc., and the inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphorous acid, etc. It also includes salts of amino acids, such as arginine salts or analogues thereof, and analogues of organic acids such as glucuronic acid or galacturonic acid. Some specific compounds of this disclosure have basic and acidic functionalities that convert the compound into a basic or acidic moiety (addition) salt. Other examples of salts are well known through the literature to which this invention pertains.

[0130] As used herein, the phrase "one or more compounds of the present invention" includes any one or more compounds of Formula 1, as well as their clathrates, hydrates, solvates, or polymorphs. Furthermore, even if the term "one or more compounds of the present invention" does not refer to their pharmaceutically acceptable salts, the term includes their salts. In one embodiment, the compounds of this disclosure include stereochemically pure compounds, such as those substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee). That is, if a compound of Formula 1 according to this disclosure or its salts is a tautomer and / or a stereoisomer (e.g., a geometric isomer and a conformational isomer), such individual isomers and mixtures thereof are also included within the scope of this disclosure. If the compounds of this disclosure or their salts have an asymmetric carbon in their structure, their active optical isomers and their racemic mixtures are also included within the scope of this disclosure.

[0131] As used herein, the term "polymorph" refers to the solid crystalline form of a compound or a complex thereof disclosed herein. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which can affect bioavailability). Differences in stability can be caused by changes in chemical reactivity (e.g., differential oxidation, causing dosage forms to discolor more quickly when containing one polymorph than when containing another) or mechanical properties (e.g., tablets break during storage as a kinetically favorable polymorph transforms into a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more prone to decomposition at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates or may be more difficult to filter or wash away impurities due to, for example, the shape or size distribution of its particles.

[0132] As used herein, the term "solvent" refers to a compound or salt thereof according to this disclosure that also contains a stoichiometric amount of a solvent bound by non-covalent intermolecular forces or a non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and acceptable when applied to humans in trace amounts.

[0133] As used herein, the term "hydrate" means a compound or salt thereof according to the present disclosure that also contains a stoichiometric amount of water bound by non-covalent intermolecular forces or a non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0134] As used herein, the term "inclusion compound" refers to a compound or salt thereof that contains a lattice form having spaces (e.g., channels) containing guest molecules (e.g., solvents or water) trapped therein.

[0135] As used herein, the term "purified" means that, when separated, the purity of the isolate is greater than 90%, in one embodiment greater than 95%, in another embodiment greater than 99%, and in yet another embodiment greater than 99.9%.

[0136] Medical uses and treatments of the compounds according to the present invention

[0137] The present invention also provides a method for treating a disease or symptom in a subject suffering from or susceptible to such a disease or symptom by administering a therapeutically effective amount of one or more of the compounds described above to the subject. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In yet another embodiment, the treatment is restorative treatment.

[0138] 1. Disease or symptoms

[0139] The compounds of the present invention for degrading AR can be used for a variety of therapeutic or preventative purposes (e.g., cancer, prostate cancer, Kennedy's disease). These compounds can be used to degrade AR to reduce AR activity, or to treat AR-related diseases or prevent the worsening of these diseases. Therefore, the present invention provides a method for degrading AR in cells. In this method, cells are contacted with an effective amount of the compound of the present invention. In one embodiment, the cells are present in a subject. The method of the present invention includes administering to a subject requiring treatment or prevention a pharmaceutical composition comprising a therapeutically effective amount or a preventatively effective amount of the compound of the present invention.

[0140] In one embodiment, the present invention provides a method for degrading AR in cells of AR-related diseases. For example, the present invention can be used to degrade AR in the cells of a subject suffering from an AR-related disease (which will be described later), and thus reduce AR activity. In another embodiment of the invention, the present invention can be used to degrade AR in cancer cells, particularly prostate cancer.

[0141] In another embodiment, the present invention provides a method for treating AR-related diseases, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. This method comprises administering to a subject requiring treatment an amount sufficient to degrade AR (i.e., a therapeutically effective amount) of the compound of the present invention. In this method, the compound of the present invention may be administered to the subject in the form of a pharmaceutical composition described herein.

[0142] In this invention, AR-related diseases include, but are not limited to, asthma, multiple sclerosis, cancer (especially prostate cancer, breast cancer (especially androgen receptor-positive triple-negative breast cancer (AR+TNBC))), Kennedy's disease, acne, hair loss (especially androgenetic alopecia), skin trauma, hirsutism, cilia, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome. In a preferred embodiment of this invention, the AR-related disease is cancer, more preferably, prostate cancer.

[0143] In other words, the present invention provides a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for medical use in treating or preventing the aforementioned diseases.

[0144] 2. Subjects

[0145] Suitable subjects for treatment according to the present invention include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, pigs, rodents, rabbits, primates, etc., and include mammals in the womb.

[0146] In one embodiment, the suitable subject to be treated according to the invention is a human being.

[0147] 3. Application and dosage

[0148] The compounds of the present invention are typically administered in therapeutically effective amounts.

[0149] As used herein, "effective amount" means an amount of the compound of the present invention sufficient to slow or minimize the progression of AR-related disease or to provide therapeutic benefit in the treatment or management of AR-related disease. "Effective amount" also means an amount sufficient to inhibit or reduce AR activity in vitro or in vivo.

[0150] The compounds of the present invention can be administered via any suitable route in the form of a pharmaceutical composition suitable for such route and at a dose effective for the intended treatment. The effective dose range is generally from about 0.001 mg / kg body weight / day to about 100 mg / kg body weight / day, preferably from about 0.01 mg / kg / day to about 50 mg / kg / day, in a single dose or in multiple doses. Depending on age, species, and the disease or condition to be treated, dose levels below the lower limit of this range may be appropriate. In other cases, larger doses may be used without harmful side effects. Larger doses may also be divided into several smaller doses for administration throughout the day.

[0151] Pharmaceutical compositions of the compounds of the present invention

[0152] In another embodiment, 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 excipient. In one embodiment of the invention, the pharmaceutical composition is used to treat or prevent AR-related diseases, preferably prostate cancer, as described above.

[0153] The term "pharmaceutical acceptable" means suitable for use as a pharmaceutical preparation and generally considered safe for such use. This term also implies that it has been formally approved for use by a national regulatory authority, or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0154] Pharmaceutical compositions, dosage forms and routes of administration

[0155] To treat the above-mentioned diseases or symptoms, the compounds described herein or their pharmaceutically acceptable salts may be administered in the following manner:

[0156] Oral administration

[0157] The compounds of the present invention can be administered orally, including by swallowing, so that the compounds enter the gastrointestinal tract, or directly absorbed from the mouth into the bloodstream (e.g., buccal or sublingual administration).

[0158] Suitable compositions for oral administration include solid, liquid, gel, or powder formulations, and have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0159] Compositions for oral administration may optionally be enteric-coated and may exhibit delayed or sustained release through enteric coating. That is, compositions for oral administration according to the invention may be formulations having an immediate release mode or a modified release mode.

[0160] Liquid formulations may include solutions, syrups, and suspensions, which can be contained in soft or hard capsules. Such formulations may include pharmaceutically acceptable carriers such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also include one or more emulsifiers and / or suspending agents.

[0161] In tablet dosage forms, the amount of the active pharmaceutical ingredient present can be from about 0.05% to about 95% of the dosage form weight, more typically from about 2% to about 50% of the dosage form weight. In addition, tablets may contain a disintegrant comprising from about 0.5% to about 35% of the dosage form weight, more typically from about 2% to about 25%. Examples of disintegrants include, but are not limited to, lactose, starch, sodium carboxyacetic acid starch, crospovidone, crospovidone carboxymethyl cellulose, maltodextrin, or mixtures thereof.

[0162] Suitable lubricants for tablets may be present in amounts from about 0.1% to about 5% by weight, and include, but are not limited to, talc, silica, stearic acid, calcium stearate, zinc stearate or magnesium stearate, sodium stearoyl fumarate, etc.

[0163] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, glucose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0164] Suitable solubilizers for tablets may be present in amounts from about 0.1% by weight to about 3% by weight, and include, but are not limited to, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM Caprylic acid / caprylic acid mono / diglycerides, sorbitan fatty acid esters, and Solutol HS TM .

[0165] External application

[0166] The compounds disclosed herein can be directly administered into the bloodstream, muscles, or internal organs. Suitable parenteral administration methods include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, and intracranial administration. Suitable parenteral administration devices include syringes (including needle-based and needle-free syringes) and infusion methods.

[0167] Compositions for parenteral administration can be formulated as immediate-release or modulated-release forms, including delayed-release or sustained-release.

[0168] Most parenteral preparations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredients, salts, buffers, isotonic agents, etc., according to the present invention.

[0169] Parenteral preparations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These preparations can be used with suitable carriers such as sterile water. Solubilizers can also be used in the preparation of parenteral solutions.

[0170] Topical application

[0171] The compounds of this invention can be applied topically to the skin or transdermally. Such topically applied formulations may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topically applied formulations may include water, alcohols, mineral oils, glycerin, polyethylene glycol, etc. Topical application can also be performed via electroporation, iontophoresis, sonic electroosmosis, etc.

[0172] Compositions for topical application can be formulated as immediate-release or modulated-release, including delayed-release or sustained-release.

[0173] Beneficial effects

[0174] This disclosure provides compounds capable of exhibiting a variety of pharmacological activities by degrading AR, pharmaceutical compositions comprising the compounds as active ingredients, their medical uses (particularly for prostate cancer), and methods of treatment or prevention, wherein the methods of treatment or prevention include administering the compound to a subject in need of such treatment or prevention. The compounds according to the invention, or pharmaceutically acceptable salts thereof, are excellent in many respects, such as efficacy, (metabolic) stability, and physicochemical properties. Detailed Implementation

[0175] The invention is described in considerable detail below, and embodiments are provided to aid those skilled in the art in understanding it. However, the following embodiments are provided by way of illustration and are not intended to limit the scope of the invention. It will be apparent that various changes can be made without departing from the spirit and scope of the invention or sacrificing all its substantial advantages.

[0176] Preparation of the compounds of the present invention

[0177] In the following, methods for synthesizing some of the compounds of the present invention will be described, and other compounds not mentioned below can be prepared in a similar manner by replacing the starting materials, intermediates and / or reactants.

[0178] Intermediate 1-1: 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid

[0179]

[0180] 4-Fluoro-2-(trifluoromethyl)benzylnitrile (5.00 g, 26.4 mmol), piperidine-4-carboxylic acid (3.41 g, 15.9 mmol), and DIPEA (11.0 mL, 79.2 mmol) were suspended in DMSO (20.0 mL) and stirred at 90 °C for 16 hours. Distilled water (30 mL) was added to the reaction solution, and the solution was extracted with EtOAc (25 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized (EtOAc) to give 5.98 g (76%) of a grayish-white solid. m / z 299.06 [M+H] + .

[0181] Intermediate 1-2: 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid

[0182]

[0183] Intermediate 1-2 was synthesized in a manner similar to that used for intermediate 1-1.

[0184] Intermediate 1-3: 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-methylpiperidine-4-carboxylic acid

[0185]

[0186] Intermediate 1-3 was synthesized in a manner similar to that used for intermediate 1-1.

[0187] Intermediate 1-4: 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-hydroxypiperidine-4-carboxylic acid

[0188]

[0189] Step 1: Synthesis of 1-benzyl-4-hydroxypiperidine-4-carboxylic acid hydrochloride

[0190] 1-Benzyl-4-hydroxypiperidine-4-carboxynitrile hydrochloride (500 mg, 1.97 mmol) was suspended in 2.0 mL of 6N HCl aqueous solution and stirred in a microwave at 120 °C for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to give 542 mg of white solid.

[0191] Step 2: Synthesis of 4-hydroxypiperidine-4-carboxylic acid hydrochloride

[0192] 1-Benzyl-4-hydroxypiperidine-4-carboxylic acid hydrochloride (542 mg, 1.66 mmol) was dissolved in EtOH (20 mL), and Pd / C (10 wt% Pd, 180 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give 237 mg of a white solid.

[0193] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-hydroxypiperidine-4-carboxylic acid

[0194] 4-Hydroxypiperidine-4-carboxylic acid hydrochloride (77 mg, 0.43 mmol), 4-fluoro-2-(trifluoromethyl)benzyl nitrile (100 mg, 0.529 mmol), and DIPEA (0.18 mL, 1.06 mmol) were suspended in DMSO (3.0 mL) and stirred at 90 °C for 16 hours. Distilled water (3.0 mL) was added to the reaction solution, followed by extraction with EtOAc (2.5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized (EtOAc) to give 35 mg (26%) of a white solid. m / z 496.10 [M+H] + .

[0195] Intermediates 1-5: 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid

[0196]

[0197] Step 1: Synthesis of ethyl 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylate. 4-fluoro-2-(trifluoromethyl)benzylnitrile (100 mg, 0.529 mmol), ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (123 mg, 0.582 mmol), and K₂CO₃ (146 mg, 1.06 mmol) were suspended in DMSO (5.0 mL) and stirred at 100 °C for 16 hours. Distilled water (3.0 mL) was added to the reaction solution, followed by extraction with EtOAc (2.5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (30% EtOAc / hexane) to give 191 mg of a white solid. m / z 345.40 [M+H] + .

[0198] Step 2: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid

[0199] Ethyl 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid (255 mg) was suspended in THF (3.0 mL) and distilled water (1.0 mL), then LiOH·H₂O (89 mg, 2.12 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and extracted with distilled water. 1 N HCl was added to the aqueous layer again, and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 112 mg (67% in two steps) of white solid. m / z 317.03 [M+H] + .

[0200] Intermediate 1-6: 2-(1-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-3-yl)acetic acid

[0201]

[0202] Intermediates 1-6 were synthesized in a manner similar to that used for intermediates 1-5.

[0203] Intermediate 1-7: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid

[0204]

[0205] Step 1: Synthesis of Ethyl 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate. 5-Bromo-3-(trifluoromethyl)-2-pyridinecarboxylonitrile (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 hour. Distilled water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (30% EtOAc / hexane) to give 449 mg (69%) of white solid. m / z 328.09 [M+H] + .

[0206] Step 2: Synthesis of 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid

[0207] Ethyl 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidin-4-carboxylic acid (449 mg, 1.37 mmol) was suspended in THF (10.0 mL) and distilled water (5.0 mL), then LiOH·H₂O (230 mg, 5.49 mmol) was added and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent and extracting with distilled water, 1 N HCl was added to the aqueous layer and extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 327 mg (81%) of a white liquid. m / z 300.05 [M+H] + .

[0208] Intermediate 1-8: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-fluoropiperidine-4-carboxylic acid

[0209]

[0210] Intermediates 1-8 were synthesized in a manner similar to that used for intermediates 1-7.

[0211] Intermediate 2-1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione

[0212]

[0213] 5-Fluorobenzofuran-1,3-dione (5.00 g, 30.1 mmol), 3-aminopiperidine-2,6-dione hydrochloride (4.95 g, 30.1 mmol), and sodium acetate (4.94 mg, 60.2 mmol) were suspended in AcOH (50 mL) and stirred at 120 °C for 24 hours. The solvent was concentrated under reduced pressure, and distilled water (30 mL) was added to the reaction solution. The resulting solid was filtered to give 7.55 g (90%) of a purple solid.

[0214] Intermediate 2-2: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione

[0215]

[0216] Intermediate 2-2 was synthesized in a manner similar to that used for intermediate 2-1.

[0217] Intermediate 2-3: 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

[0218]

[0219] Intermediate 2-3 was synthesized in a manner similar to that used for intermediate 2-1.

[0220] Intermediate 2-4: 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

[0221]

[0222] Step 1: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-nitrobenzamide

[0223] 5-Fluoro-2-nitrobenzoic acid (2.00 g, 10.8 mmol), 3-aminopiperidine-2,6-dione hydrochloride (2.14 g, 13.0 mmol), EDCI (2.48 g, 13.0 mmol), HOBt (1.75 g, 13.0 mmol), and DIPEA (3.76 mL, 21.6 mmol) were suspended in DMF (10.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (20 mL) to the reaction solution, extraction was performed with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (EtOAc) to give 2.28 g (72%) of a grayish-white solid.

[0224] Step 2: Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-fluorobenzamide

[0225] N-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-nitrobenzamide (2.28 mg, 7.72 mmol) was dissolved in a mixture of DMF (10 mL) and MeOH (10 mL), and Pd / C (10 wt% Pd, 228 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give a brown solid (1.62 g, 79%).

[0226] Step 3: Synthesis of 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

[0227] 1.60 g (6.04 mmol) of 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-fluorobenzamide was suspended in AcOH (10.0 mL), followed by the addition of sodium nitrite (631 mg, 9.16 mmol), and the mixture was stirred at room temperature for 2 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization of the residue (EtOAc) yielded 756 mg (45%) of a grayish-white solid.

[0228] Intermediate 2-5: 3-(7-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

[0229]

[0230] Intermediate 2-5 was synthesized in a manner similar to that used for intermediate 2-4.

[0231] Intermediate 2-6: 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione

[0232]

[0233] Step 1: Synthesis of methyl 2-(bromomethyl)-6-chloronicotinate

[0234] 6-Chloro-2-methylnicotinic acid methyl ester (1.00 g, 5.38 mmol), N-bromosuccinimide (1.44 g, 8.08 mmol), and AHCN (130 mg, 0.0538 mmol) were suspended in ACN (10.0 mL) and stirred in a microwave oven at 110 °C for 4 hours. Distilled water (10 mL) was added to the reaction mixture, followed by extraction with EtOAC (10 mL × 2). The organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% EtOAc / hexane) to give 980 mg of a white solid. m / z 263.99 [M+H] + .

[0235] Step 2: Synthesis of 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione

[0236] 2-(bromomethyl)-6-chloronicotinic acid methyl ester (980 mg), 3-aminopiperidine-2,6-dione hydrochloride (686 mg, 4.17 mmol), and DIPEA (1.05 mL, 10.4 mmol) were suspended in ACN (10.0 mL) and stirred at 110 °C for 2 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized (MeOH) to give 244 mg (16% in two steps) of a grayish-white solid. m / z 280.09 [M+H] + .

[0237] Intermediate 2-7: 3-((3-aminophenyl)amino)piperidine-2,6-dione

[0238]

[0239] Step 1: Synthesis of tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate

[0240] Tert-butyl (3-aminophenyl)carbamate (300 mg, 1.44 mmol) and 3-bromopiperidin-2,6-dione (331 mg, 1.73 mmol) were suspended in DMF (5.0 mL), followed by the addition of NaHCO3 (241 mg, 2.88 mmol), and stirring at 50 °C for 16 hours. Distilled water (30 mL) was added to the reaction solution, and the resulting solid was filtered to give 323 mg (70%) of a green solid. m / z 342.20 [M+Na] + .

[0241] Step 2: Synthesis of 3-((3-aminophenyl)amino)piperidine-2,6-dione

[0242] After suspending tert-butyl (3-((2,6-dioxopiridine-3-yl)amino)phenyl)carbamate (100 mg, 0.313 mmol) in DCM (1.00 ml), two... The reaction mixture was stirred for 1 hour at room temperature with 4M HCl in alkane (0.39 ml, 1.57 mmol). The reaction solution was concentrated, and 15 ml of NaHCO3 aqueous solution was added. Extraction was performed with DCM (20 ml × 2), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give 34 mg (51%) of a brown solid. m / z 220.20 [M+H] + .

[0243] Intermediate 2-8: 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0244] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione 5-methylisobenzofuran-1,3-dione (2.18 g, 13.44 mmol), 3-aminopiperidin-2,6-dione hydrochloride (2.21 g, 13.44 mmol), and NaOAc (2.20 g, 26.89 mmol) were suspended in AcOH (22 mL) and then refluxed at 120 °C with stirring for 16 hours. After concentrating the reaction solution under reduced pressure, distilled water (100 mL) was added, and the precipitated solid was filtered to give 3.2 g (87%) of a purple solid.

[0245] Step 2: Synthesis of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0246] 2-(2,6-dioxadiazine-3-yl)-5-methylisoindoline-1,3-dione (541.8 mg, 1.99 mmol), N-bromosuccinimide (390.0 mg, 2.19 mmol), and ACHN (97.7 mg, 0.4 mmol) were suspended in 10 mL of ACN and then refluxed and stirred at 80 °C for 11 hours. After concentrating the reaction solution under reduced pressure, the resulting residue was treated by MPLC (40% EtOAc / hexane) to give 420 mg (60%) of white solid.

[0247] Intermediate 3-1: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde

[0248]

[0249] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0250] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 300 mg, 1.09 mmol), piperidin-4-ylmethanol (149 mg, 1.30 mmol), and DIPEA (0.29 mL, 1.64 mmol) were suspended in DMSO (5.0 mL) and stirred at 100 °C for 16 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / hexane) to give 332 mg (82%) of a yellow solid.

[0251] Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde

[0252] 2-(2,6-dioxadiazin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (332 mg, 0.894 mmol) was suspended in DCM (5.0 mL). Then, DMP (569 mg, 1.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After adding 10 mL of Na₂S₂O₃ aqueous solution to the reaction solution, extraction was performed with DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / DCM) to give 303 mg (92%) of a yellow solid.

[0253] Intermediate 3-2 to Intermediate 3-13

[0254] Intermediates 3-2 to 3-13 were synthesized in a manner similar to that used for intermediate 3-1.

[0255] [Table 2]

[0256]

[0257]

[0258] Intermediate 3-14: 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]non-7-yl)isoindoline-1,3-dione

[0259]

[0260] Step 1: Synthesis of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid

[0261] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 500 mg, 1.81 mmol), 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (473 mg, 2.09 mmol), and DIPEA (0.63 mL, 3.62 mmol) were suspended in DMSO (4.0 mL) and stirred at 100 °C for 16 hours. Distilled water (20 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 748 mg (86%) of a yellow solid.

[0262] Step 2: Synthesis of 2-(2,6-dioxadiazin-3-yl)-5-(2,7-diazaspiro[3.5]non-7-yl)isoindoline-1,3-dione

[0263] 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) was suspended in DCM (1.0 mL). Then, 4 M HCl was added. Alkane (0.5 mL, 2.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to give 84 mg (96%) of a grayish-white solid.

[0264] Intermediate 3-15: 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)glycine

[0265]

[0266] Intermediate 3-15 was synthesized in a manner similar to that used for intermediate 3-14.

[0267] Intermediate 4-1: (S)-4-(pyrrolidone-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester

[0268]

[0269] Step 1: Synthesis of (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester

[0270] (S)-pyrrolidine-3-ylmethanol (1.00 g, 9.87 mmol) was suspended in ACN (10.0 mL), and benzyl chloroformate (1.55 mL, 10.9 mmol) and TEA (1.52 mL, 10.9 mmol) were added at 0 °C, followed by stirring at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction mixture, and extraction was performed with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / DCM) to give 2.07 g (89%) of a colorless liquid.

[0271] Step 2: Synthesis of (S)-3-formylpyrrolidine-1-carboxylic acid benzyl ester

[0272] (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (2.07 g, 8.79 mmol) was suspended in DCM (20.0 mL), followed by the addition of DMP (4.48 mg, 10.6 mmol) and stirring at room temperature for 2 hours. An aqueous solution of Na₂S₂O₃ (20 mL) was added to the reaction mixture, followed by extraction with DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / DCM) to give 1.62 g (79%) of a colorless liquid.

[0273] Step 3: Synthesis of (R)-4-((1-((benzyloxy)carbonyl)pyrrolidine-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0274] (S)-3-formylpyrrolidine-1-carboxylic acid benzyl ester (1.12 g, 4.80 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.07 g, 5.76 mmol) were suspended in ACN (20.0 mL), followed by the addition of sodium triacetoxyborohydride (3.05 g, 14.4 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (20 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 1.32 g (68%) of a colorless liquid.

[0275] Step 4: Synthesis of (S)-4-(pyrrolidone-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester

[0276] (R)-4-((1-((benzyloxy)carbonyl)pyrrolidine-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (1.39 g, 3.27 mmol) was dissolved in MeOH (10 mL), followed by the addition of Pd / C (10 wt% Pd, 132 mg) and stirring at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give a white solid (874 mg, 99%).

[0277] Intermediate 4-2 to Intermediate 4-8

[0278] Intermediates 4-2 to 4-8 were synthesized in a manner similar to that used for intermediate 4-1.

[0279] [Table 3]

[0280]

[0281]

[0282] Intermediate 4-9: 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0283]

[0284] Step 1: Synthesis of benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate

[0285] Piperazine-1-carboxylic acid benzyl ester (1.03 g, 4.54 mmol) and 4-oxopiperidinium-1-carboxylic acid tert-butyl ester (905 mg, 4.45 mmol) were suspended in MeOH (20.0 mL), followed by the addition of sodium triacetoxyborohydride (1.92 g, 9.08 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (20 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 880 mg (48%) of a colorless liquid.

[0286] Step 2: Synthesis of tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylic acid

[0287] Benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate (880 mg, 2.39 mmol) was dissolved in MeOH (20 mL), followed by the addition of Pd / C (10 wt% Pd, 88 mg) and stirring at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give a white solid (600 mg, 93%).

[0288] Intermediate 4-10: 4-(piperazin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester

[0289]

[0290] Intermediate 4-10 was synthesized in a manner similar to that used for intermediate 4-9.

[0291] Intermediate 4-11: 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester

[0292]

[0293] 2-(piperazin-1-yl)ethane-1-ol (300 mg, 2.30 mmol) was suspended in THF (15.0 mL), and then di-tert-butyl dicarbonate (0.90 mL, 3.92 mmol) and TEA (0.96 mL, 6.90 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 3 hours. Distilled water (15 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 205 mg (39%) of a colorless liquid.

[0294] Example 1: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0295]

[0296] Step 1: Synthesis of (1-(6-nitropyridin-3-yl)piperidin-4-yl)methanol

[0297] 5-Chloro-2-nitropyridine (5.00 g, 31.5 mmol), piperidin-4-ylmethanol (5.45 g, 47.3 mmol), and DIPEA (11.1 mL, 63.0 mmol) were suspended in DMSO (20.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 5.66 g (76%) of a yellow solid.

[0298] Step 2: Synthesis of 1-(6-nitropyridin-3-yl)piperidine-4-carboxaldehyde

[0299] (1-(6-nitropyridin-3-yl)piperidin-4-yl)methanol (2.00 g, 8.43 mmol) was suspended in DCM (3.0 mL), followed by the addition of DMP (5.36 g, 12.6 mmol) and stirring at room temperature for 4 hours. An aqueous solution of Na₂S₂O₃ (15 mL) was added to the reaction mixture, followed by extraction with DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 1.90 g (96%) of a yellow solid.

[0300] Step 3: Synthesis of 4-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0301] 1-(6-nitropyridin-3-yl)piperidine-4-carboxaldehyde (300 mg, 1.28 mmol) and piperazine-1-carboxylic acid tert-butyl ester (285 mg, 1.53 mmol) were suspended in MeOH (20.0 mL), followed by the addition of sodium triacetoxyborohydride (814 mg, 3.84 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 419 mg (81%) of a yellow solid. m / z 406.38 [M+H] + .

[0302] Step 4: Synthesis of tert-butyl 4-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid

[0303] 4-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (419 mg, 1.03 mmol) was dissolved in a mixed solution of DCM (20 mL) and MeOH (10 mL), then Pd / C (10 wt% Pd, 84 mg) was added and the mixture was stirred at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give a brown solid (374 mg, 97%). m / z 376.42 [M+H] + .

[0304] Step 5: Synthesis of 4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0305] 4-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (374 mg, 0.996 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 356 mg, 1.20 mmol), HATU (456 mg, 1.20 mmol), and DIPEA (0.35 mL, 1.99 mmol) were suspended in DMF (3.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 453 mg (69%) of a brown solid.

[0306] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0307] After suspending 4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (453 mg, 0.680 mmol) in DCM (3.00 ml), di... The reaction mixture was added to 4M HCl in alkane (1.31 mL, 3.40 mmol) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and then 15 mL of aqueous NaHCO3 solution was added, followed by extraction with DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 305 mg (76%) of white solid.

[0308] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0309] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide (50 mg, 0.094 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 39 mg, 0.14 mmol), and DIPEA (0.033 mL, 0.19 mmol) were suspended in DMSO (3.0 mL) and stirred at 90 °C for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 24 mg (31%) of a yellow solid.

[0310] Example 2: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0311]

[0312] Example 2 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0313] Example 3: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0314]

[0315] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide (11 mg, 0.020 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(2-iodoethoxy)isoindoline-1,3-dione (WO2018 / 119448A1, 8.6 mg, 0.020 mmol), and K2CO3 (5.52 mg, 0.04 mmol) were suspended in DMF (2.0 mL) and stirred at 70 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 2.3 mg (13%) of yellow solid.

[0316] Example 4: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0317]

[0318] Example 4 was synthesized in a manner similar to that of Example 3, using 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 2-8) instead of 2-(2,6-dioxopiperidin-3-yl)-5-(2-iodoethoxy)isoindoline-1,3-dione (WO2018 / 119448A1).

[0319] Example 5: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)glycyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0320]

[0321] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide (35 mg, 0.059 mmol), (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)glycine (intermediate 3-15, 30 mg, 0.071 mmol), HATU (27 mg, 0.071 mmol), and DIPEA (0.04 mL, 0.24 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 6 mg (12%) of yellow solid.

[0322] Example 6: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0323]

[0324] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide (35 mg, 0.063 mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1, 28 mg, 0.076 mmol) were suspended in ACN (20.0 mL), and sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added. The mixture was then stirred at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 7 mg (12%) of yellow solid.

[0325] Example 7: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0326]

[0327] Example 7 was synthesized in a manner similar to that used in Examples 1 and 6, with 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0328] Example 8: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0329]

[0330] Example 8 was synthesized in a manner similar to that used in Examples 1 and 6, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid (intermediate 1-5) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0331] Example 9: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0332]

[0333] Example 9 was synthesized in a manner similar to that used in Examples 1 and 6, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (intermediate 1-7) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0334] Example 10: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0335]

[0336] Example 10 was synthesized in a manner similar to that used in Examples 1 and 6, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-fluoropiperidine-4-carboxylic acid (intermediate 1-8) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0337] Example 11: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0338]

[0339] Example 11 was synthesized in a manner similar to that of Example 6, using 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0340] Example 12: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0341]

[0342] Example 12 was synthesized in a manner similar to that used in Examples 1 and 6, with 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediate 3-1).

[0343] Example 13: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0344]

[0345] Example 13 was synthesized in a manner similar to that of Example 6, using 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-carboxaldehyde (intermediate 3-1) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde.

[0346] Example 14: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0347]

[0348] Example 14 was synthesized in a manner similar to that of Example 6, using (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-4) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0349] Example 15: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0350]

[0351] Example 15 was synthesized in a manner similar to that of Example 6, using (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-5) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0352] Example 16: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0353]

[0354] Example 16 was synthesized in a manner similar to that of Example 6, using (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-3-carboxaldehyde (intermediate 3-6) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0355] Example 17: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0356]

[0357] Example 17 was synthesized in a manner similar to that of Example 6, using (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-3-carboxaldehyde (intermediate 3-7) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0358] Example 18: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0359]

[0360] Example 18 was synthesized in a manner similar to that of Example 6, using 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde.

[0361] Example 19: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0362]

[0363] Example 19 was synthesized in a manner similar to that of Example 6, using (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-10) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0364] Example 20: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0365]

[0366] Example 20 was synthesized in a manner similar to that of Example 6, using 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-9) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0367] Example 21: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(4-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidin-4-carboxamide

[0368]

[0369] Example 21 was synthesized in a manner similar to that used in Examples 1 and 6, using 4-fluoronitrobenzene instead of 5-chloro-2-nitropyridine.

[0370] Example 22: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(4-(4-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidin-4-carboxamide

[0371]

[0372] Example 22 was synthesized in a manner similar to that used in Examples 1 and 6, with 4-fluoronitrobenzene and (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-4) instead of 5-chloro-2-nitropyridine and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0373] Example 23: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0374]

[0375] Example 23 was synthesized in a manner similar to that used in Examples 1 and 6, using (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0376] Example 24: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0377]

[0378] Example 24 was synthesized in a manner similar to that used in Examples 1 and 6, with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of piperazine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0379] Example 25: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0380]

[0381] Example 25 was synthesized in a manner similar to that used in Examples 1 and 6, using (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0382] Example 26: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0383]

[0384] Example 26 was synthesized in a manner similar to that used in Examples 1 and 6, with (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of piperazine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0385] Example 27: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0386]

[0387] Example 27 was synthesized in a manner similar to that used in Examples 1 and 6, using aziridine-3-ylmethanol instead of piperidin-4-ylmethanol.

[0388] Example 28: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0389]

[0390] Example 28 was synthesized in a manner similar to that used in Examples 1 and 6, with aziridine-3-ylmethanol and (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-4) instead of piperidin-4-ylmethanol and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0391] Example 29: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0392]

[0393] Example 29 was synthesized in a manner similar to that used in Examples 1 and 6, with aziridine-3-ylmethanol and (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-5) instead of piperidin-4-ylmethanol and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0394] Example 30: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0395]

[0396] Example 30 was synthesized in a manner similar to that used in Examples 1 and 6, with aziridine-3-ylmethanol and 1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)aziridine-3-carboxaldehyde (intermediate 3-3) instead of piperidin-4-ylmethanol and 1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediate 3-1).

[0397] Example 31: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-(((2R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-2-methylpiperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0398]

[0399] Example 31 was synthesized in a manner similar to that used in Examples 1 and 6, with aziridine-3-ylmethanol, (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)aziridine-4-carboxaldehyde (intermediate 3-3) instead of piperidin-4-ylmethanol, piperidin-1-carboxylic acid tert-butyl ester, and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0400] Example 32: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-(((3R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-3-methylpiperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0401]

[0402] Example 32 was synthesized in a manner similar to that used in Examples 1 and 6, with aziridine-3-ylmethanol, (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)aziridine-4-carboxaldehyde (intermediate 3-1) instead of piperidin-4-ylmethanol, piperidin-1-carboxylic acid tert-butyl ester, and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1).

[0403] Example 33: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)azacyclobutane-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0404]

[0405] Step 1: Synthesis of tert-butyl 3-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)azacyclobutane-1-carboxylic acid 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide (200 mg, 0.360 mmol) and tert-butyl 3-oxozycyclobutane-1-carboxylic acid (74 mg, 0.432 mmol) were suspended in ACN (20.0 ml), sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 ml) was added to the reaction mixture, followed by extraction with EtOAc (25 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 129 mg (50%) of white solid. m / z 711.35 [M+H] + .

[0406] Step 2: Synthesis of N-(5-(4-((4-(azacyclobutane-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide

[0407] 3-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (129 mg, 0.181 mmol) was suspended in DCM (1.00 ml), and then di... The reaction mixture was stirred for 1 hour at room temperature with 4M HCl in alkane (0.23 mL, 0.905 mmol). The reaction solution was concentrated, and 15 mL of NaHCO3 aqueous solution was added. Extraction was performed with DCM (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give 109 mg (99%) of white solid. m / z 611.44 [M+H] + .

[0408] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)azacyclobutane-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0409] N-(5-(4-((4-(azacyclobutan-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide (30 mg, 0.046 mmol), 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6, 16 mg, 0.056 mmol), and DIPEA (0.02 mL, 0.092 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 18 mg (45%) of off-white solid.

[0410] Example 34: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0411]

[0412] Example 34 was synthesized in a manner similar to that of Example 33, using 4-formylpiperidine-1-carboxylic acid tert-butyl ester instead of 3-oxozylidene-1-carboxylic acid tert-butyl ester.

[0413] Example 35: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0414]

[0415] Example 35 was synthesized in a manner similar to that of Example 33, using 2-(2,6-dioxadipin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1) instead of 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6).

[0416] Example 36: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0417]

[0418] Example 36 was synthesized in a manner similar to that used in Examples 1 and 33, with aziridine-3-ylmethanol and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1) instead of piperidin-4-ylmethanol and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (intermediate 2-6).

[0419] Example 37: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3S)-1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0420]

[0421] Example 37 was synthesized in a manner similar to that of Example 33, using (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester instead of 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester.

[0422] Example 38: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0423]

[0424] Example 38 was synthesized in a manner similar to that of Example 33, using (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (intermediates 2-3) instead of 3-oxozyracyclobutane-1-carboxylic acid tert-butyl ester and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediates 2-6).

[0425] Example 39: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3R)-1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0426]

[0427] Example 39 was synthesized in a manner similar to that of Example 33, using (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester instead of 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester.

[0428] Example 40: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3R)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0429]

[0430] Example 40 was synthesized in a manner similar to that used in Examples 1 and 33, with (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1) instead of piperazine-1-carboxylic acid tert-butyl ester and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6).

[0431] Example 41: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2R)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0432]

[0433] Example 41 was synthesized in a manner similar to that used in Examples 1 and 33, with (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1) instead of piperazine-1-carboxylic acid tert-butyl ester and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6).

[0434] Example 42: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2R)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0435]

[0436] Example 42 was synthesized in a manner similar to that used in Examples 1 and 33, respectively, replacing piperazine-1-carboxylate tert-butyl ester, 4-oxopiperidine-1-carboxylate tert-butyl ester, and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0437] Example 43: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2R)-4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0438]

[0439] Example 43 was synthesized in a manner similar to that used in Examples 1 and 33, replacing piperazine-1-carboxylic acid tert-butyl ester and 4-oxopiperidin-1-carboxylic acid tert-butyl ester, respectively.

[0440] Example 44: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2R)-4-((1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0441]

[0442] Example 44 was synthesized in a manner similar to that used in Examples 1 and 33, replacing piperazine-1-carboxylic acid tert-butyl ester and 4-formylpiperidine-1-carboxylic acid tert-butyl ester, respectively.

[0443] Example 45: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2S)-4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0444]

[0445] Example 45 was synthesized in a manner similar to that used in Examples 1 and 33, replacing piperazine-1-carboxylic acid tert-butyl ester and 4-oxopiperidin-1-carboxylic acid tert-butyl ester, respectively.

[0446] Example 46: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2S)-4-((1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0447]

[0448] Example 46 was synthesized in a manner similar to that used in Examples 1 and 33, replacing piperazine-1-carboxylic acid tert-butyl ester and 4-formylpiperidine-1-carboxylic acid tert-butyl ester, respectively.

[0449] Example 47: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3R)-4-((1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0450]

[0451] Example 47 was synthesized in a manner similar to that used in Examples 1 and 33, replacing piperazine-1-carboxylic acid tert-butyl ester and 4-formylpiperidine-1-carboxylic acid tert-butyl ester, respectively.

[0452] Example 48: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3S)-4-((1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0453]

[0454] Example 48 was synthesized in a manner similar to that used in Examples 1 and 33, replacing piperazine-1-carboxylic acid tert-butyl ester and 4-formylpiperidine-1-carboxylic acid tert-butyl ester, respectively.

[0455] Example 49: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0456]

[0457] Example 49 was synthesized in a manner similar to that of Example 1, using 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0458] Example 50: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0459]

[0460] Example 50 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0461] Example 51: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-methylpiperidin-4-carboxamide

[0462]

[0463] Example 51 was synthesized in a manner similar to that of Example 1, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-methylpiperidine-4-carboxylic acid (intermediate 1-3) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0464] Example 52: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazine-7-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0465]

[0466] Example 52 was synthesized in a manner similar to that of Example 1, using 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and 3-(7-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (intermediate 2-5) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0467] Example 53: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0468]

[0469] 2,7-diazaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester and 3-(6-fluoro-4-oxo)

[0470] Example 53 was synthesized in a manner similar to that of Example 1, replacing piperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1) with benzo[d][1,2,3]triazine-3(4H)-yl)piperidin-2,6-dione (intermediate 2-4).

[0471] Example 54: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0472]

[0473] Example 54 was synthesized in a manner similar to that of Example 1, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid (intermediates 1-5) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediates 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0474] Example 55: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-hydroxypiperidin-4-carboxamide

[0475]

[0476] Example 55 was synthesized in a manner similar to that of Example 1, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-hydroxypiperidine-4-carboxylic acid (intermediate 1-4) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0477] Example 56: 2-(1-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-3-yl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)acetamide

[0478]

[0479] Example 56 was synthesized in a manner similar to that of Example 1, using 2-(1-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-3-yl)acetic acid (intermediate 1-6) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0480] Example 57: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0481]

[0482] Example 57 was synthesized in a manner similar to that of Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (intermediate 1-7) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0483] Example 58: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0484]

[0485] Example 58 was synthesized in a manner similar to that of Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-fluoropiperidine-4-carboxylic acid (intermediates 1-8) and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediates 1-1) and piperazine-1-carboxylic acid tert-butyl ester.

[0486] Example 59: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperidin-4-carboxamide

[0487]

[0488] Example 59 was synthesized in a manner similar to that of Example 1, using 2-chloro-5-nitropyridine and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 5-chloro-2-nitropyridine and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0489] Example 60: 1-(3-chloro-4-cyanophenyl)-N-(6-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperidin-4-carboxamide

[0490]

[0491] Example 60 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2), 2-chloro-5-nitropyridine, and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1), 5-chloro-2-nitropyridine, and piperazine-1-carboxylic acid tert-butyl ester.

[0492] Example 61: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(((3S)-3-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)pyrrolidine-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0493]

[0494] Example 61 was synthesized in a manner similar to that of Example 1, using (R)-pyrrolidine-3-ylmethanol and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0495] Example 62: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((3R)-3-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)pyrrolidine-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0496]

[0497] Example 62 was synthesized in a manner similar to that of Example 1, using (S)-pyrrolidine-3-ylmethanol and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0498] Example 63: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0499]

[0500] Example 63 was synthesized in a manner similar to that of Example 1, using 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0501] Example 64: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0502]

[0503] Example 64 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0504] Example 65: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0505]

[0506] N-(5-(4-((2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide hydrochloride (50 mg, 0.079 mmol), 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (WO2019 / 186343, 25 mg, 0.095 mmol), HATU (36 mg, 0.095 mmol), and DIPEA (0.03 mL, 0.16 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 18 mg (27%) of white solid.

[0507] Example 66: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0508]

[0509] Example 66 was synthesized in a manner similar to that of Example 1, using 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0510] Example 67: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0511]

[0512] Example 67 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0513] Example 68: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0514]

[0515] Example 68 was synthesized in a manner similar to that of Example 1, using 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0516] Example 69: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0517]

[0518] Example 69 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0519] Example 70: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0520]

[0521] Example 70 was synthesized in a manner similar to that of Example 1, using 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 4-9) instead of piperazine-1-carboxylic acid tert-butyl ester.

[0522] Example 71: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0523]

[0524] Example 71 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 4-9) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0525] Example 72: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0526]

[0527] Example 72 was synthesized in a manner similar to that of Example 1, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid (intermediates 1-5) and 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediates 4-9) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediates 1-1) and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0528] Example 73: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0529]

[0530] Example 73 was synthesized in a manner similar to that of Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (intermediates 1-7) and 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediates 4-9) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediates 1-1) and piperazine-1-carboxylic acid tert-butyl ester.

[0531] Example 74: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0532]

[0533] Example 74 was synthesized in a manner similar to that of Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-fluoropiperidine-4-carboxylic acid (intermediates 1-8) and 4-(piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediates 4-9) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediates 1-1) and piperazine-1-carboxylic acid tert-butyl ester.

[0534] Example 75: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0535]

[0536] Example 75 was synthesized in a manner similar to that of Example 1, using 4-(piperazin-1-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate 4-9) and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0537] Example 76: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0538]

[0539] Example 76 was synthesized in a manner similar to that of Example 1, using 4-(piperazin-1-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate 4-9) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (intermediate 2-2) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0540] Example 77: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)azacyclobutane-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0541]

[0542] Example 77 was synthesized in a manner similar to that of Example 1, using 4-(azacyclobutane-3-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-6) instead of piperazine-1-carboxylic acid tert-butyl ester.

[0543] Example 78: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((3-(4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperazin-1-yl)azacyclobutane-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0544]

[0545] Example 78 was synthesized in a manner similar to that of Example 1, using 4-(azacyclobutane-3-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-6) and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (intermediate 2-6) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0546] Example 79: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0547]

[0548] Example 79 was synthesized in a manner similar to that of Example 1, using 4-(azacyclobutane-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (Examples 4-5) instead of piperazine-1-carboxylic acid tert-butyl ester.

[0549] Example 80: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((3-((4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0550]

[0551] Example 80 was synthesized in a manner similar to that of Example 1, using 4-(azacyclobutane-3-ylmethyl)piperazine-1-carboxylate tert-butyl ester (Examples 4-5) and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (intermediate 2-6) instead of piperazine-1-carboxylate tert-butyl ester and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0552] Example 81: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0553]

[0554] Example 81 was synthesized in a manner similar to that of Example 1, using 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3) instead of piperazine-1-carboxylic acid tert-butyl ester.

[0555] Example 82: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0556]

[0557] Example 82 was synthesized in a manner similar to that of Example 1, using (S)-4-(pyrrolidine-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-1) instead of piperazine-1-carboxylic acid tert-butyl ester.

[0558] Example 83: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((3R)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0559]

[0560] Example 83 was synthesized in a manner similar to that of Example 1, using (R)-4-(pyrrolidine-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-2) instead of piperazine-1-carboxylic acid tert-butyl ester.

[0561] Example 84: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0562]

[0563] Example 84 was synthesized in a manner similar to that of Example 1, using 4-((methylamino)methyl)piperidine-1-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0564] Example 85: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0565]

[0566] Example 85 was synthesized in a manner similar to that of Example 1, using hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.

[0567] Example 86: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0568]

[0569] Example 86 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol instead of piperidin-4-ylmethanol.

[0570] Example 87: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0571]

[0572] Example 87 was synthesized in a manner similar to that of Example 1, using 1-(3-chloro-4-cyanophenyl)piperidin-4-carboxylic acid (intermediate 1-2) and 2-(piperidin-4-yl)ethanol-1-ol instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1) and piperidin-4-ylmethanol, respectively.

[0573] Example 88: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0574]

[0575] Example 88 was synthesized in a manner similar to that of Example 1, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid (intermediate 1-5) and 2-(piperidine-4-yl)ethanol-1-ol instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperidin-4-ylmethanol.

[0576] Example 89: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0577]

[0578] Example 89 was synthesized in a manner similar to that of Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (intermediate 1-7) and 2-(piperidine-4-yl)ethanol-1-ol instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1) and piperidin-4-ylmethanol.

[0579] Example 90: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0580]

[0581] Example 90 was synthesized in a manner similar to that of Example 1, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-fluoropiperidin-4-carboxylic acid (intermediate 1-8) and 2-(piperidin-4-yl)ethanol-1-ol instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1) and piperidin-4-ylmethanol.

[0582] Example 91: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0583]

[0584] Example 91 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 4-(piperazin-1-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate 4-9) instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0585] Example 92: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0586]

[0587] Example 92 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6) instead of piperidin-4-ylmethanol and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0588] Example 93: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0589]

[0590] Example 93 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (intermediate 2-2) instead of piperidin-4-ylmethanol and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0591] Example 94: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0592]

[0593] Example 94 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0594] Example 95: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0595]

[0596] Example 95 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0597] Example 96: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(2-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2,7-diazaspiro[3.5]non-7-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0598]

[0599] Example 96 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol, 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6) instead of piperidin-4-ylmethanol, piperazine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0600] Example 97: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)azacyclobutane-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0601]

[0602] Example 97 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 4-(azacyclobutane-3-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediates 4-6) instead of piperidin-4-ylmethanol and pipeazine-1-carboxylic acid tert-butyl ester, respectively.

[0603] Example 98: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(3-(4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperazin-1-yl)azacyclobutane-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0604]

[0605] Example 98 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol, 4-(azacyclobutane-3-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-6) and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6) instead of piperidin-4-ylmethanol, piperazine-1-carboxylic acid tert-butyl ester, and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0606] Example 99: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0607]

[0608] Example 99 was synthesized in a manner similar to that used in Examples 1 and 33, with 2-(piperidin-4-yl)ethanol-1-ol and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1) instead of piperidin-4-ylmethanol and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione (intermediate 2-6).

[0609] Example 100: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)azacyclobutane-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0610]

[0611] Example 100 was synthesized in a manner similar to that used in Examples 1 and 33, using 2-(piperidin-4-yl)ethanol-1-ol instead of piperidin-4-ylmethanol.

[0612] Example 101: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0613]

[0614] Example 101 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0615] Example 102: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)(methyl)amino)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0616]

[0617] Example 102 was synthesized in a manner similar to that of Example 1, using 2-(piperidin-4-yl)ethanol-1-ol and 4-(methylamino)piperidin-1-carboxylic acid tert-butyl ester instead of piperidin-4-ylmethanol and piperazine-1-carboxylic acid tert-butyl ester, respectively.

[0618] Example 103: 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperazine-1-carboxamide

[0619]

[0620] Step 1: Synthesis of 4-(piperazin-1-yl)-2-(trifluoromethyl)benzyl nitrile

[0621] 4-Fluoro-2-(trifluoromethyl)benzyl nitrile (1.00 g, 5.29 mmol) and piperazine (683 mg, 7.93 mmol) were suspended in DMF (5.0 mL) and stirred at 85 °C for 1 hour. Distilled water (20 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% DCM / MeOH) to give 968 mg (72%) of a white solid. m / z 256.13 [M+H] + .

[0622] Step 2: Synthesis of 2-((1-(5-(4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-carboxamido)pyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0623] 100 mg (0.24 mmol) of 2-((1-(5-aminopyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (ACN) was suspended in 5.0 mL of ACN. Then, phenyl chloroformate (0.04 mL, 0.26 mmol), triethylamine (0.04 mL, 0.26 mmol), and DMAP (30 mg, 0.24 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 3 hours. Distilled water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was suspended in ACN (5.0 mL), and 4-(piperazin-1-yl)-2-(trifluoromethyl)benzyl nitrile (91 mg, 0.36 mmol) and pyridine (0.02 mL, 0.26 mmol) were added. The mixture was stirred at 90 °C for 16 hours. Distilled water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 33 mg (19%) of a purple solid. m / z 697.47 [M+H] + .

[0624] Step 3: Synthesis of N-(6-(4-((2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)-4-(4-cyano-3-(trifluoromethyl)phenyl)piperazine-1-carboxamide hydrochloride

[0625] After suspending 2-((1-(5-(4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-carboxamido)pyridin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (33 mg, 0.47 mmol) in DCM (0.5 mL), di... The reaction mixture was added to an alkane with 4M HCl (0.2 mL, 0.47 mmol) and stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to give 29 mg (99%) of a purple solid.

[0626] Step 4: Synthesis of 4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperazine-1-carboxamide

[0627] N-(6-(4-((2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)-4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-carboxamide hydrochloride (29 mg, 0.050 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 21 mg, 0.075 mmol), and DIPEA (0.013 mL, 0.075 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 3 mg (7%) of yellow solid.

[0628] Example 104: 4-(3-chloro-4-cyanophenyl)-N-(6-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperazin-1-carboxamide

[0629]

[0630] Example 104 was synthesized in a manner similar to that of Example 103, using 2-chloro-4-fluorobenzanilonitrile instead of 4-fluoro-2-(trifluoromethyl)benzanilonitrile.

[0631] Example 105: 5-(4-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridineamide

[0632]

[0633] Step 1: Synthesis of tert-butyl 4-(1-(6-(methoxycarbonyl)pyridin-3-yl)piperidin-4-yl)piperazine-1-carboxylic acid

[0634] Methyl 5-bromopyridinecarboxylate (100 mg, 0.463 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (intermediate 4-4, 125 mg, 0.463 mmol), Pd2(dba)3 (12 mg, 0.0139 mmol), Ruphos (21 mg, 0.0463 mmol), and Cs2CO3 (452 ​​mg, 1.39 mmol) were suspended in toluene (10.0 mL) and stirred at room temperature for 2 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 66 mg (35%) of white solid. m / z 405.41 [M+Na] + .

[0635] Step 2: Synthesis of methyl 5-(4-(piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate hydrochloride

[0636] After suspending 66 mg (0.16 mmol) of 4-(1-(6-(methoxycarbonyl)pyridin-3-yl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester in DCM (1.0 ml), diethylcarboxylic acid was added. The reaction mixture was added to 4M HCl (0.20 mL, 0.82 mmol) in alkane and stirred at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to give 54 mg (100%) of a white solid.

[0637] Step 3: Synthesis of methyl 5-(4-(4-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate

[0638] Methyl 5-(4-(piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate hydrochloride (54 mg, 0.16 mmol) and 1-(6-nitropyridin-3-yl)piperidin-4-carboxaldehyde (37 mg, 0.16 mmol) were suspended in ACN (5.0 mL), followed by the addition of sodium triacetoxyborohydride (101 mg, 0.48 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 34 mg (41%) of a yellow solid. m / z 524.28 [M+H] + .

[0639] Step 4: Synthesis of methyl 5-(4-(4-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate

[0640] Methyl 5-(4-(4-(((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate (34 mg, 0.065 mmol) was dissolved in a mixture of DCM (3 mL) and MeOH (1 mL), followed by the addition of Pd / C (10 wt% Pd, 3 mg) and stirring at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated. 31 mg (97%) of a purple solid was obtained. m / z 494.38 [M+H] + .

[0641] Step 5: Synthesis of methyl 5-(4-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate

[0642] Methyl 5-(4-(4-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate (31 mg, 0.063 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 22 mg, 0.076 mmol), HATU (28 mg, 0.076 mmol), and DIPEA (0.02 mL, 0.13 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 20 mg (41%) of gray solid. m / z 796.49 [M+Na] + .

[0643] Step 6: Synthesis of 5-(4-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylic acid

[0644] Methyl 5-(4-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylate (20 mg, 0.026 mmol) was suspended in THF (3.0 mL) and distilled water (1.0 mL), then LiOH·H₂O (4 mg, 0.11 mmol) was added and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent and extracting with distilled water, 1 N HCl was added to the aqueous layer, and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 18 mg (91%) of white solid. m / z 760.51 [M+H] + .

[0645] Step 7: Synthesis of 5-(4-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridineamide

[0646] 5-(4-(4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)pyridinecarboxylic acid (18 mg, 0.024 mmol), 3-aminopiperidin-2,6-dione hydrochloride (5 mg, 0.028 mmol), HATU (11 mg, 0.028 mmol), and DIPEA (0.01 mL, 0.048 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 10 mg (48%) of a yellow solid.

[0647] Example 106: 5-(4-((4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridineamide

[0648]

[0649] Example 106 was synthesized in a manner similar to that of Example 105, using 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3) instead of 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-4).

[0650] Example 107: 5-(4-(2-(1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridineamide

[0651]

[0652] Example 107 was synthesized in a manner similar to that of Example 105, using 2-(1-(6-nitropyridin-3-yl)piperidin-4-yl)acetaldehyde and piperazine-1-carboxylic acid tert-butyl ester instead of 1-(6-nitropyridin-3-yl)piperidin-4-carboxaldehyde and 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-4).

[0653] Example 108: 5-(4-(((R)-4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridineamide

[0654]

[0655] Step 1: Synthesis of methyl (R)-5-(4-((4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridinecarboxylate

[0656] (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((2-methyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (70 mg, 0.010 mmol), methyl 5-fluoropyridinecarboxylate (23 mg, 0.15 mmol), and DIPEA (0.03 mL, 0.20 mmol) were suspended in DMSO (1.0 mL) and stirred at 70 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 26 mg (33%) of a grayish-white solid.

[0657] Step 2: Synthesis of (R)-5-(4-((4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridinecarboxylic acid

[0658] Methyl (R)-5-(4-((4-(((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridinecarboxylate (26 mg, 0.040 mmol) was suspended in THF (3.0 mL) and distilled water (1.0 mL), and LiOH·H₂O (7 mg, 0.16 mmol) was added and stirred at room temperature for 3 hours. After evaporating the solvent and extracting with distilled water, 1 N HCl was added to the aqueous layer, and extraction was performed with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 25 mg (98%) of white solid was obtained. m / z 788.51 [M+H] + .

[0659] Step 3: Synthesis of 5-(4-(((R)-4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine amide

[0660] (R)-5-(4-((4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridinecarboxylic acid (27 mg, 0.034 mmol), 3-aminopiperidin-2,6-dione hydrochloride (6.8 mg, 0.041 mmol), HATU (16 mg, 0.041 mmol), and DIPEA (0.01 mL, 0.068 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 10 mg (32%) of white solid.

[0661] Example 109: 5-(4-(((S)-4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridineamide

[0662]

[0663] Example 109 was synthesized in a manner similar to that of Example 108, using (S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride instead of (R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride).

[0664] Example 110: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0665]

[0666] Step 1: Synthesis of 2-(methyl((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)amino)ethanol-1-ol)

[0667] 1-(6-nitropyridin-3-yl)piperidine-4-carboxaldehyde (200 mg, 0.850 mmol) and 2-(methylamino)ethanol-1-ol (77 mg, 1.02 mmol) were suspended in MeOH (10.0 mL), followed by the addition of sodium triacetoxyborohydride (540 mg, 2.55 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 149 mg (60%) of a yellow solid. m / z 295.06 [M+H] + .

[0668] Step 2: Synthesis of 2-chloro-N-methyl-N-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)ethyl-1-amine

[0669] 2-(methyl((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)amino)ethanol-1-ol (49 mg, 0.17 mmol), toluenesulfonyl chloride (63 mg, 0.33 mmol), and DMAP (11 mg, 0.09 mmol) were suspended in DCM (10.0 mL), followed by the addition of TEA (0.05 mL, 0.33 mmol) and stirring at room temperature for 12 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / hexane) to give 39 mg (73%) of a yellow solid. m / z 313.18 [M+H] + .

[0670] Step 3: Synthesis of tert-butyl 4-(2-(methyl((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)amino)ethyl)piperazine-1-carboxylic acid

[0671] 2-Chloro-N-methyl-N-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)ethyl-1-amine (39 mg, 0.12 mmol), piperazine-1-carboxylic acid tert-butyl ester (835 mg, 0.19 mmol), K₂CO₃ (33 mg, 0.24 mmol), and KI (10 mg, 0.088 mmol) were suspended in DMF (1.0 mL) and stirred at 70 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 53 mg (95%) of a yellow solid. m / z 463.37 [M+H] + .

[0672] Step 4: Synthesis of tert-butyl 4-(2-(((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperazine-1-carboxylic acid

[0673] 4-(2-(methyl((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)amino)ethyl)piperazine-1-carboxylic acid tert-butyl ester (53 mg, 0.11 mmol) was suspended in a mixture of DCM (3 mL) and MeOH (9 mL), then Pd / C (10 wt% Pd, 11 mg) was added and the mixture was stirred at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated. A gray solid (43 mg, 91%) was obtained. m / z 433.38 [M+H] + .

[0674] Step 5: Synthesis of 4-(2-(((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperazine-1-carboxylic acid tert-butyl ester: 4-(2-(((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperazine-1-carboxylic acid tert-butyl ester (43 mg, 0.10 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 36 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol), and DIPEA (0.03 mL, 0.03 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding 15 ml of distilled water to the reaction solution, extraction was performed using EtOAc (20 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 57 mg (80%) of a grayish-white solid. m / z 713.48 [M+H] + .

[0675] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride)

[0676] 4-(2-(((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperazine-1-carboxylic acid tert-butyl ester (57 mg, 0.080 mmol) was suspended in DCM (1.00 ml), and then dimethyl methacrylate (DMSO) was added. The reaction mixture was added to an alkane with 4M HCl (0.1 mL, 0.40 mmol) and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to give 51 mg (98%) of a white solid.

[0677] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(((2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0678] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (51 mg, 0.079 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 32 mg, 0.12 mmol), and DIPEA (0.02 mL, 0.12 mmol) were suspended in DMSO (3.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 34 mg (50%) of yellow solid.

[0679] Example 111: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexanoyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0680]

[0681] Step 1: Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid

[0682] 5-Chloro-2-nitropyridine (1 g, 6.31 mmol), N-Boc-piperazine (1.41 g, 7.57 mmol), and DIPEA (3.3 mL, 3.3 mmol) were suspended in DMSO (10.0 mL) and stirred at 110 °C for 16 hours. Distilled water (5 mL) and 1N HCl aqueous solution (5 mL) were added to the reaction mixture, followed by extraction with EtOAc (5 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EA / hexane) to give 1.88 g (97%) of a yellow solid.

[0683] Step 2: Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid

[0684] 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (830 mg, 2.69 mmol) and 10% Pd / C (287 mg, 0.27 mmol) were suspended in EtOH (8.0 mL) and stirred at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 686 mg (92%) of a brown solid.

[0685] Step 3: Synthesis of tert-butyl 4-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperazine-1-carboxylic acid

[0686] 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 167 mg, 1.68 mmol), 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.68 mmol), HATU (957 mg, 2.52 mmol), and DIPEA (0.58 mL, 3.36 mmol) were suspended in DMF (5 mL) and stirred at room temperature for 16 hours. After adding distilled water (2 mL) and 1N HCl aqueous solution (2 mL) to the reaction solution, extraction was performed with EtOAc (5 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 810 mg (87%) of a yellow solid.

[0687] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride

[0688] After suspending 810 mg (1.45 mmol) of 4-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester in DCM (5 mL), two... The reaction solution was dissolved in 4N HCl (0.7 mL, 2.90 mmol) in alkane and stirred at room temperature for 16 hours. The reaction solution was then concentrated under reduced pressure to give 717 mg (99%) of a yellow solid.

[0689] Step 5: Synthesis of tert-butyl carbamate (6-(4-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperazin-1-yl)-6-oxohexyl)carbamate

[0690] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride (100 mg, 0.22 mmol), 6-((tert-butoxycarbonyl)amino)hexanoic acid (50 mg, 0.22 mmol), HATU (124 mg, 0.33 mmol), and DIPEA (0.12 mL, 0.73 mmol) were suspended in DMF (1 mL) and stirred at room temperature for 16 hours. After adding distilled water (1 mL) and 1N HCl aqueous solution (1 mL) to the reaction mixture, extraction was performed with EtOAc (1 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 105 mg (71%) of a yellow solid.

[0691] Step 6: Synthesis of N-(5-(4-(6-aminohexanoyl)piperazin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride

[0692] (85 mg, 0.14 mmol) of tert-butyl carbamate (6-(4-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperazin-1-yl)-6-oxohexyl)carbamate was suspended in DCM (1 mL), and then diethylcarbamate was added. The reaction mixture was added to an alkane with 4N HCl (0.07 mL, 0.28 mmol) and stirred at room temperature for 16 hours. The reaction solution was then concentrated under reduced pressure to give 82 mg (99%) of a yellow solid.

[0693] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexanoyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0694] N-(5-(4-(6-aminohexanoyl)piperazin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride (82 mg, 0.14 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 38 mg, 0.14 mmol), and DIPEA (0.07 mL, 0.41 mmol) were suspended in DMSO (1 mL) and stirred at 90 °C for 16 hours. Distilled water (1 mL) was added to the reaction solution, followed by extraction with EtOAc (1 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 10 mg (9%) of a yellow solid.

[0695] Example 112: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexanoyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0696]

[0697] Example 112 was synthesized in a manner similar to that of Example 111, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0698] Example 113: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0699]

[0700] Step 1: Synthesis of 5-((5-chloropentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0701] 2-(2,6-dioxadiazin-3-yl)-5-hydroxyisoindoline-1,3-dione (1.0 g, 3.65 mmol), 1-bromo-5-chloropentane (0.48 mL, 3.64 mmol), and K₂CO₃ (756 mg, 5.47 mmol) were suspended in DMF (10 mL) and stirred at 70 °C for 16 hours. After adding distilled water (50 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2). The organic layer was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (60% EA / Hex) to give 100 mg (8%) of white solid.

[0702] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((5-iodopentyl)oxy)isoindoline-1,3-dione

[0703] 5-((5-chloropentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (96.5 mg, 0.26 mmol) was suspended in acetone (5 mL), and then NaI (153.8 mg, 1.0 mmol) was added and the mixture was refluxed at 80 °C with stirring for 16 hours. Sodium thiosulfate solution (15 mL) was added to the reaction solution, and the mixture was extracted with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 90 mg (75%) of a white solid.

[0704] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0705] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride (23.3 mg, 0.05 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-((5-iodopentyl)oxy)isoindoline-1,3-dione (23.8 mg, 0.05 mmol), and DIPEA (0.02 mL, 0.1 mmol) were suspended in DMSO (1 mL) and stirred at 70 °C for 6 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (10 mL × 2). The organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (3% MeOH / DCM) to give 12.1 mg (30%) of white solid.

[0706] Example 114: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0707]

[0708] Example 114 was synthesized in a manner similar to that used in Examples 111 and 113, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0709] Example 115: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0710]

[0711] Example 115 was synthesized in a manner similar to that of Example 113, using 1-bromo-4-chlorobutane instead of 1-bromo-5-chloropentane.

[0712] Example 116: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0713]

[0714] Example 116 was synthesized in a manner similar to that used in Examples 111 and 113, respectively, by replacing 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) and 1-bromo-4-chlorobutane.

[0715] Example 117: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0716]

[0717] Step 1: Synthesis of tert-butyl 4-(2-(4-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperazin-1-yl)ethoxy)piperidin-1-carboxylic acid

[0718] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride (31.6 mg, 0.063 mmol) and 4-(2-(toluenesulfonyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester (25.2 mg, 0.063 mmol) were suspended in DMF (1 ml), and DIPEA (0.03 ml, 0.19 mmol) was added and the mixture was stirred at 70 °C for 4 hours. Distilled water (5 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (5 ml × 2). The organic layer was washed with brine (3 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (5% MeOH / DCM) to give 22.4 mg (52%) of white solid.

[0719] Step 2: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(piperidin-4-yloxy)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride

[0720] After suspending 13 mg (0.019 mmol) of 4-(2-(4-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperazin-1-yl)ethoxy)piperidin-1-carboxylic acid tert-butyl ester in DCM (0.5 ml), diethylcarboxylic acid was added. The reaction mixture was stirred in 4N HCl in alkane (0.005 mL, 0.16 mmol) at room temperature for 30 minutes. The reaction solution was then concentrated. 10 mg (90%) of a white solid was obtained.

[0721] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0722] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(piperidin-4-yloxy)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (18 mg, 0.03 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 8 mg, 0.03 mmol) were suspended in DMSO (1 ml), followed by the addition of DIPEA (0.02 ml, 0.09 mmol) and stirring in a microwave at 120 °C for 1 hour. Distilled water (10 ml) was added to the reaction mixture, and extraction was performed with EtOAc (10 ml × 2). The organic layer was washed with brine (10 ml × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with PTLC (5% MeOH / DCM) to give 3.2 mg (13%) of yellow solid.

[0723] Example 118: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0724]

[0725] Example 118 was synthesized in a manner similar to that used in Examples 111 and 117, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0726] Example 119: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0727]

[0728] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride (60 mg, 0.12 mmol) and 2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)acetaldehyde (intermediate 3-13, 55 mg, 0.14 mmol) were suspended in ACN (20.0 mL), followed by the addition of sodium triacetoxyborohydride (76 mg, 0.36 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 11 mg (11%) of white solid.

[0729] Example 120: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0730]

[0731] Example 120 was synthesized in a manner similar to that used in Examples 111 and 119, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0732] Example 121: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)piperidin-4-carboxamide

[0733]

[0734] Example 121 was synthesized in a manner similar to that used in Examples 111 and 119, respectively, by replacing piperazine-1-carboxylic acid tert-butyl ester with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)acetaldehyde (intermediate 3-13).

[0735] Example 122: 1-(3-chloro-4-cyanophenyl)-N-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)piperidin-4-carboxamide

[0736]

[0737] Example 122 was synthesized in a manner similar to that used in Examples 111 and 119, with 1-(3-chloro-4-cyanophenyl)piperidin-4-carboxylic acid (intermediates 1-2), 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1), piperazine-1-carboxylic acid tert-butyl ester and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)acetaldehyde.

[0738] Example 123: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)piperidin-4-carboxamide

[0739]

[0740] Example 123 was synthesized in a manner similar to that used in Examples 111 and 119, with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)acetaldehyde (intermediate 3-13).

[0741] Example 124: 1-(3-chloro-4-cyanophenyl)-N-(5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)piperidin-4-carboxamide

[0742]

[0743] Example 124 was synthesized in a manner similar to that used in Examples 111 and 119, using 1-(3-chloro-4-cyanophenyl)piperidin-4-carboxylic acid (intermediates 1-2), 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1), piperazine-1-carboxylic acid tert-butyl ester, and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)acetaldehyde.

[0744] Example 125: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(7-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)piperidin-4-carboxamide

[0745]

[0746] Example 125 was synthesized in a manner similar to that used in Examples 111 and 119, with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediates 3-4) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)acetaldehyde (intermediates 3-13).

[0747] Example 126: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)piperidin-4-carboxamide

[0748]

[0749] Example 126 was synthesized in a manner similar to that used in Examples 111 and 119, with 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carboxaldehyde (intermediate 3-5) instead of piperazine-1-carboxylic acid tert-butyl ester and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)acetaldehyde (intermediate 3-13).

[0750] Example 127: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide

[0751]

[0752] Step 1: Synthesis of tert-butyl 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid

[0753] 5-Chloro-2-nitropyridine (1.0 g, 6.31 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylic acid (1.43 g, 6.31 mmol), and TEA (2.6 mL, 18.93 mmol) were suspended in DMSO (10.0 mL) and stirred in a microwave reactor at 90 °C for 1 hour. Distilled water (10 mL) was added to the reaction mixture, followed by extraction with EtOAc (10 mL × 2). The organic layer was washed with brine (10 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized (MeOH / hexane) to give 2.12 g (97%) of a yellow solid.

[0754] Step 2: Synthesis of 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane hydrochloride. 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (750 mg, 2.15 mmol) was suspended in MeOH (5 mL), and then 4N HCl was added. The reaction solution (1 mL, 4.3 mmol) was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and recrystallized (MeOH / hexane) to give 391 mg (73%) of a yellow solid.

[0755] Step 3: Synthesis of tert-butyl 4-((7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidine-1-carboxylic acid

[0756] 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane hydrochloride (152 mg, 0.612 mmol) and 1-Boc-4-piperidinecarbaldehyde (157 mg, 0.735 mmol) were suspended in MeOH (10.0 mL), followed by the addition of sodium triacetoxyborohydride (259 mg, 1.22 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 196 mg (72%) of a yellow solid. m / z 446.31 [M+H] + .

[0757] Step 4: Synthesis of tert-butyl 4-((7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidine-1-carboxylic acid

[0758] 4-((7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (196 mg, 0.440 mmol) was dissolved in a mixture of DCM (10 mL) and MeOH (5 mL), followed by the addition of Pd / C (10 wt% Pd, 39 mg) and stirring at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered and concentrated. 156 mg (85%) of brown solid was obtained. m / z 416.26 [M+H] + .

[0759] Step 5: Synthesis of tert-butyl 4-((7-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-carboxylic acid

[0760] 4-((7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (80 mg, 0.19 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 69 mg, 0.23 mmol), HATU (87 mg, 0.23 mmol), and DIPEA (0.066 mL, 0.38 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 100 mg (76%) of brown solid. m / z 696.45 [M+H] + .

[0761] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride

[0762] After suspending 100 mg (0.144 mmol) of 4-(7-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester in DCM (1.00 ml), diethylcarboxylic acid was added. The mixture was stirred with 4M HCl (0.36 mL, 1.44 mmol) in an alkane at room temperature for 1 hour. The reaction solution was concentrated. 89 mg (98%) of a white solid was given. m / z 596.36 [M+H] + .

[0763] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide

[0764] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (30 mg, 0.047 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 20 mg, 0.071 mmol), and DIPEA (0.02 mL, 0.094 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to obtain 12 mg (30%) of yellow solid.

[0765] Example 128: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide

[0766]

[0767] Example 128 was synthesized in a manner similar to that of Example 127, using 3-formylazetane-1-carboxylic acid tert-butyl ester instead of 1-Boc-4-piperidinecarboxaldehyde.

[0768] Example 129: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide

[0769]

[0770] Step 1: Synthesis of tert-butyl 4-(7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidine-1-carboxylic acid

[0771] 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane hydrochloride (90 mg, 0.36 mmol), N-Boc-piperidine-4-carboxylic acid (100 mg, 0.43 mmol), HATU (163 mg, 0.43 mmol), and DIPEA (0.13 mL, 0.72 mmol) were suspended in DMF (3.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, extraction was performed with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 116 mg (70%) of a yellow solid. m / z 482.20 [M+Na] + .

[0772] Step 2: Synthesis of tert-butyl 4-(7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidine-1-carboxylic acid

[0773] 4-(7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (116 mg, 0.252 mmol) was suspended in a mixture of DCM (10 mL) and MeOH (5 mL), followed by the addition of Pd / C (10 wt% Pd, 23 mg) and stirring at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered and concentrated. A brown solid (105 mg, 96%) was obtained. m / z 430.22 [M+H] + .

[0774] Step 3: Synthesis of tert-butyl 4-(7-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-carboxylic acid

[0775] 4-(7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (105 mg, 0.244 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 57 mg, 0.293 mmol), HATU (111 mg, 0.293 mmol), and DIPEA (0.085 mL, 0.488 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 116 mg (67%) of purple solid. m / z 710.35 [M+H] + .

[0776] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperidin-4-carbonyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride

[0777] After suspending 4-(7-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-carboxylic acid tert-butyl ester (116 mg, 0.163 mmol) in DCM (1.00 ml), di... The reaction mixture was stirred for 1 hour at room temperature with 4M HCl (0.41 mL, 1.63 mmol) in alkane. The solution was then concentrated. 102 mg (97%) of a pink solid was obtained. m / z 610.28 [M+H] + .

[0778] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide

[0779] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperidin-4-carbonyl)-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (40 mg, 0.065 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 27 mg, 0.097 mmol), and DIPEA (0.02 mL, 0.13 mmol) were suspended in DMSO (1.00 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 15 mg (27%) of yellow solid.

[0780] Example 130: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0781]

[0782] Example 130 was synthesized in a manner similar to that used in Examples 127 and 5, by replacing tert-butyl piperazine-1-carboxylate with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate.

[0783] Example 131: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)pyridin-2-yl)piperidin-4-carboxamide

[0784]

[0785] Step 1: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-iodopyridin-2-yl)piperidine-4-carboxamide

[0786] 5-Iodopyridin-2-amine (300 mg, 1.36 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 406 mg, 1.36 mmol), HATU (620 mg, 1.63 mmol), and DIPEA (0.47 mL, 2.72 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% EtOAc / hexane) to give 207 mg (30%) of white solid. m / z 501.03 [M+H] + .

[0787] Step 2: Synthesis of tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)ethynyl)piperidin-1-carboxylic acid

[0788] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-iodopyridin-2-yl)piperidin-4-carboxamide (300 mg, 0.60 mmol), 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (190 mg, 0.90 mmol), Pd(PPh3)2Cl2 (20 mg, 0.03 mmol), CuI (6 mg, 0.03 mmol), and TEA (0.17 mL, 1.2 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 2 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (25% EtOAc / hexane) to give 302 mg (87%) of a brown solid. m / z 604.29 [M+Na] + .

[0789] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-ylethynyl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride

[0790] After suspending 302 mg (0.437 mmol) of 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)ethynyl)piperidin-1-carboxylic acid tert-butyl ester in DCM (2.00 ml), diethylcarboxylic acid was added. The mixture was stirred with 4M HCl (1.0 mL, 4.37 mmol) in an alkane for 1 hour at room temperature. The reaction solution was concentrated. 221 mg (89%) of a light brown solid was obtained. m / z 482.24 [M+H] + .

[0791] Step 4: Synthesis of 4-((4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)ethynyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester

[0792] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-ylethynyl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (100 mg, 0.21 mmol) and 1-Boc-4-piperidinaldehyde (81 mg, 0.386 mmol) were suspended in MeOH (10.0 mL), followed by the addition of sodium triacetoxyborohydride (123 mg, 0.579 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 30 mg (21%) of a light brown solid. m / z 679.35 [M+H] + .

[0793] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)ethynyl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride

[0794] After suspending 30 mg (0.044 mmol) of 4-((4-((6-((1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)ethynyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester in DCM (1.00 ml), di... The mixture was stirred with 4M HCl (0.1 mL, 0.44 mmol) in an alkane for 1 hour at room temperature. The reaction solution was concentrated. 27 mg (98%) of a brown solid was obtained. m / z 579.26 [M+H] + .

[0795] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)pyridin-2-yl)piperidin-4-carboxamide

[0796] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)ethynyl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (27 mg, 0.043 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 18 mg, 0.065 mmol), and DIPEA (0.01 mL, 0.063 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 7 mg (19%) of a yellow solid.

[0797] Example 132: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperidin-4-yl)ethynyl)pyridin-2-yl)piperidin-4-carboxamide

[0798]

[0799] Example 132 was synthesized in a manner similar to that of Example 131, using 3-formylaziridine-1-carboxylic acid tert-butyl ester instead of 4-formylpiperidine-1-carboxylic acid tert-butyl ester.

[0800] Example 133: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[0801]

[0802] Step 1: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperidin-4-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[0803] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-ylethynyl)pyridin-2-yl)piperidin-4-carboxamide (58 mg, 0.12 mmol) was dissolved in MeOH (10 mL), followed by the addition of Pd / C (10 wt% Pd, 12 mg) and stirring at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated. 56 mg (96%) of a white solid was obtained. m / z 486.26 [M+H] + .

[0804] Step 2: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[0805] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperidin-4-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide (56 mg, 0.12 mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1, 53 mg, 0.14 mmol) were suspended in ACN (5.0 mL), followed by the addition of sodium triacetoxyborohydride (76 mg, 0.36 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 26 mg (25%) of a pale yellow solid.

[0806] Example 134: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-1-yn-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0807]

[0808] Step 1: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-hydroxyprop-1-yn-1-yl)pyridin-2-yl)piperidine-4-carboxamide

[0809] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-iodopyridin-2-yl)piperidin-4-carboxamide (1.00 g, 1.99 mmol), propan-2-yn-1-ol (0.17 mL, 2.99 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol), CuI (7.6 mg, 0.04 mmol), and TEA (0.55 mL, 4.0 mmol) were suspended in DMF (2.0 mL) and stirred in a microwave at 120 °C for 30 min. Distilled water (2 mL) was added to the reaction solution, followed by extraction with EtOAc (2 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (25% EtOAc / hexane) to give 434 mg (51%) of a yellow solid.

[0810] Step 2: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-1-yn-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0811] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-hydroxyprop-1-yn-1-yl)pyridin-2-yl)piperidin-4-carboxamide (9.2 mg, 0.02 mmol), TEA (0.04 mL, 0.04 mmol), and methanesulfonyl chloride (0.02 mL, 0.03 mmol) were suspended in DCM (0.3 mL) and stirred at room temperature for 5 minutes. The reaction solution was concentrated. The resulting residue was suspended in DMF (0.3 mL), and Cs₂CO₃ (7 mg, 0.02 mmol) and 2-(2,6-dioxopiridin-3-yl)-5-(2,7-diazaspiro[3.5]non-2-yl)isoindoline-1,3-dione (intermediate 3-14, 13.5 mg, 0.03 mmol) were added. The mixture was then stirred at room temperature for 16 hours. After adding distilled water (0.5 ml) to the reaction solution, extraction was performed with EtOAc (1 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 3.2 mg (19%) of yellow solid.

[0812] Example 135: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0813]

[0814] Step 1: Synthesis of tert-butyl 7-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid

[0815] 5-Bromophthalide (3.00 g, 14.1 mmol), 2-Boc-2,7-diazaspiro[3,5]nonane (3.19 g, 14.1 mmol), and K3PO4 (5.99 g, 28.2 mmol) were suspended in DMF (20.0 mL), followed by the addition of Pd2(dba)3 (1.29 g, 1.41 mmol) and Xantphos (815 mg, 1.41 mmol), and stirring at 100 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 2.53 g (50%) of a brown solid. m / z 359.23 [M+H] + .

[0816] Step 2: Synthesis of 4-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl)-2-(hydroxymethyl)benzoic acid

[0817] 7-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.53 g, 7.06 mmol) was suspended in a mixture of THF (5.0 mL), MeOH (5.0 mL), and distilled water (5.0 mL), followed by the addition of NaOH (1.13 g, 28.2 mmol) and stirring at room temperature for 1 hour. The solvent was evaporated and extracted with distilled water, and the aqueous layer was extracted with 1 N HCl and EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized (EtOAc / hexane) to give 1.75 g (66%) of a yellow solid. m / z 377.22 [M+H] + .

[0818] Step 3: Synthesis of tert-butyl 7-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid

[0819] 4-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl)-2-(hydroxymethyl)benzoic acid (1.75 g, 4.65 mmol) was suspended in MeOH (10.0 mL) and EtOAc (10.0 mL), and then trimethylsilyldiazomethane (6.98 mmol, 14.0 mL) was added at -10 °C, and the mixture was stirred at -10 °C for 2 hours. Distilled water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / hexane) to give 1.24 g (68%) of a yellow solid. m / z 391.28 [M+H] + .

[0820] Step 4: Synthesis of tert-butyl 7-(3-formyl-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid

[0821] 620 mg (1.59 mmol) of 7-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was suspended in DCM (20.0 ml), followed by the addition of DMP (1.10 g, 2.59 mmol) and stirring at room temperature for 2 hours. An aqueous solution of Na2S2O3 (15 ml) was added to the reaction solution, followed by extraction with DCM (25 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (30% EtOAc / hexane) to give 523 mg (85%) of a yellow solid. m / z 389.22 [M+H] + .

[0822] Step 5: Synthesis of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid

[0823] 7-(3-formyl-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (523 mg, 1.35 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (333 mg, 2.03 mmol) were suspended in MeOH (10.0 mL), followed by the addition of sodium triacetoxyborohydride (858 mg, 4.05 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 227 mg (36%) of gray solid. m / z 469.29 [M+H] + .

[0824] Step 6: Synthesis of 3-(1-oxo-5-(2,7-diazaspiro[3.5]non-7-yl)isoindoline-2-yl)piperidine-2,6-dione hydrochloride

[0825] After suspending 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (227 mg, 0.484 mmol) in DCM (2.0 ml), 2... The reaction mixture was added to an alkane with 4M HCl (0.61 mL, 2.42 mmol) and stirred at room temperature for 1 hour. The reaction solution was then concentrated. 194 mg (99%) of a brown solid was obtained.

[0826] Step 7: Synthesis of 3-(5-(2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0827] 3-(1-oxo-5-(2,7-diazaspiro[3.5]non-7-yl)isoindoline-2-yl)piperidine-2,6-dione hydrochloride (200 mg, 0.494 mmol) and 1-(6-nitropyridin-3-yl)piperidine-4-carboxaldehyde (128 mg, 0.543 mmol) were suspended in MeOH (5.0 mL), followed by the addition of sodium triacetoxyborohydride (419 mg, 1.98 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 95 mg (33%) of white solid. m / z 588.36 [M+H] + .

[0828] Step 8: Synthesis of 3-(5-(2-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0829] 3-(5-(2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (95 mg, 0.17 mmol) was dissolved in a mixture of DCM (10 mL) and MeOH (5 mL), followed by the addition of Pd / C (10 wt% Pd, 19 mg) and stirring at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered and concentrated. 56 mg (59%) of a brown solid was obtained. m / z 558.33 [M+H] + .

[0830] Step 9: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0831] 3-(5-(2-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (20 mg, 0.033 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 12 mg, 0.039 mmol), HATU (15 mg, 0.039 mmol), and DIPEA (0.01 mL, 0.066 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (25 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 5 mg (16%) of yellow solid.

[0832] Example 136: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0833]

[0834] Example 136 was synthesized in a manner similar to that of Example 135, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidine-4-carboxylic acid (intermediate 1-5) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0835] Example 137: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0836]

[0837] Example 137 was synthesized in a manner similar to that of Example 135, using 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (intermediate 1-7) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0838] Example 138: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0839]

[0840] Example 138 was synthesized in a manner similar to that of Example 135, using 2-(1-(6-nitropyridin-3-yl)piperidin-4-yl)acetaldehyde instead of 1-(6-nitropyridin-3-yl)piperidin-4-carboxaldehyde.

[0841] Example 139: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0842]

[0843] Example 139 was synthesized in a manner similar to that of Example 135, using piperazine-1-carboxylic acid tert-butyl ester and 2-(1-(6-nitropyridin-3-yl)piperidin-4-yl)acetaldehyde instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and 1-(6-nitropyridin-3-yl)piperidin-4-carboxaldehyde.

[0844] Example 140: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0845]

[0846] Example 140 was synthesized in a manner similar to that of Example 135, using 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-4) instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester.

[0847] Example 141: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0848]

[0849] Example 141 was synthesized in a manner similar to that of Example 135, using 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-4) and 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidin-4-carboxylic acid (intermediate 1-5) instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1).

[0850] Example 142: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0851]

[0852] Example 142 was synthesized in a manner similar to that of Example 135, using 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-4) and 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidin-4-carboxylic acid (intermediate 1-7) instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1).

[0853] Example 143: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0854]

[0855] Example 143 was synthesized in a manner similar to that of Example 135, using 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3) instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester.

[0856] Example 144: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-4-fluoropiperidin-4-carboxamide

[0857]

[0858] Example 144 was synthesized in a manner similar to that of Example 135, using 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3) and 1-(4-cyano-3-(trifluoromethyl)phenyl)-4-fluoropiperidin-4-carboxylic acid (intermediate 1-5) instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1).

[0859] Example 145: 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0860]

[0861] Example 145 was synthesized in a manner similar to that of Example 135, using 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3) and 1-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)piperidin-4-carboxylic acid (intermediate 1-7) instead of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1).

[0862] Example 146: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0863]

[0864] Step 1: Synthesis of dimethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)phthalate

[0865] Dimethyl 4-hydroxyphthalate (300 mg, 1.43 mmol), 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (315 mg, 1.57 mmol), and triphenylphosphine (1.13 g, 4.29 mmol) were suspended in THF (15.0 mL), followed by the addition of DEAD (0.67 mL, 4.29 mmol) and stirring at 40 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (30% EtOAc / hexane) to give 512 mg (91%) of a colorless liquid.

[0866] Step 2: Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)phthalic acid

[0867] Dimethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)phthalate (512 mg, 1.30 mmol) was suspended in a mixture of THF (10.0 mL), MeOH (10.0 mL), and distilled water (10.0 mL). NaOH (311 g, 7.80 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and extracted with distilled water. The aqueous layer was then extracted with EtOAc (25 mL × 2) by adding 1 N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 416 mg (88%) of a white solid was obtained.

[0868] Step 3: Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-carboxylic acid

[0869] 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)phthalic acid (416 mg, 1.14 mmol) and 3-aminopiperidin-2,6-dione hydrochloride (206 mg, 1.25 mmol) were suspended in pyridine (4.0 mL) and stirred at 110 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (30% EtOAc / hexane) to give 396 mg (76%) of a blue solid.

[0870] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione

[0871] After suspending 396 mg (0.87 mmol) of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-carboxylic acid tert-butyl ester in DCM (3.00 ml), two... The mixture was stirred for 1 hour at room temperature with 4M HCl (1.01 mL, 4.03 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 15 mL of aqueous NaHCO3 solution using DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 255 mg (88%) of white solid.

[0872] Step 5: Synthesis of 2-(2,6-dioxopiridine-3-yl)-5-((1-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)isoindoline-1,3-dione

[0873] 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione (100 mg, 0.279 mmol) and 1-(6-nitropyridin-3-yl)piperidin-4-carboxaldehyde (66 mg, 0.279 mmol) were suspended in MeOH (20.0 mL), followed by the addition of sodium triacetoxyborohydride (177 mg, 0.837 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 123 mg (77%) of a yellow solid. m / z 577.15 [M+H] + .

[0874] Step 6: Synthesis of 5-((1-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0875] 2-(2,6-dioxopiperidin-3-yl)-5-((1-((1-(6-nitropyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)isoindoline-1,3-dione (123 mg, 0.213 mmol) was dissolved in a mixture of DCM (5 mL) and MeOH (10 mL), followed by the addition of Pd / C (10 wt% Pd, 25 mg) and stirring at room temperature for 4 hours under a hydrogen stream. The reaction solution was filtered and concentrated. A yellow solid (100 mg, 86%) was obtained. m / z 547.42 [M+H] + .

[0876] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0877] 5-((1-((1-(6-aminopyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg, 0.091 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 32 mg, 0.11 mmol), HATU (42 mg, 0.11 mmol), and DIPEA (0.02 mL, 0.18 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, the mixture was extracted with EtOAc (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to obtain 29 mg (38%) of off-white solid.

[0878] Example 147: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0879]

[0880] Example 147 was synthesized in a manner similar to that of Example 146, using 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester instead of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester.

[0881] Example 148: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0882]

[0883] Example 148 was synthesized in a manner similar to that of Example 146, using 1-(6-nitropyridin-3-yl)azacyclobutane-3-carboxaldehyde instead of 1-(6-nitropyridin-3-yl)piperidine-4-carboxaldehyde.

[0884] Example 149: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(3-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)methyl)piperidin-1-yl)methyl)azacyclobutane-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0885]

[0886] Example 149 was synthesized in a manner similar to that of Example 146, using 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester and 1-(6-nitropyridin-3-yl)azacyclobutane-3-carboxaldehyde instead of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester and 1-(6-nitropyridin-3-yl)piperidine-4-carboxaldehyde.

[0887] Example 150: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0888]

[0889] Step 1: Synthesis of methyl 2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)acetate

[0890] 5-Chloro-2-nitropyridine (801.3 mg, 5.05 mmol) and methyl 2-(piperidin-4-yloxy)acetate hydrochloride (1.06 g, 5.05 mmol) were suspended in DMSO (8.5 mL), followed by the addition of TEA (2.8 mL, 20.2 mmol) and stirring in a microwave at 120 °C for 1 hour. Distilled water (20 mL) was added to the reaction solution, and extraction was performed using EtOAc (15 mL × 2). The organic layer was washed with brine (15 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 1.0 g (67%) of a yellow solid.

[0891] Step 2: Synthesis of 2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)ethanol-1-ol

[0892] 430 mg (1.46 mmol) of methyl 2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)acetate was suspended in anhydrous THF (10 mL), and 2 M LAH was slowly added to THF (0.23 mL, 5.1 mmol) while stirring at room temperature for 2 hours. Distilled water (10 mL) and 1 N HCl aqueous solution (0.5 mL) were added to the reaction solution, followed by extraction with EtOAc (15 mL × 2). The organic layer was washed with brine (5 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by PTLC (0.5% MeOH / DCM) to give 82 mg (21%) of a yellow solid.

[0893] Step 3: Synthesis of 2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)acetaldehyde

[0894] 2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)ethane-1-ol (70.6 mg, 0.28 mmol) was suspended in DCM (13 mL), followed by the addition of DMP (134.4 mg, 0.31 mmol) and stirring at room temperature for 2 hours. An aqueous solution of Na₂S₂O₃ (10 mL) was added to the reaction mixture, followed by extraction with DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (5% MeOH / DCM) to give 41.3 mg (55%) of a yellow solid.

[0895] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione

[0896] 2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)acetaldehyde (41.3 mg, 0.155 mmol) and 2-(2,6-dioxopiridine-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (68.4 mg, 0.155 mmol) were suspended in MeOH (1.0 mL) and DCM (0.5 mL), followed by the addition of sodium triacetoxyborohydride (66 mg, 0.311 mmol) and stirring at room temperature for 30 minutes. An aqueous solution of NaHCO3 (3 mL) was added to the reaction solution, followed by extraction with EtOAc (3 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (5% MeOH / DCM) to give 35 mg (38%) of a yellow solid.

[0897] Step 5: Synthesis of 5-(4-(2-((1-(6-aminopyridin-3-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0898] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-((1-(6-nitropyridin-3-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione (38 mg, 0.064 mmol) was dissolved in MeOH (1.0 mL), and Pd / C (10 wt% Pd, 3.8 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give a yellow solid (24 mg, 72%).

[0899] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0900] 5-(4-(2-((1-(6-aminopyridin-3-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12.5 mg, 0.02 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 6.56 mg, 0.02 mmol), HATU (12.5 mg, 0.03 mmol), and DIPEA (0.01 mL, 0.03 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (1 mL) to the reaction solution, the mixture was extracted with EtOAc (1 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (5% MeOH / DCM) to give 6 mg (32%) of brown solid.

[0901] Example 151: 1-(3-chloro-4-cyanophenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0902]

[0903] Example 150 was synthesized in a manner similar to that of Example 151, using 1-(3-chloro-4-cyanophenyl)piperidine-4-carboxylic acid (intermediate 1-2) instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1).

[0904] Example 152: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperazin-1-yl)ethoxy)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0905]

[0906] Example 152 was synthesized in a manner similar to that of Example 150, using 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione instead of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione.

[0907] Example 153: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)-4-hydroxypiperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0908]

[0909] Step 1: Synthesis of tert-butyl 4-hydroxy-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylic acid

[0910] 2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)acetic acid (100 mg, 0.38 mmol) and 2M trimethylsilyldiazomethane (0.82 mL, 1.17 mmol) in hexane were suspended in MeOH:EtOAc = 1:1 (4 mL) and stirred at -10 °C for 1 hour. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (5% MeOH / DCM) to give 96 mg (93%) of a clear oil.

[0911] Step 2: Synthesis of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylic acid

[0912] 4-Hydroxy-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (89 mg, 0.33 mmol) was suspended in THF (3.3 mL), and 2M LAH (0.4 mL, 0.81 mmol) in THF was slowly added, followed by stirring at room temperature for 1 hour. 1N HCl was slowly added to the reaction mixture, followed by distilled water (20 mL), and extraction was performed with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (5% MeOH / DCM) to give 44 mg (55%) of a clear oil.

[0913] Step 3: Synthesis of 4-(2-hydroxyethyl)piperidine-4-ol hydrochloride

[0914] After suspending 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (42 mg, 0.17 mmol) in DCM (1.7 ml), diethyl ester was added. The mixture was added to alkane with 4M HCl (0.26 mL, 1.03 mmol) and stirred at room temperature for 4 hours. The reaction solution was then concentrated. 30 mg (97%) of a white solid was obtained.

[0915] Step 4: Synthesis of 4-(2-hydroxyethyl)-1-(6-nitropyridin-3-yl)piperidine-4-ol

[0916] 4-(2-hydroxyethyl)piperidine-4-ol hydrochloride (30 mg, 0.17 mmol), 5-chloro-2-nitropyridine (26 mg, 0.17 mmol), and DIPEA (0.09 mL, 0.5 mmol) were suspended in DMSO (1.65 mL) and stirred in a microwave at 120 °C for 1 hour. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (5% MeOH / DCM) to give 19 mg (34%) of a yellow solid.

[0917] Step 5: Synthesis of 2-(4-hydroxy-1-(6-nitropyridin-3-yl)piperidin-4-yl)ethyl 4-methylbenzenesulfonate

[0918] 4-(2-hydroxyethyl)-1-(6-nitropyridin-3-yl)piperidin-4-ol (17 mg, 0.06 mmol), 4-toluenesulfonyl chloride (12.2 mg, 0.06 mmol), DMAP (1.56 mg, 0.013 mmol), and TEA (0.02 mL, 0.13 mmol) were suspended in DCM (0.64 mL) at 0 °C and stirred at room temperature for 5 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with DCM (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (5% MeOH / DCM) to give 22 mg (82%) of a yellow solid.

[0919] Step 6: Synthesis of tert-butyl 4-(2-(4-hydroxy-1-(6-nitropyridin-3-yl)piperidin-4-yl)ethyl)piperazine-1-carboxylic acid

[0920] 2-(4-hydroxy-1-(6-nitropyridin-3-yl)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (40 mg, 0.09 mmol), piperazine-1-carboxylic acid tert-butyl ester (34 mg, 0.14 mmol), and K₂CO₃ (26 mg, 0.19 mmol) were suspended in DMF (1 mL) and stirred at 70 °C for 8 hours. Distilled water (20 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (3% MeOH / DCM) to give 26 mg (63%) of a yellow solid.

[0921] Step 7: Synthesis of 4-(2-(1-(6-aminopyridin-3-yl)-4-hydroxypiperidin-4-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0922] 30 mg (0.07 mmol) of 4-(2-(4-hydroxy-1-(6-nitropyridin-3-yl)piperidin-4-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in MeOH (0.7 mL), followed by the addition of palladium (10 wt%, 15 mg on activated carbon) and stirring at room temperature for 2 hours under a hydrogen stream. The reaction solution was filtered and concentrated under reduced pressure to obtain 28 mg (99%) of a brown solid.

[0923] Step 8: Synthesis of 4-(2-(1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)-4-hydroxypiperidin-4-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0924] 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 21 mg, 0.07 mmol), 4-(2-(1-(6-aminopyridin-3-yl)-4-hydroxypiperidine-4-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (28 mg, 0.07 mmol), HATU (32 mg, 0.08 mmol), and DIPEA (0.03 mL, 0.14 mmol) were suspended in DMF (0.7 mL) and stirred at room temperature for 18 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (5% MeOH / DCM) to give 20 mg (43%) of a brown solid.

[0925] Step 9: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-hydroxy-4-(2-(piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride

[0926] 4-(2-(1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)-4-hydroxypiperidin-4-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (19 mg, 0.03 mmol) was suspended in DCM (0.3 ml), and then diethylpiperazine-1-carboxylic acid tert-butyl ester was added. The reaction mixture was added to alkane with 4M HCl (0.04 mL, 0.16 mmol) and stirred at room temperature for 2 hours. The reaction solution was then concentrated. 18 mg (97%) of a white solid was obtained.

[0927] Step 10: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)-4-hydroxypiperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0928] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-hydroxy-4-(2-(piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide hydrochloride (18 mg, 0.03 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 8 mg, 0.03 mmol), and DIPEA (0.015 mL, 0.08 mmol) were suspended in DMSO (0.3 mL) and stirred at 90 °C for 18 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 5 mg (22%) of a yellow solid.

[0929] Example 154: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0930]

[0931] Step 1: Synthesis of 1-(6-nitropyridin-3-yl)piperidine-4-carboxylic acid

[0932] 5-Chloro-2-nitropyridine (1 g, 6.31 mmol), piperidine-4-carboxylic acid (896 mg, 6.91 mmol), and TEA (2.6 mL, 18.93 mmol) were suspended in DMSO (10 mL) and stirred in a microwave reactor at 120 °C for 2 hours. Distilled water (10 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL) to remove byproducts, and the aqueous layer was concentrated under reduced pressure. 650 mg (41%) of a yellow solid was obtained.

[0933] Step 2: Synthesis of tert-butyl 2-(1-(6-nitropyridin-3-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid

[0934] 1-(6-nitropyridin-3-yl)piperidine-4-carboxylic acid (232 mg, 0.93 mmol), 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl hydrochloride (242 mg, 0.93 mmol), HATU (527 mg, 0.39 mmol), and DIPEA (0.47 mL, 2.77 mmol) were suspended in DMF (3 mL) and stirred at room temperature for 16 hours. Distilled water (2 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3 mL × 2). The organic layer was washed with brine (2 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 199 mg (47%) of a yellow solid.

[0935] Step 3: Synthesis of tert-butyl 2-(1-(6-aminopyridin-3-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid

[0936] 2-(1-(6-nitropyridin-3-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (199 mg, 0.43 mmol), 10% Pd / C (194 mg, 0.086 mmol), were suspended in MeOH (1 mL) and DCM (1 mL) and stirred at room temperature for 16 hours under a hydrogen stream. The reaction solution was filtered and concentrated under reduced pressure to obtain 207 mg (100%) of a brown solid.

[0937] Step 4: Synthesis of 2-(1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0938] 2-(1-(6-aminopyridin-3-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (207 mg, 0.48 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 144 mg, 0.48 mmol), HATU (275 mg, 0.72 mmol), and DIPEA (0.25 mL, 1.45 mmol) were suspended in DMF (2 mL) and stirred for 16 hours. After adding distilled water (2 mL) to the reaction mixture, the mixture was extracted with EtOAc (3 mL × 2). The organic layer was washed with brine (2 mL) and distilled water (2 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 135 mg (39%) of dark gray solid.

[0939] Step 5: Synthesis of N-(5-(4-(2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide hydrochloride

[0940] After suspending 2-(1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)piperidin-4-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (135 mg, 0.19 mmol) in DCM (1 mL), di... The reaction solution was concentrated under reduced pressure with 0.2 mL of 4N HCl in an alkane and stirred at room temperature for 16 hours. 123 mg (100%) of a dark gray solid was obtained.

[0941] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[0942] N-(5-(4-(2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-yl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide hydrochloride (38 mg, 0.06 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 19 mg, 0.07 mmol), and DIPEA (0.03 mL, 0.17 mmol) were suspended in DMSO (1 mL) and stirred in a microwave at 100 °C for 1 hour. After adding distilled water (1 mL) to the reaction mixture, the mixture was extracted with EtOAc (1 mL × 2). The organic layer was washed with brine (1 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with PTLC to obtain 5.1 mg (10%) of yellow solid.

[0943] Example 155: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyrazin-2-yl)piperidin-4-carboxamide

[0944]

[0945] Step 1: Synthesis of tert-butyl 2-((1-(5-aminopyrazin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid

[0946] 5-Bromopyrazin-2-amine (50 mg, 0.29 mmol), 2-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (intermediate 4-7, 140 mg, 0.44 mmol), CuI (11 mg, 0.058 mmol), 2-acetylcyclohexanone (0.008 mL, 0.058 mmol), and Cs₂CO₃ (189 mg, 0.58 mmol) were suspended in DMF (1.0 mL) and stirred in a microwave reactor at 130 °C for 1 hour. Distilled water (10 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 17 mg (14%) of a brown solid. m / z 417.33 [M+H] + .

[0947] Step 2: Synthesis of 2-((1-(5-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyrazin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0948] 2-((1-(5-aminopyrazin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (45 mg, 0.11 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 39 mg, 0.13 mmol), HATU (49 mg, 0.13 mmol), and DIPEA (0.04 mL, 0.22 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, extraction was performed with EtOAc (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 35 mg (45%) of a brown solid. m / z 697.40 [M+H] + .

[0949] Step 3: Synthesis of N-(5-(4-((2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyrazin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide hydrochloride

[0950] 2-((1-(5-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyrazin-2-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (35 mg, 0.050 mmol) and di 4M HCl (0.06 mL, 0.25 mmol) in alkane was suspended in DCM (0.5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 31 mg (98%) of orange solid. m / z 597.33 [M+H] + .

[0951] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyrazin-2-yl)piperidin-4-carboxamide

[0952] N-(5-(4-((2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)pyrazin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide hydrochloride (30 mg, 0.047 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 19 mg, 0.071 mmol), and DIPEA (0.02 mL, 0.094 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 6 mg (15%) of yellow solid.

[0953] Example 156: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrazin-2-yl)piperidin-4-carboxamide

[0954]

[0955] Example 156 was synthesized in a manner similar to that of Example 155, using 4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-8) instead of 2-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (intermediate 4-7).

[0956] Example 157: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0957]

[0958] Step 1: Synthesis of 5-bromo-N-(4-methoxybenzyl)pyrimidine-2-amine

[0959] 5-Bromo-2-chloropyrimidine (1.00 g, 5.17 mmol) and 4-methoxybenzylamine (0.64 mL, 10.3 mmol) were suspended in ethanol (10.0 mL) and stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and distilled water (20 mL) was added. The resulting solid was filtered and dried to give 772 mg (51%) of a white solid. m / z 294.97 [M+H] + .

[0960] Step 2: Synthesis of tert-butyl 4-((1-(2-((4-methoxybenzyl)amino)pyrimidin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid

[0961] 5-Bromo-N-(4-methoxybenzyl)pyrimidin-2-amine (403 mg, 1.37 mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3, 428 mg, 1.51 mmol), Pd(OAc)2 (62 mg, 0.274 mmol), Xphos (158 mg, 0.274 mmol), and sodium tert-butoxide (197 mg, 2.06 mmol) were suspended in toluene (15.0 mL) and stirred at 110 °C for 48 hours. Distilled water (10 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 156 mg (23%) of a yellow solid. m / z 497.28 [M+H] + .

[0962] Step 3: Synthesis of 5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-amine

[0963] 4-((1-(2-((4-methoxybenzyl)amino)pyrimidin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (156 mg, 0.314 mmol) was suspended in DCM (1.50 mL), followed by the addition of TFA (1.50 mL) and stirring at 40 °C for 16 hours. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 475 mg of a brown liquid.

[0964] Step 4: Synthesis of 4-((1-(2-aminopyrimidin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0965] 475 mg of 5-(piperazin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-amine was suspended in DCM (10.0 mL), and then 102 mg (0.471 mmol) of ditert-butyl dicarbonate and 0.13 mL (0.942 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 1 hour. Distilled water (15 mL) was added to the reaction mixture, and the mixture was extracted with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 99 mg (84% in two steps) of a yellow solid. m / z 377.24 [M+H] + .

[0966] Step 5: Synthesis of 4-((1-(2-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyrimidin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0967] Oxaloyl chloride (0.07 mL, 0.792 mmol) and DMF (0.01 mL) were suspended in DCM, and 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 138 mg, 0.396 mmol) was added and the mixture was stirred at room temperature for 3 hours. 4-((1-(2-aminopyrimidin-5-yl)piperidine-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (99 mg, 0.264 mmol) and TEA (0.09 mL, 0.528 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Distilled water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 135 mg (78%) of a grayish-white solid. m / z657.23[M+H] + .

[0968] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0969] After suspending 135 mg (0.206 mmol) of 4-((1-(2-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyrimidin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester in DCM (1.00 ml), diethyl ether was added. The mixture was stirred for 1 hour at room temperature with 4M HCl (0.26 mL, 1.03 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 115 mg (98%) of white solid. m / z 557.29 [M+H] + .

[0970] Step 7: Synthesis of 4-((4-((1-(2-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyrimidin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester

[0971] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide (65 mg, 0.12 mmol) and tert-butyl 4-formylpiperidin-1-carboxylic acid (30 mg, 0.14 mmol) were suspended in ACN (2.0 mL), followed by the addition of sodium triacetoxyborohydride (74 mg, 0.35 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 48 mg (54%) of a grayish-white solid. m / z 754.34 [M+H] + .

[0972] Step 8: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0973] After suspending 4-((4-((1-(2-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyrimidin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (89 mg, 0.12 mmol) in DCM (1.00 ml), di... The mixture was stirred for 1 hour at room temperature with 4M HCl (0.15 mL, 0.59 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 76 mg (97%) of white solid. m / z 654.44 [M+H] + .

[0974] Step 9: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0975] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide (35 mg, 0.054 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 22 mg, 0.081 mmol), and DIPEA (0.02 mL, 0.11 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to obtain 40 mg (80%) of yellow solid.

[0976] Example 158: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0977]

[0978] Example 158 was synthesized in a manner similar to that of Example 157, using (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester instead of 4-formylpiperidine-1-carboxylic acid tert-butyl ester.

[0979] Example 159: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0980]

[0981] Example 159 was synthesized in a manner similar to that of Example 157, using 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (intermediate 2-3) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0982] Example 160: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-2-yl)piperidin-4-carboxamide

[0983]

[0984] Example 160 was synthesized in a manner similar to that of Example 157, using (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (intermediate 2-3) instead of 4-formylpiperidin-1-carboxylic acid tert-butyl ester and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1).

[0985] Example 161: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[0986]

[0987] Step 1: Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-2-amine (6-aminopyridine-3-yl)methanol (500 mg, 4.02 mmol) was suspended in DCM (20.0 mL) and DMF (5.0 mL). TBDMSCl (850 mg, 5.64 mmol), DIPEA (1.05 mL, 6.03 mmol), and DMAP (9.82 mg, 0.0804 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction mixture, followed by extraction with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 816 mg (85%) of a yellow solid.

[0988] Step 2: Synthesis of N-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide

[0989] 5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-2-amine (300 mg, 1.26 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 450 mg, 1.51 mmol), HATU (574 mg, 1.51 mmol), and DIPEA (0.43 mL, 2.52 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 457 mg (70%) of a white solid.

[0990] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(hydroxymethyl)pyridin-2-yl)piperidine-4-carboxamide

[0991] After suspending N-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide (457 mg, 0.881 mmol) in DCM (3.00 ml), two... The mixture was stirred with 4M HCl (1.10 mL, 4.41 mmol) in alkane for 1 hour at room temperature. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 260 mg (73%) of white solid. m / z 405.23 [M+H] + .

[0992] Step 4: Synthesis of N-(5-(chloromethyl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide

[0993] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(hydroxymethyl)pyridin-2-yl)piperidin-4-carboxamide (260 mg, 0.643 mmol) was suspended in DCM (10.0 mL), followed by the addition of methanesulfonyl chloride (0.10 mL, 1.29 mmol) and DIPEA (0.45 mL, 2.57 mmol), and stirred at room temperature for 1 hour. Distilled water (15 mL) was added to the reaction mixture, followed by extraction with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 266 mg (98%) of white solid was obtained. m / z 423.23 [M+H] + .

[0994] Step 5: Synthesis of 4-((1-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)methyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0995] N-(5-(chloromethyl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide (100 mg, 0.236 mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3, 80 mg, 0.249 mmol), and NaHCO3 (40 mg, 0.472 mmol) were suspended in DMF (2.0 mL) and stirred at 50 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / DCM) to give 100 mg (63%) of white solid. m / z 670.30 [M+H] + .

[0996] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[0997] After suspending 100 mg (0.149 mmol) of 4-((1-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)methyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester in DCM (1.00 ml), diethylcarboxylic acid was added. The mixture was stirred for 1 hour at room temperature with 4M HCl (0.19 mL, 0.747 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 84 mg (99%) of white solid. m / z 570.30 [M+H] + .

[0998] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[0999] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide (40 mg, 0.070 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 31 mg, 0.011 mmol), and DIPEA (0.03 mL, 0.15 mmol) were suspended in DMSO (1.00 mL) and stirred at 90 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 20 mg (34%) of a yellow solid.

[1000] Example 162: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1001]

[1002] Example 162 was synthesized in a manner similar to that of Example 161, using 4-(piperazin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 4-10) instead of 4-(piperidine-4-ylmethyl)piperazin-1-carboxylic acid tert-butyl ester (intermediate 4-3).

[1003] Example 163: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1004]

[1005] Step 1: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-(hydroxymethyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1006] N-(5-(chloromethyl)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide (50 mg, 0.12 mmol), piperidin-4-ylmethanol (16 mg, 0.14 mmol), and NaHCO3 (20 mg, 0.24 mmol) were suspended in DMF (1.0 mL) and stirred at 50 °C for 16 hours. Distilled water (1.0 mL) was added to the reaction solution, followed by extraction with EtOAc (1 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / DCM) to give 37 mg (62%) of a white solid. m / z 502.26 [M+H] + .

[1007] Step 2: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-formylpiperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1008] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(((4-(hydroxymethyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide (37 mg, 0.074 mmol) was suspended in DCM (5.0 mL), followed by the addition of DMP (38 mg, 0.089 mmol) and stirring at room temperature for 2 hours. An aqueous solution of Na₂S₂O₃ (10 mL) was added to the reaction mixture, followed by extraction with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / hexane) to give 30 mg (81%) of a white solid. m / z 500.26 [M+H] + .

[1009] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1010] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(((4-formylpiperidin-1-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide (30 mg, 0.060 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione (24 mg, 0.066 mmol) were suspended in ACN (5.0 mL), followed by the addition of sodium triacetoxyborohydride (38 mg, 0.18 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (10 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 28 mg (55%) of a white solid.

[1011] Example 164: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1012]

[1013] Step 1: Synthesis of tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperidine-1-carboxylic acid

[1014] 5-Bromopyridin-2-amine (190 mg, 1.10 mmol), tert-butyl 4-methylenepiperidin-1-carboxylic acid (255 mg, 1.20 mmol), Pd(dppf)Cl2·DCM (27 mg, 0.033 mmol), 0.5 M 9-BBN in THF (3.87 mL, 1.98 mmol), and K2CO3 (194 mg, 1.43 mmol) were suspended in DMF (2.4 mL) and stirred at room temperature for 2 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 179 mg (56%) of a yellow solid. m / z 292.25 [M+H] + .

[1015] Step 2: Synthesis of tert-butyl 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)methyl)piperidin-1-carboxylic acid

[1016] 4-((6-aminopyridin-3-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (179 mg, 0.614 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 220 mg, 0.737 mmol), HATU (280 mg, 0.737 mmol), and DIPEA (0.21 mL, 1.23 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 271 mg (77%) of white solid. m / z 572.18 [M+H] + .

[1017] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-ylmethyl)pyridin-2-yl)piperidin-4-carboxamide

[1018] After suspending 271 mg (0.398 mmol) of 4-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester in DCM (3.00 ml), diethyl ether was added. The mixture was stirred for 1 hour at room temperature with 4M HCl (0.50 mL, 1.99 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 138 mg (62%) of white solid. m / z 472.25 [M+H] + .

[1019] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)pyridin-2-yl)piperidin-4-carboxamide

[1020] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(piperidin-4-ylmethyl)pyridin-2-yl)piperidin-4-carboxamide (40 mg, 0.096 mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-carboxaldehyde (intermediate 3-1, 39 mg, 0.11 mmol) were suspended in ACN (1.0 mL), followed by the addition of sodium triacetoxyborohydride (61 mg, 0.29 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (1.5 mL) was added to the reaction solution, followed by extraction with EtOAc (2.0 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 45 mg (64%) of a yellow solid.

[1021] Example 165: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[1022]

[1023] Step 1: Synthesis of 2-(6-nitropyridin-3-yl)ethanol-1-ol

[1024] Ethyl 2-(6-nitropyridin-3-yl)ethyl acetate (500 mg, 2.38 mmol) was suspended in anhydrous THF (10 mL), and 1 M BH3·THF (7.14 mL, 7.14 mmol) was slowly added, followed by stirring at 60 °C for 2 hours. Distilled water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (15 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / hexane) to give 300 mg (74%) of a white solid.

[1025] Step 2: Synthesis of 5-(2-bromoethyl)-2-nitropyridine

[1026] 2-(6-nitropyridin-3-yl)ethanol-1-ol (358 mg, 2.13 mmol) was suspended in DCM (20.0 mL), followed by the addition of triphenylphosphine (614 mg, 2.34 mmol) and carbon tetrabromide (918 mg, 2.77 mmol) and stirring at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 490 mg (99%) of a white solid.

[1027] Step 3: Synthesis of tert-butyl 4-((1-(2-(6-nitropyridin-3-yl)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid

[1028] 5-(2-bromoethyl)-2-nitropyridine (100 mg, 0.430 mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-3, 147 mg, 0.520 mmol), and K₂CO₃ (119 mg, 0.600 mmol) were suspended in ACN (1.0 mL) and stirred at 70 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 161 mg (86%) of white solid. m / z 434.11 [M+H] + .

[1029] Step 4: Synthesis of 4-((1-(2-(6-aminopyridin-3-yl)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[1030] 4-((1-(2-(6-nitropyridin-3-yl)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (161 mg, 0.065 mmol) was suspended in a mixture of DCM (15 mL) and MeOH (5 mL), then Pd / C (10 wt% Pd, 32 mg) was added and the mixture was stirred at room temperature for 4 hours under a hydrogen stream. The reaction solution was filtered and concentrated. A black solid (133 mg, 89%) was obtained. m / z 404.27 [M+H] + .

[1031] Step 5: Synthesis of 4-((1-(2-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[1032] 4-((1-(2-(6-aminopyridin-3-yl)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (133 mg, 0.330 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 118 mg, 0.396 mmol), HATU (140 mg, 0.396 mmol), and DIPEA (0.11 mL, 0.660 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 65 mg (29%) of white solid. m / z 684.53 [M+H] + .

[1033] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[1034] After suspending 4-((1-(2-(6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)ethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (65 mg, 0.095 mmol) in DCM (1.00 ml), diethyl ester was added. The mixture was stirred for 1 hour at room temperature with 4M HCl (0.12 mL, 0.48 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 1.5 mL of NaHCO3 aqueous solution using DCM (2.0 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 33 mg (60%) of white solid. m / z 584.38 [M+H] + .

[1035] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[1036] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide (33 mg, 0.057 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (intermediate 2-1, 23 mg, 0.085 mmol), and DIPEA (0.02 mL, 0.11 mmol) were suspended in DMSO (1.0 mL) and stirred at 90 °C for 16 hours. Distilled water (10 mL) was added to the reaction solution, followed by extraction with EtOAc (2.0 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 17 mg (36%) of a yellow solid.

[1037] Example 166: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[1038]

[1039] Example 166 was synthesized in a manner similar to that of Example 165, using 4-(piperazin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 4-10) instead of 4-(piperidine-4-ylmethyl)piperazin-1-carboxylic acid tert-butyl ester (intermediate 4-3).

[1040] Example 167: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[1041]

[1042] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(6-nitropyridin-3-yl)ethyl)piperidin-4-yl)oxy)isoindoline-1,3-dione

[1043] 5-(2-bromoethyl)-2-nitropyridine (50 mg, 0.22 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione (116 mg, 0.32 mmol), and K₂CO₃ (61 mg, 0.44 mmol) were suspended in ACN (1.0 mL) and stirred at 70 °C for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 49 mg (44%) of white solid. m / z 508.10 [M+H] + .

[1044] Step 2: Synthesis of 5-((1-(2-(6-aminopyridin-3-yl)ethyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1045] 2-(2,6-dioxadiazin-3-yl)-5-((1-(2-(6-nitropyridin-3-yl)ethyl)piperidin-4-yl)oxy)isoindoline-1,3-dione (49 mg, 0.097 mmol) was dissolved in a mixture of DCM (10 mL) and MeOH (5 mL), followed by the addition of Pd / C (10 wt% Pd, 10 mg) and stirring at room temperature for 4 hours under a hydrogen stream. The reaction solution was filtered and concentrated. 41 mg (89%) of purple solid was obtained. m / z 478.29 [M+H] + .

[1046] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)ethyl)pyridin-2-yl)piperidin-4-carboxamide

[1047] 5-((1-(2-(6-aminopyridin-3-yl)ethyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (41 mg, 0.086 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxylic acid (intermediate 1-1, 30 mg, 0.10 mmol), HATU (38 mg, 0.10 mmol), and DIPEA (0.03 mL, 0.17 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 10 mg (15%) of white solid.

[1048] Example 168: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1049]

[1050] Step 1: Synthesis of tert-butyl 4-(2-((6-nitropyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid

[1051] 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11, 195 mg, 0.845 mmol) was suspended in THF, and 60% NaH (33 mg, 0.845 mmol) was added at 0 °C and stirred at room temperature for 1 hour. 5-fluoro-2-nitropyridine (100 mg, 0.704 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Distilled water (15 ml) was added to the reaction solution, and extraction was performed with EtOAc (25 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (50% EtOAc / hexane) to give 125 mg (52%) of white solid.

[1052] Step 2: Synthesis of 4-(2-((6-aminopyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[1053] 4-(2-((6-nitropyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (125 mg, 0.355 mmol) was dissolved in a mixture of DCM (10 mL) and MeOH (5 mL), followed by the addition of Pd / C (10 wt% Pd, 25 mg) and stirring at room temperature for 2 hours under a hydrogen stream. The reaction solution was filtered and concentrated to give 111 mg (97%) of a purple solid. m / z 323.42 [M+H] + .

[1054] Step 3: Synthesis of 4-(2-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[1055] 4-(2-((6-aminopyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (111 mg, 0.334 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 112 mg, 0.378 mmol), HATU (143 mg, 0.378 mmol), and DIPEA (0.11 mL, 0.688 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (10% MeOH / DCM) to give 179 mg (86%) of white solid. m / z 603.31 [M+H] + .

[1056] Step 4: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)piperidine-4-carboxamide

[1057] After suspending 179 mg (0.297 mmol) of 4-(2-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester in DCM (1.00 ml), diethyl ester was added. The mixture was stirred for 1 hour at room temperature with 4M HCl (0.37 mL, 1.49 mmol) in alkane. The reaction mixture was concentrated, and then extracted with 15 mL of NaHCO3 aqueous solution using DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 135 mg (91%) of white solid was given. m / z 503.27 [M+H] + .

[1058] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1059] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)piperidine-4-carboxamide (50 mg, 0.099 mmol) and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediate 3-1, 44 mg, 0.12 mmol) were suspended in ACN (10.0 mL), followed by the addition of sodium triacetoxyborohydride (62 mg, 0.30 mmol) and stirring at room temperature for 16 hours. An aqueous solution of NaHCO3 (10 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (10% MeOH / DCM) to give 38 mg (45%) of yellow solid.

[1060] Example 169: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidin-4-carboxamide

[1061]

[1062] Example 169 was synthesized in a manner similar to that of Example 168, using 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11).

[1063] Example 170: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidin-4-carboxamide

[1064]

[1065] Example 170 was synthesized in a manner similar to that of Example 168, using 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediates 3-8) instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediates 4-11) and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediate 3-1).

[1066] Example 171: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidin-4-carboxamide

[1067]

[1068] Example 171 was synthesized in a manner similar to that of Example 168, using 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-carboxaldehyde (intermediate 3-3) instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11) and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediate 3-1).

[1069] Example 172: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-3-methylazacyclobutane-3-yl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)piperidin-4-carboxamide

[1070]

[1071] Example 172 was synthesized in a manner similar to that of Example 168, using 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)-3-methylazacyclobutane-3-carboxaldehyde (intermediate 3-12) instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11) and 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carboxaldehyde (intermediate 3-1).

[1072] Example 173: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)azacyclobutane-3-yl)oxy)pyridin-2-yl)piperidin-4-carboxamide

[1073]

[1074] Example 173 was synthesized in a manner similar to that of Example 168, using 3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11).

[1075] Example 174: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)pyridin-2-yl)piperidin-4-carboxamide

[1076]

[1077] Example 174 was synthesized in a manner similar to that of Example 168, using 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11).

[1078] Example 175: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1079]

[1080] Example 175 was synthesized in a manner similar to that of Example 168, using 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester instead of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 4-11).

[1081] Example 176: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1082]

[1083] Step 1: Synthesis of methyl 2-(4-(2-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)acetate

[1084] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)piperidine-4-carboxamide (70 mg, 0.14 mmol) was suspended in THF (1.0 mL), followed by the addition of methyl bromoacetate (0.013 mL, 0.14 mmol) and TEA (0.06 mL, 0.42 mmol), and stirred at room temperature for 2 hours. Distilled water (1.0 mL) was added to the reaction solution, followed by extraction with EtOAc (2.0 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / hexane) to give 50 mg (62%) of white solid. m / z 575.26 [M+H] + .

[1085] Step 2: Synthesis of 2-(4-(2-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)acetic acid

[1086] Methyl 2-(4-(2-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)acetate (50 mg, 0.087 mmol) was suspended in THF (2.0 mL) and distilled water (2.0 mL), then LiOH·H₂O (14 mg, 0.35 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and extracted with distilled water. The aqueous layer was then extracted with EtOAc (2.0 mL × 2) by adding 1 N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 20 mg (41%) of white solid was obtained. m / z 561.28 [M+H] + .

[1087] Step 3: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1088] 2-(4-(2-((6-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamido)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)acetic acid (20 mg, 0.036 mmol), 3-((3-aminophenyl)amino)piperidin-2,6-dione (intermediate 2-7, 9.5 mg, 0.043 mmol), HATU (16 mg, 0.043 mmol), and DIPEA (0.01 mL, 0.072 mmol) were suspended in DMF (1.0 mL) and stirred at room temperature for 16 hours. Distilled water (10 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 12 mg (44%) of white solid.

[1089] Example 177: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-((4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide

[1090]

[1091] Example 177 was synthesized in a manner similar to that of Example 176, using 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)piperidin-4-carboxamide instead of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide.

[1092] Example 178: 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1093]

[1094] Step 1: Synthesis of 2-((tert-butyldimethylsilyl)oxy)ethanol-1-ol

[1095] Ethane-1,2-diol (500 mg, 8.06 mmol) was suspended in THF, and 60% NaH (388 mg, 9.67 mmol) was added at 0 °C and the mixture was stirred at room temperature for 1 hour. TBDMSCl (1.46 g, 9.67 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 16 hours. Distilled water (15 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (30% EtOAc / hexane) to give 665 mg (46%) of white solid.

[1096] Step 2: Synthesis of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-nitropyridine

[1097] 2-((tert-butyldimethylsilyl)oxy)ethanol-1-ol (629 mg, 3.57 mmol), 5-hydroxy-2-nitropyridine (500 mg, 3.57 mmol), and triphenylphosphine (1.13 g, 4.28 mmol) were suspended in THF (15.0 mL), followed by the addition of DEAD (0.67 mL, 4.28 mmol) and stirring at 40 °C for 4 hours. Distilled water (15 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (30% EtOAc / hexane) to give 650 mg (61%) of a colorless liquid. m / z 299.14 [M+H] + .

[1098] Step 3: Synthesis of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine-2-amine

[1099] 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-nitropyridine (320 mg, 1.07 mmol) was dissolved in MeOH (10 mL), followed by the addition of Pd / C (10 wt% Pd, 64 mg) and stirring at room temperature for 2 hours under a hydrogen stream. The reaction solution was filtered and concentrated to obtain a purple solid (288 mg, 100%). m / z 269.27 [M+H] + .

[1100] Step 4: Synthesis of N-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxamide

[1101] 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine-2-amine (288 mg, 1.07 mmol), 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (intermediate 1-1, 384 mg, 1.29 mmol), HATU (490 mg, 1.29 mmol), and DIPEA (0.37 mL, 2.14 mmol) were suspended in DMF (2.0 mL) and stirred at room temperature for 16 hours. After adding distilled water (15 mL) to the reaction solution, extraction was performed with EtOAc (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 356 mg (61%) of white solid. m / z 549.23 [M+H] + .

[1102] Step 5: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-hydroxyethoxy)pyridin-2-yl)piperidine-4-carboxamide

[1103] After suspending N-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)-1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-carboxamide (156 mg, 0.284 mmol) in DCM (1.00 ml), add di... The reaction mixture was stirred for 1 hour at room temperature with 4M HCl (0.36 mL, 1.42 mmol) in alkane. The reaction solution was concentrated, and 15 mL of NaHCO3 aqueous solution was added, followed by extraction with DCM (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 111 mg (90%) of white solid. m / z 435.27 [M+H] + .

[1104] Step 6: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-oxoethoxy)pyridin-2-yl)piperidine-4-carboxamide

[1105] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-hydroxyethoxy)pyridin-2-yl)piperidin-4-carboxamide (61 mg, 0.14 mmol) was suspended in DCM (5.0 mL), followed by the addition of DMP (72 mg, 0.17 mmol) and stirring at room temperature for 2 hours. An aqueous solution of Na₂S₂O₃ (10 mL) was added to the reaction mixture, followed by extraction with DCM (25 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated by MPLC (50% EtOAc / DCM) to give 40 mg (66%) of white solid. m / z 433.21 [M+H] + .

[1106] Step 7: Synthesis of 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)piperidin-1-yl)ethoxy)pyridin-2-yl)piperidin-4-carboxamide

[1107] 1-(4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(2-oxoethoxy)pyridin-2-yl)piperidin-4-carboxamide (40 mg, 0.093 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione (33 mg, 0.093 mmol) were suspended in ACN (5.0 mL), followed by the addition of sodium triacetoxyborohydride (59 mg, 0.28 mmol) and stirring at room temperature for 30 minutes. An aqueous solution of NaHCO3 (10 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated by MPLC (10% MeOH / DCM) to give 10 mg (14%) of a white solid.

[1108] The following embodiments were synthesized using a method similar to that of the previous method.

[1109] [Table 4]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117] The NMR and / or LC / MS results of the compounds synthesized above are summarized in Table 5 below.

[1118] [Table 5]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142] Experimental Example 1: Androgen Receptor (AR) Protein Degradation Assay

[1143] After treating LNCaP cells with the synthesized compound from the examples, the amount of AR protein present in the cells was measured. The amount of AR protein was determined using Western blotting. The experimental protocol using LNCaP cells is as follows:

[1144] [Cultivation] LNCaP cells were resuspended in RPMI 1640 MEDIUM (Hyclone, SH30027.01), 10% FBS (Hyclone, SV30207.02), and 1% penicillin-streptomycin (Welgene, LS202-02) medium to a concentration of 3 × 10⁻⁶ cells / mL. 5 / mL. Then, inoculate each 1mL well into a 12-well plate. After that, incubate them for 3 days.

[1145] [Compound Treatment] Add 10 μl of the final compound treatment concentrations of 0.1 μM, 1 μM, 10 μM and 100 μM, and 100 times the stock solution of 0.001 μM, 0.01 μM, 0.1 μM and 1 μM to 1 ml of culture medium in each well, and harvest the cells after 20 hours.

[1146] [Cell Lysis] Cell clumps were resuspended in 1% SDS lysis buffer (50 mM Tris, 1 mM EDTA, 1% SDS, pH 8.0, 0.5 mM PMSF, 1x protease / phosphatase inhibitor mixture (Cell Signaling Technology, 5872s)) and sonicated (70% AMP, 5 cycles (30 sec on / 59 sec off)). Cell lysates were obtained after centrifugation at 15000g for 20 min at 4°C.

[1147] [Protein Quantification] BCA protein was determined using a 96-well microplate (SMART). TMBCA Protein Assay Kit (iNtRON Biotechnology, 21071). After adding 5 μl of cell lysate and 5 μl of 1% SDS lysis buffer to each well of a 96-well plate, add an additional 200 μl of BCA reagent (Reagent A: Reagent B = 50:1). Incubate at 37°C for 30 min, then cool to room temperature for 10 min. Measure the absorbance at 562 nm. Unknown protein concentrations were measured using a BSA standard curve (0, 0.125 mg / ml, 0.25 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml). The assay was performed by adding cell lysate, 1% SDS lysis buffer, and 4X Bolt... TM LDS sample buffer (Invitrogen, B0008) and 10X Bolt TM The protein blot sample was prepared by mixing the sample reducing agent (Invitrogen, B0009) and boiling the mixture at 70°C for 10 minutes.

[1148] [Electrophoresis] 8 μg protein sample loaded into a 17-well Bolt microsphere. TM After filling each well with 4 to 12% Bis-Tris, 1.0 mm mini protein gel (Invitrogen, NW04127BOX), use Bolt. TM Electrophoresis was performed at 200V (constant V) for 50 minutes using MES SDS electrophoresis buffer (Invitrogen, B0002).

[1149] [Transfer] Using electrophoresis gels and Turbo TM The transfer initiation system (Bio-RAD, #17001918, Mini Nitrocellulose) was used for 15 minutes at 1.3A (constant A) and 25V (limiting V). To confirm protein transfer, staining was performed for 1 minute with 15 ml of Ponceau S solution (Sigma, P7170-1L), followed by washing to confirm the extent of transfer.

[1150] [Blocking] Block the membranes used for AR detection for 45 minutes 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). Block the membranes used for GAPDH and β-actin detection for 45 minutes with Odyssey blocking buffer: 0.1% TBST = 1:1 (Odyssey blocking buffer: Li-COR Biosciences, 927-50000).

[1151] [Antibody and Detection] The AR primary antibody (androgen receptor: CST, 5153s) was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:1000 and incubated at room temperature for 3 hours. The β-actin primary antibody (GeneTex, 629630) was mixed with 5% BSA / 0.2% TBST at a ratio of 1:2000 and incubated at room temperature for 3 hours. The GAPDH primary antibody (GeneTex, 100118) was mixed with 5% BSA / 0.2% TBST at a ratio of 1:2000 and incubated at room temperature for 3 hours. After 3 hours, the antibody was washed three times with TBST (0.2% Tween 20) for 5 minutes each time. The secondary antibody containing anti-rabbit IgG, HRP-linked antibody (CST, 7074s), and AR antibody was mixed with 5% skim milk / 0.2% TBST at a ratio of 1:5000 and incubated at room temperature for 45 minutes. 800CW goat anti-rabbit IgG secondary antibody and Secondary antibodies containing 680RD goat anti-mouse IgG (LI-COR, 926-32211, 926-68070), anti-β-actin antibody, and GAPDH antibody were mixed with 5% BSA / 0.2% TBST at a ratio of 1:10000 and attached at room temperature for 45 minutes. After 45 minutes, the mixture was washed five times with TBST (0.2% Tween 20) for 5 minutes each time. SuperSignal was then used... TM After the West Pico Plus chemiluminescent substrate (Thermo Scientific, 34580) reacts with the membrane, it is used... The Fc imaging system (LI-COR, 2800) was used for testing.

[1152] These evaluation results are summarized in Table 6 below.

[1153] [Table 6]

[1154]

[1155]

[1156]

[1157]

[1158] As shown in Table 6, the compounds of the present invention exhibit good activity in degrading androgen receptors.

[1159] In particular, the compounds of Examples 6, 11, 14, 15, 18, 19, 20, 34, 35, 38, 43, 44, 49, 66, 70, 75, 86, 121, 133, 140, 143, 146, 147, 164, 169, 170, 173, 174, 175, 181, 182, 185, 187 and 197 are preferred in several aspects, such as androgen receptor degradation activity.

Claims

1. A compound of formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the chemical formula 1, R1 is H, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy R2 is H, C 1-4 Alkyl, halogen or halogenated C 1-4 alkyl, X1, X3, X4, and X5 are each independently CH or N. X2 is CR3, where, R3 is H, C 1-6 Alkyl, halogen, or -OH n is 0 or 1, m is 0 or 1. L is the following chemical formula 2: [Chemical Formula 2] In the chemical formula 2, A1, A2, and A3 are each independently directly connected to -O-, -N(R4)-, -C(O)-, -CC-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, or -C(O)CH2O-, where R4 is H, C 1-6 Alkyl or halogenated C 1-6 alkyl, B1, B2, and B3 are each independently directly connected, or any of the following substituents: Where R4' represents H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, halogen or -OH, q1 to q6 are each an independent integer from 0 to 4. E is one of the following chemical formulas: 3 or 4: [Chemical Formula 3] [Chemical Formula 4] In chemical formulas 3 and 4, X6, X7, X8, and X9 are each independently CH or N. Y is -C(R6)2-, -C(O)-, or -N=N-. Z is directly connected, -C(R6)2-, -N(R6)-, or -C(O)NH-. R5 and R5' are independently H and C. 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy R6 is H, C 1-4 Alkyl or halogenated C 1-4 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein in chemical formula 1, R1 is a halogen or halogenated C. 1-6 alkyl, R2 is H. X1 is N or CH. X3, X4, and X5 are any of the following combinations: N, CH, and CH; N, N, and CH; or CH, N, and N. X2 is CR3, where R3 is H, F, or CH3. n is 1, m is 0, L is the following chemical formula 2: [Chemical Formula 2] In the chemical formula 2, A2 is a direct connection, and A1 and A3 are each independently a direct connection or -O-. B1, B2, and B3 are each independently directly linked, or any of the following substituents: in, R4' is independently either H or C. 1-4 alkyl, q1 to q6 are each an independent integer between 0 and 2. E is the following chemical formula 3: [Chemical Formula 3] In the chemical formula 3, X6 is CH or N. Y is either -C(O)- or -CH2-. R5 is H or halogen.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following:

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following:

5. A composition comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for degrading or inhibiting androgen receptors, comprising, as an active ingredient, any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is used to treat or prevent cancer, Kennedy's disease, acne, hair loss, skin trauma, or hirsutism.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is used for the treatment or prevention of prostate cancer.

9. Use of a therapeutically effective amount of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of androgen receptor-related diseases, wherein the treatment or prevention comprises administration of the medicament to a subject in need of it.

10. The use as claimed in claim 9, wherein the androgen receptor-related disease is cancer, Kennedy's disease, acne, hair loss, skin trauma, or hirsutism.

11. The use as described in claim 10, wherein the androgen receptor-related disease is prostate cancer.

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