Aurora-A kinase selective degradation inducing compound based on 2, 4-diphenylamine pyrimidine

Abstract

The invention discloses a novel Aurora-A kinase (AURKA) degradation agent based on 2, 4-diphenylamine pyrimidine and a preparation method of the Aurora-A kinase degradation agent based on 2, 4-diphenylamine pyrimidine. The AURKA degrading agent of the present invention is a proteolytic targeting chimera (PROTAC), which recruits the AURKA protein into an optimized CRBN E3 ubiquitin ligase via a linker. The compounds can induce selective AURKA degradation and are useful in the treatment of cancer.

Description

Technical Field

[0001] This disclosure relates to novel Aurora-A kinase selective degradation-inducing compounds containing modified cereblon conjugates, methods for preparing the compounds, and their uses. Background Technology

[0002] Aurora kinases belong to the serine / threonine kinase family and are crucial for cell proliferation. The two main Aurora kinases (Aurora-A and Aurora-B) are closely related in their kinase domain sequences but have distinctly different functions during mitosis. Among small molecule-based Aurora kinase inhibitors, selective inhibitors of Aurora-A kinase (AURKA) have been extensively studied as potential anticancer therapeutics (Borisa, Ankit C., and Hardik G. Bhatt. "A comprehensive review on Aurora kinase: Small molecule inhibitors and clinicaltrial studies." European journal of medicinal chemistry 140(2017):1-19).

[0003] While the catalytic activity of AURKA is crucial for its mitotic function, recent reports have also highlighted additional non-catalytic functions that are difficult to target with conventional small molecules. As an alternative approach, PROTAC-mediated AURKA depletion suggests that AURKA has an important non-catalytic function during DNA replication (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-Diphenylamine pyrimidine derivatives have been reported as excellent selective AURKA inhibitors (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 the synthesis of novel PROTAC compounds by linking 2,4-diphenylamine pyrimidine derivatives via a linker to von Hippel-Lindau (VHL) or cereblon (CRBN) conjugates (e.g., thalidomide), which mediate the selective degradation of AURKA.

[0005] In current PROTAC technology, regulating the chemical composition of CRBN conjugates is a crucial step in optimizing protein degraders, and even small structural changes can have a profound impact on the overall characteristics of PROTACs (including targeted degradation depth, off-target effects, and other drug-like properties) (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, by using a low molecular weight glutarimide-based CRBN conjugate, the inventors successfully synthesized a novel optimized AURKA degrader that exhibits effective selective degradation of AURKA and / or cytotoxicity against cancer cells, as well as improved drug properties. Summary of the Invention

[0006] Technical issues

[0007] The purpose of this invention is to provide a novel selective AURKA degrading agent, as well as its preparation method and uses.

[0008] Technical solution

[0009] To address this problem, this disclosure provides a novel compound defined as Formula I, along with its preparation method and uses.

[0010] Design of novel Aurora-A kinase degrading agents

[0011] In one general aspect, this disclosure provides novel compounds represented by formula I:

[0012] [Formula I]

[0013] ULM—Connector Base—PTM

[0014] in:

[0015] PTM is the Aurora-A kinase (AURKA) binding moiety represented by the following formula II:

[0016] [Formula II]

[0017]

[0018] in:

[0019] R1 is a halogen;

[0020] R2 is -NH- or -O-;

[0021] R 3A and R 3B Each can be independently -CH- or -N-;

[0022] R 3C Is it H, halogen, or OC? 1-3 alkyl;

[0023] yes

[0024] R4 is -CO-, -CONH-, -CON(CH3)-, or -NHCO-;

[0025] It is a 5- to 6-membered cycloalkyl, heterocyclic, aryl, or heteroaryl group optionally substituted with 1 to 3 halogens;

[0026] It is optionally halogenated or C 1-3 Alkyl-substituted phenyl or 5- to 6-membered heteroaryl; and

[0027] It is a covalent bond connected to the linker base; and

[0028] ULM is the CRBN E3 ubiquitin ligase-binding moiety represented by the following formula: III-1, III-2A, or III-2B:

[0029] [Formula III-1]

[0030]

[0031] [Formula III-2A]

[0032]

[0033] [Formula III-2B]

[0034]

[0035] in:

[0036] U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-;

[0037] U2 is CH or N;

[0038] It is optionally divided by 1 to 3 halogens, C 1-3 Alkyl or OC 1-3 Alkyl-substituted phenyl or 6-membered heteroaryl; and

[0039] It is a covalent bond connected to the linker base; and

[0040] The linker group is a linker group represented by the following formula IV:

[0041] [Form IV]

[0042]

[0043] in:

[0044] L U It is a covalent bond, -CH2-, -NH-, -O-, CH2CH2-, -NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -CH=CH-, or -CC-;

[0045] L M It is a covalent bond, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -COCH2-, -CH2CO-, -CH2NH-, -NHCH2-, -CH2N(CH3)-, -N(CH3)CH2-, -CH2CH2CH2-, -COCH2CH2-, -CH2COCH2-, -CH2CH2CO-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -N(CH3)CH2CH2-, -CH2N(CH3)CH2- or -CH2CH2N(CH3);

[0046] L PIt is -CH2-, -O-, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -N(CH3)CH2-, -CH2N(CH3)-, -CO-, -COCH2-, -NHCO-, -CH2NHCO-, -CONHCH2-, -NHCOCH2-, -CONH-, or -CH2CONH-;

[0047] L W1 and L W2 Each independently can be arbitrarily assigned to one to three Cs. 1-3 Alkyl or OH-substituted 3- to 11-membered cycloalkyl, heterocyclic, aryl, or heteroaryl groups; and

[0048] L U and L P Through respectively Connect to ULM and PTM.

[0049] The novel compound represented by Formula I is a proteolytically targeted chimeric compound (PROTAC), a bispecific molecule containing a target protein conjugate and an E3 ubiquitin ligase conjugate linked by a linker. By recruiting the CRBN E3 ubiquitin ligase to the target protein AURKA, PROTAC promotes ubiquitination and eventual proteasome degradation of the target protein. Figure 1 ).

[0050] (1) Aurora-A kinase-binding moiety (PTM)

[0051] In Formula I, the PTM represented by Formula II is a 2,4-diphenylamine pyrimidine-based moiety with selective Aurora-A kinase (AURKA) binding affinity.

[0052] Aurora-A kinase (AURKA) is a serine / threonine protein kinase encoded by the AURKA gene (e.g., NCBI reference sequence: NP_001310234.1) in the human body. AURKA is involved in important processes during mitosis and meiosis, and its normal function is essential for healthy cell proliferation. AURKA is activated through one or more phosphorylation processes, and its activity peaks during the G2-M phase transition in the cell cycle. AURKA expression is significantly higher in cancerous tissues than in normal control tissues across various tumor types. AURKA activation has been demonstrated to play a crucial role in a variety of cancers.

[0053] In one implementation, equation II is the following equation II-1:

[0054] [Formula II-1]

[0055]

[0056] in:

[0057] R1 is a halogen;

[0058] R2 is -NH- or -O-;

[0059] R 3A and R 3B Each can be independently -CH- or -N-;

[0060] R 3C Is it H, halogen, or -OC? 1-3 alkyl;

[0061] R4 is -CONH-, -CON(CH3)-, or -NHCO-;

[0062] R5 is CH or N;

[0063] It is a cyclohexyl or phenyl group optionally substituted with 1 to 3 halogens; and

[0064] It is a covalent bond connected to the linker base.

[0065] In one implementation, formula II-1 is one of the following formulas: II-1A, II-1B, II-1C, II-1D, or II-1E:

[0066] [Formula II-1A]

[0067]

[0068] Where R1 is a halogen; R 3C R6 is H, a halogen, or OCH3; R7 is H or a halogen; and R8 is H or CH3.

[0069] [Formula II-1B]

[0070]

[0071] Where R1 is a halogen; R 3A and R 3B Each is independently CH or N; and R6 is H or a halogen.

[0072] In one implementation, R in formula II-1B 3A and R 3B One of them is N; and the other is CH.

[0073] [Formula II-1C]

[0074]

[0075] R1 is a halogen; R6 is H or a halogen; and R7 is H or CH3.

[0076] [Formula II-1D]

[0077]

[0078] Where R1 is a halogen; R 3C It is H or a halogen; and R6 is H or a halogen.

[0079] [Formula II-1E]

[0080]

[0081] Where R1 is a halogen; R2 is -NH- or -O-; R5 is CH or N; and R6 is H or a halogen.

[0082] In one embodiment, R6 in formula II-1A, II-1B, II-1C, II-1D or II-1E is connected to its parent ring via an adjacent, inter-adjacent or anti-adjacent (preferably adjacent) position.

[0083] In one implementation, equation II is the following equation II-2:

[0084] [Formula II-2]

[0085]

[0086] in:

[0087] R1 is a halogen; and

[0088] It is optionally halogenated or C 1-3 Alkyl-substituted phenyl or pyrazolyl groups.

[0089] In one implementation, formula II-2 is either formula II-2A or II-2B:

[0090] [Formula II-2A]

[0091]

[0092] [Formula II-2B]

[0093]

[0094] R8 is H, halogen, or C. 1-3 alkyl.

[0095] (2) Cereblon E3 ubiquitin ligase-binding moiety (ULM)

[0096] In Formula I, the ULM represented by Formula III-1, III-2A or III-2B is an optimized cereblon conjugate in which the glutarimide moiety is directly or mediated by a short linker group to an aryl or heteroaryl ring.

[0097] Cereblon (CRBN) is a subunit of the E3 ubiquitin ligase protein encoded by the CRBN gene in the human body. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullins1 regulatory factor (ROC1), thereby leading to substrate protein ubiquitination.

[0098] In one implementation, equation III-1 is equation III-1A:

[0099] [Formula III-1A]

[0100]

[0101] in:

[0102] U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-;

[0103] U2 is CH or N;

[0104] U 3A and U 3B Each is independently CH or N; and

[0105] U 4A and U 4B Each is independently H, halogen, C 1-3 Alkyl or OC 1-3 alkyl.

[0106] In one implementation, equation III-1A is the following:

[0107]

[0108] U 4A and U 4B Each is independently H, halogen, C 1-3 Alkyl or OC 1-3 alkyl.

[0109] In one implementation, equation III-1A is the following:

[0110]

[0111] Among them, U2, U 3A and U3B At least one of them is N; and the rest are CH.

[0112] In one implementation, equation III-1A is the following:

[0113]

[0114] U 4A and U 4B Each is independently H, halogen, C 1-3 Alkyl or OC 1-3 Alkyl; and U5 is H or CH3. In one embodiment, formula III-1A is the following:

[0115]

[0116] U 3A It is CH or N; and U 4B It is H, halogen, C 1-3 Alkyl or OC 1-3 alkyl.

[0117] In one implementation, equation III-1 is the following equation III-1B:

[0118] [Formula III-1B]

[0119]

[0120] in:

[0121] U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-; and

[0122] U 4A It is H, halogen, C 1-3 Alkyl or OC 1-3 alkyl.

[0123] In one implementation, formula III-2A is equivalent to formula III-2C:

[0124] [Formula III-2C]

[0125]

[0126] U5 is H or a halogen.

[0127] In one implementation, equation III-2B is equivalent to equation III-2D:

[0128] [Formula III-2D]

[0129]

[0130] U5 is H or a halogen.

[0131] (3) Connecting base

[0132] In Formula I, the linker represented by Formula IV is the linker group that connects ULM and PTM, thereby causing the AURKA and CRBN E3 ubiquitin ligases recruited by PTM and ULM to come into close proximity.

[0133] In one embodiment, the linker represented by Formula IV is a linker group with a minimum length of 4 to 20 atoms, preferably 8 to 14 atoms, that links ULM and PTM.

[0134] In equation IV, L W1 and L W2 Each can be independently represented as Equation IV-1:

[0135] [Formula IV-1]

[0136]

[0137] in:

[0138] Z1 and Z2 are each independently CH or N;

[0139] Z X It is H, CH3 or OH;

[0140] p1 is 0, 1, or 2; and

[0141] p2 is 1, 2, or 3;

[0142] In one embodiment, formula IV-1 is one of the following groups LW-1 to 12:

[0143] [Table 1]

[0144]

[0145]

[0146] In equation IV, L W1 and L W2 Each can be independently represented as Equation IV-2:

[0147] [Formula IV-2]

[0148]

[0149] in:

[0150] Z3 and Z4 are each independently CH or N;

[0151] q1 and q3 are each independently 0, 1, or 2; and

[0152] q2 and q4 are each independently 1 or 2.

[0153] In one embodiment, formula IV-2 is one of the following groups LW-13 to 19:

[0154] [Table 2]

[0155]

[0156] In equation IV, L W1 and L W2 Each can be independently represented as Formula IV-3:

[0157] [Formula IV-3]

[0158]

[0159] in:

[0160] Z5 and Z6 are each independently CH or N; and

[0161] r1 to r4 are each independently 0 or 1.

[0162] In one embodiment, formula IV-2 is one of the following groups LW-20 to 23:

[0163] [Table 3]

[0164]

[0165] In equation IV, L W1 and L W2 Each can be independently one of the following groups:

[0166]

[0167] In one implementation, Formula IV is selected from linker-1 to linker-68 in Table 4, wherein and These are covalent bonds connected to the ULM and PTM respectively:

[0168] [Table 4]

[0169]

[0170]

[0171]

[0172]

[0173] In one embodiment of this disclosure, the compound represented by Formula I is selected from compounds 1 to 123.

[0174] In one embodiment, the compounds of this disclosure may be in the form of a salt (preferably a pharmaceutically acceptable salt). In this disclosure, a pharmaceutically acceptable salt refers to any organic or inorganic acid addition salt having a relatively non-toxic, harmless concentration that is effective for the patient, wherein side effects caused by the salt do not impair the beneficial efficacy of the novel compounds of this disclosure.

[0175] In one embodiment, the compounds disclosed herein may be in the form of racemic, enantiomer, rotational isomer, tautomer, N-oxide, or any stereoisomer, as each is specifically described unless the context explicitly excludes it.

[0176] In one embodiment, the compounds disclosed herein may be in the form of their hydrates or solvates.

[0177] In one embodiment, the compounds disclosed herein may be in the form of chimeric molecules formed by conjugation of a functional macromolecule via a chemical linker. In some embodiments, the macromolecule is a biomolecule, including nucleic acids, aptamers, carbohydrates, peptides or fragments thereof, antibodies or fragments thereof.

[0178] In this disclosure, "optionally replaced by" means that a chemical group is unsubstituted or that at least one hydrogen atom in the group is replaced by a substituent.

[0179] In this disclosure, the term "substituent" refers to a portion of a parent molecule in which at least one hydrogen atom is replaced by at least one covalent bond.

[0180] In this disclosure, the term "alkyl" refers to an alkane substituent, which is a saturated acyclic hydrocarbon and can be straight-chain or branched. For example, "C n "Alkyl" refers to an alkyl group having n carbon atoms.

[0181] In this disclosure, the term "cycloalkyl" refers to a cycloalkane substituent, which is a saturated cyclic hydrocarbon.

[0182] In this disclosure, the term "heterocyclic group" refers to a substituent in a heterocyclic compound consisting of at least one ring having atoms of at least two different elements as its ring members. For example, a heterocyclic group may contain carbon and nitrogen as its ring members, such as azacyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, and so on.

[0183] In this disclosure, the term "aryl" is a substituent of a cyclic compound comprising at least one aromatic ring.

[0184] In this disclosure, the term "heteroaryl" is a substituent of a cyclic compound comprising at least one aromatic ring having atoms of at least two different elements as its ring members. For example, heteroaryl groups may comprise carbon and nitrogen as their ring members, such as pyrrole, pyrazole, imidazole, triazole, triazine, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, indolizine, azaindolizine, purine, indazole, imidazopyridine, imidazotriazine, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyridopyrimidine, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinazine, phthalazine, naphthidine, quinoxaline, quinazoline, cinnazoline, pteridine, pyrazinopyridazine, etc.

[0185] In this disclosure, the term "n-ary" means that the number of elements other than hydrogen in the substituent is n.

[0186] In this disclosure, the terms "cycloalkyl", "aryl", "heterocyclic", and "heteroaryl" can be monocyclic, fused-ring (e.g., spirocyclic or bicyclic), and polycyclic. For example, cycloalkyl, aryl, heterocyclic, and heteroaryl can be azaspiro, diazaspiro, bicyclic, azabicyclic, diazabicyclic, diazabicyclic (bridged), or tetrahydroisoquinoline, etc.

[0187] Synthesis of a novel AURKA degrading agent

[0188] In one embodiment, the novel compounds of this disclosure can be prepared, for example, via reaction routes 1 to 3, synthetic methods known in the field of organic chemistry, or techniques that are obvious to those skilled in the art.

[0189] [Reaction Route 1]

[0190]

[0191] PTM—Connector Base—ULM

[0192] [Reaction Route 2]

[0193]

[0194] PTM—Connector Base—ULM

[0195] [Reaction Route 3]

[0196] (i)

[0197] (ii)

[0198] (iii) PTM—Connector 1—RG 2b +RG 3a -Connector 2—ULM→PTM—Connector 1—Connector 2—ULM→PTM—Connector—ULM

[0199] In the reaction pathway, PTM, linker, and ULM are the same as defined above.

[0200] In the field of organic synthesis, RG 1 RG 2 RG 2a RG 2b RG 3 RG 3a RG 3b and RG 4 It is the part that includes a suitable reactive group that can be linked to the intermediate of PROTAC by forming a covalent bond. The formation of the covalent bond can be achieved through synthetic reactions, such as amide formation, ester formation, carbamate formation, urea formation, ether formation, amine formation, as well as the formation of single and double bonds between individual carbons, click chemistry, etc., depending on the specific reactive group, but not limited to these.

[0201] Each step in the above reaction route may include one or more synthetic steps. The separation and purification of the products can be achieved using standard procedures known to those skilled in the art of organic chemistry.

[0202] Applications of the novel AURKA degrading agent

[0203] In one embodiment, the novel compound disclosed herein is an AURKA degrader that induces the degradation of AURKA protein in cells.

[0204] The PROTAC of the present invention can induce the proteasome degradation of AURKA in cells by recruiting CRBN ubiquitin ligase to AURKA (supported by experimental examples of the present disclosure). For example, the present disclosure discloses that compounds 1 to 123 have AURKA-degrading activity (confirmed by luciferase assays on the HeLa LgBit cell system), thereby resulting in inhibitory activity against cancer cell viability (confirmed by cell viability assays on the small cell lung cancer (SCLC) cell line NCI-H446).

[0205] The inventors have revealed that newly designed PROTACs with CRBN E3 ubiquitin ligase-binding moieties, represented by formulas III-1, III-2A, or III-2B, exhibit sufficient AURKA degradation efficiency levels across the entire range. These surprising results are unprecedented in the field of PROTACs, as were earlier PROTACs with thalidomide-based CRBN conjugates.

[0206] In one embodiment, by depleting the target protein rather than inhibiting it, the PROTAC of the present invention exhibits better therapeutic efficacy than small AURKA inhibitors from which PROTACs are derived. Therefore, the PROTAC of the present invention can be used to treat AURKA-related conditions or illnesses, wherein aberrant expression of the AURKA protein is involved in the onset and / or progression of the disease.

[0207] In this disclosure, AURKA-related conditions or illnesses refer to any disease or illness that can be treated, delayed, suppressed, or prevented by inducing AURKA degradation or inhibiting AURKA activity. AURKA-related conditions or illnesses include, but are not limited to, cancer, benign tumors, or neurological disorders.

[0208] In one embodiment, the PROTAC of the present invention exhibits anticancer activity against AURKA-expressing cancer cells by depleting AURKA (a key oncogenic regulator of the cell cycle). Cancer includes all cancers that can exhibit preventative or therapeutic efficacy due to inhibition of AURKA activity, and can be solid tumors or hematologic malignancies. For example, the cancer may be selected from one or more of the following: 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 fibroid cancer, esophageal cancer, small bowel 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, liver tumor, breast cancer, colon cancer, colorectal cancer, endometrial cancer 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, adrenocorticotropic tumor. Cancer includes, but is not limited to, tumors, T-cell lymphoma / leukemia, neuroendocrine carcinoma, neuroendocrine tumors, cholangiocarcinoma, etc. Cancer includes not only primary cancer but also metastatic cancer.

[0209] Benign tumors include all benign tumors that can exhibit preventive or therapeutic effects by inhibiting AURKA activity, such as precancerous benign tumors, and can be solid tumors or hematologic malignancies. For example, a tumor can be one or more of the following, but is not limited to: Barrett's esophagus, colonic adenomas and polyps, breast fibroadenomas and cysts, monoclonal gammopathy of undetermined significance (MGUS), monoclonal lymphocytosis, etc.

[0210] Neurological disorders include all neurological disorders that can exhibit preventive or therapeutic effects due to inhibition of AURKA activity, and specifically may be one or more of the following: central nervous system disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, stroke, and neurological damage and axonal degeneration-related disorders following brain or spinal cord injury, but are not limited thereto.

[0211] To improve drug activity, any known strategy in the field of PROTACs can be applied to the PROTACs of this invention, including photochemically controlled PROTACs (PHOTACs), hypoxia-activated PROTACs, folic acid-encapsulated PROTACs, antibody-PROTAC conjugates (Ab-PROTACs) and aptamer-PROTAC conjugates (APCs), as well as BCL-XL PROTACs, etc. (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).

[0212] In one embodiment, the PROTAC of the present invention can be used as a payload for antibody-drug conjugates (ADCs) (e.g., antibody-PROTAC conjugates (Ab-PROTAC)). ADCs can specifically deliver cytotoxic payloads to cancer cells, enabling maximum effect 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 for improving the tissue- and cell-type selectivity of PROTACs.

[0213] In one embodiment, this disclosure provides a pharmaceutical composition comprising the PROTAC of the present invention, wherein the compound is conjugated to an antibody or an antigen-binding fragment thereof via a linker.

[0214] In one embodiment, this disclosure provides an antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof and the PROTAC of the present invention, wherein the compound is conjugated to the antibody or the antigen-binding fragment thereof via a linker.

[0215] In some embodiments, the linker chemically links an antibody or its antigen-binding fragment to the PROTAC of the present invention, wherein functional groups within the compound are modified to form covalent bonds with the linker moiety. In some embodiments, the functional group is an amine group within the PROTAC linker or E3L conjugate moiety of the compound.

[0216] In some embodiments, the antibody or its antigen-binding fragment is cancer cell specific and comprises one or more molecules of a compound of formula I. In some embodiments, the linker is a cleavable or non-cleavable linker.

[0217] This disclosure also provides pharmaceutical compositions comprising the PROTAC of the present invention and at least one pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises an effective amount of at least one PROTAC compound of the present invention, and optionally an effective amount of one or more other active ingredients for combination therapy. In one embodiment, the pharmaceutical composition comprises more than one pharmaceutically acceptable amount of an additive or excipient.

[0218] Another embodiment of this disclosure is a method for degrading AURKA by administering the PROTAC of the present invention to a sample in vitro. The sample may include, but is not limited to, mammalian (including human) cells, cell cultures, body fluids, or tissues.

[0219] Beneficial effects of the present invention

[0220] The novel compounds disclosed herein can induce AURKA degradation in cells throughout the range; therefore, they can be effectively used to treat AURKA-related symptoms or conditions.

[0221] Brief description of the attached diagram

[0222] Figure 1 The mechanism of PROTAC-driven target protein degradation is described, in which the recruitment of E3 ubiquitin ligase to the target protein leads to ubiquitination and proteasome degradation of the target protein AURKA.

[0223] Best way to carry out the invention

[0224] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in this specification is for describing particular embodiments only and is not intended to limit this disclosure.

[0225] This disclosure provides methods for synthesizing compounds 1 to 123 and results on their biological activity.

[0226] [Table 5]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] The compounds of the present invention were purified and their structures analyzed according to the following methods.

[0249] instrument

[0250] LCMS: Shimadzu LCMS-2020

[0251] HPLC: Agilent 1260II LC, Agilent 1200 / G6410B

[0252] NMR: BRUKER AVANCE / 400MHZ

[0253] LCMS Analysis

[0254] LCMS data were recorded using a Shimadzu LCMS-2020 equipped with an ESI (electrospray ionization) system. Water (solvent A) containing 0.0375% TFA and ACN (solvent B) containing 0.01875% TFA were used as mobile phases. Kinetex EVO C18 (2.1 × 30 mm, 5 μm) or HALO C18 (3.0 × 30 mm, 2.7 μm) were used as columns.

[0255] HPLC analysis

[0256] For HPLC analysis, an Agilent 1260II LC or Agilent 1200 / G6410B was used. The mobile phase consisted of water (solvent A) containing 0.0375% TFA and ACN (solvent B) containing 0.01875% TFA. For the column, a Zobrax Eclipse Plus C18 (4.6 × 150 mm, 3.5 μm) or YMC ODS A (4.6 × 150 mm, 3 μm) was used.

[0257] NMR analysis

[0258] 1 1H NMR spectra were recorded using a Bruker AVANCE III 400MHz / 5mm probe (BBO).

[0259] Example 1. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 1)

[0260]

[0261] Step 1. Synthesis of ethyl (4-bromophenyl)piperidine-4-carboxylate (2)

[0262] Under N2, Pd2(dba)3 (582.48 mg, 636.00 μmol), Xantphos (552.08 mg, 954.00 μmol), and Cs2CO3 (31.09 g, 95.40 mmol) were added to a toluene (50 mL) solution of 1-bromo-4-iodobenzene (9.00 g, 31.80 mmol) and piperidine-4-carboxylate (5 g, 31.80 mmol, 4.90 mL). The mixture was stirred at 100 °C for 16 h. LCMS showed a main peak with the desired mass. The mixture was filtered, and the filtrate was concentrated under vacuum to give 1-(4-bromophenyl)piperidine-4-carboxylate (7.7 g, 23.92 mmol, 75.23% yield, 97% purity) as a yellow oil. MS (M+H) + =313.0.

[0263] Step 2.1 -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperidine-4-methyl Synthesis of ethyl acetate (3)

[0264] Under N2, 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 to a solution of ethyl 1-(4-bromophenyl)piperidine-4-carboxylate (3 g, 9.61 mmol) in dioxane (30 mL). The resulting mixture was stirred at 100 °C for 16 hours. LCMS showed a main peak with the desired mass. The mixture was filtered, and the filtrate was concentrated under vacuum. The filtrate was analyzed by rapid silica gel chromatography (Biotage, 10 g). The crude product was purified by rapid silica gel column chromatography (eluting with a 2–10% EtOAc / petroleum ether gradient at 50 mL / min) to give ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperidine-4-carboxylate (2.9 g, 5.49 mmol, 57.12% yield, 68% purity) as a yellow solid. MS (M+H) + =360.2.

[0265] Step 3.1 Synthesis of ethyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate (4)

[0266] Ethyl piperidine-4-carboxylate (2.9 g, 8.07 mmol) and 2,6-dibenzyloxy-3-bromopyridine (2.99 g, 8.07 mmol) in dioxane (20 mL) and H₂O (4 mL) were added to a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)phenyl)piperidine-4-carboxylate (2.99 g, 8.07 mmol) in dioxane (20 mL) and H₂O (4 mL). The mixture was stirred at 90 °C for 16 h. LCMS showed a peak of 32% with the desired mass. The mixture was filtered, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (20 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The solution was analyzed by rapid silica gel chromatography (Biotage, 25 g). The crude product was purified by silica gel rapid column chromatography (eluting with a 4–70% EtOAc / petroleum ether gradient at 55 mL / min) to give ethyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-carboxylate (0.9 g, 1.55 mmol, 19.20% yield, 90% purity), which was a yellow oil. MS (M+H) + =533.1.

[0267] Step 4. Synthesis of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol (5)

[0268] Under N2, LAH (92.80 mg, 2.45 mmol) was added to a solution of ethyl 1-(4-(2,6-dibenzyloxy-3-pyridyl)phenyl)piperidin-4-carboxylate (0.9 g, 1.72 mmol) in 10 mL of THF. The mixture was stirred at 25 °C for 1 hour. LCMS showed a main peak with the desired mass. The reaction mixture was quenched at 0 °C with H2O (0.09 mL), NaOH aqueous solution (15%, 0.09 mL), and H2O (0.27 mL). The mixture was then filtered and washed with EtOAc. The filtrate was dried over Na2SO4 and concentrated under reduced pressure to give (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol (700 mg, crude) as a yellow oil. MS (M+H) + =481.2.

[0269] Step 5.3 Synthesis of (4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (6)

[0270] Pd / C (300 mg, 10% purity) was added to a solution of (700 mg, 1.46 mmol) of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol in CF3CH2OH (10 mL) under H2. The mixture was degassed three times with N2 and then stirred at H2 (15 psi) and 25 °C for 16 h. LCMS showed a main peak with the desired quality. The mixture was filtered, and the filtrate was concentrated under vacuum to give 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (400 mg, crude) as a yellow oil. MS (M+H) + =303.1.

[0271] Step 6.1 Synthesis of (4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (7)

[0272] DMP (168.33 mg, 396.87 μmol, 122.87 μL) was added to a solution of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (100 mg, 330.72 μmol) in DCM (2 mL), and the mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether:EtOAc = 1:1) showed that most of the starting material was consumed and new spots were formed. The reaction mixture was filtered, and the filtrate was concentrated to give 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (120 mg, crude product) as a brown oil. This crude product was used directly in the next step. MS (M+H) + =301.1.

[0273] Step 7. N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide Synthesis of (Compound 1)

[0274] NaOAc (12.38 mg, 150.88 μmol) was added to a DCE (6 mL) solution of N-(2-chlorophenyl)-4-((5-fluoro-2-((4-(2-oxo-2-(piperazin-1-yl)ethyl)phenyl)amino)pyrimidin-4-yl)amino)benzamide (90 mg, 150.88 μmol). The mixture was stirred at 25 °C for 10 min, and then AcOH (9.06 mg, 150.88 μmol, 8.63 μL) and 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (67.98 mg, 226.33 μmol) were added. After stirring at 25 °C for 0.5 h, NaBH(OAc)3 (47.97 mg, 226.33 μmol) was added. The resulting mixture was stirred at 25 °C for 2.5 h. LCMS showed a peak of 40% with the desired mass. The mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was subjected to rapid silica gel chromatography (Biotage, 4 g). The sample was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 40%-70%, 8 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (12.5 mg, 13.63 μmol, 9.04% yield, 92.1% purity) as a white powder. MS (M+H) + =844.3.

[0275] 1H NMR (400MHz, DMSO-d6) δ=10.77(s,1H),9.89(s,1H),9.66(s,1H),9.29(s,1H),8.19(d,J=3.7Hz,1H),8.07-8.01(m,2H),8.00-7.95 (m,2H),7.66(dd,J=1.3,8.1Hz,1H),7.61(d,J=8.6Hz,2H),7.57(dd,J=1.3,8.1Hz,1H),7.43-7.37(m,1H),7.32-7.27(m,1H),7.13( d,J=8.4Hz,2H),7.02(d,J=8.7Hz,2H),6.86(d,J=8.8Hz,2H),3.71(dd,J=5.1,10.6Hz,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).

[0276] Example 2. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 2)

[0277]

[0278] Step 1.4-((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-methyl Synthesis of tert-butyl ester (2)

[0279] At 20 °C, AcOH (37.64 mg, 626.85 μmol, 35.85 μL) was added to an 8 mL solution of 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxaldehyde (0.3 g, 626.85 μmol) and tert-butyl piperazine-1-carboxylate (116.75 mg, 626.85 μmol) in DCM. Then, NaBH(OAc)3 (398.57 mg, 1.88 mmol) was slowly added at 20 °C, and the resulting mixture was stirred at 20 °C for 12 h. LCMS showed that 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxaldehyde was completely consumed and showed a 20% peak with the desired mass. The reaction mixture was diluted with 15 mL of H2O and extracted with DCM (10 mL × 3). The organic layer was washed with saturated NaHCO3 (10 mL × 3), dried over Na2SO4, filtered, and concentrated. The solution was then analyzed by rapid silica gel chromatography (10 g). The residue was purified by a silica gel rapid column chromatography with an eluent of 0–33% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 4-((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (183 mg, 262.30 μmol, 41.84% yield, 93% purity). MS (M+H) + =649.3.

[0280] Step 2.4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert- Synthesis of Butyl Acetate (3)

[0281] Under a H2 atmosphere, Pd / C (0.1 g, 10% purity) and TFA (32.16 mg, 282.05 μmol, 20.88 μL) were added to a CF3CH2OH (5 mL) solution of tert-butyl piperazine-1-carboxylate (183 mg, 282.05 μmol). The suspension was degassed and purged three times with H2. The mixture was stirred for 12 hours at 20 °C with H2 (15 Psi). LCMS showed that the starting material was completely consumed and showed peaks with the desired mass. The reaction mixture was diluted with CF3CH2OH (15 mL) and filtered. The filtrate was concentrated under vacuum to obtain tert-butyl 4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (133 mg, crude product), which was a colorless oil. MS (M+H) + =471.3.

[0282] Step 3.3 Synthesis of (3-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (4)

[0283] TFA (161.12 mg, 1.41 mmol, 104.63 μL) was added to a 2 mL solution of 4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-carboxylic acid tert-butyl ester (133 mg, 282.62 μmol) in DCM at 20 °C, and the resulting mixture was stirred at 20 °C for 0.5 h. LC-MS showed that the starting material was completely consumed and showed peaks with the desired mass. The reaction mixture was concentrated under vacuum to give 3-(3-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (137 mg, crude, TFA) as a yellow oil. MS (M+H) + =371.3.

[0284] Step 4. N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl) Piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide Synthesis of (Compound 2)

[0285] HATU (85.03 mg, 223.62 μmol) and DIPEA (52.55 mg, 406.59 μmol, 70.82 μL) were added to a DMF (2 mL) solution of 2-(4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenyl)acetic acid (100 mg, 203.29 μmol). The mixture was stirred at 20 °C for 10 min, and a solution of 3-(3-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (137 mg, 282.76 μmol, TFA) in DMF (2 mL) was added along with DIPEA (105.10 mg, 813.17 μmol, 141.64 μL), and the resulting mixture was stirred at 20 °C for 1 h. LCMS showed that the starting material was completely consumed and showed a 25% peak with the desired mass. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL × 3). The organic layer was washed with brine (15 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1), followed by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 47%-77%, 8 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (23.5 mg, 26.44 μmol, 13.01% yield, 95% purity) as a white solid. MS (M+H) + =844.3.

[0286] 1H NMR(400MHz,DMSO-d6)δ=10.78(br s,1H),9.88(s,1H),9.65(s,1H),9.28(s,1H),8.18(d,J=3.7Hz,1H),8.07-7.94(m,4H),7.70-7.53(m,4H),7.39( dt,J=1.2,7.6Hz,1H),7.32-7.25(m,1H),7.17-7.09(m,3H),6.82-6.74(m,2H),6.57(d,J=7.6Hz,1H),3.74(dd,J= 5.0,11.1Hz,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).

[0287] Example 3. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 3)

[0288]

[0289] Step 1.4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-carboxylic acid tert- Synthesis of Butyl Acetate (3)

[0290] To a solution of 3-(4-(piperazin-1-yl)phenyl)piperidin-2,6-dione (0.2 g, 645.60 μmol, HCl) in DCM (5 mL), tert-butyl 4-formylpiperidin-1-carboxylate (275.38 mg, 1.29 mmol) and HOAc (1.94 mg, 32.28 μmol, 1.85 μL) were added. The mixture was stirred at 25 °C for 0.5 h. Then, NaBH(OAc)3 (273.66 mg, 1.29 mmol) was added, and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed a main peak with the desired quality. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 5). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The results were obtained by rapid silica gel chromatography (…). 20g The residue was purified by silica gel rapid column chromatography with an eluent of 0–40% petroleum ether:EtOAc / EtOH (V / V = 5:1) gradient at 80 mL / min to give tert-butyl 4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-carboxylate (220 mg, 455.33 μmol, 70.53% yield, 97.4% purity) as a white solid. MS (M+H) + =471.3.

[0291] Step 2.3 Synthesis of (4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (4)

[0292] HCl / dioxane (4M, 5 mL) was added to a solution of tert-butyl piperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (220 mg, 467.49 μmol) in dioxane (5 mL). The mixture was stirred at 25 °C for 1 hour. LC-MS showed that the starting material was completely consumed. The mixture was concentrated under reduced pressure to give 200 mg, crude 3-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (HCl) as a white solid. MS (M+H) + =371.2.

[0293] Step 3. N-(2-chlorophenyl)-4-((2-((4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin The synthesis of azinon-1-yl)methyl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 3) become

[0294] 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) were added to a DMF (5 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (150.00 mg, 313.89 μmol). The mixture was stirred at 25 °C for 0.5 h. Then, 3-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (127.74 mg, 313.89 μmol, HCl) was added, and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed a peak of 67% with the desired mass. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL × 5). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was passed through preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 13%–43%, 10 min) and then through preparative HPLC (column: Phenomenex Synergi Polar-RP). 100×25mm×4μm; mobile phase: [water (TFA)-ACN]; B%: 24%-54%, 9 min) purified and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a white solid (44.2 mg, 45.54 μmol, 63.02% yield, 97.3% purity, TFA). MS (M+H) + =830.2.

[0295] 1H NMR (400MHz, CD3OD) δ = 8.11 (d, J = 4.2Hz, 1H), 8.01-7.97 (m, 2H), 7.93-7.89 (m, 2H), 7.73 ( dd,J=1.6,7.9Hz,1H),7.66(d,J=8.6Hz,2H),7.54(dd,J=1.3,7.9Hz,1H),7.42-7.38(m,3H ),7.32-7.26(m,1H),7.21(d,J=8.7Hz,2H),6.99(d,J=8.8Hz,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).

[0296] Example 4. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(((1-(4-((2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 4)

[0297]

[0298] Step 1.3 Synthesis of (4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione (2) become

[0299] Under H2, TFA (153.50 mg, 1.35 mmol, 0.1 mL) and Pd / C (101.81 mg, 95.67 μmol, 10% purity) were added to a solution of 3-(4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)-2,6-bis(benzyloxy)pyridine (0.5 g, 956.69 μmol) in CF3CH2OH (10 mL). The resulting mixture was stirred at 25 °C and H2 (15 psi) for 24 hours. LCMS showed that the starting material was completely consumed and showed a peak with the desired mass. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-(4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione (770 mg, crude) as a black oil. MS (M+H) + =345.1.

[0300] Step 2.1 Synthesis of (4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (3)

[0301] To a mixture of 3-(4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione (770 mg, 2.24 mmol) in H₂O (7 mL), HCl / dioxane (4 M, 3.35 mL) was added. The resulting mixture was stirred at 50 °C for 16 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residual aqueous solution was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 1-(4-(2,6-dioxolane-3-yl)phenyl)piperidin-4-carboxaldehyde (0.4 g, 679.20 μmol, 30.38% yield, 51% purity) as a yellow solid. MS (M + H₂O + H) + =319.2.

[0302] Step 3. (4-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino)cyclohexane) Synthesis of tert-butyl carbamate (5)

[0303] A mixture of 1-(4-(2,6-dioxopiridin-3-yl)phenyl)piperidin-4-carboxaldehyde (320 mg, 543.36 μmol), tert-butyl (4-aminocyclohexyl)carbamate (116.44 mg, 543.36 μmol), 4AMS (170 mg), and TEA (54.98 mg, 543.36 μmol, 75.63 μL) in DCM (3 mL) was stirred at 25 °C for 0.5 h. Then, NaBH(OAc)3 (345.48 mg, 1.63 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed a main peak with the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain tert-butyl (4-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino)cyclohexyl)carbamate (390 mg, crude product), as a brown solid. MS (M+H) + =499.3.

[0304] Step 4. (4-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino) Synthesis of tert-butyl cyclohexyl carbamate (6)

[0305] A mixture of tert-butyl carbamate (350 mg, 682.68 μmol), HOAc (41.00 mg, 682.68 μmol), and HCHO (277.04 mg, 3.41 mmol, 37% purity) in MeOH (4 mL) was stirred at 20 °C for 0.5 h. Then, NaBH3CN (214.50 mg, 3.41 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. LCMS showed that the starting material was completely consumed and a main peak of the desired quality was observed. The reaction mixture was concentrated under reduced pressure. The final product was analyzed by rapid silica gel chromatography (…). 12g The residue was purified by silica gel rapid column chromatography, using a gradient of 0–100% EtOAc / petroleum ether to 0–50% MeOH / EtOAc at 100 mL / min, yielding a yellow solid (80 mg, 106.11 μmol, 15.54% yield, 68% purity). MS (M+H) + =513.4.

[0306] Step 5.3-(4-(4-(((4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2, Synthesis of 6-dione (7)

[0307] To a solution of tert-butyl carbamate (80 mg, 156.04 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 20 °C for 1 hour. LC-MS showed that the starting material was completely consumed and a main peak of the desired quality was observed. The reaction mixture was concentrated under reduced pressure to give a yellow solid of 3-(4-(4-(((4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (70 mg, crude, HCl). MS (M+H) + =413.3.

[0308] Step 6. N-(2-chlorophenyl)-4-((2-((4-((4-(((1-(4-((2,6-dioxopiperidin-3-yl)phenyl)piperidin) (Pyridine-4-yl)methyl)(methyl)amino)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzyl) Synthesis of amide (compound 4)

[0309] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (1 mL) was stirred at 25 °C for 0.5 h. Then, 3-(4-(4-(((4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-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 h. LCMS showed a main peak of the desired quality. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 31%-61% B, for 10 min) to give N-(2-chlorophenyl)-4-((2-((4-((4-(((1-(4-((4-(4-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (20.2 mg, 13.02 μmol, 13.92% yield, 93% purity, 5TFA). MS (M+H) + =872.4.

[0310] 1H NMR (400MHz, 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=3.3Hz,1H),8.09-7.97(m,4H),7.86(br d,J=6.5Hz,1H),7.85-7.76(m,3H),7.65(br d,J=7.8Hz,1H),7.57(d,J=7.6Hz,1H),7.45-7.38(m,1H),7.33-7.27(m,1H),7.09(br d,J=8.2Hz,2H),6.98(br d,J=8.1Hz,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).

[0311] Example 5. 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)

[0312]

[0313] Step 1. Synthesis of tert-butyl (1-(2-chloroacetyl)piperidin-4-yl)carbamate (2)

[0314] TEA (606.29 mg, 5.99 mmol) was added to a DCM (10 mL) solution of piperin-4-ylcarbamate (1 g, 4.99 mmol) and 2-chloroacetyl chloride (451.15 mg, 3.99 mmol). The mixture was stirred at 25 °C for 2 hours. LC-MS showed that the starting material was completely consumed and showed a peak of 73.5% with the desired mass. The reaction mixture was concentrated under reduced pressure to give 1.38 g (crude) of (1-(2-chloroacetyl)piperidin-4-yl)carbamate as a yellow solid. MS (M+H) + =277.7.

[0315] Step 2. (1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetyl)piperidin-4- Synthesis of tert-butyl carbamate (4)

[0316] DIPEA (813.53 mg, 6.29 mmol, 1.10 mL) was added to a DMF (5 mL) solution of (1-(2-chloroacetyl)piperidin-4-yl)carbamate (1.16 g, 4.20 mmol) and 3-(4-(piperazin-1-yl)phenyl)piperidin-2,6-dione (0.65 g, 2.10 mmol, HCl). The mixture was stirred at 100 °C for 24 h. LCMS showed a peak of 66.8% with the desired mass. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a high-speed silica gel column (eluting with 0–90% EtOAc / MeOH at 100 mL / min) to yield a yellow solid, tert-butyl (1-(2-(4-(4-(2,6-dioxopiridin-3-yl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (0.971 g, 1.49 mmol, 71.09% yield, 78.9% purity). MS (M+H) + =514.3.

[0317] Step 3.3-(4-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)piperidin-2, Synthesis of 6-dione (5)

[0318] HCl / dioxane (4M, 10 mL) was added to a solution of tert-butyl carbamate (0.971 g, 1.89 mmol) in dioxane (10 mL). The mixture was stirred at 25 °C for 16.5 h. LC-MS showed a main peak with the desired mass. The reaction mixture was concentrated under reduced pressure to give 1.1 g, crude, HCl, as a yellow solid of 3-(4-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione. MS (M+H) + =414.3.

[0319] Step 4. N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperazine-1-yl)acetyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide Synthesis of (Compound 5)

[0320] HATU (190.96 mg, 502.22 μmol) and DIPEA (162.27 mg, 1.26 mmol, 218.70 μL) were added to a DMF (2 mL) solution of 3-(4-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)piperidin-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) (162.27 mg, 1.26 mmol, 218.70 μL). The mixture was stirred at 25 °C for 12 h. LCMS showed that the starting material was completely consumed. The mixture was poured into H2O (10 mL) and filtered. The filter cake was collected and purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B, for 10 min) and lyophilized to give 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 as a white solid (24.8 mg, 26.04 μmol, 6.22% yield, 91.7% purity). MS (M+H) + =873.3.

[0321] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.93 (s, 1H), 9.76 (s, 1H), 9.63 (s, 1H), 8.25 (d, J = 3.5Hz, 1H), 8.13 (br d,J=7.5Hz,1H),8.06-7.99(m,4H),7.80-7.76(m,4H),7.66-7.62(m,1H),7.57(dd,J=1.3,7.9Hz,1H),7 .43-7.37(m,1H),7.32-7.27(m,1H),7.12(d,J=8.6Hz,2H),6.96(d,J=8.8Hz,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).

[0322] Example 6. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(1-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl-2-yl)piperidin-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 6)

[0323]

[0324] Step 1. Synthesis of tert-butyl 4-(1-hydroxypropyl-2-yl)piperidine-1-carboxylate (2)

[0325] LiAlH4 (2.5 M, 3 mL) was added dropwise to a THF (20 mL) solution of 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (1 g, 3.50 mmol) at 0 °C under N2 over 15 minutes. The mixture was then stirred at 0 °C for 45 minutes. TLC (petroleum ether:EtOAc = 2:1) showed complete consumption of the starting material and the formation of new, highly polar spots. The reaction mixture was quenched by careful addition of H2O (0.29 mL), 15% NaOH aqueous solution (0.29 mL), and H2O (0.86 mL). The resulting mixture was filtered and washed with EtOAc. The filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-(1-hydroxypropyl-2-yl)piperidine-1-carboxylate (0.9 g, crude) as a colorless oil. MS (M+H) +=244.3.

[0326] Step 2.4 Synthesis of tert-butyl 1-(1-(toluenesulfonyloxy)propyl-2-yl)piperidine-1-carboxylate (3)

[0327] TosCl (658.11 mg, 3.45 mmol) was added to a solution of tert-butyl 4-(1-hydroxypropyl-2-yl)piperidin-1-carboxylate (0.7 g, 2.88 mmol) and TEA (582.17 mg, 5.75 mmol, 800.78 μL) in 10 mL of DCM at 20 °C. The resulting mixture was stirred at 20 °C for 16 hours. LCMS showed that the starting material was completely consumed and a main peak with the desired mass was observed. The reaction mixture was concentrated under reduced pressure to give a residue, which was then analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–18% EtOAc / petroleum ether gradient at 100 mL / min to yield tert-butyl 4-(1-(toluenesulfonyloxy)propyl-2-yl)piperidin-1-carboxylate (660 mg, 1.64 mmol, 57.14% yield, 99% purity), as a colorless oil. MS (M-100+H) + =298.1.

[0328] Step 3.4-(1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl-2-yl)piperidin-1- Synthesis of tert-butyl formate (5)

[0329] A mixture of tert-butyl 4-(1-(toluenesulfonyloxy)propyl-2-yl)piperidin-1-carboxylate (0.54 g, 1.36 mmol), 3-(4-(piperazin-1-yl)phenyl)piperidin-2,6-dione (420.82 mg, 1.36 mmol, HCl), DIPEA (526.68 mg, 4.08 mmol, 709.81 μL), and NaI (20.36 mg, 135.84 μmol) in DMF (5 mL) was stirred at 60 °C for 16 hours. LC-MS showed a main peak of the desired quality. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue, which was then subjected to rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min to yield tert-butyl 4-(1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl-2-yl)piperidin-1-carboxylate (180 mg, 324.87 μmol, 23.92% yield, 90% purity), as a pale yellow solid. MS (M+H) + =499.4.

[0330] Step 4.3 Synthesis of (4-(4-(2-(piperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (6) become

[0331] To a solution of tert-butyl piperidin-3-yl)phenyl)piperazin-1-yl)propyl-2-yl)piperidin-1-carboxylate (180 mg, 360.97 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 20 °C for 1 hour. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give 160 mg, crude 3-(4-(4-(2-(piperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (HCl) as a yellow solid. MS (M+H) + =399.3.

[0332] Step 5.3-(4-(4-(2-(1-nitrosopiperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (7) Synthesis

[0333] At 0 °C, TEA (89.33 mg, 882.76 μmol, 122.87 μL) was added to a THF (2 mL) solution of 3-(4-(4-(2-(piperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (128 mg, 294.25 μmol, HCl) (2 mL). Then, a THF (1 mL) solution of t-BuONO (91.03 mg, 882.76 μmol, 104.99 μL) (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 60 °C for 12 hours. LCMS showed that the starting material was completely consumed and showed a main peak with the desired mass. The reaction mixture was concentrated under reduced pressure to give a residue, which was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min, yielding a yellow solid 3-(4-(4-(2-(1-nitrosopiperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (100 mg, 215.19 μmol, 73.13% yield, 92% purity). MS (M+H) + =428.3.

[0334] Step 6.3-(4-(4-(2-(1-aminopiperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (8) Synthesis

[0335] Zn (30.59 mg, 467.79 μmol) was added to a solution of 3-(4-(4-(2-(1-nitrosopiperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (50 mg, 116.95 μmol) and NH4Cl (25.02 mg, 467.79 μmol) in THF (2 mL) and H2O (0.5 mL) at 0 °C, and the mixture was stirred at 20 °C for 16 hours. LCMS showed a main peak with the desired mass. The reaction mixture was filtered and washed with THF (10 mL). The filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-(4-(4-(2-(1-aminopiperazin-4-yl)propyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (75 mg, crude) as a yellow solid. MS (M+H) + =414.3.

[0336] Step 7. N-(2-chlorophenyl)-4-((2-((4-((4-(1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperazin-1-yl)propyl-2-yl)piperidin-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide Synthesis of (Compound 6)

[0337] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (0.5 mL) was stirred at 25 °C for 0.5 h. Then, 3-(4-(4-(2-(1-aminopiperidin-4-yl)propyl)piperazin-1-yl)phenyl)piperidin-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 h. LCMS showed that the starting material was completely consumed and a main peak with the desired quality was observed. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, 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 (TFA)-ACN]; gradient: 20%-50% B, for 10 minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((4-(1-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl-2-yl)piperidin-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (13.3 mg, 11.71 μmol, 6.46% yield, 97% purity, 2TFA). MS (M+H) + =873.4.

[0338] 1H NMR (400MHz, 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=3.1Hz,1H),8.07-7.98(m,4H),7.78(br d,J=8.9Hz,2H),7.73-7.67(m,2H),7.65(br d,J=7.5Hz,1H),7.57(br d,J=8.1Hz,1H),7.40(br t,J=7.6Hz,1H),7.35-7.26(m,1H),7.12(br d,J=7.7Hz,2H),6.98(br d,J=7.7Hz,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).

[0339] Example 7. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 7)

[0340]

[0341] Step 1. (4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl) Synthesis of tert-butyl carbamate (3)

[0342] At 20 °C, DIPEA (425.55 mg, 3.29 mmol, 573.52 μL) and NaI (32.90 mg, 219.52 μmol) were added to a DMF (8 mL) 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 ester of 4-methylbenzenesulfonic acid (437.40 mg, 1.10 mmol). The mixture was stirred at 60 °C for 16 h. LCMS showed a peak of 19% residual 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione and a peak of 22% with the desired mass. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over NaSO4, filtered, and concentrated under vacuum. 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) and lyophilized to give a yellow oily substance, tert-butyl (4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (85 mg, 170.12 μmol, 15.50% yield, 80% purity). MS (M+H) + =500.4.

[0343] Step 2.3-(4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (4) Synthesis

[0344] TFA (300 mg, 2.7 mmol, 0.2 mL) was added to a solution of tert-butyl carbamate (85 mg, 170.12 μmol) in DCM (1 mL) at 20 °C, and the mixture was stirred at 20 °C for 2 hours. LC-MS showed that the starting material was completely consumed and showed a peak of 93% with the desired mass. The reaction mixture was concentrated under vacuum to give 125 mg, crude TFA, as a yellow oily solid. MS (M+H) + =400.3.

[0345] Step 3. N-(2-chlorophenyl)-4-((2-((4-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperazine-1-yl)ethyl)piperidin-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (chemical) Synthesis of compound 7)

[0346] At 20 °C, HATU (101.80 mg, 267.74 μmol) and DIPEA (157.29 mg, 1.22 mmol, 211.98 μL) were added to a DMF (2 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (116.32 mg, 243.40 μmol). The mixture was stirred at 20 °C for 30 min, and then a DMF (2 mL) solution of 3-(4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (125 mg, 243.40 μmol, TFA) was added, and the reaction mixture was stirred at 20 °C for 12 h. LCMS showed that the starting material was completely consumed and showed a peak of 18% with the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over NaSO4, filtered, and concentrated under vacuum. The crude product was subjected to preparative TLC (SiO2, DCM:MeOH = 10:1), followed by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 10 min) purification and lyophilization to obtain N-(2-chlorophenyl)-4-((2-((4-((4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (7.1 mg, 5.04 μmol, 2.07% yield, 93.4% purity, 4TFA) as a white solid. MS (M+H) + =859.4.

[0347] 1H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.94 (s, 1H), 9.81-9.73 (m, 1H), 9.6 6(s,1H),9.57-9.40(m,2H),8.25(d,J=3.5Hz,1H),8.06-7.97(m,4H),7.81- 7.76(m,2H),7.71(d,J=8.9Hz,2H),7.67-7.62(m,1H),7.57(dd,J=1.4,8.0H z,1H),7.43-7.37(m,1H),7.33-7.28(m,1H),7.12(d,J=8.5Hz,2H),6.98(br d,J=8.6Hz,2H),3.84(br d,J=12.4Hz,2H),3.76(br dd,J=4.8,11.4Hz,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).

[0348] Example 8. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 8)

[0349]

[0350] Step 1.3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl Synthesis of ester (3)

[0351] A mixture of piperidine-4-ylcarbamate benzyl ester (3.5 g, 14.94 mmol), 3-formylazetane-1-tert-butyl carbamate (3.04 g, 16.43 mmol), and HOAc (897.09 mg, 14.94 mmol) in MeOH (35 mL) was stirred at 25 °C for 0.5 h. Then, NaBH3CN (2.82 g, 44.82 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed a main peak with the desired quality. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO3 solution (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The final concentration was determined by rapid silica gel chromatography (80 g). The residue was purified by silica gel rapid column chromatography (elution buffer: 30–100% EtOAc / petroleum ether gradient @ 200 mL / min) to give tert-butyl 3-((4-((((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azacyclobutane-1-carboxylate (9 g) as a colorless oil. MS (M+H) + =404.2.

[0352] Step 2. Synthesis of (1-(azacyclobutane-3-ylmethyl)piperidin-4-yl)carbamate (4)

[0353] TFA (3.07 g, 26.92 mmol, 2.00 mL) was added to a solution of tert-butyl 3-((4-((((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azacyclobutane-1-carboxylate (1 g, 2.48 mmol) in DCM (10 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed that the starting material was completely consumed and a main peak with the desired quality was observed. The reaction mixture was concentrated under vacuum to give benzyl (1 g, TFA salt) as a colorless oil, which was used directly. MS (M+H) + =304.2.

[0354] Step 3. (1-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperyl Synthesis of pyridin-4-yl)carbamate (6)

[0355] Under nitrogen atmosphere, Cs₂CO₃ (1.17 g, 3.59 mmol), RuPhos (33.54 mg, 71.87 μmol), and Pd₂(dba)₃ (54.84 mg, 59.89 μmol) were added to a solution of (1-(azacyclobutane-3-ylmethyl)piperidin-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) in dioxane (20 mL). The mixture was stirred at 100 °C for 16 h. LCMS showed that (1-(azacyclobutane-3-ylmethyl)piperidin-4-yl)carbamate was completely consumed and showed a main peak with the desired mass. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated under vacuum. Rapid silica gel chromatography (20g) The residue was purified by silica gel rapid column chromatography, using a gradient of 50–100% EtOAc / petroleum ether to 0–20% MeOH / EtOAc at 100 mL / min, yielding a yellow solid (680 mg, 904.88 μmol, 75.54% yield, 89% purity). MS (M+H) + =669.4.

[0356] Step 4. (1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperidin- Synthesis of tert-butyl 4-yl)carbamate (7)

[0357] Under a nitrogen atmosphere, Boc₂O (332.84 mg, 1.53 mmol, 350.36 μL) and Pd / C (200 mg, 10% purity) were added to a THF (10 mL) solution of (1-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperidin-4-yl)carbamate (340 mg, 508.36 μmol). The mixture was degassed under vacuum and purged several times with H₂. The resulting mixture was stirred at 30 °C for 40 h under a H₂ (50 psi) atmosphere. LCMS showed 25% residue of the intermediate and 30% of the expected mass was detected. The reaction mixture was filtered and washed with THF (200 mL). The filtrate was concentrated under reduced pressure to give the residue. Under a nitrogen atmosphere, Pd / C (0.4 g, 10% purity) was added to a 20 mL THF solution of the residue, and the suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 30 °C for 16 hours under a 50 psi H2 atmosphere. LC-MS showed that the intermediate was completely consumed and 35% of the desired mass was detected. The reaction mixture was filtered and washed with 200 mL THF. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to give tert-butyl (1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperidin-4-yl)carbamate (120 mg, 262.83 μmol, 20.00% yield) as a white solid. MS (M+H) + =457.2.

[0358] Step 5.3-(4-(3-((4-aminopiperidin-1-yl)methyl)azacyclobutane-1-yl)phenyl)piperidin-2,6-di Synthesis of ketone (8)

[0359] A mixture of (1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperidin-4-yl)tert-butyl carbamate (120 mg, 262.83 μmol) and TFA (1.54 g, 13.46 mmol, 1 mL) in DCM (4 mL) was stirred at 15 °C for 1 hour. LCMS showed that the starting material was completely consumed. The mixture was concentrated under vacuum to give 3-(4-(3-((4-aminopiperidin-1-yl)methyl)azacyclobutane-1-yl)phenyl)piperidin-2,6-dione (160 mg, 2 TFA salt) as a colorless gel, which was used directly. MS (M+H) + =357.2.

[0360] Step 6. N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)nitrogen Heterocyclic butane-3-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzoyl Synthesis of amine (compound 8)

[0361] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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 25 °C for 15 min. Then, 3-(4-(3-(((4-aminopiperidin-1-yl)methyl)azacyclobutane-1-yl)phenyl)piperidin-2,6-dione (160 mg, 273.73 μmol, 2 TFA salt) was added. The resulting mixture was stirred at 15 °C for 1 h. LCMS showed complete consumption of 3-(4-(3-((4-aminopiperidin-1-yl)methyl)azacyclobutan-1-yl)phenyl)piperidin-2,6-dione, exhibiting a peak of 56% with the desired mass. The mixture was treated with TFA to adjust the pH to <7, and the resulting mixture was purified by preparative HPLC (column: Phenomenex luna C18150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B, 10 min) and lyophilized to give the crude product. F NMR and H NMR indicated that the product was impure. The residue was ground with a mixture (H2O:ACN:DCM:MeOH = 4:1:1:1, 21 mL) for 10 min and filtered. The filter cake was collected and dried. The crude product was ground with a mixture (H₂O:THF:ACN:DCM:MeOH = 1:1:2:3:1, 16 mL) for 10 minutes and then lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a gray solid (77.3 mg, 85.51 μmol, 31.43% yield, 90.3% purity). MS (M+H) + =816.3.

[0362] 1H NMR(400MHz, 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).

[0363] Example 9. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 9)

[0364]

[0365] Step 1.3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3) Synthesis

[0366] AcOH (256.31 mg, 4.27 mmol) and NaBH(OAc)3 (1.81 g, 8.54 mmol) were added to a MeOH (30 mL) solution of N-(4-piperidinyl)carbamate (1 g, 4.27 mmol) and 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (1.02 g, 5.12 mmol) (30 mL). The mixture was stirred at 25 °C for 14 h. LCMS showed a peak of 71% with 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 EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel rapid column (eluting with 0–10% MeOH / DCM @ 85 mL / min) to give tert-butyl 3-((4-((((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate (1.7 g, 3.79 mmol, 88.71% yield, 93% purity) as a white solid. MS (M+H) + =418.3.

[0367] Step 2. Synthesis of (1-(pyrrolidone-3-ylmethyl)piperidin-4-yl)carbamate (4)

[0368] HCl / dioxane (4M, 10 mL) was added to a solution of tert-butyl tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl tert-butyl ester (1.7 g, 4.07 mmol) in dioxane (10 mL). The mixture was stirred at 25 °C for 6 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give N-[1-(pyrrolidine-3-ylmethyl)-4-piperidinyl]carbamate (1.45 g, crude, HCl) as a yellow solid. MS (M+H) + =318.2.

[0369] Step 3. (1-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidine- Synthesis of 4-yl)benzyl carbamate (6)

[0370] Pd2(dba)3 (129.82 mg, 141.77 μmol), Cs2CO3 (923.80 mg, 2.84 mmol), and DavePhos (55.79 mg, 141.77 μmol) were added to a solution of (1-(pyrrolidone-3-ylmethyl)piperidin-4-yl)carbamate (675 mg, 2.13 mmol) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (632.75 mg, 1.42 mmol) in THF (30 mL) and H2O (3 mL). The mixture was stirred at 100 °C for 14 h under N2. LCMS showed a peak of 27% with the desired mass. The residue was diluted with H2O (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel rapid column with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min, yielding a yellow solid (583 mg, 665.95 μmol, 23.49% yield, 78% purity). MS (M+H) + =683.4.

[0371] Step 4. (1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidin-4-yl) Synthesis of tert-butyl carbamate (7)

[0372] Boc₂O (340.71 mg, 1.56 mmol, 358.64 μL), Pd / C (83.07 mg, 78.06 μmol, 10% purity), and AcOH (46.87 mg, 780.55 μmol, 44.68 μL) were added to a solution of (1-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidin-4-yl)carbamate (533 mg, 780.55 μmol, 3 mL) in THF (3 mL) and CF₃CH₂OH (5 mL). The resulting mixture was stirred at 25 °C and H₂ (15 psi) for 72 hours. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column with an eluent of 0–100% EtOAc / petroleum ether gradient at 45 mL / min to give tert-butyl (1-((1-(4-(2,6-dioxopiridin-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidin-4-yl)carbamate (56 mg, 97.58 μmol, 12.50% yield, 82% purity) as a white solid. MS (M+H) + =471.2.

[0373] Step 5.3-(4-(3-((4-aminopiperidin-1-yl)methyl)pyrrolidine-1-yl)phenyl)piperidin-2,6-dione (8) Synthesis

[0374] To a solution of N-[1-[[1-[4-(2,6-dioxo-3-piperidinyl)phenyl]pyrrolidine-3-yl]methyl]-4-piperidinyl]tert-butyl carbamate (56 mg, 119.00 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 25 °C for 12 hours. LC-MS showed a peak of 36% with the desired mass. The reaction mixture was concentrated under reduced pressure to give 103 mg, crude 3-(4-(3-((4-aminopiperidin-1-yl)methyl)pyrrolidine-1-yl)phenyl)piperidin-2,6-dione (HCl) as a yellow solid. MS (M+H) + =371.2.

[0375] Step 6. N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyridine (P-3-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide) Synthesis of compound 9)

[0376] HATU (44.85 mg, 117.95 μmol) and DIPEA (38.11 mg, 294.88 μmol) were added to a DMF (0.5 mL) solution of 3-(4-(3-(((4-aminopiperidin-1-yl)methyl)pyrrolidin-1-yl)phenyl)piperidin-2,6-dione (40 mg, 98.29 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (40.00 mg, 83.70 μmol)). The resulting mixture was stirred at 20 °C for 1 hour. LCMS showed a peak with the desired mass (44%). The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 22%-52% B, for 10 minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((1-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (10 mg, 12.04 μmol, 12.25% yield, 90% purity) as a white solid. MS (M+H) + =830.2.

[0377] 1H NMR (400MHz, 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 = 3.4Hz, 1H), 8.0 5-7.98(m,5H),7.79-7.76(m,3H),7.68-7.63(m,1H),7.56(dd,J=1.3,8.0Hz,1H),7.43-7.36(m,1H),7.32-7.25(m,1H) ,6.99(d,J=8.6Hz,2H),6.47(d,J=8.7Hz,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).

[0378] Example 10. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1S,2R)-2-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclopentyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 10)

[0379]

[0380] Step 1.1 Synthesis of 4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (2)

[0381] HCl / dioxane (4M, 1.70 mL) was added to a solution of 3-(4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione (390 mg, 1.13 mmol) in H₂O (5 mL). The mixture was stirred at 50 °C for 16 h. LC-MS showed that the starting material was completely consumed and showed a peak of 76% with the desired mass. The mixture was diluted with NaHCO₃ (20 mL) and extracted with EtOAc solvent (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 1-(4-(2,6-dioxolane-3-yl)phenyl)piperidin-4-carboxaldehyde (242 mg, 729.98 μmol, 64.46% yield, 90.6% purity) as a brown solid. MS (M+H) + =301.4.

[0382] Step 2. ((1S,2R)-2-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino Synthesis of tert-butyl cyclopentyl carbamate (4)

[0383] To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (220 mg, 732.48 μmol) and ((1S,2R)-2-aminocyclopentyl)carbamate tert-butyl ester (146.70 mg, 732.48 μmol) in MeOH (5 mL), NaBH(OAc)3 (155.24 mg, 732.48 μmol) and AcOH (87.97 mg, 1.46 mmol, 83.86 μL) were added. The mixture was stirred at 25 °C for 38 h. LCMS showed that the starting material was completely consumed and showed a peak of 39.6% with the desired mass. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then subjected to rapid silica gel chromatography. 40g Purification was performed using a silica gel rapid column with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min, yielding a white solid ((1S,2R)-2-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino)cyclopentyl)carbamate tert-butyl ester (170 mg, 308.34 μmol, 42.10% yield, 87.9% purity). MS (M+H) + =485.3.

[0384] Step 3. ((1S,2R)-2-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl) Synthesis of tert-butyl carbamate (5)

[0385] To a solution of tert-butyl carbamate (150 mg, 309.51 μmol) in MeOH (3 mL), HCHO (37.68 mg, 464.27 μmol, 37% purity) and NaBH(OAc)3 (131.20 mg, 619.03 μmol) were added. The mixture was stirred at 20 °C for 18 hours. LC-MS showed a peak of 40% with the desired mass. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue, which was subjected to rapid silica gel chromatography (…). 4g Purification was performed using a silica gel rapid column with an eluent of 0–100% EtOAc / petroleum ether gradient at 45 mL / min, yielding tert-butyl ((1S,2R)-2-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclopentyl)carbamate as a white solid (100 mg, 200.54 μmol, 64.79% yield). MS (M+H) + =499.3.

[0386] Step 4.3-(4-(4-((((1R,2S)-2-aminocyclopentyl)(methyl)amino)methyl)piperidin-1-yl)phenyl) Synthesis of piperidine-2,6-dione (6)

[0387] HCl (4M, 150.40 μL) was added to a solution of tert-butyl carbamate (100 mg, 200.54 μmol) in dioxane (5 mL). The mixture was stirred at 20 °C for 14 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give 160 mg, crude 3-(4-((((1R,2S)-2-aminocyclopentyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (160 mg, crude, HCl) as a white solid. MS (M+H) + =399.2.

[0388] Step 5. N-(2-chlorophenyl)-4-((2-((4-(((1S,2R)-2-(((1-(4-(2,6-dioxopiperidine-3- (yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclopentyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl) Synthesis of (amino)benzamide (compound 10)

[0389] HATU (146.85 mg, 386.21 μmol) and DIPEA (124.79 mg, 965.51 μmol, 168.18 μL) were added to a DMF (3 mL) solution of 3-(4-(4-((((1R,2S)-2-aminocyclopentyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (140 mg, 321.84 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (153.80 mg, 321.84 μmol) (153.80 mg, 321.84 μmol). The mixture was stirred at 25 °C for 6 hours. LCMS showed that the starting material was completely consumed and showed a peak of 29% with the desired mass. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1), followed by preparative HPLC (Phenomenex luna C18 column 150×25mm×10um; mobile phase: [water(FA)-ACN]; gradient: 17%-47% B, for 10 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(((1S,2R)-2-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclopentyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (10.2 mg, 11.53 μmol, 3.58% yield, 97% purity) as a white solid. MS (M+H) + =858.4.

[0390] 1H NMR (400MHz, DMSO-d6) δ = 10.73 (s, 1H), 9.90 (s, 1H), 9.74 (s, 1H), 9.64 (s, 1H), 8.24 (d, J = 3.5Hz, 1H), 8.10-8.00 (m, 4H), 7.82 (d, J = 8.8Hz, 2H), 7. 70(d,J=8.8Hz,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=8.3Hz,2H),6.68(br d,J=8.8Hz,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).

[0391] Example 11. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((3-(((1-(4-((2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclobutyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 11)

[0392]

[0393] Step 1. Synthesis of tert-butyl (3-((4-methoxybenzyl)(methyl)amino)cyclobutyl)carbamate (2)

[0394] At 20 °C, AcOH (648.44 mg, 10.80 mmol, 618.15 μL) was added to a DCM (40 mL) solution of (3-oxocyclobutyl)carbamate (2 g, 10.80 mmol) and 1-(4-methoxyphenyl)-N-methylmethylamine (1.63 g, 10.80 mmol). The mixture was stirred at 20 °C for 30 min, then NaBH(OAc)3 (2.29 g, 10.80 mmol) was slowly added, and the resulting mixture was stirred at 20 °C for 12 h. LCMS showed that the starting material was completely consumed and showed a peak of 87% with the desired mass. The reaction mixture was filtered. The filtrate was diluted with H2O (80 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with NaHCO3 (30 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The results were obtained by rapid silica gel chromatography (20 g). The residue was purified by silica gel rapid column chromatography with 0–50% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl (3 g, 9.39 mmol, 86% yield) as a yellow oil. MS (M+H) + =321.4.

[0395] Step 2. Synthesis of tert-butyl (3-(methylamino)cyclobutyl)carbamate (3)

[0396] Under a H2 atmosphere, Pd / C (1 g, 10% purity) was added to a solution of (3-((4-methoxybenzyl)(methyl)amino)cyclobutyl)carbamate (3 g, 9.36 mmol) in EtOH (40 mL). The suspension was degassed and purged three times with H2, and stirred at 25 °C for 16 h under H2 (50 Psi). LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered and washed with EtOH (50 mL). The filtrate was concentrated under vacuum to give a crude product. The crude product was diluted with H2O (50 mL), adjusted to pH 3 with HCl (1 M), extracted with EtOAc (30 mL × 3), and the aqueous phase was lyophilized to give tert-butyl (3-(methylamino)cyclobutyl)carbamate (1.58 g, 7.89 mmol, 98.75% yield) as a pale yellow solid. MS (M+H) + =201.1.

[0397] Step 3. (3-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino) Synthesis of tert-butyl cyclobutylcarbamate (5)

[0398] At 20 °C, AcOH (47.48 mg, 790.57 μmol, 45.26 μL) was added to a DCM (4 mL) solution of (3-(methylamino)cyclobutyl)carbamate (190 mg, 948.69 μmol) and 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxaldehyde (237.45 mg, 790.57 μmol). The mixture was stirred at 20 °C for 30 min, and then NaBH(OAc)3 (502.66 mg, 2.37 mmol) was slowly added at 20 °C, and the resulting mixture was stirred at 20 °C for 16 h. LCMS showed that the starting material was completely consumed and showed a peak of 42% with the desired mass. The reaction mixture was diluted with H2O (40 mL) and adjusted to pH = 10 with Na2CO3, and then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (SiO₂, DCM:MeOH = 10:1) to obtain a grayish-white solid, tert-butyl (3-(((1-(4-(2,6-dioxoperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclobutyl)carbamate (40 mg, 74.28 μmol, 9.40% yield, 90% purity). MS (M+H) + =485.4.

[0399] Step 4.3-(4-(4-(((3-aminocyclobutyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2, Synthesis of 6-dione (6)

[0400] At 20°C, HCl / dioxane (4M, 20.63 μL) was added to a solution of tert-butyl carbamate (40 mg, 82.54 μmol) in dioxane (1 mL). The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired mass was observed. The reaction mixture was concentrated under vacuum to give 3-(4-(4-(((3-aminocyclobutyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (40 mg, crude, HCl) as a white solid. MS (M+H) + =385.3.

[0401] Step 5. N-(2-chlorophenyl)-4-((2-((4-((3-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin) (Pyridine-4-yl)methyl)(methyl)amino)cyclobutyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzyl) Synthesis of amide (compound 11)

[0402] At 20°C, HATU (18.06 mg, 47.51 μmol) and DIPEA (18.42 mg, 142.53 μmol, 24.83 μL) were added to a DMF (0.2 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (15.89 mg, 33.26 μmol) (1.2 mL). The mixture was stirred at 20°C for 1 hour, and then a DMF (0.1 mL) solution of 3-(4-(4-(((3-aminocyclobutyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (20 mg, 47.51 μmol, HCl) was added at 20°C, and the resulting mixture was stirred at 20°C for 1 hour. LCMS showed that the starting material was completely consumed and the desired mass was achieved. The reaction mixture was diluted with H₂O (4 mL) and extracted with EtOAc (2 mL × 3). The organic layer was washed with brine (2 mL × 3), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, DCM:MeOH = 10:1), then ground with a mixture solution (10 mL, ACN:H₂O = 1:4) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((3-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclobutyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a white solid (5.1 mg, 5.74 μmol, 10.77% yield, 95% purity). MS (MH) + =843.8.

[0403] 1H NMR (400MHz, 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=7.5Hz,1H),8.25(d,J=3.5Hz,1H),8.07-7.97(m,4H),7.82-7.74(m,4H),7.68-7.62(m,1H),7.55(dd,J=1.2,8.0Hz,1H),7.38(t,J =7.2Hz,1H),7.31-7.24(m,1H),7.02(d,J=8.7Hz,2H),6.87(d,J=8.6Hz,2H),4.14-4.04(m,1H),3.71(dd,J=5.2,10.9Hz,1H),3.64(br d,J=11.1Hz,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).

[0404] Example 12. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(3-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)propionyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 12)

[0405]

[0406] Step 1. (1-(3-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)propionyl)piperidin Synthesis of pyridin-4-yl)carbamate (3)

[0407] Ruphos-Pd-G (190.53 mg, 224.05 μmol) and Cs₂CO₃ (2.19 g, 6.72 mmol) were added to a solution of (1-(3-(piperidin-4-yl)propionyl)piperidin-4-yl)carbamate (1.50 g, 3.66 mmol, HCl) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1 g, 2.24 mmol) in dioxane (80 mL). The resulting mixture was stirred at 100 °C for 32 h under N₂. LCMS showed a peak (17%) with the desired mass. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The results were obtained by rapid silica gel chromatography (…). 40g The residue was purified by silica gel rapid column chromatography with 0–100% EtOAc / petroleum ether gradient @ 80 mL / min to give a yellow solid (0.5 g, 534.57 μmol, 23.86% yield, 79% purity). MS (M+H) + =739.4.

[0408] Step 2.3-(4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperidin-1-yl)phenyl)piperidin-2, Synthesis of 6-dione (4)

[0409] Under a nitrogen atmosphere, TFA (154.31 mg, 1.35 mmol) and Pd / C (100 mg, 93.97 μmol, 10% purity) were added to a solution of (1-(3-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)propionyl)piperidin-4-yl)carbamate (0.5 g, 676.67 μmol) in CF3CH2OH (20 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 16 h under H2 (15 Psi). LCMS showed a main peak with the desired quality. The mixture was filtered and the filtrate was concentrated to give a yellow oily substance, 3-(4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (0.4 g, crude product, TFA). MS (M+H) + =427.4.

[0410] Step 3. N-(2-chlorophenyl)-4-((2-((4-((1-(3-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperidin-4-yl)propionyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide Synthesis of (Compound 12)

[0411] DIPEA (239.08 mg, 1.85 mmol) was added to a DMF (5 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (176.80 mg, 369.98 μmol) and HATU (168.81 mg, 443.97 μmol), and the mixture was stirred at 20 °C for 1 h. Then, 3-(4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (200 mg, 369.98 μmol, TFA) was added, and the resulting mixture was stirred at 20 °C for 12 h. LCMS showed a peak (50%) of the desired mass. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 80 mg of crude product. This crude product was further purified by preparative HPLC (column: Waters Xbridge 150*25mm 10µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B, for 10 minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((1-(3-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)propionyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (21.5 mg, 23.50 μmol, 6.35% yield, 96.9% purity). MS (M+H) + =886.6.

[0412] 1H NMR (400MHz, DMSO-d6) δ=10.77(s,1H),9.93(s,1H),9.74(s,1H),9.62(s,1H),8.26(d,J=3.5Hz,1H),8.08-7.98(m,5H),7.79-7.74(m,4H) ,7.66(dd,J=1.5,7.9Hz,1H),7.57(dd,J=1.3,8.1Hz,1H),7.40(dt,J=1.3,7.7Hz,1H),7.34-7.25(m,1H),7.03(d,J=8.6Hz,2H),6.89(d,J= 8.8Hz,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).

[0413] Example 13. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)phenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 13)

[0414]

[0415] Step 1. (4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)phenyl)aminomethyl) Synthesis of tert-butyl ester (3)

[0416] At 20 °C, TEA (293.97 mg, 2.91 mmol, 404.36 μL) and 4AMS (200 mg) were added to a DCE (7 mL) solution of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (300 mg, 968.40 μmol HCl) and (4-formylphenyl)carbamate tert-butyl ester (214.26 mg, 968.40 μmol). The mixture was stirred at 20 °C for 30 min, then NaBH(OAc)3 (615.73 mg, 2.91 mmol) was slowly added, and the resulting mixture was stirred at 20 °C for 12 h. LCMS showed that the starting material was completely consumed and showed a peak of 57% with the desired mass. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The solution was analyzed by rapid silica gel chromatography (12 g). The residue was purified by a silica gel rapid column chromatography with an eluent of 0–100% EtOAc / petroleum ether gradient at 200 mL / min to give tert-butyl (4-(4-(4-(2,6-dioxopiridin-3-yl)phenyl)piperazin-1-yl)methyl)phenyl)carbamate (225 mg, 446.63 μmol, 46.12% yield, 95% purity) as a white solid. MS (M+H) + =479.3.

[0417] Step 2.3 Synthesis of (4-(4-(4-(4-aminobenzyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (4)

[0418] At 20°C, HCl / dioxane (4M, 9.20 mL) was added to a solution of tert-butyl (4-((4-(4-(2,6-dioxadiidine-3-yl)phenyl)piperazin-1-yl)methyl)phenyl)carbamate (225 mg, 470.14 μmol) in dioxane (3 mL). The mixture was stirred at 20°C for 4 hours. LCMS showed 8% residual tert-butyl (4-((4-(4-(2,6-dioxadiidine-3-yl)phenyl)piperazin-1-yl)methyl)phenyl)carbamate and showed a peak of 83% with the desired mass. The reaction mixture was concentrated under vacuum to give 130 mg crude 3-(4-(4-(4-aminobenzyl)piperazin-1-yl)phenyl)piperidine-2,6-dione in HCl as a white solid. MS (M+H) + =379.3.

[0419] Step 3. N-(2-chlorophenyl)-4-((2-((4-((4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin Azine-1-yl)methyl)phenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 13) Synthesis

[0420] At 20 °C, HATU (80.64 mg, 212.09 μmol) and DIPEA (74.75 mg, 578.41 μmol, 100.75 μL) were added to a DMF (2 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (92.14 mg, 192.80 μmol). The mixture was stirred at 20 °C for 30 min, then a DMF (2 mL) solution of 3-(4-(4-(4-aminobenzyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (80 mg, 192.80 μmol HCl) was added, and the reaction mixture was stirred at 20 °C for 12 h. LCMS showed that the starting material was completely consumed and showed a peak of 40% with the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over brine (10 mL × 3), filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1), followed by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; B%: 38%-68%, 10 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((4-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)phenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (45.3 mg, 33.14 μmol, 17.19% yield, 94.7% purity, 4TFA) as a white solid. MS (M+H) + =838.1.

[0421] 1 H NMR (400MHz, MeOD) δ = 8.12 (d, J = 3.9Hz, 1H), 8.07-8.00 (m, 2H), 7.99-7.91 (m, 4H), 7.88 (d,J=8.4Hz,2H),7.82-7.76(m,3H),7.55-7.47(m,3H),7.37(dt,J=1.5,7.8Hz,1H),7.2 9-7.22(m,1H),7.18(d,J=8.7Hz,2H),7.01(d,J=8.8Hz,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).

[0422] Example 14. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 14)

[0423]

[0424] Step 1. Synthesis of 3-(4-bromophenyl)piperidine-2,6-dione (2)

[0425] At 0 °C, t-BuOK (1 M, 21.83 mL) was added to a DMF (50 mL) 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:EtOAc = 1:1) showed that the starting material was completely consumed and new, highly polar spots were formed. The reaction mixture was poured into cold water, filtered, and washed with H₂O (50 mL). The filter cake was collected and dried to give 3-(4-bromophenyl)piperidin-2,6-dione (2.5 g, 9.23 mmol, 42.29% yield, 99% purity) as a white solid. MS (M+H) + =268.1.

[0426] 1 H NMR(400MHz,DMSO-d6)δ=10.86(br s,1H),7.53(d,J=8.3Hz,2H),7.20(d,J=8.4Hz,2H),3.88(dd,J=4.9,12.0Hz,1H),2. 74-2.62(m,1H),2.56-2.50(m,1H),2.20(dq,J=4.3,12.5Hz,1H),2.07-1.96(m,1H).

[0427] Step 2.4 Synthesis of tert-butyl piperidine-1-carboxylate (4) become

[0428] Under N2, Pd(PPh3)2Cl2 (157.08 mg, 223.79 μmol) and CuI (85.24 mg, 447.58 μmol) were added to a DMF (10 mL) solution of 3-(4-bromophenyl)piperidin-2,6-dione (1.2 g, 4.48 mmol), 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (936.72 mg, 4.48 mmol), and TEA (1.36 g, 13.43 mmol, 1.87 mL). The resulting mixture was stirred at 80 °C for 16 h. LCMS showed that 3-(4-bromophenyl)piperidin-2,6-dione was completely consumed and showed 39% of the desired mass. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Rapid silica gel chromatography (12g) The residue was purified by silica gel rapid column chromatography with 0–60% EtOAc / petroleum ether gradient at 100 mL / min to give 1.8 g of tert-butyl 4-((4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)piperidin-1-carboxylate as a yellow solid. MS (M+H) + =397.2.

[0429] Step 3.3 Synthesis of (4-(piperidin-4-ylethynyl)phenyl)piperidin-2,6-dione (5)

[0430] To a solution of tert-butyl piperidine-1-carboxylate (1.8 g, 4.54 mmol) in dioxane (10 mL), HCl / dioxane (4 M, 20 mL) was added. The resulting solution was stirred at 20 °C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a yellow solid of 3-(4-(piperidin-4-ylethynyl)phenyl)piperidine-2,6-dione (1.5 g, HCl salt). MS (M+H) + =297.2.

[0431] Step 4.4-((4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-carboxylic acid tert- Synthesis of Butyl Acetate (7)

[0432] A mixture of 3-(4-(piperidin-4-ylethynyl)phenyl)piperidin-2,6-dione (1.4 g, 4.21 mmol, HCl salt), tert-butyl 4-oxopiperidin-1-carboxylate (921.93 mg, 4.63 mmol), and TEA (851.30 mg, 8.41 mmol, 1.17 mL) in DCM (14 mL) was stirred at 20 °C for 0.5 h. Then, NaBH(OAc)3 (2.67 g, 12.62 mmol) was added, and the resulting mixture was stirred at 20 °C for 3 h. LCMS showed a peak of 70% with the desired mass. The reaction mixture was diluted with NaHCO3 solution (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, for 10 min) and lyophilized to give tert-butyl 4-((4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-carboxylic acid (1.8 g, 3.45 mmol, 82.08% yield, 92% purity) as a white solid. MS (M+H) + =480.3.

[0433] Step 5.3 Synthesis of (4-([1,4'-piperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione (8)

[0434] To a solution of tert-butyl 4-((4-(2,6-dioxadiazin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate (0.4 g, 834.01 μmol) in dioxane (4 mL), HCl / dioxane (4 M, 4 mL) was added, and the mixture was stirred at 20 °C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a yellow solid, 3-(4-([1,4'-bipiperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione (0.36 g, HCl salt), which was used directly. MS (M+H) + =380.3.

[0435] Step 6. N-(2-chlorophenyl)-4-((2-((4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetylene (1,4'-Bipiperidine]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 14) synthesis

[0436] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (1 mL) was stirred at 25 °C for 0.5 h. Then, a mixture of 3-(4-([1,4'-piperidin]-4-ylethynyl)phenyl)piperidin-2,6-dione (90 mg, 216.37 μmol, HCl salt) in DMF (1 mL) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed that the starting material was completely consumed and showed a peak of 68% with the desired mass. The reaction mixture was diluted with 20 mL of H₂O and extracted with THF (10 mL × 3). The combined organic layers were washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified twice by preparative TLC (SiO₂, DCM:MeOH = 7:1) to give N-(2-chlorophenyl)-4-((2-((4-(4-((4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a white solid (19.3 mg, 22.07 μmol, 37.06% yield, 96% purity). MS (M+H) + =839.2.

[0437] 1H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.91 (s, 1H), 9.72 (s, 1H), 9.55 (s, 1H), 8.23 ​​(d, J = 3.5Hz, 1H), 8.07-7.93 (m, 4H), 7.74 (d, J=8.6Hz,2H),7.66(dd,J=1.3,7.9Hz,1H),7.56(dd,J=1.3,7.9Hz,1H),7.39(dt,J=1.3,7.6Hz,1H),7.37-7.25(m,5H),7.20(d,J= 8.2Hz,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),2.3 9-2.29(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).

[0438] Example 15. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 15)

[0439]

[0440] Step 1. N-(2-chlorophenyl)-4-((2-((4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetylene (1,4'-Bipiperidine)-1'-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (chemical) Synthesis of compound 15

[0441] A mixture of 2-(4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (1 mL) was stirred at 25 °C for 0.5 h. Then, a solution of 3-(4-([1,4'-bipiperidine]-4-ylethynyl)phenyl)piperidine-2,6-dione (90 mg, 216.37 μmol, HCl salt) in DMF (1 mL) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed that 3-(4-([1,4'-bipiperidin]-4-ylethynyl)phenyl)piperidin-2,6-dione was completely consumed and showed a peak of 61% with the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with THF (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified twice by preparative TLC (SiO2, DCM:MeOH = 10:1) to give N-(2-chlorophenyl)-4-((2-((4-(2-(4-((4-(2,6-dioxopiperidin-3-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a white solid (17.2 mg, 18.70 μmol, 31.92% yield, 92.8% purity). MS (M+H) + =853.2.

[0442] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.89 (s, 1H), 9.65 (s, 1H), 9.28 (s, 1H), 8.18(d,J=3.5Hz,1H),8.07-8.00(m,2H),7.99-7.92(m,2H),7.65(dd,J=1.4,8. 0Hz,1H),7.63-7.58(m,2H),7.56(dd,J=1.3,7.9Hz,1H),7.39(dt,J=1.4,7.7H z,1H),7.36-7.26(m,3H),7.19(d,J=8.2Hz,2H),7.12(d,J=8.6Hz,2H),4.39(br dd,J=1.3,12.0Hz,1H),3.97(br d,J=11.5Hz,1H),3.87(dd,J=4.8,11.6Hz,1H),3.69-3.57(m,2H),2.94(br t,J=12.3Hz,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),2.30-2.1 1(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).

[0443] Example 16. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 16)

[0444]

[0445] Step 1. ((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexane Synthesis of tert-butyl carbamate (3)

[0446] 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)methyl methanesulfonate (266.34 mg, 866.42 μmol), DIPEA (559.90 mg, 4.33 mmol, 754.58 μL), and KI (143.83 mg, 866.42 μmol) in DMF (7 mL) was stirred at 60 °C for 16 h. LCMS showed 19% residue of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione and 54% of the expected mass was detected. (1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)methyl methanesulfonate (79.90 mg, 259.93 μmol) was added to the mixture, and then stirred at 60 °C for 16 h. LCMS showed 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 treated with CH3COOH to adjust the pH to <7. The resulting mixture was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B, for 10 min) and lyophilized to give a brown solid of tert-butyl ((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamate (170 mg, 283.97 μmol, 32.78% yield, TFA salt). MS (M+H) + =485.2.

[0447] Step 2.3-(4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-di Synthesis of ketones (4)

[0448] A mixture of ((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (125 mg, 208.80 μmol, TFA salt) and TFA (1.54 g, 13.46 mmol, 1 mL) in DCM (4 mL) was stirred at 15 °C for 1 hour. LCMS showed that the starting material was completely consumed. The mixture was concentrated under vacuum to give 3-(4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (125 mg, 2 TFA salt) as a brown gel, which was used directly. MS (M+H) + =385.2.

[0449] Step 3. N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl) (Phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide Synthesis of (Compound 16)

[0450] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (5 mL) was stirred at 15 °C for 15 min, and then 3-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (165 mg, 269.36 μmol, 2TFA salt) was added. The resulting mixture was stirred at 15 °C for 1 h. LCMS showed that 3-(4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione was completely consumed and showed 59% of the expected mass. The mixture was diluted with H2O (30 mL) and extracted with a mixture of EtOAc / THF (2 / 1, 10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 28%-58% B, 9 min) and lyophilized. The product was diluted with a mixture of EtOAc:THF:ACN (4:2:1, 60 mL) and treated with NaHCO3 solution (5 mL) to adjust pH > 7. The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, DCM:MeOH = 8:1) to give N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (51.2 mg, 56.94 μmol, 22.67% yield, 93.9% purity), as a light brown solid. MS (M+H) + =844.2.

[0451] 1H NMR(400MHz, DMSO-d6)δ=10.77(s,1H),9.93(s,1H),9.73(s,1H),9.59(s,1H), 8.25(d,J=3.5Hz,1H),8.11-7.94(m,5H),7.80-7.72(m,4H),7.65(dd,J=1.3,7. 9Hz,1H),7.56(dd,J=1.3,7.9Hz,1H),7.40(dt,J=1.3,7.7Hz,1H),7.34-7.25( m,1H),7.05(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,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).

[0452] Example 17. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 17)

[0453]

[0454] Step 1. Synthesis of 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl ester of 4-methylbenzenesulfonic acid (2)

[0455] 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) were added to a DCM (30 mL) solution of ((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)carbamate (2.5 g, 10.27 mmol). The mixture was stirred at 20 °C for 16 hours. LCMS showed a main peak with the desired quality. The reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The final concentration was determined by rapid silica gel chromatography (…). 20g The residue was purified by silica gel rapid column chromatography (eluting with a 20–30% EtOAc / petroleum ether gradient at 80 mL / min) to give 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonic acid (1.86 g, 4.68 mmol, 45.54% yield) as a white solid. MS (M+H) + =398.1.

[0456] Step 2. ((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclo Synthesis of hexyl) tert-butyl carbamate (4)

[0457] To a solution of 3-(4-(piperazin-1-yl)phenyl)piperidin-2,6-dione (2 g, 6.46 mmol, HCl salt) and ethyl 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylbenzenesulfonic acid (2.57 g, 6.46 mmol) in DMSO (20 mL), NaI (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 h. LCMS showed a peak of 42% for the desired compound. The residue was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was ground with MTBE at 25°C for 30 minutes to obtain a yellow solid of tert-butyl ((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (1.66 g, 3.33 mmol, 51.56% yield). MS (M+H) + =499.3.

[0458] Step 3.3-(4-(4-(2-((1r,4r)-4-aminocyclohexyl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6- Synthesis of diketone (5)

[0459] Add HCl / dioxane (4M, 20 mL) to a solution of ((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate tert-butyl ester (1.77 g, 3.55 mmol) in dioxane (20 mL). Stir the mixture at 25 °C for 2 hours. LC-MS showed a main peak with the desired quality. Concentrate the reaction mixture under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×40mm×15μm; mobile phase: [water (TFA)-ACN]; gradient: 0%-30% B, for 10 min) and lyophilized to give a yellow solid of 3-(4-(4-(2-((1r,4r)-4-aminocyclohexyl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (1.6 g, 2.98 mmol, 83.93% yield, 81% purity). MS (M+H) + =399.2.

[0460] Step 4. N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidine-3- yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzoyl Synthesis of amine (compound 17)

[0461] To a DMF (10 mL) solution of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (800 mg, 1.67 mmol), 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)piperazin-1-yl)phenyl)piperidin-2,6-dione (1.08 g, 2.01 mmol, 81% purity) were added. The resulting mixture was stirred at 25 °C for 2 hours. LCMS showed a main peak with the desired quality. The reaction mixture was poured into water (50 mL) and filtered. The filter cake was collected and purified by preparative HPLC (column: Phenomenex luna C18 150×40mm×15μm; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B, for 10 min), then lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (849.5 mg, 700.56 μmol, 41.85% yield, 99% purity, 3TFA) as a pale yellow solid. MS (M+H) + =858.3.

[0462] 1 H NMR (400MHz, CD3OD) δ=8.12(d,J=4.4Hz,1H),8.02(br d,J=8.6Hz,2H),7.90(br d,J=8.6Hz,2H),7.84-7.76(m,3H),7.65(br d,J=8.5Hz,2H),7.53(br d,J=8.3Hz,1H),7.39(br t,J=7.7Hz,1H),7.32-7.25(m,1H),7.19(br d,J=8.5Hz,2H),7.02(br d,J=8.4Hz,2H),3.91-3.77(m,4H),3.68(br d,J=11.4Hz,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).

[0463] Example 18. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 18)

[0464]

[0465]

[0466] Step 1. Synthesis of tert-butyl piperazine-1-carboxylate (3)

[0467] At 25 °C, Pd(dppf)Cl2 (494.08 mg, 675.24 μmol) was added to a mixture of 2,6-bis(benzyloxy)-3-bromopyridine (5 g, 13.50 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (5 g, 12.88 mmol), and K3PO4 (8.60 g, 40.51 mmol) in dioxane (100 mL) and H2O (15 mL). The resulting mixture was purged with N2 and degassed three times, heated to 100 °C, and stirred for 14 hours. LCMS showed that 2,6-bis(benzyloxy)-3-bromopyridine was completely consumed, and a main peak with the desired mass (R0) was detected.f =1.179 min, 82% area). The reaction mixture was diluted with EtOAc (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (40 g silica gel column, EtOAc / petroleum ether = 0–6%, 100 mL / min) to give tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate (7 g, 12.56 mmol, 93.02% yield, 99% purity) as a white solid. MS (M+H) + =552.4.

[0468] Step 2. Synthesis of tert-butyl piperazine-1-carboxylate (4)

[0469] A mixture of tert-butyl tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylic acid (7 g, 12.69 mmol), HOAc (761.98 mg, 12.69 mmol), and Pd / C (1.35 g, 1.27 mmol, 10% purity) in EtOH (50 mL) and THF (20 mL) was purged with H2 and degassed three times, and then stirred at 25 °C for 16 hours under H2 (15 Psi). LCMS showed that the feed was completely consumed and a main peak (R) with the desired quality was detected. f =0.984 min, 96% area). The reaction mixture was filtered, washed with THF (100 mL), and concentrated under vacuum to give tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (4.7 g, 11.96 mmol, 94.23% yield, 95% purity) as a gray solid, which was used directly. MS (M+H) + =374.2.

[0470] Step 3. Synthesis of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (5)

[0471] HCl / dioxane (4M, 50 mL) was added to a solution of 4-(4-(2,6-dioxadiazin-3-yl)phenyl)piperazine-1-carboxylate (4.7 g, 12.59 mmol) in dioxane (50 mL). The mixture was stirred at 20 °C for 2 hours. LCMS showed that the starting material was completely consumed and a main peak with the desired mass (R0) was detected. f =0.245 min, 95% area). The mixture was concentrated under vacuum to give 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (5.8 g, 2HCl salt) as a white solid, which was used directly. MS (M+H) + =274.2.

[0472] Step 4.3 Synthesis of (4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (7)

[0473] 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 h. LCMS showed 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) and treated with saturated Na2CO3 solution (30 mL). The resulting mixture was extracted with EtOAc (40 mL × 7). The combined organic layers were washed with brine (10 mL × 5), dried over Na2SO4, filtered, and concentrated under vacuum. The solution was then analyzed by rapid silica gel chromatography (12 g). The residue was purified by rapid silica gel column chromatography, using a gradient of 50–100% EtOAc / petroleum ether to 0–20% MeOH / EtOAc at 100 mL / min, yielding a brown solid 3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (450 mg, 1.25 mmol, 22.50% yield). MS (M+H) + =362.2.

[0474] Step 5.2 Synthesis of (4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetaldehyde (8)

[0475] 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, 40% purity) in H₂O (5 mL) was stirred at 40 °C for 16 hours. LCMS showed that the starting material was completely consumed and a main peak (R₁, R₂) with the desired quality was detected. f =0.421 min, 33% area). The reaction mixture was treated with aqueous Na₂CO₃ to adjust to pH = 8 and extracted with EtOAc (15 mL × 5). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to give 2-(4-(4-(2,6-dioxopiridin-3-yl)phenyl)piperazin-1-yl)acetaldehyde as a brown solid (185 mg, 563.16 μmol, 45.23% yield, 96% purity). MS (M+H) + =316.1.

[0476] Step 6. (1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl) Synthesis of tert-butyl carbamate (10)

[0477] 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetaldehyde (160 mg, 507.35 μmol), piperin-4-ylcarbamate tert-butyl ester (121.93 mg, 608.82 μmol), A mixture of 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 h. Then, NaBH(OAc)3 (322.58 mg, 1.52 mmol) was added, and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed that 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)acetaldehyde was completely consumed, and a main peak with the desired mass (R0) was detected. f =0.786 min, 60% area). The reaction mixture was diluted with H2O (30 mL) and extracted with THF (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The solution was then analyzed by rapid silica gel chromatography (4 g). The residue was purified by a rapid silica gel column elution with a gradient of 50–100% EtOAc / petroleum ether to 0–20% MeOH / EtOAc at 100 mL / min to give a yellow solid (150 mg, 255.18 μmol, 50.30% yield, 85% purity). MS (M+H) + =500.4.

[0478] Step 7.3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (11) Synthesis

[0479] A mixture of (1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl)tert-butyl carbamate (150 mg, 300.21 μmol) and TFA (2.30 g, 20.19 mmol, 1.5 mL) in DCM (5 mL) was stirred at 15 °C for 1 hour. LCMS showed that the starting material was completely consumed and the desired mass was detected. The mixture was concentrated under vacuum to give 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (190 mg, 2 TFA salt) as a brown gel, which was used directly. MS (M+H) + =400.2.

[0480] Step 8. N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperazine-1-yl)ethyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (chemical) Synthesis of compound 18

[0481] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (2 mL) was stirred at 15 °C for 15 min. Then, 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidin-2,6-dione (190 mg, 302.75 μmol, 2 TFA salt) was added, and the resulting mixture was stirred at 15 °C for 1 h. LCMS showed a peak at 55% of the desired mass. The mixture was treated with TFA to adjust the pH to <7 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, for 10 minutes) and lyophilized. F NMR and H NMR indicated impurities in the product. The impure product was added to a mixture (EtOAc:THF:ACN = 4:1:1, 80 mL), the mixture was diluted with H2O (50 mL) and treated with NaHCO3 solution (10 mL) to adjust the pH to >7, the organic phase was separated and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 8:1) to obtain the product, which was diluted with a mixture (ACN:H2O:THF = 15:15:4, 34 mL) and freeze-dried to give N-(2-chlorophenyl)-4-((2-((4-((1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a brown solid (19.9 mg, 22.07 μmol, 7.53% yield, 95.3% purity). MS (M+H) + =859.3.

[0482] 1H NMR (400MHz, DMSO-d6) δ=10.78(s,1H),9.94(s,1H),9.75(s,1H),9.62(s,1H),8.25(d,J=3.4Hz,1H),8.12-7.95(m,5 H),7.80-7.75(m,4H),7.65(d,J=7.9Hz,1H),7.56(d,J=7.9Hz,1H),7.39(t,J=7.6Hz,1H),7.34-7.25(m,1H),7.05(br d,J=8.2Hz,2H),6.89(br d,J=8.6Hz,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).

[0483] Example 19. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(2-(1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 19)

[0484]

[0485] Step 1. Synthesis of (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (2)

[0486] HCl / dioxane (4M, 12.00 mL) was added to a solution of tert-butyl (1-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidin-1-carboxylate (600 mg, 1.35 mmol) in dioxane (6 mL). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed that the starting material was completely consumed and showed the desired mass. The reaction mixture was concentrated under reduced pressure to give benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (440 mg, crude, HCl) as a white solid. MS (M+H) + =346.2.

[0487] Step 2. (1-(2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin- Synthesis of 4-yl)benzyl carbamate (4)

[0488] A mixture of (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (380 mg, 994.92 μmol, HCl), 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (487.99 mg, 994.92 μmol), Cs₂CO₃ (972.50 mg, 2.98 mmol), and Pd-PEPPSI-IHeptCl (48.39 mg, 49.75 μmol) in dioxane (4 mL) was degassed and purged three times with N₂, then heated to 100 °C and stirred under N₂ atmosphere for 16 hours. LC-MS showed that the starting material was completely consumed. The mixture was filtered and concentrated under reduced pressure to give the residue. This residue was analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a high-speed silica gel column (eluting with 0–10% MeOH / EtOAc at 80 mL / min) to yield a yellow solid (135 mg, 184.20 μmol, 18.51% yield, 97% purity). MS (M+H) + =711.5.

[0489] Step 3.3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (5) Synthesis

[0490] Under H2, Pd / C (40 mg, 10% purity) and Pd(OH)2 / C (40 mg, 20% purity) were added to a solution of (1-(2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (135 mg, 189.90 μmol) and TFA (21.65 mg, 189.90 μmol, 14.11 μL) in CF3CH2OH (1.3 mL). The mixture was degassed and purged several times with H2, and stirred at 25 °C for 16 h under H2 (15 psi). LCMS showed that the feed was completely consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown oily substance, 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (97 mg, 189.24 μmol, 99.66% yield, TFA). MS (M+H) + =399.2.

[0491] Step 4. N-(2-chlorophenyl)-4-((2-((4-((1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl) Piperidin-4-yl)ethyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (chemical) Synthesis of compound 19

[0492] HATU (72.33 mg, 190.22 μmol) and DIPEA (81.95 mg, 634.07 μmol, 110.44 μL) were added to a DMF (0.5 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (60.60 mg, 126.81 μmol). The mixture was stirred at 25 °C for 0.5 h. Then, 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (65 mg, 126.81 μmol, TFA) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed that 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione was completely consumed and showed the desired mass. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with 10 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 20g The sample was purified by preparative HPLC (column: Phenomenexluna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 22%-52% B, 9 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((1-(2-(1-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (10 mg, 11.53 μmol, 9.09% yield, 99% purity) as a white solid. MS (M+H) + =858.3.

[0493] 1H NMR (400MHz, DMSO-d6) δ = 10.76 (br s, 1H), 9.92 (s, 1H), 9.73 (br d,J=2.0Hz,1H),9.60(s,1H),8.24(d,J=3.5Hz,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=8.7Hz,2H),6.88(d,J=8.8Hz,2H),3.79-3.68(m,2H),3.64(br d,J=11.9Hz,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=10.5Hz,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).

[0494] Example 20. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethynyl)-[1,4'-bipiperidin]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 20)

[0495]

[0496] Step 1. Synthesis of 3-(5-bromopyridin-2-yl)piperidine-2,6-dione (2)

[0497] Acrylamide (926.87 mg, 13.04 mmol, 899.87 μL) and t-BuOK (1 M, 13.04 mL) were added to a DMF (30 mL) solution of ethyl 2-(5-bromopyridin-2-yl)acetate (3 g, 13.04 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. TLC (petroleum ether:EtOAc = 1:1) showed that the starting material was consumed and new spots were formed. The mixture was poured into water (50 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na₂SO₄, filtered, and concentrated to obtain a residue. This residue was then ground with EtOAc / MTBE (20 mL, 1:1) at 20 °C for 1 hour to give a pale yellow solid of 3-(5-bromopyridin-2-yl)piperidin-2,6-dione (900 mg, 3.34 mmol, 25.65% yield). MS (M+H) + =269.0.

[0498] Step 2.4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethynyl)piperidin-1-carboxylic acid tert-butyl ester (4) Synthesis

[0499] Under N2, Pd(PPh3)2Cl2 (67.08 mg, 95.56 μmol) and CuI (36.40 mg, 191.13 μmol) were added to a DMF (5 mL) solution of 3-(5-bromopyridin-2-yl)piperidin-2,6-dione (514.31 mg, 1.91 mmol), 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (0.4 g, 1.91 mmol), and TEA (580.20 mg, 5.73 mmol, 798.08 μL). The resulting solution was stirred at 80 °C for 16 hours. LCMS showed a main peak with the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min to obtain 0.78 g (crude) of tert-butyl 4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethynyl)piperidin-1-carboxylate as a yellow solid. MS (M+H) + =398.2.

[0500] Step 3.3 Synthesis of (5-(piperidin-4-ylethynyl)pyridin-2-yl)piperidin-2,6-dione (5)

[0501] HCl / dioxane (4M, 10.00 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (0.78 g, 1.96 mmol) in dioxane (10 mL). The resulting mixture was stirred at 20 °C for 2 hours. LC-MS showed that the starting material was completely consumed and a main peak of the desired quality was observed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H₂O (30 mL) and extracted with EtOAc (10 mL × 3). The aqueous phase was lyophilized to give a yellow solid of 3-(5-(piperidin-4-ylethynyl)pyridin-2-yl)piperidine-2,6-dione (1 g, crude). MS (M+H) + =298.2.

[0502] Step 4.4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethynyl)-[1,4'-bipiperidin]-1'- Synthesis of tert-butyl formate (6)

[0503] A mixture of 3-(5-(piperidin-4-ylethynyl)pyridin-2-yl)piperidin-2,6-dione (0.9 g, 2.70 mmol, HCl), tert-butyl 4-oxopiperidin-1-carboxylate (590.91 mg, 2.97 mmol), and TEA (545.64 mg, 5.39 mmol) in DCM (10 mL) was stirred at 20 °C for 0.5 h. Then, NaBH(OAc)3 (1.71 g, 8.09 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was diluted with NaHCO3 solution (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, 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, for 10 min) to obtain tert-butyl 4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylic acid (180 mg, 269.42 μmol, 9.99% yield, 89% purity, TFA) as a yellow solid. MS (M+H) + =481.3.

[0504] Step 5.3 Synthesis of (5-([1,4'-bipiperidine]-4-ylethynyl)pyridin-2-yl)piperidine-2,6-dione (7)

[0505] HCl / dioxane (4M, 2 mL) was added to a solution of tert-butyl 4-((6-(2,6-dioxadiidine-3-yl)pyridin-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate (180 mg, 374.53 μmol) in dioxane (2 mL). The mixture was stirred at 20 °C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give 160 mg, crude, HCl, as a yellow solid of 3-(5-([1,4'-bipiperidine]-4-ylethynyl)pyridin-2-yl)piperidine-2,6-dione. MS (M+H) + =381.3.

[0506] Step 6. N-(2-chlorophenyl)-4-((2-((4-(4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethyl alkynyl)-[1,4'-bipiperidine]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 20) Synthesis

[0507] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (1 mL) was stirred at 25 °C for 0.5 h. Then, a solution of 3-(5-([1,4'-piperidin]-4-ylethynyl)pyridin-2-yl)piperidin-2,6-dione (80 mg, 191.87 μmol, HCl) in DMF (1 mL) was added, and the mixture was stirred at 25 °C for 16 h. LCMS showed a main peak with the desired mass. The reaction mixture was diluted with H2O (20 mL) and extracted with THF (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B, for 10 min) followed by preparative TLC (SiO2, DCM:MeOH = 10:1) to obtain N-(2-chlorophenyl)-4-((2-((4-(4-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)ethynyl)-[1,4'-bipiperidin]-1'-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (9.3 mg, 10.73 μmol, 5.59% yield, 97% purity). MS(M+H) + =840.3.

[0508] 1H NMR (400MHz, DMSO-d6) δ=10.87(s,1H),9.91(s,1H),9.72(s,1H),9.55(s,1H),8.51(d,J= 1.5Hz,1H),8.22(d,J=3.7Hz,1H),8.03-7.96(m,4H),7.78(dd,J=1.9,8.1Hz,1H),7.73(br d,J=8.7Hz,2H),7.65(br d,J=6.8Hz,1H),7.56(d,J=7.2Hz,1H),7.40-7.27(m,5H),4.05(dd,J=5.3,9.7Hz,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).

[0509] Example 21. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 21)

[0510]

[0511] Step 1.8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro [4.5] Synthesis of decane (3)

[0512] 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) in toluene (30 mL) was degassed and purged three times with N2. The resulting mixture was stirred at 100 °C for 16 h under N2 atmosphere. LCMS showed that 2,6-bis(benzyloxy)-3-(4-bromo-3-fluorophenyl)pyridine was completely consumed and showed the desired mass. The reaction mixture was quenched by adding H₂O (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue, which was then subjected to rapid silica gel chromatography (…). 25g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–20% EtOAc / petroleum ether gradient at 50 mL / min, yielding a yellow oily substance, 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (2.21 g, 3.74 mmol, 86.89% yield, 89.18% purity). MS (M+H) + =527.3.

[0513] Step 2.3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidine-2,6-dione (4) Synthesis

[0514] Under a H2 atmosphere, Pd / C (300 mg, 10% purity) was added to a CF3CH2OH (30 mL) solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (2.2 g, 4.18 mmol). The suspension was degassed and purged three times with H2, and then stirred at 25 °C for 16 h under H2 (15 Psi). LCMS showed a peak of 68% residual 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane and 23% of the desired compound. The mixture was stirred for another 16 h. LC-MS showed that 8-(4-(2,6-bis(benzyloxy)pyridin-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 give 3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidin-2,6-dione (1.3 g, 3.73 mmol, 89.32% yield) as a yellow solid. This crude product was used directly in the next step. MS (M+H) + =349.2.

[0515] Step 3. Synthesis of 3-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (5)

[0516] HCl (6 M, 1.85 mL) was added to a solution of 0.645 g (1.85 mmol) of 3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidine-2,6-dione in acetone (10 mL). The mixture was stirred at 25 °C for 48 h. LCMS showed 24% residual 3-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidine-2,6-dione and showed a peak of 63% with the desired mass. The mixture was diluted with H2O (20 mL) and neutralized with NaHCO3 solution, and then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a blue oily substance, 3-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidin-2,6-dione (0.555 g, 1.82 mmol, 98.50% yield). This crude product was used directly in the next step. MS (M+H) + =305.0.

[0517] Step 4. (7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro Synthesis of [3.5]non-2-yl)carbamate (7)

[0518] A solution of 3-(3-fluoro-4-(4-oxopiridin-1-yl)phenyl)piperidin-2,6-dione (0.769 g, 1.26 mmol, 50% purity) in DCM (7 mL) was supplemented with (7-azaspiro[3.5]non-2-yl)benzyl 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 h. Then NaBH(OAc)3 (803.35 mg, 3.79 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed that 3-(3-fluoro-4-(4-oxopiridin-1-yl)phenyl)piperidin-2,6-dione was completely consumed and showed the desired mass. The reaction mixture was poured into water (30 mL) and extracted with DCM (15 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue, which was then subjected to rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column with 0–30% MeOH / EtOAc eluent at 50 mL / min, yielding a white solid (0.41 g, 692.23 μmol, 54.79% yield, 95% purity) benzyl 7-(1-(4-(2,6-dioxopiridin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)carbamate. MS (M+H)+ =563.3.

[0519] Step 5.3-(4-(4-(2-amino-7-azaspiro[3.5]non-7-yl)piperidin-1-yl)-3-fluorophenyl)piperidin- Synthesis of 2,6-dione (8)

[0520] A solution of (7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-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 h. LC-MS showed that (7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)carbamate was completely consumed and showed the desired mass. The reaction mixture was concentrated under reduced pressure to give a brown oily substance, 3-(4-(4-(2-amino-7-azaspiro[3.5]non-7-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (0.053 g, 97.68 μmol, 98.15% yield, TFA). This crude product was used directly in the next step. MS (M+H) + =429.2.

[0521] Step 6. N-(2-chlorophenyl)-4-((2-((4-((7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorobenzene) (3.5)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino) Synthesis of benzamide (compound 21)

[0522] A solution of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (232.94 mg, 365.59 μmol, 75% purity), HATU (208.51 mg, 548.38 μmol), and DIPEA (236.25 mg, 1.83 mmol, 318.40 μL) in DMF (2 mL) was stirred at 25 °C for 0.5 h. Then, 3-(4-(4-(2-amino-7-azaspiro[3.5]non-7-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (0.17 g, 365.59 μmol, HCl) was added, and the mixture was stirred at 25 °C for 16 h. LCMS showed that 3-(4-(4-(2-amino-7-azaspiro[3.5]non-7-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione was completely consumed and showed the desired mass. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 12g The sample was purified by preparative HPLC (column: Waters Xbridge 150*25mm 10µm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 10 min) and lyophilized to obtain N-(2-chlorophenyl)-4-((2-((4-((7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (9.5 mg, 9.62 μmol, 2.63% yield, 90% purity) as a white solid. MS (M+H) + =888.3.

[0523] 1 H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.93 (s, 1H), 9.73 (s, 1H), 9.62 (s, 1H), 8.34 (br d,J=7.7Hz,1H),8.25(d,J=3.4Hz,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=8.7Hz,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).

[0524] Example 22. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-((7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)amino)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 22)

[0525]

[0526] Step 1. N-(2-chlorophenyl)-4-((2-((4-(2-((7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro) phenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)amino)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidine-4- Synthesis of (amino)benzamide (compound 22)

[0527] A mixture of 2-(4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (2 mL) was stirred at 25 °C for 0.5 h. Then, 3-(4-(4-(2-amino-7-azaspiro[3.5]non-7-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (0.17 g, 313.33 μmol, TFA) was added, and the resulting mixture was stirred at 25 °C for 16 h. LCMS showed that 3-(4-(4-(2-amino-7-azaspiro[3.5]non-7-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione was completely consumed and showed the desired mass. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 20g The sample was purified by preparative HPLC (column: Waters Xbridge 150*25mm 10µm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 10 min) and lyophilized to obtain N-(2-chlorophenyl)-4-((2-((4-(2-((7-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-7-azaspiro[3.5]non-2-yl)amino)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (22 mg, 22.18 μmol, 7.08% yield, 91% purity) as a white solid. MS (M+H) + =902.3.

[0528] 1H NMR (400MHz, 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).

[0529] Example 23. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((7-((1-(4-((2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]non-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 23)

[0530]

[0531] Step 1.1 Synthesis of 4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-carboxaldehyde (2)

[0532] DMP (2.98 g, 7.02 mmol) was added to a solution of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (1.5 g, 4.68 mmol) in DCM (30 mL), and the resulting mixture was stirred at 25 °C for 2 hours. TLC (petroleum ether:EtOAc = 1:1) showed that 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione was completely consumed and new spots were formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-carboxaldehyde (1.5 g, crude) as a yellow oil. MS (M+H) + =319.1.

[0533] Step 2. (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-aza Synthesis of spiro[3.5]non-2-yl)carbamate (4)

[0534] To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-carboxaldehyde (1.28 g, 4.02 mmol) and (7-azaspiro[3.5]non-2-yl)carbamate (1.25 g, 4.02 mmol, HCl) in DCM (30 mL), NaOAc (494.87 mg, 6.03 mmol) and NaBH(OAc)3 (1.28 g, 6.03 mmol) were added, and the resulting mixture was stirred at 25 °C for 14 h. LCMS showed a peak (54%) with the desired mass. The mixture was poured into water (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The results were obtained by rapid silica gel chromatography (…). 20g The residue was purified by silica gel rapid column chromatography with 0–30% MeOH / EtOAc gradient at 80 mL / min to give a yellow solid (1.1 g, 1.91 mmol, 47.43% yield) of (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]non-2-yl)carbamate. MS (M+H) + =577.3.

[0535] Step 3.3-(4-(4-((2-amino-7-azaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl) Synthesis of piperidine-2,6-dione (5)

[0536] A mixture of (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]non-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. LCMS showed that the starting material was completely consumed and showed 89% of the expected mass. The mixture was concentrated under reduced pressure to give 0.4 g (crude) of 3-(4-(((2-amino-7-azaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione as a yellow oil. MS (M+H) + =443.3.

[0537] Step 4. N-(2-chlorophenyl)-4-((2-((4-((7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorobenzene) (3.5)piperidin-4-yl)methyl)-7-azaspiro[3.5]non-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl) Synthesis of (amino)benzamide (compound 23)

[0538] DIPEA (104.49 mg, 808.49 μmol, 140.82 μL) and HATU (122.97 mg, 323.40 μmol) were added to a DMF (5 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (287.13 mg, 600.84 μmol), and the resulting mixture was stirred at 25 °C for 1 hour. Then, 3-(4-(((2-amino-7-azaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (150 mg, 269.50 μmol, TFA) was added, and the resulting mixture was stirred at 25 °C for 1 hour. LCMS showed a main peak with the desired quality. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The crude product was passed through preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 10 min), followed by preparative HPLC (column: Phenomenex luna C18). 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10 min) purified and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((7-((1-(4-((2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]non-2-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (37.4 mg, 39.43 μmol, 14.63% yield, FA) as a white solid. MS (M+H) + =902.7.

[0539] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.94 (s, 1H), 9.75 (s, 1H), 9.62 (s, 1H), 8.36 (br d,J=7.1Hz,1H),8.25(d,J=3.5Hz,1H),8.15(s,1H),8.06-7.98(m,4H),7.79-7.77(m,4H),7.66(dd,J=1.5,8 .0Hz,1H),7.57(dd,J=1.4,8.0Hz,1H),7.40(dt,J=1.3,7.7Hz,1H),7.34-7.27(m,1H),7.05-6.92(m,3H),4. 44-4.32(m,1H),3.80(dd,J=4.8,11.6Hz,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).

[0540] Example 24. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 24)

[0541]

[0542] Step 1. Synthesis of tert-butyl piperazine-1-carboxylate (3)

[0543] K₂CO₃ (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 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (2.3 g, 6.70 mmol, HOAc) in MeCN (30 mL). The mixture was stirred at 25 °C for 16 hours. LC-MS showed a main peak with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. This residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 4-((1-(4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.9 g, 4.37 mmol, 65.23% yield, 93% purity) as a yellow solid. MS (M+H) + =405.2.

[0544] Step 2. Synthesis of tert-butyl piperazine-1-carboxylate (4)

[0545] Fe (786.93 mg, 14.09 mmol) was added to a mixture of tert-butyl 4-(1-(4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.9 g, 4.70 mmol) and NH4Cl (1.01 g, 18.79 mmol) in EtOH (10 mL) and H2O (10 mL) at 80 °C. The resulting mixture was stirred at 80 °C for 1 hour. LCMS showed that the starting material was completely consumed. The reaction mixture was poured into a NaHCO3 solution (50 mL), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was then subjected to rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 4-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.5 g, 3.80 mmol, 81.00% yield, 95% purity) as a brown solid. MS (M+H) + =375.2.

[0546] Step 3.4-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin Synthesis of tert-butyl 1-azine-carboxylate (6)

[0547] Pd-PEPPSI-IHeptCl (194.80 mg, 200.26 μmol) was added to a mixture of tert-butyl piperidin-4-ylmethyl piperazine-1-carboxylate (1.5 g, 4.01 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (1.48 g, 4.01 mmol), and Cs₂CO₃ (3.91 g, 12.02 mmol) in dioxane (20 mL). The resulting mixture was stirred at 90 °C under N₂ for 16 h. LC-MS showed a main peak with the desired quality. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue, which was subjected to rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column with an eluent of 0–60% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 4-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (2.5 g, 3.62 mmol, 90.27% yield, 96% purity). MS (M+H) + =664.4.

[0548] Step 4.4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1- Synthesis of tert-butyl formate (7)

[0549] Under H2, CH3COOH (113.08 mg, 1.88 mmol) and Pd / C (200.39 mg, 188.30 μmol, 10% purity) were added to a solution of 4-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (1.25 g, 1.88 mmol) in CF3CH2OH (40 mL) and THF (8 mL). The resulting mixture was stirred at 25 °C for 16 hours under H2 (15 psi). LCMS showed that the starting material was still present. Another portion of Pd / C (200.39 mg, 188.30 μmol, 10% purity) was added, and the mixture was stirred at 25 °C for 6 hours under H2 (15 psi). LCMS showed that the starting material was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure to give 1.5 g (crude) of tert-butyl 4-((1-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate as a black solid. The crude product was used in the next step without further purification. MS (M+H) + =486.3.

[0550] Step 5.3-((4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione(8) synthesis

[0551] To a solution of tert-butyl piperazine-1-carboxylate (200 mg, 411.85 μmol) in dioxane (2 mL), HCl / dioxane (4 M, 2 mL) was added. The resulting mixture was stirred at 25 °C for 2 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give 180 mg, crude 3-((4-(4-(piperazin-1-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (HCl) as a black solid. The crude product was used in the next step without further purification. MS (M+H) + =386.4.

[0552] Step 6. N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino) (Phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzyl) Synthesis of amide (compound 24)

[0553] A mixture of 2-(4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (2 mL) was stirred at 25 °C for 0.5 h. Then, a solution of 3-((4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (173 mg, 409.99 μmol, HCl) and DIPEA (158.96 mg, 1.23 mmol, 214.24 μL) in DMF (2 mL) was added. The resulting mixture was stirred at 25 °C for 16 h. LCMS showed a main peak of the desired quality. The reaction mixture was diluted with H2O (50 mL) and extracted with THF (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column with elution buffers ranging from 0–100% EtOAc / petroleum ether to 0–50% MeOH / EtOAc gradient at 100 mL / min. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 12%-32%, 10 min) followed by preparative TLC (SiO2, DCM:MeOH = 15:1) to obtain N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (7 mg, 7.49 μmol, 1.83% yield, 92% purity) as a yellow solid. MS (M+H) + =859.3.

[0554] 1 H NMR (400MHz, 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=7.9Hz,1H),7.60(br d,J=7.5fHz,2H),7.56(br d,J=8.4Hz,1H),7.39(br t,J=7.7Hz,1H),7.33-7.26(m,1H),7.12(br d,J=7.8Hz,2H),6.73(br d,J=7.7Hz,2H),6.58(br d,J=8.1Hz,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).

[0555] Example 25. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 25)

[0556]

[0557] Step 1. Synthesis of tert-butyl piperazine-1-carboxylate (3)

[0558] A mixture of 1-iodo-3-nitrobenzene (1 g, 4.02 mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (1.66 g, 4.82 mmol, HOAc), Pd2(dba)3 (367.75 mg, 401.60 μmol), RuPhos (374.80 mg, 803.20 μmol), and Cs2CO3 (6.54 g, 20.08 mmol) in dioxane (2 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 16 hours under N2 atmosphere. LCMS showed that 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester was completely consumed and showed the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–20% EtOAc / petroleum ether gradient at 50 mL / min, yielding a yellow solid of tert-butyl 4-((1-(3-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.23 g, 2.86 mmol, 71.23% yield, 94.08% purity). MS (M+H) + =405.2.

[0559] Step 2.4 Synthesis of tert-butyl piperazine-1-carboxylate (4)

[0560] To a solution of 4-((1-(3-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.23 g, 2.86 mmol, 94.08% purity) in EtOH (10 mL), NH4Cl (765.13 mg, 14.30 mmol) in H2O (2 mL) was added, followed by the addition of Fe (479.28 mg, 8.58 mmol). The resulting mixture was stirred at 80 °C for 1 hour. LCMS showed that 4-((1-(3-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate was completely consumed and showed the desired mass. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL × 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–80% EtOAc / petroleum ether gradient at 50 mL / min, yielding a yellow solid of tert-butyl 4-((1-(3-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (0.519 g, 1.33 mmol, 46.53% yield, 96.05% purity). MS (M+H) + =375.3.

[0561] Step 3.4-((1-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin Synthesis of tert-butyl 1-azine-carboxylate (6)

[0562] A mixture of tert-butyl 4-((1-(3-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (0.4 g, 1.03 mmol, 96.05% purity), 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 Cs2CO3 (1.00 g, 3.08 mmol) in dioxane (8 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 14 h under N2 atmosphere. LCMS showed that tert-butyl 4-((1-(3-aminophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate was completely consumed and showed the desired mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to rapid silica gel chromatography. 20g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–45% EtOAc / petroleum ether gradient at 50 mL / min, yielding a yellow solid of tert-butyl 4-((1-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (0.519 g, 777.19 μmol, 75.76% yield, 99.41% purity). MS (M+H) + =664.5.

[0563] Step 4.4-((1-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1- Synthesis of tert-butyl formate (7)

[0564] Under a H2 atmosphere, Pd / C (50 mg, 10% purity) was added to a CF3CH2OH (3 mL) solution of tert-butyl piperazine-1-carboxylate (120 mg, 180.76 μmol). The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 16 h under H2 (15 Psi). LCMS showed that tert-butyl piperazine-1-carboxylate was completely consumed and showed a main peak (89%) with the desired mass. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl 4-((1-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (100 mg, 172.98 μmol, 95.69% yield, 84% purity) as a yellow solid. MS (M+H) + =486.5.

[0565] Step 5.3-((3-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione(8) synthesis

[0566] TFA (1.54 g, 13.51 mmol, 1 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (200.00 mg, 411.85 μmol) in DCM (3 mL). The mixture was stirred at 20 °C for 2 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give 3-((3-(4-(piperazin-1-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (0.2 g, 400.38 μmol, 97.22% yield, TFA) as a blue solid. The crude product was used directly in the next step. MS (M+H) + =454.2.

[0567] Step 6. N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-((2,6-dioxopiridine-3-yl)amino) (Phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzyl) Synthesis of amide (compound 25)

[0568] DIPEA (310.48 mg, 2.40 mmol, 418.43 μL) was added to a DMF (3 mL) solution of 2-(4-(4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenyl)acetic acid (246.18 mg, 400.38 μmol, 80% purity) and HATU (228.35 mg, 600.57 μmol). The mixture was stirred at 20 °C for 0.5 h. Then 3-((3-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (0.2 g, 400.38 μmol, TFA) was added, and the resulting mixture was stirred at 20 °C for 16 h. LCMS showed that 3-((3-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione was completely consumed and showed the desired mass. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 12g The sample was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 45%-75%, 8 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(2-(4-((1-(3-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (5 mg, 5.64 μmol, 1.41% yield, 97% purity) as a white solid. MS (M+H) + =859.5.

[0569] 1H NMR (400MHz, DMSO-d6) δ = 10.74 (s, 1H), 9.92 (s, 1H), 9.65 (s, 1H), 9.32 (s, 1H), 8.18 (d, J = 3.5Hz, 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=8.4Hz,2H),6.88(t,J=8.0Hz,1H),6.24(s,1H),6.17(br d,J=7.8Hz,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).

[0570] Example 26. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 26)

[0571]

[0572] Step 1. ((1r,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl Synthesis of tert-butyl cyclohexyl carbamate (3)

[0573] 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)methyl methanesulfonate (208.35 mg, 677.78 μmol), DIPEA (625.70 mg, 4.84 mmol, 843.27 μL), and KI (160.73 mg, 968.26 μmol) in DMF (7 mL) was stirred at 60 °C for 16 hours. LCMS showed a peak of 18% residual 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, and a peak of 72% with the desired mass. Another sample of ((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)methyl methanesulfonate (59.53 mg, 193.65 μmol) was added, and the resulting mixture was stirred at 60 °C for 16 h. LCMS showed that 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was completely consumed, showing a peak with 92% of the desired mass. The mixture was treated with AcOH to adjust the pH to <7 and purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B, for 10 min). The eluent was lyophilized to give a black solid, tert-butyl ((1r,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamate (175 mg, 285.17 μmol, 29.45% yield, TFA salt). MS (M+H) + =500.3.

[0574] Step 2.3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)amino)piperidine- Synthesis of 2,6-dione (4)

[0575] A solution of ((1r,4r)-4-((4-((((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamate tert-butyl ester (130 mg, 211.84 μmol, TFA salt) and TFA (1.54 g, 13.46 mmol, 1 mL) in DCM (4 mL) was stirred at 15 °C for 1 hour. LC-MS showed that the starting material was completely consumed. The mixture was concentrated under vacuum to give a black gel-like substance of 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione (135 mg, 2 TFA salt), which was used directly. MS (M+H) + =400.2.

[0576] Step 3. N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-((2,6-dioxopiperidine-3- (1-yl)amino)phenyl)piperazine-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino) Synthesis of benzamide (compound 26)

[0577] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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 min. Then, 3-((4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-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 h. LCMS revealed trace amounts of 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, with a peak at 60% of the desired mass. The mixture was diluted with H₂O (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 26%-56% B, 9 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (24.0 mg, 15.95 μmol, 8.47% yield, 95% purity, 5TFA salt) as a brown solid. MS (M+H) + =859.2.

[0578] 1H NMR (400MHz, 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=3.7Hz,1H),8.16-7.97(m,6H),7.85-7.79(m,4H),7.65(dd,J=1. 3,7.9Hz,1H),7.57(dd,J=1.3,7.9Hz,1H),7.46-7.36(m,1H),7.35-7.23(m,1H),6.83(br d,J=8.8Hz,2H),6.67(d,J=8.9Hz,2H),4.24(dd,J=4.7,11.2Hz,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),3.0 0-2.86(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).

[0579] Example 27. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1-(((1R,5S,6S)-3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 27)

[0580]

[0581]

[0582] Step 1. (1R,5S,6r)-6-((toluenesulfonyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid Synthesis of tert-butyl ester (2)

[0583] At 25 °C, TosCl (1.34 g, 7.03 mmol) and TEA (948.92 mg, 9.38 mmol, 1.31 mL) were added to a DCM (10 mL) solution of (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1 g, 4.69 mmol) (9.1.0 mL). The mixture was stirred at 25 °C for 12 hours. LCMS showed that the starting material was consumed and the desired mass was observed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The results were obtained by rapid silica gel chromatography (12 g). The residue was purified by silica gel rapid column chromatography (eluting with a 0–20% EtOAc / petroleum ether gradient at 100 mL / min) to give (1R,5S,6r)-6-((toluenesulfonyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (920 mg, 2.50 mmol, 53.40% yield) as a colorless oil. MS (M+H) + =368.1.

[0584] Step 2. (1R,5S,6S)-6-((4-((((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)-3-azabicyclo [3.1.0] Synthesis of tert-butyl hexane-3-carboxylate (3)

[0585] At 20 °C, K₂CO₃ (415.23 mg, 3.00 mmol), benzyl piperidinium-4-carbamate (645.26 mg, 2.75 mmol), and KI (41.56 mg, 250.37 μmol) were added to a DMF (10 mL) solution of (1R,5S,6r)-6-((toluenesulfonyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carbamate (tert-butyl ester) (920 mg, 2.50 mmol) and KI (41.56 mg, 250.37 μmol). The resulting mixture was stirred at 80 °C for 4 hours. LCMS showed a peak of 60% with the desired mass. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum and then subjected to rapid silica gel chromatography (12 g). Purification was performed using a rapid silica gel column, eluing with a gradient of 0–100% EtOAc / petroleum ether to 0–10% MeOH / DCM at 100 mL / min, yielding a yellow oily product (1R,5S,6S)-6-((4-((((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (780 mg, 1.74 mmol, 69.63% yield, 96% purity). MS (M+H) + =430.4.

[0586] Step 3. (1-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)aminomethyl Synthesis of benzyl ester (4)

[0587] At 20°C, HCl / dioxane (4M, 9mL) was added to a solution of (1R,5S,6S)-6-((4-((((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (780 mg, 1.82 mmol) in dioxane (3 mL). The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was completely consumed and showed a peak of 55% with the desired mass. The reaction mixture was concentrated under vacuum to give (1-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperidin-4-yl)carbamate (800 mg, crude, HCl) as a yellow oil. MS (M+H) + =330.2.

[0588] Step 4. (1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperyl Synthesis of pyridin-4-yl)carbamate (6)

[0589] At 20 °C, K₂CO₃ (604.35 mg, 4.37 mmol) and 1-fluoro-4-nitrobenzene (370.20 mg, 2.62 mmol) were added to a DMF (10 mL) solution of (1-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidin-4-yl)carbamate (800 mg, 2.19 mmol, HCl). The mixture was stirred at 50 °C for 16 h. Then another portion of K₂CO₃ (906.52 mg, 6.56 mmol) was added, and the reaction mixture was stirred at 50 °C for 19 h. LCMS showed that the starting material was completely consumed and showed the desired mass. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was then analyzed by rapid silica gel chromatography (12g). Purification was performed using a silica gel rapid column with an eluent of 0–10% MeOH / DCM gradient at 100 mL / min, yielding a yellow solid (1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)carbamate (634 mg, 1.29 mmol, 59.21% yield, 92% purity). MS (M+H) + =451.2.

[0590] Step 5.1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidine Synthesis of pyridine-4-amine (7)

[0591] A TFA (6 mL) solution of (580 mg, 1.29 mmol) of 1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)carbamate was stirred at 40 °C for 5 hours. LC-MS showed a desired mass of 32%. The mixture was concentrated under reduced pressure to give 0.6 g, crude TFA, as a yellow oil. MS (M+H) + =317.1.

[0592] Step 6. (1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperyl Synthesis of tert-butyl 4-pyridyl)carbamate (8)

[0593] To a THF (10 mL) solution of 1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidin-4-amine (0.6 g, 1.39 mmol, TFA), NaOH (1 M, 11.15 mL) and Boc₂O (608.47 mg, 2.79 mmol, 640.49 μL) were added, and the mixture (pH = 8) was stirred at 20 °C for 14 h. NaOH (1 M, 0.7 mL) was added, and the mixture was stirred at 20 °C for 18 h. The mixture was extracted with EtOAc (10 mL × 2), the combined organic layers were washed with water (10 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography (5 g) Purification was performed using a silica gel rapid column with an eluent of 80–100% EtOAc / petroleum ether to a gradient of 10–30% MeOH / EtOAc at 50 mL / min, followed by preparative HPLC purification (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 20%–50% B, for 9 min). The eluent was adjusted to pH 9 with saturated NaHCO3 and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with water (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid, (1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)tert-butyl carbamate (170 mg, 408.15 μmol, 29.28% yield). MS (M+H) + =417.2.

[0594] Step 7. (1-(((1R,5S,6S)-3-(4-aminophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperyl Synthesis of tert-butyl 4-pyridyl)carbamate (9)

[0595] Fe (105.00 mg, 1.88 mmol) was added to a solution of (1-(((1R,5S,6S)-3-(4-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidin-4-yl)carbamate tert-butyl ester (150 mg, 360.13 μmol) and NH4Cl (97.50 mg, 1.82 mmol) in EtOH (7 mL) and H2O (3 mL), and the mixture was stirred at 80 °C for 1 hour. LCMS showed 89% of the desired mass. The mixture was filtered, and the filter cake was washed with EtOH (20 mL) and THF (20 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with EtOAc (10 mL) and water (10 mL), and the mixture was then adjusted to pH 9 with saturated Na2CO3. The mixture was extracted with EtOAc (10 mL × 3), the combined organic layers were washed with water (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a yellow solid of tert-butyl (1-(((1R,5S,6S)-3-(4-aminophenyl)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)carbamate (140 mg, crude). MS (M+H) + =387.3.

[0596] Step 8. (1-(((1R,5S,6S)-3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-azabi Synthesis of cyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)tert-butyl carbamate (10)

[0597] NaHCO3 (79 mg, 940.40 μmol, 36.59 μL) was added to a solution of (1-(((1R,5S,6S)-3-(4-aminophenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidin-4-yl)carbamate tert-butyl ester (120 mg, 310.45 μmol) and 3-bromopiperidin-2,6-dione (90 mg, 468.72 μmol) in MeCN (1.5 mL), and the mixture was stirred at 80 °C for 14 h. LCMS showed 49% of the expected mass. The mixture was concentrated under reduced pressure. The concentration was determined by rapid silica gel chromatography (5 g) The residue was purified by silica gel rapid column chromatography (eluting with a 10% MeOH / DCM gradient at 30 mL / min) to give a yellow solid (1-(((1R,5S,6S)-3-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)carbamate tert-butyl ester (130 mg, 261.24 μmol, 84.15% yield, 100% purity). MS (M+H) + =498.3.

[0598] Step 9.3 -((4-((1R,5S,6S)-6-((4-aminopiperidin-1-yl)methyl)-3-azabicyclo[3.1.0] Synthesis of hex-3-yl)phenyl)amino)piperidine-2,6-dione (11)

[0599] At 0 °C, TFA (460.50 mg, 4.04 mmol, 0.3 mL) was added to a solution of tert-butyl carbamate (130 mg, 261.24 μmol) in DCM (1.3 mL), and the mixture was stirred at 0 °C for 1 hour. LCMS showed 78% of the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-((1R,5S,6s)-6-((4-aminopiperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hex-3-yl)phenyl)amino)piperidin-2,6-dione (140 mg, crude, TFA) as a blue oil. MS(M+H) + =398.4.

[0600] Step 10. N-(2-chlorophenyl)-4-((2-((4-((1-(((1R,5S,6S)-3-(4-((2,6-dioxopiperidine- 3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino Synthesis of 5-fluoropyrimidin-4-ylaminobenzamide (compound 27)

[0601] DIPEA (445.20 mg, 3.44 mmol, 0.6 mL) was added to a DMF (1.5 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (120 mg, 251.11 μmol) and HATU (114.58 mg, 301.33 μmol), and the mixture was stirred at 20 °C for 15 min. Then a DMF (1.5 mL) solution of 3-((4-((1R,5S,6S)-6-((4-aminopiperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hex-3-yl)phenyl)amino)piperidin-2,6-dione (140 mg, 273.69 μmol, TFA) was added, and the mixture was stirred at 20 °C for 1 h. LCMS showed 66% of the expected mass. The mixture was diluted with water (50 mL) and EtOAc (10 mL) and then filtered. The filter cake was washed with water (10 mL) and EtOAc (10 mL). The filter cake was collected and the solvent was removed under reduced pressure to give a crude product (60 mg, 73% purity). The filtrate was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with water (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give another fraction of the crude product (140 mg, 67% purity). The combined crude products were purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, for 9 minutes), and the eluent was lyophilized to obtain the product (90 mg, 91% purity, 3TFA). This product was then purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 27%-57%). B, after several minutes, was further purified and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((1-(((1R,5S,6S)-3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-azabicyclo[3.1.0]hexyl-6-yl)methyl)piperidin-4-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a red solid (13.3 mg, 14.43 μmol, 5.75% yield, 93% purity). MS (M+H) + =857.3.

[0602] 1H NMR(400MHz,DMSO-d6)δ=10.74(br s,1H),9.93(s,1H),9.74(s,1H),9.61(s,1H),8.25(d,J=3.5Hz,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=8.8Hz,2H),6.41(br d,J=8.8Hz,2H),5.10(d,J=7.1Hz,1H),4.16-4.06(m,1H),3.80-3.67(m,1H),3.47(br d,J=8.9Hz,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).

[0603] Example 28. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 28)

[0604]

[0605] Step 1. Synthesis of tert-butyl heptane-2-carboxylate (2)

[0606] NMO (720 mg, 6.15 mmol) was added to a solution of tert-butyl 2-azadicyclo[2.2.1]hept-5-en-2-carboxylate (1 g, 5.12 mmol) and K₂O₄·2H₂O (94 mg, 255.12 μmol) in THF (10 mL) and H₂O (2.5 mL), and the mixture was stirred at 20 °C for 14 h. LCMS showed 58% of the desired mass. The mixture was quenched with saturated NaHSO₃ solution (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and subjected to rapid silica gel chromatography (12 g) The residue was purified by silica gel rapid column chromatography (eluting with a 30% EtOAc / petroleum ether gradient @ 80 mL / min) to give tert-butyl 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (660 mg, 2.88 mmol, 56.21% yield) as a yellow oil. MS (M+H) + =230.2.

[0607] Step 2.2 Synthesis of tert-butyl 4-dicarboxypyrrolidine-1-carboxylate (3)

[0608] NaIO4 (784.00 mg, 3.67 mmol, 203.11 μL) was slowly added to a solution of 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (560 mg, 2.44 mmol) in H2O (2.5 mL) and MeOH (10 mL), and the mixture was stirred at 20 °C for 2 h. LC-MS showed that the starting material was completely consumed. The mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The filtrate was quenched with saturated Na2SO3 solution (20 mL) and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with Na2SO3 solution (10 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum to give 2,4-dicarboxypyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, crude) as a yellow oil. MS (M+H) + =228.2.

[0609] Step 3.3 Synthesis of tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (4)

[0610] A solution of tert-butyl 2,4-dicarboxypyrrolidine-1-carboxylate (510 mg, 2.24 mmol) and BnNH2 (235.92 mg, 2.20 mmol) in MeOH (10 mL) was stirred at 20 °C for 10 min, followed by the addition of NaBH3CN (423.08 mg, 6.73 mmol). The resulting mixture was stirred at 20 °C for 14 h. LCMS showed a peak at 72% of the desired mass. The mixture was concentrated under reduced pressure. The final concentration was determined by rapid silica gel chromatography (5 g / mL). The residue was purified by silica gel rapid column chromatography (eluting with 80–100% EtOAc / petroleum ether gradient @ 50 mL / min) to give tert-butyl 3-benzyl-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (450 mg, 1.49 mmol, 66.31% yield) as a yellow oil. MS (M+H) + =303.3.

[0611] Step 4.3, Synthesis of tert-butyl 6-diazabicyclo[3.2.1]octane-6-carboxylate (5)

[0612] Under a nitrogen atmosphere, Pd / C (50 mg, 10% purity) and Pd(OH)₂ / C (50 mg, 20% purity) were slowly added to a solution of tert-butyl 3-benzyl-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (450 mg, 1.49 mmol) in EtOH (10 mL), and the mixture was stirred at 60 °C for 14 hours under a hydrogen atmosphere (45 Psi). LCMS showed trace amounts of the starting material and the desired mass was detected. The mixture was filtered, and the filter cake was washed with EtOH (20 mL) and THF (20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (330 mg, crude) as a white solid. This crude product was used directly for the next step.

[0613] Step 5.3 Synthesis of (4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (7)

[0614] K₂CO₃ (644.52 mg, 4.66 mmol) was added to a DMF (6 mL) solution of 1-fluoro-4-nitrobenzene (250 mg, 1.77 mmol, 187.97 μL) and 3,6-diazabicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (330 mg, 1.55 mmol), and the mixture was stirred at 40 °C for 14 h. LC-MS showed a peak at 65% of the desired mass. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The filtrate was analyzed by rapid silica gel chromatography (5 g). The residue was purified by silica gel rapid column chromatography (eluting with a 30–50% EtOAc / petroleum ether gradient at 50 mL / min) to give tert-butyl 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (440 mg, 1.32 mmol, 84.90% yield, 100% purity) as a yellow solid. MS (M+Na) + =356.2.

[0615] Step 6. Synthesis of 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane (8)

[0616] A solution of tert-butyl 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (440 mg, 1.32 mmol) in DCM (8 mL) was added with HCl / dioxane (4 M, 8 mL), and the mixture was stirred at 20 °C for 1 hour. LC-MS showed a main peak with the desired mass. The mixture was concentrated under reduced pressure to give 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane (350 mg, crude, HCl) as a yellow solid. MS (M+H) +=234.2.

[0617] Step 7.4-(3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidine-1-carboxylic acid tert-butyl Synthesis of ester (10)

[0618] Add TEA (392.58 mg, 3.88 mmol, 540 μL) to a solution of 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane (350 mg, 1.30 mmol, HCl) in DCM (10 mL) and DMF (4 mL). MS (100 mg) and tert-butyl 4-oxopiperidinium-1-carboxylate (388 mg, 1.95 mmol). After stirring at 20 °C for 30 min, NaBH(OAc)3 (825.05 mg, 3.89 mmol) was added, and the resulting mixture was stirred at 20 °C for 14 h. LCMS showed a main peak with the desired quality. The mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH 9 with saturated Na2CO3 solution, and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The mixture was analyzed by rapid silica gel chromatography (12 g). The residue was purified by silica gel rapid column chromatography (eluting with a 5–30% EtOH / EtOAc gradient at 100 mL / min) to give tert-butyl 4-(3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidine-1-carboxylate (0.5 g, 1.18 mmol, 90.66% yield, 98% purity). MS (M+H) + =417.2.

[0619] Step 8.4-(3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidine-1-carboxylic acid tert-butyl Synthesis of ester (11)

[0620] Under N2 atmosphere, Pd / C (0.1 g, 10% purity) was slowly added to a solution of 0.5 g (1.20 mmol) of 4-(3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidine-1-carboxylic acid tert-butyl ester (EtOH) in 10 mL of EtOH, and the mixture was stirred at 25 °C for 14 h under H2 atmosphere (45 Psi). LCMS showed a peak at 78% of the desired mass. The mixture was filtered, and the filter cake was washed with EtOH (20 mL) and THF (50 mL). The filtrate was concentrated under reduced pressure to give 4-(3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidine-1-carboxylic acid tert-butyl ester (450 mg, crude) as a yellow solid. MS (M+H) + =387.3.

[0621] Step 9.4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1] Synthesis of tert-butyl octyl-6-yl)piperidine-1-carboxylate (13)

[0622] To a solution of tert-butyl 4-(3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidin-1-carboxylate (400 mg, 1.03 mmol) and 3-bromopiperidin-2,6-dione (328.00 mg, 1.71 mmol) in ACN (4 mL), NaHCO3 (304.00 mg, 3.62 mmol) was added, and the mixture was stirred at 80 °C for 14 hours. LCMS showed the desired mass. The mixture was filtered and washed with EtOAc (10 mL) and THF (20 mL). The filtrate was concentrated under reduced pressure. The filtrate was analyzed by rapid silica gel chromatography (5 g). The residue was purified by silica gel rapid column chromatography (eluting with a 20–30% MeOH / EtOAc gradient at 50 mL / min) to give tert-butyl 4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidin-1-carboxylic acid (0.4 g, 803.81 μmol, 77.67% yield, 100% purity) as a yellow solid. MS (M+H) + =498.3.

[0623] Step 10.3-((4-(6-(piperidin-4-yl)-3,6-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)piperidin Synthesis of pyridine-2,6-dione (14)

[0624] TFA (706.10 mg, 6.19 mmol, 460 μL) was added to a solution of tert-butyl piperidine-1-carboxylate (0.2 g, 401.91 μmol) in DCM (2 mL), and the mixture was stirred at 20 °C for 1 hour. LCMS showed the desired mass, and the starting material was consumed. The mixture was concentrated under reduced pressure to give 0.2 g, crude product, TFA, as a blue oil.

[0625] Step 11. N-(2-chlorophenyl)-4-((2-((4-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) [3.2.1]oct-6-yl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzene Synthesis of formamide (compound 28)

[0626] DIPEA (86.55 mg, 669.63 μmol, 116.64 μL) was added to a DMF (3 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (160 mg, 334.82 μmol) and HATU (153 mg, 402.39 μmol), and the mixture was stirred at 20 °C for 15 minutes. Then, a solution of 3-((4-(6-(piperidin-4-yl)-3,6-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)piperidin-2,6-dione (0.2 g, 390.98 μmol, TFA) and DIPEA (445.20 mg, 3.44 mmol, 0.6 mL) in DMF (3 mL) (0 °C) was added, and the mixture was stirred at 20 °C for 14 hours. LCMS showed a peak at 66% of the desired mass. The mixture was diluted with water (10 mL) and then filtered. The filter cake was washed with water (10 mL) and purified by preparative HPLC (column: Phenomenex luna C18150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B, for 10 min). The crude product was diluted with MeCN (3 mL), water (10 mL), and DCM (10 mL). The mixture was adjusted to pH 8 with saturated NaHCO3 solution and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative TLC (SiO2, DCM:MeOH = 10:1). The product was further purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 27%-57% B, 9 min) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (24.6 mg, 26.40 μmol, 50.29% yield, 92% purity). MS (M+H) + =857.4.

[0627] 1H NMR (400MHz, 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=8.2Hz,2H),7.65(d,J=7.6Hz,1H),7.53(d,J=8.3Hz,1H),7.40-7.34(m,1H ),7.33-7.25(m,3H),6.69-6.57(m,4H),5.22(brd,J=7.2Hz,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,6 H),2.43-2.31(m,1H),2.16-2.05(m,1H),1.98-1.75(m,4H),1.52-1.29(m,3H).

[0628] Example 29. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(4-((3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 29)

[0629]

[0630] Step 1.4-((3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidine-1-methyl Synthesis of tert-butyl ester (2)

[0631] At 0 °C, TEA (305.34 mg, 3.02 mmol) was added to a solution of 3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]octane (160 mg, 593.19 μmol, HCl) in DCM (3 mL) and DMF (3 mL). MS (50 mg) was added, followed by the addition of tert-butyl 4-formylpiperidin-1-carboxylate (189 mg, 886.19 μmol). After stirring at 20 °C for 0.5 h, NaBH(OAc)3 (377 mg, 1.78 mmol) was added. The resulting mixture was stirred at 20 °C for 14 h. LCMS showed a main peak with the desired quality. The mixture was filtered and washed with EtOAc (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 Na2CO3 solution. The mixture was then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and then subjected to rapid silica gel chromatography (5 g). Purification was performed using a silica gel rapid column with an eluent of 0–10% EtOH / EtOAc gradient at 50 mL / min, yielding a yellow oily product of tert-butyl 4-((3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidin-1-carboxylate (160 mg, 364.19 μmol, 61.40% yield, 98% purity). MS (M+H) + =431.2.

[0632] Step 2.4-((3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidine-1-methyl Synthesis of tert-butyl ester (3)

[0633] Under a nitrogen atmosphere, a solution of tert-butyl 4-((3-(4-nitrophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidin-1-carboxylate (160 mg, 371.63 μmol) in CF3CH2OH (5 mL) was added to a mixture of Pd / C (50 mg, 10% purity) in CF3CH2OH (5 mL). The mixture was stirred at 25 °C for 14 hours under a nitrogen atmosphere (45 Psi). LC-MS showed the desired mass. The mixture was filtered and washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-((3-(4-aminophenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidin-1-carboxylate (140 mg, crude) as a yellow solid. MS (M+H) + =401.4.

[0634] Step 3.4-((3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1] Synthesis of tert-butyl octyl-6-yl)methyl)piperidine-1-carboxylate (4)

[0635] NaHCO3 (88.08 mg, 1.05 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (140 mg, 349.51 μmol) and 3-bromopiperidine-2,6-dione (101 mg, 526.01 μmol) in ACN (1.4 mL), and the mixture was stirred at 80 °C for 14 h. LCMS showed a peak at 50% of the desired mass. The mixture was filtered and the filtrate was concentrated under reduced pressure. The filtrate was analyzed by rapid silica gel chromatography (5 g / mL). The crude product was purified by silica gel rapid column chromatography (eluting with a 10–20% MeOH / EtOAc gradient at 50 mL / min) to give tert-butyl 4-((3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidin-1-carboxylic acid (160 mg, 287.69 μmol, 82.31% yield, 92% purity) as a gray solid. MS (M+H) + =512.4.

[0636] Step 4.3-((4-(6-(piperidin-4-ylmethyl)-3,6-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino Synthesis of 2,6-piperidine-2,6-dione (5)

[0637] TFA (614.00 mg, 5.39 mmol, 0.4 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (160 mg, 312.71 μmol) in DCM (1.5 mL), and the mixture was stirred at 20 °C for 1 hour. LC-MS showed a main peak with the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-(6-(piperidin-4-ylmethyl)-3,6-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)piperidine-2,6-dione (170 mg, crude, TFA) as a blue oil. MS (M+H) + =412.2.

[0638] Step 5. N-(2-chlorophenyl)-4-((2-((4-(4-((3-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) [3.2.1]oct-6-yl)methyl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino Synthesis of Benzamide (Compound 29)

[0639] DIPEA (445.20 mg, 3.44 mmol, 0.6 mL) was added to a DMF (2 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (150 mg, 313.89 μmol) and HATU (143.22 mg, 376.67 μmol), and the mixture was stirred at 20 °C for 15 min. Then, a DMF (2 mL) solution of 3-((4-(6-(piperidin-4-ylmethyl)-3,6-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)piperidin-2,6-dione (170 mg, 323.46 μmol, TFA) was added at 0 °C, and the mixture was stirred at 20 °C for 2 h. LCMS showed the desired mass. The mixture was diluted with water (10 mL) and then filtered. Wash the filter cake with water (5 mL). Purify the filter cake by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B, for 10 min), and freeze-dry the eluent. Dilute the product with water (5 mL) and THF (10 mL), and then adjust the pH of the mixture to 7 with saturated NaHCO3. Extract the mixture with THF / DCM = 1 / 1 (10 mL × 2), and concentrate the combined organic layers under reduced pressure. Dilute the product with EtOAc / MeOH = 20 / 1 (2 mL), and stir the mixture at 20 °C for 0.5 h. Filter the mixture, and wash the filter cake with EtOAc / MeOH = 20 / 1 (10 mL) and water (5 mL). The filter cake was further purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B, for several minutes) and lyophilized to obtain N-(2-chlorophenyl)-4-((2-((4-(4-((3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,6-diazabicyclo[3.2.1]oct-6-yl)methyl)piperidin-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (18.7 mg, 19.53 μmol, 6.22% yield, 91% purity). MS (M+H) + =871.4.

[0640] 1H NMR(400MHz,DMSO-d6)δ=10.74(br s,1H),9.92(s,1H),9.72(s,1H),9.55(s,1H),8.22(d,J=3.5Hz,1H),8.03-7.96(m,4H),7.74(d,J=8.5Hz,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=7.1Hz,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),2.48-2.4 2(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).

[0641] Example 30. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(1-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-6-azaspiro[2.5]octane-6-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 30)

[0642]

[0643] Step 1. Synthesis of tert-butyl 1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (2)

[0644] At 0 °C, BH3-Me2S (10 M, 1.57 mL) was added to a THF (40 mL) solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (2 g, 7.83 mmol). The mixture was stirred at 20 °C for 16 h. TLC (petroleum ether:EtOAc = 10:1) indicated that 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid was completely consumed and a new spot was formed. The reaction mixture was quenched by adding MeOH (20 mL) at 20 °C and stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give a residue, which was subjected to rapid silica gel chromatography (20 g) (20 g). Purification was performed using a silica gel fast column with an eluent of 0–40% EtOAc / petroleum ether gradient at 40 mL / min to obtain tert-butyl 1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (1.8 g, 7.46 mmol, 95.22% yield) as a colorless oil.

[0645] 1 H NMR (400MHz, DMSO-d6) δ = 4.41 (t, J = 5.1Hz, 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).

[0646] Step 2.1 Synthesis of tert-butyl 6-formyl-6-azaspiro[2.5]octane-6-carboxylate (3)

[0647] DMP (1.37 g, 3.23 mmol, 1.00 mL) was added to a DCM (25 mL) solution of 1-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (600 mg, 2.49 mmol), and the mixture was stirred at 20 °C for 2 hours. TLC (petroleum ether:EtOAc = 1:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was diluted with Na2SO3 solution (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with NaHCO3 solution (10 mL × 3) and brine (10 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum to give 1-formyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (600 mg) as a colorless oil.

[0648] 1 H NMR (400MHz, CDCl3-d) δ = 9.56 (br d,J=3.5Hz,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=4.7,7.9Hz,1H).

[0649] Step 3. 1-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-6-nitrogen Synthesis of tert-butyl spiro[2.5]octane-6-carboxylate (5)

[0650] 1-Formyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (450 mg, 1.88 mmol), 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (488.61 mg, 1.50 mmol, HCl salt), A mixture of MS (0.2 g, 1.88 mmol) and TEA (761.11 mg, 7.52 mmol, 1.05 mL) in DCM (20 mL) was stirred at 15 °C for 0.5 h, followed by the addition of NaBH(OAc)3 (1.59 g, 7.52 mmol). The resulting mixture was stirred at 15 °C for 12 h. LCMS showed complete consumption of the starting material and a peak at 34% of the desired mass. The mixture was diluted with H2O (50 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The final product was obtained by rapid silica gel chromatography (20 g). The residue was purified using a silica gel fast column with an eluent of 10–20% EtOAc / petroleum ether gradient at 100 mL / min. Further purification of the residue by preparative TLC (SiO2, DCM:MeOH = 5:1) yielded a black solid, tert-butyl 1-((4-(4-((2,6-dioxopiridin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-6-azaspiro[2.5]octane-6-carboxylate (295 mg, 576.56 μmol, 30.66% yield). MS (M+H) + =512.3.

[0651] Step 4.3 -((4-(4-((6-azaspiro[2.5]oct-1-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine- Synthesis of 2,6-dione (6)

[0652] A mixture of 1-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (160 mg, 312.71 μmol) and TFA (2.63 g, 23.08 mmol, 1.71 mL) in DCM (5 mL) was stirred at 15 °C for 1 hour. LCMS showed that the starting material was completely consumed and showed the desired mass. The mixture was concentrated under vacuum to give 3-((4-(4-((6-azaspiro[2.5]oct-1-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione (200 mg, 2 TFA salt) as a dark blue gel, which was used directly. MS (M+H) + =412.2.

[0653] Step 5. N-(2-chlorophenyl)-4-((2-((4-(1-((4-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) (2,5)piperazine-1-yl)methyl)-6-azaspiro[2,5]octane-6-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzene Synthesis of formamide (compound 30)

[0654] A mixture of 4-((4-((4-(((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-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) in DMF (2 mL) was stirred at 15 °C for 15 min, and then 3-((4-(((6-azaspiro[2.5]oct-1-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione (200 mg, 312.70 μmol, 2TFA salt) was added. The resulting mixture was stirred at 15 °C for 1 h. LCMS showed that 3-((4-(4-((6-azaspiro[2.5]oct-1-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione was completely consumed and showed a peak at 43% of the desired mass. The mixture was treated with TFA to adjust to pH < 7 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, for 10 min). Impurities were added to the mixture (EtOAc:THF:ACN = 4:1:1, 80 mL) and treated with NaHCO3 solution (10 mL). The organic phase was separated and concentrated under vacuum. The residue was further purified by preparative TLC (SiO2, DCM:MeOH = 8:1) to give N-(2-chlorophenyl)-4-((2-((4-(1-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-6-azaspiro[2.5]octane-6-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a gray solid (48.4 mg, 53.10 μmol, 16.92% yield, 95.6% purity). MS (M+H) + =871.3.

[0655] 1H NMR (400MHz, DMSO-d6) δ=10.76(s,1H),9.93(s,1H),9.73(s,1H),9.56(s,1H),8.23(d,J=3.5Hz,1H),8.08-7.94(m,4H ),7.74(d,J=8.7Hz,2H),7.69-7.61(m,1H),7.56(dd,J=1.2,7.9Hz,1H),7.44-7.36(m,1H),7.36-7.23(m,3H),6.74(br d,J=8.8Hz,2H),6.60(d,J=8.8Hz,2H),5.37(d,J=7.2Hz,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),1.4 3-1.35(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).

[0656] Example 31. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(6-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 31)

[0657]

[0658] Step 1.6-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-methyl Synthesis of tert-butyl ester (3) 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.37 g, 11.69 mmol), TEA (3.55 g, 35.07 mmol, 4.88 mL), MS (500 mg) and a DCM (33 mL) solution of 4-formylpiperidin-1-carboxylic acid benzyl ester (2.89 g, 11.69 mmol) were stirred at 25 °C for 1 hour. NaBH(OAc)3 (7.43 g, 35.07 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 14 hours. LCMS showed that 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was completely consumed, and the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) at 20 °C and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. This residue was analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel rapid column chromatography with 90% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 6-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-2,6-diazaspiro[3,3]heptane-2-carboxylate (4.35 g, 8.71 mmol, 74.50% yield, 86% purity) as a colorless oil. MS (M+H) + =430.2.

[0659] Step 2. Synthesis of tert-butyl 2-(piperidin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4)

[0660] Under a nitrogen atmosphere, Pd / C (1 g, 10% purity) and Pd(OH)₂ / C (1 g, 20% purity) were added to a THF (30 mL) solution of 6-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.91 g, 5.83 mmol). The suspension was degassed under vacuum and purged several times with H₂. The mixture was stirred at 25 °C for 20 h under a H₂ (15 Psi) atmosphere. LCMS showed that 6-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was completely consumed. The mixture was filtered and washed with THF (200 mL). The filtrate was concentrated under reduced pressure to obtain 1.85 g (crude product) of tert-butyl 6-(piperidin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate, a white solid. MS (M+H) + =296.1.

[0661] Step 3.6-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid Synthesis of tert-butyl ester (6)

[0662] K₂CO₃ (2.22 g, 16.08 mmol) was added to a DMF (9.5 mL) solution of 6-(piperidin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (950 mg, 3.22 mmol) and 1-fluoro-4-nitrobenzene (907.49 mg, 6.43 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed that 6-(piperidin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was completely consumed. The reaction mixture was diluted with H₂O (50 mL) at 20 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel rapid column with 60% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 6-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow solid (915 mg, 2.04 mmol, 63.53% yield, 93% purity). MS (M+H) + =417.2.

[0663] Step 4.6-((1-(4-aminophenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid Synthesis of tert-butyl ester (7)

[0664] To a solution of 6-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (915 mg, 2.04 mmol) in EtOH (30 mL) and H2O (6 mL), NH4Cl (1.09 g, 20.43 mmol) and Fe (570.47 mg, 10.22 mmol) were added. The resulting mixture was stirred at 80 °C for 1 hour. LCMS showed that the starting material was completely consumed. The reaction mixture was diluted with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-[[1-(4-aminophenyl)-4-piperidinyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (820 mg, crude) as a brown solid. MS(M+H) + =387.2.

[0665] Step 5. 6-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,6- Synthesis of diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (9)

[0666] NaHCO3 (201.69 mg, 2.40 mmol, 93.42 μL) was added to a solution of tert-butyl 6-((1-(4-aminophenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (160 mg, 413.94 μmol) and 3-bromopiperidin-2,6-dione (198.70 mg, 1.03 mmol) in ACN (0.8 mL). The mixture was stirred at 80 °C for 5 hours. LCMS showed that the starting material was completely consumed. The reaction mixture was diluted with H2O (20 mL) at 20 °C and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column with 0–20% MeOH / EtOAc eluent at 50 mL / min to yield tert-butyl 6-((1-(4-((2,6-dioxopiridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 261.24 μmol, 63.11% yield) as a black solid. MS (M+H) + =498.4.

[0667] Step 6.3-((4-(4-((2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin Synthesis of pyridine-2,6-dione (10)

[0668] TFA (767.50 mg, 6.73 mmol, 0.5 mL) was added to a solution of tert-butyl 6-((1-(4-((2,6-dioxadiazin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 261.24 μmol) in DCM (1.5 mL). The mixture was stirred at 25 °C for 0.5 h. LCMS showed that the starting material was completely consumed. The mixture was concentrated under reduced pressure to give 3-((4-(4-((2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (133 mg, 260.00 μmol, 99.53% yield, TFA) as a green oil. MS (M+H) + =398.3.

[0669] Step 7. N-(2-chlorophenyl)-4-((2-((4-(6-((1-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) (3.3)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino Synthesis of Benzamide (Compound 31)

[0670] HATU (114.38 mg, 300.81 μmol) and DIPEA (259.19 mg, 2.01 mmol, 349.31 μL) were added to a DMF (1.3 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (115 mg, 240.65 μmol). After stirring at 25 °C for 0.5 h, 3-((4-(4-((2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (129.85 mg, 200.54 μmol, TFA) was added, and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed that 3-((4-(4-((2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione was completely consumed. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 32%-62% B, for several minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(6-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (41 mg, 43.99 μmol, 21.94% yield, 92% purity). MS (M+H) + =857.3.

[0671] 1H NMR (400MHz, 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=3.5Hz,1H),8.10-7.98(m,4H),7.76(d,J=8.7Hz,2H),7.65(d,J=8.2H z,1H),7.61-7.51(m,3H),7.44-7.35(m,1H),7.33-7.25(m,1H),6.73(d,J=8.7Hz,2H),6.59(d,J=8.9Hz,2H),5.36(d,J= 7.3Hz,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).

[0672] Example 32. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 32)

[0673]

[0674] Step 1. Synthesis of tert-butyl nonane-2-carboxylate (2) (piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

[0675] Under a nitrogen atmosphere, Pd / C (232.56 mg, 218.53 μmol, 10% purity) was added to a solution of 7-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (1 g, 2.19 mmol) in CF3CH2OH (10 mL). The resulting mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere (15 Psi). LC-MS showed that the starting material was completely consumed and showed 56% of the desired compound. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1.1 g, crude 7-(piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester as a brown solid. MS (M+H) + =324.2.

[0676] Step 2.7-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid Synthesis of tert-butyl ester (3)

[0677] K₂CO₃ (1.28 g, 9.27 mmol) was added to a DMF (10 mL) solution of 1-fluoro-4-nitrobenzene (436.20 mg, 3.09 mmol, 327.97 μL) and 7-(piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (1 g, 3.09 mmol). The mixture was stirred at 50 °C for 12 h. LCMS showed a peak of 54% for the desired compound. The reaction mixture was diluted with H₂O (50 mL) and extracted with solvent EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column (eluting with a 50% EtOAc / petroleum ether gradient at 75 mL / min) to give tert-butyl 7-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]-2,7-diazaspiro[4,4]nonane-2-carboxylate (617 mg, 1.39 mmol, 44.89% yield, 100% purity) as a yellow solid. MS (M+H) + =445.3.

[0678] Step 3.7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid Synthesis of tert-butyl ester (4)

[0679] Fe (408.26 mg, 7.31 mmol) and NH4Cl (391.05 mg, 7.31 mmol) were added to a solution of 7-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (650 mg, 1.46 mmol) in EtOH (10 mL) and H2O (4 mL). The resulting mixture was stirred at 80 °C for 2 hours. LCMS showed that the starting material was completely consumed and showed a peak at 86% of the desired mass. The mixture was diluted with NaHCO3 solution (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 5%-35% B, for 10 min) to give tert-butyl 7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (317 mg, 711.10 μmol, 48.64% yield, 93% purity) and tert-butyl 7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (163 mg, 314.53 μmol, 21.51% yield, 80% purity). MS (M+H) + =415.4.

[0680] Step 4. 7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,7- Synthesis of diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (6)

[0681] NaHCO3 (180.54 mg, 2.15 mmol) was added to a solution of 3-bromopiperidin-2,6-dione (206.33 mg, 1.07 mmol) and 7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (297 mg, 716.38 μmol) in MeCN (0.2 mL). The mixture was stirred at 80 °C for 4 hours. LCMS showed a peak of 30% of the desired compound. 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, for 10 min) and lyophilized to give 7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (257 mg, 488.89 μmol, 68.24% yield, 100% purity) as a white solid. MS (M+H) + =526.3.

[0682] Step 5.3-((4-(4-((2,7-diazaspiro[4.4]non-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin Synthesis of pyridine-2,6-dione (7)

[0683] HCl / dioxane (4M, 733.33 μL) was added to a solution of tert-butyl 7-((1-(4-((2,6-dioxadiazin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (257 mg, 488.89 μmol) in DCM (5 mL). The mixture was stirred at 25 °C for 3.5 h. LCMS showed 9% of the starting material remaining and a peak of 53% of the desired compound. The reaction mixture was concentrated under reduced pressure to give 245 mg crude 3-((4-((2,7-diazaspiro[4.4]non-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (245 mg, crude, HCl) as a white solid. MS (M+H) + =426.3.

[0684] Step 6. N-(2-chlorophenyl)-4-((2-((4-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) (4.4)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino Synthesis of Benzamide (Compound 32)

[0685] DIPEA (83.92 mg, 649.31 μmol, 113.10 μL) and HATU (98.76 mg, 259.73 μmol) were added to a DMF (1 mL) solution of 3-((4-(((2,7-diazaspiro[4.4]non-2-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (100 mg, 216.44 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (103.43 mg, 216.44 μmol) (1 mL). The mixture was stirred at 25 °C for 2 h. LCMS showed a peak of 51% of the desired compound. The residue was diluted with H2O (20 mL) and extracted with EtOAc solvent (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by preparative HPLC (column: Waters Xbridge C18150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 33%-63% B, for several minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide as a white solid (45.3 mg, 48.96 μmol, 22.62% yield, 95.7% purity). MS (M+H) + =885.4.

[0686] 1H NMR (400MHz, 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=3.2Hz,1H),8.10-7.98(m,4H),7.78-7.72(m,2H),7.65(br d,J=8.2Hz,1H),7.56(d,J=7.9Hz,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),2.2 4-2.06(m,3H),1.91-1.59(m,8H),1.52-1.36(m,1H),1.26-1.08(m,2H).

[0687] Example 33. Synthesis of N-(2-chlorophenyl)-4-[[2-[4-[8-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl]-2,8-diazaspiro[4,5]decane-2-carbonyl]anilino]-5-fluoro-pyrimidin-4-yl]amino]benzamide (compound 33)

[0688]

[0689] Step 1.8-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-2,8-diazaspiro[4,5]decane-2-carboxylic acid tert- Synthesis of Butyl Acetate (3)

[0690] TEA (491.03 mg, 4.85 mmol, 675.42 μL) was added to a DCM (8 mL) solution of 4-formylpiperidin-1-carboxylic acid benzyl ester (400 mg, 1.62 mmol) and 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (388.76 mg, 1.62 mmol) and MS (100 mg). After stirring at 15 °C for 30 min, NaBH(OAc)3 (1.03 g, 4.85 mmol) was added, and the resulting mixture was stirred at 15 °C for 5 h. LCMS showed a main peak (94%) with the desired quality. The reaction mixture was diluted with NH4Cl aqueous solution (20 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The mixture was then analyzed by rapid silica gel chromatography (12 g). The residue was purified by silica gel rapid column chromatography (eluting with 80% EtOAc / petroleum ether gradient @ 60 mL / min) to give tert-butyl 8-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-2,8-diazaspiro[4,5]decane-2-carboxylate (850 mg, 1.37 mmol, 84.68% yield, 95% purity) as a colorless oil. MS (M+H) + =472.3.

[0691] 1 H NMR (400MHz, 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).

[0692] Step 2. Synthesis of tert-butyl 2-(4-piperidinylmethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (4)

[0693] Under a nitrogen atmosphere, tert-butyl 8-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-2,8-diazaspiro[4,5]decane-2-carboxylate (850 mg, 1.80 mmol) in THF (5 mL) was added 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 THF (5 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 30 °C for 16 hours under a H2 (50 Psi) atmosphere. LCMS showed a peak (38%) with the mass of the desired product. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give tert-butyl 8-(4-piperidinylmethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (600 mg, crude), a gray oil, which was used directly in the next step. MS (M+H) + =338.2.

[0694] Step 3.8-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid Synthesis of tert-butyl ester (5)

[0695] To a DMF (10 mL) solution of tert-butyl 8-(4-piperidinylmethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (600 mg, 1.78 mmol), K₂CO₃ (737.10 mg, 5.33 mmol) and 1-fluoro-4-nitrobenzene (250.84 mg, 1.78 mmol, 188.61 μL) were added. The mixture was stirred at 80 °C for 16 h. LC-MS showed a peak (65%) of the desired product mass. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na₂SO₄, filtered, and concentrated. The results were obtained by rapid silica gel chromatography (12 g). The residue was purified by a silica gel rapid column chromatography with an eluent of 0–20% EtOAc / petroleum ether gradient at 60 mL / min to obtain a crude product. This crude product was further purified by grinding with 5 mL of EtOAc and 3 mL of MeCN to give tert-butyl 8-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]-2,8-diazaspiro[4,5]decane-2-carboxylate (250 mg, 501.54 μmol, 28.21% yield, 92% purity) as a yellow solid. MS (M+H) + =459.3.

[0696] Step 4.8-[[1-(4-aminophenyl)-4-piperidinyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid Synthesis of tert-butyl ester (6)

[0697] Fe (91.33 mg, 1.64 mmol) and NH4Cl (145.80 mg, 2.73 mmol) were added to a solution of 8-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (250 mg, 545.15 μmol) in EtOH (3 mL) and H2O (3 mL). The mixture was stirred at 80 °C for 1 h. LCMS showed a main peak with the desired mass. The reaction mixture was filtered through a diatomaceous earth pad and concentrated under reduced pressure. The residue was diluted with water (20 mg) and extracted with EtOAc (20 mL × 3). Solid NaHCO3 (1 g) was added to the aqueous phase and the mixture was extracted with DCM (20 mL × 3). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give tert-butyl 8-[[1-(4-aminophenyl)-4-piperidinyl]methyl]-2,8-diazaspiro[4,5]decane-2-carboxylate (200 mg, 457.29 μmol, 83.88% yield, 98% purity), a brown solid. MS (M+H) + =429.2.

[0698] Step 5.8-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl]-2,8-di Synthesis of tert-butyl 2-carboxylate (7) of azirospiro[4.5]decane-2-carboxylate

[0699] NaHCO3 (141.12 mg, 1.68 mmol) was added to a solution of tert-butyl 8-[[1-(4-aminophenyl)-4-piperidinyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (180 mg, 419.96 μmol) and 3-bromopiperidin-2,6-dione (201.59 mg, 1.05 mmol) in ACN (1 mL). The mixture was stirred at 80 °C for 16 h. LCMS showed a peak (76%, 254 nm) with the mass of the desired product. The reaction mixture was diluted with EtOAc (10 mL) and filtered to give the residue. The residue was washed with water to give crude 8-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl]-2,8-diazaspiro[4,5]decane-2-carboxylic acid tert-butyl ester (110 mg, 195.66 μmol, 46.59% yield, 96% purity) as a black solid. MS (M+H) + =540.3.

[0700] Step 6.3 - [4-[4-(2,8-diazaspiro[4.5]dec-8-ylmethyl)-1-piperidinyl]anilino]piperidine-2, Synthesis of 6-dione (8)

[0701] To a solution of 8-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (110 mg, 203.81 μmol) in 1,4-dioxane (2 mL), HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at 15 °C for 2 hours. LC-MS showed a peak (94%) of the desired product mass. The reaction mixture was concentrated under reduced pressure to give 3-[4-[4-(2,8-diazaspiro[4.5]dec-8-ylmethyl)-1-piperidinyl]anilino]piperidin-2,6-dione (90 mg, 189.05 μmol, 92.76% yield, HCl) as a black solid. MS (M+H) + =440.3.

[0702] Step 7. N-(2-chlorophenyl)-4-[[2-[4-[8-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]benzene] [4,8-diazaspiro[4,5]decane-2-carbonyl]anilino]-5-fluoro-pyrimidin-4-yl]amino] Synthesis of benzamide (compound 33)

[0703] HATU (116.77 mg, 307.10 μmol) and DIPEA (79.38 mg, 614.21 μmol, 106.98 μL) were added to a DMF (1 mL) solution of 3-[4-[4-(2,8-diazaspiro[4.5]dec-8-ylmethyl)-1-piperidinyl]anilino]piperidin-2,6-dione (90 mg, 204.74 μmol) and 4-[[4-[4-[(2-chlorophenyl)carbamoyl]anilino]-5-fluoro-pyrimidin-2-yl]amino]benzoic acid (78.27 mg, 163.79 μmol) (78.27 mg, 163.79 μmol). The resulting mixture was stirred at 15 °C for 16 h. LCMS showed a peak (57%) with the mass of the desired product. The reaction mixture was poured into water (20 mL) and filtered to give a crude product as a solid. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 21%-51% B, for 10 minutes) and then lyophilized. The product was then further purified and lyophilized by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%-58% B, for 10 minutes) to obtain N-(2-chlorophenyl)-4-[[2-[4-[8-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl]-2,8-diazaspiro[4.5]decane-2-carbonyl]anilino]-5-fluoro-pyrimidin-4-yl]amino]benzamide (15.6 mg, 16.13 μmol, 7.88% yield, 93% purity). MS (M+H) + =899.4.

[0704] 1H NMR (400MHz, DMSO-d6) δ = 10.76 (br s, 1H), 9.94 (s, 1H), 9.75 (s, 1H), 9.59 (brd, J = 4.9Hz, 1H), 8.24 (br d, J = 2.0Hz, 1H), 8.10-8.00 (m, 4H), 7.75 (br dd,J=7.3,10.8Hz,2H),7.69-7.62(m,1H),7.57(br d,J=7.9Hz,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).

[0705] Example 34. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(3-((5-(4-((2,6-dioxopiridine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 34)

[0706]

[0707] Step 1. Synthesis of tert-butyl 5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3)

[0708] K₂CO₃ (2.94 g, 21.26 mmol) was added to a DMF (30 mL) solution of 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate (1.65 g, 7.80 mmol). The mixture was stirred at 40 °C for 16 hours. LCMS showed that the starting material was completely consumed and showed a peak with 96% of the desired mass. The reaction mixture was diluted with H₂O (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over Na₂SO₄, and concentrated under vacuum to give tert-butyl 5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.30 g, 6.76 mmol, 95.40% yield, 98% purity), as a yellow solid. MS (M+H) + =334.4.

[0709] Step 2. Synthesis of tert-butyl 5-(4-aminophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (4)

[0710] Fe (1.93 g, 34.50 mmol) and NH4Cl (1.48 g, 27.60 mmol) were added to a solution of tert-butyl 5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.3 g, 6.90 mmol) in EtOH (20 mL) and H2O (20 mL) at 20 °C. The mixture was stirred at 80 °C for 2 hours. LCMS showed that the starting material was completely consumed and showed a peak of 81% with the desired mass. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was diluted with H2O (100 mL) and adjusted to pH 10 with Na2CO3, and then extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain tert-butyl 5-(4-aminophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (2 g, 6.39 mmol, 92.68% yield, 97% purity), a pale yellow solid. MS (M+H) + =304.4.

[0711] Step 3.5-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2 Synthesis of (1H)-tert-butyl formate (6)

[0712] NaHCO3 (1.38 g, 16.48 mmol) was added to a MeCN (10 mL) 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). The mixture was stirred at 80 °C for 16 hours. LCMS showed that the starting material was completely consumed and showed a peak (R) of 58% with the desired mass. t =0.700 min). The reaction mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated under vacuum to obtain a residue, which was subjected to rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column chromatography with an elution buffer of 80% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 5-(4-((2,6-dioxopiridin-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid as a grayish-white solid (658 mg, 1.59 mmol, 48.16% yield). MS (M+H) + =415.2.

[0713] Step 4.3-((4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)amino)piperidine-2,6-dione (7) Synthesis

[0714] At 20 °C, HCl / dioxane (4 M, 10 mL) was added to a solution of tert-butyl 5-(4-(((2,6-dioxadiidine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate (558 mg, 1.35 mmol) in dioxane (2 mL). The mixture was stirred at 20 °C for 1 hour. LC-MS showed that the starting material was completely consumed and showed a peak of 97% with the desired mass. The reaction mixture was concentrated under vacuum to give 3-((4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)amino)piperidine-2,6-dione (473 mg, crude, HCl) as a green solid. MS (M+H) + =315.2.

[0715] Step 5.3-((5-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrole- Synthesis of tert-butyl 2(1H)-methyl)azacyclobutane-1-carboxylate (9)

[0716] TEA (409.26 mg, 4.04 mmol) was added to a DCM (7 mL) solution of 3-((4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)amino)piperidin-2,6-dione (473 mg, 1.35 mmol, HCl). MS (100 mg) and tert-butyl 3-formylazetane-1-carboxylate (249.71 mg, 1.35 mmol) were added. After stirring at 20 °C for 10 min, NaBH(OAc)3 (857.21 mg, 4.04 mmol) was slowly added. The resulting mixture was stirred at 20 °C for 16 h. LCMS showed that the starting material was completely consumed and showed a peak (R) of 67% with the desired mass. t =0.583 min). The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue. The residue was diluted with H2O (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude product. The crude product was analyzed by rapid silica gel chromatography (…). 20g The crude product was purified by rapid silica gel column elution with 50-100% EtOAc / petroleum as eluent, followed by a 0-20% MeOH / DCM gradient elution at 100 mL / min. This crude product was further purified by preparative HPLC (column: Phenomenexluna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 10%-40% B, for 10 min) and lyophilized to obtain a dark purple solid, tert-butyl 3-((5-(4-((2,6-dioxopiridine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-carboxylic acid (340 mg, 563.23 μmol, 41.78% yield, 99% purity, TFA). MS (M+H) + =484.3.

[0717] Step 6.3-((4-(5-(azacyclobutane-3-ylmethyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)benzene Synthesis of (10)amino)piperidine-2,6-dione

[0718] TFA (778.42 mg, 6.83 mmol) was added to a solution of tert-butyl 3-((5-(4-((2,6-dioxopiridine-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-carboxylate (340 mg, 568.92 μmol, TFA) in DCM (3 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed that the starting material was completely consumed and the desired mass (R) was achieved. t =0.150 min). The reaction mixture was concentrated under vacuum to give a blue-black oily substance, 3-((4-(5-(azacyclobutane-3-ylmethyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)amino)piperidin-2,6-dione (250 mg, crude, TFA). MS (M+H) + =384.3.

[0719] Step 7. N-(2-chlorophenyl)-4-((2-((4-(3-((5-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) (I) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)azacyclobutane-1-carbonyl)phenyl)amino)-5-fluoropyrimidine- Synthesis of 4-yl)amino)benzamide (compound 34)

[0720] At 20°C, HATU (171.96 mg, 452.25 μmol) and DIPEA (292.25 mg, 2.26 mmol, 393.87 μL) were added to a DMF (2 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (216.12 mg, 452.25 μmol)). After stirring for 10 minutes, a DMF (2 mL) solution of 3-((4-(5-(azacyclobutane-3-ylmethyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)amino)piperidin-2,6-dione (225 mg, 452.25 μmol, TFA) and DIPEA (667.80 mg, 5.17 mmol) was added at 20°C. The resulting mixture was stirred at 20°C for 1 hour. LCMS showed that the feedstock was completely consumed and the desired mass (R) was achieved. t =0.677 minutes). Dilute the reaction mixture with H2O (20 mL) and EtOAc (30 mL). Filter the mixture. The filter cake was washed with EtOH (20 mL) and concentrated under vacuum to obtain a crude product. This crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B, for 10 minutes) and lyophilized to obtain a purple solid, N-(2-chlorophenyl)-4-((2-((4-(3-((5-(4-((2,6-dioxoperidin-3-yl)amino)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (111.4 mg, 86.46 μmol, 19.12% yield, 92% purity, 3TFA). MS (M+H) + =843.1.

[0721] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.96 (s, 1H), 9.78 (s, 1H), 9.67 (s, 2H), 8.2 5(d,J=3.5Hz,1H),8.05-7.95(m,4H),7.77(d,J=8.7Hz,2H),7.64(d,J=7.7Hz,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).

[0722] Example 35. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(5-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)methyl)octahydropyrrolo[3,4-c]pyrrolo-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 35)

[0723]

[0724] Step 1. Synthesis of (1-(4-nitrophenyl)azacyclobutane-3-yl)methanol (3)

[0725] K₂CO₃ (7.35 g, 53.15 mmol) was added to a DMF (30 mL) solution of 1-fluoro-4-nitrobenzene (2.5 g, 17.72 mmol, 1.88 mL) and aziridine-3-ylmethanol (2.19 g, 17.72 mmol, HCl) at 20 °C. The reaction mixture was stirred at 40 °C for 16 hours. LCMS showed a peak with 79% of the desired mass (R₁₀₅₀₅₂) detected. t =0.621 min). The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum, and then subjected to rapid silica gel chromatography (40 g). Purification was performed using a silica gel rapid column with an eluent of 10-50% EtOAc / petroleum ether gradient at 100 mL / min, yielding a red solid (3.4 g, 16.17 mmol, 91.24% yield, 99% purity) of (1-(4-nitrophenyl)azacyclobutane-3-yl)methanol. MS (M+H) + =209.5.

[0726] Step 2. Synthesis of 4-methylbenzenesulfonic acid (1-(4-nitrophenyl)azacyclobutane-3-yl)methyl ester (4)

[0727] TEA (2.92 g, 28.82 mmol, 4.01 mL) and TosCl (2.75 g, 14.41 mmol) were added to a DCM (20 mL) solution of (1-(4-nitrophenyl)azacyclobutane-3-yl)methanol (2 g, 9.61 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 hours. LCMS showed that the starting material was completely consumed and 87% of the peak with the desired mass (R) was detected. t =0.851 minutes). The reaction mixture was concentrated under vacuum and then subjected to rapid silica gel chromatography (20 g). Purification was performed using a silica gel rapid column chromatography with an eluent of 10–30% EtOAc / petroleum ether gradient at 100 mL / min to give methyl 4-methylbenzenesulfonic acid [1-(4-nitrophenyl)azacyclobutane-3-yl] ester (3.02 g, 8.17 mmol, 85.02% yield, 98% purity) as a yellow solid. MS (M+H) + =363.1.

[0728] Step 3.5-((1-(4-nitrophenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2 Synthesis of (1H)-tert-butyl formate (5)

[0729] At 20 °C, K₂CO₃ (1.60 g, 11.59 mmol) was added to a DMF (20 mL) solution of methyl 4-methylbenzenesulfonic acid (1-(4-nitrophenyl)azacyclobutane-3-yl) methyl ester (1.4 g, 3.86 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate (820.10 mg, 3.86 mmol). The mixture was stirred at 40 °C for 16 h. LCMS showed residual methyl 4-methylbenzenesulfonic acid (1-(4-nitrophenyl)azacyclobutane-3-yl) methyl ester and the desired mass was detected. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum and then subjected to rapid silica gel chromatography (12 g). Purification was performed using a silica gel rapid column with an eluent of 0–40% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 5-((1-(4-nitrophenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (900 mg, 2.24 mmol, 57.88% yield), which appeared as a yellow oil. MS (M+H) + =403.2.

[0730] Step 4.5-((1-(4-aminophenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2 Synthesis of (1H)-tert-butyl formate (6)

[0731] Fe (499.50 mg, 8.94 mmol) and NH4Cl (478.45 mg, 8.94 mmol) were added to a solution of 5-((1-(4-nitrophenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester (900 mg, 2.24 mmol) in EtOH (10 mL) and H2O (10 mL) at 20 °C. The mixture was stirred at 80 °C for 1.5 h. LCMS showed that the starting material was completely consumed and showed a peak of 73% with the desired mass. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was diluted with water (60 mL) and adjusted to pH 10 with saturated Na2CO3, and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to give tert-butyl 2-[[1-(4-aminophenyl)azacyclobutane-3-yl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid (800 mg, 2.15 mmol, 96.04% yield) as a yellow solid. MS (M+H) + =373.4.

[0732] Step 5.5-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)methyl) Synthesis of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (8)

[0733] At 20 °C, NaHCO3 (541.25 mg, 6.44 mmol) was added to a MeCN (3 mL) solution of 5-((1-(4-aminophenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester (800 mg, 2.15 mmol) and 3-bromopiperidin-2,6-dione (288.66 mg, 1.50 mmol). The mixture was stirred at 80 °C for 2 hours. LCMS showed that all starting materials were completely consumed and a peak of 27% with the desired mass was detected. The reaction mixture was filtered and washed with EtOAc:MeOH:THF = 1:2:1 (40 mL). The filtrate was concentrated under vacuum and then subjected to rapid silica gel chromatography (12 g). Purification was performed using a silica gel rapid column with eluents ranging from 30–100% EtOAc / petroleum ether to a gradient of 0–20% MeOH / DCM at 100 mL / min. The crude product was further purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 5%–35% B, for 10 min) and lyophilized to obtain a purple solid of tert-butyl 5-((1-(4-((2,6-dioxopiridin-3-yl)amino)phenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (370 mg, 594.35 μmol, 27.67% yield, 96% purity, TFA). MS (M+H) + =484.3.

[0734] Step 6.3-((4-(3-((hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-yl) Synthesis of phenyl)amino)piperidine-2,6-dione (9)

[0735] At 0 °C, TFA (767.50 mg, 6.73 mmol, 0.5 mL) was added to a solution of tert-butyl 5-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate (0.2 g, 334.66 μmol, TFA) in DCM (1.5 mL), and the mixture was stirred at 0 °C for 1 hour. LC-MS showed 95% of the desired mass. The mixture was concentrated under reduced pressure (0 °C) to give a yellow oil of 3-((4-(3-((hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-yl)phenyl)amino)piperidin-2,6-dione (170 mg, crude, TFA). MS (M+H) + =384.3.

[0736] Step 7. N-(2-chlorophenyl)-4-((2-((4-(5-((1-(4-((2,6-dioxopiperidin-3-yl)amino)benzene) (3-yl) aziridine-3-yl) methyl) octahydropyrrolo[3,4-c]pyrrolo-2-carbonyl) phenyl) amino)-5-fluoropyrimidine-4- Synthesis of (amino)benzamide (compound 35)

[0737] DIPEA (432.73 mg, 3.35 mmol, 583.19 μL) was added to a DMF (1.5 mL) solution of 4-((4-((((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (160 mg, 334.82 μmol) and HATU (153 mg, 402.39 μmol), and the mixture was stirred at 20 °C for 15 min. Then, a DMF (1.5 mL) solution of 3-((4-(3-((hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)azacyclobutane-1-yl)phenyl)amino)piperidin-2,6-dione (170 mg, 341.70 μmol, TFA) was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. LCMS showed 58% of the desired mass. The mixture was diluted with water (50 mL) and then filtered. The filter cake was washed with water (30 mL). The filter cake was collected and the solvent was removed under reduced pressure, and then purified by preparative TLC (DCM:MeOH = 7:1). The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 18%-48% B, 9 min) and lyophilized to obtain N-(2-chlorophenyl)-4-((2-((4-(5-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)methyl)octahydropyrrolo[3,4-c]pyrrolo-2-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (64.5 mg, 47.15 μmol, 56.49% yield, 95% purity, 4TFA). MS (M+H) + =843.3.

[0738] 1H NMR(400MHz, 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=3.5Hz,1H),8.05 -7.98(m,4H),7.76(d,J=8.7Hz,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).

[0739] Example 36. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 36)

[0740]

[0741] Step 1. Synthesis of tert-butyl 6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-formate (2)

[0742] DIPEA (3.12 g, 24.16 mmol, 4.21 mL) was added to a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-formate (2 g, 8.05 mmol) in DCM (30 mL) at 20 °C, followed by dropwise addition of Cb2Cl (1.65 g, 9.66 mmol, 1.38 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 16 hours. LCMS showed that the starting material was completely consumed and a peak with 82% of the desired mass was detected. The reaction mixture was concentrated under vacuum to give the residue. This residue was analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–20% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 7.84 mmol, 97.39% yield) as a colorless oil. MS (M+H) + =383.4.

[0743] Step 2. Synthesis of (1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (3)

[0744] A solution of tert-butyl 6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 7.84 mmol) in HCl / dioxane (4 M, 30 mL) was stirred at 20 °C for 1 hour. LC-MS showed that the starting material was completely consumed and a peak with the desired mass (R) was detected at 68%. t =0.667 min). The reaction mixture was concentrated under vacuum to give benzyl (1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate as a white solid (2.5 g, 5.33 mmol, 67.98% yield, 68% purity, HCl). MS (M+H) + =283.2.

[0745] Step 3.3-(6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azacyclobutane-1- Synthesis of tert-butyl formate (4)

[0746] At 20°C, TEA (2.29 g, 22.58 mmol, 3.14 mL) was added to a DCM (40 mL) solution of (1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (2.4 g, 7.53 mmol, HCl). MS (200 mg) and tert-butyl 3-oxoazacyclobutane-1-carboxylate (1.42 g, 8.28 mmol) were added. After stirring for 20 min, NaBH(OAc)3 (4.79 g, 22.58 mmol) was slowly added at 20 °C. The mixture was stirred at 20 °C for 16 h. LCMS showed a peak of 8% residual (1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate and detected 62% of the peak with the expected mass (R). t =0.796 min). The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue. The residue was diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with NaHCO3 (30 mL × 3), dried over Na2SO4, and concentrated under vacuum to obtain a crude product, which was subjected to rapid silica gel chromatography (…). 40g Purification was performed using a silica gel rapid column chromatography with an eluent of 0–40% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azacyclobutane-1-carboxylate (2.7 g, 6.17 mmol, 81.97% yield) as a white solid. MS (M+H) + =438.3.

[0747] Step 4. (2-(azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (5) synthesis

[0748] TFA (8.44 g, 74.05 mmol, 5.50 mL) was added to a solution of 20 mL of DCM (2.7 g, 6.17 mmol) of 3-(6-((benzyloxy)carbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azacyclobutane-1-carboxylate at 20 °C. The mixture was stirred at 20 °C for 2 hours. LC-MS showed that the starting material was completely consumed and a peak with 93% of the desired mass was detected. The reaction mixture was concentrated under vacuum to give benzyl (2.6 g, crude, TFA) as a white solid. MS (M+H) + =338.2.

[0749] Step 5. (2-(1-(4-nitrophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino Synthesis of benzyl formate (6)

[0750] At 20 °C, K₂CO₃ (4.78 g, 34.56 mmol) was added to a DMSO (40 mL) solution of (2-(azacyclobutan-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). The mixture was stirred at 40 °C for 16 h. LCMS showed 11% residue of (2-(azacyclobutan-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate, and a peak with 87% of the desired mass was detected. The reaction mixture was diluted with H₂O (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over Na₂SO₄, and concentrated under vacuum to give the residue. The residue was detected by rapid silica gel chromatography (…). 20g Purification was performed using a rapid silica gel column with an eluent of 0–50% EtOAc / petroleum ether gradient at 200 mL / min, yielding a yellow solid (2.3 g, 5.02 mmol, 87.10% yield) of (2-(1-(4-nitrophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate. MS (M+H) + =459.3.

[0751] Step 6. (2-(1-(4-aminophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino Synthesis of benzyl formate (7)

[0752] At 20 °C, Fe (1.40 g, 25.08 mmol) and NH₄Cl (1.07 g, 20.07 mmol) were added to a solution of (2-(1-(4-nitrophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (2.3 g, 5.02 mmol) in EtOH (20 mL) and H₂O (20 mL). The mixture was stirred at 80 °C for 3 hours. LCMS showed that (2-(1-(4-nitrophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate was completely consumed, and a peak with 94% of the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the residue. The residue was diluted with H₂O (60 mL) and adjusted to pH 10 with Na₂CO₃, then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to give a yellow solid of (2-(1-(4-aminophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (820 mg, 1.84 mmol, 84.23% yield, 96% purity). MS (M+H) + =429.2.

[0753] Step 7. (2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)-1,2, Synthesis of 3,4-tetrahydroisoquinoline-6-yl)carbamate (8)

[0754] At 20 °C, NaHCO3 (372.47 mg, 4.43 mmol, 172.52 μL) was added to a solution of (2-(1-(4-aminophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (380 mg, 886.76 μmol) and 3-bromopiperidin-2,6-dione (119.19 mg, 620.73 μmol) in ACN (2.5 mL). The mixture was stirred at 80 °C for 16 hours. LCMS showed 24% residual (2-(1-(4-aminophenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate, and a peak of 38% with the desired mass was detected. The reaction mixture was filtered. The filter cake was washed with a mixed solution (40 mL, EtOAc:MeOH:DCM = 1:1.5:1.5), and the filtrate was concentrated under vacuum to obtain a crude product. This crude product was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) and concentrated under vacuum to obtain product A (125 mg), with a purity of 55% (by LCMS). Product A was combined with another batch (72 mg) for further purification. The mixture was further purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 21%-51% B, 9 min) and lyophilized to give a purple solid of (2-(1-(4-((2,6-dioxoperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamate (130 mg, 226.45 μmol, 25.54% yield, 94% purity, TFA). MS (M+H) + =540.3.

[0755] Step 8.3-((4-(3-(6-amino-3,4-dihydroisoquinoline-2(1H)-yl)azacyclobutane-1-yl)phenyl) Synthesis of (amino)piperidine-2,6-dione (9)

[0756] The mixture of (2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-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 h. LCMS showed that the starting material was completely consumed and the desired mass (R) was detected. t=0.110 min). The reaction mixture was concentrated under vacuum to give 3-((4-(3-(6-amino-3,4-dihydroisoquinoline-2(1H)-yl)azacyclobutane-1-yl)phenyl)amino)piperidin-2,6-dione (120 mg, crude, TFA) as a dark green solid. MS (M+H) + =406.3.

[0757] Step 9. N-(2-chlorophenyl)-4-((2-((4-((2-(1-(4-((2,6-dioxopiperidin-3-yl)amino) (phenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidine- Synthesis of 4-yl)amino)benzamide (compound 36)

[0758] At 20°C, HATU (73.19 mg, 192.49 μmol) and DIPEA (74.63 mg, 577.46 μmol) were added to a DMF (0.5 mL) solution of 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (73.59 mg, 153.99 μmol). After stirring for 10 minutes, a solution of 3-((4-(3-(6-amino-3,4-dihydroisoquinoline-2(1H)-yl)azacyclobutane-1-yl)phenyl)amino)piperidin-2,6-dione (100 mg, 192.49 μmol, TFA) in DMF (0.5 mL) was added with DIPEA (298.53 mg, 2.31 mmol, 402.33 μL). The reaction mixture was stirred at 20°C for 1 hour. LCMS showed a peak of 1% residual 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid, and 73% of the peaks with the expected mass (R) were detected. t =0.802 minutes). Dilute the reaction mixture with H2O (5 mL) and EtOAc (5 mL). Filter the mixture. Wash the filter cake with EtOAc (8 mL) and concentrate under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 26%-56% B, for 10 minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-((2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azacyclobutane-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (37 mg, 27.16 μmol, 14.11% yield, 97% purity, 4TFA). MS (M+H) + =865.1.

[0759] 1 H NMR(400MHz, 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=3.5Hz,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=1.3,7.9Hz,1H),7.39 (dt,J=1.3,7.7Hz,1H),7.33-7.27(m,1H),7.18(d,J=8.9Hz,1H),6.70(br d,J=8.7Hz,2H),6.42(br d,J=8.4Hz,2H),4.64-4.44(m,1H),4.41-4.26(m,2H),4.21(br dd,J=4.4,11.0Hz,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).

[0760] Example 37. Synthesis of N-(2-chlorophenyl)-4-((2-((4-((1R,5S,6S)-6-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 37)

[0761]

[0762] Step 1. (1R,5S,6r)-6-((toluenesulfonyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid Synthesis of tert-butyl ester (2)

[0763] TosCl (670.43 mg, 3.52 mmol) and TEA (474.46 mg, 4.69 mmol) were added to a solution of (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g, 2.34 mmol) in DCM (8 mL). The mixture was stirred at 25 °C for 12 hours. TLC (petroleum ether:EtOAc = 3:1) showed 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 × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was then analyzed by rapid silica gel chromatography (…). 20g The residue was purified by a silica gel fast column chromatography with 0–30% petroleum ether / EtOAc gradient at 80 mL / min to give (1R,5S,6r)-6-((toluenesulfonyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (250 mg, 391.88 μmol, 16.72% yield, 57.6% purity) as a yellow oil. MS (Mt-Bu+H) + =312.1.

[0764] Step 2. (1R,5S,6S)-6-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl) Synthesis of tert-butyl methyl hexane-3-carboxylate (3)

[0765] To a solution of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (260 mg, 701.22 μmol, HCl) and (1R,5S,6r)-6-((toluenesulfonyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (257.67 mg, 701.22 μmol) in ACN (5 mL), KI (11.64 mg, 70.12 μmol) and DIPEA (181.25 mg, 1.40 mmol) were added. The mixture was stirred at 45 °C for 12 h. LCMS showed detection of 10% of the desired compound. The residue was diluted with H2O (20 mL) and extracted with solvent EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was detected by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column with an eluent of 0–50% EtOAc / petroleum ether gradient at 80 mL / min, yielding (1R,5S,6S)-6-((4-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester as a white solid (45 mg, 82.82 μmol, 11.81% yield, 89% purity). MS (M+H) + =484.2.

[0766] Step 3.3-((4-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperazin-1-yl) Synthesis of phenyl)amino)piperidine-2,6-dione (4)

[0767] To a solution of (1R,5S,6s)-6-((4-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (45 mg, 93.05 μmol) in dioxane (6 mL), HCl / dioxane (4 M, 46.53 μL) was added. The mixture was stirred at 20 °C for 5 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a purple solid of 3-((4-(4-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione (73 mg, crude, HCl). MS (M+H) + =384.3.

[0768] Step 4. N-(2-chlorophenyl)-4-((2-((4-((1R,5S,6S)-6-((4-(4-((2,6-dioxopiperidine-3- [3.1.0]hexane-3-carbonyl)phenyl)piperazine-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)phenyl)amino)-5-fluoropyrimidine Synthesis of pyridine-4-yl)amino)benzamide (compound 37)

[0769] HATU (73.88 mg, 194.31 μmol) and DIPEA (62.78 mg, 485.78 μmol, 84.61 μL) were added to a DMF (2 mL) solution of 3-((4-((((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione (68 mg, 161.93 μmol, HCl) and 4-((4-((4-((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (77.38 mg, 161.93 μmol) to be added. The mixture was stirred at 25 °C for 12 h. LCMS showed a peak of 26% of the desired compound. The residue was diluted with H2O (3 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 12%-42% B, for 10 min) and lyophilized to obtain N-(2-chlorophenyl)-4-[[2-[4-[(1R,5S)-6-[[4-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]piperazin-1-yl]methyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]anilino]-5-fluoro-pyrimidin-4-yl]amino]benzamide (10 mg, 11.25 μmol, 6.95% yield, 94.9% purity). MS (M+H) + =843.4.

[0770] 1H NMR (400MHz, 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=3.5Hz,1H),8.17(s,1H),8.10-7.95(m,4H),7.74(br d,J=8.6Hz,2H),7.65(d,J=8.4Hz,1H),7.56(d,J=7.7Hz,1H),7.45-7.38(m,3H),7.32-7.26(m,1H),6.72(br d,J=8.8Hz,2H),6.59(br d,J=8.7Hz,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).

[0771] Example 38. Synthesis of N-(2-chlorophenyl)-4-[[2-[4-[[4-[[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]carbamoyl]aniline]-5-fluoro-pyrimidin-4-yl]amino]benzamide (compound 38)

[0772]

[0773] Step 1. Synthesis of N-methyl-N-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]tert-butyl carbamate (3)

[0774] At 20 °C, K₂CO₃ (1.82 g, 13.14 mmol) was added to a DMF (15 mL) solution of N-methyl-N-(4-piperidinylmethyl)carbamate (1.5 g, 6.57 mmol) and 1-fluoro-4-nitrobenzene (926.95 mg, 6.57 mmol). The mixture was stirred at 80 °C for 16 hours. LC-MS showed a peak (84%) of the desired product mass. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over Na₂SO₄, and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (20 g). Purification was performed using a silica gel rapid column chromatography with an eluent of 0–30% EtOAc / petroleum ether gradient at 80 mL / min to give N-methyl-N-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]tert-butyl carbamate (2.15 g, 6.03 mmol, 91.79% yield, 98% purity) as a pale yellow solid. MS (M+H) + =350.2.

[0775] Step 2. Synthesis of N-methyl-1-[1-(4-nitrophenyl)-4-piperidinyl]methylamine (4)

[0776] To a solution of N-methyl-N-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]carbamate tert-butyl ester (1 g, 2.86 mmol) in dioxane (4 mL), HCl / dioxane (4 M, 4 mL) was added. The mixture was stirred at 20 °C for 1 hour. LC-MS showed a peak (97%) of the desired product mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was ground with 20 mL of EtOAc to give N-methyl-1-[1-(4-nitrophenyl)-4-piperidinyl]methylamine (700 mg, 2.81 mmol, 98.11% yield, 100% purity) as a pale yellow solid. MS (M+H) + =250.2.

[0777] Step 3. N-[4-[[methyl-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]amino]methyl]cyclohexyl]amino Synthesis of tert-butyl carbamate (6)

[0778] At 20 °C, DIPEA (1.81 g, 14.00 mmol, 2.44 mL) and NaI (104.90 mg, 699.87 μmol) were added to a DMF (15 mL) solution of N-methyl-1-[1-(4-nitrophenyl)-4-piperidinyl]methylamine (1 g, 3.50 mmol, HCl) and [4-(tert-butoxycarbonylamino)cyclohexyl]methylmethanesulfonate (2.15 g, 7.00 mmol) (2.15 g, 7.00 mmol). The mixture was stirred at 80 °C for 16 h. LCMS showed a peak (26%) with the mass of the desired product 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 h. LCMS showed a peak (53%, 254 nm) with the mass of the desired product. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid silica gel chromatography (12 g). The residue was purified by a silica gel rapid column chromatography with an eluent of 0–20% MeOH / EtOAc gradient at 60 mL / min to give N-[4-[[methyl-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]amino]methyl]cyclohexyl]tert-butyl carbamate (1.4 g, 3.04 mmol, 86.86% yield, 100% purity) as a yellow oil. MS (M+H) + =461.3.

[0779] Step 4. N-[4-[[[1-(4-aminophenyl)-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]amino Synthesis of tert-butyl formate (7)

[0780] Fe (509.22 mg, 9.12 mmol) and NH4Cl (812.92 mg, 15.20 mmol) were added to a solution of N-[4-[[methyl-[[1-(4-nitrophenyl)-4-piperidinyl]methyl]amino]methyl]cyclohexyl]tert-butyl carbamate (1.4 g, 3.04 mmol) in EtOH (10 mL) and H2O (10 mL). The mixture was stirred at 80 °C for 16 h. LCMS showed a peak (82%) of the desired product mass. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with an aqueous solution of Na2CO3 (20 mL) and extracted with DCM (10 mL × 3). The combined organic phases were concentrated under reduced pressure. The residue was ground with 15 ml of MeCN and 2 ml of EtOAc to give N-[4-[[[1-(4-aminophenyl)-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]tert-butyl carbamate as a brown solid (200 mg, 464.44 μmol, 15.28% yield, 100% purity). MS (M+H) + =431.3.

[0781] Step 5. ((1r,4r)-4-((((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl) Synthesis of tert-butyl methyl (methyl)amino)methyl)cyclohexyl)carbamate (9)

[0782] NaHCO3 (156.06 mg, 1.86 mmol) was added to a MeCN (1 mL) solution of N-[4-[[[1-(4-aminophenyl)-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]carbamate tert-butyl ester (200 mg, 464.44 μmol) and 3-bromopiperidin-2,6-dione (222.94 mg, 1.16 mmol). The mixture was stirred at 80 °C for 16 h. LCMS showed a peak (19%) with the mass of the desired product. The reaction mixture was diluted with water (10 mL) and filtered. The filter cake was collected and dried to give N-[4-[[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]tert-butyl carbamate as a black solid (150 mg, 276.89 μmol, 59.62% yield, 100% purity). MS (M+H) + =542.4.

[0783] Step 6.3 - [4-[4-[[(4-aminocyclohexyl)methyl-methyl-amino]methyl]-1-piperidinyl]aniline]piperidinyl Synthesis of pyridine-2,6-dione (10)

[0784] To a solution of N-[4-[[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]tert-butyl carbamate (150 mg, 276.89 μmol) in dioxane (1 mL), HCl / dioxane (4 M, 1 mL) was added. The mixture was stirred at 15 °C for 1 hour. LC-MS showed a peak (80%) of the desired product mass. The reaction mixture was concentrated under reduced pressure to give a blue solid of 3-[4-[4-[[(4-aminocyclohexyl)methyl-methyl-amino]methyl]-1-piperidinyl]anilino]piperidin-2,6-dione (130 mg, 271.93 μmol, 98.21% yield, HCl). MS (M+H) + =442.3.

[0785] Step 7. N-(2-chlorophenyl)-4-[[2-[4-[[4-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]benzene] [4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]carbamoyl]aniline]-5-fluoro-pyrimidin-4-yl]amino Synthesis of

[38] benzamide (compound 38)

[0786] HATU (131.23 mg, 345.14 μmol) and DIPEA (89.21 mg, 690.28 μmol) were added to a DMF (2 mL) solution of 3-[4-[4-[[(4-aminocyclohexyl)methyl-methyl-amino]methyl]-1-piperidinyl]anilino]piperidin-2,6-dione (110 mg, 230.09 μmol, HCl) and 4-[[4-[4-[(2-chlorophenyl)carbamoyl]anilino]-5-fluoro-pyrimidin-2-yl]amino]benzoic acid (109.96 mg, 230.09 μmol) (109.96 mg, 230.09 μmol). The mixture was stirred at 15 °C for 16 h. LCMS showed a peak (48%) with the mass of the desired product. The reaction mixture was diluted with EtOAc (20 mL) and filtered. The filter cake was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, for 10 minutes) and further purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 45%-75% B, for 10 minutes). The fractions were freeze-dried to give N-(2-chlorophenyl)-4-[[2-[4-[[4-[[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl-methyl-amino]methyl]cyclohexyl]carbamoyl]aniline]-5-fluoro-pyrimidin-4-yl]amino]benzamide as a white solid (6.6 mg, 7.17 μmol, 3.12% yield, 98% purity). MS (M+H) + =901.5.

[0787] 1H NMR (400MHz, DMSO-d6) δ = 10.77 (s, 1H), 9.94 (s, 1H), 9.75 (s, 1H), 9.61 (s, 1H), 8.25 (d, J = 3.4Hz, 1H), 8.07-7.93 (m, 5H),7.80-7.75(m,4H),7.70-7.62(m,1H),7.57(dd,J=1.2,7.8Hz,1H),7.43-7.35(m,1H),7.34-7.25(m,1H),6.75(d ,J=8.9Hz,2H),6.60(d,J=8.7Hz,2H),5.36(d,J=7.2Hz,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).

[0788] Example 39. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-((2,6-dioxopiridine-3-yl)amino)phenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 39)

[0789]

[0790] Step 1. Synthesis of tert-butyl 4-(4-nitrophenyl)-1,4-diazacycloheptan-1-carboxylate (3)

[0791] K₂CO₃ (5.18 g, 37.45 mmol) was added to a DMF (50 mL) solution of 1,4-diazacycloheptan-1-carboxylate (5 g, 24.97 mmol, 4.92 mL) and 1-fluoro-4-nitrobenzene (4.23 g, 29.96 mmol, 3.18 mL) at 20 °C. The mixture was stirred at 20 °C for 16 hours. LC-MS showed the desired mass was detected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over Na₂SO₄, filtered, concentrated under vacuum, and then subjected to rapid silica gel chromatography (40 g). Purification was performed using a silica gel rapid column chromatography with an eluent of 0–35% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl 4-(4-nitrophenyl)-1,4-diazacycloheptan-1-carboxylate (6.2 g, 19.10 mmol, 76.50% yield, 99% purity) as a yellow solid. MS (Mt-Bu+H) + =266.4.

[0792] Step 2.1 Synthesis of (4-nitrophenyl)-1,4-diazacycloheptane (4)

[0793] At 20°C, HCl / dioxane (4M, 30 mL) was added to a solution of tert-butyl 4-(4-nitrophenyl)-1,4-diazacycloheptan-1-carboxylate (3 g, 9.34 mmol) in dioxane (4 mL). The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under vacuum to give 1-(4-nitrophenyl)-1,4-diazacycloheptanane (3 g, crude, HCl) as a yellow solid. MS (M+H) + =222.1.

[0794] Step 3. ((1r,4r)-4-((4-(4-nitrophenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl) Synthesis of tert-butyl carbamate (6)

[0795] DIPEA (752.24 mg, 5.82 mmol, 1.01 mL), NaI (29.08 mg, 194.01 μmol), and 4-methylbenzenesulfonic acid ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester (1.12 g, 2.91 mmol) were added to a DMF (6 mL) solution of 1-(4-nitrophenyl)-1,4-diazacycloheptanane (0.5 g, 1.94 mmol, HCl). The resulting mixture was stirred at 60 °C for 14 h. LCMS showed a peak of 36% for 1-(4-nitrophenyl)-1,4-diazacycloheptanane and a peak of 43% for the desired mass. Another part of 4-methylbenzenesulfonic acid ((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexyl)methyl ester (744 mg, 1.94 mmol) was added at 20 °C, and the mixture was stirred at 60 °C for 14 hours. LCMS showed 58% of the expected mass. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The solution was obtained by rapid silica gel chromatography (5 g). The residue was purified by a silica gel rapid column chromatography with an eluent of 40–100% EtOAc / petroleum ether gradient at 50 mL / min. The product was then diluted with MTBE (10 mL) and stirred at 20 °C for 0.5 h. The mixture was filtered, and the filter cake was washed with MTBE (20 mL), collected, and dried to give tert-butyl ((1r,4r)-4-((4-(4-nitrophenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl)carbamate (0.5 g, 1.09 mmol, 56.01% yield, 94% purity) as a yellow solid. MS (M+H) + =433.4.

[0796] SFC Method Composition: Column: Chiralcel OJ-3 50×4.6mm ID, 3µm; Mobile Phase: Phase A is CO2, and Phase B is EtOH (0.05% DEA); Gradient Elution: B / A, from 5% to 40%; Flow Rate: 3mL / min; Detector: DAD; Column Temperature: 35℃; Back Pressure: 100 bar.

[0797] Step 4. ((1r,4r)-4-((4-(4-aminophenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl) Synthesis of tert-butyl carbamate (7)

[0798] Fe (258 mg, 4.62 mmol) was added to a mixture of ((1r,4r)-4-((4-(4-nitrophenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl)tert-butyl carbamate (0.4 g, 924.74 μmol) and NH4Cl (248 mg, 4.64 mmol) in EtOH (12 mL) and H2O (4 mL), and the mixture was stirred at 80 °C for 1 h. LCMS showed a peak at 82% of the desired mass. The mixture was combined with another batch (0.1 g scale) and then filtered and washed with EtOH (20 mL) and THF (30 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with EtOAc (10 mL) and water (10 mL), and the mixture was then adjusted to pH 9 with saturated Na2CO3. The mixture was extracted with EtOAc (10 mL × 3), the combined organic layers were washed with water (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 0.5 g (crude) of tert-butyl ((1r,4r)-4-((4-(4-aminophenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl)carbamate as a yellow solid. MS (M+H) + =403.4.

[0799] Step 5. ((1r,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-1,4-diazahexacyclic Synthesis of heptane-1-yl)methyl)cyclohexyl)tert-butyl carbamate (9)

[0800] A solution of tert-butyl carbamate (450 mg, 1.12 mmol), 3-bromopiperidin-2,6-dione (324 mg, 1.69 mmol), and NaHCO3 (282 mg, 3.36 mmol, 130.62 μL) in MeCN (4.5 mL) was stirred at 80 °C for 14 hours. LC-MS showed a peak at 95% of the desired mass. The mixture was filtered, and the filter cake was washed with EtOAc / MeOH = 10 / 1 (100 mL). The filtrate was concentrated under reduced pressure. The filtrate was analyzed by rapid silica gel chromatography (5 g / mL). The residue was purified by silica gel rapid column chromatography, using a gradient of 70–100% EtOAc / petroleum ether to 10–20% MeOH / EtOAc at 50 mL / min, yielding a blue solid ((1r,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl)carbamate tert-butyl ester (290 mg, 525.04 μmol, 46.97% yield, 93% purity). MS (M+H) + =514.5.

[0801] Step 6.3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)-1,4-diazacycloheptane-1-yl)benzene Synthesis of (10)amino)piperidine-2,6-dione

[0802] TFA (690.75 mg, 6.06 mmol, 450.00 μL) was added to a solution of tert-butyl carbamate (150 mg, 292.02 μmol) in DCM (1.5 mL), and the mixture was stirred at 20 °C for 1 hour. LC-MS showed a peak at 85% of the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)-1,4-diazacycloheptane-1-yl)phenyl)amino)piperidin-2,6-dione (160 mg, crude, TFA) as a dark brown oil. MS (M+H) + =414.3.

[0803] Step 7. N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-(4-((2,6-dioxopiperidine-3- (1,4-diazacycloheptan-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidine) Synthesis of pyridine-4-yl)amino)benzamide (compound 39)

[0804] DIPEA (385.84 mg, 2.99 mmol) was added to a DMF (1.5 mL) solution of 4-((4-((((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (145 mg, 303.43 μmol) and HATU (138 mg, 362.94 μmol), and the mixture was stirred at 20 °C for 15 min. Then, a DMF (1.5 mL) solution of 3-((4-(4-(((1r,4r)-4-aminocyclohexyl)methyl)-1,4-diazacycloheptane-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 h. LCMS showed a peak at 86% of the desired mass. The mixture was diluted with water (10 mL) and then filtered. The filter cake was washed with water (10 mL), collected, and dried. The crude product was purified by preparative TLC (DCM:MeOH = 7:1) and then further purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, for 10 min) and lyophilized. The product was further purified by preparative HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B, for 10 minutes) and lyophilized to give N-(2-chlorophenyl)-4-((2-((4-(((1r,4r)-4-((4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-1,4-diazacycloheptane-1-yl)methyl)cyclohexyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (42.6 mg, 31.44 μmol, 10.37% yield, 89.7% purity, 3TFA). MS (M+H) + =873.4.

[0805] 1H NMR(400MHz,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=3.5Hz,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),3.7 6-3.64(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).

[0806] Example 40. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((1R,5S,6S)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexyl-6-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 40)

[0807]

[0808] Step 1.4-(((1R,5S,6S)-6-((tert-Butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hex-3-yl)methyl Synthesis of benzyl piperidine-1-carboxylate (3)

[0809] At 20°C, TEA (1.53 g, 15.16 mmol, 2.11 mL) was added to a DCM (20 mL) solution of 4-formylpiperidine-1-carboxylic acid benzyl ester (1.25 g, 5.05 mmol) and... MS (50 mg), ((1R,5S,6S)-3-azabicyclo[3.1.0]hex-6-yl)carbamate tert-butyl ester (1.00 g, 5.05 mmol). After stirring for 10 minutes, NaBH(OAc)3 (3.21 g, 15.16 mmol) was slowly added at 20 °C. The reaction mixture was stirred at 20 °C for 16 hours. LCMS showed that the starting material was completely consumed and a peak with the desired mass (R) was detected at 58%. t=0.635 minutes). Filter the reaction mixture. Wash the filter cake with a mixed solution (50 mL, EtOAc:MeOH = 1:2). Concentrate the filtrate under vacuum to obtain the crude product. Grind the crude product with EtOAc (10 mL) at 20 °C for 1 hour and filter. Wash the filter cake with EtOAc (30 mL). Concentrate the filtrate under vacuum to obtain the crude product, which is then subjected to rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column with an eluent of 30–70% EtOAc / petroleum ether gradient at 100 mL / min to give 4-(((1R,5S,6S)-6-((tert-Butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hex-3-yl)methyl)piperidin-1-carboxylic acid benzyl ester (1.76 g, 4.10 mmol, 81.06% yield) as a colorless oil. MS (M+H) + =430.4.

[0810] Step 2. ((1R,5S,6S)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamic acid Synthesis of tert-butyl ester (4)

[0811] A mixture of 4-(((1R,5S,6S)-6-((tert-Butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hex-3-yl)methyl)piperidin-1-carboxylic acid benzyl ester (1.76 g, 4.10 mmol) and Pd / C (0.8 g, 10% purity) in EtOH (20 mL) was degassed and purged three times with H2. The resulting mixture was stirred at 20 °C for 12 h under a H2 (15 Psi) atmosphere. LCMS showed that the starting material was completely consumed and the desired mass (R) was detected. t =0.797 minutes). The reaction mixture was filtered and washed with MeOH (30 ml × 3). The filtrate was concentrated under vacuum to give 1.2 g (crude) of ((1R,5S,6S)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate as a gray solid. MS (M+H) + =296.2.

[0812] Step 3. ((1R,5S,6S)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0] Synthesis of tert-butyl hexyl-6-yl)carbamate (5)

[0813] K₂CO₃ (1.68 g, 12.19 mmol) was added to a 20 mL solution of ((1R,5S,6S)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (1.2 g, 4.06 mmol) and 1-fluoro-4-nitrobenzene (1.09 g, 7.72 mmol) in DMF at 20 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed residual ((1R,5S,6S)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate and the desired mass (R) was detected. t =0.674 min). Then, the reaction mixture was heated to 40 °C and stirred for 4 hours. LCMS showed the residue of ((1R,5S,6S)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate tert-butyl ester, and the desired mass was detected. The reaction mixture was stirred at 40 °C for 12 hours. LCMS showed that ((1R,5S,6S)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate tert-butyl ester was completely consumed, and the desired mass was detected. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to give the residue. The residue was analyzed by rapid silica gel chromatography ( 20g Purification was performed using a silica gel rapid column with an eluent of 0–100% EtOAc / petroleum ether gradient at 100 mL / min to give tert-butyl ((1R,5S,6S)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (1.2 g, 2.79 mmol, 68.80% yield, 97% purity) as a yellow solid. MS (M+H) + =417.3.

[0814] Step 4. ((1R,5S,6S)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0] Synthesis of tert-butyl hexyl-6-yl)carbamate (6)

[0815] Fe (643.57 mg, 11.52 mmol) and NH4Cl (770.56 mg, 14.41 mmol) were added to a solution of ((1R,5S,6S)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate tert-butyl ester (1.2 g, 2.88 mmol) in EtOH (10 mL) and H2O (10 mL) at 20 °C. The mixture was stirred at 80 °C for 2 hours. LCMS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under vacuum to obtain a residue. The residue was diluted with H2O (50 mL) and adjusted to pH 10 with Na2CO3, and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain a purple solid, tert-butyl ((1R,5S,6S)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (970 mg, 2.41 mmol, 83.62% yield, 96% purity). MS (M+H) + =387.4.

[0816] Step 5. ((1R,5S,6S)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl) Synthesis of tert-butyl methyl(3-azabicyclo[3.1.0]hex-6-yl)carbamate (7)

[0817] At 20 °C, NaHCO3 (543.34 mg, 6.47 mmol) was added to a solution of ((1R,5S,6S)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate tert-butyl ester (500 mg, 1.29 mmol) and 3-bromopiperidin-2,6-dione (347.73 mg, 1.81 mmol) in ACN (4 mL). The mixture was stirred at 80 °C for 16 hours. LCMS showed a peak with 86% of the desired mass. The reaction mixture was washed with a mixture solution (100 mL, MeOH:EtOAc:THF = 1:1:3) and concentrated under vacuum to give the residue. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column with eluent of 50–100% EtOAc / petroleum ether to a gradient of 0–20% DCM:MeOH at 100 mL / min. The product was further purified by preparative HPLC (column: Phenomenex Luna C18150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 1%–31% B, for 10 min) and lyophilized to obtain a purple solid, tert-butyl ((1R,5S,6S)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (300 mg, 480.67 μmol, 37.16% yield, 98% purity, TFA). MS (M+H) + =498.3.

[0818] Step 6.3-((4-(4-(((1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl)methyl)piperidine Synthesis of 1-pyridyl)phenyl)amino)piperidine-2,6-dione (8)

[0819] At 20°C, HCl / dioxane (4M, 6mL) was added to a solution of ((1R,5S,6s)-3-((1-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate tert-butyl ester (150 mg, 301.43 μmol) in dioxane (2 mL). The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired mass was achieved. The reaction mixture was concentrated under vacuum to give 3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (180 mg, crude, HCl) as a yellow solid. MS (M+H) + =398.3.

[0820] Step 7. N-(2-chlorophenyl)-4-((2-((4-(((1R,5S,6S)-3-((1-(4-((2,6-dioxopiperidine- 3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hex-6-yl)carbamoyl)phenyl)amino Synthesis of 40-(4-(4-)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 40)

[0821] At 20°C, HATU (105.14 mg, 276.51 μmol) and DIPEA (134.02 mg, 1.04 mmol) were added to a DMF (1 mL) solution of 4-((4-((((2-chlorophenyl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)benzoic acid (107.36 mg, 224.67 μmol) (1 mL). After stirring for 10 minutes, a solution of 3-((4-(4-(((1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl)methyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione (150 mg, 345.64 μmol, HCl) in DMF (1 mL) was added with DIPEA (742.00 mg, 5.74 mmol, 1.00 mL). The resulting mixture was stirred at 20°C for 1 hour. LCMS showed a peak of 60% with the desired mass. The reaction mixture was poured into water and filtered. The filter 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) and lyophilized to give N-(2-chlorophenyl)-4-[[2-[4-[[(1R,5S)-3-[[1-[4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-piperidinyl]methyl]-3-azabicyclo[3.1.0]hexyl-6-yl]carbamoyl]aniline]-5-fluoro-pyrimidin-4-yl]amino]benzamide (31.1 mg, 24.09 μmol, 6.97% yield, 92.9% purity, 3TFA) as a gray solid. MS (M+H) + =857.3.

[0822] 1H NMR (400MHz, 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 = 3.5Hz, 1H), 8 .07-7.96(m,4H),7.82-7.71(m,4H),7.65(d,J=6.9Hz,1H),7.57(dd,J=1.1,8.0Hz,1H),7.46-7.26(m,4H),6.77(brd,J=8.8Hz,2H),4.39(br dd,J=4.4,11.6Hz,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).

[0823] Example 41. Synthesis of N-(2-chlorophenyl)-4-((2-((4-(((3aR,5s,6aS)-2-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamoyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide (compound 41)

[0824]

[0825]

[0826] Step 1. Synthesis of (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2)

[0827] At 0 °C, NaBH4 (1.01 g, 26.63 mmol) was added in portions to a MeOH (45 mL) solution of (3aR,6aS)-5-oxohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2 g, 8.88 mmol). The mixture was stirred at 0 °C for 1 h. TLC (petroleum ether:EtOAc = 1:2) indicated that the starting material was completely consumed and a major new spot with high polarity was detected. The reaction mixture was quenched by adding 1N HCl (50 mL), diluted with H2O (100 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, and concentrated under vacuum to obtain (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2 g, 8.80 mmol, 99.11% yield), which was a yellow oil.

[0828] Step 2. (3aR,5s,6aS)-5-(1,3-dioxoisoindoline-2-yl)hexahydrocyclopentano[c]pyrrole-2 Synthesis of (1H)-tert-butyl formate (4)

[0829] Under a nitrogen atmosphere, at 0°C, DIAD (1.16 g, 5.72 mmol) was added dropwise to a THF (30 mL) solution of (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (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 warmed to 20°C and stirred for 1 hour. LC-MS showed a main peak with the desired mass. The reaction was quenched with MeOH (30 mL) and concentrated under reduced pressure. The final concentration was determined by rapid silica gel chromatography (Biotage; 20 g). The residue was purified twice using a silica gel rapid column with an eluent of 0–30% EtOAc / petroleum ether gradient at 80 mL / min to give (3aR,5s,6aS)-5-(1,3-dioxoisoindoline-2-yl)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.5 g, 4.21 mmol, 95.66% yield) as a white solid. MS (M+Na) + =379.2.

[0830] Step 3. Synthesis of (3aR,5s,6aS)-5-aminohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (5)

[0831] To a solution of (3aR,5s,6aS)-5-(1,3-dioxoisoindoline-2-yl)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1 g, 2.81 mmol) in EtOH (10 mL), NH₂-NH₂·H₂O (877.84 mg, 14.03 mmol, 850.62 μL, 80% purity) was added, and the resulting mixture was stirred at 80 °C for 2 h. LC-MS showed peaks with the desired mass (~70%). The reaction mixture was filtered and washed with EtOH (20 mL). The filtrate was concentrated under reduced pressure to give (3aR,5s,6aS)-5-aminohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (600 mg, 2.65 mmol, 94.49% yield) as a yellow oil, which was used directly in the next step. MS (M+H) + =227.2.

[0832] Step 4. (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid Synthesis of tert-butyl ester (6)

[0833] TEA (804.82 mg, 7.95 mmol, 1.11 mL) and Cb2Cl (542.72 mg, 3.18 mmol) were added to a DCM (10 mL) solution of (3aR,5s,6aS)-5-aminohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (600 mg, 2.65 mmol). The resulting mixture was stirred at 20 °C for 16 h. LCMS showed a main peak with the desired mass. The reaction mixture was diluted with H2O (20 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography (Biotage; 20 g) Purification was performed using a silica gel rapid column with an eluent of 0–30% EtOAc / petroleum ether gradient at 80 mL / min. Further purification was achieved by preparative HPLC (column: Waters Xbridge C18150*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 39%–69% B, for 10 min) to yield a yellow oily substance, (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (300 mg, 832.30 μmol, 60.00% yield). MS (M+H) + =361.2.

[0834] Step 5. Synthesis of ((3aR,5s,6aS)-octahydrocyclopentano[c]pyrrole-5-yl)benzyl carbamate (7)

[0835] A solution of (3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (300 mg, 832.30 μmol) in dioxane (5 mL) was mixed with HCl / dioxane (4 M, 5 mL) and stirred at 20 °C for 0.5 h. LCMS showed a main peak with the desired mass. The mixture was concentrated under vacuum to give ((3aR,5s,6aS)-octahydrocyclopentano[c]pyrrole-5-yl)carbamate benzyl ester (250 mg, crude, HCl salt) as a white solid. MS (M+H) + =261.2.

[0836] Step 6.4-(((3aR,5s,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)- Synthesis of tert-butyl methylpiperidine-1-carboxylate (9)

[0837] NaOAc (138.20 mg, 1.68 mmol) was added to a DCM (5 mL) solution of ((3aR,5s,6aS)-octahydrocyclopentano[c]pyrrole-5-yl)carbamate (250 mg, 842.34 μmol, HCl salt) and tert-butyl 4-formylpiperidin-1-carboxylate (179.65 mg, 842.34 μmol). After stirring at 20 °C for 0.5 h, NaBH(OAc)3 (535.58 mg, 2.53 mmol) was added. The resulting mixture was stirred at 20 °C for 16 h. LCMS showed a main peak with the desired quality. The reaction mixture was quenched by adding NaHCO3 solution (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. Rapid silica gel chromatography (Biotage; 12g) The residue was purified by silica gel rapid column chromatography, using a gradient of 50–100% EtOAc / petroleum ether to 10% MeOH / EtOAc at 80 mL / min, yielding a yellow oily substance, 400 mg of tert-butyl 4-(((3aR,5S,6aS)-5-(((benzyloxy)carbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)piperidine-1-carboxylic acid. MS (M+H) + =458.3.

[0838] Step 7. ((3aR,5s,6aS)-2-(piperidin-4-ylmethyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamic acid Synthesis of benzyl ester (10)

[0839] To a solution of 200 mg (437.06 μmol) of tert-butyl piperidine-1-carboxylate in dioxane (5 mL), HCl / dioxane (4 M, 5 mL) was added, and the resulting mixture was stirred at 20 °C for 0.5 h. LC-MS showed that the starting material was completely consumed and showed a peak with the desired mass. The mixture was concentrated under vacuum to give a white solid of ((3aR,5s,6aS)-2-(piperidin-4-ylmethyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamate (170 mg, 431.53 μmol, 98.73% yield, HCl salt). MS (M+H) + =358.3.

[0840] Step 8. ((3aR,5s,6aS)-2-((1-(4-nitrophenyl)piperidin-4-yl)methyl)octahydrocyclopenta[c]pyrene Synthesis of benzyl 5-yl)carbamate (12)

[0841] K₂CO₃ (238.56 mg, 1.73 mmol) was added to a DMF (5 mL) solution of ((3aR,5s,6aS)-2-(piperidin-4-ylmethyl)octahydrocyclopentano[c]pyrrolo-5-yl)carbamate (170 mg, 431.53 μmol, HCl salt) and 1-fluoro-4-nitrobenzene (100.47 mg, 712.02 μmol, 75.54 μL). The resulting mixture was stirred at 40 °C for 16 h. LCMS showed a peak (39%) with the desired mass. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum and subjected to rapid silica gel chromatography (Biotage; 10 g). The residue was purified by a silica gel rapid column chromatography with eluents ranging from 50–100% EtOAc / petroleum ether to a 10% MeOH / EtOAc gradient at 50 mL / min, yielding a yellow oily substance ((3aR,5s,6aS)-2-((1-(4-nitrophenyl)piperidin-4-yl)methyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamate (160 mg, 334.32 μmol, 77.47% yield). MS (M+H) + =479.3.

[0842] Step 9. ((3aR,5s,6aS)-2-((1-(4-aminophenyl)piperidin-4-yl)methyl)octahydrocyclopenta[c]pyrene Synthesis of benzyl 5-yl)carbamate (13)

[0843] Fe (93.35 mg, 1.67 mmol) and NH4Cl (89.42 mg, 1.67 mmol) were added to a solution of ((3aR,5s,6aS)-2-((1-(4-nitrophenyl)piperidin-4-yl)methyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamate (160 mg, 334.32 μmol) in EtOH (5 mL) and H2O (1 mL). The resulting mixture was stirred at 80 °C for 2 hours. LCMS showed a peak (58%) with the desired mass. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum. The residue was diluted with NaHCO3 solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain ((3aR,5s,6aS)-2-((1-(4-aminophenyl)piperidin-4-yl)methyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamate (140 mg, crude product), a brown oil. MS (M+H) + =449.3.

[0844] Step 10. ((3aR,5s,6aS)-2-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- Synthesis of (15) octahydrocyclopentano[c]pyrrole-5-yl)carbamate (15)

[0845] NaHCO3 (93.64 mg, 1.11 mmol) was added to a solution of ((3aR,5s,6aS)-2-((1-(4-aminophenyl)piperidin-4-yl)methyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamate (100 mg, 222.92 μmol) and 3-bromopiperidin-2,6-dione (42.80 mg, 222.92 μmol) in ACN (1 mL). The resulting mixture was stirred at 80 °C for 16 hours. LCMS showed a peak (33%) with the desired mass. The mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The filtrate was analyzed by rapid silica gel chromatography (Biotage; 12 g). The residue was purified by silica gel rapid column chromatography with 0-20% MeOH / EtOAc gradient at 80 mL / min to give a brown oily substance ((3aR,5s,6aS)-2-((1-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)octahydrocyclopentano[c]pyrrole-5-yl)carbamate (120 mg). MS (M+H) + =560.3.

[0846] Step 11.3-((4-(4-(((3aR,5s,6aS)-5-aminohexahydrocyclopentano[c]pyrrole-2(1H)-yl)methyl) Synthesis of piperidine-1-yl)phenyl)amino)piperi...

Claims

1. A compound represented by the following formula I: [Formula I] ULM—Connector Base—PTM in: PTM is the Aurora-A kinase (AURKA) binding moiety represented by the following formula II: [Formula II] in: R1 is a halogen; R2 is -NH- or -O-; R 3A and R 3B Each can be independently -CH- or -N-; R 3C Is it H, halogen, or OC? 1-3 alkyl; yes R4 is -CO-, -CONH-, -CON(CH3)-, or -NHCO-; It is a 5- to 6-membered cycloalkyl, heterocyclic, aryl, or heteroaryl group optionally substituted with 1 to 3 halogens; It is optionally halogenated or C 1-3 Alkyl-substituted phenyl or 5- to 6-membered heteroaryl; and It is a covalent bond connected to the linker base; and ULM is the CRBN E3 ubiquitin ligase-binding moiety represented by the following formula: III-1, III-2A, or III-2B: [Formula III-1] [Formula III-2A] [Formula III-2B] in: U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-; U2 is CH or N; It is optionally divided by 1 to 3 halogens, C 1-3 Alkyl or OC 1-3 Alkyl-substituted phenyl or 6-membered heteroaryl; and It is a covalent bond connected to the linker base; and The linker group is a linker group represented by the following formula IV: [Form IV] in: L U It is a covalent bond, -CH2-, -NH-, -O-, CH2CH2-, -NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -CH=CH-, or -CC-; L M It is a covalent bond, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -COCH2-, -CH2CO-, -CH2NH-, -NHCH2-, -CH2N(CH3)-, -N(CH3)CH2-, -CH2CH2CH2-, -COCH2CH2-, -CH2COCH2-, -CH2CH2CO-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -N(CH3)CH2CH2-, -CH2N(CH3)CH2- or -CH2CH2N(CH3)-; L P It is -CH2-, -O-, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -N(CH3)CH2-, -CH2N(CH3)-, -CO-, -COCH2-, -NHCO-, -CH2NHCO-, -CONHCH2-, -NHCOCH2-, -CONH-, or -CH2CONH-; L W1 and L W2 Each independently can be arbitrarily assigned to one to three Cs. 1-3 Alkyl or OH-substituted 3- to 11-membered cycloalkyl, heterocyclic, aryl, or heteroaryl groups; and L U and L P Through respectively Connect to ULM and PTM.

2. The compound according to claim 1, wherein formula II is formula II-1: [Formula II-1] in: R1 is a halogen; R2 is -NH- or -O-; R 3A and R 3B Each can be independently -CH- or -N-; R 3C Is it H, halogen, or -OC? 1-3 alkyl; R4 is -CONH-, -CON(CH3)-, or -NHCO-; R5 is CH or N; It is a cyclohexyl or phenyl group optionally substituted with 1 to 3 halogens; and It is a covalent bond connected to the linker base.

3. The compound according to claim 1, wherein formula II is formula II-2: [Formula II-2] in: R1 is a halogen; and It is optionally halogenated or C 1-3 Alkyl-substituted phenyl or pyrazolyl groups.

4. The compound according to claim 1, wherein formula III-1 is formula III-1A or III-1B: [Formula III-1A] [Formula III-1B] in: U1 is a covalent bond, -NH-, -N(CH3)-, -NHCO-, or -CONH-; U2 is CH or N; U 3A and U 3B Each is independently CH or N; and U 4A and U 4B Each is independently H, halogen, C 1-3 Alkyl or OC 1-3 alkyl.

5. The compound according to claim 1, wherein formula III-2A or III-2B is formula III-2C or III-2D: [Formula III-2C] [Formula III-2D] U5 is H or a halogen.

6. The compound according to claim 1, wherein L U It is a covalent bond or -CC-; and L P It is -CH2O-, -N(CH3)CH2-, -CO-, -COCH2-, -NHCO-, -CH2NHCO-, or -CONH-.

7. The compound according to claim 1, wherein L M It is a covalent bond, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH(CH2CH3)-, -COCH2-, -CH2CO-, -CH2N(CH3)-, -CH2CH2CH2-, -CH2CH2CO-, -CH2N(CH3)CH2-, or -CH2CH2N(CH3)-.

8. The compound according to claim 1, wherein L W1 and L W2 Each of them independently is one of the following formulas: IV-1, IV-2, or IV-3: [Formula IV-1] in: Z1 and Z2 are each independently CH or N; Z X It is H, CH3 or OH; p1 is 0, 1, or 2; and p2 is 1, 2, or 3; [Formula IV-2] in: Z3 and Z4 are each independently CH or N; q1 and q3 are each independently 0, 1, or 2; and q2 and q4 are each independently 1 or 2; [Formula IV-3] in: Z5 and Z6 are each independently CH or N; and r1 to r4 are each independently 0 or 1.

9. The compound of claim 1, wherein the compound induces the degradation of AURKA protein.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier.

11. A pharmaceutical composition for treating AURKA-related diseases, said pharmaceutical composition comprising a compound according to any one of claims 1 to 9.

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