2,4-Dianilinopyrimidine-based Aurora A kinase selective degradation-inducing compound

Abstract

A novel 2,4-dianilinopyrimidine-based Aurora A kinase (AURKA) degradation molecule is disclosed. This AURKA degradation molecule is a PROTAC (proteolysis targeting chimeras) that recruits the AURKA protein via a linker using an optimal CRBN E3 ubiquitin ligase. This compound can induce selective AURKA degradation and may be useful in the treatment of cancer.

Description

[Technical Field]

[0001] This disclosure relates to a novel aurora A kinase selective degradation-inducing compound in which the cerebron binder has been modified, a method for producing the same, and its applications. [Background technology]

[0002] Aurora kinases belong to the serine / threonine kinase family, which are central to cell division. Although the two main aurora kinases, Aurora-A and Aurora-B, are closely related in terms of kinase domain sequence, they have very different functions during mitosis. Among small molecule-based aurora kinase inhibitors, selective inhibitors of aurora A kinase (AURKA) have been extensively studied as potential anti-cancer treatments (Reference: [Borisa, Ankit C., and Hardik G. Bhatt. "A comprehensive review on aurora kinase: Small molecule inhibitors and clinical trial studies." European journal of medicinal chemistry 140(2017):1-19.]).

[0003] While AURKA's catalytic activity is crucial to its mitotic function, recent reports suggest additional non-catalytic functions that are difficult to target with conventional small molecules. As an alternative approach, the removal of AURKA mediated by PROTAC (Proteolysis targeting chimeras) demonstrates that AURKA plays an important non-catalytic role in DNA replication (Reference: Adhikari, Bikash, et al. "PROTAC-mediated degradation reveals a non-catalytic function of aurora-A kinase." Nature chemical biology 16.11(2020):1179-1188.]).

[0004] 2,4-Dianilinopyrimidine derivatives have been reported as excellent selective AURKA inhibitors (Reference [Aliagas-Martin, Ignacio, et al. "A class of 2,4-dianilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B." Journal of medicinal chemistry 52.10(2009):3300-3307.]). The applicant previously reported PROTAC-mediated selective degradation of AURKA by synthesizing novel PROTAC compounds in which 2,4-Dianilinopyrimidine derivatives were linked to von Hippel-Lindau (VHL) or cereblon (CRBN) binders (e.g., thalidomide) via a linker.

[0005] In recent PROTAC technologies, modulating the chemical composition of CRBN binders is a core step in the optimization process of proteolytic molecules, and even small structural changes can significantly impact the overall PROTAC profile, including not only the depth of on-target degradation and off-target effects, but also other drug-like properties (Reference [Norris, Stephen, et al. "Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation." Journal of Medicinal Chemistry (2023)]). In this context, using a low-molecular-weight glutarimide-based CRBN binder, we have successfully synthesized a novel, optimized AURKA degradation molecule that effectively exhibits AURKA-selective degradation and / or cytotoxicity against cancer cells, as well as improved drug properties. [Overview of the project] [Problems that the invention aims to solve]

[0006] An object of the present invention is to provide a novel selective AURKA degrading molecule, a method for producing the same, and uses thereof. [Means for Solving the Problems]

[0007] To solve the above problems, the present disclosure provides not only a novel compound defined by Chemical Formula I, but also a method for producing the same and uses thereof.

[0008] · Design of a novel Aurora kinase A degrading molecule In one general aspect, the present disclosure provides a novel compound represented by the following Chemical Formula I. [Chemical Formula I] [Chemical Structure] In the above formula, PTM is an Aurora kinase A (AURKA) binding moiety represented by the following Chemical Formula II, [Chemical Formula II] [Chemical Structure] In the above formula, R1 is halo; R2 is -NH- or -O-; R 3A and R 3B are each independently -CH- or -N-; R 3C is H, halo or OC 1-3 alkyl; [Chemical Structure] R4 is -CO-, -CONH-, -CON(CH3)- or -NHCO-; [Chemical Structure] is a 5- to 6-membered cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1 to 3 halos; [Chemical formula] is phenyl or 5- to 6-membered heteroaryl optionally substituted with halo or C 1-3 alkyl; [Chemical formula] is a covalent bond linked to the Linker; ULM is a CRBN E3 ubiquitin ligase binding moiety represented by the following chemical formula III-1, III-2A or III-2B, [Chemical formula III-1] [Chemical formula] [Chemical formula III-2A] [Chemical formula] [Chemical formula III-2B] [Chemical formula] In the above formula, U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO- or -CONH-; U2 is CH or N; [Chemical formula] is phenyl or 6-membered heteroaryl optionally substituted with 1 to 3 halos, C 1-3 alkyl or OC 1-3 alkyl; [Chemical formula] is a covalent bond linked to the Linker; The Linker is a linking group represented by the following chemical formula IV, [Chemical formula IV]

Chemical formula

Chemical formula

[0009] The novel compound represented by chemical formula I is a bispecific molecule called PROTAC (Proteolysis targeting chimeras), which contains a target protein binder and an E3 ubiquitin ligase binder linked by a linker. By recruiting CRBN E3 ubiquitin ligase to the target protein AURKA, PROTAC can promote the ubiquitination and eventual proteasomal degradation of the target protein (Figure 1).

[0010] ●(1) Aurora kinase A-binding moiety (PTM) In chemical formula I, PTM, represented by chemical formula II, is a 2,4-dianilinopyrimidine-based moiety with selective aurora kinase A (AURKA) binding affinity.

[0011] Aurora kinase A (AURKA) is a serine / threonine protein kinase encoded by the AURKA gene in humans (see, e.g., reference [NCBI Reference Sequence: NP_001310234.1]). AURKA is responsible for critical processes in mitosis and meiosis, where proper function is essential for healthy cell division. AURKA is activated through one or more phosphorylations, and its function peaks during the transition from G2 to M phase in the cell cycle. AURKA is expressed at much higher levels in cancer tissue than in normal control tissue in various tumor types. AURKA activity has been shown to play a significant role in a wide range of cancers.

[0012] In one implementation, chemical formula II is the following chemical formula II-1: [Chemical formula II-1] [ka] In the above formula, R1 is a halo; R2 is either -NH- or -O-; R 3A and R 3B These are independently -CH- or -N-; R 3C is H, halo, or -OC 1-3 It is alkyl; R4 is -CONH-, -CON(CH3)-, or -NHCO-; R5 is either CH or N; [ka] is a cyclohexyl or phenyl molecule optionally substituted with one to three halos; [ka] This is a covalent bond connected to the Linker.

[0013] In one implementation, chemical formula II-1 is one of the following chemical formulas: II-1A, II-1B, II-1C, II-1D, or II-1E: [Chemical formula II-1A] [ka] In the above equation, R1 is a halo; R 3c R6 is H, halo, or OCH3; R6 is H or halo; R7 is H or CH3. [Chemical formula II-1B] [ka] In the above equation, R1 is a halo; R 3A and R 3B Each of these is independently CH or N; R6 is H or halo.

[0014] In one implementation, R in chemical formula II-1B 3A and R 3B One of them is N; the other is CH. [Chemical formula II-1C] [ka] In the above formula, R1 is a halo; R6 is H or a halo; and R7 is H or CH3. [Chemical formula II-1D] [ka] In the above equation, R1 is a halo; R 3C is H or halo; R6 is H or halo. [Chemical formula II-1E] [ka] In the above formula, R1 is a halo; R2 is -NH- or -O-; R5 is CH or N; and R6 is H or a halo.

[0015] In one embodiment, R6 in chemical formulas II-1A, II-1B, II-1C, II-1D, or II-1E is linked to its parent ring in an ortho, meta-, or para-orientation, preferably in an ortho-orientation. In one implementation, chemical formula II is the following chemical formula II-2: [Chemical formula II-2] [ka] In the above formula, R1 is a halo; [ka] is a halo or C 1-3It is a phenyl or pyrazolyl compound optionally substituted with an alkyl group.

[0016] In one implementation, chemical formula II-2 is either chemical formula II-2A or II-2B below: [Chemical formula II-2A] [ka] [Chemical formula II-2B] [ka] In the above formula, R8 is H, halo, or C 1-3 It is alkyl.

[0017] ●(2) Cerebron E3 Ubiquitin Ligase-Conjugated Moiety (ULM) In chemical formula I, ULM, represented by chemical formulas III-1, III-2A, or III-2B, is an optimized cerebron binder in which a glutarimide molecule is conjugated directly or via a short linking group to an aryl or heteroallyl ring. Cereblon (CRBN) is a subunit of the E3 ubiquitin ligase protein encoded by the CRBN gene in humans. CRBN forms an E3 ubiquitin ligase complex containing DDB1 (damaged DNA binding protein 1), CUL4A (Cullin-4A), and ROC1 (regulator of cullins 1) to induce ubiquitination of substrate proteins.

[0018] In one implementation, chemical formula III-1 is the following chemical formula III-1A: [Chemical formula III-1A] [ka] In the above formula, U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-; U2 is either CH or N; U 3A and U 3B Each is independently either CH or N; U 4A and U 4B These are H, Halo, and C, respectively, and are independent of each other. 1-3 Alkyl or OC 1-3 It is alkyl.

[0019] In one implementation, chemical formula III-1A is the following chemical formula: [ka] In the above formula, U 4A and U 4B These are H, Halo, and C, respectively, and are independent of each other. 1-3 Alkyl or OC 1-3 It is alkyl.

[0020] In one implementation, chemical formula III-1A is the following chemical formula: [ka] In the above formula, U2, U 3A and U 3B At least one of them is N; the rest are CH.

[0021] In one implementation, chemical formula III-1A is the following chemical formula: [ka] In the above formula, U 4A and U 4B These are H, Halo, and C, respectively, independently. 1-3 Alkyl or OC 1-3 It is alkyl; U5 is either H or CH3.

[0022] In one implementation, chemical formula III-1A is the following chemical formula: [ka] In the above formula, U 3A is CH or N; U 4B H, Halo, C 1-3 Alkyl or OC 1-3 It is alkyl.

[0023] In one implementation, chemical formula III-1 is the following chemical formula III-1B: [Chemical formula III-1B] [ka] In the above formula, U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-; U 4A H, Halo, C 1-3 Alkyl or OC 1-3 It is alkyl.

[0024] In one implementation, chemical formula III-2A is equivalent to the following chemical formula III-2C: [Chemical formula III-2C] [ka] In the above formula, U5 is either H or a halo.

[0025] In one implementation, chemical formula III-2B is equivalent to the following chemical formula III-2D: [Chemical formula III-2D] [ka] In the above formula, U5 is either H or a halo.

[0026] ●(3) Linker In chemical formula I, the Linker represented by chemical formula IV is a linking group that links ULM and PTM, thereby causing the AURKA and CRBN E3 ubiquitin ligases recruited by PTM and ULM, respectively, to be placed in close proximity.

[0027] In one embodiment, the Linker represented by chemical formula IV is a linking group that links ULM and PTM via 4 to 20 atoms, preferably 8 to 14 atoms, over the shortest distance.

[0028] In chemical formula IV, L W1 and L W2 Each of these may independently be chemical formula IV-1: [Chemical formula IV-1] [ka] In the above formula, Z1 and Z2 are independently CH or N; Z X is H, CH3, or OH; p1 is 0, 1, or 2; p2 is 1, 2, or 3.

[0029] In one embodiment, chemical formula IV-1 is one of the following groups LW-1 to LW-12: [Table 1] [Table 1] In chemical formula IV, L W1 and L W2 Each of these may independently be chemical formula IV-2: [Chemical formula IV-2] [ka] In the above formula, Z3 and Z4 are independently CH or N; q1 and q3 are independently 0, 1, or 2; q2 and q4 are independently either 1 or 2.

[0030] In one embodiment, chemical formula IV-2 is one of the following groups LW-13 to LW-19. [Table 2] [Table 2] In chemical formula IV, L W1 and L W2 Each of these may independently be chemical formula IV-3. [Chemical formula IV-3] [ka] In the above formula, Z5 and Z6 are independently CH or N; r1 through r4 are each independently either 0 or 1.

[0031] In one embodiment, chemical formula IV-2 is one of the following groups LW-20 to LW-23: [Table 3] [Table 3] In chemical formula IV, L W1 and L W2 Each of these may be one of the following elements, independently: [ka] , [ka] or [ka] .

[0032] In one implementation, chemical formula IV is selected from Linker-1 to Linker-68 in Table 4, where [ka] and [ka] These are covalent bonds that connect to ULM and PTM, respectively:

[0033] [Table 4] [Table 4-1]

[0034] [Table 4-2]

[0035] [Table 4-3]

[0036] [Table 4-4]

[0037] In one embodiment of this disclosure, the compound represented by chemical formula I is selected from the group consisting of compounds 1 to 123. In one embodiment, the compounds of the Disclosure may be in the form of a salt, preferably a pharmaceutically acceptable salt. In the Disclosure, a pharmaceutically acceptable salt means any organic or inorganic acid addition salt at a concentration that is relatively non-toxic and harmless, and that acts effectively on the patient, such that the side effects induced by the salt do not impair the beneficial efficacy of the novel compounds of the Disclosure.

[0038] In one embodiment, the compounds of the present disclosure may be in the form of racemates, enantiomers, rotational isomers, tautomers, N-oxides, or any stereoisomer, as specifically described, unless otherwise excluded in the context. In one embodiment, the compound of the present disclosure may be in the form of a hydrate or solvate.

[0039] In one embodiment, the compounds of the present disclosure may be in the form of a chimeric molecule conjugated to a functional macromolecule via a chemical linker. In a particular embodiment, the macromolecule is a biomolecule including nucleic acids, aptamers, carbohydrates, peptides or their slices, antibodies or their slices. In this disclosure, "optionally substituted" means that a particular chemical group is either left unsubstituted or one or more hydrogen atoms within the group are replaced by a substituted atom.

[0040] In this disclosure, the term "substituted compound" means a molecule of the parent molecule in which one or more hydrogen atoms(s) in the parent molecule are replaced by one or more covalent bonds(s). In this disclosure, the term "alkyl" means a substituent of an alkane, which is a saturated, acyclic hydrocarbon that may be linear or branched. For example, "C n "Alkyl" refers to an alkyl group having n carbon atoms.

[0041] In this disclosure, the term "cycloalkyl" means a substituted product of a cycloalkane, which is a saturated cyclic hydrocarbon. In this disclosure, the term "heterocyclyl" refers to a substituted heterocyclic compound comprising one or more cyclic structures containing atoms of two or more different elements as members of its ring. For example, heterocyclyls may contain carbon and nitrogen as members of their ring, such as azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl.

[0042] In this disclosure, the term "aryl" refers to a substituted compound of a cyclic compound containing one or more aromatic rings. In this disclosure, the term "heteroaryl" refers to a substituted compound of a cyclic compound containing one or more aromatic rings, each containing atoms of two or more different elements as members of its ring. For example, heteroaryls may contain carbon and nitrogen as members of their ring, such as pyrrole, pyrazole, imidazole, triazole, triazine, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, indidine, azaindidine, purine, indazole, imidazopyridine, imidazotriazine, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyridopyrimidine, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolidine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, and pyrazinopyridazine.

[0043] In this disclosure, the term "n members" means that the number of elements excluding hydrogen in the substitution body is n. In this disclosure, the terms "cycloalkyl," "aryl," "heterocyclyl," and "heteroaryl" may be monocyclic, fusion cyclic (e.g., spiro or bicyclic), or polycyclic. For example, the cycloalkyl, aryl, heterocyclyl, and heteroaryl may be azaspiro, diazaspiro, bicyclo, azabicyclo, diazabicyclo, diazabicyclo (crosslinked), or tetrahydroisoquinoline.

[0044] • Synthesis of novel AURKA degradation molecules In one embodiment, the novel compounds of the present disclosure may be produced, for example, by synthetic methods known in the field of organic chemistry or modification techniques obvious to the ordinary art, according to the following reaction formulas 1 to 3. [Reaction Equation 1] [ka] [Reaction Equation 2] [ka] [Reaction Equation 3] [ka]

[0045] In the reaction equation, PTM, Linker, and ULM are as defined above. RG 1 RG 2 RG 2a RG 2b RG 3 RG 3a RG 3b and RG 4This is a moiety in the field of organic synthesis that contains suitable reactive groups that can be linked with PROTAC intermediates through the formation of covalent bonds. The formation of covalent bonds can be achieved by synthetic reactions such as amide formation, ester formation, carbamate formation, urea formation, ether formation, amine formation, and various carbon-carbon single and double bond formations, click chemistry, etc., depending on the specific reactive groups, but is not limited to these. Each step in the above reaction equation may include one or more synthesis steps. Separation and purification of the products can be achieved by standard procedures that are well known to the average technician in the field of organic chemistry.

[0046] • Applications of novel AURKA degradation molecules In one embodiment, the novel compound of this disclosure is an AURKA degradation molecule that induces AURKA protein degradation in cells. As supported by the experimental examples of this disclosure, the PROTACs of the present invention can induce proteasomal degradation of AURKA in cells by recruiting CRBN ubiquitin ligase to AURKA. For example, this disclosure shows that compounds 1 to 123 have AURKA degradation activity, as described by luciferase assays in the HeLa LgBit cell system, and induce inhibitory activity against cancer cell survival, as described by cell survival assays against the small cell lung cancer (SCLC) cell line NCI-H446.

[0047] The inventors have demonstrated that a novelly designed PROTAC containing a CRBN E3 ubiquitin ligase-conjugated moiety represented by chemical formula III-1, III-2A, or III-2B exhibits a sufficient level of AURKA degradation efficacy across its entire range. In the field of PROTAC, this is a surprising result that was not expected from earlier PROTACs containing thalidomide-based CRBN binders.

[0048] In one embodiment, the PROTAC of the present invention has better therapeutic efficacy than low-molecular-weight AURKA inhibitors derived from PROTACs by removing rather than inhibiting the target protein. Thus, the PROTAC of the present invention can be used to treat AURKA-related disorders or conditions in which abnormal expression of AURKA proteins is involved in the onset and / or progression of the disease.

[0049] In this disclosure, AURKA-related disorder or condition means any disease or condition that can be treated, delayed, suppressed or prevented by inducing degradation or inhibiting the activity of AURKA. AURKA-related disorder or condition means, but is not limited to, cancer, benign tumors or neurological disorders.

[0050] In one embodiment, the PROTAC of the present invention can have anticancer activity against cancer cells expressing AURKA by removing AURKA, a core oncogenesis regulator of the cell cycle. Cancer includes all cancers that can exert preventive or therapeutic efficacy by inhibiting AURKA activity, and may be solid tumors or hematological cancers. For example, cancer includes squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, skin cancer, melanoma of the skin or eye, rectal cancer, anal muscle cancer, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, pancreatic cancer, glioblastoma, neuroblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer Cancer may be one or more selected from the group consisting of bladder cancer, liver tumors, breast cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, bone cancer, large cell lymphoma, adrenocorticotropin-secreting adenoma, T-cell lymphoma / leukemia, neuroendocrine carcinoma, neuroendocrine tumor, and cholangiocarcinoma, etc., but is not limited to these. Cancer includes not only primary cancer but also metastatic cancer.

[0051] Benign tumors include all benign tumors that can be prevented or treated by inhibiting AURKA activity, such as precancerous benign tumors, and may be solid tumors or hematological malignancies. For example, tumors may be one or more selected from the group consisting of Barrett's esophagus, colorectal adenomas and polyps, mammary fibroadenomas and cysts, monoclonal gammopathy of undetermined significance (MGUS), and monoclonal lymphocytosis, but are not limited to these.

[0052] Neurological diseases include all neurological diseases for which prophylactic or therapeutic effects can be exerted by suppressing AURKA activity, and may include, but are not limited to, one or more selected from the group consisting of central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, amyotrophic lateral sclerosis, stroke, post-brain or spinal cord injury nerve injury and axonal degeneration-related diseases.

[0053] To improve drug activity, any strategy known in the field of proteolysis, including photochemically controllable proteolysis (PHOTAC), hypoxia-activated proteolysis (PHOTAC), folate-caged proteolysis (FORTAC), antibody-PROTAC conjugates (Ab-PROTAC), aptamer-PROTAC conjugates (APC), and BCL-XL proteolysis (BCL-XL). (Reference: Zhao, Chunlong, and Frank J. Dekker. "Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras." ACS Pharmacology & Translational Science 5.9(2022):710-723.)

[0054] In one embodiment, the PROTAC of the present invention can be used as a payload in an antibody-drug conjugate (ADC), such as an antibody-PROTAC conjugate (Ab-PROTAC). The ADC can specifically deliver a cytotoxic payload to cancer cells in a way that achieves maximum efficacy against cancer cells while minimizing undesirable effects on non-cancer cells. Therefore, Ab-PROTACs utilizing the PROTAC of the present invention can be a strategy to improve the tissue and cell type selectivity of the PROTAC.

[0055] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a PROTAC compound of the present invention, wherein the compound is conjugated to an antibody or an antigen-binding section via a linker.

[0056] In one embodiment, the present disclosure provides an antibody-drug conjugate comprising an antibody or an antigen-conjugated section thereof and a PROTAC compound of the present invention, wherein the compound is conjugated to the antibody or the antigen-conjugated section via a linker.

[0057] In a particular embodiment, the linker chemically links the antibody or its antigen-binding section with the PROTAC compound of the present invention, where the functional group within the compound is modified to form a covalent bond with the linker moiety. In a particular embodiment, the functional group is an amine group within the PROTAC linker or E3L binder moiety of the compound.

[0058] In a particular embodiment, the antibody or its antigen-binding section is cancer cell-specific and contains one or more molecules of a compound of chemical formula I. In a particular embodiment, the linker is either cleavable or incleavable.

[0059] This disclosure also provides pharmaceutical compositions comprising the PROTAC of the present invention and one or more pharmaceutically acceptable carriers. In one embodiment, the pharmaceutical composition comprises an effective amount of one or more PROTAC compounds according to the present invention and optionally an effective amount of one or more other active ingredients(etc.) for combination therapy. In one embodiment, the pharmaceutical composition comprises one or more pharmaceutically acceptable amounts of additives or excipients.

[0060] Another mode of implementation of this disclosure is a method of degrading AURKA by treating a sample in vitro with the PROTAC of the present invention. The sample may, but is not limited to, cells, cell cultures, body fluids, or tissues of mammals, including humans. [Effects of the Invention]

[0061] The novel compounds described herein can induce intracellular AURKA degradation over a wide range. Therefore, they can be effectively utilized for the treatment of AURKA-related disorders or conditions. [Brief explanation of the drawing]

[0062] [Figure 1] This demonstrates the principle of target protein degradation induced by PROTAC, where E3 ubiquitin ligase recruitment as the target protein induces ubiquitination and proteasomal degradation of the target protein AURKA. [Modes for carrying out the invention]

[0063] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as that generally understood by a person of ordinary skill in the art to which this disclosure pertains. The terms used in this description are solely for the purpose of describing specific embodiments and are not intended to limit this disclosure.

[0064] This disclosure provides synthesis methods and biological activity results for compounds 1 to 123. [Table 5] Table 5-1

[0065] Table 5-2

[0066] Table 5-3

[0067] Table 5-4

[0068] Table 5-5

[0069] Table 5-6

[0070] Table 5-7

[0071] Table 5-8

[0072] Table 5-9

[0073] Table 5-10

[0074] Table 5-11

[0075] Table 5-12

[0076] Table 5-13

[0077] Table 5-14

[0078] Table 5-15

[0079] Table 5-16

[0080] Table 5-17

[0081] Table 5-18

[0082] Table 5-19

[0083] Table 5-20

[0084] Table 5-21

[0085] [Table 5-22]

[0086] The compounds of the present invention were purified and their structures analyzed by the following method. ·device LCMS: Shimadzu LCMS-2020 HPLC: Agilent 1260 II LC, Agilent 1200 / G6410B NMR: BRUKER AVANCE / 400 MHz

[0087] ·LCMS analysis LCMS data were recorded using a Shimadzu LCMS-2020 with an ESI (Electron Spray Ionization) system. 0.0375% TFA in water (solvent A) and 0.01875% TFA in CAN (solvent B) were used as mobile phases. Kinetex EVO C18 (2.1 × 30 mm, 5 μm) or HALO C18 (3.0 × 30 mm, 2.7 μm) columns were used.

[0088] ·HPLC analysis For HPLC analysis, an Agilent 1260 II LC or Agilent 1200 / G6410B was used. 0.0375% TFA in water (solvent A) and 0.01875% TFA in CAN (solvent B) were used as mobile phases. Zobrax Eclipse Plus C18 (4.6 × 150 mm, 3.5 μm) or YMC ODS A (4.6 × 150 mm, 3 μm) columns were used.

[0089] • NMR Analysis 1 The 1H NMR spectrum was recorded using a Bruker AVANCE III 400 MHz / 5mm Probe (BBO).

[0090] ●Example 1. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (Compound 1) [ka]

[0091] Step 1. Synthesis of ethyl 1-(4-bromophenyl)piperidine-4-carboxylate (2) To a solution of 1-bromo-4-iodobenzene (9.00 g, 31.80 mmol) and ethylpiperidine-4-carboxylate (5 g, 31.80 mmol, 4.90 mL) in toluene (50 mL), Pd2(dba)3 (582.48 mg, 636.00 μmol), xanthophos (552.08 mg, 954.00 μmol), and cesium carbonate (31.09 g, 95.40 mmol) were added under N2 conditions, and the mixture was stirred at 100°C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (7.7 g, 23.92 mmol, yield 75.23%, purity 97%) as a yellow oil. MS(M+H) + =313.0.

[0092] Step 2. Synthesis of ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylate (3) In 30 mL of dioxane, BPD (3.66 g, 14.41 mmol), KOAc (1.89 g, 19.22 mmol), and Pd(dppf)Cl2 (351.56 mg, 480.46 μmol) were added under N2 to a solution of ethyl 1-(4-bromophenyl)piperidine-4-carboxylate (3 g, 9.61 mmol). The resulting mixture was stirred at 100 °C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage, 10 g SepaFlash® silica flash column, eluent 2-10% ethyl acetate / petroleum ether gradient @ 50 mL / min) to obtain the title compound (2.9 g, 5.49 mmol, yield 57.12%, purity 68%) as a yellow solid. MS(M+H) + = 360.2.

[0093] Step 3. Synthesis of ethyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carboxylate (4) In dioxane (20 mL) and H2O (4 mL), a solution of ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylate (2.9 g, 8.07 mmol) and 2,6-dibenzyloxy-3-bromopyridine (2.99 g, 8.07 mmol) was added, to which tripotassium phosphate (5.14 g, 24.22 mmol) and Pd(dppf)Cl2 (295.32 mg, 403.60 μmol). The mixture was stirred at 90°C for 16 hours. A peak at the desired mass of 32% was confirmed by LC-MS. The mixture was filtered, the filtrate was diluted with water (30 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage, 25g SepaFlash® silica flash column, eluent gradient of 4-70% ethyl acetate / petroleum ether @ 55 mL / min) to obtain the title compound (0.9 g, 1.55 mmol, yield 19.20%, purity 90%) as a yellow oily substance. MS(M+H) + = 533.1.

[0094] Step 4. Synthesis of (1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)methanol (5) In 10 mL of THF, 0.9 g, 1.72 mmol of ethyl 1-(4-(2,6-dibenzyloxy-3-pyridyl)phenyl)piperidine-4-carboxylate solution was added under N2 conditions with LAH (92.80 mg, 2.45 mmol). The mixture was stirred at 25°C for 1 hour. The major peak of the desired mass was confirmed by LC-MS. The reaction was stopped at 0°C with H2O (0.09 mL), aqueous solution of sodium hydroxide (15%, 0.09 mL), and H2O (0.27 mL). The mixture was then filtered and washed with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (700 mg, crude product) as a yellow oil. MS(M+H) + = 481.2.

[0095] • Step 5. Synthesis of 3-(4-(4-(hydroxymethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (6) In CF3CH2OH (10 mL), a solution of (1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)methanol (700 mg, 1.46 mmol) was added to Pd / C (300 mg, 10% purity) under H2. The mixture was degassed three times with N2 and then stirred for 16 hours under H2 (15 psi) at 25°C. The major peak at the desired mass was confirmed by LC-MS. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (400 mg, crude product) as a yellow oil. MS(M+H) + = 303.1.

[0096] • Step 6. Synthesis of 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (7) In 2 mL of DCM, a solution of 3-(4-(4-(hydroxymethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (100 mg, 330.72 μmol) was mixed with DMP (168.33 mg, 396.87 μmol, 122.87 μL), and the mixture was stirred at 25°C for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1) confirmed that most of the starting material had been consumed and new spots had formed. The reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound (120 mg, crude product) as a brown oily substance. The crude product was used directly in the next step. MS(M+H) + = 301.1.

[0097] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 1) In 6 mL of DCE, sodium acetate (12.38 mg, 150.88 μmol) was added to a solution of N-(2-chlorophenyl)-4-((5-fluoro-2-((4-(2-oxo-2-(piperazine-1-yl)ethyl)phenyl)amino)pyrimidine-4-yl)amino)benzamide (90 mg, 150.88 μmol). The mixture was stirred at 25°C for 10 minutes, after which acetic acid (9.06 mg, 150.88 μmol, 8.63 μL) and 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (67.98 mg, 226.33 μmol) were added. After stirring at 25°C for 0.5 hours, sodium triacetoxyborohydride (47.97 mg, 226.33 μmol) was added. The resulting mixture was stirred at 25°C for 2.5 hours. LC-MS confirmed a peak at 40% of the desired mass. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent gradient of 4-100% ethyl acetate / petroleum ether @ 50 mL / min), then purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 min), lyophilized, and the title compound (12.5 mg, 13.63 μmol, yield 9.04%, purity 92.1%) was obtained as a white powder. MS(M+H) + = 844.3.

[0098] 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 9.89(s, 1H), 9.66(s, 1H), 9.29(s, 1H), 8.19(d, J=3.7 Hz, 1H), 8.07-8.01(m, 2H), 8.00-7.95(m, 2H), 7.66(dd, J=1.3, 8.1 Hz, 1H), 7.61(d, J=8.6 Hz, 2H), 7.57(dd, J=1.3, 8.1 Hz, 1H), 7.43-7.37(m, 1H), 7.32-7.27(m, 1H), 7.13(d, J=8.4 Hz, 2H), 7.02(d, J=8.7 Hz, 2H), 6.86(d, J=8.8 Hz, 2H), 3.71(dd, J=5.1, 10.6 Hz, 1H), 3.68-3.58(m, 4H), 3.49-3.42(m, 4H), 2.67-2.55(m, 3H), 2.30-2.22(m, 4H), 2.20 -2.12(m, 3H), 2.05-1.95(m, 1H), 1.80-1.72(m, 2H), 1.67-1.55(m, 1H), 1.28-0.99(m, 3H).

[0099] ●Example 2. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 2) [ka]

[0100] Step 1. Synthesis of tert-butyl 4-((1-(3-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (2) In 8 mL of DCM, a solution of 1-(3-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carbaldehyde (0.3 g, 626.85 μmol) and tert-butylpiperazine-1-carboxylate (116.75 mg, 626.85 μmol) was mixed with acetic acid (37.64 mg, 626.85 μmol, 35.85 μL) at 20°C. Then, sodium triacetoxyborohydride (398.57 mg, 1.88 mmol) was slowly added at 20°C, and the resulting mixture was stirred at 20°C for 12 hours. LC-MS confirmed the complete consumption of 1-(3-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carbaldehyde, with a peak indicating the desired 20% mass being observed. The reaction mixture was diluted with H2O (15 mL) and extracted using DCM (10 mL x 3). The organic layer was washed with saturated sodium bicarbonate (10 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-33%, gradient @ 100 mL / min) to obtain the title compound (183 mg, 262.30 μmol, yield 41.84%, purity 93%) as a yellow oil. MS(M+H) + = 649.3.

[0101] Step 2. Synthesis of tert-butyl 4-((1-(3-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (3) In CF3CH2OH (5 mL), a solution of tert-butyl 4-((1-(3-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (183 mg, 282.05 μmol) was added under an H2 atmosphere to Pd / C (0.1 g, 10% purity) and TFA (32.16 mg, 282.05 μmol, 20.88 μL). The suspension was degassed and purged three times with H2. The mixture was stirred for 12 hours under H2 (15 Psi) at 20°C. LC-MS confirmed complete consumption of the starting material and the peak at the desired mass. The reaction mixture was diluted with CF3CH2OH (15 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (133 mg, crude product) as a colorless oil. MS(M+H) + = 471.3.

[0102] • Step 3. Synthesis of 3-(3-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (4) In 2 mL of DCM, a solution of tert-butyl 4-((1-(3-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (133 mg, 282.62 μmol) was added to TFA (161.12 mg, 1.41 mmol, 104.63 μL) at 20°C, and the resulting mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed complete consumption of the starting material and the peak corresponding to the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (137 mg, crude product, TFA) as a yellow oil. MS(M+H) + = 371.3.

[0103] Step 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 2) In 2 mL of DMF, a solution of 2-(4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenyl)acetic acid (100 mg, 203.29 μmol) was added to HATU (85.03 mg, 223.62 μmol) and DIPEA (52.55 mg, 406.59 μmol, 70.82 μL). The mixture was stirred at 20°C for 10 minutes, and a solution of 3-(3-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (137 mg, 282.76 μmol, TFA) was added to 2 mL of DMF and DIPEA (105.10 mg, 813.17 μmol, 141.64 μL), and the resulting mixture was stirred at 20°C for 1 hour. LC-MS completely consumed the starting material, and a peak at the desired 25% mass was confirmed. The reaction mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with brine (15 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1), then purified by preparative HPLC (column:Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 47%~77%, 8 min), lyophilized, and the title compound (23.5 mg, 26.44 μmol, yield 13.01%, purity 95%) was obtained as a white solid. MS(M+H) + = 844.3.

[0104] 1H NMR (400 MHz, DMSO-d6) δ=10.78(br s, 1H), 9.88(s, 1H), 9.65(s, 1H), 9.28(s, 1H), 8.18(d, J=3.7 Hz, 1H), 8.07-7.94(m, 4H), 7.70-7.53(m, 4H), 7.39(dt, J=1.2, 7.6 Hz, 1H), 7.32-7.25(m, 1H), 7.17-7.09(m, 3H), 6.82-6.74(m, 2H), 6.57(d, J=7.6 Hz, 1H), 3.74(dd, J=5.0, 11.1 Hz, 1H), 3.69-3.58(m, 4H), 3.50-3.43(m, 4H), 2.68-2.55(m, 3H), 2.48-2.41(m, 1H), 2.31-2.20(m, 4H), 2.20 -2.14(m, 1H), 2.14-2.07(m, 2H), 2.06-1.96(m, 1H), 1.78-1.69(m, 2H), 1.68-1.54(m, 1H), 1.25-1.08(m, 2H).

[0105] ●Example 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-((2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 3) [ka]

[0106] Step 1. Synthesis of tert-butyl 4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (3) In 5 mL of DCM, tert-butyl 4-formylpiperidine-1-carboxylate (275.38 mg, 1.29 mmol) and acetic acid (1.94 mg, 32.28 μmol, 1.85 μL) were added to a solution of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (0.2 g, 645.60 μmol, HCl). The mixture was stirred at 25°C for 0.5 hours. Then sodium triacetoxyborohydride (273.66 mg, 1.29 mmol) was added, and the resulting mixture was stirred at 25°C for 2 hours. The major peak of the desired mass was confirmed by LC-MS. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL x 5). The mixed organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-40% petroleum ether:ethyl acetate / ethanol (V / V=5:1) gradient @ 80 mL / min) to obtain the title compound (220 mg, 455.33 μmol, yield 70.53%, purity 97.4%) as a white solid. MS(M+H) + = 471.3.

[0107] • Step 2.3 Synthesis of 3-(4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (4) In 5 mL of dioxane, a solution of tert-butyl 4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (220 mg, 467.49 μmol) was added, to which HCl / dioxane (4 M, 5 mL) was added. The mixture was stirred at 25°C for 1 hour. LC-MS confirmed that the starting material was completely consumed. The mixture was concentrated under reduced pressure to obtain the title compound (200 mg, crude product, HCl) as a white solid. MS(M+H) + = 371.2.

[0108] Step 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 3) In 5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (150.00 mg, 313.89 μmol) was mixed with EDCI (90.26 mg, 470.84 μmol), DIPEA (162.27 mg, 1.26 mmol, 218.70 μL), and HOBt (63.62 mg, 470.84 μmol). The mixture was stirred at 25°C for 0.5 hours. Then, 3-(4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (127.74 mg, 313.89 μmol, HCl) was added, and the resulting mixture was stirred at 25°C for 2 hours. LC-MS confirmed a peak at 67% of the desired mass. The mixture was diluted with water (30 ml) and extracted with ethyl acetate (20 mL x 5). The mixed organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 13%~43%, 10 min), followed by purification by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 24%~54%, 9 min), lyophilized, and the title compound (44.2 mg, 45.54 μmol, yield 63.02%, purity 97.3%, TFA) as a white solid. MS(M+H) + = 830.2.

[0109] 1H NMR (400 MHz, CD3OD) δ=8.11(d, J=4.2 Hz, 1H), 8.01-7.97(m, 2H), 7.93-7.89(m, 2H), 7.73(dd, J=1.6, 7.9 Hz, 1H), 7.66(d, J=8.6 Hz, 2H), 7.54(dd, J=1.3, 7.9 Hz, 1H), 7.42-7.38(m, 3H), 7.32-7.26(m, 1H), 7.21(d, J=8.7 Hz, 2H), 6.99(d, J=8.8 Hz, 2H), 4.04-3.34(m, 6H), 3.18-2.92(m, 8H), 2.81-2.53(m, 3H), 2.26-2.16(m, 3H), 1.96-1.89(m, 2H), 1.43-1.34(m, 2H).

[0110] ●Example 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 4) [ka]

[0111] • Step 1. Synthesis of 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione (2) In CF3CH2OH (10 mL), a solution of 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)phenyl)-2,6-bis(benzyloxy)pyridine (0.5 g, 956.69 μmol) was added under H2 conditions to TFA (153.50 mg, 1.35 mmol, 0.1 mL) and Pd / C (101.81 mg, 95.67 μmol, 10% purity). The resulting mixture was stirred for 24 hours under H2 (15 psi) at 25°C. LC-MS confirmed complete consumption of the starting material and identified a peak at a desired mass. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (770 mg, crude product) as a black oily substance. MS(M+H)+ =345.1.

[0112] • Step 2.1 Synthesis of (4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (3) HCl / dioxane (4M, 3.35 mL) was added to a mixture of 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione (770 mg, 2.24 mmol) in H2O (7 mL). The resulting mixture was stirred at 50°C for 16 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residual aqueous solution was extracted with ethyl acetate (10 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.4 g, 679.20 μmol, yield 30.38%, purity 51%) as a yellow solid. MS(M+H2O+H) + = 319.2.

[0113] Step 3. Synthesis of tert-butyl(4-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)amino)cyclohexyl)carbamate (5) A mixture of 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (320 mg, 543.36 μmol), tert-butyl(4-aminocyclohexyl)carbamate (116.44 mg, 543.36 μmol), 4A MS (170 mg), and TEA (54.98 mg, 543.36 μmol, 75.63 μL) was stirred at 25°C for 0.5 hours in DCM (3 mL). Then sodium triacetoxyborohydride (345.48 mg, 1.63 mmol) was added, and the resulting mixture was stirred at 25°C for 16 hours. A major peak of one desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (390 mg, crude product) as a brown solid. MS(M+H) +=499.3。

[0114] · Step 4. Synthesis of tert-butyl (4-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6) A mixture of tert-butyl (4-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino)cyclohexyl)carbamate (350 mg, 682.68 μmol), acetic acid (41.00 mg, 682.68 μmol) and formaldehyde (277.04 mg, 3.41 mmol, purity 37%) in methanol (4 mL) was stirred at 20 °C for 0.5 h. Then sodium cyanoborohydride (214.50 mg, 3.41 mmol) was added and the resulting mixture was stirred at 20 °C for 16 h. LCMS showed complete consumption of the starting material and confirmed a major peak of one desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 12 g SepaFlash (registered trademark) silica flash column, eluent: ethyl acetate / petroleum ether 0 - 100% to 0 - 50% methanol / ethyl acetate gradient @ 100 mL / min) to give the title compound (80 mg, 106.11 μmol, yield 15.54%, purity 68%) as a yellow solid. MS (M+H) + =513.4。

[0115] · Step 5. Synthesis of 3-(4-(4-(((4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (7) HCl / dioxane (4M, 2mL) was added to a solution of tert-butyl(4-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (80 mg, 156.04 μmol) in dioxane (2 mL). The mixture was stirred at 20°C for 1 hour. LC-MS confirmed complete consumption of the starting material and identified a major peak of one desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (70 mg, crude product, HCl) as a yellow solid. MS(M+H) + = 413.3.

[0116] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 4) A mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (59.60 mg, 93.54 μmol), DIPEA (36.27 mg, 280.61 μmol, 48.88 μL), and HATU (42.68 mg, 112.24 μmol) was stirred at 25°C for 0.5 hours in DMF (1 mL). Then, 3-(4-(4-(((4-aminocyclohexyl)(methyl)amino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (70 mg, 93.54 μmol, HCl) and DIPEA (36.27 mg, 280.61 μmol, 48.88 μL) were added to DMF (1 mL), and the resulting mixture was stirred at 25°C for 2 hours. A single major peak with a desired mass was identified by LC-MS. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 31%~61% B, 10 minutes) to obtain the title compound (20.2 mg, 13.02 μmol, yield 13.92%, purity 93%, 5 TFA) as a white solid. MS(M+H) + = 872.4.

[0117] 1H NMR (400 MHz, DMSO-d6) δ=10.78(s, 1H), 9.94(s, 1H), 9.77(s, 1H), 9.64(s, 1H), 8.84(br s, 1H), 8.25(d, J=3.3 Hz, 1H), 8.09-7.97(m, 4H), 7.86(br d, J=6.5 Hz, 1H), 7.85-7.76(m, 3H), 7.65(br d, J=7.8 Hz, 1H), 7.57(d, J=7.6 Hz, 1H), 7.45-7.38(m, 1H), 7.33-7.27(m, 1H), 7.09(br d, J=8.2 Hz, 2H), 6.98(br d, J=8.1 Hz, 2H), 4.10(br s, 1H), 3.80-3.65(m, 3H), 3.18-3.09(m, 1H), 3.36-3.04(m, 1H), 2.99-2.85(m, 1H), 2.84-2.72(m, 4H), 2.70-2.60(m, 3 H), 2.47-2.45(m, 1H), 2.18-2.09(m, 1H), 2.04-1.91(m, 5H), 1.88-1.75(m, 4H), 1.70-1.59(m, 2H), 1.44-1.29(m, 2H).

[0118] ●Example 5. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)acetyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 5) [ka]

[0119] Step 1. Synthesis of tert-butyl(1-(2-chloroacetyl)piperidine-4-yl)carbamate (2) In 10 mL of DCM, a solution of tert-butylpiperidine-4-ylcarbamate (1 g, 4.99 mmol) and 2-chloroacetyl chloride (451.15 mg, 3.99 mmol) was mixed with TEA (606.29 mg, 5.99 mmol). The mixture was stirred at 25°C for 2 hours. LC-MS confirmed complete consumption of the starting material and a peak at 73.5% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.38 g, crude product) as a yellow solid. MS(M+H) + = 277.7.

[0120] Step 2. Synthesis of tert-butyl(1-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)acetyl)piperidine-4-yl)carbamate (4) In 5 mL of DMF, a solution of tert-butyl(1-(2-chloroacetyl)piperidine-4-yl)carbamate (1.16 g, 4.20 mmol) and 3-(4-(piperazine-1-yl)phenyl)piperidine-2,6-dione (0.65 g, 2.10 mmol, HCl) was mixed with DIPEA (813.53 mg, 6.29 mmol, 1.10 mL). The mixture was stirred at 100°C for 24 hours. LC-MS confirmed a peak at 66.8% of the desired mass. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent 0-90% ethyl acetate / methanol @ 100 mL / min) to obtain the title compound (0.971 g, 1.49 mmol, yield 71.09%, purity 78.9%) as a yellow solid. MS(M+H) + = 514.3.

[0121] • Step 3. Synthesis of 3-(4-(4-(2-(4-aminopiperidine-1-yl)-2-oxoethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (5) In dioxane (10 mL), HCl / dioxane (4 M, 10 mL) was added to a solution of tert-butyl (1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (0.971 g, 1.89 mmol). The mixture was stirred at 25 °C for 16.5 h. The major peak of the desired mass was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure to give the title compound (1.1 g, crude product, HCl) as a yellow solid. MS (M+H) + = 414.3

[0122] · Step 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (Compound 5) In DMF (2 mL), HATU (190.96 mg, 502.22 μmol) and DIPEA (162.27 mg, 1.26 mmol, 218.70 μL) were added to a solution of 3-(4-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (207.68 mg, 461.53 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (0.2 g, 418.52 μmol). The mixture was stirred at 25 °C for 12 h. It was confirmed by LCMS that the starting materials were completely consumed. The mixture was poured into H2O (10 mL) and the mixture was filtered. The filter cake was recovered and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10um; mobile phase: [water (TFA)-ACN]; gradient: 38% - 68% B, 10 min), and lyophilized to give the title compound (24.8 mg, 26.04 μmol, yield 6.22%, purity 91.7%) as a white solid. MS (M+H) + = 873.3

[0123] 1 H NMR (400 MHz, DMSO-d6) δ=10.79(s, 1H), 9.93(s, 1H), 9.76(s, 1H), 9.63(s, 1H), 8.25(d, J=3.5 Hz, 1H), 8.13(br d, J=7.5 Hz, 1H), 8.06-7.99(m, 4H), 7.80-7.76(m, 4H), 7.66-7.62(m, 1H), 7.57(dd, J=1.3, 7.9 Hz, 1H), 7.43-7.37(m, 1H), 7.32-7.27(m, 1H), 7.12(d, J=8.6 Hz, 2H), 6.96(d, J=8.8 Hz, 2H), 4.52-4.44(m, 1H), 4.43-4.32(m, 2H), 4.09-4.02(m, 1H), 3.80-3.70(m, 4H), 3.29-3.11(m, 6H), 2.94-2.86(m, 1H), 2.65-2.59(m, 1H), 2.54-2.52(m, 2H), 2.21-2.09(m, 1H), 2.05-1.95(m, 1H), 1.94-1.86(m, 2H), 1.56-1.38(m, 2H).

[0124] ●Example 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(1-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)propan-2-yl)piperidine-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 6) [ka] [ka]

[0125] Step 1. Synthesis of tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (2) To a solution of tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (1 g, 3.50 mmol) in THF (20 mL), lithium aluminum hydride (2.5 M, 3 mL) was added dropwise for 15 minutes under N2 at 0°C. The mixture was then stirred at 0°C for 45 minutes. TLC (petroleum ether:ethyl acetate = 2:1) confirmed that the starting material was completely consumed and that new spots of high polarity were formed. The reaction was carefully stopped by adding H2O (0.29 mL), 15% aqueous sodium hydroxide solution (0.29 mL), and H2O (0.86 mL) to the reaction mixture. The resulting mixture was filtered and washed with ethyl acetate. The filtrate was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.9 g, crude product) as a colorless oil. MS(M+H) + = 244.3.

[0126] Step 2. Synthesis of tert-butyl 4-(1-(tosyloxy)propan-2-yl)piperidine-1-carboxylate (3) TosCl (658.11 mg, 3.45 mmol) was added at 20°C to a solution of tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (0.7 g, 2.88 mmol) and TEA (582.17 mg, 5.75 mmol, 800.78 μL) in DCM (10 mL). The resulting mixture was stirred at 20°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a major peak of one desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-18% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (660 mg, 1.64 mmol, yield 57.14%, purity 99%) as a colorless oil. MS (M-100+H) + = 298.1.

[0127] Step 3. Synthesis of tert-butyl 4-(1-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)propan-2-yl)piperidine-1-carboxylate (5) A mixture of tert-butyl 4-(1-(tosyloxy)propan-2-yl)piperidine-1-carboxylate (0.54 g, 1.36 mmol), 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (420.82 mg, 1.36 mmol, HCl), DIPEA (526.68 mg, 4.08 mmol, 709.81 μL), and sodium iodide (20.36 mg, 135.84 μmol) was stirred at 60°C for 16 hours in DMF (5 mL). A major peak of one desired mass was identified by LC-MS. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (180 mg, 324.87 μmol, yield 23.92%, purity 90%) as a pale yellow solid. MS(M+H) + = 499.4.

[0128] • Step 4. Synthesis of 3-(4-(4-(2-(piperidine-4-yl)propyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (6) In 2 mL of dioxane, a solution of tert-butyl 4-(1-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)propan-2-yl)piperidine-1-carboxylate (180 mg, 360.97 μmol) was added, to which HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (160 mg, crude product, HCl) as a yellow solid. MS(M+H) += 399.3.

[0129] • Step 5. Synthesis of 3-(4-(4-(2-(1-nitrosopiperidine-4-yl)propyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (7) In 2 mL of THF, a solution of 3-(4-(4-(2-(piperidine-4-yl)propyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (128 mg, 294.25 μmol, HCl) was mixed with TEA (89.33 mg, 882.76 μmol, 122.87 μL) at 0°C. Then, t-BuONO (91.03 mg, 882.76 μmol, 104.99 μL) was added dropwise to 1 mL of THF at 0°C. The resulting mixture was stirred at 60°C for 12 hours. LC-MS confirmed complete consumption of the starting material and identified a major peak with one desired mass. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (100 mg, 215.19 μmol, yield 73.13%, purity 92%) as a yellow solid. MS(M+H) + = 428.3.

[0130] • Step 6. Synthesis of 3-(4-(4-(2-(1-aminopiperidine-4-yl)propyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (8) In THF (2 mL) and H2O (0.5 mL), a solution of 3-(4-(4-(2-(1-nitrosopiperidine-4-yl)propyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (50 mg, 116.95 μmol) and ammonium chloride (25.02 mg, 467.79 μmol) was prepared. Zinc (30.59 mg, 467.79 μmol) was added at 0°C, and the mixture was stirred at 20°C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was filtered and washed with THF (10 mL). The filtrate was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (75 mg, crude product) as a yellow solid. MS(M+H) + = 414.3.

[0131] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(1-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)propane-2-yl)piperidine-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 6) A mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (115.55 mg, 181.35 μmol), DIPEA (70.32 mg, 544.06 μmol, 94.77 μL), and HATU (82.75 mg, 217.63 μmol) was stirred at 25°C for 0.5 hours in DMF (0.5 mL). Then, 3-(4-(4-(2-(1-aminopiperidine-4-yl)propyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (75 mg, 181.35 μmol) was added to DMF (0.5 mL), and the resulting mixture was stirred at 25°C for 16 hours. LC-MS confirmed complete consumption of the starting material and identified a major peak of one desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 20%~50% B, 10 minutes), lyophilized, and the title compound (13.3 mg, 11.71 μmol, yield 6.46%, purity 97%, 2TFA) was obtained as a white solid. MS(M+H) + = 873.4.

[0132] 1H NMR (400 MHz, DMSO-d6) δ=10.79(s, 1H), 9.98(s, 1H), 9.77(s, 1H), 9.62(s, 1H), 9.28-9.26(m, 1H), 9.22-9.10(m, 1H), 8.25(br d, J=3.1 Hz, 1H), 8.07-7.98(m, 4H), 7.78(br d, J=8.9 Hz, 2H), 7.73-7.67(m, 2H), 7.65(br d, J=7.5 Hz, 1H), 7.57(br d, J=8.1 Hz, 1H), 7.40(br t, J=7.6 Hz, 1H), 7.35-7.26(m, 1H), 7.12(br d, J=7.7 Hz, 2H), 6.98(br d, J=7.7 Hz, 2H), 3.86-3.68(m, 4H), 3.28-3.18(m, 2H), 3.12-3.02(m, 5H), 2.81-2.60(m, 4H), 2.24-2.09(m, 1H), 2.08-1.88(m, 2H), 1.69-1.56(m, 2H), 1.52-1.37(m, 2H), 1.37-1.18(m, 2H), 1.04-0.94(m, 3H).

[0133] ●Example 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 7) [ka]

[0134] Step 1. Synthesis of tert-butyl(4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-1-yl)carbamate (3) In 8 mL of DMF, a solution of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (300 mg, 1.10 mmol) and 2-(1-((tert-butoxycarbonyl)amino)piperidine-4-yl)ethyl 4-methylbenzene sulfonate (437.40 mg, 1.10 mmol) was mixed with DIPEA (425.55 mg, 3.29 mmol, 573.52 μL) and sodium iodide (32.90 mg, 219.52 μmol) at 20°C. The mixture was stirred at 60°C for 16 hours. LC-MS revealed 19% residual 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione and a peak at the desired mass of 22%. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (15 mL x 3), dried over NaSO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [water (TFA)-ACN]; B%: 19%~49%, 10 min), lyophilized, and the title compound (85 mg, 170.12 μmol, yield 15.50%, purity 80%) was obtained as a yellow oil. MS(M+H) + = 500.4.

[0135] • Step 2. Synthesis of 3-(4-(4-(2-(1-aminopiperidine-4-yl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (4) In 1 mL of DCM, a solution of tert-butyl(4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-1-yl)carbamate (85 mg, 170.12 μmol) was added to TFA (300 mg, 2.7 mmol, 0.2 mL) at 20°C, and the mixture was stirred at 20°C for 2 hours. LC-MS confirmed complete consumption of the starting material and a peak at 93% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (125 mg, crude product, TFA) as a yellow oily solid. MS(M+H) + = 400.3.

[0136] Step 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 7) In 2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (116.32 mg, 243.40 μmol) was added to HATU (101.80 mg, 267.74 μmol) and DIPEA (157.29 mg, 1.22 mmol, 211.98 μL) at 20°C. The mixture was stirred at 20°C for 30 minutes, and then a solution of 3-(4-(4-(2-(1-aminopiperidine-4-yl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (125 mg, 243.40 μmol TFA) was added to 2 mL of DMF, and the reaction mixture was stirred at 20°C for 12 hours. LC-MS completely consumed the starting material, and a peak at the desired mass of 18% was confirmed. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (15 mL x 3), dried over NaSO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1), followed by preparative HPLC (column:Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; B%: 30%~60%, 10 min), lyophilized, and the title compound (7.1 mg, 5.04 μmol, yield 2.07%, purity 93.4%, 4 TFA) as a white solid. MS(M+H) + = 859.4.

[0137] 1H NMR (400 MHz, DMSO-d6) δ=10.80(s, 1H), 9.94(s, 1H), 9.81-9.73(m, 1H), 9.66(s, 1H), 9.57-9.40(m, 2H), 8.25(d, J=3.5 Hz, 1H), 8.06-7.97(m, 4H), 7.81-7.76(m, 2H), 7.71(d, J=8.9 Hz, 2H), 7.67-7.62(m, 1H), 7.57(dd, J=1.4, 8.0 Hz, 1H), 7.43-7.37(m, 1H), 7.33-7.28(m, 1H), 7.12(d, J=8.5 Hz, 2H), 6.98(br d, J=8.6 Hz, 2H), 3.84(br d, J=12.4 Hz, 2H), 3.76(br dd, J=4.8, 11.4 Hz, 1H), 3.63-3.60(m, 2H), 3.30-3.20(m, 3H), 3.20-3.11(m, 3H), 3.00-2.92(m, 2H), 2.85-2.75(m, 2H), 2.70-2.65(m, 1H), 2.56-2.55(m, 1H), 2.21-2.09(m, 1H), 2.05-1.96(m, 1H), 1.78-1.69(m, 2H), 1.68-1.60(m, 2H), 1.43-1.30(m, 3H).

[0138] ●Example 8. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)azetidine-3-yl)methyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 8) [ka] [ka]

[0139] Step 1. Synthesis of tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)methyl)azetidine-1-carboxylate (3) A mixture of benzylpiperidine-4-ylcarbamate (3.5 g, 14.94 mmol), tert-butyl 3-formylazetidine-1-carboxylate (3.04 g, 16.43 mmol), and acetic acid (897.09 mg, 14.94 mmol) was stirred in methanol (35 mL) at 25°C for 0.5 hours. Then sodium borohydride (2.82 g, 44.82 mmol) was added, and the resulting mixture was stirred at 25°C for 16 hours. The major peak of the desired mass was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (80g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 30-100%, gradient @ 200mL / min) to obtain the title compound (9g) as a colorless oil. MS(M+H) + = 404.2.

[0140] Step 2. Synthesis of benzyl(1-(azetidine-3-ylmethyl)piperidine-4-yl)carbamate(4) In 10 mL of DCM, a solution of tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)methyl)azetidine-1-carboxylate was added, to which TFA (3.07 g, 26.92 mmol, 2.00 mL) was added. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed complete consumption of the starting material and a single major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1 g, TFA salt) as a colorless oil, which was used directly. MS(M+H) + = 304.2.

[0141] Step 3. Synthesis of benzyl(1-((1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)azetidine-3-yl)methyl)piperidine-4-yl)carbamate (6) In 20 mL of dioxane, a solution of benzyl(1-(azetidine-3-ylmethyl)piperidine-4-yl)carbamate (600.00 mg, 1.44 mmol, TFA salt) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (534.63 mg, 1.20 mmol) was mixed with cesium carbonate (1.17 g, 3.59 mmol), RuPhos (33.54 mg, 71.87 μmol), and Pd2(dba)3 (54.84 mg, 59.89 μmol) under nitrogen. The mixture was stirred at 100°C for 16 hours. LC-MS confirmed the complete consumption of benzyl(1-(azetidine-3-ylmethyl)piperidine-4-yl)carbamate and identified a major peak of one desired mass. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20g SepaFlash® silica flash column, eluent: 50-100% ethyl acetate / petroleum ether to 0-20% methanol / ethyl acetate, gradient @ 100 mL / min) to obtain the title compound (680 mg, 904.88 μmol, yield 75.54%, purity 89%) as a yellow solid. MS(M+H) + = 669.4.

[0142] Step 4. Synthesis of tert-butyl(1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)azetidine-3-yl)methyl)piperidine-4-yl)carbamate (7) In 10 mL of THF, a solution of benzyl (1-((1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)azetidine-3-yl)methyl)piperidine-4-yl)carbamate (340 mg, 508.36 μmol) was added to 332.84 mg of Boc2O (1.53 mmol, 350.36 μL) and 200 mg of Pd / C (10% purity) under an N2 atmosphere. The mixture was degassed under vacuum and purged several times with H2. The resulting mixture was stirred for 40 hours under an H2 (50 psi) atmosphere at 30°C. LCMS revealed 25% of the intermediate remaining and 30% of the desired mass was detected. The reaction mixture was filtered and washed with 200 mL of THF. The filtrate was concentrated under reduced pressure to obtain the residue. In 20 mL of THF, Pd / C (0.4 g, 10% purity) was added to the residue solution under an N2 atmosphere. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred for 16 hours under an H2 (50 psi) atmosphere at 30°C. LC-MS confirmed that the intermediate had been completely consumed, and 35% of the desired mass was detected. The reaction mixture was filtered and washed with 200 mL of THF. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1) to obtain the title compound (120 mg, 262.83 μmol, yield 20.00%) as a white solid. MS(M+H) + = 457.2.

[0143] • Step 5. Synthesis of 3-(4-(3-((4-aminopiperidine-1-yl)methyl)azetidine-1-yl)phenyl)piperidine-2,6-dione (8) A mixture of tert-butyl(1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)azetidine-3-yl)methyl)piperidine-4-yl)carbamate (120 mg, 262.83 μmol) and TFA (1.54 g, 13.46 mmol, 1 mL) was stirred at 15°C for 1 hour in DCM (4 mL). LC-MS confirmed that the starting materials were completely consumed. The mixture was concentrated under reduced pressure to obtain the title compound (160 mg, 2 TFA salt) as a colorless gum, which was used directly. MS(M+H) + = 357.2.

[0144] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)azetidine-3-yl)methyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 8) A mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (130 mg, 272.04 μmol), HATU (134.47 mg, 353.65 μmol), and DIPEA (351.59 mg, 2.72 mmol, 473.84 μL) in DMF (2 mL) was stirred at 15°C for 15 minutes, after which 3-(4-(3-((4-aminopiperidine-1-yl)methyl)azetidine-1-yl)phenyl)piperidine-2,6-dione (160 mg, 273.73 μmol, 2TFA salt) was added. The resulting mixture was stirred at 15°C for 1 hour. LC-MS confirmed the complete consumption of 3-(4-(3-((4-aminopiperidine-1-yl)methyl)azetidine-1-yl)phenyl)piperidine-2,6-dione, with a peak at 56% of the desired mass being observed. The mixture was adjusted to pH < 7 with TFA, and the resulting mixture was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes), lyophilized, and the crude product was obtained. 1F NMR and 1H NMR confirmed that the product was not pure. The residue was ground with a mixture (H2O:ACN:DCM:methanol = 4:1:1:1, 21 mL) for 10 minutes and filtered. The filtered cake was collected and dried. The crude product was ground with a mixture (H2O:THF:ACN:DCM:methanol = 1:1:2:3:1, 16 mL) for 10 minutes, lyophilized, and the title compound (77.3 mg, 85.51 μmol, yield 31.43%, purity 90.3%) was obtained as a gray solid. MS(M+H) + = 816.3.

[0145] 1 H NMR(400 MHz, DMSO-d6)δ=10.99-10.55(m, 1H), 10.15-9.87(m, 1H), 9.83-9.69(m, 1H), 9.68-9.41(m, 1H) , 8.32-8.19(m, 1H), 8.17-7.91(m, 5H), 7.91-7.71(m, 4H), 7.69-7.51(m, 2H), 7.48-7.22(m, 2H) , 7.17-6.84(m, 2H), 6.63-6.18(m, 2H), 4.12-3.81(m, 2H), 3.80-3.61(m, 2H), 3.50-3.42(m, 2H) , 3.05-2.72(m, 4H), 2.41-2.29(m, 2H), 2.25-1.89(m, 5H), 1.80-1.70(m, 2H), 1.66-1.44(m, 2H).

[0146] ●Example 9. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 9) [ka]

[0147] Step 1. Synthesis of tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)methyl)pyrrolidine-1-carboxylate (3) In methanol (30 mL), a solution of benzyl N-(4-piperidyl)carbamate (1 g, 4.27 mmol) and tert-butyl 3-formylpyrrolidine-1-carboxylate (1.02 g, 5.12 mmol) was mixed with acetic acid (256.31 mg, 4.27 mmol, 244.34 μL) and sodium triacetoxyborohydride (1.81 g, 8.54 mmol). The mixture was stirred at 25°C for 14 hours. LC-MS confirmed a peak at 71% of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The residue was diluted with H2O (30 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent: methanol / DCM 0-10%, @85mL / min) to obtain the title compound (1.7g, 3.79 mmol, yield 88.71%, purity 93%) as a white solid. MS(M+H) + = 418.3.

[0148] Step 2. Synthesis of benzyl(1-(pyrrolidine-3-ylmethyl)piperidine-4-yl)carbamate (4) In 10 mL of dioxane, a solution of tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)methyl)pyrrolidine-1-carboxylate (1.7 g, 4.07 mmol) was added to HCl / dioxane (4 M, 10 mL). The mixture was stirred at 25°C for 6 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.45 g, crude product, HCl) as a yellow solid. MS(M+H) + = 318.2.

[0149] Step 3. Synthesis of benzyl(1-((1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidine-4-yl)carbamate (6) In THF (30 mL) and H2O (3 mL), a solution of benzyl(1-(pyrrolidine-3-ylmethyl)piperidine-4-yl)carbamate (675 mg, 2.13 mmol) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (632.75 mg, 1.42 mmol) was added, to which Pd2(dba)3 (129.82 mg, 141.77 μmol), cesium carbonate (923.80 mg, 2.84 mmol), and DavePhos (55.79 mg, 141.77 μmol). The mixture was stirred at 100°C under N2 for 14 hours. A peak at the desired mass of 27% was confirmed by LC-MS. The residue was diluted with H2O (30 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (583 mg, 665.95 μmol, yield 23.49%, purity 78%) as a yellow solid. MS(M+H) + = 683.4.

[0150] Step 4. Synthesis of tert-butyl(1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidine-4-yl)carbamate (7) In THF (3 mL) and CF3CH2OH (5 mL), a solution of benzyl (1-((1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidine-4-yl)carbamate (533 mg, 780.55 μmol) was added, to which Boc2O (340.71 mg, 1.56 mmol, 358.64 μL), Pd / C (83.07 mg, 78.06 μmol, 10% purity) and acetic acid (46.87 mg, 780.55 μmol, 44.68 μL) were added. The resulting mixture was stirred at 25°C under H2 (15 psi) for 72 hours. LC-MS confirmed that the starting materials were completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 45 mL / min) to obtain the title compound (56 mg, 97.58 μmol, yield 12.50%, purity 82%) as a white solid. MS(M+H) + = 471.2.

[0151] • Step 5. Synthesis of 3-(4-(3-((4-aminopiperidine-1-yl)methyl)pyrrolidine-1-yl)phenyl)piperidine-2,6-dione (8) In 2 mL of dioxane, a solution of tert-butyl N-[1-[[1-[4-(2,6-dioxo-3-piperidyl)phenyl]pyrrolidine-3-yl]methyl]-4-piperidyl]carbamate (56 mg, 119.00 μmol) was added, to which HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 25°C for 12 hours. LC-MS confirmed a peak at 36% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (103 mg, crude product, HCl) as a yellow solid. MS(M+H) + = 371.2.

[0152] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 9) In 0.5 mL of DMF, HATU (44.85 mg, 117.95 μmol) and DIPEA (38.11 mg, 294.88 μmol) were added to a solution of 3-(4-(3-((4-aminopiperidine-1-yl)methyl)pyrrolidine-1-yl)phenyl)piperidine-2,6-dione (40 mg, 98.29 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (40.00 mg, 83.70 μmol). The resulting mixture was stirred at 20°C for 1 hour. The desired mass peak (44%) was confirmed by LC-MS. The reaction mixture was filtered. The filtrate was separated and purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 22%~52% B, 10 minutes), lyophilized, and the title compound (10 mg, 12.04 μmol, yield 12.25%, purity 90%) was obtained as a white solid. MS(M+H) + = 830.2.

[0153] 1H NMR (400 MHz, DMSO-d6) δ=10.74(s, 1H), 9.93(s, 1H), 9.74(s, 1H), 9.60(s, 1H), 8.29(s, 1H), 8.25(d, J=3.4 Hz, 1H), 8.05-7.98(m, 5H), 7.79-7.76(m, 3H), 7.68-7.63(m, 1H), 7.56(dd, J=1.3, 8.0 Hz, 1H), 7.43-7.36(m, 1H), 7.32-7.25(m, 1H), 6.99(d, J=8.6 Hz, 2H), 6.47(d, J=8.7 Hz, 2H), 3.77-3.74(m, 1H), 3.70-3.65(m, 1H), 3.25-3.20(m, 2H), 2.97-2.85(m, 3H), 2.65-2.57(m, 1H), 2.46-2.40(m, 1H), 2.39-2.27(m, 3H), 2.18-1.93(m, 6H), 1.80-1.68(m, 3H), 1.64-1.54(m, 2H).

[0154] ●Example 10. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclopentyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (Compound 10) [ka]

[0155] • Step 1. Synthesis of 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (2) HCl / dioxane (4M, 1.70 mL) was added to a solution of 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione (390 mg, 1.13 mmol) in H2O (5 mL). The mixture was stirred at 50°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a peak at 76% of the desired mass. The mixture was diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (242 mg, 729.98 μmol, yield 64.46%, purity 90.6%) as a brown solid. MS(M+H) + =301.4.

[0156] Step 2. Synthesis of tert-butyl((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)amino)cyclopentyl)carbamate (4) In methanol (5 mL), a solution of 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (220 mg, 732.48 μmol) and tert-butyl((1S,2R)-2-aminocyclopentyl)carbamate (146.70 mg, 732.48 μmol) was added, to which sodium triacetoxyborohydride (155.24 mg, 732.48 μmol) and acetic acid (87.97 mg, 1.46 mmol, 83.86 μL). The mixture was stirred at 25°C for 38 hours. LC-MS confirmed complete consumption of the starting material and a peak at the desired mass of 39.6% was observed. The reaction mixture was concentrated under reduced pressure, and methanol was removed. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (170 mg, 308.34 μmol, yield 42.10%, purity 87.9%) as a white solid. MS(M+H) + = 485.3.

[0157] Step 3. Synthesis of tert-butyl((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclopentyl)carbamate (5) In methanol (3 mL), a solution of tert-butyl((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)amino)cyclopentyl)carbamate (150 mg, 309.51 μmol) was added, along with formaldehyde (37.68 mg, 464.27 μmol, purity 37%) and sodium triacetoxyborohydride (131.20 mg, 619.03 μmol). The mixture was stirred at 20°C for 18 hours. A peak at the desired mass of 40% was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure, and methanol was removed. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 45 mL / min) to obtain the title compound (100 mg, 200.54 μmol, yield 64.79%) as a white solid. MS(M+H) + = 499.3.

[0158] • Step 4. Synthesis of 3-(4-(4-((((1R,2S)-2-aminocyclopentyl)(methyl)amino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (6) In 5 mL of dioxane, a solution of tert-butyl((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclopentyl)carbamate (100 mg, 200.54 μmol) was added, to which HCl (4 M, 150.40 μL) was added. The mixture was stirred at 20°C for 14 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (160 mg, crude product, HCl) as a white solid. MS(M+H) + =399.2.

[0159] Step 5. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclopentyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 10) In 3 mL of DMF, HATU (146.85 mg, 386.21 μmol) and DIPEA (124.79 mg, 965.51 μmol, 168.18 μL) were added to a solution of 3-(4-(4-((((1R,2S)-2-aminocyclopentyl)(methyl)amino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (140 mg, 321.84 μmol) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (153.80 mg, 321.84 μmol). The mixture was stirred at 25°C for 6 hours. LC-MS confirmed complete consumption of the starting material and a peak at the desired mass of 29%. The reaction mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1), followed by preparative HPLC (column:Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 17%~47% B, 10 minutes), lyophilized, and the title compound (10.2 mg, 11.53 μmol, yield 3.58%, purity 97%) as a white solid. MS(M+H) + = 858.4.

[0160] 1H NMR (400 MHz, DMSO-d6) δ=10.73(s, 1H), 9.90(s, 1H), 9.74(s, 1H), 9.64(s, 1H), 8.24(d, J=3.5 Hz, 1H), 8.10-8.00(m, 4H), 7.82(d, J=8.8 Hz, 2H), 7.70(d, J=8.8 Hz, 2H), 7.67-7.63(m, 1H), 7.59-7.53(m, 1H), 7.43-7.39(m, 1H), 7.38-7.34(m, 1H), 7.32-7.26(m, 1H), 6.93(d, J=8.3 Hz, 2H), 6.68(br d, J=8.8 Hz, 2H), 4.19-4.11(m, 1H), 3.69-3.62(m, 1H), 3.59-3.47(m, 2H), 2.69-2.54(m, 6H), 2.19 -2.13(m, 4H), 2.00-1.80(m, 5H), 1.75-1.55(m, 6H), 1.15-1.02(m, 1H), 0.99-0.83(m, 1H).

[0161] ●Example 11. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((3-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclobutyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (Compound 11) [ka]

[0162] Step 1. Synthesis of tert-butyl(3-((4-methoxybenzyl)(methyl)amino)cyclobutyl)carbamate (2) In 40 mL of DCM, 648.44 mg of acetic acid (10.80 mmol, 618.15 μL) was added at 20°C to a solution of tert-butyl (3-oxocyclobutyl) carbamate (2 g, 10.80 mmol) and 1-(4-methoxyphenyl)-N-methylmethaneamine (1.63 g, 10.80 mmol). The mixture was stirred at 20°C for 30 minutes, then sodium triacetoxyborohydride (2.29 g, 10.80 mmol) was slowly added, and the resulting mixture was stirred at 20°C for 12 hours. LC-MS confirmed complete consumption of the starting material and a peak at 87% of the desired mass. The reaction mixture was filtered. The filtrate was diluted with H2O (80 mL) and extracted with ethyl acetate (40 mL x 3). The mixed organic layer was washed with sodium bicarbonate (30 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed by flash silica gel chromatography (20g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-50%, gradient @ 100mL / min) to obtain the title compound (3g, 9.39 mmol, yield 86%) as a yellow oil. MS(M+H) + = 321.4.

[0163] Step 2. Synthesis of tert-butyl (3-(methylamino)cyclobutyl)carbamate (3) In ethanol (40 mL), a solution of tert-butyl (3-((4-methoxybenzyl)(methyl)amino)cyclobutyl) carbamate (3 g, 9.36 mmol) was added to Pd / C (1 g, 10% purity) under an H2 atmosphere. The suspension was degassed, purged three times with H2, and stirred for 16 hours under H2 (50 psi) at 25°C. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was filtered and washed with ethanol (50 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with H2O (50 mL), pH adjusted to 3 with HCl (1 M), extracted with ethyl acetate (30 mL x 3), and the aqueous phase was freeze-dried to obtain the title compound (1.58 g, 7.89 mmol, yield 98.75%) as a pale yellow solid. MS(M+H) + =201.1.

[0164] Step 3. Synthesis of tert-butyl(3-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclobutyl)carbamate (5) In 4 mL of DCM, a solution of tert-butyl (3-(methylamino)cyclobutyl)carbamate (190 mg, 948.69 μmol) and 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde (237.45 mg, 790.57 μmol) was added to acetic acid (47.48 mg, 790.57 μmol, 45.26 μL) at 20°C. The mixture was stirred at 20°C for 30 minutes, and then sodium triacetoxyborohydride (502.66 mg, 2.37 mmol) was slowly added at 20°C. The resulting mixture was stirred at 20°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a peak at the desired mass of 42%. The reaction mixture was diluted with H2O (40 mL), pH adjusted to 10 with sodium carbonate, and then extracted with ethyl acetate (20 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1) to obtain the title compound (40 mg, 74.28 μmol, yield 9.40%, purity 90%) as an off-white solid. MS(M+H) + = 485.4.

[0165] • Step 4. Synthesis of 3-(4-(4-(((3-aminocyclobutyl)(methyl)amino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (6) In 1 mL of dioxane, a solution of tert-butyl(3-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclobutyl)carbamate (40 mg, 82.54 μmol) was added to HCl / dioxane (4 M, 20.63 μL) at 20°C. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed that the starting material was completely consumed and the desired mass was obtained. The reaction mixture was concentrated under reduced pressure to obtain the title compound (40 mg, crude product, HCl) as a white solid. MS(M+H) + = 385.3.

[0166] Step 5. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((3-(((1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)methyl)(methyl)amino)cyclobutyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 11) In 0.2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (15.89 mg, 33.26 μmol) was added to HATU (18.06 mg, 47.51 μmol) and DIPEA (18.42 mg, 142.53 μmol, 24.83 μL) at 20°C. The mixture was stirred at 20°C for 1 hour, and then a solution of 3-(4-(4-(((3-aminocyclobutyl)(methyl)amino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (20 mg, 47.51 μmol, HCl) was added to 0.1 mL of DMF at 20°C, and the resulting mixture was stirred at 20°C for 1 hour. The starting material was completely consumed and the desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (4 mL) and extracted with ethyl acetate (2 mL x 3). The organic layer was washed with brine (2 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1), ground with the mixed solution (10 mL, ACN:H2O = 1:4), and freeze-dried to obtain the title compound (5.1 mg, 5.74 μmol, yield 10.77%, purity 95%) as a white solid. MS(MH) + =843.8.

[0167] 1H NMR (400 MHz, DMSO-d6) δ=10.78(s, 1H), 9.94(s, 1H), 9.78-9.69(m, 1H), 9.60(s, 1H), 8.35(br d, J=7.5 Hz, 1H), 8.25(d, J=3.5 Hz, 1H), 8.07-7.97(m, 4H), 7.82-7.74(m, 4H), 7.68-7.62(m, 1H), 7.55(dd, J=1.2, 8.0 Hz, 1H), 7.38(t, J=7.2 Hz, 1H), 7.31-7.24(m, 1H), 7.02(d, J=8.7 Hz, 2H), 6.87(d, J=8.6 Hz, 2H), 4.14-4.04(m, 1H), 3.71(dd, J=5.2, 10.9 Hz, 1H), 3.64(br d, J=11.1 Hz, 2H), 2.67-2.58(m, 3H), 2.45-2.41(m, 1H), 2.41-2.34(m, 2H), 2.18-2.08(m, 1H), 2.04(s, 3H) , 2.01-1.98(m, 1H), 1.88-1.73(m, 4H), 1.65-1.51(m, 1H), 1.32-1.23(m, 3H), 1.20-1.10(m, 2H).

[0168] ●Example 12. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(3-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)propanoyl)piperidine-4-yl)carbamoyl)phenyl)amino)5-fluoropyrimidine-4-yl)amino)benzamide (compound 12) [ka]

[0169] Step 1. Synthesis of benzyl(1-(3-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)propanoyl)piperidine-4-yl)carbamate (3) In 80 mL of dioxane, a solution of benzyl(1-(3-(piperidine-4-yl)propanoyl)piperidine-4-yl)carbamate (1.50 g, 3.66 mmol, HCl) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1 g, 2.24 mmol) was added, to which Ruphos-Pd-G (190.53 mg, 224.05 μmol) and cesium carbonate (2.19 g, 6.72 mmol) were added. The resulting mixture was stirred at 100°C under N2 for 32 hours. The desired mass peak (17%) was confirmed by LC-MS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 80 mL / min) to obtain the title compound (0.5 g, 534.57 μmol, yield 23.86%, purity 79%) as a yellow solid. MS(M+H) + = 739.4.

[0170] Step 2. Synthesis of 3-(4-(4-(3-(4-aminopiperidine-1-yl)-3-oxopropyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (4) In CF3CH2OH (20 mL), a solution of benzyl(1-(3-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)propanoyl)piperidine-4-yl)carbamate (0.5 g, 676.67 μmol) was added to TFA (154.31 mg, 1.35 mmol) and Pd / C (100 mg, 93.97 μmol, purity 10%) under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred for 16 hours under H2 (15 psi) at 25°C. The major peak at the desired mass was confirmed by LC-MS. The mixture was filtered, and the filtrate was concentrated to obtain the title compound (0.4 g, crude product, TFA) as a yellow oil. MS(M+H) + = 427.4.

[0171] Step 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(3-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)propanoyl)piperidine-4-yl)carbamoyl)phenyl)amino)5-fluoropyrimidine-4-yl)amino)benzamide (compound 12) In 5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (176.80 mg, 369.98 μmol) and HATU (168.81 mg, 443.97 μmol) was mixed with DIPEA (239.08 mg, 1.85 mmol) and the mixture was stirred at 20°C for 1 hour. Then, 3-(4-(4-(3-(4-aminopiperidine-1-yl)-3-oxopropyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (200 mg, 369.98 μmol, TFA) was added and the resulting mixture was stirred at 20°C for 12 hours. The desired mass peak (50%) was confirmed by LC-MS. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / methanol = 10 / 1) to obtain 80 mg of crude product, which was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%~65% B, 10 minutes), lyophilized, and the title compound (21.5 mg, 23.50 μmol, yield 6.35%, purity 96.9%) was obtained as a white solid. MS(M+H) + = 886.6.

[0172] 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 9.93(s, 1H), 9.74(s, 1H), 9.62(s, 1H), 8.26(d, J=3.5 Hz, 1H), 8.08-7.98(m, 5H), 7.79-7.74(m, 4H), 7.66(dd, J=1.5, 7.9 Hz, 1H), 7.57(dd, J=1.3, 8.1 Hz, 1H), 7.40(dt, J=1.3, 7.7 Hz, 1H), 7.34-7.25(m, 1H), 7.03(d, J=8.6 Hz, 2H), 6.89(d, J=8.8 Hz, 2H), 4.44-4.30(m, 1H), 4.09-3.97(m, 1H), 3.95-3.84(m, 1H), 3.76-3.71(m, 1H), 3.70-3.62(m, 2H), 3.17-3.06(m, 1H), 2.65-2.57(m, 5H), 2.42-2.35(m, 2H), 2.16-2.08(m, 1H), 2.05-1.98(m, 1H), 1.89-1 .75(m, 4H), 1.52-1.45(m, 2H), 1.43-1.34(m, 2H), 1.32-1.15(m, 3H).

[0173] ●Example 13. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-(4-((2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)phenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 13) [ka]

[0174] Step 1. Synthesis of tert-butyl(4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)phenyl)carbamate (3) In 7 mL of DCE, a solution of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (300 mg, 968.40 μmol HCl) and tert-butyl(4-formylphenyl)carbamate (214.26 mg, 968.40 μmol) was mixed with TEA (293.97 mg, 2.91 mmol, 404.36 μL) and 4A MS (200 mg) at 20°C. The mixture was stirred at 20°C for 30 minutes, after which sodium triacetoxyborohydride (615.73 mg, 2.91 mmol) was slowly added, and the resulting mixture was stirred at 20°C for 12 hours. LC-MS confirmed complete consumption of the starting material and a peak at 57% of the desired mass. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 200 mL / min) to obtain the title compound (225 mg, 446.63 μmol, yield 46.12%, purity 95%) as a white solid. MS(M+H) + = 479.3.

[0175] • Step 2.3 Synthesis of (4-(4-(4-aminobenzyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (4) To a solution of tert-butyl(4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)phenyl)carbamate (225 mg, 470.14 μmol) in dioxane (3 mL), HCl / dioxane (4 M, 9.20 mL) was added at 20 °C. The mixture was stirred at 20 °C for 4 hours. LC-MS revealed 8% of tert-butyl(4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)phenyl)carbamate remaining, and a peak at the desired mass of 83% was confirmed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (130 mg, crude product, HCl) as a white solid. MS(M+H) + = 379.3.

[0176] Step 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-(4-((2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)phenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 13) In 2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (92.14 mg, 192.80 μmol) was added to HATU (80.64 mg, 212.09 μmol) and DIPEA (74.75 mg, 578.41 μmol, 100.75 μL) at 20°C. The mixture was stirred at 20°C for 30 minutes, and then a solution of 3-(4-(4-(4-aminobenzyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (80 mg, 192.80 μmol HCl) was added to 2 mL of DMF, and the reaction mixture was stirred at 20°C for 12 hours. LC-MS confirmed complete consumption of the starting material and a peak at the desired 40% mass. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over brine (10 mL x 3), filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1), then purified by preparative HPLC (column:Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; B%: 38%~68%, 10 min), lyophilized, and the title compound (45.3 mg, 33.14 μmol, yield 17.19%, 94.7% purity, 4 TFA) was obtained as a white solid. MS(M+H) + = 838.1.

[0177] 1H NMR (400 MHz, MeOD) δ=8.12(d, J=3.9 Hz, 1H), 8.07-8.00(m, 2H), 7.99-7.91(m, 4H), 7.88(d, J=8.4 Hz, 2H), 7.82-7.76(m, 3H), 7.55-7.47(m, 3H), 7.37(dt, J=1.5, 7.8 Hz, 1H), 7.29-7.22(m, 1H), 7.18(d, J=8.7 Hz, 2H), 7.01(d, J=8.8 Hz, 2H), 4.92-4.87(m, 4H), 3.93-3.77(m, 3H), 3.66-3.49(m, 2H), 3.11-2.96(m, 2H), 2.75-2.55(m, 2H), 2.26-2.14(m, 2H).

[0178] ●Example 14. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-((2,6-dioxopiperidine-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 14) [ka] [ka]

[0179] • Step 1. Synthesis of 3-(4-bromophenyl)piperidine-2,6-dione (2) In 50 mL of DMF, t-BuOK (1 M, 21.83 mL) was added at 0°C to a solution of ethyl 2-(4-bromophenyl)acetate (5 g, 21.83 mmol) and acrylamide (1.55 g, 21.83 mmol), and the mixture was stirred at 0°C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1) confirmed that the starting material was completely consumed and that new spots of greater polarity were formed. The reaction mixture was poured into cold water, filtered, and washed with H2O (50 mL). The filtered cake was collected and dried to obtain the title compound (2.5 g, 9.23 mmol, yield 42.29%, purity 99%) as a white solid. MS(M+H)+ = 268.1.

[0180] 1 H NMR (400 MHz, DMSO-d6) δ=10.86 (br s, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 3.88 (dd, J=4.9, 12.0 Hz, 1H), 2.74-2.62(m, 1H), 2.56-2.50(m, 1H), 2.20(dq, J=4.3, 12.5 Hz, 1H), 2.07-1.96(m, 1H).

[0181] Step 2. Synthesis of tert-butyl 4-((4-(2,6-dioxopiperidine-3-yl)phenyl)ethynyl)piperidine-1-carboxylate (4) In 10 mL of DMF, a solution of 3-(4-bromophenyl)piperidine-2,6-dione (1.2 g, 4.48 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (936.72 mg, 4.48 mmol), and TEA (1.36 g, 13.43 mmol, 1.87 mL) was prepared by adding Pd(PPh3)2Cl2 (157.08 mg, 223.79 μmol) and CuI (85.24 mg, 447.58 μmol) under N2. The resulting mixture was stirred at 80°C for 16 hours. LC-MS confirmed that 3-(4-bromophenyl)piperidine-2,6-dione was completely consumed, and 39% of the desired mass was confirmed. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-60% ethyl acetate / petroleum ether gradient @ 100 mL / min) to obtain the title compound (1.8 g) as a yellow solid. MS(M+H) + =397.2.

[0182] • Step 3. Synthesis of 3-(4-(piperidine-4-ylethynyl)phenyl)piperidine-2,6-dione (5) In 10 mL of dioxane, a solution of tert-butyl 4-((4-(2,6-dioxopiperidine-3-yl)phenyl)ethynyl)piperidine-1-carboxylate (1.8 g, 4.54 mmol) was added to HCl / dioxane (4 M, 20 mL). The resulting solution was stirred at 20°C for 2 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.5 g, HCl salt) as a yellow solid. MS(M+H) + = 297.2.

[0183] Step 4. Synthesis of tert-butyl 4-((4-(2,6-dioxopiperidine-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate (7) A mixture of 3-(4-(piperidine-4-ylethynyl)phenyl)piperidine-2,6-dione (1.4 g, 4.21 mmol, HCl salt), tert-butyl 4-oxopiperidine-1-carboxylate (921.93 mg, 4.63 mmol), and TEA (851.30 mg, 8.41 mmol, 1.17 mL) was stirred at 20°C for 0.5 hours in DCM (14 mL). Then sodium triacetoxyborohydride (2.67 g, 12.62 mmol) was added, and the resulting mixture was stirred at 20°C for 3 hours. A peak at 70% of the desired mass was confirmed by LC-MS. The reaction mixture was diluted with sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 20%~50% B, 10 minutes), lyophilized, and the title compound (1.8g, 3.45 mmol, yield 82.08%, purity 92%) was obtained as a white solid. MS(M+H) + = 480.3.

[0184] • Step 5. Synthesis of 3-(4-([1,4'-bipiperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione (8) In 4 mL of dioxane, a solution of tert-butyl 4-((4-(2,6-dioxopiperidine-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate (0.4 g, 834.01 μmol) was added, and the mixture was stirred at 20°C for 2 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.36 g, HCl salt) as a yellow solid, which was used directly. MS(M+H) + = 380.3.

[0185] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-((2,6-dioxopiperidine-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 14) A mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (93.06 mg, 194.73 μmol), DIPEA (55.93 mg, 432.74 μmol, 75.37 μL), and HATU (90.50 mg, 238.01 μmol) was stirred at 25°C for 0.5 hours. Then, a mixture of 3-(4-([1,4'-bipiperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione (90 mg, 216.37 μmol, HCl salt) was added to the DMF (1 mL), and the resulting mixture was stirred at 25°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a peak at 68% of the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with THF (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by preparative TLC (silicon dioxide, DCM:methanol = 7:1) to obtain the title compound (19.3 mg, 22.07 μmol, yield 37.06%, purity 96%) as a white solid. MS(M+H) + = 839.2.

[0186] 1H NMR (400 MHz, DMSO-d6) δ=10.84(s, 1H), 9.91(s, 1H), 9.72(s, 1H), 9.55(s, 1H), 8.23(d, J=3.5 Hz, 1H), 8.07-7.93(m, 4H), 7.74(d, J=8.6 Hz, 2H), 7.66(dd, J=1.3, 7.9 Hz, 1H), 7.56(dd, J=1.3, 7.9 Hz, 1H), 7.39(dt, J=1.3, 7.6 Hz, 1H), 7.37-7.25(m, 5H), 7.20(d, J=8.2) Hz, 2H), 4.61-4.09(m, 1H), 4.09-3.59(m, 2H), 3.03-2.84(m, 1H), 2.83-2.71(m, 2H), 2.70-2.56(m, 2H), 2.49-2.46(m, 1H), 2.39 -2.29(m, 2H), 2.28-2.10(m, 2H), 2.05-1.95(m, 1H), 1.88-1.68(m, 4H), 1.63-1.50(m, 2H), 1.47-1.32(m, 2H), 1.31-1.20(m, 1H).

[0187] ●Example 15. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((4-((2,6-dioxopiperidine-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 15) [ka]

[0188] Step 1. N-(2-chlorophenyl)-4-((2-((4-(2-(4-((4-((2,6-dioxopiperidine-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 15) A mixture of 2-(4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenyl)acetic acid (95.79 mg, 194.73 μmol), DIPEA (55.93 mg, 432.74 μmol), and HATU (90.50 mg, 238.01 μmol) was stirred at 25°C for 0.5 hours in DMF (1 mL). Then, a solution of 3-(4-([1,4'-bipiperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione (90 mg, 216.37 μmol, HCl salt) was added to DMF (1 mL), and the resulting mixture was stirred at 25°C for 16 hours. LC-MS completely consumed 3-(4-([1,4'-bipiperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione, and a peak with the desired mass of 61% was confirmed. The reaction mixture was diluted with H2O (20 mL) and extracted with THF (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified twice by preparative TLC (silicon dioxide, DCM:methanol = 10:1) to obtain the title compound (17.2 mg, 18.70 μmol, yield 31.92%, purity 92.8%) as a white solid. MS(M+H) + = 853.2.

[0189] 1H NMR (400 MHz, DMSO-d6) δ=10.85(s, 1H), 9.89(s, 1H), 9.65(s, 1H), 9.28(s, 1H), 8.18(d, J=3.5 Hz, 1H), 8.07-8.00(m, 2H), 7.99-7.92(m, 2H), 7.65(dd, J=1.4, 8.0 Hz, 1H), 7.63-7.58(m, 2H), 7.56(dd, J=1.3, 7.9 Hz, 1H), 7.39(dt, J=1.4, 7.7 Hz, 1H), 7.36-7.26(m, 3H), 7.19(d, J=8.2 Hz, 2H), 7.12(d, J=8.6 Hz, 2H), 4.39(br dd, J=1.3, 12.0 Hz, 1H), 3.97(br d, J=11.5 Hz, 1H), 3.87(dd, J=4.8, 11.6 Hz, 1H), 3.69-3.57(m, 2H), 2.94(br t, J=12.3 Hz, 1H), 2.75-2.60(m, 3H), 2.59-2.54(m, 1H), 2.47-2.44(m, 1H), 2.43-2.36(m, 1H), 2.30-2.11(m, 3H), 2.06-1.96(m, 1H), 1.88-1.72(m, 2H), 1.71-1.59(m, 2H), 1.59-1.45(m, 2H), 1.30-1.07(m, 3H).

[0190] ●Example 16. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 16) [ka]

[0191] Step 1. Synthesis of tert-butyl((1r,4r)-4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamate (3) A mixture of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (300 mg, 866.42 μmol, 2HCl salt), ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (266.34 mg, 866.42 μmol), DIPEA (559.90 mg, 4.33 mmol, 754.58 μL), and potassium iodide (143.83 mg, 866.42 μmol) in DMF (7 mL) was stirred at 60°C for 16 hours. LC-MS revealed that 19% of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione remained, and 54% of the desired mass was detected. ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (79.90 mg, 259.93 μmol) was added to the mixture, and the mixture was stirred at 60°C for a further 16 hours. LC-MS revealed that 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione was completely consumed, and 81% of the desired mass was detected. The mixture was adjusted to pH < 7 with CH3COOH. The resulting mixture was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes), lyophilized, and the title compound (170 mg, 283.97 μmol, yield 32.78%, TFA salt) was obtained as a brown solid. MS(M+H) + = 485.2.

[0192] • Step 2. Synthesis of 3-(4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (4) A mixture of tert-butyl((1r,4r)-4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamate (125 mg, 208.80 μmol, TFA salt) and TFA (1.54 g, 13.46 mmol, 1 mL) was stirred at 15°C for 1 hour in DCM (4 mL). LC-MS confirmed that the starting materials were completely consumed. The mixture was concentrated under reduced pressure to obtain the title compound (125 mg, 2 TFA salt) as a brown gum, which was used directly. MS(M+H) + = 385.2.

[0193] Step 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 16) In 5 mL of DMF, a mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (120 mg, 251.11 μmol), HATU (124.12 mg, 326.45 μmol), and DIPEA (324.54 mg, 2.51 mmol) was stirred at 15°C for 15 minutes, after which 3-(4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (165 mg, 269.36 μmol) was added. 3-(4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazine-1-yl)phenyl)piperidine-2,6-dione was completely consumed by LC-MS, and 59% of the desired mass was confirmed. The mixture was diluted with H2O (30 mL) and extracted with a mixed solvent of ethyl acetate / THF (2 / 1, 10 mL x 2). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (column: Phenomenex). The product was purified by luna C18 (150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 28%~58% B, 9 minutes) and lyophilized. The product was diluted in a mixed solvent of ethyl acetate:THF:ACN (4:2:1, 60 mL) and adjusted to pH > 7 with sodium bicarbonate solution (5 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 8:1) to obtain the title compound (51.2 mg, 56.94 μmol, yield 22.67%, purity 93.9%) as a light brown solid. MS(M+H) + = 844.2.

[0194] 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 9.93(s, 1H), 9.73(s, 1H), 9.59(s, 1H), 8.25(d, J=3.5 Hz, 1H), 8.11-7.94(m, 5H), 7.80-7.72(m, 4H), 7.65(dd, J=1.3, 7.9 Hz, 1H), 7.56(dd, J=1.3, 7.9 Hz, 1H), 7.40(dt, J=1.3, 7.7 Hz, 1H), 7.34-7.25(m, 1H), 7.05(d, J=8.7 Hz, 2H), 6.89(d, J=8.7 Hz, 2H), 3.79-3.63(m, 2H), 3.30(br s, 1H), 3.15-3.05(m, 4H), 2.66-2.55(m, 2H), 2.45-2.40(m, 2H), 2.21-2.08(m, 3H), 2.05-1.95(m, 1 H), 1.90-1.75(m, 4H), 1.55-1.45(m, 1H), 1.36-1.27(m, 2H), 1.26-1.19(m, 1H), 1.02-0.88(m, 2H).

[0195] ●Example 17. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 17) [ka]

[0196] • Step 1. Synthesis of 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzene sulfonate (2) In 30 mL of DCM, a solution of tert-butyl ((1r,4r)-4-(2-hydroxyethyl)cyclohexyl) carbamate (2.5 g, 10.27 mmol) was mixed with TsCl (1.09 g, 15.41 mmol), TEA (3.12 g, 30.82 mmol, 4.29 mL), and DMAP (125.51 mg, 1.03 mmol). The mixture was stirred at 20°C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The mixed organic layer was washed with water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 20-30% ethyl acetate / petroleum ether, gradient @ 80 mL / min) to obtain the title compound (1.86 g, 4.68 mmol, yield 45.54%) as a white solid. MS(M+H) + =398.1.

[0197] Step 2. Synthesis of tert-butyl((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)cyclohexyl)carbamate (4) In DMSO (20 mL), a solution of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (2 g, 6.46 mmol, HCl salt) and 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzene sulfonate (2.57 g, 6.46 mmol) was added, to which sodium iodide (193.54 mg, 1.29 mmol) and DIPEA (4.17 g, 32.28 mmol, 5.62 mL) were added. The resulting mixture was stirred at 80°C for 16 hours. 42% of the target compound peak was confirmed by LC-MS. The residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground with MTBE at 25°C for 30 minutes to obtain the title compound (1.66 g, 3.33 mmol, yield 51.56%) as a yellow solid. MS(M+H) + = 499.3.

[0198] • Step 3. Synthesis of 3-(4-(4-(2-((1r,4r)-4-aminocyclohexyl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (5) In 20 mL of dioxane, a solution of tert-butyl((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)cyclohexyl)carbamate (1.77 g, 3.55 mmol) was added, to which HCl / dioxane (4 M, 20 mL) was added. The mixture was stirred at 25°C for 2 hours. A major peak of one desired mass was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (TFA)-ACN]; gradient: 0%~30% B, 10 minutes), lyophilized, and the title compound (1.6 g, 2.98 mmol, yield 83.93%, purity 81%) was obtained as a yellow solid. MS(M+H) + =399.2.

[0199] Step 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 17) In 10 mL of DMF, HATU (954.80 mg, 2.51 mmol), DIPEA (1.08 g, 8.37 mmol, 1.46 mL), and 3-(4-(4-(2-((1r,4r)-4-aminocyclohexyl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (1.08 g, 2.01 mmol, purity 81%) were added to a solution of 4-((4-((4-((2-((1r,4r)-4-aminocyclohexyl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (1.08 g, 2.01 mmol, purity 81%). The resulting mixture was stirred at 25°C for 2 hours. A major peak of one desired mass was identified by LC-MS. The reaction mixture was poured into water (50 mL) and filtered. The filtered cake was collected and purified by preparative HPLC (column: Phenomenex luna C18 150×40mm×15μm; mobile phase: [water (TFA)-ACN]; gradient: 25%~55% B, 10 minutes), then lyophilized to obtain the title compound (849.5 mg, 700.56 μmol, yield 41.85%, purity 99%, 3TFA) as a pale yellow solid. MS(M+H) + = 858.3.

[0200] 1H NMR (400 MHz, CD3OD) δ=8.12(d, J=4.4 Hz, 1H), 8.02(br d, J=8.6 Hz, 2H), 7.90(br d, J=8.6 Hz, 2H), 7.84-7.76(m, 3H), 7.65(br d, J=8.5 Hz, 2H), 7.53(br d, J=8.3 Hz, 1H), 7.39(br t, J=7.7 Hz, 1H), 7.32-7.25(m, 1H), 7.19(br d, J=8.5 Hz, 2H), 7.02(br d, J=8.4 Hz, 2H), 3.91-3.77(m, 4H), 3.68(br d, J=11.4 Hz, 2H), 3.28-3.19(m, 4H), 3.11-2.97(m, 2H), 2.76-2.56(m, 2H), 2.28-2.14(m, 2H), 2.06 -1.96(m, 2H), 1.91-1.82(m, 2H), 1.77-1.66(m, 2H), 1.48-1.33(m, 3H), 1.27-1.12(m, 2H).

[0201] ●Example 18. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 18) [ka]

[0202] Step 1. Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperazine-1-carboxylate (3) Pd(dppf)Cl2 (494.08 mg, 675.24 μmol) was added at 25°C to a mixture of dioxane (100 mL) and H2O (15 mL) containing 2,6-bis(benzyloxy)-3-bromopyridine (5 g, 13.50 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (5 g, 12.88 mmol) and tripotassium phosphate (8.60 g, 40.51 mmol). The resulting mixture was purged with N2 three times, degassed, heated to 100°C, and stirred for 14 hours. LCMS confirmed the complete consumption of 2,6-bis(benzyloxy)-3-bromopyridine, and a major peak (R) of one desired mass was identified. f The compound (=1.179 min, 82% area) was detected. The reaction mixture was diluted with ethyl acetate (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g silica gel column, ethyl acetate / petroleum ether = 0-6%, 100 mL / min) to obtain the title compound (7 g, 12.56 mmol, yield 93.02%, purity 99%) as a white solid. MS(M+H) + = 552.4.

[0203] Step 2. Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-carboxylate (4) A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperazine-1-carboxylate (7 g, 12.69 mmol), acetic acid (761.98 mg, 12.69 mmol), and Pd / C (1.35 g, 1.27 mmol, purity 10%) was purged with H2 three times, degassed, and stirred for 16 hours under H2 (15 psi) at 25°C. LC-MS detected a major peak (Rf = 0.984 min, 96% area) of one desired mass, indicating complete consumption of the starting material. The reaction mixture was filtered, washed with THF (100 mL), and concentrated under reduced pressure to obtain the title compound (4.7 g, 11.96 mmol, yield 94.23%, purity 95%) as a gray solid, which was used directly. MS(M+H) + = 374.2.

[0204] • Step 3. Synthesis of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (5) In 50 mL of dioxane, a solution of tert-butyl 4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-carboxylate (4.7 g, 12.59 mmol) was added to HCl / dioxane (4 M, 50 mL). The mixture was stirred at 20°C for 2 hours. LC-MS detected a major peak (Rf = 0.245 min, 95% area) at one desired mass, indicating complete consumption of the starting material. The mixture was concentrated under reduced pressure to obtain the title compound (5.8 g, 2HCl salt) as a white solid, which was used directly. MS(M+H) + = 274.2.

[0205] • Step 4. Synthesis of 3-(4-(4-(2,2-dimethoxyethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (7) A mixture of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (1 g, 2.89 mmol, 2HCl salt), 2-bromo-1,1-dimethoxyethane (634.57 mg, 3.75 mmol, 440.68 μL), and DIPEA (1.87 g, 14.44 mmol, 2.52 mL) in DMF (10 mL) was stirred at 100 °C for 16 hours. LC-MS detected that 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione was completely consumed, and 28% of the desired mass was detected. The mixture was diluted with H₂O (30 mL), treated with saturated sodium carbonate solution (30 mL), extracted with ethyl acetate (40 mL x 7), washed with brine (10 mL x 5), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent: 50-100% ethyl acetate / petroleum ether to 0-20% methanol / ethyl acetate, gradient @ 100 mL / min) to obtain the title compound (450 mg, 1.25 mmol, yield 22.50%) as a brown solid. MS(M+H) + = 362.2.

[0206] • Step 5. Synthesis of 2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)acetaldehyde (8) A mixture of 3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (0.45 g, 1.25 mmol) and HBr (14.90 g, 73.66 mmol, 10 mL, purity 40%) was stirred at 40°C for 16 hours in H2O (5 mL). LC-MS detected a major peak (Rf = 0.421 min, 33% area) of one desired mass, indicating complete consumption of the starting material. The reaction mixture was adjusted to pH = 8 with aqueous sodium carbonate and extracted with ethyl acetate (15 mL x 5). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (185 mg, 563.16 μmol, yield 45.23%, purity 96%) as a brown solid. MS(M+H) + = 316.1.

[0207] Step 6. Synthesis of tert-butyl(1-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-4-yl)carbamate (10) A mixture of 2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)acetaldehyde (160 mg, 507.35 μmol), tert-butylpiperidine-4-yl carbamate (121.93 mg, 608.82 μmol), 4 angstrom MS (30 mg), and TEA (51.34 mg, 507.35 μmol, 70.62 μL) in DCM (2 mL) was stirred at 25°C for 0.5 hours. Then sodium triacetoxyborohydride (322.58 mg, 1.52 mmol) was added, and the resulting mixture was stirred at 25°C for 2 hours. LC-MS revealed that 2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)acetaldehyde was completely consumed, and a major peak (R) of one desired mass was observed. f The compound (=0.786 min, 60% area) was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with THF (15 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (4 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 50-100% to 0-20% methanol / ethyl acetate, gradient @ 100 mL / min) to obtain the title compound (150 mg, 255.18 μmol, yield 50.30%, purity 85%) as a yellow solid. MS(M+H) + = 500.4.

[0208] • Step 7. Synthesis of 3-(4-(4-(2-(4-aminopiperidine-1-yl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (11) A mixture of tert-butyl(1-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-4-yl)carbamate (150 mg, 300.21 μmol) and TFA (2.30 g, 20.19 mmol, 1.5 mL) was stirred at 15°C for 1 hour in DCM (5 mL). LC-MS detected the complete consumption of the starting material and the desired mass. The mixture was concentrated under reduced pressure to obtain the title compound (190 mg, 2 TFA salt) as a brown gum, which was used directly. MS(M+H) + = 400.2.

[0209] Step 8. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperazine-1-yl)ethyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 18) In 2 mL of DMF, a mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (140 mg, 292.96 μmol), HATU (144.81 mg, 380.85 μmol), and DIPEA (378.64 mg, 2.93 mmol, 510.29 μL) was stirred at 15°C for 15 minutes. Then, 3-(4-(4-(2-(4-aminopiperidine-1-yl)ethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione (190 mg, 302.75 μmol, 2 TFA salt) was added, and the resulting mixture was stirred at 15°C for 1 hour. A peak at 55% of the desired mass was confirmed by LC-MS. The mixture was adjusted to pH < 7 with TFA and filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 10%~40% B, 10 minutes) and lyophilized. The product was confirmed to be impure by 1H NMR and 1H NMR. A mixture (ethyl acetate:THF:ACN = 4:1:1, 80 mL) was added to the impure product, the mixture was diluted with H2O (50 mL), and the pH was adjusted to >7 with sodium bicarbonate solution (10 mL). The organic phase was separated and concentrated under reduced pressure. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 8:1) to obtain the product, which was diluted with a mixture (ACN:H2O:THF = 15:15:4, 34 mL) and lyophilized to obtain the title compound (19.9 mg, 22.07 μmol, yield 7.53%, purity 95.3%) as a brown solid. MS(M+H) + = 859.3.

[0210] 1H NMR (400 MHz, DMSO-d6) δ=10.78(s, 1H), 9.94(s, 1H), 9.75(s, 1H), 9.62(s, 1H), 8.25(d, J=3.4 Hz, 1H), 8.12-7.95(m, 5H), 7.80-7.75(m, 4H), 7.65(d, J=7.9 Hz, 1H), 7.56(d, J=7.9 Hz, 1H), 7.39(t, J=7.6 Hz, 1H), 7.34-7.25(m, 1H), 7.05(br d, J=8.2 Hz, 2H), 6.89(br d, J=8.6 Hz, 2H), 3.83-3.69(m, 2H), 3.15-3.07(m, 4H), 3.03-2.87(m, 2H), 2.64-2.55(m, 6H), 2.48 -2.38(m, 4H), 2.20-2.07(m, 2H), 2.06-1.96(m, 2H), 1.87-1.74(m, 2H), 1.69-1.47(m, 2H).

[0211] ●Example 19. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)ethyl)piperidine-4-yl)carbamoyl)phenyl)amino)5-fluoropyrimidine-4-yl)amino)benzamide (compound 19) [ka]

[0212] Step 1. Synthesis of benzyl(1-(2-(piperidine-4-yl)ethyl)piperidine-4-yl)carbamate (2) In 6 mL of dioxane, a solution of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)ethyl)piperidine-1-carboxylate (600 mg, 1.35 mmol) was added to HCl / dioxane (4 M, 12.00 mL). The mixture was stirred at 25°C for 0.5 hours. LC-MS confirmed that the starting material was completely consumed and the desired mass was obtained. The reaction mixture was concentrated under reduced pressure to obtain the title compound (440 mg, crude product, HCl) as a white solid. MS(M+H) += 346.2.

[0213] Step 2. Synthesis of benzyl(1-(2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)ethyl)piperidine-4-yl)carbamate (4) A mixture of benzyl(1-(2-(piperidine-4-yl)ethyl)piperidine-4-yl)carbamate (380 mg, 994.92 μmol, HCl), 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (487.99 mg, 994.92 μmol), cesium carbonate (972.50 mg, 2.98 mmol), and Pd-PEPPSI-IHeptCl (48.39 mg, 49.75 μmol) was degassed in 4 mL of dioxane, purged three times with N2, heated to 100°C, and stirred for 16 hours under an N2 atmosphere. LC-MS confirmed that the starting materials were completely consumed. The mixture was filtered, concentrated under reduced pressure, and the residue was obtained. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-10%, @80 mL / min) to obtain the title compound (135 mg, 184.20 μmol, yield 18.51%, purity 97%) as a yellow solid. MS(M+H) + = 711.5.

[0214] Step 3. Synthesis of 3-(4-(4-(2-(4-aminopiperidine-1-yl)ethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (5) In CF3CH2OH (1.3 mL), benzyl (1-(2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)ethyl)piperidine-4-yl)carbamate (135 mg, 189.90 μmol) and TFA (21.65 mg, 189.90 μmol, 14.11 μL) solution were mixed with Pd / C (40 mg, purity 10%) and Pd(OH)2 / C (40 mg, purity 20%) under H2. The mixture was degassed, purged several times with H2, and stirred for 16 hours under H2 (15 psi) at 25°C. LCMS confirmed that the starting materials were completely consumed. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (97 mg, 189.24 μmol, yield 99.66%, TFA) as a brown oil. MS(M+H) += 399.2.

[0215] Step 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)ethyl)piperidine-4-yl)carbamoyl)phenyl)amino)5-fluoropyrimidine-4-yl)amino)benzamide (compound 19) In 0.5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (60.60 mg, 126.81 μmol) was mixed with HATU (72.33 mg, 190.22 μmol) and DIPEA (81.95 mg, 634.07 μmol, 110.44 μL). The mixture was stirred at 25°C for 0.5 hours. Then, 3-(4-(4-(2-(4-aminopiperidine-1-yl)ethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (65 mg, 126.81 μmol, TFA) was added, and the resulting mixture was stirred at 25°C for 16 hours. LC-MS confirmed the complete consumption of 3-(4-(4-(2-(4-aminopiperidine-1-yl)ethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione and the desired mass. The reaction mixture was poured into H2O (15 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-20% methanol / ethyl acetate @ 50 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 22%-52% B, 9 minutes), lyophilized, and the title compound (10 mg, 11.53 μmol, yield 9.09%, purity 99%) was obtained as a white solid. MS(M+H) + = 858.3.

[0216] 1H NMR (400 MHz, DMSO-d6) δ=10.76(br s, 1H), 9.92(s, 1H), 9.73(br d, J=2.0 Hz, 1H), 9.60(s, 1H), 8.24(d, J=3.5 Hz, 1H), 8.07-7.95(m, 5H), 7.77(s, 4H), 7.68-7.63(m, 1H), 7.59-7.53(m, 1H), 7.42-7.37(m, 1H), 7.32-7.26(m, 1H), 7.03(d, J=8.7 Hz, 2H), 6.88(d, J=8.8 Hz, 2H), 3.79-3.68(m, 2H), 3.64(br d, J=11.9 Hz, 2H), 2.90-2.81(m, 2H), 2.64-2.58(m, 3H), 2.50-2.45(m, 1H), 2.31-2.28(m, 1H), 2.17-2.05(m, 2H), 2.03-1.97(m, 1H), 1.92(br t, J=10.5 Hz, 2H), 1.80-1.70(m, 4H), 1.60-1.50(m, 2H), 1.46-1.35(m, 3H), 1.29-1.20(m, 2H).

[0217] ●Example 20. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 20) [ka] [ka]

[0218] • Step 1.3 Synthesis of (5-bromopyridine-2-yl)piperidine-2,6-dione (2) In 30 mL of DMF, a solution of ethyl 2-(5-bromopyridine-2-yl)acetate (3 g, 13.04 mmol) was mixed with acrylamide (926.87 mg, 13.04 mmol, 899.87 μL) and t-BuOK (1 M, 13.04 mL) at 0°C. The mixture was stirred at 0°C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1) confirmed the consumption of the starting material and the formation of new spots. The mixture was poured into water (50 mL) at 0°C and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (10 mL x 3), dried over sodium sulfate, filtered, concentrated, and the residue was ground with ethyl acetate / MTBE (20 mL, 1:1) at 20°C for 1 hour to obtain the title compound (900 mg, 3.34 mmol, yield 25.65%) as a pale yellow solid. MS(M+H) + = 269.0.

[0219] Step 2. Synthesis of tert-butyl 4-((6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)ethynyl)piperidine-1-carboxylate (4) In 5 mL of DMF, a solution of 3-(5-bromopyridine-2-yl)piperidine-2,6-dione (514.31 mg, 1.91 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (0.4 g, 1.91 mmol), and TEA (580.20 mg, 5.73 mmol, 798.08 μL) was mixed with Pd(PPh3)2Cl2 (67.08 mg, 95.56 μmol) and CuI (36.40 mg, 191.13 μmol) under N2. The resulting solution was stirred at 80°C for 16 hours. A major peak of one desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (0.78 g, crude product) as a yellow solid. MS(M+H) + = 398.2.

[0220] • Step 3. Synthesis of 3-(5-(piperidine-4-ylethinyl)pyridine-2-yl)piperidine-2,6-dione (5) To a solution of tert-butyl 4-((6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)ethynyl)piperidine-1-carboxylate (0.78 g, 1.96 mmol) in dioxane (10 mL), HCl / dioxane (4 M, 10.00 mL) was added. The resulting mixture was stirred at 20°C for 2 hours. LC-MS confirmed complete consumption of the starting material and a major peak of one desired mass. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (30 mL) and extracted with ethyl acetate (10 mL x 3). The aqueous phase was freeze-dried to obtain the title compound (1 g, crude product) as a yellow solid. MS(M+H) + = 298.2.

[0221] Step 4. Synthesis of tert-butyl 4-((6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate (6) A mixture of 3-(5-(piperidine-4-ylethynyl)pyridine-2-yl)piperidine-2,6-dione (0.9 g, 2.70 mmol, HCl), tert-butyl 4-oxopiperidine-1-carboxylate (590.91 mg, 2.97 mmol), and TEA (545.64 mg, 5.39 mmol) was stirred at 20°C for 0.5 hours in DCM (10 mL). Then sodium triacetoxyborohydride (1.71 g, 8.09 mmol) was added, and the resulting mixture was stirred at 20°C for 16 hours. LC-MS confirmed that the starting materials were completely consumed. The reaction mixture was diluted with sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes) to obtain the title compound (180 mg, 269.42 μmol, yield 9.99%, purity 89%, TFA) as a yellow solid. MS(M+H) + = 481.3.

[0222] • Step 5.3-(5-([1,4'-bipiperidine]-4-ylethinyl)pyridine-2-yl)piperidine-2,6-dione (7) In 2 mL of dioxane, a solution of tert-butyl 4-((6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate (180 mg, 374.53 μmol) was added, to which HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 20°C for 2 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (160 mg, crude product, HCl) as a yellow solid. MS(M+H) + = 381.3.

[0223] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((6-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 20) A mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (82.52 mg, 172.69 μmol), DIPEA (49.60 mg, 383.75 μmol, 66.84 μL), and HATU (80.25 mg, 211.06 μmol) was stirred at 25°C for 0.5 hours in DMF (1 mL). Then, a solution of 3-(5-([1,4'-bipiperidine]-4-ylethynyl)pyridine-2-yl)piperidine-2,6-dione (80 mg, 191.87 μmol, HCl) was added to DMF (1 mL), and the mixture was stirred at 25°C for 16 hours. A major peak of one desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (20 mL) and extracted with THF (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (column: Phenomenex Luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 25%~55% B, 10 minutes), followed by preparative TLC (silicon dioxide, DCM:methanol = 10:1) to obtain the title compound (9.3 mg, 10.73 μmol, yield 5.59%, purity 97%) as a white solid. MS(M+H) + = 840.3.

[0224] 1H NMR (400 MHz, DMSO-d6) δ=10.87(s, 1H), 9.91(s, 1H), 9.72(s, 1H), 9.55(s, 1H), 8.51(d, J=1.5 Hz, 1H), 8.22(d, J=3.7 Hz, 1H), 8.03-7.96(m, 4H), 7.78(dd, J=1.9, 8.1 Hz, 1H), 7.73(br d, J=8.7 Hz, 2H), 7.65(br d, J=6.8 Hz, 1H), 7.56(d, J=7.2 Hz, 1H), 7.40-7.27(m, 5H), 4.05(dd, J=5.3, 9.7 Hz, 1H), 2.80-2.70(m, 3H), 2.69-2.65(m, 1H), 2.37-2.26(m, 4H), 2.18-2.05(m, 2H), 2.04-1.94(m, 1H), 1.89-1.69(m, 5H), 1.67-1.48(m, 3H), 1.47-1.32(m, 3H).

[0225] ●Example 21. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonane-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 21) [ka]

[0226] • Step 1: Synthesis of 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane(3) A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-3-fluorophenyl)pyridine (2 g, 4.31 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (2.00 g, 13.96 mmol, 1.78 mL), Pd2(dba)3 (400.00 mg, 436.82 μmol), s-Phos (160.00 mg, 389.74 μmol), and t-BuONa (2 M, 6.01 mL) was degassed in toluene (30 mL) and purged three times with N2. The resulting mixture was stirred for 16 hours under an N2 atmosphere at 100°C. LCMS confirmed that 2,6-bis(benzyloxy)-3-(4-bromo-3-fluorophenyl)pyridine was completely consumed and the desired mass was confirmed. The reaction mixture was stopped by adding H2O (100 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether, gradient @ 50 mL / min) to obtain the title compound (2.21 g, 3.74 mmol, yield 86.89%, purity 89.18%) as a yellow oily substance. MS(M+H) + = 527.3.

[0227] • Step 2.3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione(4) In CF3CH2OH (30 mL), a solution of 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (2.2 g, 4.18 mmol) was added to Pd / C (300 mg, 10% purity) under an H2 atmosphere. The suspension was degassed, purged three times with H2, and stirred for 16 hours under H2 (15 psi) at 25°C. LCMS revealed a 68% peak of 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane, with 23% of the target compound confirmed. The mixture was stirred for a further 16 hours. LC-MS confirmed that 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated to obtain 3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione (1.3 g, 3.73 mmol, yield 89.32%) as a yellow solid. The crude product was used directly in the next step. MS(M+H) + =349.2.

[0228] • Step 3. Synthesis of 3-(3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)piperidine-2,6-dione (5) HCl (6M, 1.85mL) was added to a solution of 3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione (0.645g, 1.85 mmol) in acetone (10 mL). The mixture was stirred at 25°C for 48 hours. LC-MS revealed that 24% of 3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione remained, and a peak at the desired mass of 63% was confirmed. The mixture was diluted with H2O (20 mL), neutralized with sodium bicarbonate solution, and then extracted with ethyl acetate (10 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.555 g, 1.82 mmol, 98.50% yield) as a blue oil. The crude product was used directly in the next step. MS(M+H) + =305.0.

[0229] Step 4. Synthesis of benzyl(7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonane-2-yl)carbamate(7) In 7 mL of DCM, a solution of 3-(3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)piperidine-2,6-dione (0.769 g, 1.26 mmol, 50% purity) was mixed with benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (340.99 mg, 1.10 mmol, HCl), 4A MS (1.5 g), and TEA (383.56 mg, 3.79 mmol, 527.59 μL). The mixture was stirred at 25°C for 0.5 hours. Then, sodium triacetoxyborohydride (803.35 mg, 3.79 mmol) was added, and the resulting mixture was stirred at 25°C for 16 hours. LC-MS completely consumed 3-(3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)piperidine-2,6-dione, and the desired mass was confirmed. The reaction mixture was poured into water (30 mL) and extracted with DCM (15 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-30%, @50 mL / min) to obtain the title compound (0.41 g, 692.23 μmol, yield 54.79%, purity 95%) as a white solid. MS(M+H) + = 563.3.

[0230] • Step 5. Synthesis of 3-(4-(4-(2-amino-7-azapiro[3.5]nonan-7-yl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione (8) A solution of benzyl(7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonan-2-yl)carbamate (56 mg, 99.52 μmol) in TFA (1.72 g, 15.13 mmol, 1.12 mL) was stirred at 40°C for 16 hours. LC-MS confirmed that the benzyl(7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonan-2-yl)carbamate was completely consumed and the desired mass was confirmed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.053 g, 97.68 μmol, yield 98.15%, TFA) as a brown oil. The crude product was used directly in the next step. MS(M+H) + = 429.2.

[0231] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonane-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 21) In 2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (232.94 mg, 365.59 μmol, purity 75%), HATU (208.51 mg, 548.38 μmol), and DIPEA (236.25 mg, 1.83 mmol, 318.40 μL) was stirred at 25°C for 0.5 hours. Then, 3-(4-(4-(2-amino-7-azaspiro[3.5]nonan-7-yl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione (0.17 g, 365.59 μmol, HCl) was added, and the mixture was stirred at 25°C for 16 hours. LC-MS confirmed the complete consumption of 3-(4-(4-(2-amino-7-azaspiro[3.5]nonan-7-yl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione and the desired mass. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-30%, @50mL / min), followed by preparative HPLC (column: Waters Xbridge 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 10 min), lyophilized, and obtained N-(2-chlorophenyl)-4-((2-((4-((7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonane-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (9.5 mg, 9.62 μmol, yield 2.63%, purity 90%) as a white solid. MS(M+H) + = 888.3.

[0232] 1H NMR (400 MHz, DMSO-d6) δ=10.80(s, 1H), 9.93(s, 1H), 9.73(s, 1H), 9.62(s, 1H), 8.34(br d, J=7.7 Hz, 1H), 8.25(d, J=3.4 Hz, 1H), 8.10-7.93(m, 4H), 7.80-7.76(m, 4H), 7.69-7.62(m, 1H), 7.59-7.54(m, 1H), 7.44-7.36(m, 1H), 7.33-7.26(m, 1H), 7.06(t, J=8.7 Hz, 1H), 6.77-6.65(m, 2H), 4.43-4.32(m, 1H), 3.93-3.82(m, 1H), 3.75-3.68(m, 2H), 3.32-3.27(m, 1H), 2.77-2.62(m, 3H), 2.46-2.41(m, 2H), 2.40-2.27(m, 3H), 2.20-2.05(m, 3H), 2.01-1.89(m, 1H), 1.80-1.72(m, 4H), 1.63-1.38(m, 6H).

[0233] ●Example 22. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-((7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonane-2-yl)amino)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 22) [ka]

[0234] Step 1. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-((7-(1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)-7-azaspiro[3.5]nonane-2-yl)amino)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 22) In 2 mL of DMF, a solution of 2-(4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenyl)acetic acid (171.25 mg, 313.33 μmol, 90% purity), HATU (178.70 mg, 469.99 μmol), and DIPEA (202.48 mg, 1.57 mmol, 272.88 μL) was stirred at 25°C for 0.5 hours. Then, 3-(4-(4-(2-amino-7-azaspiro[3.5]nonan-7-yl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione (0.17 g, 313.33 μmol, TFA) was added, and the resulting mixture was stirred at 25°C for 16 hours. LC-MS confirmed the complete consumption of 3-(4-(4-(2-amino-7-azaspiro[3.5]nonan-7-yl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione and the desired mass. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was washed by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-30%, @80mL / min), purified by preparative HPLC (column: Waters Xbridge 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 10 min), lyophilized, and the title compound (22 mg, 22.18 μmol, yield 7.08%, purity 91%) was obtained as a white solid. MS(M+H) + = 902.3.

[0235] 1H NMR(400 MHz, DMSO-d6)δ=10.80(s, 1H), 9.91(s, 1H), 9.65(s, 1H), 9.25(s, 1H), 8.31-8.12(m, 2H), 8.10-7.89(m , 4H), 7.70-7.50(m, 4H), 7.45-7.23(m, 2H), 7.21-6.99(m, 3H), 6.79-6.61(m, 2H), 4.12-4.03(m, 1H), 3. 92-3.83(m, 1H), 3.77-3.65(m, 2H), 3.43-3.40(m, 1H), 3.32-3.30(m, 2H), 2.72-2.60(m, 3H), 2.47-2.23 (m, 5H), 2.21-2.09(m, 1H), 2.09-1.86(m, 3H), 1.81-1.69(m, 2H), 1.63-1.54(m, 2H), 1.54-1.38(m, 6H).

[0236] ●Example 23. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((7-((1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 23) [ka]

[0237] • Step 1. Synthesis of 1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-carbaldehyde (2) In 30 mL of DCM, a solution of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione was added to 2.98 g of DMP (7.02 mmol), and the resulting mixture was stirred at 25°C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1) confirmed that 3-(3-fluoro-4-(4-(hydroxymethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione was completely consumed and new spots were formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g, crude product) as a yellow oily substance. MS(M+H) + =319.1.

[0238] Step 2. Synthesis of benzyl(7-((1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)methyl)-7-azaspiro[3.5]nonane-2-yl)carbamate(4) In 30 mL of DCM, a solution of 1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-carbaldehyde (1.28 g, 4.02 mmol) and benzyl(7-azaspiro[3.5]nonan-2-yl)carbamate (1.25 g, 4.02 mmol, HCl) was added to sodium acetate (494.87 mg, 6.03 mmol) and sodium triacetoxyborohydride (1.28 g, 6.03 mmol). The resulting mixture was stirred at 25°C for 14 hours. The desired mass peak (54%) was confirmed by LC-MS. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The mixed organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-30%, gradient @ 80 mL / min) to obtain the title compound (1.1 g, 1.91 mmol, yield 47.43%) as a yellow solid. MS(M+H) + = 577.3.

[0239] • Step 3. Synthesis of 3-(4-(4-((2-amino-7-azaspiro[3.5]nonanane-7-yl)methyl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione (5) A mixture of benzyl(7-((1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (0.5 g, 867.00 μmol) in TFA (7.70 g, 67.53 mmol, 5 mL) was stirred at 40 °C for 17 hours. LC-MS confirmed complete consumption of the starting material and 89% of the desired mass. The mixture was concentrated under reduced pressure to obtain the title compound (0.4 g, crude product) as a yellow oil. MS(M+H) + = 443.3.

[0240] Step 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((7-((1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-yl)methyl)-7-azaspiro[3.5]nonane-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 23) In 5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (287.13 mg, 600.84 μmol) was added to DIPEA (104.49 mg, 808.49 μmol, 140.82 μL) and HATU (122.97 mg, 323.40 μmol), and the resulting mixture was stirred at 25°C for 1 hour. Then, 3-(4-(4-((2-amino-7-azaspiro[3.5]nonane-7-yl)methyl)piperidine-1-yl)-3-fluorophenyl)piperidine-2,6-dione (150 mg, 269.50 μmol, TFA) was added, and the resulting mixture was stirred at 25°C for 1 hour. The major peak of the desired mass was confirmed by LC-MS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative HPLC (column: Waters Xbridge C18 150 *50 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 50%~80%, 10 min), followed by purification by preparative HPLC (column: Phenomenex luna C18 150 *25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 18%~48%, 10 min), lyophilized, and the title compound (37.4 mg, 39.43 μmol, yield 14.63%, FA) as a white solid. MS(M+H) + =902.7.

[0241] 1H NMR (400 MHz, DMSO-d6) δ=10.81(s, 1H), 9.94(s, 1H), 9.75(s, 1H), 9.62(s, 1H), 8.36(br d, J=7.1 Hz, 1H), 8.25(d, J=3.5 Hz, 1H), 8.15(s, 1H), 8.06-7.98(m, 4H), 7.79-7.77(m, 4H), 7.66(dd, J=1.5, 8.0 Hz, 1H), 7.57(dd, J=1.4, 8.0 Hz, 1H), 7.40(dt, J=1.3, 7.7 Hz, 1H), 7.34-7.27(m, 1H), 7.05-6.92(m, 3H), 4.44-4.32(m, 1H), 3.80(dd, J=4.8, 11.6 Hz, 1H), 3.24-3.18(m, 2H), 2.66-2.60(m, 3H), 2.56-2.50(m, 5H), 2.50-2.54(m, 2H), 2.21 -2.13(m, 3H), 2.03-1.95(m, 1H), 1.86-1.76(m, 4H), 1.71-1.54(m, 5H), 1.32-1.23(m, 2H).

[0242] ●Example 24. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 24) [ka] [ka]

[0243] Step 1. Synthesis of tert-butyl 4-((1-(4-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (3) Potassium carbonate (3.70 g, 26.79 mmol) was added to a solution of 1-fluoro-4-nitrobenzene (1.04 g, 7.37 mmol, 781.48 μL) and tert-butyl 4-(piperidine-4-ylmethyl)piperazine-1-carboxylate (2.3 g, 6.70 mmol, acetic acid) in acetonitrile (30 mL). The mixture was stirred at 25 °C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (1.9 g, 4.37 mmol, yield 65.23%, purity 93%) as a yellow solid. MS(M+H) + = 405.2.

[0244] Step 2. Synthesis of tert-butyl 4-((1-(4-aminophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (4) Iron (786.93 mg, 14.09 mmol) was added at 80°C to a mixture of tert-butyl 4-((1-(4-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1.9 g, 4.70 mmol) and ammonium chloride (1.01 g, 18.79 mmol) in ethanol (10 mL) and H2O (10 mL). The resulting mixture was stirred at 80°C for 1 hour. LC-MS confirmed that the starting materials were completely consumed. The reaction mixture was poured into a sodium bicarbonate solution (50 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The mixed organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 100 mL / min) to obtain the title compound (1.5 g, 3.80 mmol, yield 81.00%, purity 95%) as a brown solid. MS(M+H) += 375.2.

[0245] Step 3. Synthesis of tert-butyl 4-((1-(4-((2,6-bis(benzyloxy)pyridine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (6) In 20 mL of dioxane, a mixture of tert-butyl 4-((1-(4-aminophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1.5 g, 4.01 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (1.48 g, 4.01 mmol), and cesium carbonate (3.91 g, 12.02 mmol) was mixed with Pd-PEPPSI-IHeptCl (194.80 mg, 200.26 μmol). The resulting mixture was stirred at 90°C under N2 for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-60% ethyl acetate / petroleum ether gradient @ 100 mL / min) to obtain the title compound (2.5 g, 3.62 mmol, yield 90.27%, purity 96%) as a brown oily substance. MS(M+H) + = 664.4.

[0246] Step 4. Synthesis of tert-butyl 4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (7) In CF3CH2OH (40 mL) and THF (8 mL), a solution of tert-butyl 4-((1-(4-((2,6-bis(benzyloxy)pyridine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1.25 g, 1.88 mmol) was added under H2 conditions to CH3COOH (113.08 mg, 1.88 mmol) and Pd / C (200.39 mg, 188.30 μmol, 10% purity). The resulting mixture was stirred at 25°C under H2 (15 psi) for 16 hours. LC-MS confirmed that the starting material was still present. Further addition of Pd / C (200.39 mg, 188.30 μmol, 10% purity) was added, and the mixture was stirred at 25°C under H2 (15 psi) for 6 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound (1.5 g, crude product) as a black solid. The crude product was used in the next step without further purification. MS(M+H) + = 486.3.

[0247] • Step 5.3 Synthesis of ((4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (8) 2 mL of HCl / dioxane (4M, 2 mL) was added to a solution of tert-butyl 4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (200 mg, 411.85 μmol) in dioxane (2 mL). The resulting mixture was stirred at 25°C for 2 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (180 mg, crude product, HCl) as a black solid. The crude product was used in the next step without further purification. MS(M+H) + = 386.4.

[0248] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 24) A mixture of 2-(4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenyl)acetic acid (181.51 mg, 368.99 μmol), HATU (233.83 mg, 614.98 μmol), and DIPEA (158.96 mg, 1.23 mmol, 214.24 μL) was stirred at 25°C for 0.5 hours in DMF (2 mL). Then, a solution of 3-((4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (173 mg, 409.99 μmol, HCl) and DIPEA (158.96 mg, 1.23 mmol, 214.24 μL) was added to DMF (2 mL). The resulting mixture was stirred at 25°C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (50 mL) and extracted with THF (10 mL x 3). The mixed organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient to 0-50% methanol / ethyl acetate gradient @ 100 mL / min). The residue was further separated by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 12%~32%, 10 min), and then purified by preparative TLC (silicon dioxide, DCM:methanol = 15:1) to obtain the title compound (7 mg, 7.49 μmol, yield 1.83%, purity 92%) as a yellow solid. MS(M+H) + = 859.3.

[0249] 1H NMR (400 MHz, DMSO-d6) δ=10.76(brs, 1H), 9.89(s, 1H), 9.65(s, 1H), 9.28(s, 1H), 8.18(br s, 1H), 8.06-8.00(m, 2H), 8.00-7.94(m, 2H), 7.65(br d, J=7.9 Hz, 1H), 7.60(br d, J=7.5 fHz, 2H), 7.56(br d, J=8.4 Hz, 1H), 7.39(br t, J=7.7 Hz, 1H), 7.33-7.26(m, 1H), 7.12(br d, J=7.8 Hz, 2H), 6.73(br d, J=7.7 Hz, 2H), 6.58(br d, J=8.1 Hz, 2H), 5.38-5.32(m, 1H), 4.24-4.12(m, 1H), 3.63(br s, 2H), 3.55-3.45(m 4H), 2.79-2.69(m, 1H), 2.60-2.57(m, 2H), 2.46-2.40(m, 2H), 2.29-2.16(m, 4H), 2.15-2 .11(m, 3H), 1.89-1.78(m, 1H), 1.76-1.67(m, 2H), 1.54-1.46(m, 1H), 1.20-1.14(m, 2H).

[0250] ●Example 25. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 25) [ka]

[0251] Step 1. Synthesis of tert-butyl 4-((1-(3-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (3) A mixture of 1-iodo-3-nitrobenzene (1 g, 4.02 mmol), tert-butyl 4-(piperidine-4-ylmethyl)piperazine-1-carboxylate (1.66 g, 4.82 mmol, acetic acid), Pd2(dba)3 (367.75 mg, 401.60 μmol), RuPhos (374.80 mg, 803.20 μmol), and cesium carbonate (6.54 g, 20.08 mmol) in dioxane (2 mL) was degassed, purged three times with N2, and then stirred for 16 hours under an N2 atmosphere at 100°C. LC-MS confirmed that tert-butyl 4-(piperidine-4-ylmethyl)piperazine-1-carboxylate was completely consumed and the desired mass was confirmed. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether, gradient @ 50 mL / min) to obtain the title compound (1.23 g, 2.86 mmol, yield 71.23%, purity 94.08%) as a yellow solid. MS(M+H) + = 405.2.

[0252] Step 2. Synthesis of tert-butyl 4-((1-(3-aminophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (4) In ethanol (10 mL), a solution of tert-butyl 4-((1-(3-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1.23 g, 2.86 mmol, purity 94.08%) was added to H2O (2 mL) with ammonium chloride (765.13 mg, 14.30 mmol), followed by the addition of iron (479.28 mg, 8.58 mmol). The resulting mixture was stirred at 80°C for 1 hour. LC-MS confirmed the complete consumption of tert-butyl 4-((1-(3-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate and the peak corresponding to the desired mass. The reaction mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (20 mL x 5). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether, gradient @ 50 mL / min) to obtain the title compound (0.519 g, 1.33 mmol, yield 46.53%, purity 96.05%) as a yellow solid. MS(M+H) + = 375.3.

[0253] Step 3. Synthesis of tert-butyl 4-((1-(3-((2,6-bis(benzyloxy)pyridine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (6) A mixture of tert-butyl 4-((1-(3-aminophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (0.4 g, 1.03 mmol, purity 96.05%), 2,6-bis(benzyloxy)-3-bromopyridine (455.77 mg, 1.23 mmol), Pd2(dba)3 (93.94 mg, 102.58 μmol), RuPhos (95.74 mg, 205.17 μmol), and cesium carbonate (1.00 g, 3.08 mmol) was degassed in dioxane (8 mL), purged three times with N2, and then stirred under an N2 atmosphere at 100°C for 14 hours. LCMS confirmed that tert-butyl 4-((1-(3-aminophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate was completely consumed and the desired mass was confirmed. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-45% ethyl acetate / petroleum ether, gradient @ 50 mL / min) to obtain the title compound (0.519 g, 777.19 μmol, yield 75.76%, purity 99.41%) as a yellow solid. MS(M+H) + = 664.5.

[0254] Step 4. Synthesis of tert-butyl 4-((1-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (7) In CF3CH2OH (3 mL), a solution of tert-butyl 4-((1-(3-((2,6-bis(benzyloxy)pyridine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (120 mg, 180.76 μmol) was added to Pd / C (50 mg, 10% purity) under an H2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25°C under H2 (15 psi) for 16 hours. LCMS confirmed that tert-butyl 4-((1-(3-((2,6-bis(benzyloxy)pyridine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate was completely consumed, and the major peak (89%) of the desired mass was confirmed. The reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound (100 mg, 172.98 μmol, yield 95.69%, purity 84%) as a yellow solid. MS(M+H) + = 486.5.

[0255] • Step 5. Synthesis of 3-((3-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (8) In 3 mL of DCM, a solution of tert-butyl 4-((1-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate was added, to which TFA (1.54 g, 13.51 mmol, 1 mL) was added. The mixture was stirred at 20°C for 2 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.2 g, 400.38 μmol, yield 97.22%, TFA) as a blue solid. The crude product was used directly in the next step. MS(M+H) + = 454.2.

[0256] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 25) In 3 mL of DMF, a solution of 2-(4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenyl)acetic acid (246.18 mg, 400.38 μmol, 80% purity) and HATU (228.35 mg, 600.57 μmol) was mixed with DIPEA (310.48 mg, 2.40 mmol, 418.43 μL). The mixture was stirred at 20°C for 0.5 hours. Then, 3-((3-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (0.2 g, 400.38 μmol, TFA) was added, and the resulting mixture was stirred at 20°C for 16 hours. LC-MS confirmed the complete consumption of 3-((3-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione and the desired mass. The reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-100%, gradient @ 50 mL / min), followed by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min), lyophilized, and the title compound (5 mg, 5.64 μmol, yield 1.41%, purity 97%) was obtained as a white solid. MS(M+H) + = 859.5.

[0257] 1H NMR (400 MHz, DMSO-d6) δ=10.74(s, 1H), 9.92(s, 1H), 9.65(s, 1H), 9.32(s, 1H), 8.18(d, J=3.5 Hz, 1H), 8.05-7.95(m, 4H), 7.67-7.53(m, 4H), 7.43-7.36(m, 1H), 7.33-7.26(m, 1H), 7.12(d, J=8.4 Hz, 2H), 6.88(t, J=8.0 Hz, 1H), 6.24(s, 1H), 6.17(br d, J=7.8 Hz, 1H), 6.12-6.07(m, 1H), 5.61-5.56(m, 1H), 4.34-4.25(m, 1H), 3.64(s, 2H), 3.60-3.51(m, 3H), 3.49-3.42(m, 5H), 2.61-2.57(m, 2H) , 2.56-2.55(m, 1H), 2.27-2.18(m, 4H), 2.14-2.10(m, 2H), 1.90-1.79(m, 1H), 1.76-1.65(m, 2H), 1.64-1.51(m, 1H), 1.20-1.10(m, 2H).

[0258] ●Example 26. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 26) [ka]

[0259] Step 1. Synthesis of tert-butyl((1r,4r)-4-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamate (3) A mixture of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (500 mg, 968.26 μmol, 2TFA salt), ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (208.35 mg, 677.78 μmol), DIPEA (625.70 mg, 4.84 mmol, 843.27 μL), and potassium iodide (160.73 mg, 968.26 μmol) in DMF (7 mL) was stirred at 60°C for 16 hours. LC-MS revealed a residual peak of 18% of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione and a peak of 72% of the desired mass. Furthermore, ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (59.53 mg, 193.65 μmol) was added, and the resulting mixture was stirred at 60°C for 16 hours. LC-MS confirmed the complete consumption of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, with a peak at 92% of the desired mass. The mixture was adjusted to pH < 7 with acetic acid and purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes). The eluate was lyophilized to obtain the title compound (175 mg, 285.17 μmol, yield 29.45%, TFA salt) as a black solid. MS(M+H) + = 500.3.

[0260] • Step 2.3 Synthesis of ((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (4) In 4 mL of DCM, a solution of tert-butyl((1r,4r)-4-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamate (130 mg, 211.84 μmol, TFA salt) and TFA (1.54 g, 13.46 mmol, 1 mL) was stirred at 15°C for 1 hour. LC-MS confirmed that the starting materials were completely consumed. The mixture was concentrated under reduced pressure to obtain the title compound (135 mg, 2 TFA salt) as a black gum, which was used directly. MS(M+H) + = 400.2.

[0261] Step 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 26) A mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (90 mg, 188.33 μmol), HATU (93.09 mg, 244.83 μmol), and DIPEA (243.41 mg, 1.88 mmol) in DMF (4 mL) was stirred at 15°C for 30 minutes. Then, 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (130.00 mg, 207.15 μmol, 2TFA salt) was added, and the resulting mixture was stirred at 15°C for 1 hour. LC-MS revealed a residue of 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione, with a peak at 60% of the desired mass confirmed. The mixture was diluted with H2O (30 mL) and extracted with mixed ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 26%~56% B, 9 minutes), lyophilized, and the title compound (24.0 mg, 15.95 μmol, yield 8.47%, purity 95%, 5TFA salt) was obtained as a brown solid. MS(M+H) + = 859.2.

[0262] 1H NMR (400 MHz, DMSO-d6) δ=10.82(s, 1H), 9.94(s, 1H), 9.77(s, 1H), 9.63(s, 1H), 9.25 -9.15(m, 1H), 8.25(d, J=3.7 Hz, 1H), 8.16-7.97(m, 6H), 7.85-7.79(m, 4H), 7.65(dd, J=1.3, 7.9 Hz, 1H), 7.57(dd, J=1.3, 7.9 Hz, 1H), 7.46-7.36(m, 1H), 7.35-7.23(m, 1H), 6.83(br d, J=8.8 Hz, 2H), 6.67(d, J=8.9 Hz, 2H), 4.24(dd, J=4.7, 11.2 Hz, 1H), 3.80-3.70(m, 1H), 3.65-3.55(m, 4H), 3.23-3.10(m, 2H), 3.10-3.05(m, 2H), 3.00-2.86(m, 2H), 2.79-2.67(m, 1H), 2.65-2.56(m, 1H), 2.12-2.08(m, 1H), 1.98-1.87(m, 5H), 1.83-1.78(m, 1H), 1.45-1.29(m, 2H), 1.19-1.05(m, 2H).

[0263] ●Example 27. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(((1R,5S,6s)-3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 27) [ka]

[0264] Step 1. Synthesis of tert-butyl(1R,5S,6r)-6-((tosyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2) To a solution of tert-butyl(1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 4.69 mmol) in DCM (10 mL), TosCl (1.34 g, 7.03 mmol) and TEA (948.92 mg, 9.38 mmol, 1.31 mL) were added at 25°C. The mixture was stirred at 25°C for 12 hours. The starting material was consumed by LC-MS and the desired mass was confirmed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (15 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (920 mg, 2.50 mmol, yield 53.40%) as a colorless oil. MS(M+H) + =368.1.

[0265] Step 2. Synthesis of tert-butyl(1R,5S,6s)-6-((4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(3) In 10 mL of DMF, potassium carbonate (415.23 mg, 3.00 mmol), benzylpiperidine-4-ylcarbamate (645.26 mg, 2.75 mmol), and potassium iodide (41.56 mg, 250.37 μmol) were added at 20°C to a solution of tert-butyl(1R,5S,6r)-6-((tosyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (920 mg, 2.50 mmol). The resulting mixture was stirred at 80°C for 4 hours. A peak at 60% of the desired mass was confirmed by LC-MS. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (15 mL x 3), dried over sodium sulfate, and filtered. After concentrating the filtrate under reduced pressure, it was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether to 0-10% methanol in DCM, gradient @ 100mL / min) to obtain the title compound (780mg, 1.74 mmol, yield 69.63%, purity 96%) as a yellow oily substance. MS(M+H) + = 430.4.

[0266] Step 3. Synthesis of benzyl(1-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (4) In 3 mL of dioxane, a solution of tert-butyl(1R,5S,6s)-6-((4-(((benzyloxy)carbonyl)amino)piperidine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (780 mg, 1.82 mmol) was added to HCl / dioxane (4 M, 9 mL) at 20°C. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed complete consumption of the starting material and a peak at the desired mass of 55%. The reaction mixture was concentrated under reduced pressure to obtain the title compound (800 mg, crude product, HCl) as a yellow oil. MS(M+H) + = 330.2.

[0267] Step 4. Synthesis of benzyl(1-(((1R,5S,6s)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate(6) In 10 mL of DMF, a solution of benzyl (1-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (800 mg, 2.19 mmol, HCl) was added to potassium carbonate (604.35 mg, 4.37 mmol) and 1-fluoro-4-nitrobenzene (370.20 mg, 2.62 mmol) at 20°C. The mixture was stirred at 50°C for 16 hours. Then, potassium carbonate (906.52 mg, 6.56 mmol) was added, and the reaction mixture was stirred at 50°C for 19 hours. The starting material was completely consumed and the desired mass was confirmed by LC-MS. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (40 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent: methanol / DCM 0-10%, gradient @ 100 mL / min) to obtain the title compound (634 mg, 1.29 mmol, yield 59.21%, purity 92%) as a yellow solid. MS(M+H) + = 451.2.

[0268] • Step 5.1-(((1R,5S,6s)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-amine (7) A solution of benzyl(1-(((1R,5S,6s)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (580 mg, 1.29 mmol) was stirred in TFA (6 mL) at 40°C for 5 hours. LC-MS confirmed a desired mass of 32%. The mixture was concentrated under reduced pressure to obtain the title compound (0.6 g, crude product, TFA) as a yellow oil. MS(M+H) += 317.1.

[0269] Step 6. Synthesis of tert-butyl(1-(((1R,5S,6s)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (8) In 10 mL of THF, a solution of 1-(((1R,5S,6s)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-amine (0.6 g, 1.39 mmol, TFA) was added to a mixture of sodium hydroxide (1 M, 11.15 mL) and Boc2O (608.47 mg, 2.79 mmol, 640.49 μL). The mixture (pH=8) was stirred at 20°C for 14 hours. Sodium hydroxide (1 M, 0.7 mL) was added, and the mixture was stirred at 20°C for 18 hours. The mixture was extracted with ethyl acetate (10 mL x 2), the mixed organic layer was washed with water (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 80-100% to 10-30% methanol / ethyl acetate gradient @ 50 mL / min), and then purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 20-50% B, 9 minutes). The eluate was adjusted to pH=9 with saturated sodium bicarbonate, extracted with ethyl acetate (20 mL x 2), washed with water (10 mL) for the mixed organic layer, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (170 mg, 408.15 μmol, yield 29.28%) as a yellow solid. MS(M+H) + = 417.2.

[0270] Step 7. Synthesis of tert-butyl(1-(((1R,5S,6s)-3-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (9) In ethanol (7 mL) and H2O (3 mL), a solution of tert-butyl(1-(((1R,5S,6s)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (150 mg, 360.13 μmol) and ammonium chloride (97.50 mg, 1.82 mmol) was prepared, to which iron (105.00 mg, 1.88 mmol) was added. The mixture was stirred at 80°C for 1 hour. LC-MS confirmed 89% of the desired mass. The mixture was filtered, and the filter cake was washed with ethanol (20 mL) and THF (20 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with ethyl acetate (10 mL) and water (10 mL), and the mixture was adjusted to pH=9 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (10 mL x 3), the mixed organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (140 mg, crude product) as a yellow solid. MS(M+H) + = 387.3.

[0271] Step 8. Synthesis of tert-butyl(1-(((1R,5S,6s)-3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (10) In acetonitrile (1.5 mL), a solution of tert-butyl(1-(((1R,5S,6s)-3-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (120 mg, 310.45 μmol) and 3-bromopiperidine-2,6-dione (90 mg, 468.72 μmol) was added, to which sodium bicarbonate (79 mg, 940.40 μmol, 36.59 μL) was added, and the mixture was stirred at 80°C for 14 hours. The desired mass of 49% was confirmed by LC-MS. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5g SepaFlash® silica flash column, eluent 10% methanol / DCM, gradient @ 30 mL / min) to obtain the title compound (130 mg, 261.24 μmol, yield 84.15%, purity 100%) as a yellow solid. MS(M+H) + = 498.3.

[0272] • Step 9.3-((4-((1R,5S,6s)-6-((4-aminopiperidine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)phenyl)amino)piperidine-2,6-dione (11) In 1.3 mL of DCM, a solution of tert-butyl(1-(((1R,5S,6s)-3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamate (130 mg, 261.24 μmol) was added to TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. LC-MS confirmed 78% of the desired mass. The mixture was concentrated under reduced pressure to obtain the title compound (140 mg, crude product, TFA) as a blue oil. MS(M+H) + =398.4.

[0273] Step 10. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(((1R,5S,6s)-3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidine-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 27) In 1.5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (120 mg, 251.11 μmol) and HATU (114.58 mg, 301.33 μmol) was added to DIPEA (445.20 mg, 3.44 mmol, 0.6 mL), and the mixture was stirred at 20°C for 15 minutes. Then, in 1.5 mL of DMF, a solution of 3-((4-((1R,5S,6s)-6-((4-aminopiperidine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)phenyl)amino)piperidine-2,6-dione (140 mg, 273.69 μmol, TFA) was added, and the mixture was stirred at 20°C for 1 hour. The desired mass of 66% was confirmed by LC-MS. The mixture was diluted with water (50 mL) and ethyl acetate (10 mL) and then filtered. The filtered cake was washed with water (10 mL) and ethyl acetate (10 mL). The filtered cake was collected, the solvent was removed under reduced pressure, and the crude product (60 mg, purity 73%) was obtained. The filtrate was extracted with ethyl acetate (10 mL x 2). The mixed organic layer was washed with water (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product (140 mg, purity 67%) was added. The mixed crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 20%~50% B, 9 minutes), and the eluate was lyophilized to obtain the product (90 mg, purity 91%, 3TFA). This product was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 27%~57% B, minutes), and lyophilized to obtain the title compound (13.3 mg, 14.43 μmol, yield 5.75%, purity 93%) as a red solid. MS(M+H) + = 857.3.

[0274] 1H NMR (400 MHz, DMSO-d6) δ=10.74(br s, 1H), 9.93(s, 1H), 9.74(s, 1H), 9.61(s, 1H), 8.25(d, J=3.5 Hz, 1H), 8.07-7.98(m, 5H), 7.80-7.75(m, 4H), 7.67-6.63(m, 1H), 7.58-7.54(m, 1H), 7.42-7.37(m, 1H), 7.32-7.25(m, 1H), 6.60(d, J=8.8 Hz, 2H), 6.41(br d, J=8.8 Hz, 2H), 5.10(d, J=7.1 Hz, 1H), 4.16-4.06(m, 1H), 3.80-3.67(m, 1H), 3.47(br d, J=8.9 Hz, 2H), 3.02-2.90(m, 4H), 2.75-2.68(m, 1H), 2.61-2.54(m, 2H), 2.27-2.22(m, 2H), 2.15-2.07(m, 1H), 2.04-1.94(m, 2H), 1.85-1.72(m, 3H), 1.62-1.52(m, 2H), 1.48-1.44(m, 2H), 0.87-0.79(m, 1H).

[0275] ●Example 28. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-(3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 28) [ka]

[0276] Step 1. Synthesis of tert-butyl 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (2) In 10 mL of THF and 2.5 mL of H2O, 1 g of tert-butyl 2-azabicyclo[2.2.1]hepta-5-ene-2-carboxylate and a solution of K2OsO4·2H2O (94 mg, 255.12 μmol) were added, to which NMO (720 mg, 6.15 mmol) was added. The mixture was stirred at 20°C for 14 hours. LC-MS confirmed a desired mass of 58%. The reaction was stopped with a saturated NaHSO3 solution (20 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The mixed organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent 30% ethyl acetate / petroleum ether, gradient @ 80 mL / min) to obtain the title compound (660 mg, 2.88 mmol, yield 56.21%) as a yellow oily substance. MS(M+H) + = 230.2.

[0277] Step 2. Synthesis of tert-butyl 2,4-diformylpyrrolidine-1-carboxylate (3) To a solution of tert-butyl 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (560 mg, 2.44 mmol) in H2O (2.5 mL) and methanol (10 mL), sodium periodate (784.00 mg, 3.67 mmol, 203.11 μL) was slowly added, and the mixture was stirred at 20°C for 2 hours. LC-MS confirmed that the starting material was completely consumed. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was stopped with saturated Na2SO3 solution (20 mL), and then extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with Na2SO3 solution (10 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (510 mg, crude product) as a yellow oil. MS(M+H) + = 228.2.

[0278] Step 3. Synthesis of tert-butyl 3-benzyl-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (4) A solution of tert-butyl 2,4-diformylpyrrolidine-1-carboxylate (510 mg, 2.24 mmol) and BnNH2 (235.92 mg, 2.20 mmol) was stirred in methanol (10 mL) at 20°C for 10 minutes, after which sodium borohydride cyanohydride (423.08 mg, 6.73 mmol) was added. The resulting mixture was stirred at 20°C for 14 hours. LC-MS confirmed a peak at 72% of the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 80-100%, gradient @ 50 mL / min) to obtain the title compound (450 mg, 1.49 mmol, yield 66.31%) as a yellow oil. MS(M+H) + = 303.3.

[0279] Step 4. Synthesis of tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (5) To 10 mL of ethanol, a solution of tert-butyl 3-benzyl-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (450 mg, 1.49 mmol) was slowly added to Pd / C (50 mg, 10% purity) and Pd(OH)2 / C (50 mg, 20% purity) under an N2 atmosphere. The mixture was stirred for 14 hours at 60°C under an H2 (45 psi) atmosphere. LC-MS confirmed the presence of residual starting material, and the desired mass was detected. The mixture was filtered, and the filter cake was washed with ethanol (20 mL) and THF (20 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (330 mg, crude product) as a white solid. The crude product was used directly in the next step.

[0280] Step 5. Synthesis of tert-butyl 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (7) In 6 mL of DMF, potassium carbonate (644.52 mg, 4.66 mmol) was added to a solution of 1-fluoro-4-nitrobenzene (250 mg, 1.77 mmol, 187.97 μL) and tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (330 mg, 1.55 mmol), and the mixture was stirred at 40°C for 14 hours. A peak at 65% of the desired mass was confirmed by LC-MS. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL x 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5g SepaFlash® silica flash column, eluent 30-50% ethyl acetate / petroleum ether, gradient @ 50 mL / min) to obtain the title compound (440 mg, 1.32 mmol, yield 84.90%, purity 100%) as a yellow solid. MS(M+Na) + = 356.2.

[0281] • Step 6. Synthesis of 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane(8) In 8 mL of DCM, a solution of tert-butyl 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate was added to HCl / dioxane (4 M, 8 mL), and the mixture was stirred at 20°C for 1 hour. The major peak at the desired mass was confirmed by LC-MS. The mixture was concentrated under reduced pressure to obtain the title compound (350 mg, crude product, HCl) as a yellow solid. MS(M+H) + = 234.2.

[0282] Step 7. Synthesis of tert-butyl 4-(3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carboxylate (10) In 10 mL of DCM and 4 mL of DMF, 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane (350 mg, 1.30 mmol, HCl) solution was mixed with TEA (392.58 mg, 3.88 mmol, 540 μL), 4 angstrom MS (100 mg), and tert-butyl 4-oxopiperidine-1-carboxylate (388 mg, 1.95 mmol). After stirring at 20°C for 30 minutes, sodium triacetoxyborohydride (825.05 mg, 3.89 mmol) was added, and the resulting mixture was stirred at 20°C for 14 hours. The major peak at the desired mass was confirmed by LC-MS. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL), washed with saturated sodium carbonate solution, and then extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 5-30% ethanol / ethyl acetate, gradient @ 100 mL / min) to obtain the title compound (0.5 g, 1.18 mmol, yield 90.66%, purity 98%) as a yellow oil. MS(M+H) + = 417.2.

[0283] Step 8. Synthesis of tert-butyl 4-(3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carboxylate (11) In ethanol (10 mL), a solution of tert-butyl 4-(3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carboxylate (0.5 g, 1.20 mmol) was slowly added under N2 conditions, and the mixture was stirred for 14 hours under an H2 atmosphere (45 psi) at 25°C. LC-MS confirmed a peak at 78% of the desired mass. The mixture was filtered, and the filter cake was washed with ethanol (20 mL) and THF (50 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (450 mg, crude product) as a yellow solid. MS(M+H) + = 387.3.

[0284] Step 9. Synthesis of tert-butyl 4-(3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carboxylate (13) In 4 mL of ACN, a solution of tert-butyl 4-(3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carboxylate (400 mg, 1.03 mmol) and 3-bromopiperidine-2,6-dione (328.00 mg, 1.71 mmol) was added, to which sodium bicarbonate (304.00 mg, 3.62 mmol) was added, and the mixture was stirred at 80°C for 14 hours. The desired mass was confirmed by LC-MS. The mixture was filtered and washed with ethyl acetate (10 mL) and THF (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5g SepaFlash® silica flash column, eluent 20-30% methanol in ethyl acetate, gradient @ 50 mL / min) to obtain the title compound (0.4 g, 803.81 μmol, yield 77.67%, purity 100%) as a yellow solid. MS(M+H) + = 498.3.

[0285] • Step 10. Synthesis of 3-((4-(6-(piperidine-4-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)piperidine-2,6-dione (14) In 2 mL of DCM, a solution of tert-butyl 4-(3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carboxylate (0.2 g, 401.91 μmol) was added to TFA (706.10 mg, 6.19 mmol, 460 μL), and the mixture was stirred at 20°C for 1 hour. LC-MS confirmed the desired mass and the consumption of the starting material. The mixture was concentrated under reduced pressure to obtain the title compound (0.2 g, crude product, TFA) as a blue oil.

[0286] Step 11. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-(3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 28) In 3 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (160 mg, 334.82 μmol) and HATU (153 mg, 402.39 μmol) was mixed with DIPEA (86.55 mg, 669.63 μmol, 116.64 μL), and the mixture was stirred at 20°C for 15 minutes. Then, 3-((4-(6-(piperidine-4-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)piperidine-2,6-dione (0.2 g, 390.98 μmol, TFA) and DIPEA (445.20 mg, 3.44 mmol, 0.6 mL) solution (0°C) were added to DMF (3 mL), and the mixture was stirred at 20°C for 14 hours. A peak at 66% of the desired mass was confirmed by LC-MS. The mixture was diluted with water (10 mL) and filtered. The filtered cake was washed with water (10 mL) and purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes). The crude product was diluted with acetonitrile (3 mL), water (10 mL), and DCM (10 mL). The mixture was adjusted to pH=8 with saturated sodium bicarbonate solution, and the mixture was extracted with DCM (10 mL x 3). The mixed organic layer was washed with water (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1). The product was further purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 27%~57% B, 9 minutes), lyophilized, and the title compound (24.6 mg, 26.40 μmol, yield 50.29%, purity 92%) was obtained as a red solid. MS(M+H) + = 857.4.

[0287] 1H NMR (400 MHz, DMSO-d6) δ=10.74(s, 1H), 9.91(s, 1H), 9.72(s, 1H), 9.54(s, 1H), 8.24-8.21(m, 1H), 8.04-7.96(m, 4H), 7.73(br d, J=8.2 Hz, 2H), 7.65(d, J=7.6 Hz, 1H), 7.53(d, J=8.3 Hz, 1H), 7.40-7.34(m, 1H), 7.33-7.25(m, 3H), 6.69-6.57(m, 4H), 5.22(br d, J=7.2 Hz, 1H), 4.20-4.11(m, 1H), 3.60-3.52(m, 1H), 3.33-3.32(m, 4H), 3.16-2.98(m, 3H), 2.81 -2.57(m, 6H), 2.43-2.31(m, 1H), 2.16-2.05(m, 1H), 1.98-1.75(m, 4H), 1.52-1.29(m, 3H).

[0288] ●Example 29. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 29) [ka]

[0289] Step 1. Synthesis of tert-butyl 4-((3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carboxylate (2) In DCM (3 mL) and DMF (3 mL), 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane (160 mg, 593.19 μmol, HCl) solution was added at 0°C with TEA (305.34 mg, 3.02 mmol) and 4-angstrom MS (50 mg), followed by the addition of tert-butyl 4-formylpiperidine-1-carboxylate (189 mg, 886.19 μmol). The mixture was stirred at 20°C for 0.5 hours, and sodium triacetoxyborohydride (377 mg, 1.78 mmol) was added. The resulting mixture was stirred at 20°C for 14 hours. The major peak at the desired mass was confirmed by LC-MS. The mixture was filtered and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with water (10 mL) and adjusted to pH=9 with saturated sodium carbonate solution. The mixture was then extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent 0-10% ethanol / ethyl acetate, gradient @ 50 mL / min) to obtain the title compound (160 mg, 364.19 μmol, yield 61.40%, purity 98%) as a yellow oil. MS(M+H) + = 431.2.

[0290] Step 2. Synthesis of tert-butyl 4-((3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carboxylate (3) To a Pd / C (50 mg, 10% purity) mixture in CF3CH2OH (5 mL), a solution of tert-butyl 4-((3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carboxylate (160 mg, 371.63 μmol) was added to CF3CH2OH (5 mL) under an N2 atmosphere. The mixture was stirred for 14 hours under an H2 atmosphere (45 psi) at 25°C. The desired mass was confirmed by LC-MS. The mixture was filtered and washed with THF (100 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (140 mg, crude product) as a yellow solid. MS(M+H) + = 401.4.

[0291] Step 3. Synthesis of tert-butyl 4-((3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carboxylate (4) In 1.4 mL of ACN, a solution of tert-butyl 4-((3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carboxylate (140 mg, 349.51 μmol) and 3-bromopiperidine-2,6-dione (101 mg, 526.01 μmol) was added, to which sodium bicarbonate (88.08 mg, 1.05 mmol) was added, and the mixture was stirred at 80°C for 14 hours. A peak at the desired mass of 50% was confirmed by LC-MS. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (5g SepaFlash® silica flash column, eluent 10-20% methanol / ethyl acetate, gradient @ 50 mL / min) to obtain the title compound (160 mg, 287.69 μmol, yield 82.31%, purity 92%) as a gray solid. MS(M+H) + = 512.4.

[0292] • Step 4.3-((4-(6-(piperidine-4-ylmethyl)-3,6-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)piperidine-2,6-dione (5) In 1.5 mL of DCM, a solution of tert-butyl 4-((3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carboxylate (160 mg, 312.71 μmol) was added to TFA (614.00 mg, 5.39 mmol, 0.4 mL), and the mixture was stirred at 20°C for 1 hour. The major peak at the desired mass was confirmed by LC-MS. The mixture was concentrated under reduced pressure to obtain the title compound (170 mg, crude product, TFA) as a blue oil. MS(M+H) + = 412.2.

[0293] Step 5. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((3-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)methyl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 29) In 2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (150 mg, 313.89 μmol) and HATU (143.22 mg, 376.67 μmol) was mixed with DIPEA (445.20 mg, 3.44 mmol, 0.6 mL), and the mixture was stirred at 20°C for 15 minutes. Then, in 2 mL of DMF, a solution of 3-((4-(6-(piperidine-4-ylmethyl)-3,6-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)piperidine-2,6-dione (170 mg, 323.46 μmol, TFA) was added at 0°C, and the mixture was stirred at 20°C for 2 hours. The desired mass was confirmed by LC-MS. The mixture was diluted with water (10 mL) and then filtered. The filtered cake was washed with water (5 mL). The filtered cake was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 25%~55% B, 10 minutes), and the eluate was lyophilized. The product was diluted with water (5 mL) and THF (10 mL), and the mixture was adjusted to pH=7 with saturated sodium bicarbonate. The mixture was extracted with THF / DCM=1 / 1 (10 mL × 2), and the mixed organic layer was concentrated under reduced pressure. The product was diluted with ethyl acetate / methanol=20 / 1 (2 mL), and the mixture was stirred at 20 °C for 0.5 hours. The mixture was filtered, and the filtered cake was washed with ethyl acetate / methanol=20 / 1 (10 mL) and water (5 mL). The filtered cake was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%~60% B over minutes), lyophilized, and the title compound (18.7 mg, 19.53 μmol, yield 6.22%, purity 91%) was obtained as a white solid. MS(M+H) + = 871.4.

[0294] 1H NMR (400 MHz, DMSO-d6) δ=10.74(br s, 1H), 9.92(s, 1H), 9.72(s, 1H), 9.55(s, 1H), 8.22(d, J=3.5 Hz, 1H), 8.03-7.96(m, 4H), 7.74(d, J=8.5 Hz, 2H), 7.67-7.63(m, 1H), 7.57-7.53(m, 1H), 7.41-7.36(m, 1H), 7.31-7.26(m, 3H), 6.68-6.57(m, 4H), 5.21(d, J=7.1) Hz, 1H), 4.19-4.11(m, 1H), 3.60-3.53(m, 1H), 3.32-3.28(m, 4H), 3.08-2.99(m, 2H), 2.94-2.80(m, 1H), 2.76-2.63(m, 3H), 2.61-2.53(m, 2H), 2.48-2.42(m, 2H), 2.40-2.34(m, 1H), 2.15-2.05(m, 1H), 1.88-1 .76(m, 3H), 1.74-1.59(m, 2H), 1.51-1.45(m, 1H), 1.13-0.97(m, 2H).

[0295] ●Example 30. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(1-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-6-azaspiro[2.5]octane-6-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 30) [ka]

[0296] Step 1. Synthesis of tert-butyl 1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (2) In 40 mL of THF, a solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (2 g, 7.83 mmol) was added to BH3-Me2S (10 M, 1.57 mL) at 0°C. The mixture was stirred at 20°C for 16 hours. TLC (petroleum ether:ethyl acetate = 10:1) confirmed that the 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid was completely consumed and a new spot was formed. The reaction mixture was stopped at 20°C by adding methanol (20 mL) and stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-40%, gradient @ 40 mL / min) to obtain the title compound (1.8 g, 7.46 mmol, yield 95.22%) as a colorless oil.

[0297] 1 H NMR (400 MHz, DMSO-d6) δ=4.41(t, J=5.1 Hz, 1H), 3.57-3.42(m, 2H), 3.41-3.33(m, 1H), 3.31-3.18(m, 3H), 1.52-1.43(m, 1H), 1. 39(s, 9H), 1.36-1.23(m, 2H), 1.22-1.18(m, 1H), 0.86-0.77(m, 1H), 0.48-0.43(m, 1H).

[0298] Step 2. Synthesis of tert-butyl1-formyl-6-azapiro[2.5]octane-6-carboxylate (3) In 25 mL of DCM, a solution of tert-butyl 1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (600 mg, 2.49 mmol) was mixed with DMP (1.37 g, 3.23 mmol, 1.00 mL), and the mixture was stirred at 20°C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1) confirmed that the starting material was completely consumed and a new spot had been formed. The reaction mixture was diluted with 50 mL of Na2SO3 solution and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with sodium bicarbonate solution (10 mL x 3) and brine (10 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (600 mg) as a colorless oil.

[0299] 1 H NMR (400 MHz, CDCl3-d) δ=9.56(br d, J=3.5 Hz, 1H), 3.58-3.37(m, 3H), 3.35-3.24(m, 1H), 1.88-1.79(m, 1H), 1.78-1.65(m, 2H), 1.46(s, 12H), 1.14(dd, J=4.7, 7.9 Hz, 1H).

[0300] Step 3. Synthesis of tert-butyl 1-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-6-azaspiro[2.5]octane-6-carboxylate (5) In 20 mL of DCM, a mixture of tert-butyl-1-formyl-6-azaspiro[2.5]octane-6-carboxylate (450 mg, 1.88 mmol), 3-((4-(piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (488.61 mg, 1.50 mmol, HCl salt), 4 angstrom MS (0.2 g, 1.88 mmol), and TEA (761.11 mg, 7.52 mmol, 1.05 mL) was stirred at 15°C for 0.5 hours, after which sodium triacetoxyborohydride (1.59 g, 7.52 mmol) was added. The resulting mixture was stirred at 15°C for 12 hours. LC-MS confirmed complete consumption of the starting material and a peak at the desired mass of 34% was observed. The mixture was diluted with H2O (50 mL) and extracted using 3 x 20 mL DCM. The mixed organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 10-20%, gradient @ 100 mL / min). The residue was further purified by preparative TLC (silicon dioxide, DCM:methanol = 5:1) to obtain the title compound (295 mg, 576.56 μmol, yield 30.66%) as a black solid. MS(M+H) + = 512.3.

[0301] • Step 4.3 Synthesis of ((4-(4-((6-Azaspiro[2.5]octan-1-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione(6) A mixture of tert-butyl 1-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-6-azaspiro[2.5]octane-6-carboxylate (160 mg, 312.71 μmol) and TFA (2.63 g, 23.08 mmol, 1.71 mL) was stirred at 15°C for 1 hour in DCM (5 mL). The starting materials were completely consumed by LC-MS, and the desired mass was confirmed. The mixture was concentrated under reduced pressure to obtain the title compound (200 mg, 2 TFA salt) as a deep blue gum, which was used directly. MS(M+H) += 412.2.

[0302] Step 5. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(1-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-6-azaspiro[2.5]octane-6-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 30) In 2 mL of DMF, a mixture of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (150 mg, 313.89 μmol), HATU (155.16 mg, 408.06 μmol), and DIPEA (405.68 mg, 3.14 mmol, 546.74 μL) was stirred at 15°C for 15 minutes, after which 3-((4-(4-((6-azaspiro[2.5]octan-1-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, 312.70 μmol, 2TFA salt) was added. The resulting mixture was stirred at 15°C for 1 hour. LC-MS confirmed the complete consumption of 3-((4-(4-((6-azaspiro[2.5]octan-1-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione, with a peak at the desired mass of 43% confirmed. The mixture was adjusted to pH < 7 with TFA and filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes). The impure product was treated with the mixture (ethyl acetate:THF:ACN = 4:1:1, 80 mL) and sodium bicarbonate solution (10 mL). The organic phase was separated and concentrated under reduced pressure. The residue was purified by preparative TLC (silicon dioxide, DCM:methanol = 8:1) to obtain the title compound (48.4 mg, 53.10 μmol, yield 16.92%, purity 95.6%) as a gray solid. MS(M+H) + = 871.3.

[0303] 1H NMR (400 MHz, DMSO-d6) δ=10.76(s, 1H), 9.93(s, 1H), 9.73(s, 1H), 9.56(s, 1H), 8.23(d, J=3.5 Hz, 1H), 8.08-7.94(m, 4H), 7.74(d, J=8.7 Hz, 2H), 7.69-7.61(m, 1H), 7.56(dd, J=1.2, 7.9 Hz, 1H), 7.44-7.36(m, 1H), 7.36-7.23(m, 3H), 6.74(br d, J=8.8 Hz, 2H), 6.60(d, J=8.8 Hz, 2H), 5.37(d, J=7.2 Hz, 1H), 4.24-4.13(m, 1H), 3.86-3.69(m, 1H), 2.95-2.92(m, 4H), 2.78-2.67( m, 2H), 2.62-2.53(m, 6H), 2.46-2.42(m, 2H), 2.32-2.21(m, 1H), 2.15-2.06(m, 1H), 1.89-1.78(m, 1H), 1.57-1.54(m, 1H), 1.51-1.43(m, 1H), 1.43-1.35(m, 1H) ), 1.29-1.18(m, 1H), 0.85-0.74(m, 1H), 0.55-0.50(m, 1H), 0.16-0.13(m, 1H).

[0304] ●Example 31. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(6-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 31) [ka]

[0305] Step 1. Synthesis of tert-butyl 6-((1-((benzyloxy)carbonyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-carboxylate (3) In 33 mL of DCM, a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.37 g, 11.69 mmol), TEA (3.55 g, 35.07 mmol, 4.88 mL), 4 angstrom MS (500 mg), and benzyl 4-formylpiperidine-1-carboxylate (2.89 g, 11.69 mmol) was stirred at 25°C for 1 hour. Then, sodium triacetoxyborohydride (7.43 g, 35.07 mmol) was added to the reaction mixture and stirred at 25°C for 14 hours. LC-MS confirmed the complete consumption of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate and the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) at 20°C and then extracted with ethyl acetate (50 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, 90% ethyl acetate / petroleum ether eluent, gradient @ 100 mL / min) to obtain the title compound (4.35 g, 8.71 mmol, yield 74.50%, purity 86%) as a colorless oil. MS(M+H) += 430.2.

[0306] Step 2. Synthesis of tert-butyl 6-(piperidine-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4) In 30 mL of THF, a solution of tert-butyl 6-((1-((benzyloxy)carbonyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.91 g, 5.83 mmol) was added with Pd / C (1 g, 10% purity) and Pd(OH)2 / C (1 g, 20% purity) under an N2 atmosphere. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred for 20 hours under an H2 (15 psi) atmosphere at 25°C. LC-MS confirmed that tert-butyl 6-((1-((benzyloxy)carbonyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was completely consumed. The mixture was filtered and washed with 200 mL of THF. The filtrate was concentrated under reduced pressure to obtain the title compound (1.85 g, crude product) as a white solid. MS(M+H) += 296.1.

[0307] Step 3. Synthesis of tert-butyl 6-((1-(4-nitrophenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(6) Potassium carbonate (2.22 g, 16.08 mmol) was added to a solution of tert-butyl 6-(piperidine-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (950 mg, 3.22 mmol) and 1-fluoro-4-nitrobenzene (907.49 mg, 6.43 mmol) in DMF (9.5 mL). The mixture was stirred at 25 °C for 16 hours. LC-MS confirmed that tert-butyl 6-(piperidine-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was completely consumed. The reaction mixture was diluted with H2O (50 mL) at 20 °C and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, 60% ethyl acetate / petroleum ether eluent, gradient @ 100 mL / min) to obtain the title compound (915 mg, 2.04 mmol, yield 63.53%, purity 93%) as a yellow solid. MS(M+H) += 417.2.

[0308] Step 4. Synthesis of tert-butyl 6-((1-(4-aminophenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (7) In ethanol (30 mL) and H2O (6 mL), tert-butyl 6-((1-(4-nitrophenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (915 mg, 2.04 mmol) solution was mixed with ammonium chloride (1.09 g, 20.43 mmol) and iron (570.47 mg, 10.22 mmol). The resulting mixture was stirred at 80°C for 1 hour. LC-MS confirmed that the starting materials were completely consumed. The reaction mixture was diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (820 mg, crude product) as a brown solid. MS(M+H) += 387.2.

[0309] Step 5. Synthesis of tert-butyl6-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (9) In 0.8 mL of ACN, a solution of tert-butyl 6-((1-(4-aminophenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (160 mg, 413.94 μmol) and 3-bromopiperidine-2,6-dione (198.70 mg, 1.03 mmol) was mixed with sodium bicarbonate (201.69 mg, 2.40 mmol, 93.42 μL). The mixture was stirred at 80°C for 5 hours. LC-MS confirmed that the starting materials were completely consumed. The reaction mixture was diluted with H2O (20 mL) at 20°C and extracted with ethyl acetate (10 mL x 2). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-20%, @50 mL / min) to obtain the title compound (130 mg, 261.24 μmol, yield 63.11%) as a black solid. MS(M+H) += 498.4.

[0310] • Step 6.3 Synthesis of ((4-(4-((2,6-diazaspiro[3,3]heptan-2-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (10) In 1.5 mL of DCM, a solution of tert-butyl 6-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 261.24 μmol) was mixed with TFA (767.50 mg, 6.73 mmol, 0.5 mL). The mixture was stirred at 25°C for 0.5 hours. LC-MS confirmed that the starting material was completely consumed. The mixture was concentrated under reduced pressure to obtain the title compound (133 mg, 260.00 μmol, yield 99.53%, TFA) as a green oil. MS(M+H) + = 398.3.

[0311] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(6-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 31) In 1.3 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (115 mg, 240.65 μmol) was mixed with HATU (114.38 mg, 300.81 μmol) and DIPEA (259.19 mg, 2.01 mmol, 349.31 μL). After stirring at 25°C for 0.5 hours, 3-((4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (129.85 mg, 200.54 μmol, TFA) was added, and the resulting mixture was stirred at 25°C for 2 hours. LC-MS confirmed the complete consumption of 3-((4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 2). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 32%~62% B over min), lyophilized, and the title compound (41 mg, 43.99 μmol, yield 21.94%, purity 92%) was obtained as a white solid. MS(M+H) + = 857.3.

[0312] 1H NMR (400 MHz, DMSO-d6) δ=10.85-10.66(m, 1H), 9.96(br s, 1H), 9.84-9.71(m, 1H), 9.65(s, 1H), 8.24(d, J=3.5 Hz, 1H), 8.10-7.98(m, 4H), 7.76(d, J=8.7 Hz, 2H), 7.65(d, J=8.2 Hz, 1H), 7.61-7.51(m, 3H), 7.44-7.35(m, 1H), 7.33-7.25(m, 1H), 6.73(d, J=8.7 Hz, 2H), 6.59(d, J=8.9 Hz, 2H), 5.36(d, J=7.3 Hz, 1H), 4.44-4.33(m, 2H), 4.24-4.14(m, 1H), 4.13-4.00(m, 2H), 3.27-3.13(m, 5H), 2.78-2.69(m, 1H), 2.60-2.55(m, 1H), 2.50-2.40(m, 2H), 2.20-2.15(m, 2H), 2.13-2.04(m, 1H), 1.89-1.77(m, 1H), 1.70-1.60(m, 2H), 1.32-1.11(m, 4H).

[0313] ●Example 32. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(7-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 32) [ka]

[0314] Step 1. Synthesis of tert-butyl 7-(piperidine-4-ylmethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (2) In CF3CH2OH (10 mL), a solution of tert-butyl 7-((1-((benzyloxy)carbonyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g, 2.19 mmol) was added to Pd / C (232.56 mg, 218.53 μmol, purity 10%) under an N2 atmosphere. The resulting mixture was stirred at 25°C under an H2 atmosphere (15 psi) for 12 hours. LC-MS confirmed that the starting material was completely consumed and 56% of the target compound was identified. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g, crude product) as a brown solid. MS(M+H) += 324.2.

[0315] Step 2. Synthesis of tert-butyl 7-((1-(4-nitrophenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (3) Potassium carbonate (1.28 g, 9.27 mmol) was added to a solution of 1-fluoro-4-nitrobenzene (436.20 mg, 3.09 mmol, 327.97 μL) and tert-butyl 7-(piperidine-4-ylmethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g, 3.09 mmol) in DMF (10 mL). The mixture was stirred at 50°C for 12 hours. LC-MS confirmed the presence of a 54% peak of the target compound. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 50% ethyl acetate / petroleum ether, gradient @ 75 mL / min) to obtain the title compound (617 mg, 1.39 mmol, yield 44.89%, purity 100%) as a yellow solid. MS(M+H) += 445.3.

[0316] Step 3. Synthesis of tert-butyl 7-((1-(4-aminophenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (4) Iron (408.26 mg, 7.31 mmol) and ammonium chloride (391.05 mg, 7.31 mmol) were added to a solution of tert-butyl 7-((1-(4-nitrophenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (650 mg, 1.46 mmol) in ethanol (10 mL) and H2O (4 mL). The resulting mixture was stirred at 80°C for 2 hours. LC-MS confirmed complete consumption of the starting material and a peak at 86% of the desired mass. The mixture was diluted with sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (50 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (FA)-ACN]; gradient: 5%~35% B, 10 minutes) to obtain tert-butyl 7-((1-(4-aminophenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (317 mg, 711.10 μmol, yield 48.64%, purity 93%) and tert-butyl 7-((1-(4-aminophenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (163 mg, 314.53 μmol, yield 21.51%, purity 80%) as white solids. MS(M+H) + = 415.4.

[0317] Step 4. Synthesis of tert-butyl 7-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (6) Sodium bicarbonate (180.54 mg, 2.15 mmol) was added to a solution of 3-bromopiperidine-2,6-dione (206.33 mg, 1.07 mmol) and tert-butyl 7-((1-(4-aminophenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (297 mg, 716.38 μmol) in acetonitrile (0.2 mL). The mixture was stirred at 80°C for 4 hours. A peak of 30% of the target compound was confirmed by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 1%~30% B, 10 minutes), lyophilized, and the title compound (257 mg, 488.89 μmol, yield 68.24%, purity 100%) was obtained as a white solid. MS(M+H) + = 526.3.

[0318] • Step 5. Synthesis of 3-((4-(4-((2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (7) In 5 mL of DCM, a solution of tert-butyl 7-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate was added, to which HCl / dioxane (4 M, 733.33 μL) was added. The mixture was stirred at 25°C for 3.5 hours. LC-MS revealed 9% of the starting material and 53% of the target compound peak. The reaction mixture was concentrated under reduced pressure to obtain the title compound (245 mg, crude product, HCl) as a white solid. MS(M+H) + = 426.3.

[0319] Step 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(7-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 32) In 1 mL of DMF, a solution of 3-((4-(4-((2,7-diazaspiro[4,4]nonan-2-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (100 mg, 216.44 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (103.43 mg, 216.44 μmol) was prepared by adding DIPEA (83.92 mg, 649.31 μmol, 113.10 μL) and HATU (98.76 mg, 259.73 μmol). The mixture was stirred at 25°C for 2 hours. 51% of the target compound peaks were confirmed by LC-MS. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 33%~63% B over) and lyophilized to obtain the title compound (45.3 mg, 48.96 μmol, yield 22.62%, purity 95.7%) as a white solid. MS(M+H) + = 885.4.

[0320] 1H NMR (400 MHz, DMSO-d6) δ=10.75(s, 1H), 9.93(s, 1H), 9.73(s, 1H), 9.62-9.55(m, 1H), 8.23(d, J=3.2 Hz, 1H), 8.10-7.98(m, 4H), 7.78-7.72(m, 2H), 7.65(br d, J=8.2 Hz, 1H), 7.56(d, J=7.9 Hz, 1H), 7.50-7.37(m, 3H), 7.32-7.26(m, 1H), 6.78-6.67(m, 2H), 6.62-6.54(m, 2H), 5.42-5.29(m, 1H), 4.25-4.11(m, 1H), 3.57 -3.41(m, 4H), 2.82-2.57(m, 3H), 2.46-2.25(m, 6H), 2.24-2.06(m, 3H), 1.91-1.59(m, 8H), 1.52-1.36(m, 1H), 1.26-1.08(m, 2H).

[0321] ●Example 33. Synthesis of N-(2-chlorophenyl)-4-[[2-[4-[8-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carbonyl]anilino]-5-fluoropyrimidine-4-yl]amino]benzamide (compound 33) [ka] [ka]

[0322] Step 1. Synthesis of tert-butyl 8-[(1-benzyloxycarbonyl-4-piperidyl)methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (3) In 8 mL of DCM, a solution of benzyl 4-formylpiperidine-1-carboxylate (400 mg, 1.62 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (388.76 mg, 1.62 mmol) was mixed with TEA (491.03 mg, 4.85 mmol, 675.42 μL) and 4 angstrom MS (100 mg). After stirring at 15°C for 30 minutes, sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added, and the resulting mixture was stirred at 15°C for 5 hours. The desired mass of the major peak (94%) was confirmed by LC-MS. The reaction mixture was diluted with aqueous ammonium chloride (20 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The mixed organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent 80% ethyl acetate / petroleum ether, gradient @ 60 mL / min) to obtain the title compound (850 mg, 1.37 mmol, yield 84.68%, purity 95%) as a colorless oil. MS(M+H) + = 472.3.

[0323] 1 H NMR(400 MHz, CDCl3-d)δ=7.33-7.21(m, 5H), 5.05(s, 2H), 4.22-4.01(m, 2H), 3.37-3.22(m, 2H), 3.19-2.97 (m, 2H), 2.75-2.60(m, 2H), 2.54-2.00(m, 9H), 1.77-1.57(m, 6H), 1.39(s, 9H), 1.13-0.94(m, 2H).

[0324] Step 2. Synthesis of tert-butyl 8-(4-piperidylmethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (4) To a mixture of Pd / C (191.80 mg, 180.23 μmol, 10% purity) and Pd(OH)2 / C (126.55 mg, 180.23 μmol, 20% purity) in 5 mL of THF, tert-butyl 8-[(1-benzyloxycarbonyl-4-piperidyl)methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (850 mg, 1.80 mmol) was added under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 30°C for 16 hours under an H2 (50 psi) atmosphere. The peak of the target product's mass (38%) was confirmed by LC-MS. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and the title compound (600 mg, crude product) was obtained as a gray oil and used directly in the next step. MS(M+H) + = 338.2.

[0325] Step 3. Synthesis of tert-butyl 8-[[1-(4-nitrophenyl)-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (5) Potassium carbonate (737.10 mg, 5.33 mmol) and 1-fluoro-4-nitrobenzene (250.84 mg, 1.78 mmol, 188.61 μL) were added to a solution of tert-butyl 8-(4-piperidylmethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (600 mg, 1.78 mmol) in DMF (10 mL). The mixture was stirred at 80°C for 16 hours. The peak of the target product (65%) was confirmed by LC-MS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether, gradient @ 60 mL / min) to obtain the crude product. This product was pulverized with 5 ml of ethyl acetate and 3 ml of acetonitrile, and further purified to obtain the title compound (250 mg, 501.54 μmol, yield 28.21%, purity 92%) as a yellow solid. MS(M+H)+ = 459.3.

[0326] Step 4. Synthesis of tert-butyl 8-[[1-(4-aminophenyl)-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (6) In ethanol (3 mL) and H2O (3 mL), a solution of tert-butyl 8-[[1-(4-nitrophenyl)-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (250 mg, 545.15 μmol) was added, to which iron (91.33 mg, 1.64 mmol) and ammonium chloride (145.80 mg, 2.73 mmol). The mixture was stirred at 80°C for 1 hour. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was diluted with water (20 mg) and extracted with ethyl acetate (20 mL x 3). Solid sodium bicarbonate (1 g) was added to the aqueous phase, and the mixture was extracted with DCM (20 mL x 3). The mixed organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (200 mg, 457.29 μmol, yield 83.88%, purity 98%) as a brown solid. MS(M+H) + = 429.2.

[0327] Step 5. Synthesis of tert-butyl 8-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (7) In 1 mL of ACN, a solution of tert-butyl 8-[[1-(4-aminophenyl)-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (180 mg, 419.96 μmol) and 3-bromopiperidine-2,6-dione (201.59 mg, 1.05 mmol) was mixed with sodium bicarbonate (141.12 mg, 1.68 mmol). The mixture was stirred at 80°C for 16 hours. The mass peak of the target product (76%, 254 nm) was confirmed by LC-MS. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered to obtain the residue. The residue was washed with water to obtain the title compound (110 mg, 195.66 μmol, yield 46.59%, purity 96%) as a black solid. MS(M+H) + = 540.3.

[0328] • Step 6.3-[4-[4-(2,8-diazaspiro[4,5]decane-8-ylmethyl)-1-piperidyl]anilino]piperidine-2,6-dione(8) In 1,4-dioxane (2 mL), a solution of tert-butyl 8-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (110 mg, 203.81 μmol) was added, to which HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 15°C for 2 hours. The peak of mass of the target product (94%) was obtained by LC-MS. The reaction mixture was concentrated under reduced pressure to obtain the title compound (90 mg, 189.05 μmol, yield 92.76%, HCl) as a black solid. MS(M+H) + = 440.3.

[0329] Step 7. Synthesis of N-(2-chlorophenyl)-4-[[2-[4-[8-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl]-2,8-diazaspiro[4.5]decane-2-carbonyl]anilino]-5-fluoropyrimidine-4-yl]amino]benzamide (compound 33) In 1 mL of DMF, HATU (116.77 mg, 307.10 μmol) and DIPEA (79.38 mg, 614.21 μmol, 106.98 μL) were added to a solution of 3-[4-[4-(2,8-diazaspiro[4.5]decane-8-ylmethyl)-1-piperidyl]anilino]piperidine-2,6-dione (90 mg, 204.74 μmol) and 4-[[4-[4-[(2-chlorophenyl)carbamoyl]anilino]-5-fluoropyrimidine-2-yl]amino]benzoic acid (78.27 mg, 163.79 μmol). The resulting mixture was stirred at 15°C for 16 hours. The peak of mass of the target product (57%) was obtained by LC-MS. The reaction mixture was poured into water (20 mL) and filtered to obtain the crude solid product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 21%~51% B, 10 minutes) and lyophilized. Further purification was performed by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%~58% B, 10 minutes), and lyophilized to obtain the title compound (15.6 mg, 16.13 μmol, yield 7.88%, purity 93%) as a white solid. MS(M+H) + = 899.4.

[0330] 1H NMR (400 MHz, DMSO-d6) δ=10.76(br s, 1H), 9.94(s, 1H), 9.75(s, 1H), 9.59(br d, J=4.9 Hz, 1H), 8.24(br d, J=2.0 Hz, 1H), 8.10-8.00(m, 4H), 7.75(br dd, J=7.3, 10.8 Hz, 2H), 7.69-7.62(m, 1H), 7.57(br d, J=7.9 Hz, 1H), 7.53-7.37(m, 3H), 7.35-7.26(m, 1H), 6.83-6.69(m, 2H), 6.67-6.52(m, 2H), 5.44-5.30(m, 1H), 4.25 -4.15(m, 1H), 3.61-3.47(m, 2H), 2.27-1.99(m, 9H), 1.94-1.64(m, 9H), 1.62-1.38(m, 6H), 1.31-1.04(m, 3H).

[0331] ●Example 34. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(3-((5-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azetidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 34) [ka]

[0332] Step 1. Synthesis of tert-butyl 5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3) Potassium carbonate (2.94 g, 21.26 mmol) was added at 20°C to a solution of 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) and tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.65 g, 7.80 mmol) in DMF (30 mL). The mixture was stirred at 40°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a peak at 96% of the desired mass. The reaction mixture was diluted with H2O (60 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL x 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2.30 g, 6.76 mmol, yield 95.40%, purity 98%) as a yellow solid. MS(M+H) + = 334.4.

[0333] Step 2. Synthesis of tert-butyl 5-(4-aminophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (4) To a solution of tert-butyl 5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.3 g, 6.90 mmol) in ethanol (20 mL) and H2O (20 mL), iron (1.93 g, 34.50 mmol) and ammonium chloride (1.48 g, 27.60 mmol) were added at 20 °C. The mixture was stirred at 80 °C for 2 hours. LC-MS confirmed complete consumption of the starting material and a peak at 81% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (100 mL), adjusted to pH=10 with sodium carbonate, and extracted with ethyl acetate (40 mL x 3). The mixed organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (2 g, 6.39 mmol, yield 92.68%, purity 97%) as a pale yellow solid. MS(M+H) + = 304.4.

[0334] Step 3. Synthesis of tert-butyl 5-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6) Sodium bicarbonate (1.38 g, 16.48 mmol) was added at 20°C to a solution of tert-butyl 5-(4-aminophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1 g, 3.30 mmol) and 3-bromopiperidine-2,6-dione (1.14 g, 5.93 mmol) in acetonitrile (10 mL). The mixture was stirred at 80°C for 16 hours. LC-MS was performed to completely consume the starting material and to obtain the peak (R) of the desired mass at 58%. t A reaction time of 0.700 mins was confirmed. The reaction mixture was filtered and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 80% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (658 mg, 1.59 mmol, yield 48.16%) as an off-white solid. MS(M+H) + = 415.2.

[0335] • Step 4.3-((4-(Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)phenyl)amino)piperidine-2,6-dione (7) In 2 mL of dioxane, a solution of tert-butyl 5-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (558 mg, 1.35 mmol) was added to HCl / dioxane (4 M, 10 mL) at 20°C. The mixture was stirred at 20°C for 1 hour. LC-MS confirmed complete consumption of the starting material and a peak at 97% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (473 mg, crude product, HCl) as a green solid. MS(M+H) + = 315.2.

[0336] Step 5. Synthesis of tert-butyl 3-((5-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azetidine-1-carboxylate (9) In 7 mL of DCM, a solution of 3-((4-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)phenyl)amino)piperidine-2,6-dione (473 mg, 1.35 mmol, HCl) was mixed with TEA (409.26 mg, 4.04 mmol), 4 angstrom MS (100 mg), and tert-butyl 3-formylazetidine-1-carboxylate (249.71 mg, 1.35 mmol). After stirring at 20°C for 10 minutes, sodium triacetoxyborohydride (857.21 mg, 4.04 mmol) was slowly added. The resulting mixture was stirred at 20°C for 16 hours. LC-MS was performed to completely consume the starting material and to obtain the peak (R) of the desired mass at 67%. t A reaction time of 0.583 mins was confirmed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (40 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum, then eluent 0-20% methanol / DCM, gradient @ 100 mL / min) to obtain the crude product. The crude product was further purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 10%~40% B, 10 minutes), lyophilized, and the title compound (340 mg, 563.23 μmol, yield 41.78%, purity 99%, TFA) was obtained as a blackish-purple solid. MS(M+H) + = 484.3.

[0337] • Step 6. Synthesis of 3-((4-(5-(azetidine-3-ylmethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)phenyl)amino)piperidine-2,6-dione (10) In 3 mL of DCM, a solution of tert-butyl 3-((5-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azetidine-1-carboxylate (340 mg, 568.92 μmol, TFA) was added, to which TFA (778.42 mg, 6.83 mmol) was added. The mixture was stirred at 20°C for 1 hour. The starting material was completely consumed by LC-MS, and the desired mass (R) was obtained. t A reaction time of 0.150 minutes was confirmed. The reaction mixture was concentrated under reduced pressure, and the title compound (250 mg, crude product, TFA) was obtained as a deep blue oil. MS(M+H) + = 384.3.

[0338] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(3-((5-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azetidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 34) In 2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (216.12 mg, 452.25 μmol) was added to HATU (171.96 mg, 452.25 μmol) and DIPEA (292.25 mg, 2.26 mmol, 393.87 μL) at 20°C. After stirring for 10 minutes, 3-((4-(5-(azetidine-3-ylmethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)phenyl)amino)piperidine-2,6-dione (225 mg, 452.25 μmol, TFA) and DIPEA (667.80 mg, 5.17 mmol) solution were added to DMF (2 mL) at 20°C. The resulting mixture was stirred at 20°C for 1 hour. The starting material was completely consumed by LC-MS, and the desired mass (R) was obtained. t A reaction time of 0.677 mins was confirmed. The reaction mixture was diluted with H2O (20 mL) and ethyl acetate (30 mL) was added. The mixture was filtered. The filtered cake was washed with ethanol (20 mL), concentrated under reduced pressure to obtain the crude product, purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 mins), lyophilized, and the title compound (111.4 mg, 86.46 μmol, yield 19.12%, purity 92%, 3 TFA) was obtained as a purple solid. MS(M+H) + = 843.1.

[0339] 1H NMR (400 MHz, DMSO-d6) δ=10.85(s, 1H), 9.96(s, 1H), 9.78(s, 1H), 9.67(s, 2H), 8.25(d, J=3.5 Hz, 1H), 8.05-7.95(m, 4H), 7.77(d, J=8.7 Hz, 2H), 7.64(d, J=7.7 Hz, 1H), 7.60-7.52(m, 3H), 7.44-7.36(m, 1H), 7.34-7.25(m, 1H), 6.80-6.70(m, 2H), 6. 68-6.57(m, 2H), 4.57-4.43(m, 2H), 4.28-4.22(m, 1H), 4.19-4.10(m, 2H), 3.89-3.89(m 2H), 3.59-3.40(m, 3H), 3.40-3.35(m, 1H), 3.33-3.24(m, 1H), 3.24-3.12(m, 2H), 3.09-2.93(m, 2H) ), 2.90-2.81(m, 1H), 2.80-2.72(m, 1H), 2.64-2.53(m, 2H), 2.09-2.00(m, 1H), 1.93-1.77(m, 1H).

[0340] ●Example 35. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(5-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)methyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 35) [ka]

[0341] Step 1. Synthesis of (1-(4-nitrophenyl)azetidine-3-yl)methanol(3) Potassium carbonate (7.35 g, 53.15 mmol) was added to 1-fluoro-4-nitrobenzene (2.5 g, 17.72 mmol, 1.88 mL) and azetidine-3-ylmethanol (2.19 g, 17.72 mmol, HCl) in DMF (30 mL) at 20°C. The reaction mixture was stirred at 40°C for 16 hours. A peak with 79% of the desired mass (Rt = 0.621 min) was confirmed by LC-MS. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL), dried over sodium sulfate, concentrated under reduced pressure, and then purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent 10-50% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (3.4 g, 16.17 mmol, yield 91.24%, purity 99%) as a red solid. MS(M+H) + =209.5.

[0342] Step 2. Synthesis of (1-(4-nitrophenyl)azetidine-3-yl)methyl-4-methylbenzenesulfonate (4) In 20 mL of DCM, a solution of (1-(4-nitrophenyl)azetidine-3-yl)methanol (2 g, 9.61 mmol) was mixed with TEA (2.92 g, 28.82 mmol, 4.01 mL) and TosCl (2.75 g, 14.41 mmol) at 20°C. The mixture was stirred at 20°C for 16 hours. LC-MS confirmed complete consumption of the starting material and the peak at the desired mass of 87% (Rt = 0.851 min). After concentrating the reaction mixture under reduced pressure, it was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 10-30% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (3.02 g, 8.17 mmol, yield 85.02%, purity 98%) as a yellow solid. MS(M+H) + =363.1.

[0343] Step 3. Synthesis of tert-butyl 5-((1-(4-nitrophenyl)azetidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(5) Potassium carbonate (1.60 g, 11.59 mmol) was added at 20°C to a solution of (1-(4-nitrophenyl)azetidine-3-yl)methyl 4-methylbenzenesulfonate (1.4 g, 3.86 mmol) and tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (820.10 mg, 3.86 mmol) in DMF (20 mL). The mixture was stirred at 40°C for 16 hours. LC-MS detected residual (1-(4-nitrophenyl)azetidine-3-yl)methyl 4-methylbenzenesulfonate and the desired mass. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL x 3), dried over sodium sulfate, and filtered. After concentrating the filtrate under reduced pressure, it was purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-40%, gradient @ 100 mL / min) to obtain the title compound (900 mg, 2.24 mmol, yield 57.88%) as a yellow oily substance. MS(M+H) + = 403.2.

[0344] Step 4. Synthesis of tert-butyl 5-((1-(4-aminophenyl)azetidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6) Iron (499.50 mg, 8.94 mmol) and ammonium chloride (478.45 mg, 8.94 mmol) were added at 20°C to a solution of tert-butyl 5-((1-(4-nitrophenyl)azetidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (900 mg, 2.24 mmol) in ethanol (10 mL) and H2O (10 mL). The mixture was stirred at 80°C for 1.5 hours. LC-MS confirmed complete consumption of the starting material and a peak at 73% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was diluted with water (60 mL), adjusted to pH=10 with saturated sodium carbonate, and extracted with ethyl acetate (40 mL x 3). The mixed organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (800 mg, 2.15 mmol, yield 96.04%) as a yellow solid. MS(M+H) + = 373.4.

[0345] Step 5. Synthesis of tert-butyl 5-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (8) Sodium bicarbonate (541.25 mg, 6.44 mmol) was added at 20°C to a solution of tert-butyl 5-((1-(4-aminophenyl)azetidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (800 mg, 2.15 mmol) and 3-bromopiperidine-2,6-dione (288.66 mg, 1.50 mmol) in acetonitrile (3 mL). The mixture was stirred at 80°C for 2 hours. All starting materials were completely consumed by LC-MS, and a peak with the desired mass of 27% was confirmed. The reaction mixture was filtered and washed with ethyl acetate:methanol:THF = 1:2:1 (40 mL). The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (12g SepaFlash® silica flash column, eluent 30-100% ethyl acetate / petroleum ether to 0-20% methanol / DCM, gradient @ 100 mL / min). The crude product was further purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 5%-35% B, 10 minutes), lyophilized, and the title compound (370 mg, 594.35 μmol, yield 27.67%, purity 96%, TFA) was obtained as a purple solid. MS(M+H) + = 484.3.

[0346] • Step 6. Synthesis of 3-((4-(3-((Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azetidine-1-yl)phenyl)amino)piperidine-2,6-dione (9) In 1.5 mL of DCM, a solution of tert-butyl 5-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.2 g, 334.66 μmol, TFA) was added to TFA (767.50 mg, 6.73 mmol, 0.5 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. LC-MS confirmed 95% of the desired mass. The mixture was concentrated under reduced pressure (0°C) to obtain the title compound (170 mg, crude product, TFA) as a yellow oil. MS(M+H) + = 384.3.

[0347] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(5-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)methyl)octahydropyrrole o[3,4-c]pyrrole-2-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 35) In 1.5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (160 mg, 334.82 μmol) and HATU (153 mg, 402.39 μmol) was added to DIPEA (432.73 mg, 3.35 mmol, 583.19 μL), and the mixture was stirred at 20°C for 15 minutes. Then, in 1.5 mL of DMF, a solution of 3-((4-(3-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azetidine-1-yl)phenyl)amino)piperidine-2,6-dione (170 mg, 341.70 μmol, TFA) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The desired mass of 58% was confirmed by LC-MS. The mixture was diluted with water (50 mL) and filtered. The filtered cake was washed with water (30 mL). The filtered cake was collected, the solvent was removed under reduced pressure, and then purified by preparative TLC (DCM:methanol = 7:1). The crude product was purified by preparative HPLC (column:Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 18%~48% B, 9 minutes), lyophilized, and the title compound (64.5 mg, 47.15 μmol, yield 56.49%, purity 95%, 4 TFA) was obtained as a gray solid. MS(M+H) + = 843.3.

[0348] 1H NMR (400 MHz, DMSO-d6) δ=11.00-10.82(m, 1H), 10.05-9.87(m, 2H), 9.78(s, 1H), 9.64(s, 1H), 8.24(d, J=3.5 Hz, 1H), 8.05-7.98(m, 4H), 7.76(d, J=8.7 Hz, 2H), 7.66-7.61(m, 1H), 7.58-7.53(m, 1H), 7.49-7.44(m, 2H), 7.41-7.36(m, 1H) ), 7.31-7.26(m, 1H), 6.84-6.66(m, 2H), 6.62-6.47(m, 2H), 4.34-4.24(m, 1H), 4.04 -3.99(m, 1H), 3.76-3.56(m, 6H), 3.52-3.45(m, 2H), 3.12-2.97(m, 3H), 2.77-2.69( m, 1H), 2.62-2.52(m, 5H), 2.46-2.35(m, 2H), 2.10-1.97(m, 1H), 1.93-1.77(m, 1H).

[0349] ●Example 36. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((2-(1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 36) [ka]

[0350] Step 1: Synthesis of tert-butyl 6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate(2) In 30 mL of DCM, a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (2 g, 8.05 mmol) was added to DIPEA (3.12 g, 24.16 mmol, 4.21 mL) at 20°C, followed by the dropwise addition of CbzCl (1.65 g, 9.66 mmol, 1.38 mL) at 0°C. The resulting mixture was stirred at 20°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a peak at 82% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (3 g, 7.84 mmol, yield 97.39%) as a colorless oil. MS(M+H) + = 383.4.

[0351] Step 2. Synthesis of benzyl(1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (3) A solution of tert-butyl 6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 7.84 mmol) was stirred in HCl / dioxane (4 M, 30 mL) at 20°C for 1 hour. LC-MS revealed complete consumption of the starting material and a peak (R) at 68% of the desired mass. t A reaction time of 0.667 minutes was confirmed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (2.5 g, 5.33 mmol, yield 67.98%, purity 68%, HCl) as a white solid. MS(M+H) + = 283.2.

[0352] Step 3. Synthesis of tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azetidine-1-carboxylate (4) In a 40 mL DCM solution, benzyl(1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (2.4 g, 7.53 mmol, HCl) was mixed with TEA (2.29 g, 22.58 mmol, 3.14 mL), 4 angstrom MS (200 mg), and tert-butyl 3-oxoazetidine-1-carboxylate (1.42 g, 8.28 mmol) at 20°C. After stirring for 20 minutes, sodium triacetoxyborohydride (4.79 g, 22.58 mmol) was slowly added at 20°C. The mixture was stirred at 20°C for 16 hours. LC-MS revealed a peak of 8% benzyl(1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate and a peak of 62% of the desired mass (R). t A reaction time of 0.796 mins was confirmed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with sodium bicarbonate (30 mL x 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-40%, gradient @ 100 mL / min) to obtain the title compound (2.7 g, 6.17 mmol, yield 81.97%) as a white solid. MS(M+H) + = 438.3.

[0353] Step 4. Synthesis of benzyl(2-(azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (5) In 20 mL of DCM, a solution of tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azetidine-1-carboxylate was added to 8.44 g (74.05 mmol, 5.50 mL) of TFA at 20°C. The mixture was stirred at 20°C for 2 hours. LC-MS confirmed complete consumption of the starting material and a peak at 93% of the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (2.6 g, crude product, TFA) as a white solid. MS(M+H) + = 338.2.

[0354] Step 5. Synthesis of benzyl(2-(1-(4-nitrophenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (6) Potassium carbonate (4.78 g, 34.56 mmol) was added at 20°C to a solution of benzyl(2-(azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (2.6 g, 5.76 mmol, TFA) and 1-fluoro-4-nitrobenzene (893.91 mg, 6.34 mmol) in DMSO (40 mL). The mixture was stirred at 40°C for 16 hours. LC-MS revealed 11% of benzyl(2-(azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate and a peak at 87% of the desired mass was confirmed. The reaction mixture was diluted with H2O (60 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL x 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-50%, gradient @ 200 mL / min) to obtain the title compound (2.3 g, 5.02 mmol, yield 87.10%) as a yellow solid. MS(M+H) + = 459.3.

[0355] Step 6. Synthesis of benzyl(2-(1-(4-aminophenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (7) In ethanol (20 mL) and H2O (20 mL), a solution of benzyl(2-(1-(4-nitrophenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (2.3 g, 5.02 mmol) was added to a solution of iron (1.40 g, 25.08 mmol) and ammonium chloride (1.07 g, 20.07 mmol) at 20°C. The mixture was stirred at 80°C for 3 hours. LC-MS confirmed that the benzyl(2-(1-(4-nitrophenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate was completely consumed, and a peak with 94% of the desired mass was observed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (60 mL), pH adjusted to 10 with sodium carbonate, and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (820 mg, 1.84 mmol, yield 84.23%, purity 96%) as a yellow solid. MS(M+H) + = 429.2.

[0356] Step 7. Synthesis of benzyl(2-(1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (8) In a solution of benzyl(2-(1-(4-aminophenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (380 mg, 886.76 μmol) and 3-bromopiperidine-2,6-dione (119.19 mg, 620.73 μmol), sodium bicarbonate (372.47 mg, 4.43 mmol, 172.52 μL) was added at 20°C. The mixture was stirred at 80°C for 16 hours. LC-MS revealed 24% of benzyl(2-(1-(4-aminophenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate remaining and a peak at the desired mass of 38% was confirmed. The reaction mixture was filtered. The filtered cake was washed with a mixed solution (40 mL, ethyl acetate:methanol:DCM = 1:1.5:1.5), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (silicon dioxide, DCM:methanol = 10:1), concentrated under reduced pressure to obtain product A (125 mg), and the purity of product A was measured at 55% by LC-MS. Product A was mixed with another pot (72 mg) for re-purification. The mixture was re-purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 21%~51% B, 9 minutes), lyophilized, and the title compound (130 mg, 226.45 μmol, yield 25.54%, purity 94%, TFA) was obtained as a purple solid. MS(M+H) + = 540.3.

[0357] • Step 8. Synthesis of 3-((4-(3-(6-amino-3,4-dihydroisoquinoline-2(1H)-yl)azetidine-1-yl)phenyl)amino)piperidine-2,6-dione (9) A mixture of benzyl(2-(1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (110 mg, 168.29 μmol, TFA) in TFA (5.07 g, 44.43 mmol, 3.30 mL) was stirred at 60°C for 3.5 hours. The starting material was completely consumed by LC-MS, and the desired mass (R) was obtained. t A reaction time of 0.110 minutes was confirmed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (120 mg, crude product, TFA) as a blackish-green solid. MS(M+H) + = 406.3.

[0358] Step 9. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((2-(1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 36) In 0.5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (73.59 mg, 153.99 μmol) was prepared by adding HATU (73.19 mg, 192.49 μmol) and DIPEA (74.63 mg, 577.46 μmol) at 20°C. After stirring for 10 minutes, a solution of 3-((4-(3-(6-amino-3,4-dihydroisoquinoline-2(1H)-yl)azetidine-1-yl)phenyl)amino)piperidine-2,6-dione (100 mg, 192.49 μmol, TFA) was added to DMF (0.5 mL) and DIPEA (298.53 mg, 2.31 mmol, 402.33 μL) at 20°C. The reaction mixture was stirred at 20°C for 1 hour. LC-MS revealed a 1% peak of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid, and a peak of 73% of the desired mass (R tA reaction time of 0.802 mins was confirmed. The reaction mixture was diluted with H2O (5 mL) and ethyl acetate (5 mL). The mixture was filtered. The filtered cake was washed with ethyl acetate (8 mL), concentrated under reduced pressure, and the residue was obtained. The residue was washed by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 26%~56% B, 10 mins), lyophilized, and the title compound (37 mg, 27.16 μmol, yield 14.11%, purity 97%, 4 TFA) was obtained as a purple solid. MS(M+H) + = 865.1.

[0359] 1 H NMR (400 MHz, DMSO-d6) δ=10.79(s, 1H), 10.09(s, 1H), 9.93(s, 1H), 9.78(s, 1H), 9.73(s, 1H), 8.27(d, J=3.5 Hz, 1H), 8.06-8.00(m, 4H), 7.95-7.85(m, 4H), 7.74(s, 1H), 7.68-7.60(m, 2H), 7.56(dd, J=1.3, 7.9 Hz, 1H), 7.39(dt, J=1.3, 7.7 Hz, 1H), 7.33-7.27(m, 1H), 7.18(d, J=8.9 Hz, 1H), 6.70(br d, J=8.7 Hz, 2H), 6.42(br d, J=8.4 Hz, 2H), 4.64-4.44(m, 1H), 4.41-4.26(m, 2H), 4.21(br dd, J=4.4, 11.0 Hz, 1H), 4.15 - 4.05(m, 2H), 3.98-3.93(m, 2H), 3.19-2.99(m, 3H), 2.79-2.68(m, 1H), 2.58-2.52(m, 2H), 2.19-1.96(m, 2H), 1.90-1.79(m, 1H).

[0360] ●Example 37. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1R,5S,6s)-6-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 37) [ka]

[0361] Step 1. Synthesis of tert-butyl(1R,5S,6r)-6-((tosyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2) TosCl (670.43 mg, 3.52 mmol) and TEA (474.46 mg, 4.69 mmol) were added to a solution of tert-butyl(1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.5 g, 2.34 mmol) in DCM (8 mL). The mixture was stirred at 25°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1) confirmed that the starting material was completely consumed and several new spots were formed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The mixed organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-30% petroleum ether / ethyl acetate gradient @ 80 mL / min) to obtain the title compound (250 mg, 391.88 μmol, yield 16.72%, purity 57.6%) as a yellow oily substance. MS(Mt-Bu+H) + = 312.1.

[0362] Step 2. Synthesis of tert-butyl(1R,5S,6s)-6-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(3) Potassium iodide (11.64 mg, 70.12 μmol) and DIPEA (181.25 mg, 1.40 mmol) were added to a solution of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (260 mg, 701.22 μmol HCl) and tert-butyl(1R,5S,6r)-6-((tosyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (257.67 mg, 701.22 μmol) in ACN (5 mL). The mixture was stirred at 45 °C for 12 hours. 10% of the target compound was confirmed by LC-MS. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-50%, gradient @ 80 mL / min) to obtain the title compound (45 mg, 82.82 μmol, yield 11.81%, purity 89%) as a white solid. MS(M+H) + = 484.2.

[0363] • Step 3. Synthesis of 3-((4-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (4) In 6 mL of dioxane, a solution of tert-butyl(1R,5S,6s)-6-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (45 mg, 93.05 μmol) was added to HCl / dioxane (4 M, 46.53 μL). The mixture was stirred at 20°C for 5 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (73 mg, crude product, HCl) as a purple solid. MS(M+H) + = 384.3.

[0364] Step 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1R,5S,6s)-6-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 37) In 2 mL of DMF, HATU (73.88 mg, 194.31 μmol) and DIPEA (62.78 mg, 485.78 μmol, 84.61 μL) were added to a solution of 3-((4-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (68 mg, 161.93 μmol) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (77.38 mg, 161.93 μmol). The mixture was stirred at 25°C for 12 hours. LC-MS confirmed the presence of 26% of the target compound peak. The residue was washed with H2O (3 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 12%~42% B, 10 minutes), lyophilized, and the title compound (10 mg, 11.25 μmol, yield 6.95%, purity 94.9%) was obtained as a purple solid. MS(M+H) + = 843.4.

[0365] 1H NMR (400 MHz, DMSO-d6) δ=10.77-10.74(m, 1H), 9.95-9.92(m, 1H), 9.73(s, 1H), 9.57(s, 1H), 8.23(d, J=3.5 Hz, 1H), 8.17(s, 1H), 8.10-7.95(m, 4H), 7.74(br d, J=8.6 Hz, 2H), 7.65(d, J=8.4 Hz, 1H), 7.56(d, J=7.7 Hz, 1H), 7.45-7.38(m, 3H), 7.32-7.26(m, 1H), 6.72(br d, J=8.8 Hz, 2H), 6.59(br d, J=8.7 Hz, 2H), 5.41-5.32(m, 1H), 4.21-4.14(m, 1H), 4.05-3.97(m, 1H), 3.78-3.68(m, 2H), 3.51-3.47(m, 2H), 2.95 -2.85(m, 4H), 2.75-2.65(m, 1H), 2.62-2.54(m, 5H), 2.35-2.25(m, 2H), 2.15-2.05(m, 1H), 1.48-1.40(m, 2H).

[0366] ●Example 38. Synthesis of N-(2-chlorophenyl)-4-[[2-[4-[[4-[[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl-methyl-amino]methyl]cyclohexyl]carbamoyl]anilino]-5-fluoropyrimidine-4-yl]amino]benzamide (compound 38) [ka]

[0367] Step 1. Synthesis of tert-butyl N-methyl-N-[[1-(4-nitrophenyl)-4-piperidyl]methyl]carbamate (3) Potassium carbonate (1.82 g, 13.14 mmol) was added at 20°C to a solution of tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate (1.5 g, 6.57 mmol) and 1-fluoro-4-nitrobenzene (926.95 mg, 6.57 mmol) in DMF (15 mL). The mixture was stirred at 80°C for 16 hours. The peak of the target product (84%) was confirmed by LC-MS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic phase was washed with brine (20 mL x 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (20g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-30%, gradient @ 80 mL / min) to obtain the title compound (2.15 g, 6.03 mmol, yield 91.79%, purity 98%) as a pale yellow solid. MS(M+H) + = 350.2.

[0368] Step 2. Synthesis of N-methyl-1-[1-(4-nitrophenyl)-4-piperidyl]methanamine (4) In 4 mL of dioxane, a solution of tert-butyl N-methyl-N-[[1-(4-nitrophenyl)-4-piperidyl]methyl]carbamate (1 g, 2.86 mmol) was added to HCl / dioxane (4 M, 4 mL). The mixture was stirred at 20 °C for 1 hour. The mass peak (97%) of the target product was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was triturated with 20 mL of ethyl acetate to obtain the title compound (700 mg, 2.81 mmol, yield 98.11%, purity 100%) as a pale yellow solid. MS(M+H) + = 250.2.

[0369] Step 3. Synthesis of tert-butyl N-[4-[[methyl-[[1-(4-nitrophenyl)-4-piperidyl]methyl]amino]methyl]cyclohexyl]carbamate (6) In 15 mL of DMF, a solution of N-methyl-1-[1-(4-nitrophenyl)-4-piperidyl]methaneamine (1 g, 3.50 mmol, HCl) and [4-(tert-butoxycarbonylamino)cyclohexyl]methylmethanesulfonate (2.15 g, 7.00 mmol) was prepared by adding DIPEA (1.81 g, 14.00 mmol, 2.44 mL) and sodium iodide (104.90 mg, 699.87 μmol) at 20°C. The mixture was stirred at 80°C for 16 hours. LC-MS confirmed the presence of a peak in the mass of the target product (26%) and residual starting material. [4-(tert-butoxycarbonylamino)cyclohexyl]methylmethanesulfonate (1.08 g, 3.50 mmol) was added to the mixture, and the resulting mixture was stirred at 80°C for 24 hours. The mass peak (53%, 254 nm) of the target product was confirmed by LC-MS. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-20%, gradient @ 60 mL / min) to obtain the title compound (1.4 g, 3.04 mmol, yield 86.86%, purity 100%) as a yellow oil. MS(M+H) + = 461.3.

[0370] Step 4. Synthesis of tert-butyl N-[4-[[[1-(4-aminophenyl)-4-piperidyl]methyl-methyl-amino]methyl]cyclohexyl]carbamate (7) Iron (509.22 mg, 9.12 mmol) and ammonium chloride (812.92 mg, 15.20 mmol) were added to a solution of tert-butyl N-[4-[[methyl-[[1-(4-nitrophenyl)-4-piperidyl]methyl]aminomethyl]cyclohexyl]carbamate (1.4 g, 3.04 mmol) in ethanol (10 mL) and H2O (10 mL). The mixture was stirred at 80°C for 16 hours. The peak of the target product (82%) was confirmed by LC-MS. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with aqueous sodium carbonate (20 mL) and extracted with DCM (10 ml x 3). The mixed organic phase was concentrated under reduced pressure. The residue was pulverized with 15 ml of acetonitrile and 2 ml of ethyl acetate to obtain the title compound (200 mg, 464.44 μmol, yield 15.28%, purity 100%) as a brown solid. MS(M+H) + = 431.3.

[0371] Step 5. Synthesis of tert-butyl((1r,4r)-4-((((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)(methyl)amino)methyl)cyclohexyl)carbamate (9) In acetonitrile (1 mL), a solution of tert-butyl N-[4-[[[1-(4-aminophenyl)-4-piperidyl]methyl-methyl-amino]methyl]cyclohexyl]carbamate (200 mg, 464.44 μmol) and 3-bromopiperidine-2,6-dione (222.94 mg, 1.16 mmol) was mixed with sodium bicarbonate (156.06 mg, 1.86 mmol). The mixture was stirred at 80°C for 16 hours. The mass peak (19%) of the target product was confirmed by LC-MS. The reaction mixture was diluted with water (10 mL) and filtered. The filtered cake was collected and dried to obtain the title compound (150 mg, 276.89 μmol, yield 59.62%, purity 100%) as a black solid. MS(M+H) + = 542.4.

[0372] • Step 6.3-[4-[4-[[(4-aminocyclohexyl)methyl-methyl-amino]methyl]-1-piperidyl]anilino]piperidine-2,6-dione (10) In 1 mL of dioxane, a solution of tert-butyl N-[4-[[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl-methyl-amino]methyl]cyclohexyl]carbamate (150 mg, 276.89 μmol) was added, to which HCl / dioxane (4 M, 1 mL) was added. The mixture was stirred at 15°C for 1 hour. The mass peak (80%) of the target product was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure to obtain the title compound (130 mg, 271.93 μmol, yield 98.21%, HCl) as a blue solid. MS(M+H) + = 442.3.

[0373] Step 7. Synthesis of N-(2-chlorophenyl)-4-[[2-[4-[[4-[[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]methyl-methyl-amino]methyl]cyclohexyl]carbamoyl]anilino]-5-fluoropyrimidine-4-yl]amino]benzamide (compound 38) In 2 mL of DMF, HATU (131.23 mg, 345.14 μmol) and DIPEA (89.21 mg, 690.28 μmol) were added to a solution of 3-[4-[4-[[(4-aminocyclohexyl)methyl-methyl-amino]methyl]-1-piperidyl]anilino]piperidine-2,6-dione (110 mg, 230.09 μmol) and 4-[[4-[4-[(2-chlorophenyl)carbamoyl]anilino]-5-fluoropyrimidine-2-yl]amino]benzoic acid (109.96 mg, 230.09 μmol). The mixture was stirred at 15°C for 16 hours. The peak of the target product (48%) was confirmed by LC-MS. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The filtered cake was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 20%~50% B, 10 minutes), and further purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 45%~75% B, 10 minutes). The fractions were lyophilized to obtain the title compound (6.6 mg, 7.17 μmol, yield 3.12%, purity 98%) as a white solid. MS(M+H) + =901.5.

[0374] 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 9.94(s, 1H), 9.75(s, 1H), 9.61(s, 1H), 8.25(d, J=3.4 Hz, 1H), 8.07-7.93(m, 5H), 7.80-7.75(m, 4H), 7.70-7.62(m, 1H), 7.57(dd, J=1.2, 7.8 Hz, 1H), 7.43-7.35(m, 1H), 7.34-7.25(m, 1H), 6.75(d, J=8.9 Hz, 2H), 6.60(d, J=8.7 Hz, 2H), 5.36(d, J=7.2 Hz, 1H), 4.25-4.14(m, 1H), 3.80-3.62(m, 1H), 3.38-3.36(m, 1H), 2.17-2.05(m, 9H), 1.92 -1.71(m, 9H), 1.59-1.45(m, 2H), 1.34-1.28(m, 2H), 1.20-1.05(m, 4H), 0.95-0.88(m, 2H).

[0375] ●Example 39. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 39) [ka]

[0376] Step 1. Synthesis of tert-butyl 4-(4-nitrophenyl)-1,4-diazepane-1-carboxylate (3) Potassium carbonate (5.18 g, 37.45 mmol) was added at 20°C to a solution of tert-butyl 1,4-diazepane-1-carboxylate (5 g, 24.97 mmol, 4.92 mL) and 1-fluoro-4-nitrobenzene (4.23 g, 29.96 mmol, 3.18 mL) in DMF (50 mL). The mixture was stirred at 20°C for 16 hours. The desired mass was detected by LC-MS. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 3). The mixed organic layer was washed with brine (30 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. It was then purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent 0-35% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to obtain the title compound (6.2 g, 19.10 mmol, yield 76.50%, purity 99%) as a yellow solid. MS(Mt-Bu+H) + = 266.4.

[0377] • Step 2. Synthesis of 1-(4-nitrophenyl)-1,4-diazepane(4) In a solution of tert-butyl 4-(4-nitrophenyl)-1,4-diazepane-1-carboxylate (3 g, 9.34 mmol) in dioxane (4 mL), HCl / dioxane (4 M, 30 mL) was added at 20°C. The mixture was stirred at 20°C for 1 hour. LC-MS detected the complete consumption of the starting material and the desired mass. The reaction mixture was concentrated under reduced pressure to obtain the title compound (3 g, crude product, HCl) as a yellow solid. MS(M+H) + = 222.1.

[0378] Step 3. Synthesis of tert-butyl((1r,4r)-4-((4-(4-nitrophenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (6) In a 6 mL DMF solution of 1-(4-nitrophenyl)-1,4-diazepane (0.5 g, 1.94 mmol, HCl), DIPEA (752.24 mg, 5.82 mmol, 1.01 mL), sodium iodide (29.08 mg, 194.01 μmol), and ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzene sulfonate (1.12 g, 2.91 mmol) were added. The resulting mixture was stirred at 60°C for 14 hours. LC-MS revealed a 36% peak for 1-(4-nitrophenyl)-1,4-diazepane and a 43% peak for the desired mass. Furthermore, ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate (744 mg, 1.94 mmol) was added at 20°C, and the mixture was stirred at 60°C for 14 hours. LC-MS confirmed a desired mass of 58%. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent 40-100% ethyl acetate / petroleum ether, gradient @ 50 mL / min). The product was then diluted with MTBE (10 mL) and stirred at 20°C for 0.5 hours. The mixture was filtered, the filtered cake was washed with MTBE (20 mL), recovered, and dried to obtain tert-butyl((1r,4r)-4-((4-(4-nitrophenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (0.5 g, 1.09 mmol, yield 56.01%, purity 94%) as a yellow solid. MS(M+H) + = 433.4.

[0379] SFC Method Com: Column: Chiralcel OJ-3 50×4.6mm ID, 3um; Mobile phase: Phase A against CO2 and Phase B against ethanol (0.05% DEA); Gradient elution: 5%~40% of Phase B in Phase A; Flow rate: 3 mL / min; Detector: DAD; Column temperature: 35°C; Back pressure: 100 Bar.

[0380] Step 4. Synthesis of tert-butyl((1r,4r)-4-((4-(4-aminophenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (7) In ethanol (12 mL) and H2O (4 mL), a mixture of tert-butyl((1r,4r)-4-((4-(4-nitrophenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (0.4 g, 924.74 μmol) and ammonium chloride (248 mg, 4.64 mmol) was mixed with iron (258 mg, 4.62 mmol), and the mixture was stirred at 80°C for 1 hour. LC-MS confirmed a peak at 82% of the desired mass. After mixing the mixture with another batch (0.1 g scale), it was filtered and washed with ethanol (20 mL) and THF (30 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with ethyl acetate (10 mL) and water (10 mL), and the mixture was adjusted to pH=9 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (10 mL x 3), the mixed organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.5 g, crude product) as a yellow solid. MS(M+H) + = 403.4.

[0381] Step 5. Synthesis of tert-butyl((1r,4r)-4-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (9) A solution of tert-butyl((1r,4r)-4-((4-(4-aminophenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (450 mg, 1.12 mmol), 3-bromopiperidine-2,6-dione (324 mg, 1.69 mmol), and sodium bicarbonate (282 mg, 3.36 mmol, 130.62 μL) was stirred in acetonitrile (4.5 mL) for 14 hours at 80°C. LC-MS confirmed a peak with 95% of the desired mass. The mixture was filtered, and the filter cake was washed with ethyl acetate / methanol = 10 / 1 (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5g SepaFlash® silica flash column, eluent 70-100% ethyl acetate / petroleum ether to 10-20% methanol / ethyl acetate, gradient @ 50 mL / min) to obtain the title compound (290 mg, 525.04 μmol, yield 46.97%, purity 93%) as a blue solid. MS(M+H) + = 514.5.

[0382] • Step 6.3 Synthesis of ((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)-1,4-diazepan-1-yl)phenyl)amino)piperidine-2,6-dione (10) In 1.5 mL of DCM, a solution of tert-butyl((1r,4r)-4-((4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamate (150 mg, 292.02 μmol) was added to TFA (690.75 mg, 6.06 mmol, 450.00 μL), and the mixture was stirred at 20°C for 1 hour. LC-MS confirmed the peak at 85% of the desired mass. The mixture was concentrated under reduced pressure to obtain the title compound (160 mg, crude product, TFA) as a dark brown oil. MS(M+H) + = 414.3.

[0383] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-1,4-diazepan-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 39) In 1.5 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (145 mg, 303.43 μmol) and HATU (138 mg, 362.94 μmol) was added, to which DIPEA (385.84 mg, 2.99 mmol) was added, and the mixture was stirred at 20°C for 15 minutes. Then, in 1.5 mL of DMF, a solution of 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)-1,4-diazepan-1-yl)phenyl)amino)piperidine-2,6-dione (160 mg, 303.27 μmol, TFA) was added at 0°C, and the resulting mixture was stirred at 20°C for 1 hour. LC-MS confirmed a peak with 86% of the desired mass. The mixture was diluted with water (10 mL) and filtered. The filtered cake was washed with water (10 mL), collected, and dried. The crude product was purified by preparative TLC (DCM:methanol = 7:1), then re-purified by preparative HPLC (column:Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 20%~50% B, 10 min), and lyophilized. The product was further purified by preparative HPLC (column:Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 25%~55% B, 10 min), lyophilized, and the title compound (42.6 mg, 31.44 μmol, yield 10.37%, purity 89.7%, 3TFA) was obtained as a red solid. MS(M+H) + = 873.4.

[0384] 1H NMR (400 MHz, DMSO-d6) δ=10.85(br s, 1H), 9.94(s, 1H), 9.76(s, 1H), 9.62(s, 1H), 9.01-8.89(m, 1H), 8.25(d, J=3.5 Hz, 1H), 8.07-7.97(m, 5H), 7.81-7.72(m, 4H), 7.67-7.63(m, 1H), 7.59-7.55(m, 1H), 7.43-7.37(m, 1H) ), 7.33-7.26(m, 1H), 6.75-6.65(m, 3H), 4.28-4.20(m, 1H), 3.76-3.64(m, 2H), 3.62-3.47(m, 2H), 3.41 -3.27(m, 1H), 3.24-3.11(m, 1H), 3.08-3.00(m, 1H), 2.80-2.68(m, 1H), 2.44-2.36(m, 5H), 2.21-2.13( m, 2H), 2.09-2.01(m, 1H), 1.94-1.77(m, 6H), 1.74-1.65(m, 1H), 1.42-1.28(m, 2H), 1.16-1.04(m, 2H).

[0385] ●Example 40. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 40) [ka]

[0386] Step 1. Synthesis of benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)piperidine-1-carboxylate (3) In 20 mL of DCM, a solution of benzyl 4-formylpiperidine-1-carboxylate (1.25 g, 5.05 mmol) was mixed with TEA (1.53 g, 15.16 mmol, 2.11 mL), 4 angstrom MS (50 mg), and tert-butyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (1.00 g, 5.05 mmol) at 20°C. After stirring for 10 minutes, sodium triacetoxyborohydride (3.21 g, 15.16 mmol) was slowly added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. LC-MS confirmed complete consumption of the starting material and a peak at the desired mass of 58% (Rt = 0.635 min). The reaction mixture was filtered. The filtration cake was washed with a mixed solution (50 ml, ethyl acetate:methanol = 1:2). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was triturated with ethyl acetate (10 mL) at 20°C for 1 hour and filtered. The filtration cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 30-70%, gradient @ 100 mL / min) to obtain the title compound (1.76 g, 4.10 mmol, yield 81.06%) as a colorless oil. MS(M+H) + = 430.4.

[0387] Step 2. Synthesis of tert-butyl((1R,5S,6s)-3-(piperidine-4-ylmethyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (4) A mixture of benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)piperidine-1-carboxylate (1.76 g, 4.10 mmol) and Pd / C (0.8 g, 10% purity) was degassed in ethanol (20 mL) and purged three times with H2. The resulting mixture was stirred at 20°C for 12 hours under an H2 (15 psi) atmosphere. LC-MS confirmed that the starting material was completely consumed and the desired mass (Rt = 0.797 min) was obtained. The reaction mixture was filtered and washed with methanol (30 ml x 3). The filtrate was concentrated under reduced pressure to obtain the title compound (1.2 g, crude product) as a gray solid. MS(M+H) + = 296.2.

[0388] Step 3. Synthesis of tert-butyl((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (5) Potassium carbonate (1.68 g, 12.19 mmol) was added at 20°C to a solution of tert-butyl((1R,5S,6s)-3-(piperidine-4-ylmethyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (1.2 g, 4.06 mmol) and 1-fluoro-4-nitrobenzene (1.09 g, 7.72 mmol) in DMF (20 mL). The mixture was stirred at 20°C for 12 hours. LC-MS confirmed that tert-butyl((1R,5S,6s)-3-(piperidine-4-ylmethyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate remained, and the desired mass (Rt = 0.674 min) was confirmed. The reaction mixture was then heated to 40°C and stirred for 4 hours. LC-MS detected residual tert-butyl((1R,5S,6s)-3-(piperidine-4-ylmethyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate and the desired mass. The reaction mixture was stirred continuously at 40°C for 12 hours. LC-MS detected complete consumption of tert-butyl((1R,5S,6s)-3-(piperidine-4-ylmethyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate and the desired mass. The reaction mixture was diluted with H2O (60 mL) and extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to obtain the title compound (1.2 g, 2.79 mmol, yield 68.80%, purity 97%) as a yellow solid. MS(M+H) + = 417.3.

[0389] Step 4. Synthesis of tert-butyl((1R,5S,6s)-3-((1-(4-aminophenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate(6) Iron (643.57 mg, 11.52 mmol) and ammonium chloride (770.56 mg, 14.41 mmol) were added at 20°C to a solution of tert-butyl((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (1.2 g, 2.88 mmol) in ethanol (10 mL) and H2O (10 mL). The mixture was stirred at 80°C for 2 hours. The starting material was completely consumed and the desired mass was detected by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (50 mL), adjusted to pH=10 with sodium carbonate, and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (970 mg, 2.41 mmol, yield 83.62%, purity 96%) as a purple solid. MS(M+H) + = 387.4.

[0390] Step 5. Synthesis of tert-butyl((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (7) In 4 mL of ACN, a solution of tert-butyl((1R,5S,6s)-3-((1-(4-aminophenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (500 mg, 1.29 mmol) and 3-bromopiperidine-2,6-dione (347.73 mg, 1.81 mmol) was mixed with sodium bicarbonate (543.34 mg, 6.47 mmol) at 20°C. The mixture was stirred at 80°C for 16 hours. LC-MS detected a peak at 86% of the desired mass. The reaction mixture was washed with a mixed solution (100 ml, methanol:ethyl acetate:THF = 1:1:3), concentrated under reduced pressure, and the residue was obtained. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum ether to 0-20% DCM:methanol, gradient @ 100 mL / min) to obtain the product, which was further purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 1%-31% B, 10 minutes), lyophilized, and the title compound (300 mg, 480.67 μmol, yield 37.16%, purity 98%, TFA) was obtained as a purple solid. MS(M+H) + = 498.3.

[0391] • Step 6.3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (8) To a solution of tert-butyl((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (150 mg, 301.43 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 6 mL) was added at 20 °C. The mixture was stirred at 20 °C for 1 hour. The starting material was completely consumed by LC-MS and the desired mass was obtained. The reaction mixture was concentrated under reduced pressure to obtain the title compound (180 mg, crude product, HCl) as a yellow solid. MS(M+H) + = 398.3.

[0392] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 40) In 1 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (107.36 mg, 224.67 μmol) was prepared by adding HATU (105.14 mg, 276.51 μmol) and DIPEA (134.02 mg, 1.04 mmol) at 20°C. After stirring for 10 minutes, a solution of 3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (150 mg, 345.64 μmol, HCl) was added to DMF (1 mL) and DIPEA (742.00 mg, 5.74 mmol, 1.00 mL) at 20°C. The resulting mixture was stirred at 20°C for 1 hour. A peak at 60% of the desired mass was confirmed by LC-MS. The reaction mixture was poured into water and filtered. The filtered cake was collected and dried. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 23%~43% B, 7 min), lyophilized, and the title compound (31.1 mg, 24.09 μmol, yield 6.97%, purity 92.9%, 3TFA) was obtained as a gray solid. MS(M+H) + = 857.3.

[0393] 1H NMR (400 MHz, DMSO-d6) δ=10.84(s, 1H), 9.95(s, 1H), 9.78(s, 1H), 9.67(s, 1H), 9.50-9.31(m, 1H), 8.47-8.32(m, 1H), 8.26(d, J=3.5 Hz, 1H), 8.07-7.96(m, 4H), 7.82-7.71(m, 4H), 7.65(d, J=6.9 Hz, 1H), 7.57(dd, J=1.1, 8.0 Hz, 1H), 7.46-7.26(m, 4H), 6.77(br d, J=8.8 Hz, 2H), 4.39(br dd, J=4.4, 11.6 Hz, 1H), 4.09-4.13(m, 1H), 3.90-3.80(m, 1H), 3.57-3.51(m, 2H), 3.47-3.40(m, 2H), 3.33-3.28(m, 1H), 3.24-3.04(m, 2H), 2.98 -2.84(m, 1H), 2.80-2.69(m, 1H), 2.64-2.56(m, 2H), 2.18-2.11(m, 1H), 2.11-1.99(m, 5H), 1.97-1.88(m, 1H), 1.71-1.50(m, 2H).

[0394] ●Example 41. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((3aR,5s,6aS)-2-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamoyl)phenyl)amino)5-fluoropyrimidine-4-yl)amino)benzamide (compound 41) [ka]

[0395] Step 1. Synthesis of tert-butyl(3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(2) To a solution of tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2 g, 8.88 mmol) in methanol (45 mL), sodium borohydride (1.01 g, 26.63 mmol) was added in small increments at 0°C. The mixture was stirred at 0°C for 1 hour. TLC (petroleum ether:ethyl acetate = 1:2) confirmed that the starting material was completely consumed and a single novel major spot with high polarity had been formed. The reaction was stopped by adding 1N HCl (50 mL), diluted with H2O (100 mL), and extracted with ethyl acetate (50 mL x 3). The mixed organic layer was washed with brine (30 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2 g, 8.80 mmol, yield 99.11%) as a yellow oil.

[0396] Step 2. Synthesis of tert-butyl(3aR,5s,6aS)-5-(1,3-dioxoisoindolin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4) In 30 mL of THF, DIAD (1.16 g, 5.72 mmol, 1.11 mL) was added dropwise at 0°C under an N2 atmosphere to a solution of tert-butyl(3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1 g, 4.40 mmol), PPh3 (1.50 g, 5.72 mmol), and isoindoline-1,3-dione (841.49 mg, 5.72 mmol). The resulting solution was heated to 20°C and stirred for 1 hour. The major peak at the desired mass was confirmed by LC-MS. The reaction was stopped with methanol (30 mL) and concentrated under reduced pressure. The residue was purified twice by flash silica gel chromatography (Biotage; 20g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-30%, gradient @ 80 mL / min) to obtain the title compound (1.5 g, 4.21 mmol, yield 95.66%) as a white solid. MS(M+Na) + = 379.2.

[0397] Step 3. Synthesis of tert-butyl(3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(5) To 10 mL of ethanol, a solution of tert-butyl(3aR,5s,6aS)-5-(1,3-dioxoisoindorin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1 g, 2.81 mmol) was added, and NH2-NH2·H2O (877.84 mg, 14.03 mmol, 850.62 μL, purity 80%) was added. The resulting mixture was stirred at 80°C for 2 hours. The desired mass peak (~70%) was confirmed by LC-MS. The reaction mixture was filtered and washed with 20 mL of ethanol. The filtrate was concentrated under reduced pressure to obtain the title compound (600 mg, 2.65 mmol, yield 94.49%) as a yellow oil, which was used directly in the next step. MS(M+H) + = 227.2.

[0398] Step 4. Synthesis of tert-butyl(3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(6) In 10 mL of DCM, a solution of tert-butyl(3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (600 mg, 2.65 mmol) was mixed with TEA (804.82 mg, 7.95 mmol, 1.11 mL) and CbzCl (542.72 mg, 3.18 mmol). The resulting mixture was stirred at 20°C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction mixture was diluted with H2O (20 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (20 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20g SepaFlash® silica flash column, eluent: ethyl acetate / petroleum ether 0-30%, gradient @ 80 mL / min), and further purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 39%-69% B, 10 minutes) to obtain the title compound (300 mg, 832.30 μmol, yield 60.00%) as a yellow oily substance. MS(M+H) + = 361.2.

[0399] Step 5. Synthesis of benzyl((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)carbamate (7) In 5 mL of dioxane, a solution of tert-butyl(3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (300 mg, 832.30 μmol) was added, and HCl / dioxane (4 M, 5 mL) was stirred at 20°C for 0.5 hours. The major peak at the desired mass was confirmed by LC-MS. The mixture was concentrated under reduced pressure to obtain the title compound (250 mg, crude product, HCl salt) as a white solid. MS(M+H) + = 261.2.

[0400] Step 6. Synthesis of tert-butyl 4-(((3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)piperidine-1-carboxylate (9) In 5 mL of DCM, a solution of benzyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)carbamate (250 mg, 842.34 μmol, HCl salt) and tert-butyl 4-formylpiperidine-1-carboxylate (179.65 mg, 842.34 μmol) was added, to which sodium acetate (138.20 mg, 1.68 mmol) was added. After stirring at 20°C for 0.5 hours, sodium triacetoxyborohydride (535.58 mg, 2.53 mmol) was added. The resulting mixture was stirred at 20°C for 16 hours. The major peak at the desired mass was confirmed by LC-MS. The reaction was stopped by adding sodium bicarbonate solution (20 mL) to the reaction mixture, and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (20 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 12g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum ether to ethyl acetate with 10% methanol, gradient @ 80 mL / min) to obtain the title compound (400 mg) as a yellow oily substance. MS(M+H) + = 458.3.

[0401] Step 7. Synthesis of benzyl((3aR,5s,6aS)-2-(piperidine-4-ylmethyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (10) In 5 mL of dioxane, a solution of tert-butyl 4-(((3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)piperidine-1-carboxylate (200 mg, 437.06 μmol) was added, and HCl / dioxane (4 M, 5 mL) was added. The resulting mixture was stirred at 20°C for 0.5 hours. LC-MS confirmed complete consumption of the starting material and the peak at the desired mass. The mixture was concentrated under reduced pressure to obtain the title compound (170 mg, 431.53 μmol, yield 98.73%, HCl salt) as a white solid. MS(M+H) + = 358.3.

[0402] Step 8. Synthesis of benzyl((3aR,5s,6aS)-2-((1-(4-nitrophenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (12) In 5 mL of DMF, a solution of benzyl ((3aR,5s,6aS)-2-(piperidine-4-ylmethyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (170 mg, 431.53 μmol, HCl salt) and 1-fluoro-4-nitrobenzene (100.47 mg, 712.02 μmol, 75.54 μL) was mixed with potassium carbonate (238.56 mg, 1.73 mmol). The resulting mixture was stirred at 40°C for 16 hours. The desired mass peak (39%) was confirmed by LC-MS. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Biotage; 10g SepaFlash® silica flash column, eluent: 50-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate, gradient @ 50 mL / min) to obtain the title compound (160 mg, 334.32 μmol, yield 77.47%) as a yellow oily substance. MS(M+H) + = 479.3.

[0403] Step 9. Synthesis of benzyl((3aR,5s,6aS)-2-((1-(4-aminophenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (13) In ethanol (5 mL) and H2O (1 mL), a solution of benzyl((3aR,5s,6aS)-2-((1-(4-nitrophenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (160 mg, 334.32 μmol) was added, along with iron (93.35 mg, 1.67 mmol) and ammonium chloride (89.42 mg, 1.67 mmol). The resulting mixture was stirred at 80°C for 2 hours. The desired mass peak (58%) was confirmed by LC-MS. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (140 mg, crude product) as a brown oily substance. MS(M+H) + = 449.3.

[0404] Step 10. Synthesis of benzyl((3aR,5s,6aS)-2-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (15) In 1 mL of ACN, a solution of benzyl ((3aR,5s,6aS)-2-((1-(4-aminophenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (100 mg, 222.92 μmol) and 3-bromopiperidine-2,6-dione (42.80 mg, 222.92 μmol) was added, to which sodium bicarbonate (93.64 mg, 1.11 mmol) was added. The resulting mixture was stirred at 80°C for 16 hours. The desired mass peak (33%) was confirmed by LC-MS. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The mixed organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 12g SepaFlash® silica flash column, eluent: 0-20% ethyl methanol in acetic acid, gradient @ 80 mL / min) to obtain the title compound (120 mg) as a brown oily substance. MS(M+H) + = 560.3.

[0405] • Step 11. Synthesis of 3-((4-(4-(((3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (16) A mixture of benzyl((3aR,5s,6aS)-2-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamate (100 mg, 178.67 μmol) in TFA (2 mL) was stirred at 40°C for 1 hour. LC-MS confirmed complete consumption of the starting material and the desired mass peak (50%). The reaction mixture was concentrated under reduced pressure to obtain the title compound (90 mg, crude product, TFA salt) as a brown oil. MS(M+H) + = 426.3.

[0406] Step 12. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((3aR,5s,6aS)-2-((1-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5-yl)carbamoyl)phenyl)amino)5-fluoropyrimidine-4-yl)amino)benzamide (compound 41) In 2 mL of DMF, a solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoic acid (79.71 mg, 166.79 μmol) was mixed with HATU (76.10 mg, 200.15 μmol) and DIPEA (107.78 mg, 833.97 μmol). After stirring at 20°C for 0.5 hours, 3-((4-(4-(((3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (90 mg, 166.79 μmol, TFA salt) was added, and the resulting mixture was stirred at 20°C for 1 hour. The desired mass peak (20%) was confirmed by LC-MS. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The mixed organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 20%~50% B, 10 minutes). The eluate was lyophilized to obtain the title compound (11.2 mg, 11.38 μmol, yield 6.83%, purity 90%) as a green solid. MS(M+H) + = 885.3.

[0407] 1H NMR (400 MHz, DMSO-d6) δ=10.83(s, 1H), 9.94(s, 1H), 9.76(s, 1H), 9.63(s, 1H), 8.25(d, J=3.5 Hz, 1H), 8.17(d, J=7.8 Hz, 1H), 8.05-7.98(m, 4H), 7.80-7.72(m, 4H), 7.67-7.62(m, 1H), 7.59-7.55(m, 1H), 7.49-7.24(m, 5H), 7.15-6.94(m, 1H), 6.77(d, J=8.6 Hz, 1H), 4.62-4.49(m, 1H), 4.48-4.33(m, 1H), 3.87-3.78(m, 2H), 3.60-3.53(m, 4H), 2.84 -2.71(m, 5H), 2.64-2.57(m, 2H), 2.14-2.00(m, 3H), 1.97-1.82(m, 5H), 1.78-1.55(m, 4H).

[0408] ●Example 42. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((6-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 42) [ka]

[0409] Step 1. Synthesis of tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (3) Potassium carbonate (6.18 g, 44.75 mmol) was added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (4.3 g, 14.92 mmol, oxalic acid) and 1-fluoro-4-nitrobenzene (4.21 g, 29.83 mmol, 3.16 mL) in DMF (5 mL). The mixture was stirred at 25 °C for 16 hours. LC-MS confirmed that the tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate was completely consumed. The reaction mixture was diluted with H₂O (50 mL) and ethyl acetate (50 mL). The resulting mixture was filtered. The filtered cake was collected and dried to obtain tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (3.6 g, 11.27 mmol, yield 75.58%, purity 100%), a yellow solid that was part of the target product. The filtrate was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether, gradient @ 80 mL / min) to obtain the title compound (1.9 g, 3.69 mmol, yield 24.73%, purity 62%) as a yellow solid. MS(M+H) += 320.3.

[0410] • Step 2. Synthesis of 2-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane(4) In 35 mL of DCM, a solution of tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (3.5 g, 10.96 mmol) was mixed with TFA (16.88 g, 148.08 mmol, 11 mL). The mixture was stirred at 25°C for 1 hour. LC-MS confirmed that tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (3.6 g, 10.80 mmol, yield 98.56%, TFA) as a yellow oil. MS(M+H) + = 220.1.

[0411] Step 3. Synthesis of tert-butyl 4-((6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (6) In 36 mL of DCM, a solution of 2-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane (3.6 g, 10.80 mmol, TFA) and tert-butyl 4-formylpiperidine-1-carboxylate (2.30 g, 10.80 mmol) was mixed with TEA (3.28 g, 32.41 mmol, 4.51 mL) and 4-angstrom MS (800 mg). After stirring at 25°C for 0.5 hours, sodium triacetoxyborohydride (6.87 g, 32.41 mmol) was added in small increments, and the mixture was stirred at 25°C for 16 hours. LC-MS confirmed that 2-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane was completely consumed. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (60 mL x 2). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-20%, @80mL / min) to obtain the title compound (3.33g, 7.99 mmol, yield 74.01%) as a yellow solid. MS(M+H) + = 417.4.

[0412] Step 4. Synthesis of tert-butyl 4-((6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (7) In ethanol (44 mL) and H2O (11 mL), a solution of tert-butyl 4-((6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (2.2 g, 5.28 mmol) was added, to which ammonium chloride (2.83 g, 52.82 mmol) and iron (1.47 g, 26.41 mmol) were added. The mixture was stirred at 80°C for 1 hour. LC-MS confirmed that the starting materials were completely consumed. The reaction mixture was diluted with H2O (150 mL) and extracted with ethyl acetate (60 mL x 3). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1 g, 2.59 mmol, yield 48.98%) as a brown solid. MS(M+H) + = 387.3.

[0413] Step 5. Synthesis of tert-butyl 4-((6-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (9) Sodium bicarbonate (264.71 mg, 3.15 mmol) was added to a solution of tert-butyl 4-((6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (210 mg, 543.30 μmol) and 3-bromopiperidine-2,6-dione (104.32 mg, 543.30 μmol) in ACN (1 mL). The resulting mixture was stirred at 60°C for 3 hours. LC-MS confirmed the presence of 13% tert-butyl 4-((6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: 0-20% methanol in ethyl acetate, @60 mL / min) to obtain the title compound (127 mg, 222.03 μmol, yield 40.87%, purity 87%) as a black solid. MS(M+H) += 498.3.

[0414] • Step 6.3-((4-(6-(piperidine-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)piperidine-2,6-dione (10) In 1.2 mL of DCM, a solution of tert-butyl 4-((6-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (120 mg, 209.80 μmol) was mixed with TFA (614.00 mg, 5.38 mmol, 0.4 mL). The mixture was stirred at 25°C for 0.5 hours. LC-MS confirmed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (107 mg, 209.17 μmol, yield 99.70%, TFA) as a black oil. MS(M+H) + = 398.3.

[0415] Step 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((6-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carbonyl)phenyl)amino)-5-fluoropyrimidine-4-yl)amino)benzamide (compound 42) In 1 mL of DMF, a solution of 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoate (86.02 mg, 134.23 μmol) and 3-((4-(6-(piperidine-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)piperidine-2,6-dione (103.00 mg, 201.35 μmol, TFA) was added to DIPEA (173.49 mg, 1.34 mmol, 233.81 μL). The mixture was stirred at 25°C for 16 hours. LC-MS confirmed that 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine-2-yl)amino)benzoate was completely consumed. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 2). The mixed organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: methanol / ethyl acetate 0-20%, @50 mL / min). The impure product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 15%~45% B, 10 minutes), lyophilized, and the title compound (11.2 mg, 9.80 μmol, yield 7.30%, purity 85%, TFA) was obtained as a white solid. MS(M+H) + = 857.4.

[0416] 1 H NMR (400 MHz, DMSO-d6) δ=10.86(s, 1H), 9.95(s, 1H), 9.75(s, 1H)...

Claims

1. Compound represented by the following chemical formula I: [Chemical formula I] 【Chemistry 1】 In the above formula, PTM is an Aurora kinase A (AURKA)-bound molecule represented by the following chemical formula II. [Chemical formula II] 【Chemistry 2】 In the above formula, R １ It is a halo; R ２ is -NH- or -O-; R ３Ａ and R ３Ｂ These are independently -CH- or -N-; R ３Ｃ is H, halo, or OC １－３ It is alkyl; 【Transformation 3】 R ４ -CO-, -CONH-, -CON(CH ３ ) - or - NHCO -; 【Chemistry 4】 is a 5- to 6-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which is optionally substituted with one to three halos; 【Transformation 5】 is phenyl or 5- to 6-membered heteroaryl optionally substituted with halo or C １－３ alkyl; 【Transformation 6】 This is a covalent bond linked to the Linker; ULM is a CRBN E3 ubiquitin ligase-conjugated molecule represented by the following chemical formulas III-1, III-2A, or III-2B. [Chemical formula III-1] 【Transformation 7】 [Chemical formula III-2A] 【Transformation 8】 [Chemical formula III-2B] 【Chemistry 9】 In the above formula, U １ is a covalent bond, -NH-, -N(CH ３ ) -, -NHCO- or -CONH-; U ２ is CH or N; 【Chemistry 10】 C has one to three halos. １－３ Alkyl or OC １－３ A phenyl or six-membered heteroaryl optionally substituted with an alkyl group; 【Chemistry 11】 This is a covalent bond linked to the Linker; A linker is a linking group represented by the following chemical formula IV, [Chemical formula IV] 【Chemistry 12】 In the above formula, L Ｕ This is a covalent bond, -CH ２ -, -NH-, -O-, CH ２ CH ２ -, -NHCH ２ -ien-CH ２ NH-, -OCH ２ -ien-CH ２ O-, -CH=CH- or -CC-; L Ｍ is a covalent bond, -CH ２ -, -CH ２ CH ２ -, -CH(CH ３ )CH ２ -, -CH ２ CH(CH ３ )-, -CH(CH ２ CH ３ )CH ２ -, -CH ２ CH(CH ２ CH<000006>)-, -COCH ２ -, -CH ２ CO-, -CH ２ NH-, -NHCH ２ -, -CH ２ N(CH ３ )-, -N(CH ３ )CH ２ -, -CH ２ CH ２ CH ２ -, -COCH ２ CH ２ -, -CH ２ COCH ２ -, -CH ２ CH ２ CO-, -NHCH ２ CH ２ -, -CH ２ NHCH ２ -, -CH ２ CH ２ [[ID=?]]NH-, -N(CH ３ )CH ２ CH ２ -, -CH<000006?N(CH ３ )CH ２ - or -CH ２ CH ２ N(CH ３ )-; It should be noted that there seems to be an issue with the numbering in the original text (e.g., <000006?>, <000006? >), which may need to be corrected in the source for a more accurate translation. L Ｐ is, -CH ２ -, -O-, -CH ２ O-, -OCH ２ -, -NH-, -CH ２ NH-, -NHCH ２ -, -N(CH ３ )CH ２ -ien-CH ２ N(CH ３ )-, -CO-, -COCH ２ -, -NHCO-, -CH ２ NHCO-, -CONHCH ２ -, -NHCOCH ２ -, -CONH- or -CH ２ CONH- is; L Ｗ１ and L Ｗ２ Each of these independently has 1 to 3 C １－３ It is a 3- to 11-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl molecule optionally substituted with alkyl or OH groups; L Ｕ and L Ｐ teeth, 【Chemistry 13】 It is connected to ULM and PTM respectively via [this method].

2. The compound according to claim 1, wherein chemical formula II is the following chemical formula II-1: [Chemical formula II-1] 【Chemistry 14】 In the above formula, R １ It is a halo; R ２ is -NH- or -O-; R ３Ａ and R ３Ｂ These are independently -CH- or -N-; R ３Ｃ is H, halo, or -OC １－３ It is alkyl; R ４ is -CONH-, -CON(CH ３ ) - or - NHCO -; R ５ is CH or N; 【Chemistry 15】 is a cyclohexyl or phenyl molecule optionally substituted with one to three halos; 【Chemistry 16】 This is a covalent bond connected to the Linker.

3. The compound according to claim 1, wherein chemical formula II is the following chemical formula II-2: [Chemical formula II-2] 【Chemistry 17】 In the above formula, R １ It is a halo; [Chemistry 18] is a halo or C １－３ It is a phenyl or pyrazolyl compound optionally substituted with an alkyl group.

4. The compound according to claim 1, wherein chemical formula III-1 is the following chemical formula III-1A or III-1B: [Chemical formula III-1A] 【Chemistry 19】 [Chemical formula III-1B] 【Chemistry 20】 In the above formula, U １ is a covalent bond, -NH-, -N(CH ３ ) -, -NHCO- or -CONH-; U ２ is CH or N; U ３Ａ and U ３Ｂ Each is independently either CH or N; U ４Ａ and U ４Ｂ These are H, Halo, and C, respectively, independently. １－３ Alkyl or OC １－３ It is alkyl.

5. The compound according to claim 1, wherein chemical formula III-2A or III-2B is the following chemical formula III-2C or chemical formula III-2D: [Chemical formula III-2C] 【Chemistry 21】 [Chemical formula III-2D] 【Chemistry 22】 In the above formula, U ５ This is H or halo.

6. L Ｕ is covalent or -CC-; L Ｐ is, -CH ２ O-, -N(CH ３ )CH ２ -, -CO-, -COCH ２ -, -NHCO-, -CH ２ The compound according to claim 1, wherein it is NHCO- or -CONH-.

7. L Ｍ This is a covalent bond, -CH ２ -ien-CH ２ CH ２ -, -CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ ) -, -CH ２ CH (CH ２ CH ３ ) -, -COCH ２ -ien-CH ２ CO-, -CH ２ N(CH ３ ) -, -CH ２ CH ２ CH ２ -ien-CH ２ CH ２ CO-, -CH ２ N(CH ３ )CH ２ - or -CH ２ CH ２ N(CH ３ The compound according to claim 1, wherein the compound is:

8. L Ｗ１ and L Ｗ２ The compound according to claim 1, wherein each is independently of the following chemical formula IV-1, IV-2, or IV-3: [Chemical formula IV-1] 【Chemistry 23】 In the above formula, Z １ and Z ２ Each is independently either CH or N; Z Ｘ H, CH ３ or OH; p １ is 0, 1, or 2; p ２ is 1, 2, or 3; [Chemical formula IV-2] 【Chemistry 24】 In the above formula, Z ３ and Z ４ Each is independently either CH or N; q １ and q ３ Each of these is independently 0, 1, or 2; q ２ and q ４ Each is independently 1 or 2; [Chemical formula IV-3] 【Chemistry 25】 In the above formula, Z ５ and Z ６ Each is independently either CH or N; r １ 〜r ４ These are independently either 0 or 1.

9. The compound according to claim 1, which induces AURKA protein degradation.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical composition for the treatment of AURKA-related diseases, comprising the compound described in any one of claims 1 to 9.

Images