Novel PLK1 degradation-inducing compounds

Abstract

The present invention relates to novel compounds that induce PLK1 degradation, methods for producing the same, and uses thereof. The compounds of the present invention exhibit the effect of inducing PLK1 degradation. Therefore, the compounds of the present invention can be effectively used for the prevention or treatment of PLK1-related diseases.

Description

[Technical Field]

[0001] The present invention relates to novel PLK1 degradation-inducing compounds, their production methods, and uses. The present invention can specifically act on abnormal cells through the effective degradation of PLK1, and can be useful in the treatment of various diseases. [Background technology]

[0002] Polo-like kinase 1 (PLK1) is a serine / threonine kinase known to be involved in the G2 / M transition during cell growth and division. PLK1 is expressed and activated in a pulsatile manner from the S phase to the G2 / M phase, and is rapidly degraded upon completion of mitosis.

[0003] PLK1 is overexpressed in various cancers, including colorectal cancer, lung cancer, bladder cancer, and melanoma, and cancer cells that overexpress PLK1 tend to be resistant to various anticancer drugs. As PLK1 dependence has become apparent in various cancers, attempts have been made to develop PLK1 inhibitor compounds, such as volasertib (also known as BI6727).

[0004] However, existing PLK1 inhibitors have not been able to sufficiently inhibit PLK1 activity at clinically safe concentrations. Even if they temporarily delay the cell cycle of cancer cells, some cancer cells ultimately resume cell cycle resumption, resulting in insufficient clinical efficacy (see, for example, Gheghiani et al., Cell Reports, 2017, 19: 2060). Indeed, while numerous pharmaceutical companies, including Boehringer Ingelheim and GlaxoSmithKline (GSK), have attempted to develop small molecule-based PLK1 inhibitors, most have failed or been discontinued during clinical trials, and to date, no commercially available PLK1 inhibitors have been developed. This indicates that the pharmacological mechanism of small molecule inhibitors, which bind to the active site of PLK1 and inhibit its enzymatic activity, is not sufficiently effective in the development of new drugs aimed at inhibiting PLK1 activity in cancer cells to achieve anti-cancer effects.

[0005] Recently, proteolysis targeting chimeras (PROTACs) have been proposed as a small molecule-based platform technology capable of inducing proteolysis of target proteins in vivo. PROTACs are bifunctional compounds consisting of a ligand molecule that binds to a disease-related target protein and an E3 ubiquitin ligase binding moiety attached via a chemical linker. In theory, PROTAC compounds can induce target protein degradation by placing disease-related target proteins in proximity to E3 ubiquitin ligases. Based on this novel mechanism distinct from conventional inhibitors, many PROTAC compounds have been developed as therapeutic agents for cancer, inflammatory diseases, and other conditions, and are being investigated for various applications (e.g., as payloads for antibody-drug conjugates (ADCs)). However, not all types of linkers or conjugates are active in PROTACs. Numerous studies have demonstrated that for a PROTAC to exhibit the desired level of efficacy, the appropriate combination of each linker and conjugate is required (see reference [US2020-0325130A]). In particular, when targeting CRBN (cereblon) E3 ligase, depending on the type of binding moiety or the structure of the compound bound to it, there is a risk of degrading CRBN neo-substrates (e.g., GSPT1, IKZF1 / 3) or exhibiting associated off-target toxicity. Therefore, when developing PROTAC drugs, it is important to select an appropriate binding moiety and optimize the structure of all compounds to avoid unexpected toxicity.

[0006] In the case of PROTAC compounds targeting PLK1, Chinese Patent Application Publication No. 106543185A discloses a bifunctional compound in which a volasertib derivative compound and an E3 ubiquitin ligase CRBN binding moiety are linked via a chemical linker. However, while the prior art document describes limited examples of the synthesis of PROTAC compounds, the target degradation activity and selectivity of PROTACs can generally be significantly altered by selecting the target protein moiety, E3 ubiquitin ligase binding moiety, etc. (see, for example, Burslem and Crews, Chemical Reviews, 2017, 117(17): 11269).

[0007] Furthermore, the PROTAC compounds described in the literature are characterized by their ability to simultaneously degrade PLK1 and BRD4, but they also induce the degradation of various proteins, including other PLK family proteins and BRD4, in addition to PLK1, posing a problem of causing side effects due to off-target toxicity during drug development. In particular, given that it is already known that strong inhibition of BRD4 activity inevitably leads to on-target toxicity, such as hematotoxicity and gastrointestinal toxicity, along with pharmacological effects, the more effectively the PROTAC compounds described in the literature degrade BRD4, the greater the clinical side effects are expected to be (see, for example, Bolden et al. CULM Reports, 2014, 8(6): 1919).

[0008] Furthermore, according to a paper published by the inventor of the aforementioned paper [Mu et al. BBRC, 2020, 521(4):833], the PROTAC compound that simultaneously degrades PLK1 and BRD4 is far more potent at degrading BRD4 than PLK1 at the cellular level, arresting the cell cycle almost in G1 phase, and thus confirming that it actually acts solely as a BRD4 inhibitor, regardless of the way in which conventional PLK1 inhibitors exert their pharmacological effects.

[0009] Thus, there is an unmet need for effective PLK1 degradation-inducing compounds that are free of or have minimal side effects (eg, off-target toxicity). Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide novel PLK1 degradation-inducing compounds.

[0011] Specifically, another object of the present invention is to provide a method for producing a novel PLK1 degradation-inducing compound.

[0012] Another object of the present invention is to provide uses of novel PLK1 degradation-inducing compounds. [Means for solving the problem]

[0013] To achieve the above objective, the present inventors have discovered novel PROTAC compounds that act specifically on abnormal cells in which PLK1 is overexpressed, induce effective degradation of PLK1, and minimize side effects through appropriate structural combination and optimization of the E3 ubiquitin ligase binding moiety, target binding moiety, and linker, thereby completing the present invention.

[0014] PLK1 selective degradation inducer compound The present invention provides novel compounds that induce efficient degradation of PLK1. Specifically, the present invention provides bifunctional compounds in which a PLK1-binding moiety and an E3 ubiquitin ligase-binding moiety are linked by a chemical linker.

[0015] One embodiment of the present invention is a compound represented by Formula I below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the above formula I, ULM is a moiety represented by the following formula 1: [ka] PTM is a moiety represented by the following formula 2: [ka] Linker is a group that chemically links the ULM and PTM; X is CH or N; V is -NR V - or a single bond; R V is -H or -CH3; Ring U is phenyl or 5-6 membered heteroaryl, wherein one or more H in said phenyl or 5-6 membered heteroaryl ring is R U can be replaced with}; R U -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Aminoalkyl, -C 1-3 Haloalkyl, -C 1-3 alkoxy, -CN, or -halo; Y1 is CR Y or N; Y2 to Y4 are each independently CR Y and; R Y -H, -C 1-3 Alkyl, -C 1-3 is alkoxy or -halo; R1 is -C 1-4 alkyl or 5-6 membered cycloalkyl; R2 and R3 are each independently -H, -C 1-3 is alkyl or -halo; R4 is -C 1-3 It is alkyl.

[0016] In one embodiment of the present invention, ULM is a moiety represented by the following formula 1-1, formula 1-2, or formula 1-3: [ka] [ka] [ka] R V is -H or -CH3, Ring U is phenyl or pyridinyl, wherein one or more H in said phenyl or pyridinyl ring is R U can be replaced with}; R U -C 1-3 Alkyl, -C 1-3 It is -alkoxy, -CN or -halo.

[0017] In one embodiment of the present invention, ULM is [ka] TIFF2025530757000008.tif106169 and; R U1 and R U2 are each independently -C 1-3 Alkyl, -C 1-3 It is -alkoxy, -CN or -halo.

[0018] In one embodiment of the present invention, ULM is [ka] and; R U1 and R U2 are each independently -C 1-3 Alkyl, -C 1-3 It is -alkoxy, -CN or -halo.

[0019] In one embodiment, PTM is [ka] and; Y1 is CR Y or N; Y2 to Y4 are each independently CR Y and; R Y -H, -C 1-3 is alkoxy or -halo; R1 is -C 1-4 Preferably, R1 is methyl, ethyl, isopropyl or cyclopentyl, but is not limited thereto.

[0020] In one embodiment of the present invention, Linker is -L U -L1-L2-L P - and; L U is a heterocycloalkyl {wherein the heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the heterocycloalkyl ring is replaced by —C 1-4 Alkyl, -C 1-4 may be substituted with alkoxy or -halo}; L1 is -(CH2) X1 -, -(CH2) X2 -NH-(CH2) X3 -, -(CH2) X2 -N(C 1-4 alkyl)-(CH2) X3 - or a single bond {wherein X1 to X3 are each independently 0, 1, 2, 3, or 4}; L2 is a cycloalkyl or heterocycloalkyl {wherein the heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the cycloalkyl or heterocycloalkyl ring is replaced by -C 1-4 Alkyl, -C 1-4may be substituted with alkoxy or -halo}; L P is -NH-C(=O)- or -(CH2)p-heteroaryl {wherein the -C(=O)- of said -NH-C(=O)- or the heteroaryl of said -(CH2)p-heteroaryl is linked to PTM, said heteroaryl comprises endocyclic N and O atoms, and said p is 0, 1, 2, or 3}.

[0021] In one embodiment of the present invention, L U is a 4-12 membered heterocycloalkyl, wherein said 4-12 membered heterocycloalkyl is a monocyclic, bridged bicyclic or spirocyclic ring, said 4-12 membered heterocycloalkyl contains one or more N atoms in the ring, said N atom(s) is / are directly bonded to ULM, and one or more H in said 4-12 membered heterocycloalkyl ring is / are -C 1-4 may be substituted with alkyl or -halo}; L1 is -(CH2) X1 -, -(CH2) X2 -N(C 1-4 alkyl)-(CH2) X3 - or a single bond {wherein X1 to X3 are each independently 0, 1, 2, or 3}; L2 is a 4- to 6-membered cycloalkyl or a 4- to 12-membered heterocycloalkyl, wherein the 4- to 12-membered heterocycloalkyl is a monocyclic, bridged bicyclic or spirocyclic ring, the 4- to 12-membered heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the 4- to 6-membered cycloalkyl or 4- to 12-membered heterocycloalkyl ring is selected from -C 1-4 may be substituted with alkyl or -halo}; L P is —NH—C(═O)— or —(CH2)p-1,3,4-oxadiazole {wherein the —C(═O)— of —NH—C(═O)— or the 1,3,4-oxadiazole of the —(CH2)p-1,3,4-oxadiazole is linked to a PTM, and p is 0 or 1}.

[0022] Preferably, L U teeth, [ka] and L2 may be [ka] It may be, but is not limited to.

[0023] According to a specific embodiment of the present invention, the compound represented by Chemical Formula I is a compound selected from the group consisting of Compounds 1 to 77 below.

[0024] As used herein, a pharmaceutically acceptable salt refers to any organic or inorganic acid addition salt that has a relatively non-toxic, harmless effective concentration in a patient, and the side effects attributable to the salt do not diminish the beneficial efficacy of the compound represented by Formula I. For example, pharmaceutically acceptable salts may be inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid, or organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, but are not limited thereto.

[0025] Use of a compound that induces selective degradation of PLK1 One embodiment of the present invention is a composition for inducing PLK1 degradation, comprising a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof. Chemical Formula I is as defined above.

[0026] In the experimental examples of the present invention, it was confirmed that the compounds of the present invention effectively induce PLK1 protein degradation.

[0027] From the perspective of mechanism of action, the PLK1 degradation-inducing PROTAC compound of the present invention is able to fundamentally degrade the target protein, PLK1, and therefore achieves superior PLK1 inhibitory effects compared to conventional PLK1 small molecule inhibitors that simply inhibit the activity of PLK1.

[0028] Therefore, a composition comprising the compound of the present invention represented by Chemical Formula I or a pharmaceutically acceptable salt thereof can be useful for selectively degrading PLK1.

[0029] One embodiment of the present invention is a pharmaceutical composition for preventing or treating a PLK1-related disease, comprising a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a method for preventing or treating a PLK1-related disease, comprising administering such a composition. Chemical Formula I is as defined above.

[0030] In the present invention, a PLK1-associated disease refers to any disease or condition that can be treated, alleviated, delayed, inhibited, or prevented by induction of PLK1 degradation or inhibition of activity. In one embodiment, the PLK1-associated disease may be cancer (malignant tumor), benign tumor, neurological disease, or other genetic or non-genetic disease caused by excessive cell division.

[0031] The cancer includes all cancers that can be prevented or treated by inhibiting the activity of PLK1, and may be solid cancer or blood cancer.For example, the cancer includes squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, perianal adenocarcinoma, esophageal cancer, small intestine cancer, endocrine gland cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastrointestinal cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumor, breast cancer, colon cancer, The cancer may be one or more selected from the group consisting of colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, solid cancer, blood cancer, bone cancer, macrophage lymphoma, adrenocortical tumor, T-cell lymphoma / leukemia, neuroendocrine cancer, neuroendocrine tumor, cholangiocarcinoma, neuroblastoma, glioblastoma, glioma, etc. The cancer includes not only primary cancer but also metastatic cancer.

[0032] The benign tumor includes all benign tumors that can be prevented or treated by inhibiting PLK1 activity, i.e., benign tumors that are pre-cancerous, and may be solid tumors or blood tumors. For example, the tumor may be one or more selected from the group consisting of Barrett's esophagus, colon adenoma and polyp, breast fibroadenoma and cyst, monoclonal gammopathy of undetermined significance (MGUS), monoclonal lymphocytosis, etc., but is not limited thereto.

[0033] The neurological disease includes all neurological diseases that can be prevented or treated by inhibiting PLK1 activity, and specifically may be one or more selected from central nervous system diseases, degenerative neurological diseases, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, stroke, and diseases associated with nerve damage and axonal degeneration due to brain or spinal cord injury, but is not limited to these.

[0034] The pharmaceutical composition of the present invention may further contain one or more active ingredients exhibiting the same or similar pharmacological effects in addition to the compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof.

[0035] One embodiment of the present invention is a method for degrading PLK1 protein by administering a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof to a mammal, including a human.

[0036] Another embodiment of the present invention is a method for degrading PLK1 protein by administering a compound represented by Formula I or a pharmaceutically acceptable salt thereof to a sample in vitro. The sample may be, but is not limited to, a cell, a cell culture, a body fluid or a tissue of a mammal, including a human. [Effects of the Invention]

[0037] The compounds of the present invention have the effect of inducing PLK1 degradation and can therefore be effectively used in the prevention or treatment of PLK1-related diseases. DETAILED DESCRIPTION OF THE INVENTION

[0038] 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 belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the disclosure.

[0039] The present invention provides methods for synthesizing compounds 1 to 77 shown in Table 1 below.

[0040] [Table 1] TIFF2025530757000014.tif212170 TIFF2025530757000015.tif196170 TIFF2025530757000016.tif204170 TIFF2025530757000017.tif211170 TIFF2025530757000018.tif220170 TIFF2025530757000019.tif204170 TIFF2025530757000020.tif228170 TIFF2025530757000021.tif203170 TIFF2025530757000022.tif228170 TIFF2025530757000023.tif228170 TIFF2025530757000024.tif211170 TIFF2025530757000025.tif211170 TIFF2025530757000026.tif228170 TIFF2025530757000027.tif75170

[0041] The compounds of the present invention were purified and their structures analyzed by the following methods.

[0042] device LCMS: Shimadzu LCMS-2020, Agilent 1200 / G6110A, Agilent 1200 / G1956A HPLC: Agilent 1260 II LC, Agilent 1200 / G6410B NMR: BRUKER AVANCE III / 400MHz

[0043] LCMS analysis LCMS data were recorded on a Shimadzu LCMS-2020 or Agilent 1200 / G6110A or Agilent 1200 / G1956A equipped with ESI (electrospray ionization) equipment. The mobile phases used were 0.0375% TFA in water (solvent A) and 0.01875% TFA in acetonitrile (solvent B), or 0.025% NH₃·H₂O in water (solvent A) and acetonitrile (solvent B). The columns used were Kinetex EVO C18 (2.1 × 30 mm, 5 μm) or HALO C18 (3.0 × 30 mm, 2.7 μm).

[0044] HPLC analysis For HPLC analysis, an Agilent 1260 II LC or an Agilent 1200 / G6410B was used. The mobile phase consisted of 0.0375% TFA in water (solvent A) and 0.01875% TFA in acetonitrile (solvent B). The column used was a Zobrax Eclipse Plus C18 (4.6 × 150 mm, 3.5 μm) or a YMC ODS A (4.6 × 150 mm, 3 μm).

[0045] NMR analysis 1 H NMR spectra were recorded on a Bruker AVANCE III 400 MHz / 5 mm Probe (BBO).

[0046] Example 1. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 1) [ka]

[0047] Step 1. Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (3) To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (1.9 g, 5.13 mmol) and 3-hydroxyphenylboronic acid (920.17 mg, 6.67 mmol) in dioxane (20 mL) and HO (5 mL) was added Pd(PPh) (296.51 mg, 256.59 μmol) and KCO (2.13 g, 15.40 mmol). The resulting mixture was stirred at 100 °C under N for 2 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (59%). The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 0-12% EtOAc / petroleum ether gradient @ 100 mL / min) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (2 g, 5.11 mmol, 99.61% yield, 98% purity) as a yellow oil. MS (M+H) + =384.3.

[0048] Step 2. Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl trifluoromethanesulfonate (4) To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (1 g, 2.61 mmol) in DCM (20 mL) was added TEA (1.06 g, 10.43 mmol, 1.45 mL) and TfO (1.38 g, 4.88 mmol, 804.66 μL) at 0 °C. The resulting mixture was stirred at 20 °C for 12 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (87%). The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 0-1% EtOAc / petroleum ether gradient @ 100 mL / min) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl trifluoromethanesulfonate (448 mg, 842.99 μmol, 32.32% yield, 97% purity) as a colorless oil. MS (M+H) + =516.1.

[0049] Step 3. Synthesis of tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (6) To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl trifluoromethanesulfonate (395 mg, 766.25 μmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (208.10 mg, 919.50 μmol) in dioxane (6 mL) was added BINAP (47.71 mg, 76.62 μmol), Pd(OAc) (17.20 mg, 76.62 μmol), and CsCO (748.97 mg, 2.30 mmol). The resulting mixture was stirred at 100 °C under N for 12 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (54%). The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (10 g SepaFlash® silica flash column, eluent of 0 to 15% EtOAc / petroleum ether gradient @ 100 mL / min) to give tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (396 mg, 669.22 μmol, 87.34% yield) as a yellow oil. MS (M+H) + =592.3.

[0050] Step 4. Synthesis of tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (7) To a solution of tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (396 mg, 669.22 μmol) in CF3CH2OH (10 mL) was added Pd / C (0.1 g, 10% purity) and TFA (76.31 mg, 669.22 μmol, 49.71 μL). The suspension was degassed and purged with H2 three times. The resulting mixture was stirred under H2 (15 Psi) at 20 °C for 12 h. LCMS confirmed complete consumption of the starting material and the desired mass peak. The reaction mixture was diluted with CF3CH2OH (30 mL), filtered, and the filtrate was adjusted to pH = 7 using DIPEA. The resulting mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 0 to 80% EtOAc / petroleum ether gradient @ 100 mL / min) to afford tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (76 mg, 167.25 μmol, 24.99% yield, 91% purity) as a yellow oil. MS (M+H) + =414.4.

[0051] Step 5. Synthesis of 3-(3-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (8) To a solution of tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate in dioxane (1 mL) was added HCl / dioxane (4 M, 2 mL). The resulting mixture was stirred at 20°C for 1 hour. LCMS confirmed complete consumption of the starting material and a main peak of the desired mass. The reaction mixture was concentrated in vacuo to give 3-(3-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (65 mg, crude, HCl salt) as a white solid. MS (M+H) + =314.3.

[0052] Step 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 1) To a solution of 3-(3-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (61.79 mg, 176.61 μmol, HCl salt) in DCM (4 mL) was added TEA (44.68 mg, 441.53 μmol, 61.46 μL), 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-N-(4-oxopiperidin-1-yl)benzamide (80 mg, 147.18 μmol), and MS 4A (50 mg). The mixture was stirred at 20° C. for 0.5 h. To the reaction mixture, NaBH(OAc)3 (93.58 mg, 441.53 μmol) was slowly added. The resulting mixture was stirred at 20 °C for 12 hours. LCMS confirmed complete consumption of the starting material and the desired mass peak (63%). The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to obtain the crude product. The crude product was dissolved in a mixture (20 mL, ACN:H2O = 1:3). The eluate was lyophilized to obtain the residue (51 mg, 93% purity). The residue was repurified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 8 min). The eluate was lyophilized to give a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (15.3 mg, 17.28 μmol, 11.74% yield, 95% purity). MS (M+H) + =841.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.32 (s, 1H), 8.31-8.20 (m, 2H), 7.95 (s, 1H), 7.49-7.37 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.86-6.76 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 4.83-4.70 (m, 1H), 4.11-3.98 (m, 2H), 3.92 (s, 3H), 3.75 (dd, J = 4.8, 11.2 Hz, 1H), 3.33 (s, 3H), 3.12-3.03 (m, 4H), 3.02-2.88 (m, 6H), 2.79 (br t, J = 8.9 Hz, 2H), 2.72-2.59 (m, 1H), 2.48-2.42 (m, 1H), 2.25-2.15 (m, 1H), 2.15-2.06 (m, 1H), 2.04-2.01 (m, 1H), 1.98-1.88 (m, 2H), 1.85-1.74 (m, 4H), 1.73-1.64 (m, 4H), 1.60-1.56 (m, 4H), 1.37-1.22 (m, 2H).

[0053] Example 2 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 2) [ka]

[0054] Step 1. Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (15 g, 80.98 mmol) in THF (50 mL) was added LiHMDS (1 M, 97.18 mL) at −70 °C. After 0.5 h, PhNTf (31.83 g, 89.08 mmol) in THF (50 mL) was added dropwise at −70 °C. The resulting mixture was stirred at −70 °C for 2 h. TLC (petroleum ether: EtOAc = 5:1) confirmed the formation of several new spots. The reaction mixture was quenched with saturated NH Cl solution (200 mL) and extracted with EtOAc (100 mL ≈ 3). The combined organic layers were washed with saturated brine (150 mL), dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (30 g, crude) as a yellow oil. MS (Mt-Bu + H) + =261.7.

[0055] Step 2. Synthesis of tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4) The synthesis was carried out in a manner similar to that described in Step 1 of Example 1 to obtain a yellow oil, tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4 g, 4.38 mmol, 9.27% ​​yield, 27% purity). MS (M+H) + =247.1.

[0056] Step 3. Synthesis of tert-butyl 3-(piperidin-4-yl)pyrrolidine-1-carboxylate (5) To a solution of tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate in MeOH (30 mL) was added PtO (300 mg, 1.32 mmol) under N. The mixture was stirred at 50 °C under H (50 psi) for 12 h. LCMS confirmed complete consumption of tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate, with ~30% of the intermediate product (m / z = 249.2) detected. AcOH (3.15 g, 52.45 mmol, 3 mL) was added to the mixture. The mixture was stirred at 50 °C under H (50 psi) for 12 h. LCMS confirmed the desired mass as the main peak. The mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to give the residue, which was dissolved in water (50 mL). The mixture was adjusted to pH 8 with saturated NaHCO3 solution, and the mixture was extracted with EtOAc (50 mL 8). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-(piperidin-4-yl)pyrrolidine-1-carboxylate (4 g, crude) as a yellow oil. MS (M+H) + =255.1.

[0057] Step 4. Synthesis of benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)piperidine-1-carboxylate (6) To a solution of tert-butyl 3-(piperidin-4-yl)pyrrolidine-1-carboxylate (3.5 g, 13.76 mmol) in THF (10 mL) and HO (10 mL) was added KCO (3.80 g, 27.52 mmol) and CbzCl (2.35 g, 13.76 mmol, 1.96 mL). The mixture was stirred at 25 °C for 2 h. LCMS confirmed the main peak of the desired mass. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL ≈ 3). The combined organic layers were washed with saturated brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-20% petroleum ether: EtOAc gradient @ 80 mL / min) to afford benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)piperidine-1-carboxylate (2.8 g, 7.21 mmol, 52.38% yield) as a yellow oil. MS (M-Boc+H) + =289.2.

[0058] Step 5. Synthesis of benzyl 4-(pyrrolidin-3-yl)piperidine-1-carboxylate (7) Benzyl 4-(pyrrolidin-3-yl)piperidine-1-carboxylate (1.3 g, 3.64 mmol, 50.53% yield, 91% purity, HCl salt) was obtained as a gray solid by a method similar to that described in Step 5 of Example 1. MS (M+H) + =288.9.

[0059] Step 6. Synthesis of benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidine-1-carboxylate (9) A similar procedure to that described in Step 3 of Example 1 was used to synthesize the compound, except that Pd(OAc)2 and BINAP were replaced with Pd2(dba)3 (56.38 mg, 61.57 μmol) and RuPhos (28.73 mg, 61.57 μmol). A yellow oil of benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidine-1-carboxylate (0.6 g, 844.00 μmol, 27.42% yield, 94.5% purity) was obtained. MS (M+H) + =672.5.

[0060] Step 7. Synthesis of 3-(3-fluoro-4-(3-(piperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (10) The synthesis was carried out in a manner similar to that described in Step 4 of Example 1 to obtain 3-(3-fluoro-4-(3-(piperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (420 mg, crude) as a yellow oil. MS (M+H) + =360.2.

[0061] Step 8. Synthesis of 3-(3-fluoro-4-(3-(1-nitrosopiperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (11) To a solution of 3-(3-fluoro-4-(3-(piperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (320 mg, 890.28 μmol) in THF (15 mL) was added t-BuONO (183.61 mg, 1.78 mmol, 211.78 μL) and TEA (315.30 mg, 3.12 mmol, 433.71 μL). The mixture was stirred at 60 °C for 12 h. LCMS confirmed ∼54% of the desired mass. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL Х 3). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0 to 70% petroleum ether: EtOAc gradient @ 80 mL / min) to give 3-(3-fluoro-4-(3-(1-nitrosopiperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (130 mg, 314.93 μmol, 35.37% yield, 94.1% purity) as a yellow solid. MS (M+H) + =388.9.

[0062] Step 9. Synthesis of 3-(4-(3-(1-aminopiperidin-4-yl)pyrrolidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (12) To a solution of 3-(3-fluoro-4-(3-(1-nitrosopiperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (130 mg, 334.68 μmol) in THF (8 mL) was added Zn (109.42 mg, 1.67 mmol) and a solution of NH4Cl (53.71 mg, 1.00 mmol) in HO (2 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS confirmed ~85% of the desired mass. The mixture was filtered to remove solids. The filter cake was washed with THF (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: [water (FA)-ACN]; B%: 0%-25%, 10 min). The eluate was lyophilized to give a white solid, 3-(4-(3-(1-aminopiperidin-4-yl)pyrrolidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (70 mg, 186.94 μmol, 55.86% yield, 100% purity). MS (M+H) + =375.0.

[0063] Step 10. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 2) To a solution of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (78.78 mg, 186.94 μmol) in DMF (5 mL) was added DIPEA (72.48 mg, 560.82 μmol, 97.68 μL) and HATU (85.30 mg, 224.33 μmol). After 0.5 h, 3-(4-(3-(1-aminopiperidin-4-yl)pyrrolidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (70 mg, 186.94 μmol) was added to the mixture. The resulting mixture was stirred at 25° C. for 1 h. LCMS confirmed ∼32% of the desired mass. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL Х 3). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0–100% petroleum ether: EtOAc gradient @ 80 mL / min) to give the crude product. The crude product was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 32%–62%, 11 min) and repurified by prep-TLC (DCM:MeOH = 10:1). The eluate was lyophilized to give a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidin-1-yl)-3-methoxybenzamide (15.7 mg, 19.35 μmol, 10.35% yield, 99.0% purity). MS (M+H) + =778.3. 1H NMR (400 MHz, DMSO-d6) δ = 10.83-10.69 (m, 1H), 9.27 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.22 (s, 1H), 7.87 (s, 1H), 7.49-7.38 (m, 2H), 6.93 (d, J = 15.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.9 Hz, 1H), 4.90-4.87 (m, 1H), 4.03 (t, J = 13.6 Hz, 2H), 3.93 (s, 3H), 3.73 (dd. 1H), 2.22-2.11 (m, 1H), 2.10-1.92 (m, 3H), 1.84-1.67 (m, 2H), 1.65-1.51 (m, 1H), 1.50-1.27 (m, 3H), 1.25-1.23 (m, J = 6.6 Hz, 6H).

[0064] Example 3 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)-3-methoxybenzamide (Compound 3) [ka]

[0065] Step 1. Synthesis of benzyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (3) To a solution of benzyl 3-oxoazetidine-1-carboxylate (10 g, 48.73 mmol) and tert-butyl piperidin-4-ylcarbamate (9.76 g, 48.73 mmol) in MeOH (100 mL) was added AcOH (292.64 mg, 4.87 mmol, 278.97 μL). After stirring the mixture at 20 °C for 0.5 h, NaBHCN (4.59 g, 73.10 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. The desired mass was detected by LCMS. The mixture was concentrated under reduced pressure, and the crude product was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with NaHCO (20 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0–60% EtOAc / petroleum ether gradient at 100 mL / min) to give two batches. Batch 1: white solid benzyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (3.64 g, 9.35 mmol, 19.18% yield). Batch 2: impure product, which was purified by MPLC (0.1% FA conditions; 330 g flash column; TELEDYNE ISCO CombiFlash®). 150 Welch Ultimate XB_C 18 20-40 μm; 120A; 4 grams of sample dissolved in 10 mL of DMF; eluent of 5-50% ACN / HO gradient @ 100 mL / min, 35 min, 50% ACN / HO gradient @ 100 mL / min, 10 min. The eluate was lyophilized to give benzyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (2.4 g, 6.16 mmol, 12.64% yield) as a white solid. MS (M+H) + =390.3.

[0066] Step 2. Synthesis of tert-butyl (1-(azetidin-3-yl)piperidin-4-yl)carbamate (4) To a solution of benzyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (6.44 g, 16.53 mmol), AcOH (496.47 mg, 8.27 mmol, 473.28 μL) in EtOH (70 mL) was added Pd / C (600 mg, 10% purity) and Pd(OH) / C (600 mg, 20% purity) under N. The suspension was degassed, purged with H three times, and stirred under H (15 Psi) at 20 °C for 16 h. LCMS confirmed complete consumption of the starting material. The mixture was filtered, and the filtrate was concentrated in vacuo to afford tert-butyl (1-(azetidin-3-yl)piperidin-4-yl)carbamate (5.6 g, crude) as a white solid, which was used immediately. MS(M+H) + =256.2.

[0067] Step 3. Synthesis of tert-butyl (1-(1-(4-bromo-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (6) A similar procedure to that described in Step 6 of Example 2 was used to synthesize tert-butyl (1-(1-(4-bromo-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (540 mg, 1.26 mmol, 79.53% yield) as a yellow solid. MS (M+H) + =428.1.

[0068] Step 4. Synthesis of tert-butyl (1-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (8) A similar method to that described in Step 1 of Example 1 was used to synthesize Pd(PPh3)4, but with Pd(dppf)Cl2 (68.33 mg, 93.38 μmol). Yellow solid tert-butyl (1-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (586 mg, 917.39 μmol, 98.24% yield) was obtained. MS (M+H) + =639.4.

[0069] Step 5. Synthesis of tert-butyl (1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (9) The synthesis was carried out in a similar manner to that described in Step 4 of Example 1, except for the addition of THF, to give tert-butyl (1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (680 mg, crude) as a brown oil, which was used immediately. MS (M+H) + =461.2.

[0070] Step 6. Synthesis of 3-(4-(3-(4-aminopiperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (10) A mixture of tert-butyl (1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (340 mg, 738.26 μmol) and TFA (1 mL) in DCM (3 mL) was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material, with 95% of the desired mass detected. The mixture was concentrated in vacuo to give 3-(4-(3-(4-aminopiperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (360 mg, TFA salt) as a brown gum, which was used immediately. MS (M+H) + =361.2.

[0071] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)-3-methoxybenzamide (Compound 3) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)-3-methoxybenzamide (211.5 mg, 204.71 μmol, 47.92% yield, 96% purity, di-TFA salt). MS (M+H) + =764.3. 1 H NMR (400 MHz, CD3OD) δ = 8.16 (d, J = 8.3 Hz, 1H), 8.13 (s, 1H), 7.65-7.49 (m, 2H), 6.98 (s, 1H), 6.97-6.93 (m, 1H), 6.63 (t, J = 8.7 Hz, 1H), 5.11 (td, J = 6.8, 13.5 Hz, 1H), 4.39-4.29 (m, 2H), 4.21 (br d, J = 15.4 Hz, 2H), 4.17-4.07 (m, 4H), 4.01 (s, 3H), 3.80 (dd, J = 5.5, 10.6 Hz, 1H), 3.76-3.58 (m, 2H), 3.39 (s, 3H), 3.27-3.03 (m, 2H), 2.81-2.57 (m, 2H), 2.42-2.25 (m, 2H), 2.25-2.13 (m, 2H), 2.11-1.83 (m, 2H), 1.32 (d, J = 6.7 Hz, 6H).

[0072] Example 4 Synthesis of N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 4) [ka]

[0073] Step 1. Synthesis of benzyl (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (16) To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carbaldehyde (850 mg, 2.67 mmol), benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (829.91 mg, 2.67 mmol, HCl salt) in DCM (10 mL) was added NaOAc (438.05 mg, 5.34 mmol), and the resulting mixture was stirred at 20 °C for 0.5 h. Then, NaBH(OAc) (1.70 g, 8.01 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as the main peak. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL ≈3). The combined organic layers were washed with brine (90 mL Х 2), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent of 50–100% EtOAc / petroleum ether to 10% MeOH / EtOAc gradient @ 100 mL / min) and repurified by reverse-phase HPLC (column: Phenomenex Luna C18 150×40 mm×15 μm; mobile phase: [water (TFA)-ACN]; gradient: 21%–51% B over 10 min) to afford a yellow solid, benzyl (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (500 mg, 723.88 μmol, 27.11% yield, TFA salt). MS (M+H) + =577.3

[0074] Step 2. Synthesis of 3-(4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (13) A mixture of benzyl (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (200 mg, 346.80 μmol) in TFA (2 mL) was stirred at 60° C. for 16 hours. LCMS confirmed the desired mass as the main peak. The mixture was concentrated in vacuo to give 3-(4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (200 mg, crude, TFA salt) as a white solid. MS (M+H) + =443.2.

[0075] Step 3. Synthesis of N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylethanamine (3) A mixture of (1H-benzo[d][1,2,3]triazol-1-yl)methanol (2 g, 13.41 mmol) and N-benzylethanamine (1.81 g, 13.41 mmol, 1.99 mL) in EtOH (20 mL) was stirred at 15 °C for 12 h. TLC (petroleum ether: EtOAc = 3:1) confirmed complete consumption of the starting material, and a single major spot was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent of 0 to 50% EtOAc / petroleum ether gradient @ 80 mL / min) to give N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylethanamine (3.5 g, crude) as a yellow oil. MS (M+H) + =267.4.

[0076] Step 4. Synthesis of ethyl 3-(benzyl(ethyl)amino)-2,2-difluoropropanoate (5) To a suspension of Zn (1.33 g, 20.27 mmol) in THF (60 mL) was added TMSCl (2.08 g, 19.15 mmol, 2.43 mL) dropwise at 0 °C under N, maintaining the temperature below 5 °C. After stirring for 20 min, ethyl 2-bromo-2,2-difluoroacetate (3.66 g, 18.02 mmol, 2.32 mL) was added slowly at 0 °C under N, maintaining the temperature below 30 °C. The mixture was stirred for 20 min and cooled to 0 °C. A suspension of N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylethanamine (3 g, 11.26 mmol) in THF (48 mL) was added at 0 °C, maintaining the temperature below 10 °C. After 20 min, the suspension was warmed to 15 °C and stirred for 3 h. LCMS confirmed the main peak of the desired mass. The reaction mixture was filtered, and the filter cake was washed with EtOAc (100 mL) and THF (100 mL). The combined filtrate was concentrated in vacuo. The suspension was filtered, and the filter cake was washed with a solution (200 mL, petroleum ether: EtOAc = 8:1). The filtrate was concentrated in vacuo to give ethyl 3-(benzyl(ethyl)amino)-2,2-difluoropropanoate (6 g, crude) as a yellow gum. MS (M+H) + =272.3.

[0077] Step 5. Synthesis of ethyl 3-(ethylamino)-2,2-difluoropropanoate (6) To a solution of ethyl 3-(benzyl(ethyl)amino)-2,2-difluoropropanoate (5 g, 18.43 mmol) and HCl (12 M, 2.00 mL) in EtOH (100 mL) was added Pd(OH) (500.00 mg, 712.08 μmol, 20% purity) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 25 °C under H (15 psi) for 64 h. LCMS confirmed the desired mass as the main peak. The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give ethyl 3-(ethylamino)-2,2-difluoropropanoate (5 g, crude, HCl salt) as a yellow oil. MS (M+H) + =182.1.

[0078] Step 6. Synthesis of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (8) To a solution of ethyl 3-(ethylamino)-2,2-difluoropropanoate (5 g, 22.97 mmol, HCl salt) and 2,4-dichloro-5-nitropyrimidine (2.97 g, 15.32 mmol) in acetone (100 mL) was added KCO (12.70 g, 91.89 mmol), and the temperature was maintained at 0°C to 5°C. The suspension was stirred at 15°C for 16 h. TLC (petroleum ether: EtOAc = 5:1) confirmed complete consumption of the starting material. The reaction mixture was diluted with HO (100 mL), and the resulting mixture was extracted with EtOAc (100 mL Х 5), and the combined organic layers were concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent of 0-12% EtOAc / petroleum ether gradient @ 100 mL / min) to give ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (3 g, 8.86 mmol, 57.83% yield) as a yellow oil. MS (M+H) + =339.7.

[0079] Step 7. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (9) To a solution of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (3 g, 8.86 mmol) in AcOH (30 mL) was added Fe (989.30 mg, 17.72 mmol), and the mixture was stirred at 20 °C for 1 h. After that, the suspension was further heated at 80 °C for 16 h. LCMS confirmed the main peak of the desired mass. The reaction mixture was concentrated in vacuo to remove most of the solvent, and the residue was diluted with H2O (100 mL) and EtOAc (100 mL). The suspension was filtered, the filter cake was washed with EtOAc (200 mL), the organic phase was separated, and the aqueous solution was extracted with EtOAc (100 mL Х 3). The combined organic layers were washed with saturated NaHCO3 solution (300 mL Х 2), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent of 0 to 50% EtOAc / petroleum ether gradient @ 100 mL / min). The eluate was concentrated in vacuo to give the residue. The residue was triturated with a mixture (petroleum ether / EtOAc = 1 / 1, 20 mL) at 15 °C for 10 minutes, and the suspension was filtered. The filter cake was washed with a mixture (petroleum ether / EtOAc = 1 / 1, 100 mL). The filtrate was concentrated in vacuo to give a yellow solid, 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (1 g, 3.81 mmol, 42.99% yield). MS (M+H) + =263.0.

[0080] Step 8. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (10) To a solution of 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (900 mg, 3.43 mmol) in acetone (10 mL) was added K2CO3 (710.41 mg, 5.14 mmol) and MeI (486.39 mg, 3.43 mmol, 213.33 μL), and the mixture was stirred at 15 °C for 16 h. LCMS confirmed the main peak of the desired mass. The mixture was filtered through a pad of Celite. The filter cake was washed with EtOAc (10 mL). The filtrate was concentrated in vacuo to remove most of the solvent. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a gray solid, 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (1 g, crude). MS (M+H) + =277.0.

[0081] Step 9. Synthesis of 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (12) To a solution of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (300 mg, 1.08 mmol) and 4-amino-3-methoxybenzoic acid (181.26 mg, 1.08 mmol) in EtOH (2 mL) and HO (8 mL) was added HCl (12 M, 135.54 μL), and the resulting mixture was stirred at 100 °C for 16 h. LCMS confirmed the desired mass as the main peak. The mixture was concentrated in vacuo to remove half of the solvent, and the residue was filtered. The filter cake was washed with HO (10 mL), and the combined filter cake was concentrated in vacuo. The residue was triturated with EtOAc (10 mL) for 30 min. The suspension was filtered, and the filter cake was washed with EtOAc (10 mL). The filter cake was collected and dried to give a gray solid: 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (300 mg, 736.43 μmol, 67.92% yield). MS (M+H) + =408.1.

[0082] Step 10. Synthesis of N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 4) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (47.3 mg, 54.58 μmol, 31.76% yield, 96% purity). MS (M+H) + =832.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.48-8.39 (m, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.90 (s, 1H), 7.53-7.44 (m, 2H), 7.05-6.92 (m, 3H), 4.49-4.34 (m, 1H), 4.17 (t, J = 13.7 Hz, 2H), 3.94 (s, 3H), 3.84-3.75 (m, 1H), 3.70-3.59 (m, 2H), 3.50-3.33 (m, 5H), 2.72-2.56 (m, 6H), 2.49-2.42 (m, 2H), 2.26-2.10 (m, 5H), 2.04-1.94 (m, 2H), 1.88-1.74 (m, 5H), 1.66-1.56 (m, 2H), 1.35-1.15 (m, 6H).

[0083] Example 5 Synthesis of 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 5) [ka] The synthesis was carried out in a manner similar to that described in Example 4 to obtain a white solid, 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (52.5 mg, 60.34 μmol, 33.90% yield, 94% purity). MS (M+H) + =818.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.44 (d, J = 7.2 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.56-7.46 (m, 2H), 7.05-6.90 (m, 3H), 4.45-4.36 (m, 1H), 4.17 (t, J = 14.4 Hz, 2H), 3.94 (s, 3H), 3.83-3.76 (m, 1H), 3.36-3.32 (m, 5H), 3.06 (s, 3H), 2.72-2.57 (m, 4H), 2.49-2.41 (m, 3H), 2.29-2.12 (m, 5H), 2.02-1.96 (m, 1H), 1.89-1.73 (m, 5H), 1.71-1.59 (m, 4H), 1.33-1.21 (m, 3H).

[0084] Example 6 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 6) [ka]

[0085] Step 1. Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidine-4-carbaldehyde (2) To a solution of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione (0.5 g, 1.58 mmol) in DCM (30 mL) was added DMP (1.01 g, 2.37 mmol), and the mixture was stirred at 25° C. for 2 h. TLC (petroleum ether: EtOAc = 1:1) confirmed that 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione was completely consumed and a new spot was formed. The mixture was filtered, and the filtrate was concentrated to give 1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidine-4-carbaldehyde (0.5 g, crude) as a yellow oil. MS (M+H) + =315.1.

[0086] Step 2. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3) To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidine-4-carbaldehyde (0.5 g, 1.59 mmol) and tert-butyl ((1r,4r)-4-(methylamino)cyclohexyl)carbamate (363.15 mg, 1.59 mmol) in DCM (10 mL) was added NaBH(OAc) (505.62 mg, 2.39 mmol) and AcOH (105.06 mg, 1.75 mmol, 100.06 μL), and the resulting mixture was stirred at 25 °C for 12 h. LCMS confirmed the desired mass as the main peak (77%). The mixture was poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 0-30% MeOH / EtOAc gradient @ 80 mL / min) to give a yellow solid, tert-butyl ((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (0.27 g, 512.62 μmol, 32.23% yield). MS (M+H) + =527.5.

[0087] Step 3. Synthesis of 3-(4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione (4) A yellow oil of 3-(4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione (0.2 g, crude, HCl salt) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =427.3.

[0088] Step 4. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 6) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (33 mg, 37.39 μmol, 17.32% yield, 97% purity). MS (M+H) + =856.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.30-8.24 (m, 2H), 8.09 (br d, J = 8.1 Hz, 1H), 7.96 (s, 1H), 7.54-7.44 (m, 2H), 7.04-6.92 (m, 3H), 4.87-4.69 (m, 1H), 4.17-4.00 (m, 2H), 3.94 (s, 3H), 3.74 (br dd, J = 5.1, 11.1 Hz, 2H), 3.55-3.37 (m, 1H), 3.33 (s, 3H), 3.10-3.02 (m, 2H), 2.70-2.53 (m, 4H), 2.47-2.42 (m, 1H), 2.38-2.26 (m, 3H), 2.28-2.19 (m, 4H), 2.15-2.01 (m, 2H), 2.01-1.89 (m, 5H), 1.87-1.66 (m, 6H), 1.65-1.57 (m, 4H), 1.48-1.39 (m, 4H), 1.34-1.26 (m, 2H).

[0089] Example 7 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 7) [ka]

[0090] Step 1. Synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene (2) The synthesis was carried out in a similar manner to that described in Step 8 of Example 4, except that acetone was replaced with DMF (30 mL), to obtain 1,2-difluoro-4-methoxy-5-nitrobenzene (3.9 g, crude) as a yellow oil. MS (M+H) + =190.2

[0091] Step 2. Synthesis of tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (3) A yellow solid, tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (4.3 g, 12.10 mmol, 58.68% yield), was obtained by synthesizing in a manner similar to that described in Step 6 of Example 4, except that acetone was replaced with ACN. MS (M-56+H) + =300.1

[0092] Step 3. Synthesis of tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (4) A similar procedure to that described in Step 9 of Example 2 was used, except that Zn and THF were replaced with Fe (3.38 g, 60.50 mmol) and EtOH (60 mL) to obtain a brown solid, tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (4 g, 11.80 mmol, 97.53% yield, 96% purity). MS (M+H) + =326.1

[0093] Step 4. Synthesis of tert-butyl 4-(2-fluoro-4-iodo-5-methoxyphenyl)piperazine-1-carboxylate (5) To a solution of tert-butyl nitrite (1.27 g, 12.29 mmol, 1.46 mL) in ACN (40 mL) was added tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (2 g, 6.15 mmol), I2 (3.12 g, 12.29 mmol), and CuI (2.34 g, 12.29 mmol) at 0 °C, and the resulting mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass peak (23%). The reaction was filtered, and the filtrate was concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0 to 30% EtOAc / petroleum ether gradient @ 80 mL / min) to afford tert-butyl 4-(2-fluoro-4-iodo-5-methoxyphenyl)piperazine-1-carboxylate (560 mg, 1.17 mmol, 19.00% yield, 91% purity) as a yellow oil. MS (M+H) + =437.0

[0094] Step 5. Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (7) The synthesis was carried out in a manner similar to that described in Step 4 of Example 3 to obtain a yellow oil, tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (570 mg, 845.94 μmol, 65.90% yield, 89% purity). MS (M+H) + =600.3

[0095] Step 6. Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (8) A similar procedure to that described in Step 2 of Example 3 was used, except that EtOH and AcOH were replaced with CF3CH2OH (20 mL) and TFA (47.53 mg, 416.88 μmol, 30.97 μL) to obtain a brown solid, tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (0.2 g, 373.49 μmol, 89.59% yield, TFA salt). MS (M+H+Na) + =444.3

[0096] Step 7. Synthesis of 3-(5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (9) A similar procedure to that described in Step 5 of Example 1 was used, except that dioxane was replaced with DCM (2 mL), to obtain a white solid, 3-(5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (0.17 g, crude, HCl). MS (M+H) + =322.2

[0097] Step 8. Synthesis of tert-butyl (4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (11) Prepared in a manner similar to that described in Step 6 of Example 1, a yellow solid of tert-butyl (4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (60 mg, 93.12 μmol, 19.95% yield, 85% purity) was obtained. MS (M+H) + =548.3

[0098] Step 9. Synthesis of 3-(4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)piperidine-2,6-dione (12) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-(4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)piperidine-2,6-dione (50 mg, 89.04 μmol, 97.52% yield, TFA) as a brown oil. MS (M+H) + =448.3

[0099] Step 10. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 7) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (36.6 mg, 36.03 μmol, 40.47% yield, 95% purity, TFA). MS (M+H) + =851.6. 1 H NMR (400 MHz, DMSO-d6) δ = 10.74 (s, 1H), 9.53 (br s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 8.16-8.03 (m, 1H), 7.50-7.37 (m, 2H), 7.04 (d, J = 13.1 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 4.99-4.81 (m, 1H), 4.08 (s, 2H), 3.94 (s, 3H), 3.95-3.86 (m, 4H), 3.63-3.57 (m, 4H), 3.33 (s, 3H), 3.28-3.18 (m, 4H), 3.14-3.04 (m, 4H), 2.87-2.78 (m, 2H), 2.62-2.57 (m, 2H), 2.28-2.12 (m, 1H), 1.92-1.83 (m, 1H), 1.81-1.73 (m, 2H), 1.71-1.62 (m, 2H), 1.45-1.36 (m, 3H), 1.25 (d, J = 6.6 Hz, 6H).

[0100] Example 8 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 8) [ka]

[0101] Step 1. Synthesis of 3-((3-bromophenyl)amino)propanoic acid (2) To a solution of 3-bromoaniline (1 g, 5.81 mmol, 632.91 μL) in toluene (10 mL) was added acrylic acid (630.00 mg, 8.74 mmol, 0.6 mL). The mixture was stirred at 80 °C for 14 h. LCMS confirmed 96% of the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 20-40% EtOAc / petroleum ether gradient @ 100 mL / min) to give 3-((3-bromophenyl)amino)propanoic acid (890 mg, 3.50 mmol, 60.22% yield, 96% purity) as a yellow oil. MS (M+H) + =244.2.

[0102] Step 2. Synthesis of methyl 3-((3-bromophenyl)amino)propanoate (3) To a solution of 3-((3-bromophenyl)amino)propanoic acid (890 mg, 3.65 mmol) in toluene (8 mL) and MeOH (8 mL) was slowly added TMSCHN2 (2 M, 5.5 mL) and stirred at 25 °C for 14 h. LCMS confirmed 41% of the starting material and 34% of the desired mass remained. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 10-50% EtOAc / petroleum ether gradient @ 100 mL / min) to give methyl 3-((3-bromophenyl)amino)propanoate (340 mg, 1.28 mmol, 35.04% yield, 97% purity) as a yellow oil. MS (M+H) + =258.1.

[0103] Step 3. Synthesis of methyl 3-((3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)amino)propanoate (5) To a solution of tert-butyl ((1r,4r)-4-(methyl(piperidin-4-ylmethyl)amino)cyclohexyl)carbamate (396 mg, 1.22 mmol) and methyl 3-((3-bromophenyl)amino)propanoate (0.24 g, 929.83 μmol) in dioxane (5 mL) was added CsCO (607 mg, 1.86 mmol) and Pd-PEPPSI-IHeptCl (63.32 mg, 65.09 μmol) and stirred at 100 °C for 14 h. LCMS confirmed the desired mass. The mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent of 80-100% EtOAc / petroleum ether to 10% MeOH / EtOAc gradient @ 100 mL / min) and then repurified by prep-TLC (DCM:MeOH = 10:1) to give methyl 3-((3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)amino)propanoate (150 mg, 298.40 μmol, 32.09% yield) as a yellow oil. MS (M+H) + =503.5.

[0104] Step 4. Synthesis of methyl 3-(1-(3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)ureido)propanoate (6) To a solution of methyl 3-((3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)amino)propanoate (120 mg, 238.72 μmol) in AcOH (1 mL) was added KOCN (30.5 mg, 358.19 μmol) and the mixture was stirred at 25° C. for 14 h. LCMS confirmed 80% of the desired mass. The mixture was concentrated under reduced pressure. The crude product was diluted with MeCN (3 mL) and water (30 mL), and the suspension was lyophilized to give a yellow solid, methyl 3-(1-(3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)ureido)propanoate (150 mg, crude, AcOH salt). MS (M+H) + =546.6.

[0105] Step 5. Synthesis of tert-butyl ((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (7) To a solution of methyl 3-(1-(3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)ureido)propanoate (120 mg, 198.10 μmol, AcOH salt) in ACN (2.5 mL) was slowly added Triton B (552.00 mg, 1.32 mmol, 600 μL, 40% purity), and the mixture was stirred at 25 °C for 1 h. LCMS confirmed 61% of the desired mass. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3), then 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, tert-butyl ((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (90 mg, crude). MS (M+H)+ =514.5.

[0106] Step 6. Synthesis of 1-(3-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (8) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain a yellow oil of 1-(3-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (90 mg, crude, TFA). MS (M+H) + =414.4.

[0107] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 8) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (48.8 mg, 56.73 μmol, 36.26% yield, 98% purity). MS (M+H) + =843.4. 1H NMR (400 MHz, CD3CN) δ = 8.47 (d, J = 8.3 Hz, 1H), 8.30-8.19 (m, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.44-7.37 (m, 2H), 7.24 (t, J = 8.1 Hz, 1H), 6.91-6.82 (m, 3H), 6.75-6.69 (m, 1H), 4.92-4.80 (m, 1H), 4.01-3.92 (m, 5H), 3.89-3.82 (m, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.72 (br d, J = 12.5 Hz, 2H), 3.33 (s, 3H), 3.11-3.02 (m, 1H), 2.86-2.81 (m, 2H), 2.78-2.73 (m, 2H), 2.72-2.69 (m, 2H), 2.64 (s, 3H), 2.15-2.08 (m, 2H), 2.06-1.99 (m, 3H), 1.89-1.82 (m, 2H), 1.79-1.73 (m, 2H), 1.69-1.57 (m, 7H), 1.52-1.40 (m, 2H), 1.40-1.26 (m, 3H).

[0108] Example 9 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (Compound 9) [ka]

[0109] Step 1. Synthesis of benzyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate (2) A bright yellow solid, benzyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate (410 mg, crude, HCl salt), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =263.2.

[0110] Step 2. Synthesis of tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)amino)piperidine-1-carboxylate (3) A yellow solid, tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)amino)piperidine-1-carboxylate (670 mg, crude), was obtained by synthesis in a manner similar to that described in Step 6 of Example 1. MS (M+H) + =446.3.

[0111] Step 3. Synthesis of tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)(methyl)amino)piperidine-1-carboxylate (4) To a solution of tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)amino)piperidine-1-carboxylate (670 mg, 1.50 mmol, crude) in MeOH (30 mL) was added AcOH (90.29 mg, 1.50 mmol, 86.00 μL) and HCHO (1.22 g, 15.04 mmol, 1.12 mL, 37% purity). The mixture was stirred at 20° C. for 2 h. Then, NaBHCN (800 mg, 12.73 mmol) was added to the mixture at 20° C. and stirred at 20° C. for 14 h. LCMS confirmed the desired mass peak (87%). The reaction mixture was added with H2O (30 mL), concentrated to remove MeOH, diluted with EtOAc (40 mL), and saturated NaHCO3 solution was added to the mixture until pH reached 8-9 at 0 °C. The mixture was extracted with EtOAc (50 mL x 2), and the combined organic layer was washed with brine (40 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC (Column: Waters Xbridge C18 150x50mmx10µm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 54%-84%, 10 min, Column temperature: 30°C), and the eluate was lyophilized to give a bright yellow solid, tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)(methyl)amino)piperidine-1-carboxylate (300 mg, 652.71µmol, 43.41% yield). MS (M+Na) + =482.3.

[0112] Step 4. Synthesis of benzyl ((1r,4r)-4-((methyl(piperidin-4-yl)amino)methyl)cyclohexyl)carbamate (5) A bright yellow solid, benzyl ((1r,4r)-4-((methyl(piperidin-4-yl)amino)methyl)cyclohexyl)carbamate (170 mg, crude, HCl salt), was obtained by synthesis in a manner similar to that described in Step 1. MS (M+H) + =360.3.

[0113] Step 5. Synthesis of benzyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 3 of Example 8 to obtain a bright yellow solid of benzyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)carbamate (90 mg, 164.33 μmol, 36.85% yield). MS (M+H) + =548.3.

[0114] Step 6. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)methyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (8) The synthesis was carried out in a manner similar to that described in Step 2 of Example 4 to obtain 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)methyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (77 mg, crude, TFA salt) as a bright yellow oil. MS (M+H) + =414.3.

[0115] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (Compound 9) The synthesis was carried out in a manner similar to that described in step 10 of Example 2 to obtain a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (26.3 mg, 23.35 μmol, 13.06% yield, 94.7% purity, di-TFA salt). MS (M+H) + =843.5. 1 H NMR (400 MHz, CD3OD) δ = 8.36 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.18-8.14 (m, 1H), 7.86 (dd, J = 2.6, 9.2 Hz, 1H), 7.64-7.56 (m, 2H), 7.55-7.50 (m, 1H), 5.11-4.99 (m, 2H), 4.17-4.07 (m, 4H), 4.02 (s, 3H), 3.96-3.87 (m, 1H), 3.63-3.53 (m, 1H), 3.41 (s, 3H), 3.28-3.21 (m, 1H), 3.10-3.00 (m, 3H), 2.93 (s, 3H), 2.81-2.74 (m, 2H), 2.45-2.35 (m, 1H), 2.33-2.16 (m, 3H), 2.13-2.02 (m, 5H), 2.00-1.82 (m, 6H), 1.75-1.66 (m, 4H), 1.59-1.47 (m, 2H), 1.38-1.26 (m, 2H).

[0116] Example 10 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 10) [ka]

[0117] Step 1. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3) The synthesis was carried out in a manner similar to that described in Step 3 of Example 8 to obtain a bright yellow solid, tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (550 mg, 1.26 mmol, 60.27% yield). MS (M+H) + =437.2.

[0118] Step 2. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (5) A mixture of tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (400 mg, 915.30 μmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (666.67 mg, 1.60 mmol), KPO (666.67 mg, 3.14 mmol), and CataCXium A Pd G (80 mg, 119.65 μmol) in dioxane (20 mL) and water (5 mL) was degassed and purged with N gas three times. The resulting mixture was stirred under N gas at 80 °C for 16 h. LCMS confirmed complete consumption of tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate and the desired mass peak (41%). The reaction mixture was diluted with HO (15 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (90 mL × 3), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent of 2-10% DCM:MeOH gradient, 60 mL / min) to give a yellow solid, tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (520 mg, 751.55 μmol, 82.11% yield). MS (M+H) + =692.5.

[0119] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 4 of Example 1 to give a yellow oil of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (230 mg, 447.76 μmol, 96.81% yield). MS (M+H) + =514.3.

[0120] Step 4. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (7) A bright yellow solid, 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (156 mg, crude, HCl salt) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =414.3.

[0121] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 10) 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (42.0 mg, 44.82 μmol, 13.37% yield, 89.95% purity) was synthesized in a manner similar to that described in Step 10 of Example 2 to afford a white solid. MS (M+H) + =843.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.77 (s, 1H), 8.31-8.23 (m, 2H), 8.22-8.16 (m, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.53-7.44 (m, 2H), 7.35-7.27 (m, 1H), 7.15 (d, J = 8.7 Hz, 1H), 4.82-4.70 (m, 1H), 4.09-3.99 (m, 2H), 3.93 (s, 3H), 3.91-3.84 (m, 1H), 3.79-3.63 (m, 3H), 2.74-2.63 (m, 2H), 2.60-2.51 (m, 2H), 2.50-2.48 (m, 3H), 2.36-2.29 (m, 1H), 2.28-2.23 (m, 2H), 2.20 (s, 3H), 2.18-2.04 (m, 2H), 1.98-1.86 (m, 4H), 1.82-1.67 (m, 6H), 1.64-1.52 (m, 5H), 1.43-1.29 (m, 4H), 1.23-1.11 (m, 2H).

[0122] Example 11 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 11) [ka]

[0123] Step 1. Synthesis of 3-(5-bromopyridin-2-yl)piperidine-2,6-dione (2) To a solution of methyl 2-(5-bromopyridin-2-yl)acetate (2.0 g, 8.69 mmol) in DMF (15 mL) was added acrylamide (617.91 mg, 8.69 mmol, 599.91 μL) and t-BuOK (1 M, 8.69 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. TLC (petroleum ether: EtOAc = 1:1) confirmed complete consumption of the starting material and the formation of one new spot. The reaction mixture was filtered, and the filter cake was dried to obtain the crude product, which was then triturated with EtOAc:water = 1:1 at 20 °C for 30 min to obtain 3-(5-bromopyridin-2-yl)piperidine-2,6-dione (1.5 g, 5.57 mmol, 64.12% yield) as a white solid. MS (M+H) + =270.1. 1 H NMR (400 MHz, DMSO-d6) δ = 11.01-10.73 (m, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 2.4, 8.3 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 4.12-3.97 (m, 1H), 2.68-2.58 (m, 1H), 2.56-2.52 (m, 1H), 2.31-2.19 (m, 1H), 2.16-2.06 (m, 1H).

[0124] Step 2. Synthesis of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (3) A yellow solid, 3-(5-(4-(1,3-dioxolan-2-yl)-1-piperidyl)-2-pyridyl)piperidine-2,6-dione (1.1 g, 3.06 mmol, 54.85% yield, 96% purity), was obtained in a manner similar to that described in Step 3 of Example 8. MS (M+H) + =346.2 1 H NMR (400 MHz, DMSO-d6) δ = 10.77 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 2.9, 8.7 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 4.62 (d, J = 4.9 Hz, 1H), 3.91-3.84 (m, 3H), 3.81-3.73 (m, 4H), 2.74-2.63 (m, 2H), 2.59-2.53 (m, 2H), 2.25-2.05 (m, 2H), 1.74 (d, J = 13.8 Hz, 2H), 1.69-1.60 (m, 1H), 1.46-1.33 (m, 2H).

[0125] Step 3. Synthesis of 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbaldehyde (4) To a solution of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (600 mg, 1.74 mmol) in dioxane (2 mL) and HO (2 mL) was added FA (83.46 mg, 1.74 mmol, 6 mL). The mixture was stirred at 20 °C for 48 h. LCMS showed that 6% of the starting material remained, and several new peaks and the desired mass (93%) appeared. The reaction mixture was diluted with saturated aqueous NaCO (50 mL) at 0 °C and adjusted to pH = 7, then extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbaldehyde (520 mg, 1.55 mmol, 89.40% yield, 90% purity) as a yellow solid. MS (M+H+H2O) + =320.2

[0126] Step 4. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6) A yellow solid of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (200 mg, 346.62 μmol, 20.09% yield, 97% purity, FA) was obtained by synthesis in a manner similar to that described in Step 2 of Example 6. MS (M+H) + =514.4.

[0127] Step 5. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (7) A white solid, 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (110 mg, crude, HCl salt) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =414.2

[0128] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 11) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (82.1 mg, 73.77 μmol, 30.18% yield, 93.9% purity, di-TFA salt). MS (M+H) + =817.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.84 (dd, J = 3.9, 8.9 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.27-8.13 (m, 4H), 7.74-7.61 (m, 1H), 7.56-7.38 (m, 3H), 4.95-4.82 (m, 1H), 4.14-4.02 (m, 3H), 3.93 (s, 3H), 3.90-3.84 (m, 2H), 3.32 (s, 3H), 3.23-3.19 (m, 1H), 2.99-2.88 (m, 2H), 2.87-2.77 (m, 5H), 2.65-2.57 (m, 2H), 2.45-2.39 (m, 1H), 2.31-2.20 (m, 1H), 2.15-2.06 (m, 2H), 2.04-1.93 (m, 5H), 1.85-1.75 (m, 1H), 1.74-1.59 (m, 2H), 1.52-1.40 (m, 2H), 1.39-1.28 (m, 2H), 1.24 (d, J = 6.7 Hz, 6H).

[0129] Example 12 Synthesis of 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 12) [ka]

[0130] Step 1. Synthesis of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-chloro-4-methylpyridine (3) A mixture of 2-chloro-5-iodo-4-methylpyridine (6.1 g, 24.07 mmol), 4-(1,3-dioxolan-2-yl)piperidine (3.78 g, 24.07 mmol), t-BuONa (6.94 g, 72.20 mmol), and RuPhos Pd G4 (409.31 mg, 481.32 μmol) in dioxane (70 mL) was stirred at 100 °C for 16 h under N2 atmosphere. LCMS confirmed complete consumption of the starting material and the desired mass peak (60%). The mixture was filtered, and the filter cake was washed with THF (200 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 5-10% EtOAc / petroleum ether gradient @ 200 mL / min) to give 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-chloro-4-methylpyridine (4.35 g, 15.38 mmol, 63.92% yield) as a yellow solid. MS (M+H) + =283.1

[0131] Step 2. Synthesis of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-4-methyl-2,3'-bipyridine (5) A yellow solid, 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-4-methyl-2,3'-bipyridine (6 g, 11.16 mmol, 72.54% yield), was obtained by synthesizing the compound in a manner similar to that described in Step 2 of Example 10. MS (M+H) + =538.3.

[0132] Step 3. Synthesis of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (6) To a solution of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-4-methyl-2,3'-bipyridine (5 g, 9.30 mmol) in THF (200 mL) and DMF (40 mL) was added AcOH (20.98 g, 349.38 mmol, 20 mL), Pd / C (3 g, 2.82 mmol, 10% purity), and Pd(OH)2 / C (3 g, 4.27 mmol, 20% purity) at 30 °C. The mixture was stirred at 30 °C under H2 (50 Psi) for 70 h. LCMS confirmed the desired mass (81%). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The mixture was diluted with water (120 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (500 mL × 2), dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The crude product was triturated with 1:1 EtOAc / petroleum ether (50 mL) at 20 °C for 30 min to give a yellow solid: 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (2.13 g, 5.93 mmol, 63.72% yield). MS (M+H) + =360.2.

[0133] Step 4. Synthesis of 1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidine-4-carbaldehyde (7) A similar procedure to that described in Step 3 of Example 11 was used, except that FA was replaced with HCl / dioxane (4M, 20 mL), to obtain a yellow solid, 1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidine-4-carbaldehyde (240 mg, crude). MS (M+H) + =316.2.

[0134] Step 5. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 6 of Example 1 to obtain a yellow solid, tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (170 mg, 322.15 μmol, 42.33% yield). MS (M+H) + =528.3.

[0135] Step 6. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (10) A white solid, 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (150 mg, HCl salt) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =428.3.

[0136] Step 7. Synthesis of 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 12) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (36.9 mg, 44.12 μmol, 27.30% yield, 96% purity). MS (M+H) + =803.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.83-10.76 (m, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.53-7.47 (m, 2H), 7.13 (s, 1H), 4.17 (t, J = 14.4 Hz, 2H), 3.94 (s, 3H), 3.91-3.85 (m, 1H), 3.77-3.68 (m, 1H), 3.31 (s, 3H), 3.13-3.08 (m, 2H), 3.06 (s, 3H), 2.64-2.57 (m, 2H), 2.45-2.40 (m, 2H), 2.31-2.65(m, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 2.14-2.07 (m, 2H), 1.92-1.87 (m, 2H), 1.83-1.75 (m, 4H), 1.55-1.49 (m, 1H), 1.39-1.31 (m, 4H), 1.27-1.20 (m, 2H).

[0137] Example 13 Synthesis of N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 13) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (19.3 mg, 22.44 μmol, 13.89% yield, 95% purity). MS (M+H) + =817.3. 1H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 7.55-7.46 (m, 2H), 7.13 (s, 1H), 4.26-4.11 (m, 2H), 3.94 (s, 3H), 3.92-3.85 (m, 1H), 3.78-3.70 (m, 1H), 3.70-3.61 (m, 2H), 3.32 (s, 3H), 3.15-3.09 (m, 2H), 2.74-2.69 (m, 1H), 2.66-2.64 (m, 1H), 2.46-2.42 (m, 2H), 2.32-2.27 (m, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 2.15-2.07 (m, 2H), 1.94-1.88 (m, 2H), 1.85-1.75 (m, 4H), 1.59-1.49 (m, 1H), 1.43-1.26 (m, 5H), 1.25-1.19 (m, 4H).

[0138] Example 14 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 14) [ka] The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (127.4 mg, 141.23 μmol, 22.57% yield, 95% purity). MS (M+H) + =857.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.32-8.18 (m, 2H), 8.17-8.12 (m, 1H), 8.07 (br dd, J = 1.5, 6.1 Hz, 1H), 7.95 (s, 1H), 7.54-7.41 (m, 2H), 7.13 (s, 1H), 4.84-4.68 (m, 1H), 4.04 (br t, J = 14.1 Hz, 2H), 3.93 (s, 3H), 3.88 (dd, J = 5.3, 8.7 Hz, 1H), 3.75-3.70 (m, 1H), 3.36-3.55 (m, 3H), 3.17-3.07 (m, 2H), 2.67 (br dd, J = 1.7, 3.5 Hz, 2H), 2.58-2.51 (m, 5H), 2.32-2.26 (m, 2H), 2.24 (s, 3H), 2.23-2.14 (m, 3H), 2.11 (br dd, J = 6.4, 12.3 Hz, 1H), 1.92 (br dd, J = 3.1, 10.2 Hz, 4H), 1.88-1.77 (m, 3H), 1.77-1.65 (m, 3H), 1.65-1.49 (m, 5H), 1.39 (br d, J = 5.1 Hz, 4H), 1.27 (br s, 1H).

[0139] Example 15 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 15) [ka] The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (65.7 mg, 53.21 μmol, 17.25% yield, 95% purity, 3TFA salt). MS (M+H) + =831.3. 1H NMR (400 MHz, CD3OD) δ = 8.42-8.31 (m, 1H), 8.12 (s, 1H), 8.10-7.98 (m, 1H), 7.83-7.72 (m, 1H), 7.58 (s, 1H), 7.56-7.51 (m, 1H), 5.21-5.04 (m, 1H), 4.83-4.62 (m, 1H), 4.16 (br t, J = 11.8 Hz, 2H), 4.01 (s, 3H), 3.99-3.92 (m, 1H), 3.40 (s, 3H), 3.37 (br s, 3H), 3.34 - 3.27 (m, 1H), 3.12-3.03 (m, 1H), 2.94 (s, 5H), 2.85-2.73 (m, 2H), 2.63-2.51 (m, 3H), 2.50-2.38 (m, 1H), 2.37-2.28 (m, 1H), 2.28-2.13 (m, 4H), 2.12-2.00 (m, 2H), 1.99 - 1.92 (m, 1H), 1.89-1.71 (m, 2H), 1.69-1.49 (m, 4H), 1.32 (d, J = 6.7 Hz, 6H).

[0140] Example 16 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (Compound 16) [ka] The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (115.3 mg, 103.43 μmol, 25.64% yield, 95% purity, di-TFA salt). MS (M+H) + =831.3. 1 H NMR (400 MHz, CD3OD) δ = 8.35 (br d, J = 4.9 Hz, 1H), 8.14-8.05 (m, 2H), 7.75-7.65 (m, 1H), 7.58 (s, 1H), 7.54 (dd, J = 1.4, 8.4 Hz, 1H), 5.15-5.08 (m, 1H), 4.84 (br d, J = 1.0 Hz, 1H), 4.15 (br t, J = 11.9 Hz, 2H), 4.01 (s, 3H), 3.91-3.80 (m, 1H), 3.57-3.43 (m, 3H), 3.40 (s, 3H), 3.29-3.21 (m, 1H), 3.10-2.96 (m, 3H), 2.95 (s, 3H), 2.84-2.72 (m, 2H), 2.56 (br d, J = 3.3 Hz, 3H), 2.48-2.37 (m, 1H), 2.36-2.23 (m, 2H), 2.20 (br d, J = 10.5 Hz, 1H), 2.15-1.99 (m, 5H), 1.98-1.83 (m, 2H), 1.62-1.45 (m, 2H), 1.32 (d, J = 6.8 Hz, 8H).

[0141] Example 17 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 17) [ka] The synthesis was carried out in a similar manner to Step 5 of Example 12 to obtain a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (70.3 mg, 78.47 μmol, 12.37% yield, 97% purity). MS (M+H) + =869.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.44 (br d, J = 7.2 Hz, 1H), 8.34-8.23 (m, 2H), 8.13 (s, 1H), 7.97 (s, 1H), 7.57-7.43 (m, 2H), 7.13 (s, 1H), 4.86-4.69 (m, 1H), 4.49-4.31 (m, 1H), 4.05 (br t, J = 14.1 Hz, 2H), 3.95 (s, 3H), 3.89 (dd, J = 5.4, 8.7 Hz, 1H), 3.33-3.31 (m, 3H), 3.10 (br d, J = 11.0 Hz, 2H), 2.68 (br t, J = 11.4 Hz, 2H), 2.59-2.52 (m, 2H), 2.41-2.29 (m, 2H), 2.25-2.23 (m, 4H), 2.21-2.05 (m, 6H), 2.00-1.91 (m, 2H), 1.88-1.76 (m, 4H), 1.74-1.68 (m, 2H), 1.59 (br dd, J = 4.8, 12.7 Hz, 9H), 1.34-1.18 (m, 3H).

[0142] Example 18 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 18) [ka]

[0143] Step 1. Synthesis of 3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-chloro-2-methylpyridine (3) The synthesis was carried out in a manner similar to that described in Step 1 of Example 12 to obtain 3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-chloro-2-methylpyridine (1.3 g, 4.60 mmol, 58.27% yield) as a yellow oil. MS (M+H) + =283.1.

[0144] Step 2. Synthesis of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-6-methyl-2,3'-bipyridine (5) The synthesis was carried out in a manner similar to that described in Step 2 of Example 12 to obtain a bright yellow solid, 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-6-methyl-2,3'-bipyridine (1.9 g, 3.53 mmol, 90.84% ​​yield). MS (M+H) + =538.3.

[0145] Step 3. Synthesis of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione (6) The synthesis was carried out in a manner similar to that described in Step 4 of Example 1 to obtain 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione (1.0 g, crude) as a yellow oil. MS (M+H) + =360.2.

[0146] Step 4. Synthesis of 1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidine-4-carbaldehyde (7) A yellow solid, 1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidine-4-carbaldehyde (450 mg, crude), was obtained by synthesizing in a manner similar to that described in Step 4 of Example 12. MS (M+H) + =316.1.

[0147] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 18) The synthesis was carried out in a manner similar to that described in Step 5 of Example 12 to afford a bright yellow solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (92.2 mg, 102.70 μmol, 16.19% yield, 96.8% purity). MS (M+H) + =869.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 8.49-8.40 (m, 1H), 8.31-8.24 (m, 2H), 8.01-7.93 (m, 1H), 7.53-7.46 (m, 2H), 7.38-7.31 (m, 1H), 7.13-7.07 (m, 1H), 4.83-4.73 (m, 1H), 4.45-4.34 (m, 1H), 4.11-4.00 (m, 2H), 3.95 (s, 3H), 3.91-3.85 (m, 1H), 3.31-3.24 (m, 3H), 3.09-3.02 (m, 2H), 2.64-2.54 (m, 6H), 2.42-2.32 (m, 5H), 2.24-2.15 (m, 4H), 2.15-2.04 (m, 2H), 1.98-1.91 (m, 2H), 1.86-1.77 (m, 4H), 1.75-1.69 (m, 2H), 1.68-1.54 (m, 9H), 1.32-1.23 (m, 2H).

[0148] Example 19 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 19) [ka]

[0149] Step 1. Synthesis of tert-butyl 2-(4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamido)-7-azaspiro[3.5]nonane-7-carboxylate (2) The brown solid tert-butyl 2-(4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamido)-7-azaspiro[3.5]nonane-7-carboxylate (0.5 g, 706.83 μmol, 59.57% yield, 91% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =644.3.

[0150] Step 2. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-N-(7-azaspiro[3.5]nonan-2-yl)benzamide (3) A yellow solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-N-(7-azaspiro[3.5]nonan-2-yl)benzamide (0.35 g, HCl salt), was synthesized in a manner similar to that described in Step 5 of Example 1 and used immediately in the next step. MS (M+H) + =544.3.

[0151] Step 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 19) The synthesis was carried out in a manner similar to that described in Step 5 of Example 12 to give a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (13.4 mg, 11.39 μmol, 56.75% yield, 91% purity, di-TFA salt). MS (M+H) + =843.4 1H NMR (400 MHz, CD3OD) δ = 8.30 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 1.9, 8.4 Hz, 1H), 5.15-5.05 (m, 1H), 4.84-4.81 (m, 1H), 4.62-4.50 (m, 1H), 4.12 (t, J = 12.3 Hz, 2H), 4.01 (s, 3H), 3.59 (br d, J = 13.3Hz, 1H), 3.53 (br d, J = 12.8 Hz, 1H), 3.40 (s, 3H), 3.36-3.33 (m, 2H), 3.18-3.12 (m, 2H), 3.11-3.04 (m, 1H), 3.03-2.95 (m, 1H), 2.95-2.85 (m, 2H), 2.85-2.73 (m, 2H), 2.61-2.55 (m, 1H), 2.53 (s, 3H), 2.48-2.39 (m, 1H), 2.38-2.26 (m, 2H), 2.19-2.05 (m, 3H), 2.05-1.89 (m, 6H), 1.66-1.50 (m, 2H), 1.33 (d, J = 6.7 Hz, 6H).

[0152] Example 20 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 20) [ka]

[0153] Step 1. Synthesis of 5-bromo-4-fluoro-2-iodopyridine (2) To a solution of 5-bromo-4-fluoropyridin-2-amine (1 g, 5.24 mmol) in MeCN (10 mL) were added t-BuONO (2.70 g, 26.18 mmol, 3.11 mL), CuI (9.97 g, 52.36 mmol), and I2 (26.58 g, 104.71 mmol), and the resulting mixture was stirred at 20 °C for 16 h. TLC (petroleum ether: EtOAc = 5:1) confirmed complete consumption of the starting material and the appearance of two new major spots with lower polarity. The reaction mixture was quenched by the addition of ice-cold Na2SO3 (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (500 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash® silica flash column, eluent of petroleum ether gradient @ 100 mL / min) to give 5-bromo-4-fluoro-2-iodopyridine (397 mg, crude) as a yellow oil. MS (M+H) + =302.9.

[0154] Step 2. Synthesis of 2',6'-bis(benzyloxy)-5-bromo-4-fluoro-2,3'-bipyridine (4) The synthesis was carried out in a manner similar to that described in Step 1 of Example 1 to obtain 2',6'-bis(benzyloxy)-5-bromo-4-fluoro-2,3'-bipyridine (400 mg, 747.88 μmol, 60.53% yield) as a white solid. MS (M+H) + =465.1.

[0155] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridin]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6) A yellow solid of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridin]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (190 mg, 267.65 μmol, 41.51% yield) was obtained by synthesis in a manner similar to that described in Step 3 of Example 8. MS (M+H) + =710.5.

[0156] Step 4. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (7) A mixture of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridin]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (170 mg, 239.47 μmol) and Pd / C (50 mg, 46.98 μmol, 10% purity) in THF (20 mL) and AcOH (524.50 mg, 8.73 mmol, 0.5 mL) was degassed and purged with H three times. The resulting mixture was stirred under H (50 Psi) at 30 °C for 36 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (50%). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (SiO2, DCM:MeOH = 8:1) to give a yellow solid, tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (50 mg, 94.04 μmol, 39.27% ​​yield). MS (M+H) + =532.3.

[0157] Step 5. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (8) A white solid, 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (35 mg, crude, HCl salt) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =432.3.

[0158] Step 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 20) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (10.4 mg, 11.35 μmol, 15.18% yield, 94% purity). MS (M+H) + =861.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.30-8.17 (m, 3H), 8.06 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.52-7.44 (m, 2H), 7.23 (d, J = 13.4 Hz, 1H), 4.82-4.71 (m, 1H), 4.10-3.99 (m, 2H), 3.98-3.91 (m, 4H), 3.80-3.67 (m, 1H), 3.45-3.37 (m, 2H), 3.32 (s, 3H), 2.80-2.69 (m, 2H), 2.65-2.53 (m, 2H), 2.48-2.41 (m, 1H), 2.39-2.23 (m, 4H), 2.20 (s, 3H), 2.15-2.07 (m, 1H), 1.99-1.88 (m, 4H), 1.83-1.70 (m, 5H), 1.62-1.54 (m, 4H), 1.44-1.30 (m, 4H), 1.29-1.17 (m, 3H).

[0159] Example 21 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 21) [ka]

[0160] Step 1. Synthesis of tert-butyl 4-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridin]-5-yl)piperazine-1-carboxylate (3) A white solid, tert-butyl 4-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridin]-5-yl)piperazine-1-carboxylate (850 mg, 1.49 mmol, 69.31% yield), was obtained by synthesis in a manner similar to that described in Step 3 of Example 8. MS (M+H) + =571.4.

[0161] Step 2. Synthesis of tert-butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazine-1-carboxylate (4) A white solid of tert-butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazine-1-carboxylate (350 mg) was obtained by synthesis in a manner similar to that described in Step 3 of Example 12. MS (M+H) + =393.4.

[0162] Step 3. Synthesis of 3-(4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione (5) A white solid, 3-(4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione (300 mg, HCl salt), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1, and was used immediately in the next step. MS (M+H) + =293.3.

[0163] Step 4. Synthesis of tert-butyl (4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 1 of Example 4 to obtain yellow oily tert-butyl (4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (350 mg, crude). MS (M+H)+ =519.4.

[0164] Step 5. Synthesis of 3-(5-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (8) The synthesis was carried out in a manner similar to that described in Step 3 to give 3-(5-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (250 mg, 549.49 μmol, 94.99% yield, HCl salt) as a yellow oil. MS (M+H) + =419.2.

[0165] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 21) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to give a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (36.9 mg, 43.10 μmol, 7.84% yield, 96% purity). MS (M+H) + =822.5. 1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.23 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.24-8.18 (m, 2H), 7.87 (s, 1H), 7.48-7.39 (m, 2H), 7.25 (d, J = 13.4Hz, 1H), 4.98-4.78 (m, 1H), 4.10-4.00 (m, 2H), 3.99-3.84 (m, 4H), 3.32-3.31 (m, 3H), 3.14-3.04 (m, 4H), 3.03-2.94 (m, 2H), 2.80-2.69 (m, 2H), 2.65-2.52 (m, 6H), 2.39-2.32 (m, 2H), 2.29-2.19 (m, 1H), 2.14-2.06 (m, 1H), 1.80-1.65 (m, 2H), 1.48-1.38 (m, 2H), 1.36-1.27 (m, 3H), 1.24 (d, J = 6.8 Hz, 6H).

[0166] Example 22 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 22) [ka]

[0167] Step 1. Synthesis of benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1-carboxylate (3) To a solution of benzyl 4-formylpiperidine-1-carboxylate (1.15 g, 4.65 mmol) in DCM (20 mL) was added TEA (1.41 g, 13.95 mmol, 1.94 mL), 4A MS (50 mg), and tert-butyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (919.00 mg, 4.64 mmol) at 20 °C. After stirring for 10 min, NaBH(OAc) (2.96 g, 13.95 mmol) was added slowly at 20 °C, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed complete consumption of the starting material and 68% of the desired mass peak. The reaction mixture was filtered, and the filter cake was washed with MeOH (40 mL). The filtrate was concentrated in vacuo to give the crude product, which was triturated with EtOAc (10 mL) at 20 °C for 2 h and then filtered. The filtrate was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 0 to 100% EtOAc / petroleum ether to 0 to 30% DCM:MeOH gradient @ 100 mL / min) to give benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1-carboxylate (1.72 g, 3.80 mmol, 81.80% yield, 95% purity) as a colorless oil. MS (M+H) + =430.2

[0168] Step 2. Synthesis of tert-butyl ((1R,5S,6s)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (4) To a solution of benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1-carboxylate (1.72 g, 4.00 mmol) in EtOH (20 mL) was added Pd / C (0.8 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20 °C for 12 h. LCMS confirmed complete consumption of the starting material and the desired mass was detected. The reaction mixture was filtered, and the filter cake was washed with EtOH (30 ml x 3). The filtrate was concentrated in vacuo to give a gray solid, tert-butyl ((1R,5S,6s)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.15 g, crude). MS (M+H) + =296.3

[0169] Step 3. Synthesis of tert-butyl ((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (5) The synthesis was carried out in a manner similar to that described in Step 5 of Example 4, except that acetone was replaced with DMF (20 mL), to obtain a yellow solid, tert-butyl ((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.2 g, 2.65 mmol, 68.09% yield, 92% purity). MS (M+H) + =417.3

[0170] Step 4. Synthesis of tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (6) To a solution of tert-butyl ((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.2 g, 2.88 mmol) in EtOH (10 mL) and HO (10 mL) was added Fe (804.47 mg, 14.41 mmol) and NH4Cl (462.34 mg, 8.64 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 h. LCMS confirmed complete consumption of the starting material, and the desired mass (R t =0.200 min). The reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with H2O (50 mL), adjusted to pH = 10 with Na2CO3, and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow solid, tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (950 mg, 2.33 mmol, 81.04% yield, 95% purity). MS (M+H) + =387.3

[0171] Step 5. Synthesis of tert-butyl ((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (7) To a solution of tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (900 mg, 2.33 mmol) and 3-bromopiperidine-2,6-dione (625.91 mg, 3.26 mmol) in ACN (4 mL) was added NaHCO (978.01 mg, 11.64 mmol, 452.99 μL) at 20 °C. The mixture was stirred at 80 °C for 16 h. LCMS confirmed complete consumption of tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate and the desired mass was detected. The reaction mixture was filtered, and the filter cake was washed with a mixture (40 mL, MeOH: EtOAc = 1:1). The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 0-100% EtOAc / petroleum ether to 0-50% DCM:MeOH gradient @ 80 mL / min) and prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 0%-30% B over After repurification by filtration (10 min), the mixture was lyophilized to give a brown 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]hexan-6-yl)carbamate (220 mg, 397.89 μmol, 17.09% yield, 90% purity). MS (M+H) + =498.2

[0172] Step 6. Synthesis of 3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (8) A yellow solid of 3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, crude, HCl) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =398.2

[0173] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 22) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to give a gray solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (68.7 mg, 60.49 μmol, 21.88% yield, 90.6% purity, 2% TFA). MS (M+H) + =801.2 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.57-9.27 (m, 1H), 8.55-8.45 (m, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.50-7.46 (m, 2H), 7.43-7.21 (m, 2H), 6.80-6.73 (m, 2H), 4.91-4.84 (m, 1H), 4.43-4.34 (m, 2H), 4.06 (t, J = 13.3 Hz, 2H), 3.93 (s, 3H), 3.89-3.83 (m, 2H), 3.57-3.52 (m, 2H), 3.49-3.43 (m, 2H), 3.32 (s, 3H), 3.22-3.17 (m, 1H), 3.13-3.01 (m, 1H), 2.99-2.89 (m, 1H), 2.81-2.69 (m, 1H), 2.63-2.55 (m, 1H), 2.41-2.37 (m, 1H), 2.16-2.15 (m, 1H), 2.12-2.03 (m, 5H), 1.97-1.88 (m, 2H), 1.63-1.57 (m, 1H), 1.24 (d, J = 6.6 Hz, 6H).

[0174] Example 23 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 23) [ka]

[0175] Step 1. Synthesis of 2-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-ol (3) A yellow solid, 2-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-ol (1 g, 3.98 mmol, 34.54% yield, 100% purity), was obtained by synthesizing in a manner similar to that described in Step 6 of Example 4, except that acetone was replaced with ACN. MS (M+H) + =252.2.

[0176] Step 2. Synthesis of 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine (4) To a solution of 2-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-ol (1 g, 3.98 mmol) in DCM (20 mL) was added PPh3 (1.36 g, 5.17 mmol) and CBr4 (1.72 g, 5.17 mmol) at 0 °C, and the mixture was stirred at 25 °C under N2 atmosphere for 16 h. LCMS confirmed the desired mass (32%). The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0 to 50% EtOAc / petroleum ether gradient @ 80 mL / min) to give 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine (0.6 g, 1.81 mmol, 45.59% yield, 95% purity) as a yellow solid. MS(M+H) + =314.2.

[0177] Step 3. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (6) To a solution of 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine (522.94 mg, 1.66 mmol) in DMF (10 mL) was added tert-butyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (300 mg, 1.51 mmol), DIPEA (667.78 mg, 5.17 mmol, 899.98 μL), and NaI (45.36 mg, 302.63 μmol), and the mixture was stirred at 20 °C under N atmosphere for 16 h. LCMS confirmed the desired mass peak (81%). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0 to 100% EtOAc / petroleum ether gradient @ 80 mL / min) to give a yellow solid, tert-butyl ((1R,5S,6s)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (0.5 g, 1.16 mmol, 76.57% yield, 100% purity). MS (M+H) + =432.3.

[0178] Step 4. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(4-(4-aminophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to give tert-butyl ((1R,5S,6s)-3-(2-(4-(4-aminophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (0.25 g, 579.01 μmol, 49.97% yield, 93% purity) as a yellow oil. MS (M+H) + =402.3.

[0179] Step 5. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to give a black solid, tert-butyl ((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (120 mg, 215.35 μmol, 34.59% yield, 92% purity). MS (M+H) + =513.4.

[0180] Step 6. Synthesis of 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (10) The red solid 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (0.1 g, 189.92 μmol, 97.36% yield, TFA) was obtained by synthesizing in a manner similar to that described in Step 6 of Example 3. MS (M+H) + =413.2

[0181] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 23) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (55.6 mg, 64.74 μmol, 34.09% yield, 95% purity). MS (M+H) + =816.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.76 (s, 1H), 8.29 (d, J = 8.9 Hz, 1H), 8.26-8.20 (m, 2H), 7.88 (s, 1H), 7.50-7.43 (m, 2H), 6.75 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 5.37 (d, J = 7.3 Hz, 1H), 4.93-4.82 (m, 1H), 4.25-4.14 (m, 1H), 4.04 (br t, J = 13.6 Hz, 2H), 3.93 (s, 3H), 3.31 (br s, 3H), 3.12 (d, J = 8.8 Hz, 2H), 3.06-3.00 (m, 1H), 2.99-2.90 (m, 4H), 2.79-2.66 (m, 2H), 2.64-2.56 (m, 4H), 2.46-2.40 (m, 3H), 2.39-2.30 (m, 3H), 2.17-2.05 (m, 1H), 1.92-1.76 (m, 1H), 1.68 - 1.61 (m, 2H), 1.24 (d, J = 6.8 Hz, 6H).

[0182] Example 24 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 24) [ka]

[0183] Step 1. Synthesis of benzyl 4-(2-oxoethyl)piperidine-1-carboxylate (2) Benzyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.94 g, 3.71 mmol, 97.75% yield, 50% purity) was obtained as a white solid by a method similar to that described in Step 1 of Example 6. MS (M+H) + =262.2.

[0184] Step 2. Synthesis of benzyl 4-(2-((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidine-1-carboxylate (3) Benzyl 4-(2-((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidine-1-carboxylate (1.4 g, crude) was synthesized as a yellow oil in a manner similar to that described in Step 1 of Example 22. MS (M+H) + =444.3.

[0185] Step 3. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (4) The synthesis was carried out in a manner similar to that described in Step 2 of Example 22 to give tert-butyl ((1R,5S,6s)-3-(2-(piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.1 g, crude) as a bright yellow oil. MS (M+H) + =310.2.

[0186] Step 4. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (6) A yellow solid, tert-butyl ((1R,5S,6s)-3-(2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (650 mg, 1.51 mmol, 42.47% yield), was obtained by synthesizing in a manner similar to that described in Step 3 of Example 22. MS (M+H) + =431.2.

[0187] Step 5. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-aminophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to give a gray solid of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-aminophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (650 mg, 1.62 mmol, 88.44% yield). MS (M+H) + =401.3.

[0188] Step 6. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to give a gray solid of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (240 mg, 469.07 μmol, 93.94% yield). MS (M+H) + =512.4.

[0189] Step 7. Synthesis of 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (10) A blue solid of 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, crude, HCl salt) was obtained by synthesis in a manner similar to that described in Step 6 of Example 22. MS (M+H) + =412.3.

[0190] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 24) The synthesis was carried out in a manner similar to that described in Step 7 of Example 22 to give a gray solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (78.9 mg, 91.30 μmol, 24.66% yield, 94.3% purity). MS (M+H) + =815.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.75 (s, 1H), 8.30-8.27 (m, 1H), 8.25-8.22 (m, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.47-7.44 (m, 2H), 6.74 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz, 2H), 5.35 (d, J = 7.3 Hz, 1H), 4.91-4.82 (m, 1H), 4.22-4.14 (m, 1H), 4.03 (t, J = 13.6 Hz, 2H), 3.92 (s, 3H), 3.36 (s, 3H), 3.07 (d, J = 8.8 Hz, 2H), 3.01-2.98 (m, 1H), 2.78-2.69 (m, 1H), 2.61-2.57 (m, 1H), 2.56-2.54 (m, 1H), 2.47-2.44 (m, 2H), 2.44-2.39 (m, 3H), 2.29 (d, J = 7.9 Hz, 2H), 2.14-2.07 (m, 1H), 1.86-1.80 (m, 1H), 1.72 (d, J = 11.3 Hz, 2H), 1.64-1.58 (m, 2H), 1.42-1.34 (m, 3H), 1.34-1.26 (m, 2H), 1.23 (d, J = 6.8 Hz, 6H).

[0191] Example 25 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-methoxybenzamide (Compound 25) [ka]

[0192] Step 1. Synthesis of tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2) To a solution of DMSO (5.50 g, 70.33 mmol, 5.50 mL) in DCM (50 mL) was slowly added (COCl) (3.57 g, 28.13 mmol, 2.46 mL) at −70° C., and the mixture was stirred at −70° C. for 0.5 h. Then, a solution of tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3 g, 14.07 mmol) in DCM (5 mL) was added, and the mixture was stirred at −70° C. for 0.5 h. TEA (7.12 g, 70.33 mmol, 9.79 mL) was added, and the mixture was stirred at −70° C. for 0.5 h. TLC (petroleum ether / EtOAc = 2 / 1) confirmed that the starting material had been consumed and a new spot had formed. The residue was diluted with saturated aqueous NaSO (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 0 to 30% EtOAc / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.7 g, 12.78 mmol, 90.86% yield) as a yellow oil. MS (M+H) + =212.3.

[0193] Step 2. Synthesis of tert-butyl (1R,5S,6s)-6-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (3) To a suspension of methyl(triphenyl)phosphonium bromide (6.85 g, 19.17 mmol) in THF (50 mL) was added KHMDS (1 M, 19.17 mL) at 0 °C under N. The mixture was stirred at 20 °C for 1 h, and then a solution of tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.7 g, 12.78 mmol) in THF (2 mL) was added at −70 °C under N. The mixture was warmed to −10 °C and stirred at −10 °C for 1 h. TLC (petroleum ether / EtOAc = 2 / 1) confirmed the consumption of the starting material and the formation of a new spot. The residue was diluted with saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 0–20% EtOAc / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (1R,5S,6s)-6-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.4 g, 11.47 mmol, 89.73% yield) as a yellow oil. MS (M+H) + =210.3.

[0194] Step 3. Synthesis of tert-butyl (1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4) To a solution of tert-butyl (1R,5S,6s)-6-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.4 g, 11.47 mmol) in THF (50 mL) cooled at 0 °C, BH3-Me2S (10 M, 1.72 mL) solution was added under N2, and the mixture was stirred at 0 °C for 30 min. The reaction mixture was warmed to 20 °C and stirred for 1 h. The mixture was carefully treated with NaOH (3 M, 9.60 mL), followed by the addition of HO (6.80 g, 59.95 mmol, 5.76 mL, 30% purity) at 0 °C. The resulting mixture was stirred at 65 °C for 1 h. TLC (petroleum ether / EtOAc = 2 / 1) confirmed the consumption of the starting material and the formation of a new spot. The mixture was quenched by the addition of aqueous saturated NaSO (100 mL) and adjusted to pH 8 with 1N HCl. The resulting solution was extracted with EtOAc (50 mL x 3), washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 0 to 30% EtOAc / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.2 g, 5.28 mmol, 46.04% yield) as a white solid. MS (M+H) + =228.3.

[0195] Step 4. Synthesis of 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (5) The synthesis was carried out in a manner similar to that described in Step 5 of Example 1 to obtain 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (0.9 g, crude, HCl) as a colorless oil. MS (M+H) + =128.2. 1H NMR (400 MHz, CD3OD) δ = 3.64 (t, J = 6.4 Hz, 2H), 3.42-3.37 (m, 4H), 1.71-1.62 (m, 2H), 1.53 (q, J = 6.5 Hz, 2H), 0.97-0.87 (m, 1H).

[0196] Step 5. Synthesis of 2-((1R,5S,6s)-3-nitroso-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (6) To a solution of 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (0.9 g, 5.50 mmol, HCl) in HO (20 mL) was added NaNO (1.14 g, 16.50 mmol) and AcOH (1.32 g, 22.00 mmol, 1.26 mL), and the resulting mixture was stirred at 20 °C for 12 h. TLC (EtOAc) confirmed that the starting material had been consumed and a new spot had formed. The residue was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-((1R,5S,6s)-3-nitroso-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (1.2 g, crude) as a yellow oil. MS (M+H) + =157.2.

[0197] Step 6. Synthesis of tert-butyl ((1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (7) To a solution of 2-((1R,5S,6s)-3-nitroso-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (0.6 g, 3.84 mmol) in THF (10 mL) and HO (2 mL) were added NH4Cl (821.98 mg, 15.37 mmol) and Zn (1.02 g, 15.53 mmol) in portions. The mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered, and the filter cake was washed with THF (10 mL) and HO (10 mL). To the filtrate were added BocO (2.52 g, 11.53 mmol, 2.65 mL) and NaHCO3 (968.18 mg, 11.53 mmol), and the mixture was stirred at 20 °C for 12 h. TLC (EtOAc) confirmed the formation of a new spot. The residue was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 5 g SepaFlash® silica flash column, eluent of 0 to 60% EtOAc / petroleum ether gradient @ 50 mL / min) to give tert-butyl ((1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (0.2 g, 825.38 μmol, 21.48% yield) as a white solid. MS (M+H) + =243.3. 1 H NMR (400 MHz, CDCl3) δ = 5.37 (br s, 1H), 3.74-3.65 (m, 3H), 3.20 (d, J = 8.3 Hz, 2H), 2.89 (d, J = 8.6 Hz, 2H), 1.49-1.36 (m, 11H), 1.26-1.18 (m, 3H).

[0198] Step 7. Synthesis of 2-((1R,5S,6s)-3-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-6-yl)ethyl 4-methylbenzenesulfonate (8) To a solution of tert-butyl ((1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (150 mg, 619.03 μmol) in DCM (5 mL) was added TEA (187.92 mg, 1.86 mmol, 258.48 μL) and TosCl (141.62 mg, 742.84 μmol) at 20° C. The mixture was stirred at 20° C. for 16 h. LCMS confirmed the desired mass peak (80%). The residue was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent of 0 to 40% EtOAc / petroleum ether gradient @ 60 mL / min) to give 2-((1R,5S,6s)-3-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-6-yl)ethyl 4-methylbenzenesulfonate (130 mg, 327.87 μmol, 52.96% yield) as a yellow oil. MS (M+Na) + =419.2

[0199] Step 8. Synthesis of tert-butyl ((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (10) To a solution of 2-((1R,5S,6s)-3-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-6-yl)ethyl 4-methylbenzenesulfonate (130 mg, 327.87 μmol) and 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (130.00 mg, 400.24 μmol, HCl) in DMF (2 mL) was added KI (10.89 mg, 65.57 μmol) and DIPEA (127.12 mg, 983.61 μmol, 171.33 μL) and stirred at 80 °C for 2 h. LCMS confirmed the desired mass as the main peak. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluting with a 0-10% MeOH / EtOAc gradient at 60 mL / min) to afford tert-butyl ((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (80 mg, 131.09 μmol, 39.98% yield, 84% purity) as a yellow oil. MS (M+H) + =513.4

[0200] Step 9. Synthesis of 3-((4-(4-(2-((1R,5S,6s)-3-amino-3-azabicyclo[3.1.0]hexan-6-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (11) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-((1R,5S,6s)-3-amino-3-azabicyclo[3.1.0]hexan-6-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (80 mg, 151.93 μmol, 97.36% yield, TFA) as a yellow oil. MS (M+H) + =413.3

[0201] Step 10. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-methoxybenzamide (Compound 25) The brown solid 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-methoxybenzamide (13.7 mg, 15.28 μmol, 10.06% yield, 91% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =816.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.33 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.51-7.41 (m, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 6.5 Hz, 1H), 5.01-4.83 (m, 1H), 4.30-4.21 (m, 1H), 4.09 (t, J = 13.7 Hz, 2H), 3.98 (s, 3H), 3.51-3.42 (m, 5H), 3.39-3.31 (m, 3H), 3.31-2.56 (m, 2H), 3.19-3.06 (m, 2H), 3.12-3.03 (m, 4H), 2.85-2.75 (m, 1H), 2.69-2.61 (m, 2H), 2.21-2.12 (m, 1H), 1.95-1.82 (m, 1H), 1.47-1.40 (m, 2H), 1.35-1.29 (m, 8H), 1.18-1.12 (m, 1H).

[0202] Example 26 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 26) [ka]

[0203] Step 1. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3) A similar procedure to that described in Step 6 of Example 4 was used, except that acetone was replaced with DMF (50 mL), to obtain a yellow solid, tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3 g, 6.07 mmol, 79.03% yield, 94% purity). MS (M+H) + =465.4.

[0204] Step 2. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (4) To a solution of tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3 g, 6.46 mmol) in CF3CH2OH (100 mL) was slowly added Pd / C (500 mg, 10% purity) under N2. After degassing and rinsing the suspension three times with H2, the mixture was stirred under H2 (15 Psi) at 25 °C for 14 h. TLC (DCM:MeOH = 10:1) confirmed that the starting material had been consumed, and a new spot was detected. The mixture was filtered, and the filter cake was washed with EtOH (100 mL) and THF (100 mL). The filtrate was concentrated under reduced pressure to give tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (2.8 g, crude) as a yellow oil. MS (M+H) + =435.4.

[0205] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to give blue solid tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (540 mg, 761.97 μmol, 33.11% yield, 77% purity) and blue solid tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (420 mg, 677.31 μmol, 29.44% yield, 88% purity). MS (M+H) + =546.5.

[0206] Step 4. Synthesis of 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (7) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (150 mg, crude, TFA salt) as a dark brown oil. MS (M+H) + =446.5.

[0207] Step 5. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 26) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a gray solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (29.8 mg, 34.05 μmol, 14.35% yield, 97% purity). MS (M+H) + =849.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.22 (s, 1H), 8.12-8.07 (m, 1H), 7.88 (s, 1H), 7.52-7.46 (m, 2H), 6.83 (t, J = 9.3 Hz, 1H), 6.53-6.46 (m, 1H), 6.43-6.38 (m, 1H), 5.82-5.75 (m, 1H), 4.92-4.83 (m, 1H), 4.29-4.20 (m, 1H), 4.09-3.99 (m, 2H), 3.93 (s, 3H), 3.81-3.70 (m, 1H), 3.34 (s, 3H), 3.15-3.07 (m, 2H), 2.78-2.68 (m, 1H), 2.60-2.52 (m, 9H), 2.11-2.04 (m, 1H), 1.96-1.89 (m, 3H), 1.86-1.72 (m, 4H), 1.47-1.34 (m, 4H), 1.29-1.17 (m, 9H).

[0208] Example 27 Synthesis of N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 27) [ka]

[0209] Step 1. Synthesis of 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-benzoic acid (3) To a solution of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (650 mg, 2.35 mmol) and 4-amino-3-methoxybenzoic acid (400.58 mg, 2.40 mmol) in HO (16 mL) and EtOH (4 mL) was added HCl (12 M, 293.67 μL) and the mixture was stirred at 100° C. for 16 h. LCMS confirmed the desired mass peak (79%). The reaction mixture was filtered at 50°C, and the filter cake was collected to give a brown solid, 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (0.6 g, 1.44 mmol, 61.44% yield, 98% purity). MS (M+H) + =408.1.

[0210] Step 2. Synthesis of N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 27) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a gray solid, N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (48.6 mg, 39.64 μmol, 5.89% yield, 96% purity, 3TFA). MS (M+H) + =835.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.92-8.75 (m, 1H), 8.31-8.14 (m, 4H), 7.56-7.45 (m, 2H), 7.01-6.86 (m, 1H), 6.54 (d, J = 15.7 Hz, 1H), 6.46 (d, J = 7.9 Hz, 1H), 4.28-4.25 (m, 2H), 4.22-4.21 (m, 1H), 4.18-4.17 (m, 1H), 3.94 (s, 3H), 3.87-3.80 (m, 1H), 3.66 (q, J = 6.9 Hz, 2H), 3.33 (s, 3H), 3.29-3.16 (m, 4H), 3.01-2.91 (m, 1H), 2.83-2.78 (m, 3H), 2.78-2.69 (m, 2H), 2.13-1.75 (m, 10H), 1.74-1.60 (m, 2H), 1.55-1.36 (m, 4H), 1.21 (t, J = 7.0 Hz, 3H).

[0211] Example 28 Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 28) [ka]

[0212] Step 1. Synthesis of tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (2) The synthesis was carried out in a manner similar to that described in Step 1 of Example 25 to obtain tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (2.5 g, crude) as a yellow oil. MS (M+H) + =243.3

[0213] Step 2. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (4) A blue solid of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (0.2 g, 360.46 μmol, 56.17% yield, 96% purity) was obtained in a manner similar to that described in Step 6 of Example 1. MS (M+H) + =533.4

[0214] Step 3. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (5) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (150 mg, 274.45 μmol, 97.46% yield, TFA) as a yellow oil. MS (M+H) + =433.4

[0215] Step 4. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 28) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (105.3 mg, 110.26 μmol, 40.18% yield, 98% purity, TFA). MS (M+H) + =822.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.90-9.61 (m, 1H), 9.58-9.37 (m, 1H), 8.39-8.15 (m, 3H), 7.56-7.38 (m, 2H), 6.90 (t, J = 9.3 Hz, 1H), 6.56 (dd, J = 2.1, 14.9 Hz, 1H), 6.49-6.42 (m, 1H), 4.29-4.18 (m, 3H), 3.95 (s, 3H), 3.69-2.61 (m, 2H), 3.61-3.54 (m, 2H), 3.33 (s, 3H), 3.34-3.26 (m, 2H), 3.25-3.11 (m, 6H), 3.00-2.91 (m, 2H), 2.92-2.85 (m, 2H), 2.79-2.69 (m, 1H), 2.67-2.61 (m, 1H), 2.12-2.04 (m, 1H), 1.94-1.83 (m, 1H), 1.81-1.74 (m, 2H), 1.70-1.61 (m, 2H), 1.45-1.36 (m, 3H), 1.22 (t, J = 7.0 Hz, 3H).

[0216] Example 29 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 29) [ka] The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (82 mg, 67.52 μmol, 31.62% yield, 97% purity, 3TFA salt). MS (M+H) + =836.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.81-9.61 (m, 1H), 9.58-9.34 (m, 1H), 8.35-8.12 (m, 3H), 7.54-7.36 (m, 2H), 6.90 (t, J = 9.4 Hz, 1H), 6.55 (dd, J = 2.3, 14.9 Hz, 1H), 6.50-6.38 (m, 1H), 4.94-4.83 (m, 1H), 4.28 (br dd, J = 4.9, 11.6 Hz, 1H), 4.08 (br s, 2H), 3.94 (s, 3H), 3.57 (br d, J = 11.5 Hz, 2H), 3.32 (s, 3H), 3.28 (br d, J = 11.4 Hz, 2H), 3.20 (br d, J = 8.8 Hz, 3H), 3.17-3.10 (m, 3H), 3.00-2.91 (m, 2H), 2.90-2.79 (m, 2H), 2.78-2.67 (m, 1H), 2.63-2.54 (m, 1H), 2.13-2.02 (m, 1H), 1.93-1.82 (m, 1H), 1.81-1.71 (m, 2H), 1.70-1.55 (m, 2H), 1.49-1.30 (m, 3H), 1.24 (d, J = 6.7 Hz, 6H).

[0217] Example 30 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 30) [ka]

[0218] Step 1. Synthesis of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (2) The synthesis was carried out in a manner similar to that described in Step 7 of Example 25, except for the addition of DMAP (26.64 mg, 218.04 μmol) to give tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (8.56 g, 19.64 mmol, 90.08% yield, 88% purity) as a bright yellow oil. MS (M-100+H) + =284.1.

[0219] Step 2. Synthesis of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (3) To a solution of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (5 g, 13.04 mmol) and benzyl piperidin-4-ylcarbamate (3.1 g, 13.23 mmol) in ACN (80 mL) was added KCO (3.60 g, 26.08 mmol) and KI (43.29 mg, 260.76 μmol), and the mixture was stirred at 60 °C under N atmosphere for 16 h. LCMS confirmed complete consumption of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate and 98% of the desired mass. The reaction mixture was filtered, the filter cake was washed with EtOAc (50 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 25-100% EtOAc / petroleum ether to 10% MeOH / EtOAc gradient @ 200 mL / min) to give tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (5.53 g, 12.41 mmol, 95.19% yield) as a light brown solid. MS (M+H) + =446.4.

[0220] Step 3. Synthesis of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4) The synthesis was carried out in a manner similar to that described in Step 5 of Example 1 to give benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6.7 g, HCl salt) as a light brown solid, which was used immediately. MS (M+H) + =346.2.

[0221] Step 4. Synthesis of benzyl (1-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6) A mixture of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6.7 g, 17.54 mmol, HCl salt), 1,2-difluoro-4-nitrobenzene (5.58 g, 35.08 mmol, 3.88 mL), and K2CO3 (7.27 g, 52.63 mmol) in DMF (70 mL) was stirred at 20 °C for 16 h. LCMS confirmed complete consumption of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate and 39% of the desired mass. The mixture was diluted with HO (600 mL) and extracted with a mixture (EtOAc:MeOH = 10:1, 200 mL x 3). The combined organic layers were washed with brine (300 mL x 5), dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and EtOAc (5 / 1, 40 mL) for 10 minutes, the suspension was filtered, and the filter cake was washed with a mixture of petroleum ether and EtOAc (5 / 1, 40 mL). The filter cake was collected and dried in vacuo to give benzyl (1-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (5.33 g, 11.00 mmol, 62.70% yield) as a yellow solid. MS (M+H) + =485.2.

[0222] Step 5. Synthesis of benzyl (1-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to obtain a red solid of benzyl (1-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4.9 g, 10.78 mmol, 98.55% yield). MS (M+H) + =455.2.

[0223] Step 6. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (8) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to give a light gray solid of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (480 mg, 610.95 μmol, 34.72% yield, 72% purity). MS (M+H) + =566.5.

[0224] Step 7. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (9) The synthesis was carried out in a manner similar to that described in Step 2 of Example 4 to give 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (195 mg, TFA salt) as a green oil, which was used immediately. MS (M+H) + =432.2.

[0225] Step 8. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 30) A light gray solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (105.7 mg, 85.23 μmol, 23.83% yield, 97% purity, 3TFA salt), was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =861.3. 1 H NMR (400 MHz, DMSO-d6) δ = 10.82 (s, 1H), 9.59-9.32 (m, 1H), 8.47-8.35 (m, 1H), 8.33-8.25 (m, 2H), 8.23 ​​(d, J = 8.7 Hz, 1H), 7.60-7.44 (m, 2H), 7.23-7.01 (m, 1H), 6.68-6.55 (m, 1H), 6.50 (d, J = 8.1 Hz, 1H), 4.82-4.74 (m, 1H), 4.38-4.25 (m, 1H), 4.22-3.98 (m, 3H), 3.97-3.84 (m, 3H), 3.58 (d, J = 11.1 Hz, 1H), 3.45-1.13 (m, 5H), 3.20-2.87 (m, 4H), 2.07-1.99(m, 4H), 1.99-1.76 (m, 8H), 1.75-1.62 (m, 6H), 1.61-1.40 (m, 8H).

[0226] Example 31 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 31) [ka]

[0227] Step 1. Synthesis of tert-butyl 4-(2-(2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidine-1-carboxylate (3) To a solution of benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (2 g, 6.43 mmol, HCl) and tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (3 g, 7.82 mmol) in DMSO (50 mL) was added DIPEA (2.49 g, 19.30 mmol, 3.36 mL), and the resulting mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass peak (56%). The resulting mixture was poured into water (200 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (50 g SepaFlash® silica flash column, eluent of 0 to 100% EtOAc / petroleum ether gradient @ 100 mL / min) to give tert-butyl 4-(2-(2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidine-1-carboxylate (2 g, 4.12 mmol, 64.00% yield, 100% purity) as a yellow oil. MS (M+H) + =486.3

[0228] Step 2. Synthesis of benzyl (7-(2-(piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4) A yellow solid, benzyl (7-(2-(piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.0 g, crude, HCl), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =386.3

[0229] Step 3. Synthesis of benzyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) Benzyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.24 mmol, 63.06% yield, 98% purity) was synthesized in a manner similar to that described in Step 4 of Example 30 as a yellow oil. MS (M+H) + =525.4

[0230] Step 4. Synthesis of tert-butyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) A mixture of benzyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.29 mmol) in TFA (18.42 g, 161.55 mmol, 12.00 mL) was stirred at 40 °C for 2 h. The mixture was concentrated and the residue was diluted with THF (20 mL). After that, BocO (748.81 mg, 3.43 mmol, 788.22 μL) and TEA (694.36 mg, 6.86 mmol) were added, and the resulting mixture was stirred at 20 °C for 2 h. LCMS confirmed the desired mass peak (47%). The mixture was diluted with H O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 0 to 100% EtOAc / petroleum ether gradient @ 80 mL / min) to give tert-butyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.20 mmol, 96.24% yield, 90% purity) as a yellow oil. MS (M+H) + =491.2

[0231] Step 5. Synthesis of tert-butyl (7-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8) Synthesized in a manner similar to that described in Step 4 of Example 22 to give tert-butyl (7-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (0.82 g, 1.48 mmol, 60.41% yield, 83% purity) as a yellow oil. MS (M+H) + =461.4

[0232] Step 6. Synthesis of tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (10) The brown solid tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.5 g, crude) was obtained by synthesizing in a manner similar to that described in Step 5 of Example 22. MS (M+H) + =572.5

[0233] Step 7. Synthesis of 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (11) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1 g, crude, TFA) as a black oil. MS (M+H) + =472.3

[0234] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 31) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (440.4 mg, 440.84 μmol, 25.82% yield, 99% purity, TFA). MS (M+H) + =875.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.46-9.19 (m, 1H), 8.54 (d, J = 6.9 Hz, 1H), 8.50-8.37 (m, 1H), 8.25 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.57-7.49 (m, 2H), 7.22-7.07 (m, 1H), 6.66-6.56 (m, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.96-4.84 (m, 1H), 4.51-4.39 (m, 1H), 4.37-4.30 (m, 1H), 4.11 (t, J = 13.3 Hz, 2H), 4.03-3.85 (m, 4H), 3.49-3.32 (m, 6H), 3.19-2.86 (m, 5H), 2.85-2.59 (m, 3H), 2.43-2.34 (m, 1H), 2.24-1.93 (m, 5H), 1.92-1.75 (m, 6H), 1.69-1.60 (m, 2H), 1.58-1.49 (m, 3H), 1.25 (d, J = 6.6 Hz, 6H).

[0235] Example 32 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 32) [ka]

[0236] Step 1. Synthesis of tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (2) A yellow solid, tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (21 g, 64.55 mmol, 30.06% yield), was obtained by synthesis in a manner similar to that described in Step 4 of Example 30. MS (M+H) + =325.9. 1 H NMR (400 MHz, CDCl3) δ = 8.02 (t, J = 9.1 Hz, 1H), 6.69 - 6.42 (m, 2H), 3.70 - 3.54 (m, 4H), 3.48 - 3.33 (m, 4H), 1.50 (s, 9H)

[0237] Step 2. Synthesis of tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (3) The brown solid tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (19 g, crude) was obtained by synthesis in a manner similar to that described in Step 4 of Example 22. MS (M+H) + =296.1.

[0238] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (4) A green solid, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (25 g, 61.51 mmol, 95.61% yield), was obtained by synthesis in a manner similar to that described in Step 5 of Example 22. MS (M+H) + =407.1. 1 H NMR (400 MHz, CDCl3) δ = 8.45 (s, 1H), 6.75 - 6.57 (m, 3H), 4.59 - 4.45 (m, 1H), 4.06 - 3.97 (m, 1H), 3.62 - 3.51 (m, 4H), 3.04 - 2.92 (m, 4H), 2.88 - 2.79 (m, 1H), 2.78 - 2.66 (m, 1H), 2.51 - 2.43 (m, 1H), 2.00 - 1.88 (m, 1H), 1.48 (s, 9H)

[0239] Step 4. Synthesis of 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (5) A green solid, 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (21 g, crude, HCl), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =306.9.

[0240] Step 5. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 3 of Example 23 to obtain a brown solid, tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (2.9 g, 5.44 mmol, 37.33% yield). MS (M+H) + =533.3.

[0241] Step 6. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (7) The green solid 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (2.4 g, crude, HCl) was obtained by synthesis in a manner similar to that described in Step 4. MS (M+H) + =433.2.

[0242] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 32) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford an off-white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (2.43 g, 2.75 mmol, 61.43% yield, 97.4% purity). MS (M+H) + =862.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.34 - 8.24 (m, 2H), 8.12 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.55 - 7.46 (m, 2H), 6.81 - 6.69 (m, 2H), 6.63 - 6.55 (m, 1H), 5.12 - 5.02 (m, 1H), 4.82 - 4.71 (m, 1H), 4.32 - 4.21 (m, 1H), 4.05 (t, J = 14.1 Hz, 2H), 3.94 (s, 3H), 3.84 - 3.71 (m, 1H), 3.37 - 3.34 (m, 2H), 3.04 - 2.85 (m, 6H), 2.80 - 2.70 (m, 1H), 2.62 - 2.45 (m, 10H), 2.14 - 1.88 (m, 6H), 1.84 - 1.67 (m, 4H), 1.67 - 1.52 (m, 6H).

[0243] Example 33 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 33) [ka]

[0244] Step 1. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (3) The synthesis was carried out in a manner similar to that described in Step 6 of Example 1 to obtain a gray solid of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (7.8 g, 14.64 mmol, 55.78% yield). MS (M+H) + =533.3.

[0245] Step 2. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (4) The green oil 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (2.1 g, crude, TFA) was obtained by synthesis in a manner similar to that described in Step 6 of Example 3. MS (M+H) + =433.2.

[0246] Step 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 33) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford an off-white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (1.30 g, 1.52 mmol, 49.40% yield, 98.0% purity). MS (M+H) + =836.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 - 10.77 (m, 1H), 9.25 (s, 1H), 8.35 - 8.28 (m, 1H), 8.22 (s, 1H), 7.91 - 7.84 (m, 1H), 7.47 - 7.39 (m, 2H), 6.79 - 6.69 (m, 2H), 6.62 - 6.54 (m, 1H), 5.11 - 5.03 (m, 1H), 4.88 (t, J = 13.2 Hz, 1H), 4.32 - 4.22 (m, 1H), 4.08 - 4.00 (m, 2H), 3.93 (s, 3H), 3.34 - 3.31 (m, 4H), 3.04 - 2.93 (m, 6H), 2.79 - 2.68 (m, 3H), 2.61 - 2.51 (m, 2H), 2.47 - 2.43 (m, 2H), 2.37 - 2.29 (m, 2H), 2.13 - 2.06 (m, 1H), 2.00 - 1.90 (m, 1H), 1.76 - 1.66 (m, 2H), 1.46 - 1.38 (m, 2H), 1.34 - 1.27 (m, 3H), 1.25 (d, J = 6.5Hz, 6H)

[0247] Example 34 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 34) [ka] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (1.2 g, 2.68 mmol) in DMF (16 mL) was added EDCI (960.00 mg, 5.01 mmol), HOBt (660.00 mg, 4.88 mmol), DIPEA (2.23 g, 17.22 mmol, 3.00 mL) and 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (2.30 g, 4.21 mmol, TFA) at 20° C. The mixture was stirred under N2 at 20 °C for 16 h. LCMS confirmed the desired mass peak (48%). The reaction mixture was diluted with H2O (30 mL), and the mixture was extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent of 0-10% MeOH:DCM gradient, 60 mL / min). The product was repurified by prep-HPLC (column: Phenomene x luna C18 150 x 25 mm x 10 μm; mobile phase: [water (TFA)-ACN]; gradient: 21%-51% B over 10 min, column temperature: 30 °C). The eluate was lyophilized and diluted with HCl (1 M, 40 mL), and the mixture was added dropwise to NaCO (1 M, 70 mL) at 0° C. The suspension was filtered, and the filter cake was washed with HO (80 mL × 3) and then lyophilized to give an off-white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (656.9 mg, 740.01 μmol, 27.59% yield, 97.1% purity). MS(M+H)+ =862.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 - 10.76 (m, 1H), 9.28 (s, 1H), 8.35 - 8.22 (m, 2H), 7.97 (s, 1H), 7.49 - 7.35 (m, 2H), 6.81 - 6.68 (m, 2H), 6.62 - 6.56 (m, 1H), 5.10 - 5.03 (m, 1H), 4.82 - 4.72 (m, 1H), 4.31 - 4.22 (m, 1H), 4.11 - 4.00 (m, 2H), 3.93 (s, 3H), 3.37 - 3.33 (m, 4H), 3.04 - 2.87 (m, 6H), 2.83 - 2.69 (m, 3H), 2.62 - 2.51 (m, 2H), 2.49 - 2.44 (m, 2H), 2.40 - 2.30 (m, 2H), 2.13 - 2.06 (m, 1H), 2.01 - 1.89 (m, 3H), 1.77 - 1.66 (m, 4H), 1.65 - 1.55 (m, 4H), 1.47 - 1.37 (m, 2H), 1.36 - 1.23 (m, 3H).

[0248] Example 35 Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzamide (Compound 35) [ka]

[0249] Step 1. Synthesis of ethyl 3-((5-amino-2-chloropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (2) A solution of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (44.00 g, 111.72 mmol) in THF (900 mL) was stirred at 20 °C until a clear solution was obtained. The H2 backpressure regulator was adjusted to 1 MPa, the H2 flow rate was adjusted to 95 mL / min, and a fixed-bed Pt / C (30 g, 1% purity) was heated to 50 °C. The solution was then pumped into the reactor at a flow rate of 3 mL / min. After the reaction was completed, the tubing was washed with THF (100 mL), and all the reaction solution was collected. The mass was confirmed by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give ethyl 3-((5-amino-2-chloropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (42.00 g, crude) as a pale yellow oil. MS (M+H) + =309.1.

[0250] Step 2. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (3) A mixture of ethyl 3-((5-amino-2-chloropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (42.00 g, 136.05 mmol) in TFA (50 mL) was stirred at 50 °C for 4 h. LCMS confirmed the desired mass as the main peak (90%). The mixture was concentrated, and the residue was diluted with EtOAc (500 mL), washed with NaHCO (100 mL x 2) and brine (100 mL x 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE (100 mL) at 25 °C for 10 min and filtered. The filter cake was collected and dried to give a pale yellow solid, 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (26.00 g, 98.00 mmol, 72.04% yield, 99% purity). MS (M+H) + =263.1. 1H NMR (400 MHz, DMSO-d6) δ = 7.92 (s, 1H), 7.90 - 7.84 (m, 1H), 3.93 (t, J = 10.4 Hz, 2H), 3.89 - 3.81 (m, 2H), 1.31 (t, J = 6.8 Hz, 3H).

[0251] Step 3. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (4) The synthesis was carried out in a manner similar to that described in Step 8 of Example 4 to obtain a white solid, 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (25.00 g, 85.84 mmol, 86.72% yield, 95% purity). MS (M+H) + =277.1. 1 H NMR (400 MHz, DMSO-d6) δ = 8.31 (s, 1H), 4.26 (t, J = 12.8 Hz, 2H), 3.69 - 3.58 (m, 2H), 3.33 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).

[0252] Step 4. Synthesis of methyl 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoate and 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (6 & 7) The synthesis was carried out in a manner similar to that described in Step 9 of Example 4 to give a pale yellow solid mixture of 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (3.4 g, 5.68 mmol, 19.63% yield, 71% purity) and pale yellow solid methyl 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoate (7 g, 10.83 mmol, 37.47% yield, 68% purity). MS (M+H) + =426.2, 440.3.

[0253] Step 5. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzamide (Compound 35) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a gray solid: N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzamide (1.40 g, 1.64 mmol, 36.42% yield, 98.1% purity). MS (M+H) + =840.4. 1H NMR (400 MHz, DMSO-d6) δ = 8.38 (d, J = 14.4 Hz, 1H), 8.07 (s, 1H), 7.93 - 7.86 (m, 1H), 7.81 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.47 (d. (m, 2H), 3.14 - 3.27 (m, 4H), 2.93 - 2.83 (m, 1H), 2.80 - 2.67 (m, 1H), 2.66 - 2.56 (m, 6H), 2.54 - 2.41 (m, 3H), 2.05 - 1.92 (m, 1H), 1.82 - 1.74 (m, 2H), 1.57 - 1.45 (m, 4H), 1.43 - 1.38 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H).

[0254] Example 36 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 36) [ka]

[0255] Step 1. Synthesis of benzyl (7-((1-(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3) A mixture of tert-butyl (4-bromo-2-fluorophenyl)carbamate (7 g, 24.13 mmol), benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8.37 g, 20.51 mmol, HCl salt), CsCO (23.58 g, 72.38 mmol), and BrettPhos Pd G (1.09 g, 1.21 mmol) in dioxane (100 mL) was degassed and purged with N three times, after which the mixture was stirred under N at 100 °C for 16 h. LCMS confirmed 38% of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate remaining and the desired mass peak (30%). The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 20 to 80% EtOAc / petroleum ether gradient @ 80 mL / min) to give a yellow solid, benzyl (7-((1-(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.5 g, 3.87 mmol, 16.06% yield, 90% purity). MS (M+H) + =581.5.

[0256] Step 2. Synthesis of benzyl (7-((1-(4-amino-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain a yellow solid, benzyl (7-((1-(4-amino-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.2 g, 3.66 mmol, 85.06% yield, 80% purity). MS (M+H) + =481.3.

[0257] Step 3. Synthesis of benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to obtain a brown solid of benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.3 g, 3.65 mmol, 99.78% yield, 94% purity). MS (M+H) + =592.5.

[0258] Step 4. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (7) The synthesis was carried out in a manner similar to that described in Step 2 of Example 4 to obtain 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (1.2 g, crude, TFA salt) as a brown oil. MS (M+H) + =458.3.

[0259] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 36) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a gray solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (467.50 mg, 374.28 μmol, 41.50% yield, 98.5% purity, 3TFA). MS (M+H) + =887.6. 1 H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 9.15 - 8.98 (m, 1H), 8.54 - 8.48 (m, 1H), 8.29 - 8.13 (m, 3H), 7.53 - 7.47 (m, 2H), 7.24 - 6.79 (m, 3H), 4.83 - 4.73 (m, 1H), 4.47 - 4.36 (m, 2H), 4.12 - 4.03 (m, 2H), 3.94 (s, 3H), 3.59 - 3.51 (m, 2H), 3.47 - 3.36 (m, 2H), 3.33 (s, 3H), 3.10 - 3.04 (m, 2H), 3.00 - 2.91 (m, 2H), 2.89 - 2.70 (m, 2H), 2.62 - 2.54 (m, 1H), 2.41 - 2.34 (m, 1H), 2.21 - 2.13 (m, 1H), 2.09 - 1.67 (m, 16H), 1.65 - 1.43 (m, 6H).

[0260] Example 37 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 37) [ka]

[0261] Step 1. Synthesis of tert-butyl (4-(4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)carbamate (3) A yellow solid of tert-butyl (4-(4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)carbamate (3.3 g, 5.95 mmol, 64.92% yield) was obtained by synthesizing the compound in a manner similar to that described in Step 3 of Example 3. MS (M+H) + =555.4.

[0262] Step 2. Synthesis of benzyl (1-(2-(1-(4-amino-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4) A yellow solid of benzyl (1-(2-(1-(4-amino-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (3 g, crude, HCl) was obtained by synthesis in a manner similar to that described in Step 7 of Example 7. MS (M+H) + =455.2.

[0263] Step 3. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 3 of Example 36 to give benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (1.5 g, 2.65 mmol, 52.08% yield, 100% purity) as a blue solid. MS (M+H) + =566.3.

[0264] Step 4. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (7) The synthesis was carried out in a manner similar to that described in Step 4 of Example 36 to give 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (1.35 g, crude, TFA) as a brown oil. MS (M+H) + =432.3.

[0265] Step 5. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 37) The synthesis was carried out in a manner similar to that described in Step 5 of Example 36 to give a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (403.3 mg, 468.12 μmol, 18.92% yield, 99% purity). MS (M+H) + =853.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.34 - 8.22 (m, 2H), 7.98 (s, 1H), 7.20 (d, J = 6.6 Hz, 1H), 6.79 - 6.69 (m, 2H), 6.63 - 6.55 (m, 1H), 5.05 (d, J = 6.5 Hz, 1H), 4.95 - 4.80 (m, 1H), 4.32 - 4.24 (m, 1H), 4.07 (t, J = 13.4 Hz, 2H), 3.92 (s, 3H), 3.49 - 3.37 (m, 2H), 3.35 - 3.34 (m, 3H), 2.98 - 2.64 (m, 3H), 2.64 - 2.53 (m, 6H), 2.53 - 2.46 (m, 2H), 2.15 - 2.00 (m, 2H), 2.00 - 1.82 (m, 3H), 1.79 - 1.70 (m, 3H), 1.64 - 1.34 (m, 4H), 1.32 - 1.25 (m, 8H).

[0266] Example 38 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 38) [ka]

[0267] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (2) To a solution of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (2 g, 5.83 mmol, HCl salt) in DCM (30 mL) was added TEA (1.77 g, 17.50 mmol, 2.44 mL), DMAP (71.28 mg, 583.44 μmol), and (Boc)2O (1.53 g, 7.00 mmol, 1.61 mL). The mixture was stirred at 20 °C for 1.5 h. LCMS confirmed complete consumption of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione and one main peak of the desired mass. The residue was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (25 g SepaFlash® silica flash column, eluent of 0 to 50% EtOAc / petroleum ether gradient @ 100 mL / min) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1.8 g, 4.43 mmol, 75.91% yield) as a blue solid. MS (M+H) + =407.3.

[0268] Step 2. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (3) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (700 mg, 1.72 mmol) in DCM (10 mL) was added HCHO (698.90 mg, 8.61 mmol, 641.19 μL, 37% purity) and AcOH (103.42 mg, 1.72 mmol, 98.59 μL). After 30 min, NaBH(OAc) (1.10 g, 5.17 mmol) was added to the reaction mixture. The mixture was stirred at 20 °C for 16 h. LCMS showed that ∼20% of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate remained, and several new peaks appeared in the LCMS, confirming ∼73% of the desired compound. HCHO (279.56 mg, 3.44 mmol, 256.48 μL, 37% purity) and NaBH(OAc) (1.10 g, 5.17 mmol) were added to the reaction mixture. The mixture was stirred at 20 °C for 3 h. LCMS showed complete consumption of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate and one main peak of the desired mass. The residue was diluted with NaHCO solution (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 0 to 50% EtOAc / petroleum ether gradient @ 80 mL / min) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (720 mg, 1.71 mmol, 99.43% yield) as a blue solid. MS (M+H) +=421.2.

[0269] Step 3. Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (4) A blue solid, 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (305 mg, 854.77 μmol, 99.84% yield, HCl salt), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =321.2.

[0270] Step 4. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 6 of Example 1 to give a bright yellow oil of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (270 mg, 414.87 μmol, 58.05% yield, 84% purity). MS (M+H) + =547.5.

[0271] Step 5. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (7) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (138 mg, 246.17 μmol, 99.69% yield, TFA salt) as a yellow oil. MS (M+H) + =447.3.

[0272] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 38) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (32.85 mg, 37.88 μmol, 23.13% yield, 98% purity). MS (M+H) + =850.5. 1H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.26 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.47-7.38 (m, 2H), 6.98-6.84 (m, 1H), 6.75-6.62 (m, 1H), 6.60-6.48 (m, 1H), 4.93-4.85 (m, 1H), 4.84-4.76 (m, 1H), 4.04 (t, J = 13.6 Hz, 2H), 3.93 (s, 3H), 3.32-3.31(m, 3H), 3.06-2.95 (m, 3H), 2.95-2.84 (m, 3H), 2.84-2.69 (m, 4H), 2.69 (s, 3H), 2.59-2.52 (m, 2H), 2.46-2.21 (m, 5H), 1.90-1.82 (m, 1H), 1.77-1.67 (m, 2H), 1.54-1.35 (m, 2H), 1.35-1.26 (m, 3H), 1.24 (d, J = 6.7 Hz, 6H).

[0273] Example 39 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 39) [ka]

[0274] Step 1. Synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene (2) The synthesis was carried out in a manner similar to that described in Step 1 of Example 7 to obtain 1,2-difluoro-4-methoxy-5-nitrobenzene (2.3 g, 12.16 mmol, 85.18% yield) as a yellow solid. MS (M+H)+ =190.1

[0275] Step 2. Synthesis of tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (4) A similar procedure to that described in Step 4 of Example 30 was used, except that DMF was replaced with MeCN (30 mL), to give a yellow solid, tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (2.2 g, 6.19 mmol, 50.90% yield). MS (M+H) + =356.4

[0276] Step 3. Synthesis of tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (5) A purple solid, tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (1 g, 3.07 mmol, 99.29% yield), was obtained by synthesis in a manner similar to that described in Step 4 of Example 22. MS (M+H) + =326.4

[0277] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (7) A green solid, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (1.02 g, 2.34 mmol, 95.05% yield), was obtained by synthesis in a manner similar to that described in Step 5 of Example 22. MS (M+H) + =437.2.

[0278] Step 5. Synthesis of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (8) A blue solid, 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (550 mg, crude, HCl salt), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =337.1.

[0279] Step 6. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (10) The synthesis was carried out in a manner similar to that described in Step 6 of Example 1 to give a bright yellow solid of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (340 mg, 604.26 μmol, 45.06% yield). MS (M+H) + =563.3.

[0280] Step 7. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (11) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (350 mg, crude, TFA salt) as a brown oil. MS (M+H) + =463.3.

[0281] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 39) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (120.4 mg, 133.48 μmol, 33.09% yield, 96% purity). MS (M+H) + =866.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.24 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.22 (s, 1H), 7.87 (s, 1H), 7.49-7.37 (m, 2H), 6.61 (d, J = 7.9 Hz, 1H), 6.54 (d, J = 14.5 Hz, 1H), 5.08 (d, J = 6.4 Hz, 1H), 4.93-4.82 (m, 1H), 4.31-4.20 (m, 1H), 4.03 (t, J = 13.5 Hz, 2H), 3.93 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 3.08-2.94 (m, 3H), 2.94-2.86 (m, 4H), 2.85-2.69 (m, 4H), 2.42-2.26 (m, 4H), 2.16-2.09 (m, 1H), 1.97-1.88 (m, 1H), 1.76-1.68 (m, 2H), 1.46-1.38 (m, 2H), 1.37-1.27 (m, 4H), 1.24 (d, J = 6.7 Hz, 6H).

[0282] Example 40 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 40) [ka]

[0283] Step 1. Synthesis of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (2) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (500 mg, 1.15 mmol) in dioxane (1 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 20°C for 3 hours. LCMS confirmed complete consumption of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate. The reaction mixture was concentrated under reduced pressure to remove the solvent and afford a blue solid, 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (500 mg, crude, HCl salt). MS (M+H) + =337.1.

[0284] Step 2. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (4) To a solution of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (500 mg, 1.34 mmol, HCl salt) and tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (487.46 mg, 2.01 mmol) in DCM (10 mL) was added TEA (135.71 mg, 1.34 mmol, 186.67 μL) and 4A MS (50 mg, 134.11 μmol). After 30 min, NaBH(OAc) (852.72 mg, 4.02 mmol) was added to the reaction mixture. The mixture was stirred at 20 °C for 16 h. LCMS confirmed complete consumption of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione and one main peak of the desired mass. The residue was diluted with NaHCO3 solution (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 10-20% MeOH / EtOAc ether gradient @ 80 mL / min) to give a bright yellow solid, tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (390 mg, 693.12 μmol, 51.68% yield). MS (M+H) + =563.3.

[0285] Step 3. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (5) To a solution of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (390 mg, 693.12 μmol) in DCM (6 mL) was added TFA (3.07 g, 26.93 mmol, 2 mL). The mixture was stirred at 20° C. for 1 h. LCMS confirmed ∼3% of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate remaining, confirming ∼75% of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent, yielding 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (410 mg, crude, TFA salt) as a brown oil. MS (M+H) + =463.2.

[0286] Step 4. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 40) To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (210 mg, 469.34 μmol) in DMF (4 mL) was added HATU (267.69 mg, 704.01 μmol), DIPEA (303.29 mg, 2.35 mmol, 408.75 μL), and 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (405.92 mg, 704.01 μmol, TFA salt). The mixture was stirred at 20° C. for 2 hours. LCMS confirmed complete consumption of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione, with one main peak of the desired mass. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 10–20% MeOH / EtOAc gradient @ 80 mL / min) and prep-HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 34%–64% B over The eluate was re-purified by HPLC (10 min) and lyophilized to give a pink solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (111.7 mg, 123.47 μmol, 26.31% yield, 98.6% purity). MS (M+H) +=892.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.96-10.73 (m, 1H), 9.28 (s, 1H), 8.30-8.21 (m, 2H), 7.96 (s, 1H), 7.45-7.37 (m, 2H), 6.60 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 14.4 Hz, 1H), 5.09 (d, J = 6.5 Hz, 1H), 4.83-4.69 (m, 1H), 4.30-4.19 (m, 1H), 4.05 (t, J = 14.0 Hz, 2H), 3.93 (s, 3H), 3.79 (s, 3H), 3.33-3.32 (m, 3H), 3.04-2.96 (m, 2H), 2.95-2.86 (m, 4H), 2.85-2.72 (m, 3H), 2.62-2.51 (m, 4H), 2.40-2.30 (m, 3H), 2.16-2.09 (m, 1H), 1.99-1.88 (m, 3H), 1.75-1.66 (m, 4H), 1.64-1.55 (m, 4H), 1.47-1.38 (m, 2H), 1.36-1.24 (m, 3H).

[0287] Example 41 Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 41) [ka]

[0288] Step 1. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2) The synthesis was carried out in a manner similar to that described in Step 5 of Example 1 to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.15 g, HCl salt) as a light brown solid, which was used immediately. MS (M+H) + =463.2.

[0289] Step 2. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 41) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford an off-white solid: N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (78.7 mg, 64.53 μmol, 13.14% yield, 97.9% purity, 3TFA salt). MS (M+H) + =852.3. 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 9.92-9.69 (m, 1H), 9.66-9.36 (m, 1H), 8.42-8.30 (m, 1H), 8.28-8.12 (m, 2H), 7.51-7.33 (m, 2H), 6.69-6.45 (m, 2H), 4.31-4.19 (m, 3H), 3.94 (s, 3H), 3.81 (s, 3H), 3.68-3.64 (m, 2H), 3.57 (d, J = 11.4 Hz, 2H), 3.35-3.30 (m, 5H), 3.25-3.11 (m, 6H), 3.08-2.98 (m, 2H), 2.87-2.84 (m, 2H), 2.82-2.73 (m, 1H), 2.59-2.56 (m, 1H), 2.15-2.06 (m, 1H), 2.01-1.89 (m, 1H), 1.85-1.75 (m, 2H), 1.70-1.60 (m, 2H), 1.45-1.30 (m, 3H), 1.21 (t, J = 7.0 Hz, 3H).

[0290] Example 42 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 42) [ka] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (1.61 g, 3.47 mmol) in DMF (30 mL) was added HATU (1.58 g, 4.16 mmol) and DIPEA (1.34 g, 10.41 mmol, 1.81 mL), and the resulting mixture was stirred at 20° C. for 1 h, after which 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2 g, 3.47 mmol, TFA salt) was added, and the mixture was stirred at 20° C. for 2 h. LCMS confirmed the desired mass peak (66%). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-10% MeOH / EtOAc gradient @ 100 mL / min) to give 1.7 g of impure product, which was triturated with ACN (50 mL) and filtered. The filter cake was collected to give 1.6 g of the desired product as a brown solid. The product was purified by prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B over The mixture was re-purified by HPLC (10 min) and the eluate was lyophilized to give 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (1.16 g, 1.12 mmol, 32.20% yield, 99% purity, TFA salt) as a white solid. MS (M+H) +=910.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 9.61 - 9.49 (m, 1H), 9.25 (br s, 1H), 8.31 (s, 1H), 8.24 (d, J = 13.0 Hz, 1H), 8.15 (s, 1H), 7.16 (d, J = 6.5 Hz, 1H), 6.66 - 6.56 (m, 2H), 4.87 - 4.80 (m, 1H), 4.29 (br dd, J = 4.8, 11.9 Hz, 1H), 4.10 (br t, J = 13.9 Hz, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.57 (br d, J = 11.1 Hz, 2H), 3.38 - 3.31 (m, 5H), 3.23 - 3.03 (m, 8H), 2.87 - 2.68 (m, 3H), 2.61 - 2.54 (m, 1H), 2.16 - 2.07 (m, 1H), 2.02 - 1.91 (m, 3H), 1.82 - 1.60 (m, 10H), 1.44 - 1.25 (m, 3H).

[0291] Example 43 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 43) A yellow solid of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (803 mg, 796.60 μmol, 20.88% yield, 99% purity, TFA salt) was obtained by synthesis in a manner similar to that described in Step 1 of Example 42. MS (M+H) + =884.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 9.66 - 9.48 (m, 1H), 9.23 (br s, 1H), 8.34 - 8.20 (m, 2H), 8.11 (s, 1H), 7.16 (d, J = 6.6 Hz, 1H), 6.70 - 6.50 (m, 2H), 4.93 - 4.88 (m, 1H), 4.29 (br dd, J = 5.1, 11.9 Hz, 1H), 4.09 (br t, J = 13.3 Hz, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.57 (br d, J = 11.6 Hz, 2H), 3.34 (s, 5H), 3.26 - 2.99 (m, 8H), 2.85 - 2.66 (m, 3H), 2.57 (br s, 1H), 2.16 - 2.06 (m, 1H), 2.02 - 1.87 (m, 1H), 1.82 - 1.57 (m, 4H), 1.45 - 1.30 (m, 3H), 1.27 (d, J = 6.6 Hz, 6H).

[0292] Example 44 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-3-methoxybenzamide (Compound 44) [ka]

[0293] Step 1. Synthesis of 4-bromo-3-fluoro-2-methoxyaniline (2) To a solution of 3-fluoro-2-methoxyaniline (8 g, 56.68 mmol) in AcOH (30 mL) was added dropwise a mixture of Br2 (7.25 g, 45.34 mmol, 2.34 mL) in AcOH (30 mL), and the resulting mixture was stirred at 20 °C for 0.5 h. TLC (SiO2, petroleum ether: EtOAc = 5:1) confirmed the presence of a trace of starting material and a highly polar main spot. The suspension was filtered, and the filter cake was washed with petroleum ether (50 mL) and a mixture (petroleum ether: EtOAc = 3:1, 20 mL). The combined filter cake was dried in vacuo and purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 3-10% EtOAc / petroleum ether gradient @ 200 mL / min). The eluate was concentrated in vacuo to give 4-bromo-3-fluoro-2-methoxyaniline (8 g, 29.09 mmol, 51.32% yield, 80% purity) as an off-white solid. MS (M+H) + =220.0.

[0294] Step 2. Synthesis of methyl 4-amino-2-fluoro-3-methoxybenzoate (3) A solution of 4-bromo-3-fluoro-2-methoxyaniline (8 g, 29.09 mmol) and TEA (23.99 g, 237.09 mmol, 33 mL) in MeOH (100 mL) and DMF (50 mL) was treated with Pd(dppf)Cl 2. CHCl (2.7 g, 3.31 mmol) was added under N. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred at 80° C. under CO (50 psi) for 120 h. LCMS confirmed complete consumption of the starting material and 40% of the desired mass. The mixture was filtered, and the filter cake was washed with MeOH (300 mL). The filtrate was concentrated in vacuo to remove MeOH, after which the residue was diluted with brine (200 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL×4), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (80 g SepaFlash® silica flash column, eluent of 10-12% EtOAc / petroleum ether gradient @ 200 mL / min) to give methyl 4-amino-2-fluoro-3-methoxybenzoate (3.13 g, 15.71 mmol, 54.03% yield) as an off-white solid. MS (M+H) + =200.4. 1 H NMR (400 MHz, DMSO-d6) δ = 7.36 (t, J = 8.3 Hz, 1H), 6.49 (dd, J = 1.1, 8.8 Hz, 1H), 6.09 (s, 2H), 3.74 (d, J = 5.4 Hz, 6H).

[0295] Step 3. Synthesis of methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoate (5) A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (6 g, 18.94 mmol), methyl 4-amino-2-fluoro-3-methoxybenzoate (3.30 g, 16.57 mmol), Pd(dba) (1 g, 1.09 mmol), Xantphos (1 g, 1.73 mmol), and KPO (12.00 g, 56.53 mmol) in dioxane (100 mL) was stirred at 100 °C for 16 h under N atmosphere. LCMS confirmed complete consumption of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one and 64% of the desired mass. The mixture was diluted with brine (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 15-35% EtOAc / petroleum ether gradient @ 200 mL / min) to give methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoate (6.17 g, 12.87 mmol, 67.93% yield) as a light brown solid. MS (M+H) + =480.3.

[0296] Step 4. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoic acid (6) A mixture of methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoate (6.17 g, 12.87 mmol) and NaOH (2 M, 30 mL) in MeOH (30 mL) and THF (30 mL) was stirred at 20 °C for 12 h. LCMS confirmed complete consumption of the starting material and the desired mass. The reaction mixture was concentrated in vacuo to remove the organic solvent, and the residue was adjusted to pH < 2 by adding HCl solution (12 M). ACN (20 mL) and EtOAc (20 mL) were added to the suspension, and the resulting mixture was stirred at 15 °C for 10 min. The suspension was filtered. The filter cake was washed with EtOAc (20 mL), and the filter cake was collected and dried. The filter cake was diluted with HCl solution (12 M, 30 mL) and concentrated in vacuo at 75 °C. The residue was triturated with a mixture (MeCN: EtOAc = 1:3, 60 mL) for 10 minutes, the suspension was filtered, and the filter cake was washed with a mixture (MeCN: EtOAc = 1:3, 40 mL). The filter cake was collected and dried in vacuo to give 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoic acid (5.64 g, 12.12 mmol, 94.16% yield) as an off-white solid. MS (M+H) + =466.3.

[0297] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-3-methoxybenzamide (Compound 44) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-3-methoxybenzamide (522.2 mg, 567.84 μmol, 61.82% yield, 98.95% purity). MS (M+H) + =910.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.58 (s, 1H), 8.92 - 8.62 (m, 1H), 8.27 (s, 1H), 8.16 - 7.95 (m, 2H), 7.34 - 6.98 (m, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 14.1 Hz, 1H), 5.01 (d, J = 6.4 Hz, 1H), 4.87 - 4.67 (m, 1H), 4.29 - 4.17 (m, 1H), 4.02 (t, J = 14.0 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 3H), 3.36 (s, 3H), 3.04 - 2.88 (m, 6H), 2.86 - 2.77 (m, 1H), 2.76 - 2.63 (m, 2H), 2.63 - 2.57 (m, 2H), 2.56 (s, 3H), 2.45 - 1.99 (m, 2H), 2.25 - 2.16 (m, 1H), 1.98 (dd, J = 4.7, 10.9 Hz, 2H), 1.95 - 1.87 (m, 1H), 1.82 - 1.68 (m, 4H), 1.67 - 1.57 (m, 4H), 1.53 - 1.41 (m, 2H), 1.41 - 1.27 (m, 3H).

[0298] Example 45 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxybenzamide (Compound 45) [ka]

[0299] Step 1. Synthesis of 4-amino-5-fluoro-2-methoxybenzonitrile (2) To a solution of MeOH (23.75 g, 741.35 mmol, 30.00 mL) in THF (100 mL) was added dropwise t-BuOK (1 M, 160.00 mL) under N2 gas at 0 °C, and the mixture was stirred at 20 °C for 0.5 h. Then, 4-amino-2,5-difluorobenzonitrile (10 g, 64.89 mmol) was added, and the resulting mixture was stirred at 70 °C for 3 h. LCMS confirmed complete consumption of the starting material and 99% of the desired mass. The mixture was concentrated in vacuo to remove most of the solvent. The residue was diluted with H2O (300 mL) and extracted with MTBE (150 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 8 to 28% EtOAc / petroleum ether gradient @ 200 mL / min) to give 4-amino-5-fluoro-2-methoxybenzonitrile (9.85 g, 59.28 mmol, 91.37% yield) as a gray solid. MS (M+H) + =167.5.

[0300] Step 2. Synthesis of 4-amino-5-fluoro-2-methoxybenzoic acid (3) A mixture of 4-amino-5-fluoro-2-methoxybenzonitrile (2.98 g, 17.94 mmol), NaOH (8 M, 16 mL), and EtOH (15 mL) was stirred in a sealed can at 110 °C for 20 h. LCMS confirmed complete consumption of the starting material, and the desired mass was detected. After cooling to room temperature, the mixture was combined with the three batches and concentrated in vacuo to remove most of the solvent. The residue was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was acidified with 6 M HCl solution to pH = 4. The resulting mixture was extracted with a mixture (200 mL x 5, 200 mL of EtOAc:MeOH), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford 4-amino-5-fluoro-2-methoxybenzoic acid (10.73 g) as a light brown solid, which was used immediately. MS(M+H) + =186.1.

[0301] Step 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-5-fluoro-2-methoxybenzoic acid (4) A similar procedure to that described in Step 3 of Example 44 was used, except that KCO (4.00 g, 28.94 mmol) was used instead of KPO to obtain a gray solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-5-fluoro-2-methoxybenzoic acid (3.15 g, 7.17 mmol, 52.10% yield). MS (M+H) + =440.3. 1H NMR (400 MHz, DMSO-d6) δ = 9.64 (s, 1H), 8.30 (s, 1H), 7.71 (d, J = 6.6 Hz, 1H), 7.59 (d, J = 11.1 Hz, 1H), 5.04 - 4.93 (m, 1H), 4.17 (t, J = 12.8 Hz, 2H), 3.85 (s, 3H), 3.37 (s, 3H), 1.21 (d, J = 6.7 Hz, 6H).

[0302] Step 4. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxybenzamide (Compound 45) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a bright pink solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxybenzamide (660.01 mg, 727.64 μmol, 53.42% yield, 97.45% purity). MS (M+H) + =884.5. 1H NMR (400 MHz, DMSO-d6) δ = 10.69 - 10.44 (m, 1H), 8.79 - 8.67 (m, 1H), 8.64 - 8.40 (m, 1H), 8.20 (s, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.56 - 7.41 (m, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 14.3 Hz, 1H), 5.00 (d, J = 6.4 Hz, 1H), 4.97 - 4.80 (m, 1H), 4.29 - 4.16 (m, 1H), 3.98 (t, J = 13.4 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.34 (s, 3H), 3.01 (d, J = 1.1 Hz, 2H), 2.99 - 2.88 (m, 4H), 2.86 - 2.76 (m, 1H), 2.76 - 2.63 (m, 2H), 2.62 - 2.53 (m, 2H), 2.54 - 2.50 (m, 3H), 2.43 - 2.35 (m, 2H), 2.24 - 2.15 (m, 1H), 1.96 - 1.85 (m, 1H), 1.79 - 1.64 (m, 2H), 1.50 - 1.40 (m, 2H), 1.40 - 1.26 (m, 3H), 1.20 (d, J = 6.6 Hz, 6H).

[0303] Example 46 Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxo-3-piperidyl)amino)-2-fluoro-5-methoxy-phenyl)piperazin-1-yl)ethyl)-1-piperidyl)-4-methoxy-pyridine-2-carboxamide (Compound 46) [ka]

[0304] Step 1. Synthesis of 7,7-difluoro-9-isopropyl-2-((4-methoxybenzyl)amino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2) To 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (5.00 g, 17.20 mmol) and (4-methoxyphenyl)methanamine (3.54 g, 25.80 mmol) in t-BuOH (5 mL) was added DIPEA (4.45 g, 34.40 mmol). The mixture was stirred at 100 °C for 26 h. LCMS confirmed ~74% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was triturated with MTBE (30 mL) at 25 °C for 10 min to give 7,7-difluoro-9-isopropyl-2-((4-methoxybenzyl)amino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (5.20 g, 7.97 mmol, 46.34% yield, 60% purity). MS (M+H) + =392.2.

[0305] Step 2. Synthesis of 2-amino-7,7-difluoro-9-isopropyl-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (3) 7,7-Difluoro-9-isopropyl-2-((4-methoxybenzyl)amino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (5.20 g, 7.97 mmol) in TFA (50 mL) was stirred at 25 °C for 16 h. LCMS confirmed ~51% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCO3 solution (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was triturated with MTBE (30 mL) at 25 °C for 10 min to give a pale yellow solid, 2-amino-7,7-difluoro-9-isopropyl-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (2.30 g, 5.94 mmol, 74.46% yield, 70% purity). MS (M+H) + =272.1.

[0306] Step 3. Synthesis of methyl 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylate (5) The synthesis was carried out in a manner similar to that described in Step 3 of Example 3 to obtain a pale yellow solid, methyl 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylate (1.25 g, 2.72 mmol, 62.03% yield, 95% purity). MS (M+H) + =437.2.

[0307] Step 4. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylic acid (6) To a solution of methyl 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylate (1.25 g, 2.72 mmol) in MeOH (10 mL) and THF (10 mL) was added NaOH / HO (2 M, 10 mL). The mixture was stirred at 25 °C for 16 h. LCMS confirmed ~91% of the desired compound. The mixture was adjusted to pH = 2 with HCl / dioxane (2 M) and concentrated to give 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylic acid (2 g, crude) as a yellow solid. The crude product was used immediately without further purification. MS (M+H) + =423.2.

[0308] Step 5. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxo-3-piperidyl)amino)-2-fluoro-5-methoxy-phenyl)piperazin-1-yl)ethyl)-1-piperidyl)-4-methoxy-pyridine-2-carboxamide (compound 46) The pale yellow solid 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxo-3-piperidyl)amino)-2-fluoro-5-methoxy-phenyl)piperazin-1-yl)ethyl)-1-piperidyl)-4-methoxy-pyridine-2-carboxamide (702 mg, 795.18 μmol, 27.99% yield, 98.2% purity) was obtained by synthesizing in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =867.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.35 (s, 1H), 9.10 (s, 1H), 8.21 - 8.16 (m, 2H), 7.62 (s, 1H), 6.10 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 14.4 Hz, w1H), 5.13 - 5.05 (m, 1H), 4.85 - 4.74 (m, 1H), 4.30 - 4.20 (m, 1H), 4.08 - 3.95 (m, 5H), 3.79 (s, 3H), 3.32 - 3.29 (m, 5H), 3.00 - 2.85 (m, 6H), 2.85 - 2.75 (m, 1H), 2.75 - 2.65 (m, 2H), 2.59 - 2.54 (m, 1H), 2.40 - 2.30 (m, 2H), 2.17 - 2.08 (m, 1H), 1.98 - 1.84 (m, 1H), 1.77 - 1.65 (m, 2H), 1.47 - 1.37 (m, 2H), 1.35 - 1.31 (m, 3H), 1.29 - 1.23 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).

[0309] Example 47 Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-methoxypicolinamide (Compound 47) [ka]

[0310] Step 1. Synthesis of 9-cyclopentyl-2-((2,4-dimethoxybenzyl)amino)-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2) A similar procedure to that described in Step 1 of Example 46 was used, except that PMBNH was replaced with DMBNH (13.36 g, 79.88 mmol, 12.00 mL) to obtain a yellow solid, 9-cyclopentyl-2-((2,4-dimethoxybenzyl)amino)-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (13 g, crude). MS (M+H) + =448.3.

[0311] Step 2. Synthesis of 2-amino-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (3) A yellow solid, 2-amino-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (6.13 g, 20.21 mmol, 69.55% yield, 98% purity), was obtained by synthesizing the compound in a manner similar to that described in Step 2 of Example 46. MS (M+H) + =298.2.

[0312] Step 3. Synthesis of methyl 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinate (5) A similar procedure to that described in Step 3 of Example 46 was used, except that CsCO was replaced with KPO (12.96 g, 61.08 mmol), to give a yellow solid, methyl 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinate (7.61 g, 16.13 mmol, 79.51% yield, 98% purity). MS (M+H) + =463.2.

[0313] Step 4. Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (6) The synthesis was carried out in a manner similar to that described in Step 4 of Example 46 to give a white solid, 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (6.46 g, 13.11 mmol, 79.66% yield, 91% purity). MS (M+H) + =449.3.

[0314] Step 5. Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-methoxypicolinamide (Compound 47) A yellow solid of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-methoxypicolinamide (149.8 mg, 166.41 μmol, 4.97% yield, 99% purity) was obtained by synthesis in a manner similar to that described in Step 5 of Example 46. MS (M+H) + =893.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.33 (s, 1H), 9.01 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.62 (s, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 14.5 Hz, 1H), 5.08 (d, J = 6.4 Hz, 1H), 4.70 - 4.58 (m, 1H), 4.30 - 4.20 (m, 1H), 4.06 - 3.93 (m, 5H), 3.79 (s, 3H), 3.32 (s, 3H), 3.31 - 3.25 (m, 4H), 3.01 - 2.87 (m, 6H), 2.84 - 2.75 (m, 1H), 2.72 - 264 (m, 2H), 2.58 - 2.53 (m, 1H), 2.35 (t, J = 7.1 Hz, 2H), 2.17 - 2.08 (m, 1H), 1.96 - 1.80 (m, 3H), 1.75 - 1.61 (m, 4H), 1.59 - 1.47 (m, 4H), 1.45 - 1.38 (m, 2H), 1.36 - 1.26 (m, 3H).

[0315] Example 48 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 48) [ka]

[0316] Step 1. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (3) The synthesis was carried out in a manner similar to that described in Step 3 of Example 23, with the addition of MeCN (24 mL) to give a gray solid of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (1.59 g, 2.77 mmol, 34.41% yield, 98% purity). MS (M+H) + =563.4.

[0317] Step 2. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (4) The procedure was similar to that described in Step 5 of Example 1, except that dioxane was replaced with DCM (10 mL) to obtain a gray solid, 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.4 g, crude, HCl). MS (M+H) + =463.3.

[0318] Step 3. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 48) The yellow solid 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (1.65 g, 1.84 mmol, 68.49% yield, 99.4% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =892.6. 1 H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.31 - 8.22 (m, 2H), 8.18 - 8.06 (m, 1H), 7.96 (s, 1H), 7.53 - 7.43 (m, 2H), 6.64 - 6.49 (m, 2H), 5.09 (d, J = 6.7 Hz, 1H), 4.82 - 4.69 (m, 1H), 4.29 - 4.21 (m, 1H), 4.04 (t, J = 13.9 Hz, 2H), 3.94 (s, 3H), 3.84 - 3.72 (m, 4H), 3.34 - 3.33 (m, 6H), 2.96 - 2.86 (m, 6H), 2.83 - 2.73 (m, 1H), 2.64 - 2.52 (m, 6H), 2.16 - 1.86 (m, 6H), 1.84 - 1.51 (m, 10H).

[0319] Example 49 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 49) [ka]

[0320] Step 1. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (3) The synthesis was carried out in a manner similar to that described in Step 3 of Example 23 to give a blue solid of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (4.5 g, 8.00 mmol, 49.69% yield). MS (M+H) + =563.3.

[0321] Step 2. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (4) The synthesis was carried out in a manner similar to that described in Step 3 of Example 3 to obtain 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2 g, 3.47 mmol, 97.59% yield, TFA salt) as a brown oil. MS (M+H) + =463.3.

[0322] Step 3. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 49) The blue solid 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (1.67 g, 1.81 mmol, 52.30% yield, 99% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =910.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (br s, 1H), 8.30 (s, 1H), 8.25 (d, J = 13.3 Hz, 1H), 8.04 (s, 1H), 7.89 (br dd, J = 2.8, 7.3 Hz, 1H), 7.20 (d, J = 6.6 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 14.3 Hz, 1H), 5.09 (br d, J = 6.4 Hz, 1H), 4.83 (br t, J = 8.1 Hz, 1H), 4.32 - 4.18 (m, 1H), 4.08 (br t, J = 13.9 Hz, 2H), 3.92 (s, 3H), 3.83 - 3.72 (m, 4H), 3.31 (br s, 2H), 2.93 - 2.76 (m, 7H), 2.59 - 2.51 (m, 6H), 2.49 - 2.42 (m, 4H), 2.16 - 1.90 (m, 6H), 1.84 - 1.70 (m, 4H), 1.67 - 1.51 (m, 6H).

[0323] Example 50 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 50) [ka]

[0324] Step 1. Synthesis of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (3) A white solid, tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (7.7 g, 16.93 mmol, 81.90% yield, 98% purity), was obtained by synthesis in a manner similar to that described in Step 6 of Example 1. MS (M+H) + =446.3.

[0325] Step 2. Synthesis of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4) A white solid of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6.5 g, crude, HCl) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =346.1. 1H NMR (400 MHz, CD3OD) δ = 7.44 - 7.19 (m, 5H), 5.22 - 4.96 (m, 2H), 3.73 -3.62 (m, 4H), 3.47 - 3.36 (m, 2H), 3.25 - 3.14 (m, 2H), 3.14 - 2.89 (m, 4H), 2.19 - 1.93 (m, 4H), 1.90 - 1.66 (m, 4H), 1.56 - 1.37 (m, 2H).

[0326] Step 3. Synthesis of benzyl (1-(2-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 2 of Example 7 to obtain a yellow solid, benzyl (1-(2-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (3 g, 5.83 mmol, 34.26% yield, 100% purity). MS (M+H) + =515.3.

[0327] Step 4. Synthesis of benzyl (1-(2-(1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 1 of Example 35 to obtain a brown solid, benzyl (1-(2-(1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (5.6 g, 10.75 mmol, 80.15% yield, 93% purity). MS (M+H) + =485.2.

[0328] Step 5. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to obtain a brown solid of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (3 g, 4.63 mmol, 74.84% yield, 92% purity). MS (M+H) + =596.2.

[0329] Step 6. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (10) The brown oil 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2.5 g, crude, TFA) was obtained by synthesis in a manner similar to that described in Step 2 of Example 4. MS (M+H) + =462.3.

[0330] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 50) The purple solid 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (507.3 mg, 561.92 μmol, 41.34% yield, 97.8% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =883.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.34 - 8.24 (m, 2H), 7.97 (s, 1H), 7.93 - 7.80 (m, 1H), 7.20 (d, J = 6.8 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 14.3 Hz, 1H), 5.08 (d, J = 6.8 Hz, 1H), 4.95 - 4.85 (m, 1H), 4.29 - 4.20 (m, 1H), 4.07 (t, J = 13.6 Hz, 2H), 3.92 (s, 3H), 3.78 (s, 3H), 3.34 (s, 3H), 3.18 - 3.11 (m, 2H), 2.86 - 2.76 (m, 2H), 2.66 - 2.53 (m, 4H), 2.40 - 2.26 (m, 2H), 2.16 - 2.08 (m, 1H), 2.04 - 1.89 (m, 3H), 1.85 - 1.72 (m, 4H), 1.63 - 1.51 (m, 2H), 1.44 - 1.24 (m, 12H).

[0331] Example 51 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 51) [ka]

[0332] Step 1. Synthesis of benzyl (7-((1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3) Benzyl (7-((1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (11.26 g, 19.16 mmol, 90.33% yield, 92% purity) was obtained as a yellow oil by a method similar to that described in Step 4 of Example 30. MS (M+H) + =541.4.

[0333] Step 2. Synthesis of benzyl (7-((1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to obtain benzyl (7-((1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (9.14 g, crude) as a red oil. MS (M+H) + =511.3.

[0334] Step 3. Synthesis of benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22, with the addition of TBAI (1.87 g, 5.08 mmol) to give a gray solid of benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.8 g, 2.78 mmol, 16.43% yield, 96% purity). MS (M+H) + =622.3.

[0335] Step 4. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) To a solution of Pd / C (1 g, 10% purity) in THF (60 mL) was added a solution of BocO (3.58 g, 16.41 mmol, 3.77 mL), AcOH (340 mg, 5.66 mmol, 324.12 μL), and benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6.8 g, 10.94 mmol) in THF (100 mL) under N atmosphere. The mixture was stirred at 25 °C under H atmosphere (45 psi) for 28 h. The desired mass was detected by LCMS. The mixture was filtered, and the filter cake was washed with THF (500 mL). The filtrate was concentrated under reduced pressure (25 °C). The residue was diluted with EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaHCO3 (50 mL) and water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, then diluted with MTBE / EtOH = 4 / 1 (65 mL), and the mixture was stirred at 25 °C for 14 h. The collected filter cake was triturated with MTBE / EtOH = 4 / 1 (30 mL, twice), and then filtered. The filter cake was collected and dried to give a blue solid, tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4.74 g, 8.07 mmol, 73.74% yield). The filtrate was concentrated under reduced pressure and triturated with MTBE / EtOH = 4 / 1 (20 mL) at 25 °C for 14 hours. The mixture was filtered, and the filter cake was washed with MTBE / EtOH = 4 / 1 (10 mL). The filter cake was collected to give a blue solid, tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (680 mg, 1.16 mmol, 10.58% yield, 100% purity). MS (M+H) + =588.3.

[0336] Step 5. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (8) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain a yellow oil, 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.83 g, crude, TFA). MS (M+H) + =488.2.

[0337] Step 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 51) The yellow solid 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (1.18 g, 1.27 mmol, 51.66% yield, 98.7% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =917.6. 1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.42 (d, J = 7.3 Hz, 1H), 8.29 - 8.25 (m, 2H), 7.96 (s, 1H), 7.51 - 7.46 (m, 2H), 6.60 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 14.2 Hz, 1H), 5.07 (d, J = 7.0 Hz, 1H), 4.82 - 4.71 (m, 1H), 4.44 - 4.35 (m, 1H), 4.29 - 4.20 (m, 1H), 4.04 (t, J = 14.0 Hz, 2H), 3.94 (s, 3H), 3.77 (s, 3H), 3.33 (s, 3H), 3.17 - 3.10 (m, 2H), 2.84 - 2.75 (m, 1H), 2.64 - 2.54 (m, 3H), 2.35 - 2.09 (m, 9H), 1.99 - 1.88 (m, 3H), 1.85 - 1.78 (m, 2H), 1.77 - 1.67 (m, 4H), 1.65 - 1.52 (m, 9H), 1.29 - 1.17 (m, 2H).

[0338] Example 52 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (Compound 52) The yellow solid 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (905.6 mg, 968.38 μmol, 38.68% yield, 97.2% purity) was obtained by synthesis in a manner similar to that described in Example 51. MS (M+H) + =909.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.90 - 10.77 (m, 1H), 8.31 - 8.16 (m, 3H), 7.96 (s, 1H), 7.19 (d, J = 6.7 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 14.3 Hz, 1H), 5.06 (d, J = 6.2 Hz, 1H), 4.94 - 4.85 (m, 1H), 4.43 - 4.31 (m, 1H), 4.29 - 4.21 (m, 1H), 4.11 - 4.01 (m, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 3.31 - 3.27 (m, 3H), 3.17 - 3.09 (m, 2H), 2.86 - 2.75 (m, 1H), 2.64 - 2.53 (m, 3H), 2.36 - 2.08 (m, 9H), 1.97 - 1.84 (m, 1H), 1.83 - 1.71 (m, 4H), 1.66 - 1.49 (m, 5H), 1.33 - 1.15 (m, 8H).

[0339] Example 53 Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-methoxypicolinamide (Compound 53) To a solution of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (1.5 g, 3.55 mmol) and HATU (1.62 g, 4.26 mmol) in DMF (20 mL) was added DIPEA (4.59 g, 35.51 mmol, 6.19 mL) and the mixture was stirred at 25° C. for 15 min. A solution of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2.4 g, 3.99 mmol, TFA) in DMF (20 mL) was then added and the mixture was stirred at 25° C. for 3 h. LCMS confirmed 53% of the desired mass and 27% of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione remained. Then, a solution of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (450 mg, 1.07 mmol), HATU (419 mg, 1.10 mmol), and DIPEA (371.00 mg, 2.87 mmol, 0.5 mL) in DMF (5 mL) was added, and the mixture was stirred at 25 °C for 1 h. LCMS confirmed 77% of the desired mass. The mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO (100 mL), followed by extraction with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 7-13% MeOH / DCM gradient at 100 mL / min). The product was diluted with 1 N HCl (60 mL) and the mixture was stirred at 25° C. for 10 min. The mixture was washed with EtOAc (30 mL x 3), and the aqueous phase was slowly added to saturated aqueous NaHCO (200 mL).The mixture was then filtered, and the filter cake was washed with deionized water (30 mL x 3). The filter cake was collected, and the solvent was removed under reduced pressure to give a white solid: 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-methoxypicolinamide (2.08 g, 2.30 mmol, 64.74% yield, 98.6% purity). MS (M+H). + =892.6. 1 H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.12 (s, 1H), 8.83 - 8.71 (m, 1H), 8.23 ​​- 8.14 (m, 2H), 7.64 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 14.1Hz, 1H), 5.11 - 5.04 (m, 1H), 4.85 - 4.75 (m, 1H), 4.49 - 4.35 (m, 1H), 4.30 - 4.21 (m, 1H), 4.08 - 3.95 (m, 5H), 3.78 (s, 3H), 3.32 (s, 3H), 3.18 - 3.10 (m, 2H), 2.86 - 2.73 (m, 1H), 2.66 - 2.55 (m, 4H), 2.30 - 2.05 (m, 7H), 1.99 - 1.70 (m, 7H), 1.65 - 1.48 (m, 4H), 1.29 - 1.14 (m, 8H).

[0340] Example 54 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 54) [ka]

[0341] Step 1. Synthesis of tert-butyl 4-(2-fluoro-3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (3) A yellow solid, tert-butyl 4-(2-fluoro-3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (16.3 g, 43.58 mmol, 82.41% yield, 95% purity), was obtained by synthesis in a manner similar to that described in Step 4 of Example 30. MS (Mt-Bu + H) + =300.1.

[0342] Step 2. Synthesis of tert-butyl 4-(4-amino-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (4) A red solid, tert-butyl 4-(4-amino-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (14 g, 43.03 mmol, 95.56% yield), was obtained by adding MeOH (160 mL) in a manner similar to that described in Step 1 of Example 35. MS (M+H) + =326.1.

[0343] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (6) A blue solid, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (5.3 g, 12.02 mmol, 78.23% yield, 99% purity), was obtained by synthesis in a manner similar to that described in Step 5 of Example 22. MS (M+H) + =437.2.

[0344] Step 4. Synthesis of 3-((3-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7) A blue solid, 3-((3-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (5 g, crude, HCl) was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =337.1.

[0345] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 6 of Example 1 to obtain a blue solid of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (1.4 g, 2.39 mmol, 44.53% yield, 96% purity). MS (M+H) + =563.3.

[0346] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (10) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.3 g, 2.25 mmol, 97.59% yield, TFA) as a brown oil. MS (M+H) + =463.4.

[0347] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 54) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (481.7 mg, 524.37 μmol, 23.26% yield, 97.1% purity). MS (M+H) + =892.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.29 (s, 1H), 8.31 - 8.19 (m, 2H), 7.97 (s, 1H), 7.49 - 7.37 (m, 2H), 6.64 (t, J = 8.3 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 5.26 (s, 1H), 4.82 - 4.72 (m, 1H), 4.36 - 4.24 (m, 1H), 4.05 (t, J = 13.9 Hz, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.33 (s, 3H), 3.09 - 2.97 (m, 3H), 2.95 - 2.86 (m, 3H), 2.84 - 2.72 (m, 4H), 2.61 - 2.52 (m, 3H), 2.49 - 2.25 (m, 3H), 2.16 - 2.07 (m, 1H), 2.05 - 1.87 (m, 3H), 1.79 - 1.68 (m, 4H), 1.65 - 1.55 (m, 4H), 1.53 - 1.39 (m, 2H), 1.38 - 1.23 (m, 3H).

[0348] Example 55 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 55) [ka]

[0349] Step 1. Synthesis of 1,3-difluoro-2-methoxy-4-nitrobenzene (2) To a solution of 2,6-difluoro-3-nitrophenol (5 g, 28.56 mmol) in DMF (70 mL) was added K2CO3 (7.89 g, 57.11 mmol) and MeI (6.16 g, 43.37 mmol, 2.7 mL), and the mixture was stirred at 25 °C for 14 h. TLC (petroleum ether: EtOAc = 1:0) confirmed the consumption of the starting material, and a new spot was detected. The mixture was diluted with EtOAc (50 mL) and brine (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 1,3-difluoro-2-methoxy-4-nitrobenzene (6 g, crude) as a yellow oil.

[0350] Step 2. Synthesis of tert-butyl 4-(3-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (4) To a solution of 1,3-difluoro-2-methoxy-4-nitrobenzene (6 g, 31.73 mmol) and K2CO3 (5.26 g, 38.07 mmol) in DMF (200 mL) was added tert-butyl piperazine-1-carboxylate (5.4 g, 28.99 mmol), and the mixture was stirred at 100 °C for 1 h. LCMS confirmed the desired mass. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with MTBE (50 mL) at 25 °C for 14 h. The mixture was filtered, and the filter cake was washed with MTBE (10 mL). The filter cake was collected, and the solvent was removed under reduced pressure to give 4.74 g of product with a purity of 97%. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (120 g SepaFlash® silica flash column, eluent of 10-20% EtOAc / petroleum ether gradient @ 100 mL / min) to give 3.46 g of product. The two batches of product were combined to give tert-butyl 4-(3-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (8.2 g, 22.38 mmol, 70.55% yield, 97% purity) as a yellow solid. MS (M+H) + =356.2. 1 H NMR (400 MHz, DMSO-d6) δ = 7.85 (dd, J = 8.5, 9.4 Hz, 1H), 6.88 (dd, J = 1.5, 9.5 Hz, 1H), 3.83 (s, 3H), 3.53 - 3.46 (m, 4H), 3.31 - 3.27 (m, 4H), 1.42 (s, 9H).

[0351] Step 3. Synthesis of tert-butyl 4-(4-amino-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (5) To a solution of tert-butyl 4-(3-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (8.2 g, 23.08 mmol) and NH₄Cl (3.70 g, 69.22 mmol) in EtOH (150 mL) and HO (50 mL) was added Fe (3.87 g, 69.23 mmol), and the mixture was stirred at 80°C for 1 h. LCMS confirmed 84% of the desired mass. The mixture (80°C) was filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure and then adjusted to pH = 8 with saturated aqueous NaHCO₃. The mixture was extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with water (50 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid, tert-butyl 4-(4-amino-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (7.6 g, crude). MS (M+H) + =326.2.

[0352] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (7) A solution of tert-butyl 4-(4-amino-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (8.5 g, 26.12 mmol), 3-bromopiperidine-2,6-dione (10.03 g, 52.25 mmol), TBAI (964.92 mg, 2.61 mmol), and NaHCO (8.78 g, 104.49 mmol, 4.07 mL) in MeCN (20 mL) was stirred at 80 °C for 28 h. LCMS confirmed 84% of the desired mass. The mixture was diluted with EtOAc (200 mL) and filtered. The filter cake was washed with EtOAc (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (80 g SepaFlash® silica flash column, eluent of 40 to 80% EtOAc / petroleum ether gradient @ 100 mL / min) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (8.73 g, 17.40 mmol, 66.61% yield, 87% purity) as a blue solid. MS (M+H) + =437.3.

[0353] Step 5. Synthesis of 3-((2-fluoro-3-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (8) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (4 g, 7.97 mmol) in DCM (50 mL) was added HCl / dioxane (2 M, 100 mL), and the mixture was stirred at 25° C. for 3 h. The mixture was concentrated under reduced pressure (25° C.) to give 3-((2-fluoro-3-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.8 g, crude, HCl) as a blue solid. MS (M+H) + =337.2.

[0354] Step 6. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (10) To a solution of 3-((2-fluoro-3-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.6 g, 9.66 mmol, HCl) in DMF (60 mL) and DCM (60 mL) were added TEA (3.14 g, 31.04 mmol, 4.32 mL) and MgSO (2.32 g, 19.31 mmol), followed by tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (3.04 g, 12.55 mmol), and the mixture was stirred at 25 °C for 0.5 h. NaBH(OAc) (4.09 g, 19.31 mmol) was added, and the mixture was stirred at 25 °C for 14 h. tert-Butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (1.1 g, 4.54 mmol) was added, and the mixture was stirred at 25° C. for 1 h. LCMS confirmed 70% of the desired mass. The mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 10–20% MeOH / EtOAc gradient @ 100 mL / min) and purified by reverse-phase HPLC (0.1% TFA condition, 330 g flash column Welch Ultimate XB_C column). 18The eluate was repurified using a 20-40 μm eluent (20-40 μm; 120 A solvent for sample dissolution; approximately 3.00 grams of sample dissolved in 100 mL of MeCN; flow rate: 100 mL / min; mobile phase: MeCN / HO; gradient B%: 30-50% 45 min; % min Instrument: ISCO). The eluate was lyophilized to give a blue solid, tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (2.7 g, 3.83 mmol, 39.67% yield, 96% purity, TFA). MS (M+H) + =563.4.

[0355] Step 7. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-3-methoxyphenyl)amino)piperidine-2,6-dione (11) To a solution of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (2.7 g, 4.80 mmol) in DCM (10 mL) was added TFA (8.29 g, 72.70 mmol, 5.4 mL), and the mixture was stirred at 25 °C for 4 h. LCMS confirmed 93% of the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-3-methoxyphenyl)amino)piperidine-2,6-dione (2.78 g, crude, TFA) as a blue oil. MS (M+H) + =463.4.

[0356] Step 8. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 55) To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (1.6 g, 3.58 mmol) and HATU (1.63 g, 4.29 mmol) in DMF (10 mL) was added DIPEA (4.62 g, 35.76 mmol, 6.23 mL) and the mixture was stirred at 15° C. for 0.5 h. Then, a solution of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-3-methoxyphenyl)amino)piperidine-2,6-dione (2.78 g, 4.83 mmol, TFA) in DMF (10 mL) was added at 0 °C, and the mixture was stirred at 15 °C for 1 h. LCMS confirmed 55% of the desired mass. The mixture was diluted with water (10 mL) and saturated aqueous NaHCO (30 mL), and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 3 g of product. The product (1 g) was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B over The mixture was purified by HPLC (10 min) and the eluate was lyophilized to give a yellow solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (312.40 mg, 273.34 μmol, 7.64% yield, 98% purity, 2% TFA). MS (M+H) + =892.6. 1H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.79 - 9.31 (m, 2H), 8.30 - 8.12 (m, 3H), 7.53 - 7.38 (m, 2H), 6.66 - 6.60 (m, 1H), 6.55 - 6.47 (m, 1H), 4.84 - 4.75 (m, 1H), 4.37 - 4.30 (m, 1H), 4.13 - 4.04 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.61 - 3.55 (m, 2H), 3.45 - 3.37 (m, 2H), 3.33 (s, 3H), 3.26 - 3.09 (m, 6H), 2.95 - 2.83 (m, 4H), 2.80 - 2.70 (m, 1H), 2.62 - 2.56 (m, 1H), 2.09 - 1.88 (m, 4H), 1.81 - 1.54 (m, 10H), 1.44 - 1.31 (m, 3H). The product (2 g) was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 10% MeOH / EtOAc to 10% MeOH / DCM gradient @ 100 mL / min). The product was triturated with MTBE / EtOH = 2:1 (30 mL) at 15 °C for 14 h. The mixture was filtered, and the filter cake was washed with MTBE / EtOH = 2:1 (10 mL). The filter cake was collected and diluted with 1 N HCl (30 mL). The mixture was slowly added to saturated aqueous NaHCO3 (200 mL), and a large amount of white precipitate formed. The suspension was filtered, and the filter cake was washed with water (50 mL). The filter cake was collected, and the solvent was removed by lyophilization under reduced pressure. The product was triturated with water (50 mL) at 15 °C for 0.5 h. The suspension was filtered, and the filter cake was washed with water (20 mL). The filter cake was collected and the solvent removed by lyophilization under reduced pressure to give a yellow solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (328 mg, 349.34 μmol, 9.77% yield, 95% purity). MS (M+H) + =892.6. 1H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.27 (s, 1H), 8.30 - 8.23 ​​(m, 2H), 7.96 (s, 1H), 7.45 - 7.39 (m, 2H), 6.60 - 6.55 (m, 1H), 6.52 - 6.44 (m, 1H), 5.27 (d, J = 6.6 Hz, 1H), 4.82 - 4.71 (m, 1H), 4.35 - 4.25 (m, 1H), 4.04 (t, J = 13.8 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.35 - 3.15 (m, 5H), 3.04 - 2.97 (m, 2H), 2.94 - 2.82 (m, 4H), 2.81 - 2.69 (m, 3H), 2.61 - 2.53 (m, 3H), 2.39 - 2.30 (m, 2H), 2.12 - 2.01 (m, 1H), 2.01 - 1.88 (m, 3H), 1.79 - 1.66 (m, 4H), 1.65 - 1.52 (m, 4H), 1.48 - 1.37 (m, 2H), 1.35 - 1.24 (m, 3H).

[0357] Example 56 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 56) [ka]

[0358] Step 1. Synthesis of tert-butyl 4-(5-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (3) A yellow solid, tert-butyl 4-(5-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (7.95 g, 22.37 mmol, 42.74% yield), was obtained by synthesizing the compound in a manner similar to that described in Step 2 of Example 7. MS (M+H) + =356.3. 1 H NMR (400 MHz, CD3OD) δ = 7.61 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 13.6 Hz, 1H), 3.92 (s, 3H), 3.66 - 3.50 (m, 4H), 3.26 - 3.15 (m, 4H), 1.48 (s, 9H).

[0359] Step 2. Synthesis of tert-butyl 4-(4-amino-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (4) To a mixture of Pd / C (2 g, 10% purity) in THF (60 mL) and MeOH (60 mL) was added tert-butyl 4-(5-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (7.95 g, 22.37 mmol) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25 °C for 16 h. LCMS confirmed complete consumption of the starting material and 76% of the desired mass. The mixture was filtered, and the filter cake was washed with MeOH (200 mL) and THF (200 mL). The filtrate was concentrated in vacuo. The residue was triturated with a mixture of 1:15 EtOAc and petroleum ether (80 mL) for 10 minutes, the suspension was filtered, the filter cake was washed with petroleum ether (30 mL), and the filter cake was collected and dried to give tert-butyl 4-(4-amino-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (6.56 g, 20.16 mmol, 90.12% yield) as a purple solid. MS (M+H) + =326.4. 1H NMR (400 MHz, DMSO-d6) δ = 6.66 (d, J = 12.9 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 4.79 (s, 2H), 3.72 (s, 3H), 3.52 - 3.40 (m, 4H), 2.84 - 2.73 (m, 4H), 1.45 (s, 9H).

[0360] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (6) A gray solid, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (2.9 g, 6.64 mmol, 32.95% yield), was obtained by synthesis in a manner similar to that described in Step 3 of Example 51. MS (M+H) + =437.3.

[0361] Step 4. Synthesis of 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7) A purple solid, 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.65 g, HCl salt), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1 and used immediately. MS (M+H) + =337.2.

[0362] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9) A mixture of 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.55 g, 9.52 mmol, HCl salt), TEA (5.45 g, 53.88 mmol, 7.5 mL), tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (4 g, 16.51 mmol), and MgSO (4 g, 33.23 mmol) in DCM (120 mL) and DMF (120 mL) was stirred at 20 °C for 16 h, after which NaBH(OAc) (6.5 g, 30.67 mmol) was added in portions, and the resulting mixture was stirred at 20 °C for 4 h. LCMS confirmed 37% of 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione remaining, confirming 54% of the desired mass. The mixture was further stirred at 20 °C for 12 h, and LCMS confirmed complete consumption of 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, confirming 92% of the desired mass. The mixture was quenched by the addition of HO (400 mL), treated with NaHCO solution to adjust the pH to > 7, and extracted with a mixture (DCM:MeOH = 10:1, 200 mL × 3). The combined organic layers were washed with brine (300 mL × 5), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 100% EtOAc to 6% MeOH / DCM gradient @ 150 mL / min) and repurified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 100% EtOAc to 6% MeOH / DCM gradient @ 150 mL / min) to give tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (1.62 g, 2.88 mmol, 30.24% yield) as a blue solid. MS (M+H) + =563.5.

[0363] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-5-methoxyphenyl)amino)piperidine-2,6-dione (10) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain a green viscous substance, 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-5-methoxyphenyl)amino)piperidine-2,6-dione (2.32 g, 3 TFA salt), which was used immediately. MS (M+H) + =463.3.

[0364] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 56) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford an off-white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (710.60 mg, 783.83 μmol, 62.71% yield, 98.39% purity). MS (M+H) + =892.5. 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 9.31 - 9.14 (m, 1H), 8.33 - 8.18 (m, 2H), 7.96 (s, 1H), 7.50 - 7.30 (m, 2H), 6.67 (d, J = 13.4 Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 5.26 - 5.09 (m, 1H), 4.82 - 4.69 (m, 1H), 4.45 - 4.33 (m, 1H), 4.13 - 3.99 (m, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 3.32 (s, 3H), 3.00 (d, J = 9.9 Hz, 2H), 2.90 - 2.78 (m, 4H), 2.78 - 2.67 (m, 3H), 2.60 - 2.54 (m, 1H), 2.39 - 2.28 (m, 3H), 2.14 - 1.95 (m, 3H), 1.95 - 1.83 (m, 2H), 1.76 - 1.67 (m, 4H), 1.67 - 1.49 (m, 5H), 1.45 - 1.37 (m, 2H), 1.37 - 1.04 (m, 4H).

[0365] Example 57 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 57) [ka]

[0366] Step 1. Synthesis of tert-butyl 4-(2,5-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3) A yellow solid, tert-butyl 4-(2,5-difluoro-4-nitrophenyl)piperazine-1-carboxylate (1.3 g, 3.75 mmol, 66.38% yield, 99% purity), was obtained by synthesizing the compound in a manner similar to that described in Step 4 of Example 30. MS (M+H-Boc) + =244.2 1 H NMR (400 MHz, CDCl3) δ = 7.83 (dd, J = 7.1, 12.8 Hz, 1H), 6.64 (dd, J = 7.2, 13.0 Hz, 1H), 3.71-3.51 (m, 4H), 3.35-3.16 (m, 4H), 1.49 (s, 9H).

[0367] Step 2. Synthesis of tert-butyl 4-(4-amino-2,5-difluorophenyl)piperazine-1-carboxylate (4) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to give tert-butyl 4-(4-amino-2,5-difluorophenyl)piperazine-1-carboxylate (1.1 g, 3.16 mmol, 83.44% yield, 90% purity) as a yellow oil. MS (M+H-Boc) + =214.0

[0368] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazine-1-carboxylate (6) The synthesis was carried out in a manner similar to that described in Step 5 of Example 22 to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazine-1-carboxylate (1.2 g, 2.43 mmol, 69.26% yield, 86% purity) as a brown solid. MS (M+H) + =425.3

[0369] Step 4. Synthesis of 3-((2,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7) A blue solid, 3-((2,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (0.8 g, crude, HCl), was obtained by synthesis in a manner similar to that described in Step 2 of Example 48. MS (M+H) + =325.2

[0370] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 6 of Example 1 to give a gray solid of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (0.23 g, 396.81 μmol, 16.09% yield, 95% purity). MS (M+H) + =551.3

[0371] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (10) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (0.17 g, 301.13 μmol, 97.54% yield, TFA) as a yellow oil. MS (M+H) + =451.2

[0372] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 57) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (72.6 mg, 72.31 μmol, 24.01% yield, 99% purity, TFA). MS (M+H) + =880.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.82-9.61 (m, 1H), 9.58-9.39 (m, 1H), 8.33-8.11 (m, 3H), 7.53-7.38 (m, 2H), 7.08-6.89 (m, 1H), 6.79 (br dd, J = 8.2, 14.3 Hz, 1H), 4.82-4.76 (m, 1H), 4.39 (br t, J = 8.2 Hz, 1H), 4.09 (br t, J = 13.9 Hz, 2H), 3.94 (s, 3H), 3.62-3.54 (m 2H), 3.33 (s, 5H), 3.26-3.09 (m, 6H), 3.02-2.81 (m, 4H), 2.79-2.69 (m, 1H), 2.07-1.99 (m, 2H), 1.99-1.90 (m, 2H), 1.84-1.54 (m, 11H), 1.42-1.36 (m, 3H).

[0373] Example 58 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 58) [ka] The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (110.4 mg, 97.65 μmol, 40.84% ​​yield, 95.7% purity, 2% TFA). MS (M+H) + =854.4 1H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.69-9.32 (m, 2H), 8.27 (br d, J = 8.2 Hz, 1H), 8.23 ​​(s, 1H), 8.17-8.10 (m, 1H), 7.50-7.41 (m, 2H), 6.97 (dd, J = 8.3, 13.0 Hz, 1H), 6.78 (dd, J = 8.4, 14.6 Hz, 1H), 5.75-5.51 (m, 1H), 4.92-4.85 (m, 1H), 4.40-4.36 (m, 1H), 4.10-4.04 (m, 2H), 3.93 (s, 3H), 3.61-3.52 (m, 2H), 3.37-3.29 (m, 5H), 3.24-3.07 (m, 6H), 3.00-2.90 (m, 2H), 2.87-2.74 (m, 2H), 2.73-2.54 (m, 1H), 2.07-1.99 (m, 2H), 1.80-1.70 (m, 2H), 1.64 (br s, 2H), 1.45-1.30 (m, 3H), 1.24 (d, J = 6.7 Hz, 6H).

[0374] Example 59 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 59) [ka] A yellow solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (1.52 g, 1.66 mmol, 35.97% yield, 98% purity), was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =898.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 8.28-8.21 (m, 1H), 8.04 (s, 1H), 7.14 (d, J = 6.4 Hz, 1H), 6.84 (br dd, J = 8.1, 13.0 Hz, 1H), 6.73 (br dd, J = 8.2, 14.6 Hz, 1H), 5.49 (br d, J = 8.4 Hz, 1H), 4.88-4.77 (m, 1H), 4.38-4.31 (m, 1H), 4.08 (br t, J = 13.9 Hz, 2H), 3.91 (s, 3H), 3.33 (s, 3H), 3.09-2.98 (m 2H), 2.95-2.84 (m, 5H), 2.77-2.62 (m, 5H), 2.39-2.30 (m, 2H), 2.09-1.92 (m, 5H), 1.77-1.59 (m, 9H), 1.44-1.27 (m, 5H).

[0375] Example 60 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 60) The yellow solid 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (1.60 g, 1.79 mmol, 65.04% yield, 97.4% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =872.4. 1H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.98 (d, J = 1.8 Hz, 1H), 8.33-8.16 (m, 2H), 7.97 (s, 1H), 7.14 (d, J = 6.5 Hz, 1H), 6.84 (dd, J = 8.1, 13.1 Hz, 1H), 6.78-6.68 (m, 1H), 5.49 (br d, J = 8.1 Hz, 1H), 4.90 (td, J = 6.6, 13.4 Hz, 1H), 4.42-4.28 (m, 1H), 4.06 (br t, J = 13.4 Hz, 2H), 3.91 (s, 3H), 3.39-3.31 (m, 5H), 3.10-3.01 (m, 2H), 2.91-2.81 (m, 4H), 2.80-2.56 (m, 4H), 2.48-2.41 (m, 2H), 2.39-2.28 (m, 2H), 2.12-1.96 (m, 2H), 1.78-1.70 (m, 2H), 1.47-1.38 (m, 2H), 1.36-1.21 (m, 9H).

[0376] Example 61 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 61) [ka]

[0377] Step 1. Synthesis of benzyl (7-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3) Benzyl (7-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3.9 g, 7.19 mmol, 97.84% yield) was synthesized as a yellow oil in a manner similar to that described in Step 4 of Example 30. MS (M+H) + =543.3.

[0378] Step 2. Synthesis of benzyl (7-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4) Benzyl (7-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3.6 g, 7.02 mmol, 97.71% yield) was synthesized as a brown oil in a manner similar to that described in Step 4 of Example 22. MS (M+H) + =513.3.

[0379] Step 3. Synthesis of benzyl (7-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) The brown oil benzyl (7-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1 g, 1.25 mmol, 35.51% yield) was obtained by synthesis in a manner similar to that described in Step 3 of Example 1. MS (M+H) + =802.2.

[0380] Step 4. Synthesis of tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) A similar procedure to that described in Step 4 of Example 51 was used to synthesize the compound by adding Pd(OH) (0.5 g, 712.07 μmol, 20% purity) to give a blue solid, tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (400 mg, 678.29 μmol, 77.71% yield). MS (M+H) + =590.4.

[0381] Step 5. Synthesis of 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (8) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (500 mg, 828.33 μmol, 97.70% yield, TFA salt) as a brown oil. MS (M+H) + =490.3.

[0382] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 61) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (299.4 mg, 325.22 μmol, 39.26% yield, 97% purity). MS (M+H) + =893.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.45-8.38 (m, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.54-7.46 (m, 2H), 6.87-6.78 (m, 1H), 6.76-6.66 (m, 1H), 5.49-5.42 (m, 1H), 4.95-4.82 (m, 1H), 4.46-4.29 (m, 2H), 4.09-3.99 (m, 2H), 3.94 (s, 3H), 3.33-3.32 (m, 3H), 3.18-3.05 (m, 2H), 2.80-2.65 (m, 1H), 2.60-2.51 (m, 3H), 2.34-2.11 (m, 8H), 2.08-1.97 (m, 2H), 1.84-1.77 (m, 2H), 1.75-1.68 (m, 2H), 1.61-1.51 (m, 4H), 1.42-1.35 (m, 2H), 1.34-1.27 (m, 2H), 1.24 (d, J = 6.7 Hz, 7H).

[0383] Example 62 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 62) [ka]

[0384] Step 1. Synthesis of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (3) A white solid, tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (16 g, crude), was obtained by synthesis in a manner similar to that described in Step 6 of Example 1. MS (M+H) + =446.4

[0385] Step 2. Synthesis of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4) A white solid of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (10 g, crude, HCl) was obtained by synthesis in a manner similar to that described in Step 2 of Example 48. MS (M+H) + =346.3

[0386] Step 3. Synthesis of benzyl (1-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6) A yellow solid of benzyl (1-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (5 g, 9.45 mmol, 72.20% yield, 95% purity) was obtained by synthesis in a manner similar to that described in Step 4 of Example 30. MS (M+H) + =503.3

[0387] Step 4. Synthesis of benzyl (1-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (7) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to give a yellow solid of benzyl (1-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (1.48 g, 3.13 mmol, 62.96% yield, 100% purity). MS (M+H) + =473.3

[0388] Step 5. Synthesis of benzyl (1-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (9) The synthesis was carried out in a manner similar to that described in Step 1 of Example 36 to obtain a yellow solid of benzyl (1-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (1.26 g, 1.65 mmol, 78.15% yield). MS (M+H) + =762.4

[0389] Step 6. Synthesis of tert-butyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (10) The synthesis was carried out in a manner similar to that described in Step 4 of Example 61 to give a blue solid of tert-butyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (440 mg, 800.51 μmol, 57.54% yield, 100% purity). MS (M+H) + =550.4

[0390] Step 7. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (11) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to obtain 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (450 mg, crude, TFA) as a blue oil. MS (M+H) + =450.4

[0391] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 62) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to obtain a white solid, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (237.1 mg, 272.43 μmol, 35.88% yield, 98% purity). MS (M+H) + =853.5 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.22 (s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H), 7.54-7.45 (m, 2H), 6.83 (dd, J = 8.1, 13.1 Hz, 1H), 6.71 (dd, J = 8.4, 14.3 Hz, 1H), 5.49-5.42 (m, 1H), 4.94-4.81 (m, 1H), 4.39-4.29 (m, 1H), 4.03 (t, J = 13.6 Hz, 2H), 3.93 (s, 3H), 3.83-3.71 (m, 1H), 3.26 (s, 3H), 3.16-3.08 (m, 2H), 2.93-2.85 (m, 2H), 2.78-2.66 (m, 1H), 2.59-2.52 (m, 3H), 2.35-2.28 (m, 2H), 2.07-2.00 (m, 2H), 1.98-1.88 (m, 2H), 1.82-1.69 (m, 4H), 1.63-1.51 (m, 2H), 1.45-1.28 (m, 5H), 1.24 (d, J = 6.7 Hz, 6H).

[0392] Example 63 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 63) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to give a gray solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (130.7 mg, 145.73 μmol, 17.16% yield, 98% purity). MS (M+H) + =879.5 1H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.30-8.23 (m, 2H), 8.11 (d, J = 7.7 Hz, 1H), 7.96 (s, 1H), 7.53-7.44 (m, 2H), 6.83 (dd, J = 8.1, 13.2 Hz, 1H), 6.71 (dd, J = 8.3, 14.3 Hz, 1H), 5.48-5.43 (m, 1H), 4.83-4.70 (m, 1H), 4.38-4.28 (m, 1H), 4.04 (t, J = 14.1 Hz, 2H), 3.93 (s, 3H), 3.84-3.70 (m, 1H), 3.32 (s, 3H), 3.17-3.08 (m, 2H), 2.93-2.85 (m, 2H), 2.79-2.66 (m, 1H), 2.60-2.53 (m, 3H), 2.36-2.29 (m, 2H), 2.09-1.86 (m, 6H), 1.82-1.67 (m, 6H), 1.65-1.53 ​​(m, 6H), 1.45-1.22 (m, 5H)

[0393] Example 64 Synthesis of N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 64) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to give a gray solid, N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (258.3 mg, 304.83 μmol, 35.48% yield, 99% purity). MS (M+H)+ =839.4 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.23 ​​(s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.89 (s, 1H), 7.55-7.47 (m, 2H), 6.83 (dd, J = 8.1, 13.3 Hz, 1H), 6.72 (dd, J = 8.4, 14.4 Hz, 1H), 5.49-5.43 (m, 1H), 4.38-4.30 (m, 1H), 4.17 (t, J = 13.4 Hz, 2H), 3.94 (s, 3H), 3.82-3.72 (m, 1H), 3.69-3.60 (m, 2H), 3.33 (s, 3H), 3.17-3.09 (m, 2H), 2.94-2.85 (m, 2H), 2.79-2.68 (m, 1H), 2.60-2.53 (m, 3H), 2.36-2.27 (m, 2H), 2.07-1.89 (m, 4H), 1.83-1.70 (m, 4H), 1.64-1.52 (m, 2H), 1.46-1.25 (m, 5H), 1.22 (t, J = 7.0Hz, 3H).

[0394] Example 65 Synthesis of 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 65) [ka]

[0395] Step 1. Synthesis of tert-butyl 2-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoyl)hydrazine-1-carboxylate (2) A yellow solid, tert-butyl 2-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoyl)hydrazine-1-carboxylate (7.6 g, 13.40 mmol, 99.91% yield, 99% purity), was obtained by synthesizing in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =562.3

[0396] Step 2. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (3) A yellow solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (3 g, 6.50 mmol, 48.04% yield, 100% purity), was obtained by synthesizing the compound in a manner similar to that described in Step 6 of Example 3. MS (M+H) + =462.2

[0397] Step 3. Synthesis of N'-(2-chloroacetyl)-4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (5) To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.5 g, 5.42 mmol) in DCM (100 mL) was added DIPEA (1.39 g, 10.74 mmol, 1.87 mL) at 0° C., followed by the slow addition of a solution of 2-chloroacetyl chloride (490 mg, 4.34 mmol, 345.56 μL) in DCM (5 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h. LCMS confirmed 21% of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide remaining and 72% of the desired mass. A solution of 2-chloroacetyl chloride (95 mg, 841.14 μmol, 67.00 μL) in DCM (1 mL) was added and the mixture was further stirred at 0° C. for 0.5 h. LCMS confirmed 8% of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide remaining and 84% of the desired mass. A solution of 2-chloroacetyl chloride (110 mg, 973.95 μmol, 77.57 μL) in DCM (1 mL) was added, and the mixture was further stirred at 0° C. for 0.5 h. The mixture was diluted with water (50 mL) and extracted with DCM (20 mL). The organic layer was washed with water (20 mL), dried over NaSO, and filtered.The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent of 80–100% EtOAc / petroleum ether gradient @ 100 mL / min) to afford a yellow solid, N'-(2-chloroacetyl)-4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.5 g, 4.23 mmol, 78.06% yield, 91% purity). MS (M+H). + =538.2

[0398] Step 4. Synthesis of 2-((4-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (6) To a solution of N'-(2-chloroacetyl)-4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.4 g, 4.46 mmol) in toluene (50 mL) was slowly added POCl3 (13.16 g, 85.83 mmol, 8 mL) at 25 °C, and the mixture was stirred at 80 °C under N2 for 14 h. LCMS confirmed that starting material remained. Additional POCl3 (13.16 g, 85.83 mmol, 8 mL) was added at 25 °C, and the mixture was further stirred at 80 °C under N2 for 38 h. The suspension became clear. The mixture was combined with another batch (0.1 g scale) and concentrated under reduced pressure. The crude product was diluted with DCM (100 mL) and slowly poured into saturated NaHCO3 solution (100 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated NaHCO3 solution (20 mL) and water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a red solid: 2-((4-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2.16 g, crude). MS (M+H) + =520.2

[0399] Step 5. Synthesis of tert-butyl 4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (7C) Synthesized in a manner similar to that described in Step 5 of Example 56 to afford a gray solid: tert-butyl 4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (8.6 g, 16.06 mmol, 57.93% yield, 100% purity). MS (M+H) + =536.5

[0400] Step 6. Synthesis of 3-((2,5-difluoro-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7) A gray solid, 3-((2,5-difluoro-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (8 g, crude, HCl salt), was obtained by synthesis in a manner similar to that described in Step 2 of Example 48. MS (M+H) + =436.3

[0401] Step 7. Synthesis of 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 65) Two batches of product were obtained by synthesis in a manner similar to that described in Step 8 of Example 25. Batch 1: Yellow solid 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (1.81 g, 1.96 mmol, 59.91% yield, 99.3% purity). Batch 2: Yellow solid 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (628 mg, 670.38 μmol, 20.54% yield, 98% purity). MS (M+H) + =919.7 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.60-7.49 (m, 2H), 6.81 (br dd, J = 7.8, 13.2 Hz, 1H), 6.71 (br dd, J = 8.1, 14.7 Hz, 1H), 5.49-5.44 (m, 1H), 4.83-4.72 (m, 1H), 4.37-4.27 (m, 1H), 4.04 (br t, J = 13.8 Hz, 2H), 3.98 (s, 3H), 3.82 (s, 2H), 3.37 (s, 3H), 2.90-2.78 (m, 6H), 2.76-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.47-2.41 (m, 3H), 2.33-2.26 (m, 2H), 2.14-2.05 (m, 2H), 2.04-1.89 (m, 4H), 1.72-1.53 ​​(m, 9H), 1.39-1.31 (m, 2H), 1.28-1.10 (m, 3H).

[0402] Example 66 Synthesis of 3-((4-(4-(2-(1-(5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 66) [ka]

[0403] Step 1. Synthesis of 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2) To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.1 g, 4.55 mmol) in dioxane (40 mL) was added a solution of NaHCO (1.15 g, 13.66 mmol, 531.45 μL) in HO (20 mL), followed by BrCN (1.05 g, 9.91 mmol, 727.65 μL). The mixture was stirred at 25 °C under N for 13 h. The mixture was filtered, and the filter cake was washed with MTBE (30 mL) and water (30 mL). The filter cake was collected and dried under reduced pressure to give a yellow solid: 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (1.81 g, 3.53 mmol, 77.67% yield, 95% purity). The filtrate was extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (10 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was diluted with MTBE (10 mL) and stirred at 25 °C for 0.5 h. The suspension was filtered, and the filter cake was washed with MTBE (10 mL) and water (10 mL). The filter cake was collected and dried under vacuum to give a yellow solid, 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (380 mg, crude). MS (M+H) + =487.3

[0404] Step 2. Synthesis of 2-((4-(5-bromo-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (3) To a solution of CuBr (1.80 g, 12.55 mmol, 382.17 μL) in CAN (20 mL) was added t-BuONO (1.28 g, 12.41 mmol, 1.48 mL), followed by a solution of 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2 g, 4.11 mmol) in CAN (90 mL). The resulting mixture was stirred at 60 °C for 1 h. LCMS confirmed the desired mass. The mixture was cooled to 25 °C and then adjusted to pH 8 with saturated NaHCO3. The mixture was filtered, and the filter cake was washed with THF (100 mL) and EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 0-10% MeOH / EtOAc gradient @ 100 mL / min) to give a yellow solid, 2-((4-(5-bromo-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (0.6 g, 1.09 mmol, 26.52% yield). MS (M+H) + =550.3

[0405] Step 3. Synthesis of 3-((4-(4-(2-(1-(5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 66) To a solution of 3-((2,5-difluoro-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (1 g, 2.12 mmol, HCl salt) and K2CO3 (603.33 mg, 4.37 mmol, 279.45 μL) in DMF (10 mL) was added 2-((4-(5-bromo-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (0.6 g, 1.09 mmol), and the resulting mixture was stirred at 50 °C for 14 h. LCMS confirmed the desired mass peak (82%). The mixture was diluted with EtOAc (10 mL) and water (30 mL). The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent of 10-20% MeOH / DCM gradient @ 50 mL / min) followed by prep-TLC (EtOAc / MeOH = 10 / 1). The impure product was repurified by prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B over 10 min). The eluate was lyophilized to give a blue solid: 3-((4-(4-(2-(1-(5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (568.5 mg, 544.52 μmol, 49.95% yield, 97.6% purity, TFA). MS (M+H) + =905.6 1H NMR (400 MHz, CD3OD) δ = 8.33 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.58-7.56 (m, 1H), 7.52 (dd, J = 1.8, 8.5 Hz, 1H), 6.89 (dd, J = 7.7, 12.6 Hz, 1H), 6.72 (dd, J = 7.9, 13.8 Hz, 1H), 4.99-4.93 (m, 1H), 4.31 (dd, J = 5.0, 12.4 Hz, 1H), 4.14-4.05 (m, 4H), 4.03 (s, 3H), 3.66 (br d, J = 12.4 Hz, 2H), 3.46-3.39 (m, 5H), 3.30-3.24 (m, 4H), 3.22-3.14 (m, 2H), 3.11-3.02 (m, 2H), 2.87-2.78 (m, 1H), 2.75-2.68 (m, 1H), 2.33-2.25 (m, 1H), 2.10-1.99 (m, 3H), 1.94-1.87 (m, 2H), 1.84-1.75 (m, 4H), 1.74-1.64 (m, 5H), 1.50-1.38 (m, 2H).

[0406] Example 67 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 67) [ka]

[0407] Step 1. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (3) The synthesis was carried out in a manner similar to that described in Step 3 of Example 23 to give a white solid of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (4 g, 7.12 mmol, 39.51% yield, 98% purity). MS (M+H) + =551.5.

[0408] Step 2. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (4) The synthesis was carried out in a manner similar to that described in Step 3 of Example 3 to obtain 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (3 g, 5.31 mmol, 97.54% yield, TFA salt) as a yellow oil. MS (M+H) + =451.3.

[0409] Step 3. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 67) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to obtain a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (1.81 g, 2.04 mmol, 38.37% yield, 99% purity). MS (M+H) + =880.4. 1 H NMR (400 MHz, CD3OD) δ = 8.50 (d, J = 8.2 Hz, 1H), 8.20 (s, 1H), 7.60 - 7.49 (m, 2H), 6.85 (dd, J = 7.7, 13.0 Hz, 1H), 6.78 - 6.64 (m, 1H), 4.30 (dd, J = 4.8, 12.5 Hz, 1H), 4.20 - 4.09 (m, 1H), 4.08 - 3.98 (m, 5H), 3.61 - 3.49 (m, 1H), 3.42 (s, 3H), 3.24 - 3.18 (m, 2H), 3.12 - 3.00 (m, 6H), 2.93 - 2.72 (m, 9H), 2.36 - 2.29 (m, 1H), 2.26 - 2.17 (m, 2H), 2.14 - 2.06 (m, 2H), 2.05 - 1.92 (m, 3H), 1.88 - 1.81 (m, 2H), 1.79 - 1.59 (m, 5H).

[0410] Example 68 Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-4-methoxypicolinamide (Compound 68) The yellow solid 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-4-methoxypicolinamide (0.7637 g, 858.25 μmol, 40.38% yield, 99% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =881.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.05 (s, 1H), 8.81 (br d, J = 7.9 Hz, 1H), 8.62 (br s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 6.97 (dd. - 3.91 (m, 6H), 3.64 - 3.43 (m, 6H), 3.43 - 3.28 (m, 6H), 3.28 - 2.92 (m, 7H), 2.79 - 2.66 (m, 1H), 2.62 - 2.54 (m, 1H), 2.12 - 1.92 (m, 6H), 1.89 - 1.81 (m, 2H), 1.66 (br s, 2H), 1.61 - 1.47 (m, 4H).

[0411] Example 69 Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (Compound 69) [ka]

[0412] Step 1. Synthesis of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2) Benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (23 g, crude, TFA salt) was obtained as a colorless oil by synthesis in a manner similar to that described in Step 6 of Example 3. MS (M+H) + =372.2.

[0413] Step 2. Synthesis of benzyl (7-((1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4) Benzyl (7-((1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (20 g, 37.84 mmol, 79.87% yield) was obtained as a yellow solid by a method similar to that described in Step 3 of Example 62. MS (M+H) + =529.3.

[0414] Step 3. Synthesis of benzyl (7-((1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (5) Benzyl (7-((1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (20 g) was obtained as a yellow solid by synthesis in a manner similar to that described in Step 4 of Example 62. MS (M+H) + =499.3.

[0415] Step 4. Synthesis of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) Benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (16 g, 20.31 mmol, 72.32% yield) was synthesized as a brown oil in a manner similar to that described in Step 5 of Example 62. MS (M+H) + =788.4.

[0416] Step 5. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8) A blue solid of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2g) was obtained by synthesis in a manner similar to that described in Step 6 of Example 62. MS (M+H) + =576.3.

[0417] Step 6. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (9) The synthesis was carried out in a manner similar to that described in Step 2 of Example 48 to afford 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (1.78 g, 3.48 mmol, 100.00% yield, HCl salt) as a blue solid. MS (M+H) + =476.2.

[0418] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (Compound 69) The yellow solid 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (233.6 mg, 252.63 μmol, 22.66% yield, 97% purity) was obtained by synthesis in a manner similar to that described in Step 10 of Example 2. MS (M+H) + =897.2. 1H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.36-8.21 (m, 3H), 7.98 (s, 1H), 7.21 (d, J = 6.6 Hz, 1H), 6.90-6.79 (m, 1H), 6.78-6.67 (m, 1H), 5.50 (d, J = 8.0 Hz, 1H), 4.95-4.86 (m, 1H), 4.49-4.30 (m, 2H), 4.07 (t, J = 13.4 Hz, 2H), 3.92 (s, 3H), 3.33-3.32 (m, 3H), 3.18-3.13 (m, 2H), 3.06-2.84 (m, 2H), 2.79-2.65 (m, 2H), 2.63-2.52 (m, 5H), 2.35-2.10 (m, 3H), 2.09-1.96 (m, 3H), 1.95-1.59 (m, 9H), 1.47-1.22 (m, 8H).

[0419] Example 70 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 70) [ka] The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (274 mg, 296.71 μmol, 11.69% yield, 98% purity). MS (M+H) + =905.5. 1 H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.42 (br d, J = 6.9 Hz, 1H), 8.30 - 8.23 ​​(m, 2H), 7.96 (s, 1H), 7.51 - 7.44 (m, 2H), 6.87 - 6.66 (m, 2H), 5.46 (br d, J = 8.6 Hz, 1H), 4.82 - 4.71 (m, 1H), 4.46 - 4.28 (m, 2H), 4.04 (br t, J = 13.9 Hz, 2H), 3.94 (s, 3H), 3.31 (s, 3H), 3.18 - 3.08 (m, 2H), 2.80 - 2.66 (m, 1H), 2.61 - 2.52 (m, 3H), 2.36 - 2.09 (m, 7H), 2.08 - 1.90 (m, 5H), 1.87 - 1.68 (m, 6H), 1.66 - 1.48 (m, 9H), 1.31 - 1.14 (m, 2H).

[0420] Example 71 Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 71) [ka]

[0421] Step 1. Synthesis of tert-butyl 4-(2,3-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3) A white solid, tert-butyl 4-(2,3-difluoro-4-nitrophenyl)piperazine-1-carboxylate (4.8 g, 13.56 mmol, 48.03% yield, 97% purity), was obtained by synthesis in a manner similar to that described in Step 4 of Example 30. MS (M+H-55) + =288.0. 1 H NMR (400 MHz, CDCl3) δ = 7.91 - 7.77 (m, 1H), 6.66 (br t, J = 8.4 Hz, 1H), 3.61-3.59 (m, 4H), 3.30 - 3.28 (m, 4H), 1.49 - 1.46 (m, 9H).

[0422] Step 2. Synthesis of tert-butyl 4-(4-amino-2,3-difluorophenyl)piperazine-1-carboxylate (4) The synthesis was carried out in a manner similar to that described in Step 4 of Example 22 to obtain a brown solid, tert-butyl 4-(4-amino-2,3-difluorophenyl)piperazine-1-carboxylate (4.6 g, 12.48 mmol, 89.25% yield, 85% purity). MS (M+H) + =314.0.

[0423] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazine-1-carboxylate (6) A blue solid, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazine-1-carboxylate (2.7 g, 5.85 mmol, 39.87% yield, 92% purity), was obtained by synthesis in a manner similar to that described in Step 5 of Example 22. MS (M+H) + =425.2. 1 H NMR (400 MHz, CDCl3) δ = 8.37 (br s, 1H), 6.61 (br t, J = 7.9 Hz, 1H), 6.40 (br t, J = 8.1 Hz, 1H), 4.75 - 4.57 (m, 1H), 4.10 - 4.06 (m, 1H), 3.59 (br d, J = 4.4 Hz, 4H), 2.93 (br d, J = 4.4 Hz, 4H), 2.94 - 2.76 (m, 1H), 2.65 - 2.27 (m, 2H), 2.05 - 1.91 (m, 1H), 1.50 (s, 9H).

[0424] Step 4. Synthesis of 3-((2,3-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7) A blue solid, 3-((2,3-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (2.3 g, crude, HCl salt), was obtained by synthesis in a manner similar to that described in Step 5 of Example 1. MS (M+H) + =325.1.

[0425] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9) A yellow solid of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (1.05 g, 1.72 mmol, 26.92% yield, 90% purity) was obtained by synthesis in a manner similar to that described in Step 6 of Example 1. MS (M+H) + =551.3.

[0426] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,3-difluorophenyl)amino)piperidine-2,6-dione (10) The synthesis was carried out in a manner similar to that described in Step 6 of Example 3 to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,3-difluorophenyl)amino)piperidine-2,6-dione (1.08 g, crude, TFA salt) as a brown oil. MS (M+H) + =451.2.

[0427] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 71) The synthesis was carried out in a manner similar to that described in Step 10 of Example 2 to afford a white solid: 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (899 mg, 980.79 μmol, 51.27% yield, 96% purity). MS (M+H) + =880.4. 1 H NMR (400 MHz, DMSO-d6) δ = 10.82 (s, 1H), 9.90 - 9.56 (m, 2H), 8.34 - 8.13 (m, 3H), 7.54 - 7.37 (m, 2H), 6.80 - 6.68 (m, 1H), 6.66 - 6.53 (m, 1H), 4.81 - 4.76 (m, 1H), 4.43 - 4.38 (m, 1H), 4.08 (br t, J = 13.6 Hz, 2H), 3.94 (s, 3H), 3.60 - 3.52 (m, 2H), 3.40 - 3.29 (m, 5H), 3.28 - 3.09 (m, 6H), 3.07 - 2.82 (m, 4H), 2.81 - 2.65 (m, 1H), 2.63 - 2.54 (m, 1H), 2.10 - 1.87 (m, 5H), 1.83 - 1.52 (m, 10H), 1.39 (br s, 2H).

[0428] Example 72 Synthesis of N-(1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin...

Claims

1. A compound represented by the following formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above formula I, ULM is a moiety represented by the following formula 1: 【Chemistry 2】 PTM is a moiety represented by the following formula 2: 【Chemistry 3】 Linker is a group that chemically links the ULM and PTM; X is CH or N; V is -NR Ｖ - or a single bond; R Ｖ is -H or -CH ３ and Ring U is phenyl or 5-6 membered heteroaryl, wherein one or more H in said phenyl or 5-6 membered heteroaryl ring is R Ｕ may be replaced by}; R Ｕ is -C １－３ Alkyl, —C １－３ Hydroxyalkyl, —C １－３ Aminoalkyl, —C １－３ Haloalkyl, —C １－３ alkoxy, -CN or -halo; Y １ is CR Ｙ or N; Y ２ or Y ４ are each independently CR Ｙ and R Ｙ is -H, -C １－３ Alkyl, —C １－３ alkoxy or -halo; R １ is -C １－４ alkyl or 5-6 membered cycloalkyl; R ２ and R ３ are each independently —H, —C １－３ alkyl or -halo; R ４ is -C １－３ It is alkyl.

2. ULM is a moiety represented by the following formula 1-1, 1-2, or 1-3: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 R Ｖ is -H or -CH ３ and Ring U is phenyl or pyridinyl, wherein one or more H in said phenyl or pyridinyl ring is R Ｕ may be replaced by}; R Ｕ is -C １－３ Alkyl, —C １－３ alkoxy, -CN, or -halo; 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. ULM is 【Chemistry 7】 【change】 and R Ｕ１ and R Ｕ２ are each independently -C １－３ Alkyl, —C １－３ alkoxy, -CN, or -halo; 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. ULM is 【Chemistry 8】 and R Ｕ１ and R Ｕ２ are each independently -C １－３ Alkyl, —C １－３ alkoxy, -CN, or -halo; 4. The compound of claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof.

5. PTM is 【Chemistry 9】 and Y １ is CR Ｙ or N; Y ２ or Y ４ are each independently CR Ｙ and R Ｙ is -H, -C １－３ alkoxy or -halo; R １ is -C １－４ alkyl or 5-6 membered cycloalkyl; 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. Linker is -L Ｕ -L １ -L ２ -L Ｐ - and; L Ｕ is a heterocycloalkyl {wherein the heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the heterocycloalkyl ring is replaced by —C １－４ Alkyl, —C １－４ may be substituted with alkoxy or -halo); L １ is -(CH ２ ) Ｘ１ -, -(CH ２ ) Ｘ２ -NH-(CH ２ ) Ｘ３ -, -(CH ２ ) Ｘ２ -N(C １－４ alkyl)-(CH ２ ) Ｘ３ - or a single bond {wherein X1 to X3 are each independently 0, 1, 2, 3, or 4}; L ２ is a cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the cycloalkyl or heterocycloalkyl ring is replaced by —C １－４ Alkyl, —C １－４ may be substituted with alkoxy or -halo); L Ｐ is -NH-C(=O)- or -(CH ２ )p-heteroaryl {wherein the —NH—C(═O)— is —C(═O)— or the —(CH ２ ) the heteroaryl of p-heteroaryl is linked to PTM, said heteroaryl contains endocyclic N and O atoms, and said p is 0, 1, 2 or 3; 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. L Ｕ is a 4-12 membered heterocycloalkyl, wherein the 4-12 membered heterocycloalkyl is a monocyclic, bridged bicyclic or spirocyclic ring, the 4-12 membered heterocycloalkyl contains one or more N atoms in the ring, the N atom is directly bonded to ULM, and one or more H in the 4-12 membered heterocycloalkyl ring is -C １－４ may be substituted with alkyl or -halo); L １ is -(CH ２ ) Ｘ１ -, -(CH ２ ) Ｘ２ -N(C １－４ alkyl)-(CH ２ ) Ｘ３ - or a single bond {wherein X1 to X3 are each independently 0, 1, 2, or 3}; L ２ is a 4- to 6-membered cycloalkyl or a 4- to 12-membered heterocycloalkyl, wherein the 4- to 12-membered heterocycloalkyl is a monocyclic, bridged bicyclic or spirocyclic ring, the 4- to 12-membered heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the 4- to 6-membered cycloalkyl or 4- to 12-membered heterocycloalkyl ring is selected from the group consisting of -C １－４ may be substituted with alkyl or -halo); L Ｐ is -NH-C(=O)- or -(CH ２ )p-1,3,4-oxadiazole {wherein the —NH—C(═O)— is —C(═O)— or the —(CH ２ ) p-1,3,4-oxadiazole is linked to PTM, and p is 0 or 1; 7. The compound of claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound represented by Formula I is selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Table 1】

9. A pharmaceutical composition comprising the compound of any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for preventing or treating cancer, benign tumors, or neurological diseases, comprising the compound according to any one of claims 1 to 8, its stereoisomer, or a pharmaceutically acceptable salt thereof.

11. A method for treating or preventing cancer, benign tumors, or neurological diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 8, its stereoisomer, or a pharmaceutically acceptable salt thereof.

12. The method for treating or preventing cancer, benign tumor, or neurological disease according to claim 11, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof induces degradation of PLK1 protein.

13. 9. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

14. 10. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment or prevention of cancer, benign tumors or neurological disorders.

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